Conditions: Chronic Lymphocytic Leukemia
Keywords: CLL
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 51
Healthy volunteers: no

Brief summary:
The main objective of this study is to determine the progression free survival of umbralisib in participants who were intolerant to prior BTK (Bruton Tyrosine Kinase) inhibitors (ibrutinib, ACP-196, other) or prior PI3K-delta inhibitors (idelalisib, duvelisib, other).

Detailed description:

Arms:
arm 1: Participants received 800 milligrams (mg) of umbralisib, orally, once daily until disease progression, unacceptable toxicity or the end of the study for 60.7 months.

Interventions: intervention 1: Umbralisib
Intervention descriptions: intervention 1: Umbralisib was administered as a tablet(s), orally once daily.

Protocol document:
Prot_SAP_000.pdf: 
 
Offi ci al Titl e:  
 
A P h a s e 2 St u d y t o A s s e s s t h e S af et y a n d Effi c a c y of T G R -1 2 0 2  
( U m br ali si b) i n P ati e nt s wit h C hr o ni c L y m p h o c yti c L e u k e mi a ( C L L)  
w h o ar e I nt ol er a nt t o Pri or B T K or PI 3 K -D elt a I n hi bit or T h er a p y 
N C T N u m b er:  
N C T 0 2 7 4 2 0 9 0  
D o c u m e nt  D at e : 
Pr ot o c ol V er si o n 5: 0 4- A pril -2 0 1 9  
 
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
P a g e 1  of 7 1  
P r ot o c ol v e r si o n / D at e:  
V ersi o n 5 . 0 / M arc h  5 , 2 0 1 9 
L o c al P r ot o c ol #:  
Pr ot oc ol T G R -1 2 0 2 -2 0 1 -C L L  
TI T L E: A P h as e 2 St u d y t o A s s e s s t h e S af et y a n d Effi c a c y of T G R -1 2 0 2  (U m b r ali si b)  i n P ati e nt s 
wit h C h r o ni c L y m p h o c yti c L e u k e mi a ( C L L) w h o a r e I nt ol e r a nt t o P ri o r B T K o r PI 3 K -D elt a  
I n hi bit o r T h e r a p y 
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 7  
I N D N u m b e r: 
U m b r ali si b  (T G R -1 2 0 2 ) 
1 1 6, 7 6 2  
St u d y C h ai r : 
 M D 
 
      
  
 
M e di c al M o nit o r:  
 M D 
 
 
  
T el: 
 
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:   0 7  J a n u ar y 2 0 1 6 
V e r si o n:  2. 0  
D at e:   0 4 J ul y  2 0 1 6  
V e r si o n: 2. 5  
D at e:  2 1 F e br u ar y 2 0 1 7  
V e r si o n:  3. 0  
D at e:  1 3 M arc h 2 0 1 7  
V e r si o n: 4. 0  
D at e: 6  Oct o b er  2 0 1 7  
V e r si o n:  5. 0  
 D at e:  0 5 M a r c h 2 0 1 9  
T his d oc u m e nt is a c o nfi d e 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 gre 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 erei n s h all b e 
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 m e nt m a y b e discl os e d t o 




T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3  of 7 1  
 
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 as e 2 St u d y t o Ass ess t h e S af et y a n d Effic ac y of T G R -1 2 0 2  
( U m br alisi b) i n P ati e nts wit h C hr o nic L y m p h oc ytic L e u k e mi a 
( C L L) w h o ar e I nt ol er a nt t o Pri or B T K or PI 3 K -D elt a  I n hi bit or 
T h er a p y  
P r ot o c ol N u m b e r:  
T G R -1 2 0 2 -2 0 1 -C L L  
I N D N u m b er : 
 
U m b r ali si b  
1 1 6, 7 6 2  
 
 
 
D at e FI N A L:  
0 5 M arc h  2 0 1 9  
 
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 
T G R -1 2 0 2 -2 0 1 -C L L . 
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 m br alisi b  I n v esti g at or’s Br oc h ur e, 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 t h e y ar e f ull y 
i nf or m e d r e g ar di n g u m br alisi b , a n d t h e c o 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 o f 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  
 
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 4  of 7 1  
 
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  .......................................................................................................................... 1 0  
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 5  
1 I N T R O D U C TI O N  .............................................................................................................................. 1 7  
1. 1 C hr o nic L y m p h oc ytic L e u k e mi a  .............................................................................................................................. 1 7  
1. 2 U m br alisi b  ......................................................................................................................................................................... 1 7  
1. 2. 1  Pr e -Cli nic al D e v el o p m e nt of T G R -1 2 0 2  ................................................................................................................................................... 1 8  
1. 2. 2 Cli nic al D e v el o p m e nt of u m br alisi b  ........................................................................................................................................................... 2 0  
1. 3 R ati o n al e f or t h e P h as e 2 Tri al  ................................................................................................................................. 2 3  
2 O BJ E C TI V E S A N D E N D P OI N T S .................................................................................................... 2 4  
2. 1 St u d y O bj ecti v es  .............................................................................................................................................................. 2 4  
2. 2 Effic ac y E n d p oi nts  ......................................................................................................................................................... 2 4  
3 E LI GI BI LI T Y C RI T E RI A  ................................................................................................................. 2 5  
3. 1 I ncl usi o n Crit eri a  ............................................................................................................................................................ 2 5  
3. 2  E xcl usi o n Crit eri a  ........................................................................................................................................................... 2 6  
4 S T U D Y D E SI G N  ................................................................................................................................ 2 7  
4. 1 O v er vi e w of St u d y D esi g n  .......................................................................................................................................... 2 7  
4. 2 R E GI S T R A TI O N / E N R O L L M E N T ..................................................................................................................... 2 7  
4. 3 St u d y Sit es  .......................................................................................................................................................................... 2 8  
4. 4 Disc o nti n u ati o n fr o m St u d y Tr e at m e nt  .............................................................................................................. 2 8  
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  ......................................................... 2 9  
5. 1. 1 L oc al L a b or at or y Ass ess m e nts  ..................................................................................................................................................................... 3 0  
5. 1. 2 C e ntr al L a b or at or y Ass ess m e nts  ................................................................................................................................................................. 3 0  
6 T R E A T M E N T P L A N  ........................................................................................................................ 3 1  
6. 1 Tr e at m e nt S u m m ar y  ..................................................................................................................................................... 3 1  
6. 2 A g e nt A d mi nistr ati o n  ................................................................................................................................................... 3 1  
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 1  
6. 2. 2 Crit eri a f or O n g oi n g Tr e at m e nt .................................................................................................................................................................... 3 2  
6. 3 D osi n g D el a ys a n d M o d ific ati o ns ............................................................................................................................ 3 2  
6. 3. 1 D os e D el a y / M o difi c ati o ns: u m br alisi b  ..................................................................................................................................................... 3 2  
6. 4 Or d eri n g u m br alisi b  ...................................................................................................................................................... 3 4  
6. 5 D ur ati o n of T h er a p y  ...................................................................................................................................................... 3 4  
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  .................................................................... 3 6  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 5  of 7 1  
 
7. 1 U m br alisi b  ......................................................................................................................................................................... 3 6  
7. 1. 1 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 Rs)  ....................................................................................... 3 6  
8 M E A S U R E M E N T O F E F F E C T  ........................................................................................................ 3 8  
8. 1 M et h o d of Ass ess m e nt  ................................................................................................................................................. 3 8  
8. 2 R es p o ns e R e vi e w  ............................................................................................................................................................ 3 8  
8. 3 I d e ntific ati o n a n d M e as ur e m e nt of T u m or L esi o ns a n d Or g a n o m e g al y  ............................................. 3 9  
8. 3. 1 T ar g et L esi o ns  ...................................................................................................................................................................................................... 3 9  
8. 3. 2 S pl e e n a n d Li v er  .................................................................................................................................................................................................. 3 9  
8. 3. 3 N o n -T ar g et L esi o ns  ............................................................................................................................................................................................ 4 0  
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 0  
8. 5 C o m pl et e R es p o ns e  ....................................................................................................................................................... 4 0  
8. 6 P arti al R es p o ns e  ............................................................................................................................................................. 4 1  
8. 7 St a bl e Dis e as e  ................................................................................................................................................................... 4 2  
8. 8  D efi niti v e Dis e as e Pr o gr essi o n  ................................................................................................................................ 4 2  
8. 9 N o n -E v al u a bl e  .................................................................................................................................................................. 4 3  
8. 1 0 L y m p h oc yt osis D uri n g T h er a p y  ........................................................................................................................... 4 3  
9 S T A TI S TI C A L C O N SI D E R A TI O N S  ............................................................................................... 4 4  
9. 1 s a m pl e siz e  ........................................................................................................................................................................ 4 4  
9. 2 G e n er al A n al ysis C o n v e nti o n  .................................................................................................................................... 4 4  
9. 3 St u d y p o p ul ati o ns  .......................................................................................................................................................... 4 4  
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  .................................................................................... 4 4  
9. 5 M e dic al Hist or y  ............................................................................................................................................................... 4 4  
9. 6 E xt e nt of E x p os ur e  ......................................................................................................................................................... 4 4  
9. 7 Effic ac y A n al ys es  ............................................................................................................................................................ 4 5  
9. 8 Missi n g V al u e H a n dli n g Pr oc e d ur es ...................................................................................................................... 4 5  
9. 9 St atistic al A n al ys es  ........................................................................................................................................................ 4 5  
9. 9. 1 Pri m ar y effi c ac y v ari a bl e - P F S  ..................................................................................................................................................................... 4 5  
9. 9. 2 S ec o n d ar y effi c ac y O utc o m es  ........................................................................................................................................................................ 4 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  ..................................................................................... 4 7  
1 0. 1 S af et y A n al ys es  ............................................................................................................................................................. 4 7  
1 0. 2 A d v ers e E v e nt C h ar act eristics  .............................................................................................................................. 4 7  
1 0. 3 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)  .................................. 4 8  
1 0. 4 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  .......................................................... 4 8  
1 0. 4. 1 R ec or di n g of A d v ers e E v e nts  ...................................................................................................................................................................... 4 8  
1 0. 4. 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  ..................................................................................................................................... 4 9  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 6  of 7 1  
 
1 0. 4. 3  H a n dli n g of A d v ers e E v e nts  ........................................................................................................................................................................ 4 9  
1 0. 5 S eri o us A d v ers e E v e nts  ............................................................................................................................................ 5 0  
1 0. 5. 1  D efi niti o ns of S eri o us A d v ers e E v e nts  ................................................................................................................................................... 5 0  
1 0. 5. 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  ......................................................................................................................... 5 1  
1 0. 6 S p o ns or S A E R e p orti n g R e q uir e m e nts  ............................................................................................................. 5 1  
1 0. 7 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  ..................................................................... 5 2  
1 0. 8 Di a g n osis vs. Si g ns a n d S y m pt o ms  ...................................................................................................................... 5 2  
1 0. 8. 1 P ersist e nt or R ec urr e nt A d v ers e E v e nts  ............................................................................................................................................... 5 2  
1 0. 8. 2 A b n or m al L a b or at or y V al u es  ..................................................................................................................................................................... 5 3  
1 0. 8. 3 D e at hs  .................................................................................................................................................................................................................... 5 3  
1 0. 8. 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  ................................................................................................................ 5 3  
1 0. 8. 5 Pr e -E xisti n g M e di c al C o n diti o ns  ............................................................................................................................................................... 5 3  
1 0. 8. 6 Pr ot oc ol -D efi n e d S eri o us A d v ers e E v e nts  ........................................................................................................................................... 5 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  ............................................................. 5 5  
1 1. 1 Sit e M o nit ori n g Pl a n  ................................................................................................................................................... 5 5  
1 1. 2 A m e n d m e nts t o t h e Pr ot oc ol  ................................................................................................................................. 5 5  
1 1. 3 C urric ul a Vit a e a n d Fi n a nci al Discl os ur es  ....................................................................................................... 5 6  
1 1. 4 D at a O w n ers hi p a n d P u blic ati o n  ......................................................................................................................... 5 6  
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 ....................................... 5 7  
1 2. 1 I R B A p pr o v al  .................................................................................................................................................................. 5 7  
1 2. 2 R e g ul at or y A p pr o v al  .................................................................................................................................................. 5 7  
1 2. 3 I ns ur a nc e a n d I n d e m nit y  ......................................................................................................................................... 5 7  
1 2. 4 I nf or m e d C o ns e nt  ........................................................................................................................................................ 5 7  
1 2. 5 C o nfi d e nti alit y  ............................................................................................................................................................... 5 8  
1 2. 6 I n v esti g at or a n d St aff I nf or m ati o n  ...................................................................................................................... 5 9  
1 2. 7 Fi n a nci al I nf or m ati o n  ................................................................................................................................................ 5 9  
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 0  
1 3. 1 D o c u m e nt ati o n R e q uir e d t o I niti at e St u d y  ..................................................................................................... 6 0  
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 0  
1 3. 3 D at a C oll ecti o n  .............................................................................................................................................................. 6 2  
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  ................................................................................................... 6 2  
1 3. 5 Q u alit y Ass ur a nc e a n d Q u alit y C o ntr ol  ............................................................................................................. 6 2  
1 3. 6 Discl os ur e a n d P u blic ati o n P olic y  ....................................................................................................................... 6 3  
1 4 R E F E R E N C E S  ................................................................................................................................. 6 4  
1 5 A p p e n di x A –  C L L R e s p o n s e D efi niti o n  ................................................................................ 6 5  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 7  of 7 1  
 
1 6 A p p e n di x B - C o nt r a c e pti v e G ui d eli n e s a n d P r e g n a n c y  .................................................. 6 8  
1 7 A p p e n di x C –  N Y H A Cl a s sifi c ati o n s  ........................................................................................ 7 0  
1 8 A p p e n di x D –  H e p atiti s B S e r ol o gi c T e st R e s ult s  .............................................................. 7 1  
 
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 8  of 7 1  
 
V ersi o n 2. 0 ( D at e d 0 4 J ul y 2 0 1 6) 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:  
•  
S p o ns or a n d st u d y c o or di n ati o n a d dr ess u p d at e d;  
•  
Cl eric al c orr ecti o ns w er e m a d e t o I ncl usi o n Crit eri a 6 a n d 7;  
•  
I ncl usi o n crit eri a # 9 w as c h a n g e d fr o m mi ni m u m 2 c m n o d al l esi o n t o 1. 5 c m; 
•  
E xcl usi o n crit eri a 6 w as f urt h er cl arifi e d f or H B V a n d t esti n g b y P C R if r e q uir e d;  
•  
St u d y sc h e m a i n S ecti o n 4. 1 w as c orr ect e d;  
•  
T a bl e i n S ecti o n 5 a n d f o ot n ot es w er e u p d at e d t o c h a n g e “ w e e ks” t o “c ycl es” as w ell as u p d at e 
a f e w cl arific ati o ns n e e d e d i n t h e St u d y Ass ess m e nt a n d Tr e at m e nt Sc h e d ul e t a bl e;  
•  
S ecti o n 6. 2. 1 w as u p d at e d t o m a n d at e pr o p h yl a xis wit h a nti -vir al a n d P C P;  
•  
S ecti o n 7 w as u p d at e d b as e d o n t h e u p d at e d I n v esti g at or Br oc h ur e ris ks pr ofil e f or T G R -
1 2 0 2;  
•  
S ecti o n 8. 3. 1 w as u p d at e d t o cl arif y l a n g u a g e f or t ar g et l esi o n s el ecti o n  
V ersi o n 2. 5 ( D at e d 2 1 F e br u ar y 2 0 1 7) of t his Pr ot oc o l 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:  
•  
I ncl usi o n crit eri a # 8 w as cl arifi e d t o all o w Gr o wt h F act or S u p p ort at a n y ti m e d uri n g t h e 
st u d y; 
•  
I ncl usi o n crit eri a # 9 r e q uiri n g m e as ur a bl e l y m p h a d e n o p at h y w as d el ete d.  M e as ur a bl e 
dis e as e is n ot r e q uir e d f or pr ot oc ol e ntr y;  
•  
E xcl usi o n crit eri a # 8 w as cl arifi e d as pr o p h yl a xis 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 is r e q uir e d a n d n ot e nc o ur a g e d; 
•  
S ecti o n 8. 3. 1 w as u p d at e d t o r efl ect t h e c h a n g es  i n I ncl usi o n crit eri a # 9 i n r es p ect t o n o 
m e as ur a bl e dis e as e b ei n g r e q uir e d.  
V ersi o n 3. 0 ( D at e d 1 3 M arc h 2 0 1 7) of t his Pr ot oc ol is t h e t hir 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:  
•  
I ncl usi o n crit eri a # 7 
w as c h a n g ed  fr o m “ … disc o nti n u e d d u e t o i nt ol er a nc e 
wit hi n 9 
m o nt hs …” t o “ … disc o nti n u e d d u e t o i nt ol er a nc e wit hi n 1 2 m o nt hs …”  
•  
C T sc a n ass ess m e nts w er e c h a n g es fr o m “ at t h e c o m pl eti o n of C ycl es 3, 6, 9, 1 2 a n d e v er y 3 
c ycl es t h er e aft er ( + / - 7 d a y wi n d o w)” t o t h e f oll o w i n g: “ D uri n g t h e st u d y p eri o d, p ati e nts will 
b e e v al u at e d f or r es p o ns e b y C T a n d / or M RI d uri n g C ycl es 3, 6, 9, 1 2 a n d t h e n at l e ast e v er y 
6 c ycl es t h er e aft er ( + /- 1 4 d a y wi n d o w).”  
V ersi o n 4.  0 ( D ate d 0 6  Oct o b er  2 0 1 7) of t his Pr ot oc ol is t h e f o urt h a m e n d m e n t 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:  
•  
Incl usi o n crit eri a # 7  h as b e e n cl arifi e d t h at disc o nti n u ati o n of t h e pri or B T K or PI 3 K -d elt a 
i n hi bit or s h o ul d b e wit hi n 1 2 m o nt hs of tr e at m e nt i niti ati o n wit h T G R-1 2 0 2 , d efi n e d as C ycl e 
1 / D a y 1;  
•  
S ecti o n 6. 3. 1 h as b e e n u p d at e d t o pr o vi d e  a d diti o n al  g ui d a nc e o n d os e d el a y / m o dific ati o ns  
f or T G R -1 2 0 2 a n d t o i ncl u d e d os e m o dific ati o ns f or e v e nts of di arr h e a a n d c olitis.   
•  
S ecti o n  7. 1. 1 h as b e e n u p d at e d t o i ncl u d e t h e l at est C A E P R S i nf or m ati o n f o r T G R-1 2 0 2.  


T G R -1 2 0 2 -2 0 1 -C L L  
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
P a g e 9  of 7 1  
•
S ecti o n 8. 3. 1 h as b e e n u p d at e d t o r e m o v e t h e f oll o wi n g st at e m e nt t o n o w  r e q uir e m or e
acc ur at e m e as ur e m e nts of n o d al t ar g et l esi o ns: “ At f oll o w-u p ti m e p oi nts, t h e L Ds f or
i n di vi d u al l esi o ns a n d t h e S P D of all n o d al t ar g et l esi o ns will b e c o nsi der e d.   B ec a us e n o d al
t ar g et l esi o ns t h at h a v e o n e or b ot h di a m et ers > 0 c m a n d < 1. 0 c m c a n n ot b e r eli a bl y
m e as ur e d, a d ef a ult v al u e of 1. 0 c m will b e assi g n e d f or e ac h di a m et er t h at m e ets t h es e
crit eri a a n d t h e r es ulti n g P P D will b e us e d i n S P D c alc ul ati o n s. B as e d o n t his c o n v e nti o n, a C R
m a y b e ac hi e v e d e v e n if a n S P D v al u e is > 0 c m
2  (i. e., if all l y m p h n o d es m e as ur e < 1. 0 c m 2 ).”
•
A p p e n di x B h as b e e n u p d at e d t o n o w r e q uir e m al e p ati e nts t o us e hi g hl y eff ecti v e
c o ntr ac e pti o n d uri n g t h e st u d y p eri o d a n d f or 3 0 d a ys aft er.
•
U p d at e d t hr o u g h o ut t o ac k n o wl e d g e t h e g e n eric n a m e f or T G R-1 2 0 2: u m br alisi b
•
Mi n or a d mi nistr ati v e u p d at es a n d t y p o gr a p hic al err ors w er e c orr ect e d t hr o u g h o ut.
V ersi o n 5. 0 ( d at e d 5 M arc h 2 0 1 9) of t his pr ot oc ol is t h e fift h 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: 
•
S ecti o n 5. 0 St u d y Ass ess m e nt a n d Tr e at m e nt Sc h e d ul e u p d at e d t o i ncl u d e:
o
T h e sc h e d ul e f or r es p o ns e e v al u ati o ns u p d at e d t o b e p erf or m e d d uri n g c ycl es 3, 6, 9,
1 2 a n d at l e ast e v er y 6 c ycl es f or 2 4  c ycl es , t h e n e v er y 1 2 c ycl es  t h er e aft er or m or e
fr e q u e nt if w arr a nt e d.”
o
U p d at e d t o i ncl u d e C M V s ur v eill a nc e  b y P C R  f or all p ati e nts e v er y 3 m o nt hs w hil e
o n st u d y tr e at m e nt
o
U p d at e d wit h i nstr ucti o n t o p erf or m u ri n e pr e g n a nc y t est wit hi n 7 2 h o urs of D a y 1
of e ac h c ycl e  a n d a d mi nist er t est wit h e ac h dr u g dis p e ns ati o n aft er C ycl e 6.
•
S ecti o n 6. 3. 1 D os e D el a y / M o dific ati o n: U m br alisi b h as b e e n u p d at e d t o pr o vi d e a d diti o n al
g ui d a nc e o n d os e d el a y / m o dific ati o ns f or u m br alisi b a n d pr o vi d e cl arific ati o n o n t h e li v er
t o xicit y d os e m o dific ati o ns g ui d eli n es
•
S ecti o n 6  Tr e at m e nt Pl a n h as b e e n u p d at e d t o i ncl u d e:
o
A d diti o n al g ui d a nc e f or PJ P a n d a nti -vir al pr o p h yl a xis
o
R e vis e d t o all o w d os e d el a ys of a n y st u d y m e dic ati o n f or d ur ati o ns l o n g er t h a n 2 8
d a ys t o r ec o v er fr o m t o xicit y
•
S ecti o n 7. 1. 1 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 Rs) , h as b e e n
u p d at e d t o i ncl u d e t h e m ost r ec e nt a d v ers e e v e nt i nf or mati o n f or u m br alisi b b as e d o n t h e
I n v esti g at or’s Br oc h ur e V 6. 0
•
S ecti o n 1 0 S af et y R e p orti n g a n d A n al ysis, u p d at e d t o r efl ect e m ail a d dr ess t o  s u b mit S A E
f or ms.
•
U p d at e d t hr o u g h o ut t o ac k n o wl e d g e t h e g e n eric n a m e f or T G R -1 2 0 2: u m br alisi b
•
U p d at e d t hr o u g h o ut t o u p d at e w or d p ati e nt t o s u bj ect.
•
Mi n or a d mi nistr ati v e u p d at es a n d t y p o gr a p hic al err ors w er e c orr ect e d t hr o u g h o ut


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 1 0  of 7 1  
 
S T U D Y S Y N O P SI S  
P r ot o c ol n o.  
T G R -1 2 0 2 -2 0 1 -C L L  
St u d y Titl e  
A P h as e 2 St u d y t o Ass ess t h e S af et y a n d Effic ac y of T G R -1 2 0 2 i n P ati e nts wit h 
C hr o nic L y m p h oc ytic L e u k e mi a ( C L L) w h o ar e i nt ol er a nt t o Pri or B T K or PI 3 K -
D elt a  I n hi bit or T h er a p y 
S p o n s o r  
T G T h er a p e utics, I nc. ( N e w Y or k, N Y, U S A)  
I N D # 
U m br alisi b ( T G R -1 2 0 2 ): 1 1 6 , 7 6 2 
St u d y C h ai r  
, M D 
  
 
St u d y 
Sit e s 
& 
E n r oll m e nt  
•  
T his st u d y will b e c arri e d o ut i n u p t o 2 0 c e nt ers i n t h e U nit e d St at es  
•  
E nr oll m e nt is e x p ect e d t o t a k e a p pr o xi m at el y 1 2 m o nt hs  
St u d y R ati o n al e  
Alt h o u g h ki n as e i n hi bit or ( KI) t h er a pi es ar e g e n er all y w ell t ol er at e d i n C L L 
t h er e is a s m all s u bs et of p ati e nts ( u p w ar ds of 1 2 %) w h o disc o nti n u e t h er a p y 
d u e t o t o xicit y a n d a l ar g er s u bs et w h o r e q uir e d os e i nt err u pti o n d u e t o t o xicit y 
( u p w ar ds of 3 0 %). Disc o nti n u ati o n or i nt err u pti o ns l e a d t o r es p o ns e d ur ati o ns 
t h at ar e s h ort li v e d a n d t h es e p ati e nts fr e q u e ntl y r e q uir e c o nti n u e d t h er a p y t o 
c o ntr ol t h eir dis e as e.   
 
T h e p ur p os e of t his st u d y is t o e v al u at e t h e s af et y a n d effic ac y of u m br alisi b  i n 
pr e vi o usl y tr e at e d c hr o nic l y m p h oc ytic l e u k e mi a ( C L L) p ati e nts w h o ar e 
i nt ol er a nt t o pri or B T K or PI 3 K-d elt a  i n hi bit or t h er a p y.   
 
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.  U m br alisi b  
is c urr e ntl y i n a P h as e I d os e esc al ati o n tri al a n d h as b e e n a d mi nist er e d s af el y 
at d ail y d os es u p t hr o u g h 1 2 0 0 m g Q D.  
 
I n t h e P h as e I st u d y, 2 0 C L L p ati e nts h a v e b e e n tr e at e d wit h u m br alisi b .  A Es 
( all gr a d es, all c a us alit y) i ncl u d e d n a us e a, di arr h e a, f ati g u e, h e a d ac h e, v o miti n g 
a n d c o u g h b ei n g t h e m ost c o m m o nl y r e p ort e d e v e nts, t h e m aj orit y of w hic h 
w er e Gr 1 / 2.  T h e o nl y Gr ≥3 A E  i n > 1 0 % of p ati e nts w as n e utr o p e ni a ( 1 1 %).  Of 
1 6 e v al u a bl e C L L p ati e nts, 1 4 ( 8 8 %) ac hi e v e d a n o d al P R ( m e di a n n o d al ↓ of 
7 6 %), of 
w hic h 1 0 ( 6 3 %) ac hi e v e d a 
P R p er 
H all e k 2 0 0 8 crit eri a.  
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 u m br alisi b  w as r e p ort e d i n l ess 
t h a n 5 % of p ati e nts. 
 
T h e i m p ort a nc e of d os e i nt e nsit y i n p ati e nts tr e at e d 
wit h i br uti ni b is 
hi g hli g ht e d i n t h e R E S O N A T E st u d y (i br uti ni b vs. of at u m u m a b) w h er e l o w er 
d os e i nt e nsit y w as ass oci at e d wit h a n i nf eri or pr o gr essi o n fr e e s ur vi v al ( P F S). 
Missi n g as f e w as 8 c o ns ec uti v e d a ys of i br uti ni b m o n ot h er a p y r es ult e d i n a n 
i nf eri or P F S.  T h e ki n as e i n hi bit or i nt ol er a nt p ati e nt p o p ul ati o n is t h er ef or e a 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 1 1  of 7 1  
 
u ni q u e C L L p ati e nt p o p ul ati o n i n t h at t h e y h a v e at l e ast S D t o ki n as e i n hi bit or 
t h er a p y h o w e v er, cli nic all y c a n n ot c o nti n u e wit h an acti v e m e dic ati o n d u e t o 
t o xicit y. T his r e pr es e nts a p o p ul ati o n at ris k f or i nf eri or o utc o m es a n d o n e t h at 
r e q uir es disti nct st u d y a p art fr o m p ati e nts w h o pr o gr ess w hil e r ec ei vi n g ki n as e 
i n hi bit or t h er a p y. A d diti o n all y, t h er e h a v e b e e n n o st u di es r e p ort ed t o d at e t h at 
a d dr ess t h e i m p ort a nt q u esti o n of s e q u e nci n g ki n as e i n hi bit or t h er a pi es.  
 
F ort u n at el y, ki n as e i n hi bit or t h er a pi es i n C L L a p p e ar t o h a v e s o m e w h at u ni q u e 
a n d n o n -o v er l a p pi n g t o xicit y pr ofil es.  I n p ati e nts tr e at e d wit h t h e c o m bi n ati o n 
of i d el alisi b -rit u xi m a b, at l e ast o n e s eri o us a d v ers e e v e nt occ urr e d i n 4 0 % of 
p ati e nts i n w hic h t h e m ost c o m m o n s eri o us a d v ers e e v e nts b ei n g  p n e u m o ni a, 
p yr e xi a, a n d f e bril e n e utr o p e ni a. U ni q u e t o xiciti es o bs er v e d i ncl u d e c olitis 
( gr a d e ≥ 3, 5 %), p n e u m o nitis ( gr ad e ≥ 3, 4 %),  a n d tr a ns a mi nitis ( gr a d e ≥ 3, 8 %).  
I n p ati e nts tr e at e d wit h i br uti ni b, t h e m ost c o m m o n gr a d e ≥ 3 s eri o us a d v ers e 
e v e nts w er e p n e u m o ni a ( 1 0 %), b act er e mi a ( 5 %), c ell ulitis ( 5 %), si n usitis ( 5 %), 
a n d atri al fi brill ati o n ( 4 %).  
 
D u e t o t h e diff er e n ti at e d s af et y pr ofil e, o nc e-d ail y d osi n g a n d cli nic al acti vit y i n 
C L L 
wit h u m br alisi b , t h e pri m ar y ai m of t his st u d y is t o e v al u at e t h e 
pr o gr essi o n -fr e e s ur vi v al of u m br alisi b  i n p ati e nts w h o ar e i nt ol er a nt t o pri or 
B T K or PI 3 K -d elt a  i n hi bit or t h er a p y. 
St u d y 
O bj e cti v e s  
P RI M A R Y O BJ E C TI V E  
•  
T o d et er mi n e t h e pr o gr essi o n fr e e s ur vi v al  of u m br alisi b  i n p ati e nts w h o 
w er e i nt ol er a nt t o pri or B T K a n d / or PI 3 K -d elt a i n hi bit ors .  
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 o v er a ll r es p o ns e r at e ( C R + P R) a n d d ur ati o n of  res p o ns e 
of u m br alisi b  i n p ati e nts w h o w er e i nt ol er a nt t o pri or B T K a n d / or PI 3 K -
d elt a i n hi bit ors . 
•  
T o e v al u at e Ti m e t o Tr e at m e nt F ail ur e wit h u m br alisi b  as c o m p ar e d t o 
t h e pri or ki n as e i n hi bit or t h er a p y i n p ati e nts with C L L.  
•  
T o e v al u at e t h e s af et y pr ofil e of u m br alisi b  as c o m p ar e d t o t h e s af et y 
pr ofil e of t h e pri or ki n as e i n hi bit or t h er a p y i n p ati e nts wit h C L L.  
I n cl u si o n 
C rit e ri a  
P ati e nts 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.  C o nfir m e d di a g n osis of C L L as p er t h e i w C L L ( H all e k 2 0 0 8) crit eri a 6  
2.  C L L w arr a nti n g t h er a p y as p er i n v esti g at or discr eti o n.  
3.  P ati e nts m ust b e off pri or B T K a n d / or PI 3 K -d elt a  i n hi bit or f or at l e ast 1 4 
d a ys f oll o wi n g disc o nti n u ati o n wit h o ut d oc u m e nt e d dis e as e pr o gr essi o n. 
T his is t o e ns ur e t h e r e as o n f or disc o nti n u a ti o n w as i nt ol er a nc e, n ot 
dis e as e pr o gr essi o n as list e d b el o w, # 4 - 7.  P ati e nt m a y si g n c o ns e nt 
d uri n g t h e w as h o ut p eri o d.  
4.  F or i br uti ni b / B T K  p ati e nts w h o e x p eri e nc e r el at e d h e m at ol o gic a n d n o n -
h e m at ol o gic t o xiciti es a n d disc o nti n u e t h er a p y  (s e e b ull et 7).  N o n -
h e m at ol o gic  to xiciti es ar e li mit e d t o: Atri al fi brill ati o n, H y p ert e nsi o n, 
Bl e e di n g, Art hr al gi a, R as h, Di arr h e a, I nf ecti o n, P n e u m o nitis.  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 1 2  of 7 1  
 
5.  F or i d el alisi b / d u v elisi b  p ati e nts w h o e x p eri e nc e r el at e d h e m at ol o gic  a n d 
n o n -h e m at ol o gic t o xiciti es a n d disc o nti n u e t h er a p y (s e e b ull et 7).  N o n -
h e m at ol o gic  to xiciti es ar e li mit e d t o: P n e u m o nitis, Tr a ns a mi nitis, R as h, 
C olitis, a n d I nf ecti o n.  
6.  Ot h er gr a d e  ≥ 2  n o n h e m at ol o gic t o xiciti es n ot list e d i n 4  or 5 , d es pit e d os e 
i nt err u pti o n a n d / or r e d ucti o n,  a n d d efi n e d b y t h e tr e ati n g i n v esti g at or as 
“i nt ol er a nt”, will b e e v al u at e d i n di vi d u all y b y t h e st u d y c h air as p art of 
eli gi bilit y crit eri a as p art of t h e scr e e ni n g pr oc ess.  
7.  Pri or t h er a p y wit h a B T K i n hi bit or (i br uti ni b , A C P-1 9 6, ot h er) or a PI 3 K -
d elt a  i n hi bit or (i d el alisi b, d u v elisi b, ot h er), w hic h w as disc o nti n u e d d u e t o 
i nt ol er a nc e, wit hi n 1 2  m o nt hs of t h e ti m e of tr e at m e nt i niti ati o n  wit h 
u m br alisi b  ( C ycl e 1 / D a y 1).  
a.  I nt ol er a nc e d efi n e d as u n acc e pt a bl e t o xicit y w h er e i n t h e o pi ni o n of 
t h e i n v esti g at or, tr e at m e nt s h o ul d b e disc o nti n u e d i n s pit e of o pti m al 
s u p p orti v e c ar e as a r es ult of o n e of t h e f oll o wi n g:  
i. ≥ 2 Gr a d e ≥ 2 n o n -h e m at ol o gic al t o xiciti es (s e e list a b o v e, # 4 -6) 
as a c a us e of disc o nti n u ati o n , a n d / or; 
ii. ≥ 1 Gr a d e  ≥ 3 n o n -h e m at ol o gic al t o xicit y  (s e e list a b o v e, # 4-6) , 
a n d / or;  
iii. ≥ 1 Gr a d e 3 n e utr o p e ni a wit h i nf ecti o n or f e v er, a n d / or;  
i v. Gr a d e 4 h e m at ol o gic al t o xiciti es, A N D t h e t o xiciti es p ersist e nt  t o 
t h e p oi nt t h at t h e i n v esti g at or c h os e t o disc o nti n u e t h er a p y d u e t o 
t o xicit y / n ot pr o gr essi o n.  
v.  T o xicit y m ust r es ol v e t o ≤ gr a d e 1 pri or t o u m br alisi b  d osi n g.  
8.  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) >  1, 0 0 0 / pl at el et c o u nt >  3 0, 0 0 0.  
Gr o wt h f act ors ar e p er mitt e d at a n y ti m e d uri n g  t h e st u d y. 
b.  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)  
c.  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 
d.  C alc ul at e d cr e ati ni n e cl e ar a nc e > 3 0 m L / mi n ( as c alc ul at e d b y t h e 
C oc kcr oft -G a ult or M D R D f or m ul a , 2 4 h o ur uri n e Cr cl e ar a nc e als o 
acc e pt a bl e ) 
9.  E C O G p erf or m a nc e st at us ≤ 2  
1 0.  M al e or f e m al e ≥ 1 8 y e ars of a g e  
1 1.  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  
1 2.  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 
3  d a ys pri or t o C ycl e 1, D a y 1.  
1 3.  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, a n d 
gi v e writt e n i nf or m e d c o ns e nt  
E x cl u si o n 
C ri t e ri a 
P ati e nts 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.  P ati e nts r ec ei vi n g a B T K or PI 3 K -d elt a  i n hi bit or wit hi n 1 4 d a ys of C ycl e 
1 / D a y 1.  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 1 3  of 7 1  
 
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 st u d y e ntr y 
( 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.  T o pic al or i n h al e d c ortic ost er oi ds ar e p er mitt e d  
2.  Dis e as e pr o gr essi o n as d efi n e d b y I W C L L ( H all e k 2 0 0 8) crit eri a as t h e 
i n dic ati o n f or disc o nti n u ati o n o n or wit hi n 1 4 d a ys wit h a p ri or B T K or PI 3 K 
d elt a i n hi bit or. 
3.  Tr e at m e nt wit h pri or u m br alisi b . 
4.  Pri or a ut ol o g o us st e m c ell tr a ns pl a nt wit hi n 3 m o nt hs.  Pri or a ll o g e n eic 
h e m at ol o gic s t e m c ell tr a ns pl a nt wit hi n 1 y e ar a n d e xcl u d e d if t h er e is 
acti v e gr aft v ers us h ost dis e as e .   
5.  A n a p h yl a xis t o pri or ki n as e i n hi bit or t h er a p y.  
6.  E vi d e nc e of c hr o nic acti v e H e p atitis B ( H B V, n ot i ncl u di n g p ati e nts wit h 
pri or h e p atitis B v acci n ati o n; or p ositi v e s er u m H e p atitis B a nti b o d y) or 
c hr o nic acti v e H e p atitis C i nf ecti o n ( H C V), c yt o m e g al o vir us ( C M V), 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 is p ositi v e t h e 
s u bj ect 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 D N A 
( P C R) - S e e A p p e n di x D.  
7.  K n o w n hist ol o gic al tr a nsf or m ati o n fr o m C L L t o a n a g gr essi v e l y m p h o m a 
(i. e. Richt er’s tr a nsf or m ati o n  / H o d g ki n L y m p h o m a ) 
8.  E vi d e nc e of o n g oi n g s yst e mic b act eri al, f u n g al or vir al i nf ecti o n, e x c e pt 
l oc aliz e d f u n g al i nf ecti o n of s ki n or n ails.  
9.  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 Y 
H e art Ass oci ati o n f u ncti o n al cl assific ati o n III -I V) –  S e e A p p e n di x C  
b.  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.  Q Tc F > 4 7 0 ms ec  
d.  A n gi n a n ot w ell -c ontr oll e d b y m e dic ati o n  
e.  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 ac k ( TI A), a n gi o pl ast y, c ar di ac / v asc ul ar st e nti n g  wit hi n 6 m o nt hs of 
e nr oll m e nt  
1 0.  M ali g n a nc y 
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 aliz 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 st u d y e ntr y.  
1 1.  W o m e n w h o ar e pr e g n a nt or l act ati n g.  
St u d y D e si g n  
T his st u d y is d esi g n e d as a P h as e 2, m ulti c e nt er , si n gl e-ar m tri al t o e v al u at e 
u m br alisi b  i n p ati e nts w h o disc o nti n u e a B T K or a PI 3 K -d elt a  i n hi bit or d u e t o 
i nt ol er a nc e.  A p pr o xi m at el y  5 5 p ati e nts, w h o h a v e disc o nti n u e d pri or t h er a p y 
wit h a B T K or PI 3 K -d elt a  i n hi bit or d u e t o i nt ol er a nc e, m a y b e e nr oll e d at 
a p pr o xi m at el y 2 0 sit es i n t h e U S .  Pl a n n e d a n al ysis will i ncl u d e a p pr o xi m at el y 
5 0 e v al u a bl e p ati e nts ass u mi n g a 1 0 % disc o nti n u ati o n r at e.   
E n r oll m e nt  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 1 4  of 7 1  
 
F oll o wi n g Scr e e ni n g, q u alifi e d p ati e nts will b e e nr oll e d vi a a n I W R S a n d r ec ei v e  
t h e f oll o wi n g: 
•  
U m br alisi b  at 8 0 0 m g o nc e d ail y  
 
D uri n g t h e st u d y p eri o d, all p ati e nts will b e e v al u at e d f or r es p o ns e b y C T a n d / or 
M RI d uri n g  C ycl es 3, 6, 9, 1 2 a n d t h e n  at l e ast  e v er y 6  c ycl es f or 2 4 c ycl es , t h e n 
e v er y 1 2 c ycl es  t h er e aft er.   P ati e nts will b e tr e at e d u ntil  dis e as e pr o gr essi o n, 
u n acc e pt a bl e t o xicit y or t h e e n d of t h e st u d y.  U p o n t h e e n d of t h e st u d y, 
p ati e nts wit h o ut dis e as e pr o gr essi o n m a y b e tr a nsiti o n e d t o a n o p e n l a b el 
c o m p assi o n at e us e st u d y. 
St ati sti c s  
W e will pl a n  t o e nr oll a p pr o xi m at el y 5 5 s u bj ects, a n d ass u mi n g 1 0 % attriti o n, 
w e will h a v e a p pr o xi m at el y 5 0 s u bj ects r e m ai ni n g f or a n al ysis.  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 m o nt hs wit h 2 4 m o nt hs f oll o w 
u p.  T h e s a m pl e pr o vi d es 8 2 % p o w er t o d et ect a 1 2 - m o nt h m e di a n s ur vi v al 
v ers us a n 8 m o nt h m e di a n r e pr es e nti n g t h e n ull h y p ot h esis, usi n g a o n e -si d e d 
o n e -s a m pl e l o g-r a n k t est wit h a 5 % t y p e 1 err or. 
 
T h e n u m b er of tr e at m e nt i nt err u pti o ns a n d d os e r e d ucti o ns will als o b e 
e v al u at e d b et w e e n t h e pri or t h er a p y wit h a B T K or PI 3 K -d elt a  i n hi bit or 
c o m p ar e d t o u m br alisi b . 
 
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.  
A d v ers e e v e nts will b e r ec or d e d as p er C T C A E v 4. 0, a n d  b e c o m p ar e d f or 
u m br alisi b  t o t h e pri or tr e at m e nt if d at a a v ail a bl e. 
 
 
 
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 1 5  of 7 1  
 
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  
A b b r e vi ati o n s a n d D efi niti o n s  of T e r m s  
A E  
A d v ers e E v e nt  
A L C  
A bs ol ut e l y m p h oc yt e c o u nt  
A L T  
Al a ni n e a mi n otr a nsf er as e  
A S T  
As p art at e a mi n otr a nsf er as e  
A U C  
Ar e a U n d er t h e C ur v e  
B M  
B o n e M arr o w  
B T K  
Br ut o n’s T yr osi n e Ki n as e  
C a  
C alci u m  
C B C  
C o m pl et e Bl o o d c ell C o u nt  
Cl  
Cl e ar a nc e  
C L L  
C hr o nic L y m p h oc ytic L e u k e mi a  
c m  
C e nti m et er  
C m a x  
M a xi m u m C o nc e ntr ati o n  
C R  
C o m pl et e R es p o ns e  
e C R F  
El ectr o nic C as e R e p ort F or m  
C R O  
C o ntr act R es e arc h Or g a niz ati o n  
C T  
C o m p ut e d t o m o gr a p h y  
C T C A 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  
C V A  
C er e br o -V asc ul ar Acci d e nt  
D, d  
D a y  
D S M B  
D at a S af et y M o nit ori n g B o ar d  
D L T  
D os e Li miti n g T o xicit y  
D O R  
D ur ati o n of R es p o ns e  
D R G  
D at a R e vi e w Gr o u p  
E C  
Et hics C o m mitt e e  
E C G  
El ectr oc ar di o gr a m  
E C O G  
E ast er n C o o p er ati v e O nc ol o g y Gr o u p  
F C R  
Fl u d ar a bi n e, C ycl o p h os p h a mi d e, Rit u xi m a b  
FI S H  
Fl u or esc e nc e i n -sit u h y bri diz ati o n 
G C P  
G o o d Cli nic al Pr actic e  
I E C /I R B 
I n d e p e n d e nt Et hics C o m mitt e e (I E C) or I nstit uti o n al R e vi e w B o ar d (I R B)  
I g 
I m m u n o gl o b uli n 
I C H 
I nt er n ati o nal C o nf er e nc e o n H ar m o nis ati o n  
I R C 
I n d e p e n d e nt R e vi e w C o m mitt e e 
I T T 
I nt e nt-t o-tr e at 
I W C L L 
I nt er n ati o n al W or ks h o p o n C hr o nic L y m p h oc ytic L e u k e mi a 
I V 
I ntr a v e n o us 
L D  
L o n g est Di a m et er  
L D H  
L act at e d e h y dr o g e n as e  
L P D  
L o n g est P er p e n dic ul ar Di a m et er  
L T F U  
L o n g -T er m F oll o w U p  
M D S  
M y el o d ys pl astic S y n dr o m e  
M P D  
M y el o pr olif er ati v e Dis or d er  
M R D  
Mi ni m u m R esi d u al Dis e as e  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 1 6  of 7 1  
 
A b b r e vi ati o n s a n d D efi niti o n s  of T e r m s  
M RI  
M a g n etic R es o n a nc e I m a gi n g  
M e d D R A  
M e dic al Dicti o n ar y f or R e g ul at or y Acti viti es  
N H L  
N o n -H o d g ki n’s L y m p h o m a  
O S  
O v er all s ur vi v al  
O R R  
O v er all R es p o ns e R at e  
P C R  
P ol y m er as e C h ai n R e acti o n  
P E  
P h ysic al E x a mi n ati o n  
P F S  
Pr o gr essi o n -Fr e e S ur vi v al  
P D  
P h ar m ac o d y n a mic or Pr o gr essi v e Dis e as e  
P K  
P h ar m ac o ki n etic  
P P D  
P er p e n dic ul ar Di a m et ers  
P P S  
P er Pr ot oc ol S et  
P R  
P arti al R es p o ns e  
P T  
Pr ef err e d T er m  
S A E  
S eri o us A d v ers e E v e nt  
S A P  
St atistic al A n al ysis Pl a n  
S D  
St a bl e Dis e as e  
S L L  
S m all L y m p h oc ytic L y m p h o m a  
S O C  
S yst e m Or g a n Cl ass  
S P D  
S u m of t h e Pr o d ucts  
S U V  
St a n d ar diz e d U pt a k e V al u e  
t 1 / 2 
H alf -Lif e of Eli mi n ati o n  
T T R  
Ti m e t o r es p o ns e  
U L N  
U p p er li mit of n or m al  
V  
Visit  
V d  
V ol u m e of distri b uti o n  
W H O  
W orl d H e alt h Or g a niz ati o n  
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 1 7  of 7 1  
 
1  I N T R O D U C TI O N 
1. 1  C H R O NI C L Y M P H O C Y TI C L E U K E MI A  
I n t h e U S, a n esti m at e d 1 4, 6 2 0  n e w c as es of C hr o nic L y m p h oc ytic L e u k e mi a ( C L L) will b e r e p ort e d 
i n 2 0 15  wit h d e at hs t ot ali n g 4, 6 5 0 d u e t o t h e dis e as e acc or di n g t o A m eric a n C a nc er S oci et y esti m at es 
( A m eric a n C a nc er S oci et y, 2 0 1 5). C L L aff ects m ai nl y ol d er a d ults, acc o u nts f or o n e t hir d of all 
di a g n os e d c as es of l e u k e mi a, a n d is c h ar act eriz e d b y t h e acc u m ul ati o n of cl o n al 
m at ur e B 
l y m p h oc yt es i n t h e bl o o d, b o n e m arr o w, a n d s ec o n d ar y l y m p h oi d tiss u es ( Li n K, 2 0 0 2).  C L L is a 
h et er o g e n e o us dis e as e, wit h s e v er al hi g h er ris k c yt o g e n etic a b n or m aliti es w hic h ar e g e n er all y m or e 
diffic ult t o tr e at , i ncl u di n g 1 7 p d el eti o n, P 5 3 g e n e m ut ati o n, a n d 1 1 q d el eti o n ( H all e k M, 2 0 0 8) ( Li n 
K, 2 0 0 2) .  P ati e nts wit h 1 7 p d el eti o n s h o w hi g h er r esist a nc e t o c o n v e nti o n al c h e m ot h er a pi es as w ell 
as s h ort er d ur ati o n of s ur vi v al t h a n n o n 1 7 p d el eti o n p ati e nts.   P ati e nts wit h 1 1 q d el eti o n h a v e b e e n 
ass oci at e d wit h m ar k e d l y m p h a d e n o p at h y ( H all e k M, 2 0 0 8).  P ati e nts wit h P 5 3 g e n e m ut ati o ns ar e 
ass oci at e d wit h a n a d v ers e cli nic al o utc o m e ( Li n 2 0 0 2).  
 
R ec e ntl y t h e B T K i n hi bit or, i br uti ni b  a n d t h e PI 3 K d elt a i n hi bit or, i d el alisi b w er e  a p pr o v e d b y t h e 
F D A  f or t h e tr e at m e nt of p ati e nts wit h C L L i n t h e r el a ps e d or r efr act or y s etti n g.  Alt h o u g h ki n as e 
i n hi bit or ( KI) t h er a pi es ar e g e n er all y w ell t ol er at e d i n C L L t h er e is a siz a bl e s u bs et of p ati e nts 
( u p w ar ds of 1 2 %) w h o disc o nti n u e t h er a p y d u e t o t o xicit y a n d a l ar g er s u bs et w h o r e q uir e d os e 
i nt err u pti o n d u e t o t o xicit y ( u p w ar ds of 3 0 %).  Disc o nti n u ati o n or i nt err u pti o ns l e a d t o r es p o ns e 
d ur ati o ns t h at ar e s h ort er  li v e d.  A d diti o n all y,  t h es e p ati e nts fr e q u e ntl y r e q uir e c o nti n u e d t her a p y 
t o c o ntr ol t h eir dis e as e. T h er ef or e, t h er e is a c o ns e ns us i n t h e C L L c o m m u nit y t h at fr e q u e nt 
tr e at m e nt i nt err u pti o ns or d os e r e d ucti o ns m a y l e a d t o i nf eri or o utc o m es.  T h e i m p ort a nc e of d os e 
i nt e nsit y i n p ati e nts tr e at e d wit h i br uti ni b is hi g hli g ht e d i n t h e R E S O N A T E st u d y (i br utini b vs. 
of at u m u m a b) w h er e l o w er d os e i nt e nsit y w as ass oci at e d wit h a n i nf eri or pr o gr essi o n fr e e s ur vi v al 
( P F S).1 ,2   Missi n g as f e w as 8 c o ns ec uti v e d a ys of i br uti ni b m o n ot h er a p y r es ult e d i n a n i nf eri or P F S.
2   
 
F ort u n at el y, ki n as e i n hi bit or t h er a pi es i n C L L a p p e ar t o h a v e s o m e w h at u ni q u e a n d n o n o v er l a p pi n g 
t o xicit y pr ofil es.  I n p ati e nts tr e at e d wit h t h e c o m bi n ati o n of i d el alisi b-rit u xi m a b, at l e ast o n e s eri o us 
a d v ers e e v e nt occ urr e d i n 4 0 % of p ati e nts wit h t h e m ost c o m m o n s eri o us a d v ers e e v e nts b ei n g  
p n e u m o ni a, p yr e xi a, a n d f e bril e n e utr o p e ni a. U ni q u e t o xiciti es of i d el alisi b i ncl u d e c olitis ( gr a d e ≥ 3, 
5 %), p n e u m o nitis ( gr a d e ≥ 3, 4 %),  a n d tr a ns a mi nitis ( gr a d e ≥ 3, 8 %).  I n p ati e nts tr e at e d wit h 
i br uti ni b, t h e m ost c o m m o n gr a d e ≥ 3 s eri o us a d v ers e e v e nts w er e p n e u m o ni a ( 1 0 %), b act er e mi a 
( 5 %), c ell ulitis ( 5 %), si n usitis ( 5 %), a n d atri al fi brill ati o n ( 4 %). 5  
 
W e h a v e s el ect e d u m br alisi b  t o st u d y i n t h e p ati e nt p o p ul ati o n d u e t o its s e e mi n gl y n o n- o v erl a p pi n g 
t o xicit y pr ofil e wit h a g e nts s uc h as i br uti ni b a n d i d el alisi b. 
1. 2  U M B R A LI SI B  
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. 3   U m br alisi b  is c urr e ntl y i n a P h as e I d os e esc al ati o n tri al a n d h as b e e n 
a d mi nist er e d s af el y at d ail y d os es u p t hr o u g h 1 2 0 0 m g Q D.  
 
I n a P h as e I st u d y, 2 0 C L L p ati e nts w er e  tr e at e d wit h u m br alisi b .  A Es ( all gr a d es, all c a us alit y) 
i ncl u d e d n a us e a, di arr h e a, f ati g u e, h e a d ac h e, v o miti n g a n d c o ug h b ei n g t h e m ost c o m m o nl y r e p ort e d 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 1 8  of 7 1  
 
e v e nts, t h e m aj orit y of w hic h w er e Gr 1 / 2.  T h e o nl y Gr ≥3 A E i n > 1 0 % of p ati e nts w as n e utr o p e ni a 
( 1 1 %).  Of 1 6 e v al u a bl e C L L p ati e nts, 1 4 ( 8 8 %) ac hi e v e d a n o d al P R ( m e di a n n o d al ↓ of 7 6 %), of 
w hic h 1 0 ( 6 3 %) ac hi e v e d a P R p er H all e k 2 0 0 8 crit eri a.  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 u m br alisi b  w as r e p ort e d i n l ess t h a n 5 % of p ati e nts.
4  
1. 2. 1  P R E -C LI NI C A L D E V E L O P M E N T O F T G R -1 2 0 2  
T h e p ot e nc y of T G R -1 2 0 2 a g ai nst t h e h u m a n a n d m o us e δ is of or m of PI 3 K w as e v al u at e d i n a 
h o m o g e n e o us ti m e r es ol v e d fl u or es c e nc e ( H T R F) b as e d e n z y m e ass a y i n t h e pr es e nc e of A T P at its 
K m v al u e ( 1 0 0 μ M) ( 1 1). S el ecti vit y o v er t h e ot h er t hr e e is of or ms, n a m el y, α, β, a n d γ w as als o 
d et er mi n e 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 P T -0 8, 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, 2 0 1 1) . 
D at a d e m o nstr at e d t h e s p ecificit y of T G R -1 2 0 2 t o w ar ds PI 3 K δ wit h > 1 0 0 0, 5 0 a n d 4 8 -f ol d s el ecti vit y 
o v er α, β, a n d γ, r es p ecti v el y i n a n e n z y m e b as e d ass a y, i n dic ati n g t h at t h e pri m ar y m o d e of acti o n of 
t his c o m p o u n d is vi a i n hi biti o n of t h e δ is of or m. 
FI G U R E 
1 : 
T G R-1 2 0 2 
P O T E N C Y 
A G AI N S T 
H U M A N A N D M O U S E PI 3 K  I S O F O R M S 
 
 
 
 
 
Pr olif er ati o n of i m m ort aliz e d l e u k e mic c ells r e pr es e nt ati v e of v ari o us i n dic ati o ns w as d et er mi n e d 
b y a  M T T ( 3 -( 4, 5-Di m et h ylt hi a z ol -2 -yl) -2, 5 -di p h e n yl t etr a z oli u m br o mi d e) ass a y ( 1 7). C ells w er e 
i nc u b at e d wit h T G R-1 2 0 2 f or diff er e nt ti m e -p eri o ds ( 7 2 -9 6 h) b as e d o n t h eir d o u bli n g ti m e.  D at a 
d e m o nstr at e d t h e a bilit y of T G R -1 2 0 2 t o i n hi bit l e u k e mic c ell pr ol if er ati o n al b eit wit h diff er e nt 
p ot e nci es b as e d o n t h e c ell t y p e.  
O v er all, a 5 0 % gr o wt h i n hi biti o n f or m aj orit y of B, T, a n d m o n oc ytic c ell li n es w as ac hi e v e d at a 
c o nc e ntr ati o n b et w e e n 0. 5 -7. 5 μ M of T G R -1 2 0 2.  
S u bs e q u e nt t o c ell vi a bilit y, t h e eff ect of T G R -1 2 0 2 o n A K T p h os p h or yl ati o n ( 1 2, 1 3, 1 4, 1 5, 1 6) w as 
d et er mi n e d.  A K T, a s eri n e t hr e o ni n e ki n as e m e di at es t h e d o w nstr e a m eff ects of PI 3 K acti vit y a n d 
m o d ul at es s e v er al c ell pr oc ess es i ncl u di n g s ur vi v al a n d gr o wt h.  R e d ucti o n of p h os p h or yl at e d A K T 
b y T G R -1 2 0 2 i n r e pr es e nt ati v e c ell li n es w as d et er mi n e d b y W est er n bl otti n g usi n g a p h os p h o -A K T 
( S er 4 7 3) a nti b o d y. 
 
 
PI 3 K is of o r m s 
( H u m a n) 
I C5 0  ( n M) 
α  
> 1 0, 0 0 0  
β  
1, 1 1 6  
γ  
1, 0 6 5  
δ  
2 2. 2 3  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 1 9  of 7 1  
 
FI G U R E 2 : R E D U C TI O N O F P A K T B Y T G R -1 2 0 2 I N C E L L LI N E S B Y W E S T E R N B L O T TI N G  
 
1. 2. 1. 1. 1  I N-VI V O A C TI VI T Y  
I n vi v o effic ac y of T G R-1 2 0 2 w as c o nfir m e d i n a s u bc ut a n e o us m o us e M O L T -4 x e n o gr aft m o d el.  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 : T G R-1 2 0 2 I N VI V O E F FI C A C Y  
 
1. 2. 1. 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 T G R -1 2 0 2 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.  T G R -1 2 0 2 w as a d mi nist e r 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 T G R -1 2 0 2  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 e r 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 T G R -1 2 0 2  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 di es 
c o n d uct e d t o d at e.  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 2 0  of 7 1  
 
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  SI N G L E -A G E N T  I N P A TI E N T S 
WI T H R EL 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 n o n g oi n g 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 p ati e nts 
wit h r el a ps e d a n d r efr act or y h e m at ol o gic m ali g n a nci es  ( B urris et al, A S H 2 0 1 4) .  Fift y -fi v e p ati e nts 
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 4 3  p ati e nts 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 2  y e ars (r a n g e 2 2 -8 2), 7 3 % m al e a n d 1 8 / 5 5  e nr oll e d p ati e nts h a d a di a g n osis of C L L.  
A m o n g all p ati e nts t h e m e di a n n u m b er of pri or t h er a pi es w as 3, 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.  Ot h er hist ol o gic al di a g n os es i ncl u d e d; F L ( n = 1 5 ), H L ( n =9 ), D L B C L ( n =7 ), M C L 
( n = 2), M Z L ( n = 2), H C L a n d W M  ( n = 1 e ac h).  T h e m aj orit y of p ati e nts h a d a n E C O G of 1 a n d 5 1 % 
r ec ei v e d 3 or m or e pri or t h er a pi es.     
P ati e nts 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 siz 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 niz ati o n pr oc ess , r es ulti 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  (s e e S ecti o n 1. 2. 2. 2  H e alt h y S u bj ect P h ar m ac o ki n etic St u di es  b el o w).   T h is 
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-p ati e nt d os e esc al ati o n r ul es h a v e 
all o w e d p ati e nts 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 oniz 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 p ati e nts .  Of t h e 1 4  e v al u a bl e C L L p ati e nts 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, 9 3 % 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.  A d v ers e e v e nts o bs er v e d a m o n gst 
all 5 5 p ati e nts i ncl u d ed  di arr h e a, n a us e a, f ati g u e,  c o u g h, a n or e xi a, h e a d ac h e, v o miti n g, r as h, 
n e utr o p e ni a, c o nsti p ati o n , d ys p n e a, a n d t hr o m b oc yt o p e ni a.  O n e D L T e v e nt of Gr a d e 3 r as h w as 
o bs er v e d at t h e 8 0 0 m g d os e l e v el  of t h e i niti al f or m ul ati o n , w hic h n ec essit at e d e nr oll m e nt of a n 
a d diti o n al 3 p ati e nts.  T h e Gr a d e 3 r as h r es ol v e d u p o n s us p e nsi o n of u m br alisi b  a n d c o nc o mit a nt 
m e dic ati o ns a n d di d n ot r ec ur u p o n r e -c h all e n gi n g t h e p ati e nt at 8 0 0 m g Q D.  S e e t h e u m br alisi b  
i n v esti g at ors br oc h ur e f or a c o m pl et e o v er vi e w of t h e u m br alisi b  si d e eff ect pr ofil e.   
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 p ati e nts 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 niz 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 p ati e nts wit h C L L .  D os e  e x p a nsi o n  i n 
t h e P h as e 1 st u d y c o nti n u es. 
 
 
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  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 2 1  of 7 1  
 
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 p ati e nts wit h r el a ps e d or r ef r 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 T G R -1 2 0 2 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 eti 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 T G R -1 2 0 2 ( 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 T G R-
1 2 0 2 c o nc e n tr 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 T G R-1 2 0 2 u n d er f asti n g a n d 
f e d c o n diti o n usi n g t h e ori gi n al f or m ul ati o n.  I n g e n er al, a d mi nistr ati o n of T G R-1 2 0 2 u n d er f e d 
c o n diti o ns r es ults i n a hi g h er r at e of e x p os ur e r el ati v e t o w h e n t h e pr o d uct w as gi v e n u n d er f asti n g 
c o n diti o ns.   
T h e st atistic al c o m p aris o ns of T G R -1 2 0 2 p h ar m ac o ki n etic p ar a m et ers u n d er f ast e d a n d f e d 
c o n diti o n ar e s h o w n b el o w. 
 
P a r a m et e r s  
G e o m et ri c L S M e a n s  
% G e o m et ri c 
M e a n R ati o  
C o nfi d e n c e I nt e r v al  
F a sti n g  
F e d  
A U C 0 -t ( n g∙hr / m L ) 
6 0 2 9. 8 7  
9 6 2. 0 2  
1 6 0. 7 3  
1 4 0. 2 5 –  1 8 4. 2 1  
A U C 0 -i nf  ( n g∙hr / m L ) 
8 3 9 1. 3 5  
1 4 0 4 7. 1 7  
1 6 7. 4 0  
1 4 1. 5 9 –  1 9 7. 9 2  
C m a x  ( n g / m L) 
1 7 6. 7 8  
4 8 3. 1 5  
2 7 3. 3 1  
2 3 4. 0 4 –  3 1 9. 1 7  
 
F o o d i ncr e as e d b ot h t h e e xt e nt a n d r at e of e x p os ur e of T G R -1 2 0 2.  T h e e xt e nt ( A U C 0 -t) a n d t ot al 
e xt e nt ( A U C 0 -i nf) of e x p os ur e i ncr e as e d b y 6 1 % a n d 6 7 %, r es p ecti v el y, w h e n T G R -1 2 0 2 w as 
a d mi nist er e d u n d er f e d c o n diti o ns c o m p ar e d t o f asti n g c o n diti o ns.  T h e p e a k pl as m a l e v els of T G R -
1 2 0 2 i ncr e as e d b y o v er 1 7 3 % w h e n T G R -1 2 0 2 w as a d mi nist er e d wit h f o o d.  
Usi n g t h es e m e a n v al u es, a 3 3 4 m g or al d os e of T G R -1 2 0 2 u n d er 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 G R-1 2 0 2 u n d er f e d c o n diti o ns i n t er ms of e x p os ur e 
b as e d o n A U C 0 -i nf.  
1. 2. 2. 2. 2  T G R -1 2 0 2 -P K 1 0 2: F O R M U L A TI O N E F F E C T  
St u d y T G R -1 2 0 2 -P K 1 0 2 w as a 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, r el ati v e bi o a v ail a bilit y 
a n d p h ar m ac o ki n etic bi o e q ui v al e nc e st u d y wit h t w o diff er e nt dr u g pr o d uct f or m ul ati o ns of T G R -
1 2 0 2.  I n t his st u d y, T G R -1 2 0 2 w as a d mi nist er e d u n d er f ast e d c o n d iti o ns 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 T G R -1 2 0 2 c o nc e ntr ati o n o v er ti m e f oll o wi n g a 2 0 0 
m g si n gl e d os e of t h e ori gi n al dr u g pr o d uct f or m ul ati o n a n d m o difi e d ( micr o niz e d) dr u g pr o d uct 
f or m ul ati o n of T G R-1 2 0 2. T h e m e a n r at e a n d e xt e nt of e x p os ur e t o T G R -1 2 0 2 w er e hi g h er f oll o wi n g 
a d mi nistr ati o n of t h e micr o niz e d dr u g pr o d uct f or m ul ati o n c o m p ar e d t o t h e ori gi n al dr u g pr o d uct 
f or m ul ati o n as m e a n c o nc e ntr ati o ns w er e hi g h er t hr o u g h o ut m ost of t h e s a m pli n g i nt er v al. 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 2 2  of 7 1  
 
T h e s t atistic al c o m p aris o n of t h e micr o niz e d 2 0 0 m g dr u g pr o d uct f or m ul ati o n v ers us t h e ori gi n al 
2 0 0 m g dr u g pr o d uct f or m ul ati o n ar e s h o w n b el o w:  
P a r a m et e r s  
G e o m et ri c L S M e a n s  
% 
G e o m et ri c 
M e a n R ati o  
C o nfi d e n c e 
I nt e r v al 
O ri gi n al 
F o r m ul ati o n  
Mi c r o ni z e d  
F o r m ul ati o n  
A U C 0 -t ( n g∙hr / m L ) 
5 9 0 6. 1 1  
9 4 3 9. 8 2  
1 5 9. 8 3  
1 4 9. 4 3 –  1 7 0. 9 5  
A U C 0 -i nf  ( n g∙hr / m L ) 
7 7 1 5. 6 7  
1 2 3 7 8. 1 9  
1 6 0. 4 3  
1 4 6. 4 9 –  1 7 5. 7 0  
C m a x  ( n g / m L) 
1 6 6. 2 0  
3 7 1. 7 0  
2 2 3. 6 5  
2 0 2. 3 3 –  2 4 7. 2 0  
 
T h e micr o niz e d dr u g pr o d uct f or m ul ati o n i ncr e as e d b ot h t h e e xt e nt a n d r at e of e x p os ur e of T G R -
1 2 0 2 u n d er f ast e d c o n diti o ns. T h e e xt e nt ( A U C 0 -t) a n d t ot al e xt e nt (A U C 0 -i nf ) of e x p os ur e b ot h 
i ncr e as e d b y 6 0 %, r es p ecti v el y, f oll o wi n g a d mi nistr ati o n of t h e m o difi e d dr u g pr o d uct f or m ul ati o n 
r el ati v e t o ori gi n al dr u g pr o d uct f or m ul ati o n. T h e P e a k pl as m a ( C m a x ) l e v els of T G R-1 2 0 2 i ncr e as e d 
b y o v er 1 2 4 % f oll o wi n g a d mi nistr ati o n of t h e micr o niz e d dr u g pr o d uct f or m ul ati o n r el ati v e t o 
ori gi n al dr u g pr o d uct f or m ul ati o n u n d er f ast e d c o n diti o ns.  
Usi n g t h es e m e a n v al u es, a 3 2 0 m g or al d os e of T G R -1 2 0 2 i n t h e ori gi n al f or m ul ati o n u n d er 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 
T G R -1 2 0 2 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 T G R -1 2 0 2 w as c o nfir m e d i n 
p ati e nts 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 T G R -1 2 0 2 o n D a y 1 of C ycl e 2 i n p ati e nts 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 niz e d f or m ul ati o n i n t h e f e d st at e:   
 
 
 
 
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 2 3  of 7 1  
 
1. 3  R A TI O N A L E F O R T H E P H A S E 2 T RI A L  
A  r etr os p ecti v e a n al ysis of 1 2 3 p ati e nts w h o disc o nti n u e d pri or ki n as e i n hi bit or ( KI)  t h er a p y acr oss 
1 0 l ar g e U S c a nc er c e nt ers  w as c o n d uct e d . I n v esti g at ors i d e ntifi e d 1 2 3 p ati e nts w h o disc o nti n u e d 
eit h er  i br uti ni b or i d el alisi b (ibr uti ni b = 9 3 /i d el alis b = 3 0).  I nt er esti n gl y, 1 0 % a n d 3 2 % of ibr uti ni b 
( 5% 1 4 0 m g, 5 % 2 8 0 m g d ail y) a n d i d el alisi b p ati e nts ( 3 2 % 1 0 0 m g BI D), r es p ecti v el y, w er e i niti at e d 
at d os es l ess t h a n F D A l a b el e d d os e.   F urt h er, 2 3 % a n d 4 2 % of ibr uti ni b (I br) p ati e nts  a n d 3 0 % a n d 
6 5 % i d el alisi b (I d e)  p ati e nts h a d d os es m o difi e d or h el d, r es p ecti v el y, pri or t o disc o nti n u ati o n. F or 
p ati e nts w h o disc o nti n u e d KI t h er a p y, t h e m e di a n ti m e o n KI w as 5 m o nt hs. T h e m ost c o m m o n 
r e as o ns f or KI disc o nti n u ati o n w er e t o xicit y ( 5 8 % I br, 6 0 % I d e), C L L pr o gr essi o n ( 2 4 % I br, 3 0 % 
I d e), a n d R T D L B C L ( 8 % I br, 7 % I d e) ( M at o et al, A bstr act 8 0 7 0 7, A S H 2 0 1 5 ). 
T h e “ki n as e i n hi bit or i nt ol er a nt ” p ati e nt p o p ul ati o n is t h er ef or e a u ni q u e C L L p ati e nt p o p ul ati o n i n 
t h at t h e y h a v e at l e ast S D t o ki n as e i n hi bit or h o w e v er, clinic all y c a n n ot c o nti n u e wit h t h er a p y d u e t o 
tr e at m e nt r el at e d t o xicit y.  T his r e pr es e nts a p o p ul ati o n at ris k f or i nf eri or o utc o m es a n d o n e t h at 
r e q uir es disti nct st u d y a p art fr o m p ati e nts w h o pr o gr ess w hil e r ec ei vi n g ki n as e i n hi bit or t h er a p y. 
A d diti o n all y t h er e h a v e b e e n n o pr os p ecti v e st u di es r e p ort e d t o d at e t h at a d dr ess t h e i m p ort a nt 
q u esti o n of s e q u e nci n g ki n as e i n hi bit or t h er a pi es.    
 
T h e p ur p os e of t his st u d y is t o e v al u at e t h e s af et y a n d effic ac y of u m br alisi b  i n pr e vi o usl y tr e at e d 
c hr o nic l y m p h oc ytic l e u k e mi a ( C L L) p ati e nts w h o ar e i nt ol er a nt t o pri or B T K or PI 3 K -d elt a  i n hi bit or 
t h er a p y.  T his st u d y will e v al u at e t h e pr o gr essi o n -fr e e s ur vi v al of u m br alisi b  i n p ati e nts w h o ar e 
i nt ol er a nt t o pri or KI t h er a p y w hic h is r e q uir e d t o b e a B T K (i e. i br uti ni b) or PI 3 K-d elt a  i n hi bit or 
(i d el alisi b, d u v elisi b, etc).  
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 2 4  of 7 1  
 
2  O BJ E C TI V E S A N D E N D P O I 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 d et er mi n e t h e pr o gr essi o n fr e e s ur vi v al of u m br alisi b  i n p ati e nts w h o w er e i nt ol er a nt t o 
pri or B T K a n d / or PI 3 K -d elt a i n hi bit ors.  
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 o v er all r es p o ns e r at e ( C R + P R) a n d d ur ati o n of r es p o ns e of u m br alisi b  i n 
p ati e nts w h o w er e i nt ol er a nt t o pri or B T K a n d / or PI 3 K -d elt a i n hi bit ors . 
•  
T o e v al u at e Ti m e t o Tr e at m e nt F ail ur e wit h u m br alisi b  as c o m p ar e d t o t h e pri or ki n as e 
i n hi bit or t h er a p y i n p ati e nts wit h C L L. 
•  
T o e v al u at e t h e s af et y pr ofil e of u m br alisi b  as c o m p ar e d t o t h e s af et y pr ofil e of t h e pri or 
ki n as e i n hi bit or t h er a p y i n p ati e nts wit h C L L . 
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 b as e d o n st a n d ar d 
crit eri a ( H all e k et al. 2 0 0 8) a n d occ urri n g f or a n y r e as o n (i. e., i ncr e asi n g l y m p h a d e n o p at h y, 
or g a n o m e g al y or b o n e m arr o w i n v ol v e m e nt; d ecr e asi n g pl at el et c o u nt, h e m o gl o bi n, or n e utr o p hil 
c o u nt; or w ors e ni n g of dis e as e -r el at e d s y m pt o ms) ot h er t h a n l y m p h oc yt osis .  
 
Ti me t o tre at me nt f ail ure ( T T F)   
T T F is defi ne d as a c o m p osite e n d p oi nt meas uri n g ti me fr o m C ycle 1/ Da y 1 t o disc o nti n uati o n of 
treat me nt f or a n y reas o n, i ncl u di n g dis ease pr o gressi o n, treat me nt t o xicit y, a n d deat h.  
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.   
 
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 . 
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 2 5  of 7 1  
 
3  E LI GI BI LI T Y C RI T E RI A  
P ati e nts 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 er i 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 
P ati e nts 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.  C o nfir m e d di a g n osis of C L L as p er t h e i w C L L ( H all e k 2 0 0 8) crit eri a  
2.  C L L  w arr a nti n g t h er a p y as p er i n v esti g at or discr eti o n.  
3.  P ati e nts m ust b e off pri or B T K a n d / or PI 3 K -d elt a  i n hi bit or f or at l e ast 1 4  d a ys f oll o wi n g 
disc o nti n u ati o n wit h o ut d oc u m e nt e d dis e as e pr o gr essi o n. T his is t o e ns ur e t h e r e as o n f or 
disc o nti n u ati o n w as i nt o l er a nc e, n ot dis e as e pr o gr essi o n as list e d b el o w, # 4 - 7 .  P ati e nt s m a y 
si g n c o ns e nt  d uri n g t h e w as h o ut p eri o d.  
4.  F or i br uti ni b / B T K  p ati e nts w h o e x p eri e nc e r el at e d h e m at ol o gic  a n d n o n -h e m at ol o gic t o xiciti es 
a n d disc o nti n u e t h er a p y (s e e b ull et 7).  N o n -h e m at ol o gic  t o xiciti es ar e li mit e d t o: Atri al 
fi brill ati o n, H y p ert e nsi o n, Bl e e di n g, Art hr al gi a, R as h, Di arr h e a, I nf ecti o n, P n e u m o nitis . 
5.  F or i d el alisi b / d u v elisi b  p ati e nts w h o e x p eri e nc e r el at e d h e m at ol o gic  a n d n o n -h e m at ol o gic 
t o xiciti es a n d disc o nti n u e t h er a p y (s e e b ull et 7). N o n -h e m at ol o gic  t o xiciti es ar e li mit e d t o: 
P n e u m o nitis, Tr a ns a mi nitis, R as h, C olitis, a n d I nf ecti o n . 
6.  Ot h er gr a d e  ≥ 2 n o n -h e m at ol o gic t o xiciti es n ot list e d i n 4 or 5, d es pit e d os e i nt err u pti o n a n d / or 
r e d ucti o n, a n d d efi n e d b y t h e tr e ati n g i n v esti g at or as “i nt ol er a nt”, will b e e v al u at e d i n di vi d u all y 
b y t h e st u d y c h air as p art of eli gi bilit y crit eri a as p art of t h e scr e e ni n g pr oc ess.  
7.  Pri or t h er a p y wit h a B T K i n hi bit or (i br uti ni b , A C P-1 9 6, ot h er) or  a PI 3 K -d elt a i n hi bit or 
(i d el alisi b, d u v elisi b, ot h er) w hic h w as disc o nti n u e d , d u e t o i nt ol er a nc e , wit hi n 1 2  m o nt hs of 
t h e ti m e of tr e at m e nt i niti ati o n wit h u m br alisi b  ( C ycl e 1 / D a y 1).  
a.  I nt ol er a nc e d efi n e d as u n acc e pt a bl e t o xicit y w h er e i n t h e o pi ni o n of t h e i n v esti g at or, 
tr e at m e nt s h o ul d b e disc o nti n u e d i n s pit e of o pti m al s u p p orti v e c ar e as a r es ult of o n e of 
t h e f oll o wi n g: 
i. ≥ 2 Gr a d e ≥ 2 n o n -h e m at ol o gic al t o xiciti es (s e e list a b o v e, # 4 -6 ) as a c a us e of 
disc o nti n u ati o n , a n d / or; 
ii. ≥ 1 Gr a d e  ≥ 3 n o n -h e m at ol o gic al t o xicit y  (s e e list a b o v e, # 4-6 ), a n d / or; 
iii. ≥ 1 Gr a d e 3 n e utr o p e ni a wit h i nf ecti o n or f e v er, a n d / or;  
i v. Gr a d e 4 h e m at ol o gic al t o xiciti es, A N D t h e t o xiciti es p ersist e nt  t o t h e p oi nt t h at t h e 
i n v esti g at or c h os e t o disc o nti n u e t h er a p y d u e t o t o xicit y / n ot pr o gr essi o n.  
v.  T o xicit y m ust r es ol v e t o ≤ gr a d e 1 pri or t o u m br alisi b  d osi n g.  
8.  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) >  1, 0 0 0 / pl at el et c o u nt >  3 0 , 0 0 0. Gr o wt h f act ors ar e 
p er mitt e d at a n y ti m e d uri n g t h e st u d y . 
b.  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)  
c.  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  
d.  C alc ul at e d cr e ati ni n e cl e ar a nc e > 3 0 m L / mi n ( as c alc ul at e d b y t h e C oc kcr oft -G a ult or 
M D R D f or m ul a , 2 4- h o ur uri n e Cr cl e ar a nc e als o acc e pt a bl e ) 
9.  E C O G p erf or m a nc e st at us ≤ 2  
1 0.  M al e or f e m al e ≥ 1 8 y e ars of a g e  
1 1.  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 


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D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 2 6  of 7 1  
 
1 2.  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 3  d a ys pri or t o C ycl e 1, D a y 1.  
1 3.  Willi n g n ess a n d a bilit y t o c o m pl y wi t h tri al a n d f oll o w-u p pr oc e d ur es, a n d gi v e writt e n 
i nf or m e d c o ns e nt. 
3. 2  E X C L U SI O N C RI T E RI A  
P ati e nts 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.  P ati e nts r ec ei vi n g a B T K or PI 3 K -d elt a  i n hi bit or wit hi n 1 4  d a ys of C ycl e 1 / D a y 1.  
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 st u d y e ntr y ( 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.  T o pic al or i n h al e d c ortic ost er oi ds ar e 
p er mitt e d . 
2.  Dis e as e pr o gr essi o n as d efi n e d b y I W C L L ( H all e k 2 0 0 8) crit eri a as t h e i n di c ati o n f or 
disc o nti n u ati o n o n or wit hi n 1 4 d a ys wit h a pri or B T K or PI 3 K -d elt a  i n hi bit or. 
3.  Pri or tr e at m e nt wit h u m br alisi b . 
4.  Pri or a ut ol o g o us st e m c ell tr a ns pl a nt wit hi n 3 m o nt hs.  Pri or all o g e n eic h e m at ol o gic st e m c ell 
tr a ns pl a nt wit hi n 1 y e ar a n d e xcl u d e d if t h er e is acti v e gr aft v ers us h ost dis e as e. 
5.  A n a p h yl a xis t o pri or ki n as e i n hi bit or t h er a p y.  
6.  E vi d e nc e of c hr o nic acti v e H e p atitis B ( H B V, n ot i ncl u di n g p ati e nts wit h pri or h e p atitis  B 
v acci n ati o n; or p ositi v e s er u m H e p atitis B a nti b o d y) or c hr o nic acti v e H e p atitis C i nf ecti o n 
( H C V), c yt o m e g al o vir us ( C M V), 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 
is p ositi v e t h e s u bj ect 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, HC V, or C M V b y D N A ( P C R) - 
S e e A p p e n di x D.  
7.  K n o w n hist ol o gic al tr a nsf or m ati o n fr o m C L L t o a n a g gr essi v e l y m p h o m a (i. e. Ric ht er’s 
tr a nsf or m ati o n / H o d g ki n L y m p h o m a ). 
8.  E vi d e nc e of o n g oi n g s yst e mic b act eri al, f u n g al or vir al i nf ecti o n, e x c e pt l oc aliz e d f u n g al 
i nf ecti o n of s ki n / n ails.  
9.  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 Y H e art Ass oci ati o n 
f u ncti o n al cl assific ati o n III-I V) –  S e e A p p e n di x C  
b.  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.  Q Tc F > 4 7 0 ms ec  
d.  A n gi n a n ot w ell -c o ntr oll e d b y m e dic ati o n  
e.  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 ac k ( TI A), a n gi o pl ast y, 
c ar di ac / v asc ul ar st e nti n g  wit hi n 6 m o nt hs of e nr oll m e nt . 
1 0.  M ali g n a nc y 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 aliz 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 st u d y e ntr y.  
1 1.  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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D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 2 7  of 7 1  
 
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 st u d y is d esi g n e d as a P h as e 2, m ultic e nt er , si n gl e-ar m tri al t o e v al u at e t h e P F S of u m br alisi b  i n 
C L L p ati e nts r e q uiri n g t h er a p y  w h o ar e i nt ol er a nt t o pri o r ki n as e i n hi bit or t h er a p y.  U p t o 5 5  p ati e nts 
w h o h a v e disc o nti n u e d t h eir pri or t h er a p y wit h a B T K or PI 3 K -d elt a  i n hi bit or d u e t o i nt ol er a nc e, m a y 
b e e nr oll e d.  
St u d y S c h e m a  
 
4. 2  R E GI S T R A TI O N / E N R O L L M E N T  
F oll o wi n g Scr e e ni n g, q u alifi e d p ati e nts will r ec ei v e t h e f oll o wi n g: 
•  
U m br alisi b  at 8 0 0 m g o nc e d ail 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 e nr oll  p ati e nts t o st u d y T G R-
1 2 0 2 -2 0 1 .  U p o n e nt eri n g p ati e nt 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 
p ati e nt i d 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 p ati e nt 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.  
D uri n g t h e st u d y p eri o d, all p ati e nts will b e e v al u at e d f or r es p o ns e b y C T a n d / or M RI d uri n g  C ycl es  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 2 8  of 7 1  
 
3, 6, 9, 1 2 a n d at l e ast e v er y 6 c ycl es f or 2 4 c ycl es , t h e n e v er y 1 2 c ycl es t h er e aft er or m or e fr e q u e nt 
if w arr a nt e d  
( + /- 1 4 d a y wi n d o w) .  P ati e nts will b e tr e at e d u ntil dis e as e pr o gr essi o n, u n acc e pt a bl e t o xicit y, or t h e 
e n d of t h e st u d y.  U p o n t h e e n d of t h e st u d y, p ati e nts wit h o ut dis e as e pr o gr essi o n m a y b e tr a nsiti o n e d 
t o a n o p e n l a b el c o m p assi o n at e us e st u d y. 
4. 3  S T U D Y SI T E S  
U p t o 2 0  c e nt ers i n t h e U nit e d St at es  m a y b e as k e d t o p artici p at e i n t his st u d y .  E nr oll m e n t 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  m o nt hs .   
4. 4  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  
P ati e nts 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  
•  
P ati e nt 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 p ati e nt 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  
P ati e nts 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) 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  as p er t h e St u d y Ass ess m e nt T a bl e . 
Aft er wit h dr a w al fr o m pr ot oc ol tr e at m e nt, p ati e nts 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  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 aus 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 p ati e nt ’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 p ati e nts w h o h a v e C T C A E G r a d e 3 or 4 l a b or at o r 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 G r 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 p ati e nt ’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.  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 2 9  of 7 1  
 
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  
E r r o r! R ef e r e n c e s o u r c e n ot f o u n d. T h e T a bl e b el o w  lists st u d y ass ess m e nts t h at s h o ul d b e 
p erf or m e d at e ac h st u d y visit.  
 
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  
All c y cl e s a r e 2 8 d a y s 
Scr e e ni n g  
C ycl e 1 1  
C ycl es  
2 - 6 2  
> C ycl e 6 3  
E O T  
3 0 
d a y 
F / U  
D -3 0 t o D 0  
D 1  
D 8  
D 1 5  
D 1  
E v er y 3 
c ycl es  
I nf or m e d C o ns e nt 
X  
 
 
 
 
 
 
 
M e dic al Hist or y  
X  
 
 
 
 
 
 
 
E C O G P erf or m a nc e St at us  
X  
X  
 
 
X  
X  
X  
 
P h ysic al E x a mi n ati o n / Vit al s 
( W ei g ht, T e m p, B P, H R, R R) 
X  
X  
X  
X  
X  
X  
X  
 
E K G ( Qtc F)  
X  
 
 
 
 
 
 
 
S er ol o g y H C V, H B V , C M V 
X 4  
 
 
 
 
 
 
 
C M V s ur v eill a nc e  
 
 
 
 
C 3 & 6  
X 5  
 
 
H e m at ol o g y  
X  
X  
X  
X  
X  
X  
X  
 
C h e mistr y  
X  
X  
X  
X  
X  
X  
X  
 
C T I m a gi n g ( n ec k, c h est, 
a b d o m e n, p el vis)  
X 6  
D uri n g  C ycl es 3, 6, 9, 1 2 a n d  at l e ast  e v er y 6  c ycl es f or 
2 4 c ycl es, t h e n e v er y 1 2 c ycl es t h er e aft er or m or e 
fr e q u e nt if w arr a nt e d ( + /- 1 4  d a ys)  
X 7  
 
S er u m Pr e g n a nc y T est  
X 8  
 
 
 
 
 
 
 
Uri n e Pr e g n a nc y T est 9  
 
 
 
 
X  
X  
 
 
C oll ect B ucc al S w a b f or 
S o m atic D N A 1 0  
X  
 
 
 
 
 
 
 
C orr el ati v e L a bs ( P B )1 0  
X  
 
 
 
C ycl e 2  
 
Dis e as e 
pr o gr essi o n  
 
P eri p h er al Bl o o d 1 1  
X  
 
 
 
 
 
 
 
U m br alisi b   
 
D ail y D a ys 1 –  2 8  
 
 
B o n e M arr o w Bi o ps y 1 2  
X  
 
 
 
 
 
 
 
A E Ass ess m e nt  
 
X  
X  
X  
X  
X  
X  
X 1 3  
C o n m e d Ass ess m e nt  
 
X  
X  
X  
X  
X  
X  
 
                                                             
1  P h ysic al E x a m, Vit als, E C O G, tr e at m e nt a d mi nistr ati o n, A Es, c o n m e ds, h e m at ol o g y, s er u m c h e mistr y  visit d a ys h a v e + / - 1 d a y  wi n d o w.  Ass ess m e nts m ust b e 
d o n e wit hi n t h e s p ecifi e d wi n d o w, b ut o nl y pri or t o i niti ati o n of n e xt c ycl e.  
2  P h ysic al E x a m, Vit al Si g ns, E C O G P S, tr e at m e nt a d mi nistr ati o n, A Es, c o n m e ds,  h e m at ol o g y, s er u m c h e mi str y visit d a ys h a v e + / - 3 d a y  wi n d o w i n C ycl es 2 - 6.  
Ass ess m e nts m ust b e d o n e pri or t o tr e at m e nt a d mi nistr ati o n. Ass ess m e nts m ust b e d o n e wit hi n t h e s p ecifi e d wi n d o w, b ut o nl y pr i or t o i niti ati o n of n e xt c ycl e. 
3  P h ysic al E x a m, Vit al Si g ns, E C O G P S, tr e at m e nt a d mi nistr ati o n, A Es, c o n m e ds, h e m at ol o g y, s er u m c h e mistr y  visit d a ys h a v e + / - 7 d a y wi n d o w f or C ycl es > 6.  
Ass ess m e nts m ust b e d o n e pri or t o tr e at m e nt a d mi nistr ati o n. Ass ess m e nts m ust b e d o n e wit hi n t h e s p ecifi e d wi n d o w, b ut o nl y pr i or t o i niti ati o n of n e xt c ycl e. 
4  S er u m vir ol o g y t o i n cl u d e H Bs A g, H Bs A b, H Bc a nti b o d y, H C V a nti b o d y a n d C M V.  If H Bc a nti b o d y, H C V a nti b o d y or C M V is p ositi v e, s u bj ect s m u st b e e v al u at e d 
f or t h e pr es e n c e of acti v e H B V, H C V or C M V b y D N A ( P C R). 
5  E v er y 3 m o nt hs C M V scr e e ni n g b y P C R.  C M V s ur v eill a n c e w ill disc o nti n u e 3 0 d a ys aft er l ast d os e of u m br alisi b, or as ot h er wis e cli nic all y i n dic at e d p er 
i n v esti g at or discr eti o n. 
6  B as eli n e C T sc a n wit hi n 3 0 d a ys pri or t o C ycl e 1 / D a y 1; t h e n d uri n g c ycl es 3, 6, 9, 1 2 a n d at l e ast e v er y 6 c ycl es  f or 2 4 c ycl es, t h e n e v er y 1 2 c ycl es 
t h er e aft er or m or e fr e q u e nt if w arr a nt e d  ( + /- 1 4 d a ys).  C T i m a gi n g s h o ul d b e p erf or m e d at E O T visit if it h as n’t b e e n c o m pl et e d wit hi n p ast 3 0 d a ys.  
7  If disc o nti n u e d d u e t o r e as o ns ot h er t h a n pr o gr essi o n, f oll o w u p e v er y 3 m o nt hs o n st at us of dis e as e pr o gr essi o n. P ati e nts w h o disc o nti n u e fr o m st u d y 
tr e at m e nt aft er c ycl e 1 2 (f or r e as o ns ot h er t h a n dis e as e pr o gr essi o n) s h o ul d b e f oll o w e d f or pr o gr essi o n, a p pr o xi m at el y e v er y  6 m o nt hs  f or 2 4 m o nt hs t h e n 
e v er y 1 2 m o nt hs or m or e fr e q u e nt if w arr a nt e d .  
8  S er u m pr e g n a n c y t est wit hi n 7 2 h o urs pri or t o st arti n g tr e at m e nt o n C ycl e 1 / D a y 1.   
9  Uri n e pr e g n a n c y t est wit hi n 7 2 h o urs of D a y 1 of e ac h c ycl e.  A d mi nist er t est wit h e ac h dr u g dis p e ns ati o n aft er C ycl e 6.  
1 0  P eri p h er al Bl o o d (scr e e ni n g, C ycl e 2 / D a y 1 a n d at dis e as e pr o gr essi o n) a n d b ucc al s w a b (scr e e ni n g o nl y) s a m pl es f or c orr el ati v e a n al ys es.  S e e l a b 
m a n u al.  
1 1  A d diti o n al p eri p h er al bl o o d s a m pl e will b e c oll ect e d at scr e e ni n g o nl y a n d a n al y z e d at c e ntr al l a b f or hi g h -ris k c yt o g e n etics as w ell as B T K / PI 3 K 
r esist a n c e a n d acti v ati n g m ut ati o ns / d el eti o ns of pr o g n ostic v al u e.   
1 2  B o n e M arr o w as pir at e / bi o ps y p erf or m e d at b as eli n e at t h e discr eti o n of i n v esti g at or t o e v al u at e c yt o p e ni as.  B o n e m arr o w  t o b e r e p e at e d if p ati e nt m e ets 
cli nic al crit eri a f or C R t o c o nfir m t his fi n di n g, as p er i w C L L crit eri a.  
1 3  S u bj ects w h o disc o nti n u e st u d y dr u g s h o ul d h a v e a f oll o w u p visit or t el e p h o n e c all t o ass ess f or A Es. T his s h o ul d b e d o n e 3 0 d a ys ( + / - 7 d a ys) aft er t h e l ast 
d os e of st u d y dr u g. I n a d diti o n, S A Es will b e r e p ort e d f or 3 0 d a ys aft er t h e l ast d os e of st u d y dr u g.  
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3 0  of 7 1  
 
L a b or at or y ass ess m e nts will b e c oll ect e d as s p ecifi e d i n t h e st u d y ass ess m e nts a n d tr e at m e nt sc h e m a.  
Pl e as e r ef er t o t h e st u d y /l a b m a n u al f or i nstr ucti o ns o utli ni n g c oll ecti o n a n d s hi p m e nt pr oc e d ur es 
f or l a b s a m pl es f or c e ntr al r e vi e w. 
5. 1. 1  L O C A L L A B O R A T O R Y  A S S E S S M E N T S  
1.  H e m at ol o gic pr ofil e a n d s er u m c h e mistr y t o i ncl u d e  ( wit hi n 3 0  d a ys of C ycl e 1 / D a y 1) : 
H e m at ol o gi c P r ofil e  
H e m at ocrit  
N e utr o p hils  
Pl at el et c o u nt  
H e m o gl o bi n  
L y m p h oc yt es  
A bs ol ut e l y m p h oc yt e c o u nt  
Er yt hr oc yt e c o u nt  
M o n oc yt es  
L e u k oc yt e c o u nt  
B as o p hils  
E osi n o p hils  
A bs ol ut e n e utr o p hil c o u nt  
S e r u m C h e mi st r y  
Al b u mi n  
Cr e ati ni n e  
S G O T [ A S T]  
Al k ali n e p h os p h at as e  
Gl uc os e  
S G P T [ A L T]  
Bic ar b o n at e / C O 2  
L D H  
S o di u m  
B U N  
M a g n esi u m  
T ot al bilir u bi n  
C alci u m  
P h os p h or us  
T ot al p r ot ei n 
C hl ori d e  
P ot assi u m  
Uric aci d  
H e m at ol o gi c a n d S er u m C h e mistr y wi n d o ws as f oll o ws:  
•  
C ycl e 1:  - 1 d a y wi n d o w  
•  
C ycl e s 2 –  6 :  - 3 d a y wi n d o w  
•  
>  C ycl e 6 :  - 7 d a y wi n d o w  
 
2.  S er u m β -H C G t est . 
3.  S er u m Vir ol o g y t o i ncl u d e H Bs A G, H b S A b, H Bc a nti b o d y, H C V a nti b o d y, a n d C M V.   If H Bc  
a nti b o d y, H C V a nti b o d y or C M V ar e p ositi v e t h e s u bj ect m ust b e e v al u at e d f or t h e pr es e nc e 
of acti v e H B V, H C V or C M V b y D N A ( P C R)  - S e e A p p e n di x D . 
4.  B as eli n e b o n e m arr o w as pir at e /  bi o ps y (if i n dic at e d or w arr a nt e d ). 
5.  C M V s ur v eill a nc e e v er y 3 m o nt hs b y P C R .  C M V s ur v eill a nc e will disc o nti n u e 3 0 d a ys aft er 
l ast d os e of u m br alisi b, or as ot h er wis e cli nic all y i n dic at e d p er i n v esti g at or discr eti o n. 
5. 1. 2  C E N T R A L L A B O R A T O R Y A S S E S S M E N T S  
S e e St u d y L a b M a n u al f o r f ull C e nt r al L a b d et ail s ( c oll e cti o n, p r e p a r ati o n, s hi p pi n g, et c.)  
▪ 
P eri p h er al Bl o o d s a m pl e at scr e e ni n g, C ycl e 2 / D a y 1 a n d at dis e as e pr o gr essi o n, will b e 
c oll ect e d, s hi p p e d a n d st or e d at  
 f or c orr el ati v e a n al ys es .  S e e St u d y / L a b  M a n u al f or 
d et ails.   
▪ 
A n a d diti o n al p eri p h er al bl o o d s a m pl e will b e c oll ect e d at sc r e e ni n g o nl y a n d a n al y z e d b y at 
c e ntr al l a b f or c yt o g e n etics ( 1 7 p d el, 1 1 q d el, p 5 3 m ut ati o n) a n d  B T K / PI 3 K r esist a nc e a n d 
acti v ati n g m ut ati o ns / d el eti o ns  of pr o g n ostic v al u e .  I n a d diti o n, a B ucc al S w a b will b e 
c oll ect e d at scr e e ni n g o nl y a n d s e nt t o c e ntr al l a b f or a n al ysis ( S e e St u d y / L a b  M a n u al).  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3 1  of 7 1  
 
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 alisi b  
 
•  
8 0 0 m g u m br alisi b  o nc e d ail y u ntil r e m o v al fr o m st u d y  
•  
P ati e nt di ar y will b e utiliz e d  t o d oc u m e nt miss e d d os es of st u d y dr u g 
6. 2  A G E N T A D MI NI S T R A TI O N  
U m br alisi b  will b e s elf-a d mi nist er e d or all y, all  o n a n o ut p ati e nt b asis.  
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.  
•  
A nti -micr o bi al pr o p h yl axis : 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 
wit h 
p n e u m oc ystis jir o v eci p n e u m o ni a ( P JP) a n d a nti vir al t h er a p y pri or t o C ycl e 1 D a y 1.  C h oic e 
of PJ 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 o r discr eti o n a n d i nstit uti o n al 
st a n d ar d of c ar e, wit h t h e f oll o wi n g as r ec o m m e n d ati o ns:  
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  P JP Pr o p h yl axis:  D a ps o n e 1 0 0 m g d ail y or e q ui v al e nt.  
If a nti-vir al or a nti -b act eri al pr o p h yl a xis is n ot t ol er at e d, alt er n ati n g t o a diff er e nt 
pr o p h yl actic a g e nt, r e d uci n g t h e d os e or m o dif yi n g t h e sc h e d ul e f or t h e pr o p h yl actic 
a g e nt, or disc o nti n ui n g pr o p h yl a xis is at t h e discr eti o n  of t h e i n v esti g at or .  Fi n al c h oic e of 
P JP 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.  
•  
Pre -m e dic ati o ns:  N o n e  
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 P h ar m acist of a ut h oriz e d d esi g n e e .  S u bj ects 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 ects 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 u r n t h e b ottl e t o t h e sit e. 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 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 ects  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 . D o  n ot c h e w or cr us h  u m br alisi b . 
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 miss e d 
f or 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. 
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3 2  of 7 1  
 
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  P h ar m acist or a ut h oriz e d d esi g n e 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 al i dit y is wit hi n t h e r e-t est d at 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 , 
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. 
T h e P h ar m acist or a ut h oriz e d d esi g n e e  s h o ul d r ec or d t h e d at e dis p e ns e d a n d s u bj ect’s n u m b er a n d 
i niti als, as w ell as c o m pl et e t h e acc o u nt a bilit y r ec or d i n t h e el ectr o nic dr u g acc o u nt a bilit y s yst e m  
wit h i nf or m ati o n c o nc er ni n g t h e dis p e ns ati o n of u m br alisi b .   
6. 2. 2  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 . 
•  
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 ects  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 / C T C A E_ 4. 0 3_ 2 0 1 0 -0 6 -1 4_ Q uic k R ef er e nc e_ 8. 5 x 1 1. p df E r r o r! 
H y p e rli n k r ef e r e n c e n ot v ali d. )  gr a di n g sc al e.   D os e d el a y a n d / or m o dific ati o n g ui d a nc e is f or 
a d v ers e e v e nts c o nsi d er e d at l e ast p ossi bl y r el at e d t o t h e st u d y dr u g.   If c yt o p e ni as ar e d e e m e d 
r el at e d t o t h e u n d erl yi n g dis e as e r at h er t h a n st u d y dr u g, d os e m o dific ati o ns ar e n ot  r e q uir e d a n d ar e 
p er i n v esti g at or  discr eti o n.  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 of st u d y dr u g is all o w e d 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 e s t o ≤ Gr a d e 2 or t o 
b as eli n e l e v el.    
If gr e at er t h a n 2 -c ycl e dr u g  d el a y is n ec ess ar y f or r ec o v er y of t o xiciti es, y o u m a y  co nt act T G 
T h er a p e utics pri or t o r e -i niti ati n g st u d y dr u g wit h a n y q u esti o ns.    If a s u bj ect disc o nti n u es st u d y 
dr u g  d u e t o t o xicit y, t h e s u bj ect  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  as d escri b e d i n t h e 
St u d y Ass ess m e nts a n d Tr e at m e nt Sc h e d ul e .  If a 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.  
S u bj ects s h o ul d b e r e -e d uc at e d if a d os e m o dific ati o n occ urs, t o e ns ur e t h e y ar e a w ar e of t h e r e vis e d 
n u m b er of st u d y dr u g t a bl ets .  T h e I W R S s yst e m s h o ul d b e u p d at e d i n t h e e v e nt of d os e d el a ys a n d / or 
m o dific ati o ns i n I W R S.   C o nt act s p o ns or wit h q u esti o ns r e g ar di n g d os e d el a y a n d / or m o dific ati o n.  
6. 3. 1  D O S E D E L A Y / M O DI FI C A T I O N S: U M B R A LI SI B  
T A B L E 1 : U M B R A LI SI B  D O S E D E L A Y A N D / O R M O DI FI C A TI O N S  G UI D A N C E  
N CI -C T C A E G r a d e  
D o s e D el a y a n d / or M o difi c ati o n  
H e m at ol o gi c A d v e r s e E v e nt  
N e ut r o p e ni a  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3 3  of 7 1  
 
Gr a d e ≤ 2 n e utr o p e ni a  
M ai nt ai n c urr e nt d os e. C o nsi d er s u p p orti v e c ar e as w arr a nt e d.  
Gr a d e 3 n e utr o p e ni a  
M ai nt ai n c urr e nt d os e, c o nsi d er s u p p orti v e c ar e.  If r ec urr e nc e or p ersist e nt Gr a d e 3, 
r es u m e at n e xt l o w er d os e l e v el at discr eti o n of t h e i n v esti g at or.  
Gr a d e 4 n e utr o p e ni a or 
occ urr e nc e of n e utr o p e ni c 
f e v er or i nf ecti o n 
D el a y u m br alisi b  u ntil Gr a d e ≤ 3 a n d / or n e utr o p e nic f e v er or i nf ecti o n is r es ol v e d; 
t h er e aft er, r es u m e at f ull d os e.  C o nsi d er s u p p orti v e c ar e.   
 
If r ec urr e nc e aft er r ec h all e n g e, r es u m e at n e xt l o w er d os e l e v el at discr eti o n of t h e 
i n v esti g at or. 
T h r o m b o c yt o p e ni a  
Gr a d e ≤ 3 t hr o m b oc yt o p e ni a  
M ai nt ai n c urr e nt d os e l e v el a n d pr o vi d e s u p p orti v e c ar e as cli nic all y w arr a nt e d.  
Gr a d e 4 t hr o m b oc yt o p e ni a  
D el a y u m br alisi b  u ntil Gr a d e ≤ 3; t h er e aft er, r es u m e at f ull d os e.  C o nsi d er s u p p orti v e 
c ar e i nt er v e nti o n as w arr a nt e d.     
 
If r ec urr e nc e aft er r ec h all e n g e, r es u m e at n e xt l o w er d os e l e v el at discr eti o n of t h e 
i n v esti g at or. 
P ul m o n a r y & R el at e d I nf e cti o n s *  
Gr a d e 1 & 2  
St o p all t h er a p y a n d h ol d u ntil c o m pl et e r es ol uti o n.  R est art u m br alisi b  at o n e l o w er 
d os e l e v el.   
If r ec urr e nc e aft er r e-c h all e n g e, disc o nti n u e all tr e at m e nt t h er a p y . 
Gr a d e ≥ 3  
Disc o nti n u e all t h er a p y  
*F o r si n o p ul m o n a r y i nf e cti o n s cl e a rl 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 niti s, 
u m b r ali si b  m a y b e 
c o nti n u e d at i n v e sti g at o r’ s di s c r eti o n.  W hil e p n e u m o niti s h a s b e e n mi ni m al wit h u m b r alisi b , it i s a r e p ort e d 
a d v e r s e e v e nt a ss o ci at e d wit h ot h e r PI 3 K d elt a i n hi bit o r s.  Us e of a nti -p n e u m o c y sti s a n d a nti -vi r al p r o p h yl a xi s 
i s r e q ui r e d at st a rt of t h e r a p y.  
All Ot h e r N o n -H e m at ol o gi c al A d v e r s e E v e nts  
Gr a d e ≤ 2  
M ai nt ai n c urr e nt d os e l e v el . 
 
Gr a d e ≥ 3  
Wit h h ol d u m br alisi b  u ntil Gr a d e ≤ 2.    
 
If r ec urr e nc e aft er r e-c h all e n g e, r es u m e at f ull d os e or n e xt l o w er d os e l e v el at discr eti o n 
of t h e i n v esti g at or.   
Di a r r h e a a n d / or C oliti s  
Di arr h e a Gr a d e ≤ 2  
M ai nt ai n c urr e nt d os e l e v el if t ol er a bl e or h ol d a n d t h e n r es u m e at c urr e nt d os e l e v el 
o nc e h as r es ol v e d.  
C o nsi d er s u p p orti v e c ar e.  
N O T E : If p ersist e nt gr a d e 2 di arr h e a, d es pit e s u p p orti v e c ar e, d el a y u m br alisi b  u ntil ≤ 
gr a d e 1.   If r ec urr e nc e aft er r ec h all e n g e, r es u m e at f ull d os e or n e xt l o w er d os e l e v el at 
discr eti o n of t h e i n v esti g at or.  
Di arr h e a Gr a d e ≥ 3  
Wit h h ol d u m br alisi b  u ntil Gr a d e ≤ 2.   A d mi nist er s u p p orti v e c ar e.  R es u m e at f ull d os e 
or n e xt l o w er d os e l e v el as p er discr eti o n of i n v esti g at or    
If r ec urr e nc e aft er r ec h all e n g e, r es u m e at n e xt l o w er d os e l e v el at discr eti o n of t h e 
i n v esti g at or.  
C olitis ( all Gr a d es)  
H ol d u m br alisi b . Tr e at wit h s u p p orti v e c ar e a n d aft er r es ol uti o n of c olitis, r es u m e 
u m br alisi b  at n e xt l o w er d os e l e v el  
Li v e r I nj u r y ( A L T / S G P T, A S T / S G O T, Bili r u bi n, Al k ali n e P h o s p h at a s e)  
Gr a d e 1  
•  
M ai nt ai n c urr e nt d os e   
•  
Ass ess C o nc o mit a nt M e di c ati o ns a n d Ris k F act ors*  
•  
M o nit or L a bs e v er y 1 -2 w e e ks  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3 4  of 7 1  
 
Gr a d e 2  
•  
M ai nt ai n c urr e nt d os e  
•  
Ass ess C o nc o mit a nt M e di c ati o ns a n d Ris k F act ors*   
•  
B e gi n s u p p orti v e c ar e ( pr e d nis o n e 0. 5 -1 m g / k g / d a y or e q ui v al e nt, p er 
i n v esti g at or discr eti o n)** 
•  
M o nit or l a bs at l e ast w e e kl y u ntil Gr a d e 1  
•  
O nc e r es ol v e d t o Gr a d e ≤1, t a p er pr e d nis o n e b y 1 0 m g p er w e e k u ntil off.  
o  
If li v er t o xi cit y r ec urs t o Gr a d e 2 o nc e off st er oi ds, r e-i niti at e st er oi ds wit h 
1 0 m g p er w e e k t a p er u ntil off.   
o  
C o nsi d er wit h h ol di n g u m br alisi b.   
Gr a d e ≥3  
•  
H ol d u m br alisi b     
•  
Ass ess C o nc o mit a nt M e di c ati o ns a n d Ris k F act ors*  
•  
B e gi n /c o nti n u e s u p p orti v e c ar e ( 0. 5 -1 m g / k g / d a y or e q ui v al e nt, p er i n v esti g at or 
discr eti o n)**  
•  
M o nit or l a bs at l e ast w e e kl y u ntil Gr a d e 1  
•  
O nc e r es ol v e d t o Gr a d e ≤1, t a p er pr e d nis o n e b y 1 0 m g p er w e e k u ntil off  
•  
R es u m e u m br alisi b at n e xt l o w er d os e l e v el w h e n Gr a d e ≤1  
* Ass ess f or dis or d ers of li pi ds a n d gl uc os e, t h yr oi d dis or d ers, alc o h ol us e, vir al i nf ecti o ns, etc.  
** S u p p orti v e C ar e –  A g gr essi v e m a n a g e m e nt of li pi d, gl uc os e, ot h er m et a b olic dis or d ers, vir al i nf ecti o ns, etc.  
I m p ort a nt: B ef or e i niti ati n g st er oi ds, c h ec k f or vir al h e p atitis or C M V i nf ecti o n. 
  St u d y D r u g D o s e R e d u cti o n R e c o m m e n d ati o n s   
St u d y D r u g  
St a rti n g D o s e  
1 st D os e R e d u cti o n  
2 n d  D o s e R e d u cti o n  
U m br alisi b  
8 0 0 m g  
6 0 0 m g  
4 0 0 m g  
A m a xi m u m of t w o d os e l e v el r e d ucti o ns ar e all o w e d f or u m br alisi b .   
If a s u bj ect r e q uir es a d os e r e d ucti o n of u m br alisi b  d u e t o st u d y dr u g r el at e d t o xicit y, t h e d os e m a y 
n ot b e r e -esc al at e d.  If f urt h er e v al u ati o n of t h e t o xicit y r e v e als t h e e v e nt w as n ot r el at e d t o 
u m br alisi b , t his m ust b e r ec or d e d i n t h e m e dic al r ec or d a n d d os e r e-esc al ati o n t o t h e n e xt hi g h er 
d os e l e v el m a y b e c o nsi d er e d at t h e discr eti o n of t h e i n v esti g at or.  
6. 4  O R D E RI N G  U M B R A LI SI B  
O nc e t h e cli nic al st u d y sit e r ec ei v es r e g ul at or y a p pr o v al (I R B /I E B), a n d t h e S p o ns or a n d / or S p o ns or 
d esi g n e e p erf or ms t h e Sit e I niti ati o n Visit a n d i ns p ecti o n of p h ar m ac y, a n d d et er mi n es t h e sit e t o b e 
offici all y o p e n f or e nr oll m e nt, a n d o nc e a s u bj ect is i d e ntifi e d, a s hi p m e nt of pr e-d et er mi n e d q u a ntit y 
of  u m br alisi b  will b e s hi p p e d t o t h e cli nic al st u d y sit e. 
U p o n r ec ei pt of tr e at m e nt s u p pli es, t h e P h ar m acist or a ut h oriz e d d esi g n e e  s h o ul d u p d at e t h e 
acc o u nt a bilit y f or ms f or  u m br alisi b .  If a n y ab n or m alit y o n t h e s u p pli e d  b ottl es ( u m br alisi b ) is 
o bs er v e d, t h e P h ar m acist or a ut h oriz e d d esi g n e e  m ust d oc u m e nt t h at o n t h e ac k n o wl e d g e m e nt of 
r ec ei pt a n d c o nt act t h at S p o ns or a n d / or S p o ns or d esi g n e e.  
6. 5  D U R A TI O N O F T H E R A P Y  
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), tr e at m e nt s h o ul d c o nti n u e t hro u g h C ycl e 
1 a n d b e y o n d 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. 
•  
P ati e nt 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.  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3 5  of 7 1  
 
•  
St u d y dr u g will b e m a d e a v ail a bl e t o r es p o n di n g s u bj ects f or a t ot al of t hr e e y e ars fr o m 
i niti ati o n of t h er a p y. If u m br alisi b  b ec o m e s c o m m erci all y a v ail a bl e d uri n g t h e acti v e p eri o d 
o n st u d y, a n att e m pt will b e m a d e t o o bt ai n t his a g e nt t hr o u g h c o m m erci al i ns ur a nc e. If 
c o v er a g e is n ot a v ail a bl e, it will b e pr o vi d e d f or a p eri o d of t hr e e y e ars as st at e d a b o v e.   
 
D uri n g t h e st u d y p eri o d,  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 a n d / or M RI d uri n g C ycl es 3, 
6, 9, 1 2 a n d t h e n at l e ast e v er y 6  c ycl es f or 2 4 c ycl es t h e n e v er y 1 2 c ycl es  t h er e aft er ( + /- 1 4 d a y 
wi n d o w) .  S u bj ect s s h o ul d r e m ai n o n st u d y tr e at m e nt 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 ue fr o m st u d y tr e at m e nt  a n d h a v e n ot pr o gr ess e d s h o ul d 
c o nti n u e  t o b e f oll o w ed f or pr o gr essi o n , if a gr e e a bl e, a p pr o xi m at el y e v er y 3 m o nt hs.  If t h e s u bj ect 
disc o nti n u es aft er c ycl e 1 2 f or r e as o ns ot h er t h a n dis e as e pr o gr essi o n, t h e y 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 a p pr o xi m at el y e v er y 6 m o nt hs f or 2 4 c ycl es t h e n e v er y 1 2 c ycl es t h er e aft er 
( + /- 1 4 d a y wi n d o w) .  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3 6  of 7 1  
 
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  
C h e mic al N a m e:  
U m br alisi b t os yl at e  
 
Ot h er N a m es:     
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:   
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. 1. 1  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 o ll 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 si n gl e a g e nt 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 t h e st u d y m e dic ati o n. 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 1 3 6 s u bj ec ts e x p os e d t o si n gl e a g e nt u m br alisi b wit h a 
m a xi m u m f oll o w u p of 5 + y e ars.   S e e t h e l at est u m br alisi b I n v esti g at or’s Br oc h ur e f or u p d at e d s af et y 
i nf or m ati o n.  
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 y st e m Di s o r d e r s:  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:  n a us e a, di arr h o 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: fati g u e  
7. 1. 1. 1  C O M M O N ( ≥ 2 % - <  1 0 %)  
Bl o o d a n d L y m p h ati c S y st e m Di s o r d e r s:  a n a e mi a, t hr o m b oc yt o p e ni a, l e u k oc yt osis, l y m p h oc yt osis  
E a r a n d L a b y ri nt h Di s o r d e r s:  ti n nit us 
E y e Di s o r d e r s: visi o n bl urr e d  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3 7  of 7 1  
 
G a st r oi nt e sti n al Di s o r d e r s: c o nsti p ati o n, a b d o mi n al p ai n, a b d o mi n al  dist e nsi o n, d ys p e psi a, c olitis, 
dr y  m o ut h  
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:  p yr e xi a, o e d e m a  p eri p h er al  
I nf e cti o n s a n d I nf e st ati o n s: p n e u m o ni a, or al  c a n di di asis 
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: c o nt usi o n  
I n v e sti g ati o n s: w ei g ht d ecr e as e d, al a ni n e  a mi n otr a nsf er as e i ncr e as e d, a s p art at e a mi n otr a nsf er as e 
i ncr e as e d, b l o o d cr e ati ni n e i ncr 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 ecr e as e d a p p etit e, 
d e h y dr ati o n, 
h y p er gl yc 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:  m uscl e  s p as ms, 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:  diz zi n ess, h e a d ac h e, d ys g e usi a, tr e m or  
P s y c hi at ri c Di s o r d e r s:  ins o m ni a  
R e s pi r at o r y, T h o r a ci c a n d M e di asti n al Di s o r d e r s:  co u g h  
S ki n a n d S u b c ut a n e o u s Tis s u e Di s o r d e r s:  r as h m ac ul o-p a p ul ar, al o p eci a, ni g ht  s w e ats, pr urit us, 
r as h 
  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3 8  of 7 1  
 
8  M E A S U R E M E N T O F E F F E C T  
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 a n d / or M RI d uri n g  C ycl es 
3, 6, 9, 1 2 a n d t h e n at l e ast e v er y 6  c ycl es for 2 4 c ycl es , t h e n e v er y 1 2 c ycl es  t h er e aft er or m or e 
fr e q ue nt if w arr a nt e 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 I W C L L crit eri a ( H all e k M, 2 0 0 8).   
 
C T sc a n is t h e pr ef err e d m et h o d of t u m or ass ess m e nt  b ut M RI m a y b e us e d at t h e i n v esti g at or’s 
discr eti o n.  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 s h o ul d b e us e d t o c h ar act eriz e 
e ac 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 t hr o u g h o ut t h e st u d y.   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.  
  
S u bj ect s s h o ul d r e m ai n o n st u d y tr e at m e nt 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 ( eit h er f or t o xicit y or p h ysici a n c h oic e) a n d h a v e n ot 
pr o gr ess e 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  
I n a d diti o n t o cli nic al e x a mi n ati o n, r a di o gr a p hic e v al u ati o n will b e us e d i n all s u bj ects e nr oll e d. 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. M RI sc a n ni n g m a y b e us e d at t h e 
i n v esti g at or’s discr eti o n i n s u bj ects f or w h o m t his  m a y b e a pr ef err e d alt er n ati v e t o C T sc a n ni n g; 
h o w e v er, if M RI is p erf or m e d, a n o n -c o ntr ast C T of t h e c h est s h o ul d b e p erf or m e d.  C o ntr ast -
e n h a nc e d sc a n ni n g is pr ef err e d, b ut i o di n e -c o nt ai ni n g or g a d oli ni u m c o ntr ast m at eri al m a y b e 
o mitt e d i n s u bj ects f or w h o m us e of a c o ntr ast a g e nt w o ul d b e m e dic all y c o ntr ai n dic at e d. 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, P E T, r a di o n ucli d e sc a ns, 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.  If I V c o ntr ast is n ot us e d at b as eli n e, t h e n it s h o ul d n ot b e us e d 
wit h s u bs e q u e nt r es p o ns e ass ess m e nts t o m ai nt ai n c o nsist e nc y.  
 
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 eriz e e ac 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 n ot 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 r el e v a nt cli nic al a n d r a di o gr a p hic i nf or m ati o n r e q uir e d t o m a k e e ac h t u m or st at us ass ess m e nt 
m ust b e m a d e a v ail a bl e f or s o urc e v erific ati o n.  
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.  
 
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 3 9  of 7 1  
 
8. 3  I D E N TI FI C A TI O N 
A N D 
ME A S U R E M E N T 
O F 
T U M O R 
L E SI O N S 
A N D 
O R G A N O M E G A L Y  
8. 3. 1  T A R G E T L E SI O N S  
At b as eli n e, u p t o 6 l y m p h n o d es s h o ul d b e s el ect e d as t ar g et l esi o ns (if m e as ur a bl e dis e as e is 
pr es e nt)  t h at will b e us e d t o q u a ntit at e t h e st at us of t h e dis e as e d uri n g st u d y tr e at m e nt. I d e all y, t h e 
t ar g et l esi o ns s h o ul d b e l oc at e d i n  dis p ar at e r e gi o ns of t h e b o d y. O nl y p eri p h er al n o d es n e e d b e 
s el ect e d as t ar g et l esi o ns. H o w e v er, it is o pti m al if 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 
ar e ass ess e d  w h e n e v er t h es e sit es ar e i n v ol v e d.  
 
T ar g et l esi o ns s h o ul d b e m e as ur e d a n d r ec o r d e d at b as eli n e a n d a s p er t h e st u d y ass ess m e nt 
sc h e d ul e.  T h e  cr oss -s ecti o n al di m e nsi o ns (t h e l ar g est cr oss -s ecti o n al di a m et er, i .e ., t h e L D × L P D) 
will b e  r ec or d e d (i n c m) f or e ac h t ar g et l esi o n. T h e pr o d uct of t h e p er p e n dic ul ar di a m et ers ( P P D) (i n 
c m 2 ) f or e ac h t ar g et l esi o n a n d t h e s u m of t h e pr o d ucts ( S P D) (i n c m2 ) f or all t ar g et l esi o ns will b e 
c alc ul at e d a n d r ec or d e d. T h e b as eli n e S P D will b e us e d as r ef er e nc es b y  w hic h o bj ecti v e t u m or 
r es p o ns e will b e c h ar act eriz e d d uri n g tr e at m e nt. T h e n a dir L D of  i n di vi d u al l esi o ns a n d t h e n a dir 
S P D will b e us e d as r ef er e nc es b y w hic h C L L pr o gr essi o n  will b e c h ar act eriz e d. All L D a n d L P D 
di a m et ers will b e r e p ort e d i n c e nti m e t ers a n d all P P Ds a n d S P Ds will b e r e p ort e d i n c e nti m et ers 
s q u ar e d. 
 
A n o d al m ass m a y b e s e l ect e d as a m e as ur a bl e n o d al t ar g et l esi o n if it is > 1. 5 c m i n l o n g a xis di a m et er 
a n d > 1. 0 c m i n s h ort a xis di a m et er.  
 
A n e w n o d e t h at m e as ur es > 1. 5 c m i n t h e L D a n d > 1. 0 c m i n t h e L P D will b e c o nsi d er e d pr o gr essi v e 
dis e as e.  
 
I n c as es i n w hic h a l ar g e l ym p h n o d e m ass h as s plit i nt o m ulti pl e c o m p o n e nts, all  s u bc o m p o n e nts 
r e g ar dl ess of siz e will b e us e d i n c alc ul ati n g t h e S P D. Pr o gr essi o n of t h e  l esi o n will b e b as e d o n t h e 
S P D of s u b -c o m p o n e nts. L esi o n s u b -c o m p o n e nts will h a v e t h e  tr u e P P Ds c alc ul at e d. Si mil arl y, l esi o n 
s u b-c o m p o n e nts t h at ar e visi bl e b ut n eit h er a b n or m al  n or m e as ur a bl e will h a v e t h e d ef a ult P P D of 
1. 0 c m 2  ( 1. 0 c m ×  1. 0 c m) us e d i n c alc ul ati n g  t h e S P D. 
 
If l esi o ns m er g e, a b o u n d ar y b et w e e n t h e l esi o ns will b e est a blis h e d s o t h e L D of e ac h i n di vi d u al 
l esi o n c a n c o nti n u e t o b e m e as ur e d. If t h e l esi o ns h a v e m er g e d i n a w a y t h at t h e y c a n n o l o n g er b e 
s e p ar at e d b y t his b o u n d ar y, t h e n e wl y m er g e d l esi o n will b e m e as ur e d  bi -di m e nsi o n all y.  
8. 3. 2  S P L E E N A N D LI V E R  
B ot h t h e s pl e e n a n d li v er will b e ass ess e d  b y C T / M RI sc a n a n d / or  b y p h ysic al e x a mi n ati o n at  b as eli n e 
a n d as p er t h e st u d y ass ess m e nt sc h e d ul e . T h e b as eli n e a n d n a dir v al u es f or t h e l o n g est v ertic al 
di m e nsi o n ( L V D) of e ac h or g a n 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 t h e o bj ecti v e t u m or 
r es p o ns e of t h e m e as ur a bl e di m e nsi o ns of t h e C L L d uri n g  tr e at m e nt. All s pl e e n a n d li v er L V D 
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.  
 
B y i m a gi n g, t h e s pl e e n will b e c o nsi d er e d e nl ar g e d if it is > 1 2 c m i n L V D, wit h t h e L V D b ei n g o bt ai n e d 
b y m ulti pl yi n g t h e n u m b er of s ecti o ns o n w hic h  t h e s pl e e n is vis u aliz e d b y t h e t hic k n ess of t h e 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 4 0  of 7 1  
 
s ecti o ns ( e.g ., if t h e s pl e e n is s e e n i n 1 4 c o nti g u o us cr oss -s ecti o n al i m a g es wit h 0. 5 -c m t hic k n ess, t h e 
L V D is r ec or d e d as 7 c m).  
 
F or s u bj ects wit h s pl e n o m e g al y at  b as eli n e or at t h e s pl e nic L V D n a dir, r es p ecti v e r es p o ns e  a n d 
pr o gr essi o n e v al u ati o ns of t h e s pl e e n will c o nsi d er o nl y c h a n g es r el ati v e t o t h e  e nl ar g e m e nt of t h e 
s pl e e n at b as eli n e or n a dir, n ot c h a n g es r el ati v e t o t h e t ot al s pl e nic L V D.  
 
A 5 0 % d ecr e as e ( mi ni m u m 2 c m d ecr e as e) fr o m b as eli n e i n t h e e nl ar g e m e nt of t h e s pl e e n i n  its L V D 
or d ecr e as e t o ≤ 1 2 c m b y i m a gi n g is r e q uir e d f or d ecl ar ati o n of a s pl e n o m e g al y  r es p o ns e. C o n v ers el y, 
a n i ncr e as e i n s pl e nic e nl ar g e m e nt b y ≥ 5 0 % fr o m n a dir ( mi ni m u m  i ncr e as e of 2 c m) is r e q uir e d f or 
d ecl ar ati o n of s pl e nic pr o gr essi o n.   B y i m a gi n g, t h e li v er will b e c o nsi d er e d e nl ar g e d if it is > 1 8 c m i n 
L V D.  
 
A 5 0 % d ecr e as e ( mi ni m u m 2 c m d ecr e as e) fr o m b as eli n e i n t h e e nl ar g e m e nt of t h e li v er i n its  L V D 
or d ecr e as e t o ≤ 1 8 c m is r e q uir e d f or d ecl ar ati o n of a h e p at o m e g al y r es p o ns e.  C o n v ers el y, a n 
i ncr e as e i n li v er e nl ar g e m e nt b y ≥ 5 0 % fr o m n a dir ( mi ni m u m i ncr e as e of 2 c m) is r e q uir e d f or 
d ecl ar ati o n of h e p atic pr o gr essi o n.  
8. 3. 3  N O N -T A R G E T L E SI O N S  
A n y ot h er m e as ur a bl e a n d a b n or m al n o d al l esi o ns n ot s el ect e d f or q u a ntit ati o n as t ar g et l esi o ns m a y 
b e c o nsi d er e d n o n -t ar g et l esi o ns. I n a d diti o n, n o n-m e as ur a bl e e vi d e nc e of C L L  s uc h as n o d al l esi o ns 
wit h b ot h di a m et ers < 1. 0 c m, e xtr a -n o d al l esi o ns, 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 or p eric ar di al eff usi o ns, l y m p h a n gitis of t h e s ki n or  l u n g, a b d o mi n al m ass es t h at ar e n ot 
c o nfir m e d a n d f oll o w e d b y i m a gi n g t ec h ni q u es, c ystic  l esi o ns, pr e vi o usl y irr a di at e d l esi o ns, a n d 
l esi o ns wit h artif acts m a y b e c o nsi d er e d as n o n -t ar g et d is e as e. 
 
T h e pr es e nc e or a bs e nc e of n o n -t ar g et dis e as e s h o ul d b e r ec or d e d at b as eli n e a n d as p er t h e st u d y 
ass ess m e nt sc h e d ul e . If pr es e nt at b as eli n e, u p t o 6 n o n-t ar g et l esi o ns s h o ul d b e r ec or d e d. T h e n o n -
t ar g et dis e as e at b as eli n e will b e us e d as a g e n e r al r ef er e nc e t o f urt h er  c h ar act eriz e r e gr essi o n or 
pr o gr essi o n of C L L d uri n g ass ess m e nts of t h e o bj ecti v e t u m or  r es p o ns e d uri n g tr e at m e nt. 
M e as ur e m e nts ar e n ot r e q uir e d a n d t h es e l esi o ns s h o ul d b e  f oll o w e d as “ pr es e nt” or “ a bs e nt”. 
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  
R es p o ns es will b e c at e g oriz e d as C R, P R, P R -L, S D, or P D. I n a d diti o n, a r es p o ns e  c at e g or y of n ot 
e v al u a bl e ( N E) is pr o vi d e d f or sit u ati o ns i n w hic h t h er e is i n a d e q u at e  i nf or m ati o n t o ot h er wis e 
c at e g oriz e r es p o ns e st at us . 
 
T h e b est  o v er all r es p o ns e will b e d et er mi n e d. 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 tr e at m e nt u ntil dis e as e /r ec urr e nc e pr o gr essi o n (t a ki n g as a  r ef er e nc e f or 
dis e as e pr o gr essi o n t h e s m all est m e as ur e m e nts r ec or d e d si nc e tr e at m e nt  st art e d). W h er e i m a gi n g 
d at a ar e a v ail a bl e, t h es e  d at a will s u p ers e d e p h ysic al e x a mi n ati o n d at a i n d et er mi ni n g t u m or st at us.  
8. 5  C O M P L E T E R E S P O N S E  
T o s atisf y crit eri a f or a C R, all of t h e f oll o wi n g crit eri a m ust b e m et:  
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 4 1  of 7 1  
 
•  
N o e vi d e nc e of n e w dis e as e  
•  
A L C i n p eri p h er al bl o o d of < 4 x 1 0 9 / L  
•  
R e gr essi o n of all t ar g et n o d al m ass es t o n or m al siz e ≤1. 5 c m i n t h e L D  (if a p plic a bl e) 
•  
N or m al s pl e e n a n d li v er siz e  
•  
R e gr essi o n t o n or m al of all n o d al n o n -t ar g et dis e as e a n d dis a p p e ar a nc e of all d et ect a bl e n o n -
n o d al, n o n -t ar g et dis e as e 
•  
M or p h ol o gic all y n e g ati v e b o n e m arr o w d efi n e d as < 3 0 % of n ucl e at e d c ells b ei n g  l y m p h oi d 
c ells a n d n o l y m p h oi d n o d ul es i n a b o n e m arr o w s a m pl e t h at is n or m oc ell ul ar  f or a g e 
•  
P eri p h er al bl o o d c o u nts m e eti n g all of t h e f oll o wi n g crit eri a:  
o  A N C > 1. 5 x 1 0 9 / L  wit h o ut n e e d f or e x o g e n o us gr o wt h f act ors ( e .g ., G-C S F)  
o  Pl at el et c o u nt ≥1 0 0 x 1 0 9 / L wit h o ut n e e d f or e x o g e n o us gr o wt h f act ors  
o  H e m o gl o bi n ≥1 1 0 g / L ( 1 1. 0 g / d L) wit h o ut r e d bl o o d c ell tr a nsf usi o ns or n e e d f or 
e x o g e n o us gr o wt h f act ors ( e .g ., er yt hr o p oi eti n) 
 
S u bj ect s w h o f ulfill all t h e crit eri a f or a C R (i ncl u di n g b o n e m arr o w crit eri a) b ut  w h o h a v e a p ersist e nt 
a n e mi a, t hr o m b oc yt o p e ni a, or n e utr o p e ni a or a h y p o c ell ul ar  b o n e  m arr o w r el at e d t o pri or or 
o n g oi n g dr u g t o xicit y ( n ot t o C L L) will b e  c o nsi d er e d as a C R wit h i nc o m pl et e m arr o w r ec o v er y ( C Ri).  
8. 6  P A R TI A L R E S P O N S E  
T o s atisf y crit eri a f or a P R, all of t h e f oll o wi n g crit eri a m ust b e m et:  
•  
N o e vi d e nc e of n e w dis e as e  
•  
A c h a n g e i n dis e as e st at us m e eti n g ≥2 of t h e f oll o wi n g crit eri a, wit h 2 e xc e pti o ns i n  w hic h 
o nl y 1 crit eri o n is n e e d e d: 1 ) o nl y  l y m p h a d e n o p at h y is pr es e nt at b as eli n e; 2 ) o nl y  
l y m p h a d e n o p at h y a n d l y m p h oc yt osis ar e pr es e nt at b as eli n e. I n t h es e 2 c as es, o nl y 
l y m p h a d e n o p at h y m ust i m pr o v e t o t h e e xt e nt s p ecifi e d b el o w:   
o  I n a s u bj ect wit h b as eli n e l y m p h oc yt osis ( A L C  ≥4 x 1 0 9 / L), a d ecr e as e i n p eri p h er al  
bl o o d A L C b y ≥5 0 % fr o m b as eli n e or a d ecr e as e t o < 4 x 1 0 9 / L  
o  A d ecr e as e b y ≥5 0 % fr o m t h e b as eli n e i n t h e S P D of t h e t ar g et n o d al l esi o ns  (if 
a p plic a bl e)  
o  I n a s u bj ect wit h e nl ar g e m e nt of t h e s pl e e n at b as eli n e, a s pl e n o m e g al y r es p o ns e as 
d efi n e d i n S ecti o n 8. 3. 2  
o  I n a s u bj ect wit h e nl ar g e m e nt of t h e li v er at b as eli n e, a h e p at o m e g al y r es p o ns e as 
d efi n e d i n S ecti o n 8. 3. 2  
o  A d ecr e as e b y ≥5 0 % fr o m b as eli n e i n t h e C L L m arr o w i nfiltr at e or i n B -l y m p h oi d 
n o d ul es  
•  
N o t ar g et, s pl e nic, li v er, or n o n-t ar g et dis e as e wit h w ors e ni n g t h at m e ets t h e crit eri a f or  
d efi niti v e P D  
•  
P eri p h er al bl o o d c o u nts m e eti n g 1 of t h e f oll o wi n g crit eri a:  
o  A N C > 1. 5 x 1 0 9 / L or > 5 0 % i ncr e as e o v er b as eli n e wit h o ut n e e d f or e x o g e n o us  gr o wt h 
f act ors (e. g. , G-C S F)  
o  Pl at el et c o u nt ≥1 0 0 x 1 0 9 / L or ≥5 0 % i ncr e as e o v er b as eli n e wit h o ut n e e d f or  
e x o g e n o us gr o wt h f act ors  
o  H e m o gl o bi n ≥1 1 0 g / L ( 1 1. 0 g / d L) or ≥5 0 % i ncr e as e o v er b as eli n e wit h o ut r e d bl o o d  
c ell tr a nsf usi o ns or n e e d f or e x o g e n o us gr o wt h f act ors ( e .g ., er yt hr o p oi eti n) 
 
T h e pr o p orti o n of s u bj ects w h o ac hi e v e a P R wit h l y m p h oc yt osis will b e r ec or d e d.7 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 4 2  of 7 1  
 
8. 7  S T A B L E DI S E A S E  
T o s atisf y crit eri a f or S D, t h e f oll o wi n g crit eri a m ust b e m et : 
 
•  
N o e vi d e nc e  of n e w dis e as e  
•  
T h er e is n eit h er s uffici e nt e vi d e nc e of t u m or s hri n k a g e t o q u alif y f or P R n or s uffici e nt  
e vi d e nc e of t u m or gr o wt h t o q u alif y f or d efi niti v e P D  
8. 8  D E FI NI TI V E DI S E A S E P R O G R E S SI O N  
T h e occ urr e nc e of a n y of t h e f oll o wi n g e v e nts i n dic at es d efi niti v e P D: 
•  
E vi d e nc e of a n y n e w dis e as e  
•  
A n e w n o d e t h at m e as ur es > 1. 5 c m i n t h e L D a n d > 1. 0 c m i n t h e L P D  
•  
N e w or r ec urr e nt s pl e n o m e g al y, wit h a mi ni m u m L V D of 1 4 c m  
•  
N e w or r ec urr e nt h e p at o m e g al y, wit h a mi ni m u m L V D of 2 0 c m  
•  
U n e q ui v oc al r e a p p e ar a nc e of a n e xtr a -n o d al l esi o n t h at h a d r es ol v e d  
•  
A n e w u n e q ui v oc al e xtr a -n o d al l esi o n of a n y siz e  
•  
*N e w n o n -t ar g et dis e as e ( e.g., eff usi o ns, ascit es, or ot h er or g a n a b n or m aliti es r el at e d t o C L L) . 
 
*Is ol at e d n e w eff usi o ns, ascit es, or ot h er or g a n a b nor m aliti es ar e n ot  s uffici e nt e vi d e nc e al o n e of P D 
u nl ess hist ol o gic all y c o nfir m e d. T h us, a d ecl ar ati o n  of P D s h o ul d n ot b e m a d e if t his is t h e o nl y 
m a nif est ati o n of a p p ar e ntl y n e w  dis e as e.  
 
•  
E vi d e nc e of w ors e ni n g of t ar g et l esi o ns, s pl e e n or li v er, or n o n-t ar g et dis e as e:  
o  I ncr e as e fr o m t h e n a dir b y ≥5 0 % fr o m t h e n a dir i n t h e S P D of t ar g et l esi o ns (if a p plic a bl e) 
o  I ncr e as e fr o m t h e n a dir b y ≥5 0 % i n t h e L D of a n i n di vi d u al n o d e or e xtr a -n o d al m ass  t h at 
n o w h as a n L D of > 1. 5 c m a n d a n L P D of > 1. 0 c m  (if a p plic abl e)  
o  S pl e nic pr o gr essi o n, d efi n e d as a n i ncr e as e i n s pl e nic e nl ar g e m e nt b y ≥5 0 % fr o m  n a dir 
( wit h a mi ni m u m 2 c m i ncr e as e a n d a mi ni m u m L V D of 1 4 c m)  
o  H e p atic pr o gr essi o n, d efi n e d as a n i ncr e as e i n h e p atic e nl ar g e m e nt b y ≥5 0 % fr o m  n a dir 
( wit h a mi ni m u m 2 c m i ncr e as e a n d mi ni m u m L V D of 2 0 c m) 
o  U n e q ui v oc al i ncr e as e i n t h e siz e of n o n -t ar g et dis e as e ( e .g ., eff usi o ns, ascit es, or ot h er 
or g a n a b n or m aliti es r el at e d t o C L L)  
o  Tr a nsf or m ati o n t o a m or e a g gr essi v e hist ol o g y ( e .g ., Ric ht er’s s y n dr o m e) as est a blis h e d  
b y bi o ps y ( wit h t h e d at e of t h e bi o ps y b ei n g c o nsi d er e d t h e d at e of C L L pr o gr essi o n  if t h e 
s u bj ect h as n o e arli er o bj ecti v e d oc u m e nt ati o n of C L L pr o gr essi o n).  
 
•  
D ecr e as e i n pl at el et c o u nt or h e m o gl o bi n t h at is attri b ut a bl e t o C L L, is n ot attri b ut a bl e t o  a n 
a ut oi m m u n e p h e n o m e n o n, a n d is c o nfir m e d b y b o n e m arr o w bi o ps y s h o wi n g a n i nfiltr at e of 
cl o n al C L L c ells 
o  T h e c urr e nt pl at el et c o u nt is < 1 0 0 x 1 0 9 / L a n d t h er e h as b e e n a d ecr e as e b y  > 5 0 % fr o m 
t h e hi g h est o n-st u d y pl at el et c o u nt 
o  T h e c urr e nt h e m o gl o bi n is < 1 1 0 g / L ( 1 1. 0 g / d L) a n d t h er e h as b e e n a d ecr e as e b y  > 2 0 
g / L ( 2 g / d L) fr o m t h e hi g h est o n -st u d y h e m o gl o bi n  
 
If t h er e is u nc ert ai nt y r e g ar di n g w h et h er t h er e is tr u e pr o gr essi o n, t h e s u bj ect s h o ul d c o nti n u e st u d y 
tr e at m e nt a n d r e m ai n u n d er cl os e o bs er v ati o n p e n di n g c o nfir m ati o n of pr o gr essi o n st at us b y t h e 
st u d y c h air.  I n p artic ul ar, w ors e ni n g of c o nstit uti o n al s y m pt o ms i n t h e a bs e nc e of o bj ecti v e e vi d e nc e 


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of w ors e ni n g C L L will n ot b e c o nsi d er e d  d efi niti v e dis e as e pr o gr essi o n; i n s uc h s u bj e cts, b ot h C L L -
r el at e d a n d n o n-C L L -r el at e d c a us es f or t h e c o nstit uti o n al s y m pt o ms s h o ul d b e c o nsi d er e d.  
 
W ors e ni n g of dis e as e d uri n g  t e m p or ar y i nt err u pti o n of st u d y tr e at m e nt ( e.g ., f or i nt erc urr e nt ill n ess) 
is n ot n ec ess aril y i n dic ati v e of r esist a nc e t o st ud y tr e at m e nt. I n t h es e i nst a nc es, C T / M RI or ot h er 
r el e v a nt e v al u ati o ns s h o ul d b e c o nsi d er e d i n or d er t o d oc u m e nt w h et h er d efi niti v e dis e as e  
pr o gr essi o n h as occ urr e d. If s u bs e q u e nt e v al u ati o ns s u g g est t h at t h e s u bj ect h as  e x p eri e nc e d 
p ersist e nt d efi n iti v e C L L pr o gr essi o n, t h e n t h e d at e of pr o gr essi o n s h o ul d b e t h e ti m e p oi nt at w hic h 
pr o gr essi o n w as first o bj ecti v el y d oc u m e nt e d.  
8. 9  N O N -E V A L U A B L E  
I n a s u bj ect w h o d o es n ot h a v e e vi d e nc e of P D, t h e occ urr e nc e of a n y of t h e f oll o wi n g  c o n diti o ns 
i n dic at es a r es p o ns e st at us of N E: 
•  
T h er e ar e n o i m a g es or  i n a d e q u at e or missi n g i m a g es 
•  
I m a g es of t h e li v er a n d s pl e e n ar e missi n g at t h at ti m e p oi nt ( wit h t h e e xc e pti o n t h at a bs e nc e 
of s pl e nic i m a g es will n ot r es ult i n a n N E d esi g n ati o n i n a s u bj ect k n o w n t o h a v e  u n d er g o n e 
s pl e n ect o m y). 
 
A ti m e p oi nt will b e c o nsi d er e d t o h a v e a r es p o ns e of N E if a n y t ar g et l esi o n is missi n g. P D m a y b e 
assi g n e d at a n y ti m e p oi nt r e g ar dl ess of t h e e xt e nt of missi n g t ar g et or  n o n -t ar g et l esi o ns. Missi n g 
n o n -t ar g et l esio ns will n ot i m p act t h e a bilit y t o ass ess f or  r es p o ns e or dis e as e pr o gr essi o n.  
8. 1 0  L Y M P H O C Y T O SI S D U RI N G  T H E R A P Y  
U p o n i niti ati o n of u m br alisi b , a t e m p or ar y i ncr e as e i n l y m p h oc yt e c o u nts (i. e., ≥ 5 0 % i ncr e as e fr o m 
b as eli n e a n d a b o v e a bs ol ut e l y m p h oc yt e c o u nt of 5, 0 0 0 / mc L) m a y occ ur. T h e o ns et of is ol at e d 
l y m p h oc yt osis us u all y occ urs d uri n g t h e first f e w w e e ks of u m br alisi b  t h er a p y a n d us u all y r es ol v es 
wit hi n t hr e e t o f o ur m o nt hs .  S u bj ect s wit h l y m p h oc yt osis s h o ul d b e c o nti n u e d o n st u d y dr u g 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 (i.e ., dis e as e pr o gr essi o n t h at is 
m a nif est b y 
w ors e ni n g C L L -r el at e d si g ns ot h er t h a n l y m p h oc yt osis al o n e), or t h e occ urr e nc e of a n ot h er r e as o n 
t o disc o nti n u e st u d y t h er a p y.7  
 


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9  S T A TI S TI C A L C O N SI D E R A TI O N S   
9. 1  S A M P L E SI Z E  
 
 
 
 
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  
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 . 2 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, su 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 av ail a bl e effic ac y a n d s af et y d at a.  
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 n t-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  
B as eli n e d e m o gr a p hic a n d cli nic al c h ar act eristics will b e s u m m ariz e d as p erc e nt a g es f or c at e g oric al 
v ari a bl es a n d as 
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 c o nti n u o us 
m e a s ur es. T h e a n al ys es of b as eli n e c h ar act eristics will b e p erf or m e d f or t h e I T T p o p ul ati o n.   
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.  
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 d os es of st u d y dr u g, 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 ariz 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 ariz e d b y e ac h t y p e of 
m o dific ati o n b y c ycl e 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 ariz e d.  
 


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9. 7  E F FI C A C Y A N A L Y S E S   
E ac h s u bj ect will b e assi g n e d t o o n e of t h e f oll o wi n g c at e g ori es:  1) c o m pl et e r es p o ns e, 2) p arti al 
r es p o ns e, 3) st a bl e dis e as e,  4) pr o gr essi v e dis e as e, 5) e arl y d e at h fr o m m ali g n a nt dis e as e, 6) e arl y 
d e at h fr o m t o xicit y, 7) e arl y d e at h b ec a us e of ot h er c a us e, or 8 ) u n k n o w n ( n ot ass ess a bl e, i ns uffici e nt 
d at a).  
M a n y of t h e effic ac y m e as ur es will b e b as e d o n dis e as e ass ess m e nts.  T h e  b est cli nic al r es p o ns e as 
w ell as dis e as e pr o gr essi o n will b e d et er mi n e d b y t h e tr e ati n g i n v esti g at or.  Sc a ns s h o ul d b e k e pt o n 
fil e i n c as es w h er e i n d e p e n d e nt r e vi e w or c o nfir m ati o n m a y b e w arr a nt e d.  D efi niti v e dis e as e 
pr o gr essi o n will b e b as e d o n st a n d ar d cr it eri a ( H all e k et al. 2 0 0 8, A p p e n di x A  –  C L L R es p o ns e 
D efi niti o n ) occ urri n g f or a n y r e as o n ( e. g., i ncr e asi n g l y m p h a d e n o p at h y, or g a n o m e g al y or b o n e 
m arr o w i n v ol v e m e nt; d ecr e asi n g pl at el et c o u nt, h e m o gl o bi n, or n e utr o p hil c o u nt; or w ors e ni n g of 
dis e as e -r el ate d s y m pt o ms) ot h er t h a n l y m p h oc yt osis.  
S u bj ect s will b e tr e at e d u ntil dis e as e pr o gr essi o n, u n acc e pt a bl e t o xicit y or t h e e n d of t h e st u d y.  U p o n 
t h e e n d of t h e st u d y, s u bj ects wit h o ut dis e as e pr o gr essi o n m a y b e tr a nsiti o n e d t o a n o p e n l a b el 
c om p assi o n at e us e st u d y.  
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 R I A B L E - P F S  
T h e pri m ar y effic ac y o utc o m e is pr o gr essi o n -fr e e sur vi v al  ( P F S).  Ti m e t o pr o gr essi o n e v e nt  
“ S ur vi v al” c ur v e will b e pr es e nt e d usi n g 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 of 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 mpl e ( o n e -si d e d) l o g-r a n k t est.   
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.  
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 de:  
•  
O v er all R es p o ns e R at e ( O R R)  
•  
Ti m e t o Tr e at m e nt F ail ur e ( T T F)  
•  
D ur ati o n of R es p o ns e ( D O R)  
 
 


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9. 9. 2. 1  O V E R A L L R E S P O N S E R A T E  
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 acc or di n g t o t h e crit eri a  of t h e I nt er n ati o n al 
W or ks h o p o n C hr o nic L y m p h oc ytic L e u k e mi a ( H all e k et al. 2 0 0 8).  
W e will esti m at e 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 als o esti m at e e x act  9 5 %  co 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 ad 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. 2  TI M E T O T R E A T M E N T F A I L U R E 
Ti m e t o Tr e at m e nt F ail ur e ( T T F) is d efi n e d as a c o m p osit e e n d p oi nt m e as uri n g ti m e fr o m C ycl e 
1 / D a y 1 t o disc o nti n u ati o n of tr e at m e nt f or a n y r e as o n, i ncl u di n g dis e as e pr o gr essi o n, tr e at m e nt 
t o xicit y, a n d d e at h.  Esti m at es of m e di a n T T F will b e m a d e usi n g K a pl a n -M ei er m et h o ds.  
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 
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 ariz 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.  
 
 


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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  
S af et y e v al u ati o ns will b e b as e d o n  t h e i nci d e nc e, i nt e nsit y, a n d t y p e of a d v ers e e v e nts, as w ell as o n 
cli nic all y si g nific a nt c h a n g es i n t h e s u bj ect’s p h ysic al e x a mi n ati o n, vit al si g ns, a n d cli nic al l a b or at or y 
r es ults.  S af et y a n al ys es will b e p erf or m e d usi n g t h e s af et y p o p ul ati o n.  S af et y v ari a bl es will b e 
t a b ul at e d a n d pr es e nt e d b y t h e d os e of u m br alisi b  st u d y dr u g act u all y r ec ei v e d.  E x p os u r e t o st u d y 
tr e at m e nt a n d r e as o ns f or disc o nti n u ati o n of st u d y tr e at m e nt will als o b e t a b ul at e d. 
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 utiliz 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 ur 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 m br alisi b  I n v esti g at or Br oc h ur e.   
D efi niti o ns of A d v ers e E v e nts  
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 on.  
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 
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 aliz 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. 
 


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1 0. 3  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  ( C ycl e 1 / D a y 1) 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 ( + /-7 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 i nt 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 ariz 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 w it 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. 4  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 st u 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.  
•  
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 nit 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. 4. 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 


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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 g a d mi nistr ati o n –   
u m br alisi 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 al isi 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  ( + /-7 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. 4. 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 bject  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 at i e nt 
h os pit aliz 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.  
Cli nic al L a b or at or y R es ults will b e s u m m ariz 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 ect s 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 or at or y 
r es ults will b e s u m m ariz e d b y tr e at m e n t 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 or at or y 
fi n di n g. 
1 0. 4. 3  H A N D LI 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 r es ulti n g i n disc o nti 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 ect s 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 ( + /-7 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 ).  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 o f 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.  
 
 


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1 0. 5  S E RI O U S A D V E R S E E V E N T S  
1 0. 5. 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, 
•  
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 aliz ati o n or pr ol o n g ati o n of e xisti n g 
h os pit aliz 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 al 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 aliz 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 aliz 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 I W C L L H all e k et al. 2 0 0 8), 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 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 a ss 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 aliz 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 st ill 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  
•  
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 p it e c ar e f acilit y 
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.  


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1 0. 5. 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 fr o m C ycl e 1 / D a y 1  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 fi rst 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 urri n 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).  
C L L pr o gr essi o n or d e at h d u e t o C L L 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 C L L 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 C L L 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 o rt.  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) a t s af et y-i n b o x. bi ot ec h @i q vi a.c o m 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.   
..   
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 . 
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 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. 6   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  


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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 t h 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 e d S A Es ( S U S A R) ass o ci 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 ators  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. 7  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. 8  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 niz 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 eriz 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. 8. 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  
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  e C 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 ort F o r 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  e C R F 
f or e ac h r ec urr e nc e. 


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1 0. 8. 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 aliz 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 n si 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. 8. 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 u t 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 C L L  will n ot b e r e p ort e d as a n  A d v ers e E v e nt . 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. 8. 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 LI 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. 5. 1 .   
1 0. 8. 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 
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  e C 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 n cl u di n g a p plic a bl e d escri pt ors.  
1 0. 8. 6  P R O T O C O L -D E FI N E D S E RI O U S A D V E R S E E V E N T S  
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 (t h e d efi niti o ns of 
“ w o m e n of c hil d b e ari n g p ot e nti al” ar e list e d i n A p p e n di x B - C o ntr ac e pti v e G ui d eli n es a n d Pr e g n a nc y ) 


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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 nti l 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 ect 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 a l 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 usl 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 (u m br alisi b ), 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  v s. 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  ( occ urri n g as a dir ect r es ult as st u d y dr u g a d mi nist er e d, i ncl u di n g b ut n ot li mit e d t o 
M D S) or s ec o n d pri m ar y ( u nr el at e d, n e w c a nc er, i ncl u di n g b ut n ot li mit e d t o M D S a n d M P 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 ( e C 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 et 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 p orti 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  
•  
Ris k t o s u bj ect 


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•  
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 ubst 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 F D 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 nci 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.  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 5 7  of 7 1  
 
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 a rt 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 or 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 d y 
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 missi 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 o f 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 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 c o 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 
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 G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 5 8  of 7 1  
 
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 e q 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 gni 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 nti 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, t h e s u bj ect s h o ul d b e  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 nf 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 oriz 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 oriz 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 oriz 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 oriz ati o n t o c oll ect or us e P HI, att e m pts s h o ul d b e 
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 oriz 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 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 5 9  of 7 1  
 
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 AF 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 oriz 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 es ti 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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D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 6 0  of 7 1  
 
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, c ert ai 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 ati 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 ud 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 oriz 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 or 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 a t 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 o r 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 u ti 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 oriz 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 
tr a nscri pti o ns c ertifi e d aft er v erific ati on 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. 


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P a g e 6 1  of 7 1  
 
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 aliz 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 dy -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 d y dr u g i ncl u di n g acc o u nt a bilit y r ec or ds.  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 al 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 
f or 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 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 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 t o 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 us t 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 otifi 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 
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. 
 
 


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P a g e 6 2  of 7 1  
 
1 3. 3  D A T A C O L L E C TI O N  
T h e st u d y e C 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 utiliz 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 nstr 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 dditi 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 m a y  b e c o n d uct e 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 at i 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 
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 e ctr 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.  


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P a g e 6 3  of 7 1  
 
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, to 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 dy  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 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 evi 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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P a g e 6 4  of 7 1  
 
1 4  R E F E R E N C E S  
1.  
B yr d J C, Br o w n J R, O' Bri e n S, et al. I br uti ni b v ers us Of at u m u m a b i n Pr e vi o usl y Tr e at e d 
C hr o nic L y m p h oi d L e u k e mi a. N e w E n gl a n d J o ur n al of M e dici ne ; 0( 0): n ull. 
2.  
B arr P M, Br o w n J R, Hill m e n P, et al. D os e a d h er e nc e a n d b as eli n e e x p os ur e a n al ysis of t h e 
i br uti ni b 4 2 0 
m g d os e a d mi nist er e d t o p ati e nts wit h pr e vi o usl y tr e at e d c hr o nic l y m p h oc ytic 
l e u k e mi a ( C L L). A S C O A n n u al M e eti n g Pr oc e e di n gs; 2 0 1 5: 7 0 1 2. 
3.  
Fri e d m a n D R, Si m ms T, All g o o d S D, et al. T h e PI 3 K - δ
 i n hi bit or T G R-1 2 0 2 i n d uc es 
c yt ot o xicit y a n d i n hi bi ts p h os p h or yl ati o n of A K T i n 1 7 p d el et e d a n d n o n -1 7 p d el et e d C L L c ells i n 
vitr o. C a nc er Res e arc h . 2 0 1 4; 7 4( 1 9 S u p pl e m e nt): 4 5 1 8-4 5 1 8.  
4.  
B urris H A, P at el M R, Br a n d er D M, et al. T G R -1 2 0 2, a n o v el o nc e d ail y pi 3 k δ  i n hi bit or, 
d e m o nstr at es cli nic al acti vit y wit h  a f a v or a bl e s af et y pr ofil e, l ac ki n g h e p at ot o xicit y, i n p ati e nts wit h 
c hr o nic l y m p h oc ytic l e u k e mi a a n d B -c ell l y m p h o m a. Bl o o d . 2 0 1 4; 1 2 4( 2 1): 1 9 8 4-1 9 8 4.  
5.  
F ur m a n R R, S h ar m a n J P, C o utr e S E, et al. I d el alisi b a n d Rit u xi m a b i n R el a ps e d C hr o nic 
L y m p h oc ytic L e u k e mi a. N e w E n gl a n d J o ur n al of M e dici ne . 2 0 1 4. 
6.  
H all e k M, C h es o n B D, C at o vs k y D, et al. 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 W or 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 ut e – W or ki n g Gr o u p 1 9 9 6 g ui d eli n es. Bl o o d . 2 0 0 8; 1 1 1( 1 2): 5 4 4 6-
5 4 5 6.  
7.  
C h es o n B D, B yr d J C, R ai K R, et al. N o v el t ar g et e d a g e nts a n d t h e n e e d t o r efi n e cli nic al e n d 
p oi nts i n c hr o nic l y m p h oc ytic l e u k e mi a. J o ur n al of Cli nic al O nc ol o g y; 3 0( 2 3): 2 82 0 -2 8 2 2.  
 
 


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P a g e 6 5  of 7 1  
 
1 5  A P P E N DI X A  –  C L L R E S P O N S E D E FI NI TI O N  
Ass ess m e nt of r es p o ns e will f oll o w t h e g ui d eli n es p u blis h e d b y H all e k et al. ( 2 0 0 8).  
Assess me nt of res p o nse s h o ul d i n cl u d e a c aref ul p h ysic al ex a mi n ati o n  a n d ev al u ati o n of t h e bl o o d a n d 
m arr o w.  
C o m plete 
Res p o nse:  
( C R) 
C R re q uires all of t he f oll o wi n g criteri a as assess e d at le ast  2 m o nt hs after c o m pleti o n of t her a py:  
a.  
Peri p heral bl o o d l y m p h o c yt es (e val uat e d b y bl o o d a n d differe ntial c o u nt) bel o w 4 x 1 0 9/ L 
( 4 0 0 0/ µ L). 
b.  A bse nce of si g nifica nt l y m p ha d e n o pat h y ( e. g., l y m p h n o des > 1. 5  c m i n dia met er) b y 
p h ysic al e xa mi nati o n.  (if a p plica ble)  
c.  
N o he pat o me gal y or s ple n o me g al y b y p h ysical e xa mi nati o n a n d / or C T.  
d.  A bse nce of c o nstit uti o nal s y m pt o ms.  
e.  
Bl o o d c o u nts a b o ve t he f oll o wi n g val ues:  
a.  
Ne utr o p hils > 1. 5 x 1 0 9/ L ( 1 5 0 0/ µ L) wit h o ut nee d f or e x o ge n o us gr o wt h fa ct ors. 
b.  Plat elets > 1 0 0 x 1 0 9/ L ( 1 0 0 0 0 0/ µ L) wit h o ut nee d f or e x o ge n o us gr o wt h fact ors. 
c.  
He m o gl o bi n > 1 1 0 g/ L ( 1 1. 0 g/ d L) wit h o ut re d bl o o d cell tra nsf usi o n or nee d f or 
e x o ge n o us er yt hr o p oieti n.  
 
F o r p atie nts i n cl i nic al st u dies, a m arr o w as pi r ate a n d bi o ps y s h o ul d be perf o r me d at le ast 2 
m o nt hs afte r t he l ast tre at me nt a n d if cli nic al a n d l a b o r at o r y res ults liste d 
a b o ve a -e 
de m o nst r ate t h at a C R h as bee n ac hie ve d.   T o defi ne a C R, t he marr o w sa m ple m us t be at least 
n or m o cell ular  f or a ge, wit h less t ha n 3 0 % of n ucle at e d cells bei n g l y m p h o c yt es.   L y m p h oi d n o d ules 
s h o ul d be a bse nt.   I n s o me cases, l y m p h oi d n o d ules ca n be f o u n d, w hic h oft e n reflect  resi d ual dis ease.  
T hese n o d ules s h o ul d be rec or de d as " n o d ular  P R."  M ore o ver, i m m u n o hist o c he mistr y s h o ul d be 
perf or me d t o defi ne  w het her t hese n o d ules are c o m p ose d pri maril y of T  cells or l y m p h o c yt es  ot her 
t ha n C L L cells or of C L L cells.  If t he marr o w is h y p o cell ular, a re pe at det er mi nati o n s h o ul d be 
perf or me d aft er 4  wee ks, or  u ntil p eri p heral bl o o d c o u nts ha ve rec o vere d.  H o we ver, t his  ti me i nt er val 
s h o ul d n ot e xcee d 6 m o nt hs aft er t he last tr eat me nt.   A marr o w bi o ps y s h o ul d be c o m p are d wit h t hat 
of pretr eat me nt  marr o w. I n ge neral practice, t he use of a marr o w bi o ps y f or
 e val uati n g a C R is at t he 
dis creti o n of t he p h ysicia n.   
I n cli nical st u dies ai mi n g at ma xi mizi n g t he C R rat e, t he q ualit y  of t he C R s h o ul d be assess e d f or 
M R D b y fl o w c yt o metr y or b y i m m u n o hist o c he mistr y.  
A c o ntr o ve rsi al iss ue is h o w best t o c ate g ori ze t h e res p o nse of p atie nts w h o f ulfill all t he crit e ri a 
f o r a C R (i ncl u di n g t he m arr o w e x a mi n ati o ns desc ri be d a b o ve) b ut w h o h a ve a persiste nt 
a ne mi a or t hr o m b oc yt o pe ni a or ne utr o pe ni a a p p are ntl y u nrel ate d t o C L L b ut rel ate d t o dr u g 
t o xicit y.  We rec o m me n d t ha t t hese patie nts be c o nsi d ere d as a differe nt cat e g or y of re missi o n:  C R 
wit h i nc o m plet e marr o w rec o ver y ( C Ri).  F or t he defi niti o n of t his c at e g or y, C Ri, t he marr o w 
e val uati o n ( descri be d a b o ve) s h o ul d be perf or me d wit h s cr uti n y a n d n ot s h o w a n y cl o nal i nf iltrat e.  I n 
cli nical st u d ys, C Ri patie nts s h o ul d be m o nit ore d pr os pecti vel y t o det er mi ne w het her t heir o ut c o me 
differs fr o m t hat of patie nts wit h det ect a ble resi d ual or wit h n o nc yt o pe nic C R.  


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P a g e 6 6  of 7 1  
 
C h r o ni c L y m p h o c yti c L e u k e mi a R e s p o n s e D efi niti o n ( H all e k et al. 2 0 0 8) ( c o nti n u e d)  
P arti al 
Res p o nse:  
( P R) 
T o defi ne a P R ( p arti al re missi o n): at le ast t w o of t he criteri a of Gr o u p A pl us o ne of t he criteri a 
of Gr o u p B h ave t o be m et. T he  p ar a m eters bel o w s h o ul d be d oc u m e nte d f or n o less t h a n 
2  m o nt hs.  C o nstit uti o n al sy m pt o ms persisti n g f or > 1 m o nt h s h o ul d be rec or de d. 
Gr o u p A  
a.  
Decrease i n t he n u m ber of bl o o d l y m p h o c yt es b y 5 0 % or m ore fr o m t he val ue bef ore 
t hera p y. 
b.  Re d ucti o n i n l y m p ha d e n o pat h y ( b y P E a n d C T sca ns) as defi ne d b y t he f oll o wi n g  (if 
a p plica ble) : 
•  
A decreas e i n l y m p h n o de size b y 5 0 % or m ore eit her i n t he s u m pr o d ucts of u p t o 
6 l y m p h n o des, or i n t he lar gest dia met er of t he e nlar ge d l y m p h n o de(s) det ect e d 
pri or t o t hera p y.  
•  
N o i ncrease i n a n y l y m p h n o de, a n d n o ne w e nlar ge d l y m p h n o de. I n s mall l y m p h 
n o des ( < 2 c m), a n i ncrease of less t ha n 2 5 % is n ot  c o nsi dere d t o be si g nifica nt.  
c.  
Re d ucti o n i n t he n ot e d pretreat me nt e nlar ge me nt of t he s plee n or li ver b y 5 0 % or m ore . 
Gr o u p B  
d.  Bl o o d c o u nt s h o ul d s h o w o ne of t he f oll o wi n g:  
•  
Ne utr o p hils > 1. 5 x 1 0 9/ L ( 1 5 0 0/ µ L) wit h o ut nee d f or e x o ge n o us gr o wt h fa ct ors. 
•  
Plat el et c o u nt > 1 0 0 x 1 0 9/ L ( 1 0 0 0 0 0/ µ L) or 5 0 % i m pr o ve me nt o ver baseli ne 
wit h o ut nee d f or e x o ge n o us gr o wt h fact ors.  
•  
He m o gl o bi n > 1 1 0 g/ L ( 1 1. 0 g/ d L), or 5 0 % i m pr o ve me nt o ver baseli ne wit h o ut 
re q uiri n g re d bl o o d cell tra nsf usi o ns or e x o ge n o us er yt hr o p oieti n. 
 


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 6 7  of 7 1  
 
 C h r o ni c L y m p h o c yti c L e u k e mi a R e s p o n s e D efi niti o n ( H all e k et al. 2 0 0 8) ( c o nti n u e d)  
Pr o gressive 
Dise ase:  
( P D) 
Pr o gressive dise as e d uri n g or after t her a py is c h ar acterize d  by at le ast o ne of t he f oll o wi n g:  
a.  
L y m p ha de n o pat h y:   Pr o gressi o n of l y m p ha de n o pat h y is oft e n disc o vere d b y p h ysic al 
e xa mi nati o n a n d s h o ul d be rec or de d. I n C L L, t he use of C T sca ns us uall y d o es n ot a d d m uc h 
i nf or mati o n f or t he det ecti o n of pr o gressi o n or rela pse.  T heref ore, t he use of i ma gi n g met h o ds 
t o f oll o w C L L pr o gressi o n is at t he discreti o n of t he tr eati n g p h ysicia n. Disease pr o gressi o n 
o cc urs if o ne of t he f oll o wi n g e ve nts is o bser ve d:  
•  
A p peara nce of a n y ne w lesi o n, s uc h as e nlar ge d l y m p h n o des ( > 1. 5 c m), 
s ple n o me gal y, he pat o me gal y, or ot her or ga n i nfiltr at es. 
•  
A n i ncrease b y 5 0 % or m ore  i n great est det er mi ne d dia met er of a n y pre vi o us sit e.  
b.  A n i ncrease i n t he pre vi o usl y n ot e d e nlar ge me nt of t he li ver or s plee n b y 5 0 % or m ore, or t he 
de n o v o a p peara nce of he pat o me gal y or s ple n o me gal y.  
c.  
A n i ncrease i n t he n u m ber of bl o o d l y m p h o c yt es b y 5 0 % or m ore, wit h at least 5 0 0 0  B -
l y m p h o c yt es per µ L. 
d.  Tra nsf or mati o n t o a m ore a g gressi ve hist ol o g y (e. g., Ric ht er s y n dr o me).  W he ne ver p ossi ble, 
t his dia g n osis s h o ul d be est a blis he d b y l y m p h n o de bi o ps y. 
e.  
Occ urre nce of c yt o pe nia ( ne utr o pe nia, a ne mia, or t hr o m b o c yt o pe nia) attri b ut a ble t o C L L  
•  
D uri n g t her a py:   C yt o pe nias ma y o cc ur as a si de effe ct of ma n y t hera pies.  D uri n g 
t hera p y, c yt o pe nias ca n n ot be use d t o defi ne diseas e pr o gressi o n. 
•  
After tre at me nt:  T he pr o gressi o n of a n y c yt o pe nia ( u nrelat e d t o a ut oi m m u ne  
c yt o pe nia),  as d o c u me nt e d b y a decrease of H b le vels b y > 2 0 g/ L  ( 2 g/ d L) or t o < 1 0 0 
g/ L ( 1 0 g/ d L), or b y a decreas e  of plat elet c o u nts b y > 5 0 % or t o < 1 0 0 x 1 0 9/ L 
( 1 0 0, 0 0 0/ µ L), w hic h o cc urs at le ast 3 m o nt hs aft er treat me nt,  defi nes dise ase 
pr o gressi o n, if  t he marr o w bi o ps y de m o nstrat es a n i nfiltrat e of cl o nal C L L cells.  
 
St a ble 
Dise ase:  
( S D) 
Patie nts w h o ha ve n ot ac hie ve d a C R or a P R, a n d w h o ha ve n ot  e x hi bit e d pr o gressi ve dis ease, will 
be c o nsi dere d t o ha ve st a ble  dise ase ( w hic h is e q ui vale nt t o a n o n -res p o nse). 
S o urce:   Halle k M, C hes o n B D, Cat o vs k y  D, et al.  G ui deli nes f or t he dia g n osis a n d treat me nt of c hr o nic l y m p h o c ytic 
le u ke mia: a re p ort fr o m t he I nt er nati o nal W or ks h o p o n C hr o nic L y m p h o c ytic Le u ke mia u p dati n g t he Nati o nal C a ncer 
I nstit ut e– W or ki n g Gr o u p 1 9 9 6 g ui deli nes. Bl o o d. 2 0 0 8; 1 1 1: 5 4 4 6 -5 6.  


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D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 6 8  of 7 1  
 
1 6  A P P E N DI X B - C O N T R A C E P TI V E G UI D E LI 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 a ri n g P ot e nti al a r e D efi n e d a s F oll o w s:  
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 [f or U S o nl y: 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 nt r a c e pti v e G ui d eli n e s f o r W o m e n of C hil d -B e a ri 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 hi g hl y 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  3 0 d a ys  aft er st o p pi n g 
tr e at m e nt. T h e hi g hl y 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 eriliz 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 er 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 at i 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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D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 6 9  of 7 1  
 
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 e rtil e M al e s:  
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 s 
d uri n g tr e at m e nt a n d f or 3 0 d a ys aft er disc o nti n u ati o n of t h e st u d y dr u g. T h e y  s h o ul d n ot f at h er a 
c hil d i n t his p eri o d.   
P r e g n a n ci e s  
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 o f 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 o ll 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.  


T G R -1 2 0 2 -2 0 1 -C L L  
 
 
D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 7 0  of 7 1  
 
1 7  A P P E N DI X C  –  N Y H A C L A S SI FI C A TI O N S  
N e w Y o r k H e a rt A s s o ci ati o n ( N Y H A) C l a s sifi c ati 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 ec ti 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 e cti 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 e ss 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.  
 
 
 


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D at e d: 0 5 M arc h 2 0 1 9  ( V er. 5 . 0) 
 
P a g e 7 1  of 7 1  
 
1 8  A P P E N DI X  D –  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