An Open-label Extension Study in Patients 65 Years or Older With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Who Participated in Study PCYC-1115-CA (Ibrutinib Versus Chlorambucil)
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Sponsor: Pharmacyclics LLC.



I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 2
P R O T O C O L A P P R O V A L P A G E
St u d y Title:
A n O pe n -la bel E xte nsi o n St u d y i n Patie nts 6 5 Years or Ol der wit h 
C hr o nic L y m p h oc ytic Le u ke mia ( C L L) or S m all L y m p h oc ytic 
L y m p h o ma ( S L L) W h o Partici pate d
i n St u d y P C Y C- 1 1 1 5-C A 
(I br uti ni b vers us C hl ora m b ucil)
St u d y N u m ber:
P C Y C -1 1 1 6 -C A
Ori gi n al Pr ot oc ol D a te: 2 8 Se pte m ber 2 0 1 2
Pr ot oc ol A me n d me nt 1 D ate:
2 8 Ma y
2 0 1 4
Pr ot oc ol A me n d me nt 2 D ate:
1 9 Oct o ber 2 0 1 6
Pr ot oc ol A me n d me nt 3 D ate:
1 2 J ul y 2 0 1 8
Pr ot oc ol A me n d me nt 4 D ate:
1 0 Oct o ber 2 0 2 2
I ha ve caref ull y rea d Pr ot oc ol P C Y C - 1 1 16 -C A A me n d me nt 4 e nt itle d “A n O pe n -lab el  E xte nsio n  
St u d y  in Patie nts 6 5 Years or Ol der wit h C hr o nic L y m p h oc yt ic Le u ke mia ( C L L) or S m all 
L y m p h oc y tic L y m p h o ma ( S L L) W h o Partici pate d i n St u d y P C Y C- 1 1 1 5-C A ( I br uti ni b vers us 
C hl ora m b ucil ). ”  I a gree t o c o n d uct t his st u d y as o utli ne d herei n a n d i n c om p lia nce with G o o d 
Cli nical Practices ( G C P) a n d all a p plica ble re g ulat or y  re q uire me nts. F urt her m ore, I u n dersta n d 
t hat t he S p o ns or , P har mac yclics L L C , a n d t he I nstit utio nal  Re vie w B oar d/ Researc h Et hics 
B oar d/I n de pe n de nt Et hics C o m mittee (I R B/ R E B/I E C) m ust a p pr o ve a n y c ha n ges t o t he pr ot oc ol 
i n writi n g bef ore i m ple me ntati o n.
I a gree n ot t o di v ul ge t o a n yo n e, eit her d uri n g or after t he ter mi nat i on of t he st u d y , a n y 
c o nfi de nt ial i nf or mati o n ac q uire d re gar di n g t he i n vesti gati o nal pr o d uct a n d pr ocesses or met h o ds 
of  P har mac yclics L L C . All data pertai ni n g t o t his st u d y  will be pr o vide d t o P har mac yclics L L C . 
T he p olic y of P har mac yclics L L C , re q uires t hat a n y prese ntatio n or p u blicati o n o f st u d y data b y 
clinical i n vesti gat ors be re vie we d b y P har mac yclics L L C , b efore rel ease, as s pecifie d i n t he 
pr ot oc ol .
Pri nci pal I n vesti gat or’s Si g nat ure
Date
Pri nt Na me
T he f oll o wi n g P har mac yclics L L C re prese ntati ve is a ut h orize d t o si g n t he pr ot oc ol a n d a n y 
a me n d me nts:
Me dical M o nit or’s Si g nat ure
Date
 M D
Cli nical Scie nce, P har mac yclics L L C
1 5- N o v- 2 0 2 2

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3
S Y N O P SI S
Title
A n O pe n -la bel E xte nsi o n St u d y i n Patie nts 6 5 Years or Ol der wit h C hr o nic 
L y m p h oc ytic Le u ke mia ( C L L) or S m all L y m p h oc ytic L y m p h o ma ( S L L) 
W h o Partici pate d i n St u d y P C Y C - 1 1 1 5-C A ( I br uti ni b vers us C hl ora m b ucil)
Pr ot oc ol N u m ber
P C Y C - 1 1 1 6-C A
St u d y P h ase
3
St u d y D ur ati o n
A p pr o xi matel y 1 0 years fr o m ra n d o mizati o n of t he first patie nt i n t he pare nt 
st u d y (ie, St u d y P C Y C - 1 1 1 5-C A) .
I n vesti g ati o n al Pr o d uct
I br uti ni b oral ( P O) har d gelati n ca ps ule 
Refere nce T her a p y
N o ne 
O bjecti ves

T o m o nit or pr o gressi o n -free s ur vi val ( P F S) 

T o c o nti n ue treat me nt a n d safet y assess me n t of patie nts ra n d o mize d t o 
Ar m B ( i br uti ni b) i n St u d y P C Y C- 1 1 1 5-C A (t he pare nt st u d y) w h o ha ve 
n ot pr o gresse d at t he ti me of pare nt st u d y cl os ure

T o f oll o w patie nts f or l o n g -t er m o utc o me 

T o ca pt ure o verall res p o nse rate ( O R R), d urati o n of res p o nse ( D O R), 
P F S, a n d o verall s ur vi val (O S ), a n d ti me t o ne xt t hera p y

T o f ulfill l o n g -t er m f oll o w-u p re q uire me nts of ra n d o mize d patie nts after 
cl os ure of t he pare nt st u d y, i ncl u di n g O S
St u d y Desi g n
St u d y P C Y C- 1 1 1 6- C A is a n o pe n-la bel, m ultice nter e xte nsi o n of St u d y
P C Y C - 1 1 1 5-C A (t he pare nt st u d y) , a n d it will r u n c o nc urre ntl y wit h t he 
pare nt st u d y . A patie nt will be tra nsferre d t o P C Y C - 1 1 1 6-C A after 
I n de pe n de nt Re vie w C o m mittee (I R C) c o nfir mati o n of disease pr o gressi o n 
( P D) i n t he pare nt st u d y or at cl os ure of t he pare nt st u d y b y t he S p o ns or , 
w hic he ver c o mes first . 
After P D, selecti o n of s ec o n d-li ne t hera p y, w he n cli nicall y i n dicate d, is at t he 
discreti o n of t he i n vesti gat or a n d ca n i ncl u de sec o n d -li ne i bruti ni b (f or 
patie nts ra n d o mize d t o c hl ora m b ucil i n t he pare nt st u d y w h o als o meet t he 
criteria f or sec o n d-li ne i br uti ni b t hera p y [Secti o n 4. 2 ]‡) sec o n d-li ne 
c hl ora m b ucil (f or patie nts ra n d o mize d t o i br uti ni b i n t he pare nt st u d y), or 
ot her t hera pies.
Tra nsfer of patie nts fr o m t he pare nt st u d y a n d treat me nt i n t he e xte nsi o n 
st u d y are descri be d i n Ta ble 1.
Assess me nts i n t he e xte nsi o n st u d y var y de pe n di n g o n t he treat me nt t o w hic h 
t he patie nt was ra n d o mize d i n t he pare nt st u d y, t he disease-pr o gressi o n stat us 
P har mac yclics, I nc.
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 of 9 7
                                                  
‡ N ote: sec o n d -li ne i br uti ni b is n ot a p plic a ble after i m ple me nt ati o n of Pr ot oc ol A me n d me nt 3.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4
at tra nsfer t o t he e xte nsi o n st u d y, a n d t he pla n ne d treat me nt i n t he e xte nsi o n 
st u d y; assess me nts are s u m marize d i n t he sc he d ules of assess me nts 
(A p pe n di x A , A p pe n di x B , A p pe n di x C a n d A p pe n di x D ).
Patie nts will be f oll o we d f or l o n g -t er m o utc o me, i ncl u di n g P F S, O S, O R R,
a n d w he n a p plica ble, res p o nse t o ne xt treat me nt.
After I mple me nt ati o n of Pr ot oc ol A me n d me nt 3:

Patie nts ra n d o mize d t o c hl ora m b ucil w h o ha ve n ot pr o gresse d o n t he
st u d y a n d ha ve n ot starte d s u bse q ue nt a ntica ncer t hera p y, a n d patie nts 
ra n d o mize d t o i br uti ni b will b e  f oll o we d o n t he st u d y.

Patie nts ra n d o mize d t o c hl ora m b ucil w h o pr o gresse d will e xit t he st u d y. 

Sec o n d -li ne i br uti ni b patie nts will be gi ve n t he o p p ort u nit y t o e nr oll i nt o
a se parate l o n g-t er m i br uti ni b e xte nsi o n st u d y if t he y meet t he eli gi bilit y 
criteria of t hat st u d y.
P o p ul ati o n
T his st u d y will e nr oll patie nts 6 5 years or ol der wit h C L L or S L L w h o 
pre vi o usl y partici pate d i n t he pare nt st u d y . 
Ce nters
M ultice nter,
m ulti nati o nal
Eli gi bilit y Criteri a f or 
P C Y C - 1 1 1 6-C A
T o e nr oll i n St u d y P C Y C - 1 1 1 6-C A, patie nts m ust meet all of t he f oll o wi n g 
criteria:
1.
Ra n d o mize d i n t he pare nt s t u d y, P C Y C -1 1 1 5- C A
2.
I nf orme d c o nse nt f or St u d y P C Y C -1 1 1 6- C A
3.
I R C-c o nfir me d P D i n t he pare nt st u d y or cl os ure of t he pare nt st u d y
A d diti o n al Criteri a f or 
Recei vi n g Sec o n d -li ne 
Ibr uti ni b ‡
( Sec o n d-li ne i br uti ni b will 
n o l o n ger be i nitiate d
f oll o wi n g i m ple mentati o n of 
Pr ot oc ol A me n d me nt 3)
T o recei ve sec o n d -li ne i br uti ni b, patie nts m ust meet all of t he f oll o wi n g 
criteria:
1. 
I R C- c o nfir me d disease pr o gressi o n i n t he pare nt st u d y 
( P C Y C- 1 1 1 5-C A) , or f or patie nts w h o di d n ot pr o gress i n t he pare nt 
st u d y, i n vesti gat or-deter mi ne d disease pr o gressi o n i n t he e xte nsi o n 
st u d y ( P C Y C-1 1 1 6- C A )
2.
Recei ve d at least 3 c ycles of c hl ora m b ucil t hera p y
3.
D oc u me nte d, pr ot oc ol -defi ne d reas o n f or c h l ora m b ucil disc o nti n uati o n:

N o e vi de nce of res p o nse i n ra di o gra p hicall y assesse d disease 
para meters at C ycle 5 c o m pare d t o baseli ne; n o f urt her res p o nse 
( defi ne d as fail ure t o reac h at least a P R, or a platea u of res p o nse 
wit h n o f urt her i m pr o ve me nt of di s ea s e para meters) after at least 
6 c ycles; c o ul d n ot t olerate treat me nt (a sit uati o n defi ne d b y t he 
r ec urre nce of t o xicit y of at least Gra de 3 des pite a p pr o priate d ose 
re d ucti o ns a n d o pti mal s y m pt o matic ma na ge me nt); or ma xi m u m 
treat me nt of 1 2 c ycles wit h c hl ora m b ucil
4.
De m o nstrates co nt i n uati o n of a de q uate or ga n f u ncti o n, perf or ma n c e 
stat us, a n d ot her criteria, as f oll o ws:

Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) stat us of 0- 2

A de q uate he ma t ol o gic f u ncti o n, defi ne d as A N C ≥0. 7 5 x 1 0 9/ L 
(i n de pe n de nt of gr o wt h fact or s u p p ort i n t he prece di n g 7 da ys) a n d 
platelet c o u nt ≥3 0 x 1 0 9/ L (i n de pe n de nt of tra nsf usi o n or gr o wt h 
fact or s u p p ort i n t he prece di n g 7 da ys)

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5

A de q uate he patic f u ncti o n, defi ne d as ser u m as partate tra nsa mi nase 
( A S T) a n d ala ni ne tra nsa mi nase ( A L T) < 2. 5 x u p per li mit of n or mal 
( U L N), a n d t otal bilir u bi n ≤1. 5 x U L N ( u nless d ue t o Gil bert's 
s y n dr o me)

A de q uate re nal f u ncti o n, defi ne d as a n esti mate d gl o mer ular 
filtrati o n rate ≥ 3 0 m L/ mi n usi n g t he C o c kcr oft -Ga ult e q uati o n

Patie nts m ust ha ve rec o vere d fr o m ac ute t o xicities d ue t o pri or 
c he m ot hera p y, ra di ot hera p y, i n vesti gati o nal dr u gs or e x peri me ntal 
treat me nts ( n o n-he mat ol o gic t o xicities ha ve res ol ve d t o a 
N CI C T C A E [versi o n 4. 0 3 ] Gra de of ≤2) pri or t o rece i vi n g ne xt li ne 
i br uti ni b o n t his st u d y
5.
Meets at least 1 of t he I nter nati o nal W or ks h o p o n C hr o nic L y m p h oc ytic 
Le u ke mia (I W C L L) criteria f or acti ve disease re q uiri ng tr eat me nt 
(Halle k 2 0 0 8 ):

E vi de nce of pr o gressi ve marr o w fail ure as ma nifeste d b y t he 
de vel o p me nt of, or w orse ni n g of, a ne mia ( he m o gl o bi n < 1 0 g/ d L)
a n d/ or t hr o m b oc yt o pe nia ( platelets < 1 0 0, 0 0 0/ L)

Massi ve ( ≥6 c m bel o w t he left c ostal mar gi n), pr o gressi ve, or 
s y m pt o matic s ple n o me gal y

Massi ve n o des (at least 1 0 c m l o n gest dia meter), pr o gressi ve, or 
s y m pt o matic l y m p ha de n o pat h y

Pr o gressi ve l y m p h oc yt osis wit h a n i ncrease of m ore t ha n 5 0 % o ver a 
2- m o nt h peri o d or a l y m p h oc yte d o u bli n g ti me ( L D T) of < 6 m o nt hs . 
L D T m a y be o btai ne d b y li near re gressi o n e xtra p olati o n of a bs ol ute 
l y m p h oc yte c o u nts o btai ne d at i nter vals of 2 wee ks o ver a n 
o bser vati o n peri o d of 2 t o 3 m o nt hs . I n patie nts wit h i nitial bl o o d 
l y m p h oc yte c o u nts of < 3 0, 0 0 0/L, L D T s h o ul d n ot be use d as a 
si n gle para meter t o defi ne i n dicati o n f or treat me nt. I n ad diti o n, 
fact ors c o ntri b uti n g t o l y m p h oc yt osis or l y m p ha de n o pat h y ot her t ha n 
C L L (e g, i nfecti o ns) s h o ul d be e xcl u de d.

A ut oi m m u ne he m ol ytic a ne mia a n d/ or i m m u ne t hr o mb o c yt o pe nia 
(see defi niti o ns bel o w) t hat is p o orl y res p o nsi ve t o c ortic oster oi ds or 
ot her sta n dar d t hera p y 
(D e fi niti o ns: A ut oi m m u ne he m ol ytic a ne mia is defi ne d b y at least 
1 ma r ker of he m ol ysis [i n direct bilir u bi n a b o ve t he U L N n ot d ue t o 
li ver disease, i ncrease d lactate de h y dr o ge nase [a b o ve U L N] wit h o ut 
alter nati ve eti ol o g y, or i ncrease d a bs ol ute retic ul oc yt osis [a b o ve 
U L N] or b o ne marr o w er yt hr o p oiesis i n t he a bse nce of blee di n g] ,
A N D at least 1 ma r ker of direct or i n direct a ut oi m m u ne mec ha nis m 
[ p ositi ve direct a nti gl o b uli n f or I g G or C 3 d, c ol d a g gl uti ni ns] 
[Di n g 2 0 0 7 ]. A ut oi m m u ne t hr o m b oc yt o pe nia is defi ne d b y platelets 
≤1 0 0, 0 0 0/ L a n d i ncrease d me ga kar y oc ytes o n t he b o ne marr o w 
e xa mi nati o n.)

C o nstit uti o nal s y m pt o ms, defi ne d as 1 or m ore of t he f oll o wi n g 
disease -relate d s y m pt o ms or si g ns, d oc u me nte d i n t he patie nt’s 
r ec or d pri or t o ra n d o mizati o n:

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6

U ni nte nti o nal wei g ht l oss > 1 0 % wit hi n 6 m o nt hs pri or t o 
Scree ni n g

Si g nifica nt fati g ue (i na bilit y t o w or k or perf or m us ual 
acti vities)

Fe vers > 1 0 0. 5° F or 3 8. 0° C f or 2 or m o r e wee ks pri or t o 
Scree ni n g wit h o ut e vi de nce of i nfecti o n

Ni g ht s weats f or m ore t ha n 1 m o nt h pri or t o Scree ni n g wit h o ut 
e vi de nce of i nfecti o n
6.
O btai ne d t he S p o ns or ’s a p pr o val f or sec o n d-li ne i br uti ni b t hera p y
T o recei ve sec o n d -li ne i br uti ni b, p atie nts m ust meet N O N E of t he 
f oll o wi n g criteri a:
1.
Disease pr o gressi o n i n v ol vi n g t he ce ntral ner v o us s yste m ( C N S ) or 
tra nsf or mati o n t o a n ot her hist ol o g y
2.
I nter ve ni n g c he m ot hera p y, i m m u n ot hera p y, or i n vesti gati o nal a ge nt 
s pecificall y t o treat C L L if a d mi nistere d bef ore da te of I R C c o nfir me d
pr o gr essi ve disease
3.
I n t he 4 wee ks bef ore d osi n g: ra diati o n t hera p y, maj or s ur ger y, or 
r ecei pt of a n i n vesti gati o nal dr u g 
4.
Re q uir e me nt f or treat me nt wit h a str o n g C Y P 3 A i n hi bit or
5.
U nc o ntr olle d s yste mic i nfecti o n or re q uire me nt f or I V a nti bi otics
6.
N o nc o m plia nce o n t he pare nt st u d y
E n d p oi nts
T he e n d p oi nts of P C Y C - 1 1 1 6-C A are as f oll o ws:

P F S o n first -li ne t hera p y

P F S after  i nitiati o n of s u bse q ue nt a ntica ncer t hera p y ( P F S 2)

O verall s ur vi val

Ti me t o ne xt treat me nt

O R R a n d D O R

Safet y as meas ure d b y all A Es a n d s eri o us a d verse e ve nts (S A Es )

Disease o utc o me f oll o wi n g cessati o n of i br uti ni b t hera p y after
attai n me nt of mi ni mal resi d ual disease ( M R D)-ne gati ve re missi o n i n 
t h ose patie nts recei vi n g i br uti ni b as sec o n d-li ne t hera p y
Tr a nsfer fr o m 
P are nt St u d y t o 
P C Y C - 1 1 1 6-C A
Patie nts are tra nsferre d fr o m t he pare nt st u d y t o t his e xte nsi o n st u d y a s 
descri be d i n Ta ble 1 .
St u d y Tre at me nt i n 
P C Y C - 1 1 1 6-C A
T he treat me nt o pti o ns i n t his e xte nsi o n st u d y are descri be d bel o w. 
O n g oi n g i br uti ni b 
(first-li ne t her a py)
Patie nts w h o recei ve d i br uti ni b i n t he pare nt st u d y a n d ha ve n ot pr o gresse d at 
t he ti me of pare nt st u d y cl os ure will be tra nsferre d t o St u d y P C Y C- 1 1 1 6-C A 
t o c o nti n ue o n t heir c urre nt t olerate d d ose of i br uti ni b. Treat me nt will 
c o nti n ue u ntil P D, u nacce pta ble t o xicit y, start of s u bse q ue nt a ntica ncer 
t hera p y or ot her reas o n f or treat me nt disc o nti n uati o n. 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 7
Alte r n ative a ntic a ncer 
tre at me nt (sec o n d-li ne 
t her a py)
At t he i n vesti gat or’s discreti o n, alter nati ve a ntica ncer treat me nt is a 
t hera pe utic o pti o n f or patie nts w h o e x perie nce P D d uri n g i br uti ni b t hera p y or 
d uri n g or after c hl ora m b ucil treat me nt . Alter nati ve treat me nt ca n als o be 
c o nsi dere d if dr u g is disc o nti n ue d f or ot her reas o ns (e g, i ntolera bilit y or 
a d verse e ve nt [ A E]). 
Selecti o n of t he dr u g(s) a n d treat me nt re gi me n(s) is at t he i n vesti gat or’s 
discreti o n.
F or patie nts ra n d o mize d t o i br uti ni b i n t he pare nt st u d y, chl ora m b ucil ca n be 
use d f or sec o n d -li ne t hera p y.
Sec o n d -li ne i br uti ni b t hera p y‡ is a treat me nt o pti o n f or t h ose patie nts w h o 
e x perie nce P D d uri n g or after c hl ora m b ucil treat me nt a nd meet criteria f or 
c hl ora m b ucil disc o nti n uati o n i n t he pare nt st u d y . T he patie nt s m ust meet t he 
criteria descri be d a b o ve (i n “ A d diti o nal Criteria f or Recei vi n g Sec o n d -li ne
i br uti ni b”). 
I br uti ni b d osi n g is i nitiate d at 4 2 0 m g ( 3 x 1 4 0 -m g ca ps ules), orall y, o nce 
dail y . If necessar y, t he d ose ca n be decrease d as descri be d i n t his pr ot oc ol.
At t he i n vesti gat or’s discreti o n, patie nts recei vi n g sec o n d-li ne i br uti ni b 
t hera p y‡ w h o ac hie ve a n d retai n M R D -ne gati ve re missi o n f or 6 c ycles
(i ncl u di n g 2 se q ue ntial M R D-ne gati ve assess me nts at least 2 c ycles a part t hat 
i ncl u de at least o ne b o ne marr o w as pirate) ca n ha ve t heir i br uti ni b 
disc o nti n ue d . If sec o n d-li ne i br uti ni b is disc o nti n ue d, t he patie nt will be 
f oll o we d f or M R D rec urre nce b y peri p heral bl o o d m o nit ori n g a p pr o xi matel y
e ver y 6 c ycles; i br uti ni b t hera p y ma y b e  rei nitiate d i n t he e ve nt of rec urre nce
of M R D p ositi ve s tat us or cli nical pr o gressi o n .
N o a ntic a ncer tre at me nt
Patie nts ca n elect t o f ore g o f urt her a ntica ncer t hera p y , or patie nts ma y n ot 
ha ve met I W C L L criteria f or acti ve disease re q uiri n g a ntica ncer t hera p y .
S afet y Pl a n:
A P har mac o vi gila nce C o m mittee will c o m pare a d verse e ve nts i n t he st u d y 
wit h safet y data fr o m t he e ntire cli nical trial data base f or i br uti ni b. All 
e nr olle d patie nts will be e val uate d cli nicall y a n d usi n g sta n dar d la b orat or y 
testi n g d uri n g t heir partici pati o n i n t his st u d y. 
Safet y assess me n ts will c o nsist of m o nit ori n g a n d rec or di n g A Es a n d S A Es; 
meas ure me nts of pr ot oc ol -s pecifie d he mat ol o g y, cli nical c he mistr y, a n d 
ot her la b orat or y varia bles; meas ure me nt of pr ot oc ol -s pecifie d vital si g ns; a n d 
ot her pr ot oc ol -s pecifie d tests t hat are dee me d critical t o t he safet y e val uati o n 
of t he st u d y dr u g(s).

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 8
St atistic al Met h o ds
All statistics will be descri pti ve; n o i nfere ntial h y p ot hetical tests will be 
c o n d ucte d.
Eac h efficac y e n d p oi nt will be descri pti vel y a nal yze d b ase d o n c o m bi ne d 
data fr o m t he p ar e nt st u d y a n d St u d y P C Y C - 1 1 1 6-C A as a p pr o priate.
A descri pti ve u p date of P F S o n t he ori gi nal ra n d o mize d t hera p y will be 
c o n d ucte d at t he cl ose of St u d y P C Y C -1 1 1 6- C A, al o n g wit h O S . Me dia ns 
f or P F S a n d O S a n d t heir 9 5 % c o nfi de nce i nter vals will be esti mate d usi n g 
t he Ka pla n-Meier met h o d f or all patie nts ran d o mize d i n S t u d y P C YC- 1115-C A .
T he o verall r es p o nse rate will be descri be d b y cr u de pr o p orti o n of patie nts 
ac hie vi n g a c o m plete res p o nse (C R ) or partial res p o nse ( P R ). F or patie nts 
r ecei vi n g sec o n d-li ne i br uti ni b w h o ac hie ve M R D -ne ga ti ve re missi o n, cr u de 
pr o p orti o n, d urati o n of M R D ne gati vit y, a n d t he pr o p orti o n of patie nts w h o 
r ec ur after cessati o n of treat me nt will be calc ulate d.
Ver bati m descri pti o ns of A Es will be c o de d t o a preferre d ter m a n d ma p pe d 
t o S yste m Or ga n Class usi n g t he c urre nt versi o n of t he Me dical Dicti o nar y 
f or Re g ulat or y Acti vities ( Me d D R A). A Es t hat starte d d uri n g treat me nt a n d 
u p t o 3 0 da ys after t he last d ose of st u d y dr u g are c o nsi dere d treat me nt -
e mer ge nt a n d will be ta b ulate d.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 9
T A B L E O F C O N T E N T S
P R O T O C O L A P P R O V A L P A G E ...........................................................................................2
S Y N O P SI S ................................................................................................................................. 3
T A B L E O F C O N T E N T S ..........................................................................................................9
LI S T O F I N -T E X T T A B L E S ................................................................................................. 1 3
LI S T O F I N -T E X T FI G U R E S ...............................................................................................1 3
LI S T O F A P P E N DI C E S .........................................................................................................1 3
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 .............................................................1 4
1. 
B A C K G R O U N D A N D R A TI O N A L E ...........................................................................1 6
1. 1.
I br uti ni b O ver vie w................................................................................................1 6
1. 2.
C hr o nic L y m p h oc y tic Le u ke mia a n d S mall L y m p h oc ytic L y m p h o ma ..................1 6
1. 3.
Sta n dar d Treat me nt a n d U n met Me dical Nee d ......................................................1 7
1. 4.
S u m mar y  of N o ncli nical Data...............................................................................1 7
1. 4. 1.
P har mac o l og y ...........................................................................................1 7
1. 4. 2.
S af et y P har mac o l og y  a n d T o xic o l og y .......................................................1 8
1. 5.
S u m mar y  of Cli nical Data.....................................................................................1 8
1. 5. 1.
P har mac o ki net ics a n d Pr o d uct Meta b olis m ................................................1 8
1. 5. 2.
S u m mar y  of Cli nical Safety .......................................................................1 9
1. 5. 2. 1.
M o n ot hera p y  St u dies ..................................................................1 9
1. 5. 3.
Ris ks .........................................................................................................2 0
1. 5. 3. 1.
Bl ee di n g-relate d E ve nts ..............................................................2 0
1. 5. 3. 2.
Car di ac Arr h yt hmias a n d Car diac Fail ure ....................................2 0
1. 5. 3. 3.
Ras h ............................................................................................2 0
1. 5. 3. 4.
N o n -me la n oma s ki n ca ncer .........................................................2 1
1. 5. 3. 5.
I nfecti o ns....................................................................................2 1
1. 5. 3. 6.
C y t o p e nias ..................................................................................2 1
1. 5. 3. 7.
I nterstitial L u n g Disease (I L D)....................................................2 1
1. 5. 3. 8.
T u m or L ysis S y n dr o m e ...............................................................2 1
1. 5. 3. 9.
Di arr hea ......................................................................................2 1
1. 5. 3. 1 0. H y perte nsi o n ...............................................................................2 1
1. 5. 3. 1 1. Le u k ostasi s .................................................................................2 2
1. 5. 3. 1 2. L y m p h oc y t osis............................................................................2 2
1. 5. 4.
P har mac o d y na mic Effect Lea di n g t o C haracterist ic Patter n of Res p o nse ...2 2
1. 6.
Rati o nale f or Tri al ................................................................................................. 2 3
2. 
S T U D Y O B J E C TI V E S ..................................................................................................2 4
3.
S T U D Y D E SI G N ............................................................................................................2 4
3. 1.
Cri teria f or Tra nsfer t o T his E xte nsi o n St u d y........................................................2 7
4.
S E L E C TI O N O F P A TI E N T S ........................................................................................2 8
4. 1.
Eli gi bilit y Cri t eria ................................................................................................. 2 8
4. 2.
A d dit i onal Cri t eria for Recei vi n g Sec o n d -li ne I br uti ni b‡ .......................................2 8
5.
T R E A T M E N T S ..............................................................................................................3 0

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 0
5. 1.
I de ntificati o n of Alter nati ve A ntica ncer Treat me nts ..............................................3 0
5. 1. 1.
I br uti ni b ....................................................................................................3 0
5. 1. 2.
N o n -i br uti ni b T hera pies ............................................................................3 1
5. 1. 3.
N o Treat m e nt ............................................................................................3 1
5. 2.
I br uti ni b................................................................................................................3 1
5. 2. 1.
D osa ge a n d A d mi nistrati o n .......................................................................3 1
5. 2. 2.
O ver d ose ...................................................................................................3 2
5. 2. 3.
D ose H ol d, Re d uct i on, or Disc o nt i n uati on .................................................3 2
5. 2. 4.
Treat me nt -relate d L y m p h oc yt osis .............................................................3 3
5. 2. 5.
D ose M o dificat i on f or He patic I mpaire d S u bjects ......................................3 4
5. 2. 6.
War ni n gs, Preca uti o ns, a n d A d verse Effects ..............................................3 4
5. 2. 6. 1.
War ni n gs a n d Preca utio ns........................................................... 3 4
5. 3.
N o n -i br uti ni b T hera pies........................................................................................3 5
5. 4.
Treat me nt C o m plia nce ..........................................................................................3 5
5. 5.
C o nc o mita nt Me dicati o ns D uri n g I br ut i ni b T hera p y .............................................3 5
5. 5. 1.
Per mi tte d C o nc o mita nt Me dicati o ns..........................................................3 5
5. 5. 2.
C o nc o mita nt Me dicati o ns t o be Use d wit h Ca uti o n ....................................3 6
5. 5. 2. 1.
C Y P I n hi bit i n g/I n d uci n g Dr u gs...................................................3 6
5. 5. 2. 2.
Dr u gs T hat Ma y  Ha ve T heir Plas ma C o nce ntratio ns Al tere d b y 
I br uti ni b......................................................................................3 6
5. 5. 3.
A nt i platelet A ge nts a n d A nt ic oa g ula nts .....................................................3 6
5. 5. 4.
Pr o hi bite d C o nc o mit a nt Me dicat i ons .........................................................3 7
5. 6.
G ui deli nes f or I br uti ni b Ma na ge me nt wit h S ur geries or Pr oce d ures ......................3 7
5. 6. 1.
Mi n or S ur gical Pr oce d ures ........................................................................3 7
5. 6. 2.
Maj or S ur gi cal Pr oce d ures ........................................................................3 7
6.
S T U D Y P R O C E D U R E S A N D A S S E S S M E N T S ..........................................................3 7
6. 1.
I nf or me d C o nse nt a n d Assess me nt of Eli gi bilit y ...................................................3 8
6. 2.
Ra n d o mizati o n a n d Bli n di n g .................................................................................3 8
6. 3.
Assess me nts a n d Pr oce d ures b y  Visit....................................................................3 8
6. 3. 1.
P C Y C - 1 1 1 6-C A Assess me nts Bef ore P D i n Ar m A Patie nts (ie, i n patie nts 
o n c hl ora m b ucil i n pare nt st u d y ) ...............................................................3 8
6. 3. 1. 1.
Eli gi bilit y Visi t ...........................................................................3 9
6. 3. 1. 2.
D a y  1 of E ver y  4t h M o nt h ............................................................3 9
6. 3. 1. 3.
S us pecte d -P D Vi sit .....................................................................3 9
6. 3. 2.
P C Y C - 1 1 1 6-C A Assess me nts Bef ore P D or e n d of i br ut i ni b t hera p y f or 
ot her reas o ns i n Ar m B Patie nts (ie, i n pat ient s ra n d o mize d t o I br uti ni b i n 
pare nt s t u d y) .............................................................................................4 0
6. 3. 2. 1.
Eli gi bilit y Visi t ...........................................................................4 0
6. 3. 2. 2.
D a y  1 of E ver y St u d y Visit .........................................................4 0
6. 3. 2. 3.
D a y  1 of Desi g nate d C ycles – Efficac y Assess me nts ...................4 1
6. 3. 2. 4.
S us pecte d -P D Vi sit .....................................................................4 1
6. 3. 2. 5.
E n d -of -Treat m e nt Visit ...............................................................4 2
6. 3. 2. 6.
Pre -P D F oll o w -u p Visi ts.............................................................4 2
6. 3. 3.
P C Y C - 1 1 1 6-C A Assess me nts After Disease Pr o gressi o n – Sec o n d -li ne 
I br uti ni b T hera p y‡ .....................................................................................4 3
6. 3. 3. 1.
Eli gi bilit y Visi t ...........................................................................4 3

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 1
6. 3. 3. 2.
D a y  1 of 1st C ycle o n I br uti ni b ( m ust be c o m plete d wit hi n 1 4 da ys 
of  esta blis hi n g eli gi bility) ...........................................................4 4
6. 3. 3. 3.
D a y  1 of 2n d T hr o u g h 6 t h C ycle o n I br uti ni b ................................4 4
6. 3. 3. 4.
D a y  1 of C ycles fr om 7 t h C ycle o n I br uti ni b t o St u d y  Clos ure .....4 5
6. 3. 3. 5.
S us pecte d -P D Vi sit .....................................................................4 5
6. 3. 3. 6.
E n d -of -Treat m e nt Visit ...............................................................4 6
6. 3. 3. 7.
Pre -P D F oll o w -u p Visi ts.............................................................4 6
6. 3. 4.
P C Y C - 1 1 1 6-C A Assess me nts After Disease Pr o gressi o n – N o n -i br uti ni b 
S u bse q ue nt T hera p y  or N o S u bse q ue nt T hera p y ........................................4 7
6. 3. 4. 1.
Eli gi bilit y Visi t ...........................................................................4 7
6. 3. 4. 2.
F o ll ow- u p Vi sits .........................................................................4 7
6. 4.
Descri pt i on of Assess me nts a n d Pr oce d ures ..........................................................4 8
6. 4. 1.
C o nfir mati o n o f Eli gi bilit y ........................................................................4 8
6. 4. 2.
Me dical Hist or y .........................................................................................4 8
6. 4. 3.
A d verse E ve nts .........................................................................................4 8
6. 4. 4.
P h ysical E xa mi nat i on ................................................................................4 9
6. 4. 5.
Vi t al Sig ns ................................................................................................ 4 9
6. 4. 6.
E C O G Perf or ma nce Stat us ........................................................................4 9
6. 4. 7.
C o nc o mita nt Me dicati o ns ..........................................................................4 9
6. 4. 8.
P ati e nt -re p orte d O utc o mes ........................................................................4 9
6. 4. 8. 1.
E Q - 5 D- 5 L...................................................................................4 9
6. 4. 8. 2.
F A Ci T -Fat i g ue............................................................................4 9
6. 4. 9.
H e m at olo g y ...............................................................................................5 0
6. 4. 1 0. Se r u m C he mistr y.......................................................................................5 0
6. 4. 1 1. Di sease Assess me nt...................................................................................5 0
6. 4. 1 1. 1. C o m p ute d T o m o gra p h y ( C T) Sca ns ............................................5 0
6. 4. 1 1. 2. B o ne Marr o w Bi o ps y  a n d/ or As pir at e .........................................5 0
6. 4. 1 1. 3. Di sease-relate d S y m pt o ms ..........................................................5 0
6. 4. 1 1. 4. O verall Res p o nse Assess me nt .....................................................5 0
6. 4. 1 2. C y t o ge netic, C L L FI S H Pa nel...................................................................5 1
6. 4. 1 3. E x pl or at or y  I n vestig ati o ns of  Pr o g n ostic a n d Pre dicti ve Bi o mar kers a n d 
Mec ha nis m of Treat me nt Resista nce
.........................................................5 1
6. 4. 1 4. Alt er nat i ve A ntica ncer Treat me nt ..............................................................5 1
7.
M AI N E F FI C A C Y E V A L U A TI O N S ............................................................................5 1
7. 1.
S us pecte d Disease Pr o gressi o n ..............................................................................5 2
7. 2.
G ui deli nes f or Di sease E valu ati o n .........................................................................5 2
7. 3.
S ustai ne d He mat ol o gical I m pr o ve me nt ................................................................. 5 3
7. 4.
Res o l uti on of Pretr eat me nt Disease-Relate d S y m pt o ms ........................................5 3
7. 5.
Treat me nt -Relate d Defi nit i ons ..............................................................................5 3
7. 5. 1.
C o m p ute d T o m o gra p h y Sca ns ...................................................................5 3
7. 5. 2.
B o ne Marr o w As pirate a n d/ or Bi o ps y  a n d Mi ni mal Resi d ual Disease........5 4
8.
A S S E S S M E N T O F S A F E T Y .........................................................................................5 4
8. 1.
S af et y M o ni t ori n g Pla n .........................................................................................5 5
8. 2.
Defi nit i ons ............................................................................................................5 5
8. 2. 1.
A d verse E ve nts .........................................................................................5 5
8. 2. 2.
S eri o us A d verse E ve nt ..............................................................................5 6

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 2
8. 2. 3.
Se verit y .....................................................................................................5 7
8. 2. 4.
Ca usalit y ...................................................................................................5 7
8. 2. 5.
U ne x pecte d A d verse E ve nts ......................................................................5 8
8. 3.
D oc u m e nt i n g a n d Re p orti n g of A d verse a n d Seri o us A d verse E ve nts b y 
I n vesti gat ors .........................................................................................................5 8
8. 3. 1.
A d verse E ve nt Re p orti n g P eri o d ................................................................5 8
8. 3. 2.
Assess me nt of A d verse E ve nts ..................................................................5 9
8. 3. 3.
E x pe dite d Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts ................5 9
8. 3. 4.
E ve nts of S pecial I nterest ..........................................................................5 9
8. 3. 4. 1.
Maj or H e m orr ha ge ......................................................................6 0
8. 3. 5.
Pre g na nc y ................................................................................................. 6 0
8. 3. 6.
E y e- Relate d A d verse E ve nts .....................................................................6 0
8. 3. 7.
Ot her Mali g na ncies ...................................................................................6 0
8. 4.
Re p orti n g of Seri o us A d verse E ve nts b y  S p o ns or..................................................6 1
8. 5.
S peci al Re p orti n g Sit u ati o ns ..............................................................................6 1
9.
WI T H D R A W A L O F P A TI E N T F R O M T R E A T M E N T O R S T U D Y .........................6 1
9. 1.
Di sc o nti n uatio n of  Treat me nt................................................................................6 1
9. 2.
Wit h dra wal fr o m t he St u d y ...................................................................................6 2
1 0.
S T A TI S TI C A L C O N SI D E R A TI O N S ...........................................................................6 2
1 0. 1.
E n d p oi nts ..............................................................................................................6 3
1 0. 2.
Ra n d o mizati o n ......................................................................................................6 3
1 0. 3.
S a m ple -Si ze C o nsi derat i ons ..................................................................................6 3
1 0. 4.
Pl a n ne d A nal ysis ..................................................................................................6 3
1 0. 5.
A nal ysis P o p ulat i ons .............................................................................................6 3
1 0. 5. 1. I nte nt-t o-Treat P o p ul atio n .........................................................................6 3
1 0. 5. 2. S af et y P o p ul at i on ......................................................................................6 3
1 0. 6.
C o ntr ol  for Bi as ....................................................................................................6 4
1 0. 7.
Efficac y A nal yses ................................................................................................. 6 4
1 0. 7. 1. Pr o gressi o n -free S ur vi val ..........................................................................6 4
1 0. 7. 2. O verall Res p o nse Rate ..............................................................................6 4
1 0. 7. 3. D urati o n of  Res p o nse................................................................................6 4
1 0. 7. 4. Di sease O utc o me F ollo wi n g M R D -Ne gat i ve C R.......................................6 5
1 0. 7. 5. O verall S ur vi val ........................................................................................6 5
1 0. 8.
S af et y A nal yses ....................................................................................................6 5
1 1.
S T U D Y A D MI NI S T R A TI O N A N D I N V E S TI G A T O R O B LI G A TI O N S ...................6 6
1 1. 1.
Re g ulat or y  a n d Et hical C o mplia nce ......................................................................6 6
1 1. 2.
I nstituti o nal  Re vie w B oar d (I R B), Researc h Et hics B oar d ( R E B) a n d 
I n de pe n de nt Et hics C o m mittee (I E C) A p pr o val ....................................................6 6
1 1. 3.
I nf or me d C o nse nt ................................................................................................. 6 6
1 1. 4.
Q ualit y C o ntr ol  a n d Q uality Ass ura nce ................................................................. 6 7
1 1. 5.
Pr otecte d Patie nt Healt h I nf or mat i on A ut h orizati o n ..............................................6 7
1 1. 6.
St u d y  Files a n d Rec or d Rete nti o n .........................................................................6 7
1 1. 7.
Case Re p ort F or ms a n d Rec or d Mai nte na nce ........................................................6 8
1 1. 8.
I n vesti gati onal St u d y  Dr u g Acc o u nta bility ............................................................6 9
1 1. 9.
St u d y  M o nit ori n g/ A u dit Re q uire me nts..................................................................6 9

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 3
1 1. 1 0. I n vesti gat or Res p o nsi bilities .................................................................................7 0
1 1. 1 1. S p o ns or Res p o nsi bilit ies.......................................................................................7 0
1 1. 1 2. Fi na ncial Discl o s ure..............................................................................................7 0
1 1. 1 3. Lia bilit y a n d Cli nical Trial I ns ura nce ....................................................................7 0
1 1. 1 4. Pr ot oc ol  A me n d me nts...........................................................................................7 1
1 1. 1 5. P u blicat i on of St u d y  Res ults .................................................................................7 1
1 1. 1 6. St u d y  Disc o nti nuat i on ...........................................................................................7 1
1 2.
R E F E R E N C E S ...............................................................................................................7 2
1 3.
A P P E N DI C E S ................................................................................................................7 6
LI S T O F I N -T E X T T A B L E S
Ta ble 1:
P ati e nt Tra nsfer t o St u d y P C Y C- 1 1 1 6-C A a n d Assess me nts wit hi n 
P C Y C -1 1 1 6- C A ................................................................................................. 2 5
Ta ble 2:
P ati e nt Ha n dli n g after I m ple me ntati o n o f Pr ot oc ol  A me n d me nt 3......................2 6
Ta ble 3:
Dr u g Disc o nt i n uati on Act i ons f or I br uti ni b f or E ve nts n ot S pecifie d i n 
Ta ble 4. ..............................................................................................................3 3
Ta ble 4:
I br uti ni b D ose M o dificati ons f or Car diac Fail ure or Car diac Arr h yt h mias ..........3 3
Ta ble 5:
E val ua ble Para meter Re q uire me nts ....................................................................5 3
LI S T O F I N -T E X T FI G U R E S
Fi g ure 1:
C ha n ges i n Peri p heral Bl o o d L y m p h oc y te C o u nts a n d B ur de n of 
L y m p ha de n o pat h y  in Patie nts wi t h C L L/ S L L, St u d y P C Y C- 1 1 0 2-C A ...............2 3
LI S T O F A P P E N DI C E S
A p pe n di x A.
Sc he d ule of Assess me nts:  P C Y C -1 1 1 6- C A Assess me nts Bef ore P D i n Ar m A 
P ati e nts (ie, i n pat ient s o n c hl ora m b ucil i n pare nt st u d y ) ................................. 7 7
A p pe n di x B.
Sc he d ule of Assess me nts:  P C Y C - 1 1 1 6-C A Assess me nts Bef ore P D i n Ar m B 
P ati e nts (ie, i n patient s o n I br utini b i n pare nt st u d y) ........................................7 9
A p pe n di x C.
Sc he d ule of Assess me nts:  P C Y C -1 1 1 6- C A Assess me nts After P D – Sec o n d -
li ne I br uti ni b T hera p y‡ ....................................................................................8 1
A p pe n di x D.
Sc he d ule of Assess me nts:  P C Y C - 1 1 1 6- C A Assess me nts After P D –
S u bse q ue nt T hera p y  ( N on -i br uti ni b) or N o S u bse q ue nt T hera p y .....................8 4
A p pe n di x E.
Defi nit i ons of Res p o nse ( Halle k 2 0 0 8) ............................................................8 5
A p pe n di x F.
Cri teria f or Res p o nse Cate g ories .....................................................................8 9
A p pe n di x G.
I n hi bit ors a n d I n d ucers of C Y P 3 A ..................................................................9 0
A p pe n di x H.
E C O G Stat us Sc ores .......................................................................................9 1
A p pe n di x I.  
H e mat olo gi c A d verse E ve nt Gra di n g Sc he me ( Halle k 2 0 0 8) ...........................9 2
A p pe n di x J.
E Q - 5 D- 5 L.......................................................................................................9 3
A p pe n di x K.
F A Ci T -Fat i g ue................................................................................................9 6
A p pe n di x L.
C hil d -P u g h Sc ore f or S u bjects wit h Li ver I m pair me nt * ...................................9 7

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 4
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
A b bre vi ati o n
Defi niti o n
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A N C
a bs ol ute ne utr o p hil c o u nt
A S C O
A mer ican S ociet y of Cli nical O nc ol o g y
A S T
as partate a mi n otra nsferase
A U C
ar ea u n der t he c ur ve
B C R
B- cell r ece pt or
B T K
Br ut o n’s t yr osi ne ki nase
B U N
bl o o d urea nitr o ge n
C B C
c o m plete bl o o d c o u nt
C E R T
Ce nter f or E d ucati o n a n d Researc h o n T hera pe utics
C F R
C o de of Fe deral Re g ulati o ns
c G V H D
c hr o nic graft vers us h ost disease
CI
c o nfi de nce i nter val
C L L
c hr o nic l y m p h oc ytic le u ke mia
C N S
ce ntral ner v o us s yste m
C R
c o m plete re missi o n (res p o nse)
C R F
case re p ort f or m
C Ri
C R wit h i nc o m plete b o ne marr o w rec o ver y
C T
c o m p ute d t o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C Y P
c yt oc hr o me P 4 5 0
del 1 7 p
deleti o n of t he s h ort ar m of c hr o m os o me 1 7
D O R
d urati o n of res p o nse
E C G
E lectr ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
E M R
electr o nic me dical rec or ds
E O R T C
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer
E S M O
E ur o pea n S ociet y f or Me dical O nc ol o g y
F A Ci T - F
T he F u ncti o nal Assess me nt of C hr o nic Ill ness T hera p y -Fati g ue
F D A
F o o d a n d Dr u g A d mi nistrati o n ( U nite d States)
FI S H
fl u oresce nce i n sit u h y bri dizati o n
G C P
G o o d Cli nical Practice
HI P A A
Hea lt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act
HI V
h u ma n i m m u n o deficie nc y vir us
I B
i n vesti gat or’s br oc h ure
I C5 0
half ma xi mal i n hi bit or c o nce ntrati o n
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I L D
i nterstitial l u n g disease

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 5
A b bre vi ati o n
Defi niti o n
I N R
i nter nati o nal n or malize d rati o
I R B
i nstit uti o nal re vie w b oar d
I R C
i n de pe n de nt re vie w c o m mittee
I T T
i nte nt t o treat
I V
I ntra ve n o us
I W C L L
I nter nati o nal W or ks h o p o n C hr o nic L y m p h oc ytic Le u ke mia
L D H
lactate de h y dr o ge nase
L D T
l y m p h oc yte d o u bli n g ti me
L N
l y m p h n o de
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M R D
mi ni ma l resi d ual disease
M RI
ma g netic res o na nce i ma gi n g
M Z L
ma r gi nal z o ne l y m p h o ma
N C C N
Nati o nal C o m pre he nsi ve Ca ncer Net w or k
N CI
Nati o nal Ca ncer I nstit ute
N H L
n o n- H o d g ki n’s l y m p h o ma
n P R
n o d ular partial re missi o n (res p o nse)
O R R
O verall r es p o nse rate
O S
o verall s ur vi val
P D
pr o gr essi ve disease
P F S
pr o gr essi o n-free s ur vi val
P K
p har mac o ki netic(s)
P R
partial res p o nse
P R O
patie nt -r ep orte d o utc o me
Q Tc
c orrecte d Q T i nter val
R E B
Researc h Et hics B oar d
R/ R
r ela pse d/refract or y
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S C A Rs
se vere c uta ne o us a d verse reacti o ns
S E E R
S ur veilla nce E pi de mi ol o g y a n d E n d Res ults
SJ S
Ste ve ns -J oh ns o n s y n dr o me 
S L L
s mall l y m p h oc ytic l y m p h o ma
S O P
sta n dar d o perati n g pr oce d ure
S P D
s u m of t he pr o d ucts of dia meters
T L S
t u m or l ysis s y n dr o me
T N
treat me nt nai ve
U L N
u p per li mit of n or mal
U S
U nite d States
W B C
w hite bl o o d cell
W H O
W orl d Healt h Or ga nizati o n

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 6
1.
B A C K G R O U N D A N D R A TI O N A L E
1. 1.
I br uti ni b O ver vie w
I br uti ni b (IM B R U VI C A ® ) is a first-i n-class, p ote nt, orall y a d mi nistere d c o vale nt l y-bi n di n g 
i n hi bit or of Br ut o n’s t yr osi ne ki nase ( B T K) c o -de vel o pe d b y P har mac yclics L L C a n d Ja nsse n 
Researc h & De vel o p me nt L L C (c ollect i vel y referre d t o as t he S p o ns or) f or t he treat me nt of 
B- cell mali g na ncies.
I br uti ni b has bee n a p pr o ve d i n ma n y re gi o ns, i ncl u di n g t he U nite d States ( U S ) a n d E ur o pea n 
U ni o n ( E U ), f or i n dicati ons i ncl ud i n g treat me nt of patie nts wit h ma nt le cell l y m p h oma ( M C L)
w h o ha ve recei ve d at le ast 1 pri or t hera p y , p atie nts wit h chr o nic ly m p h oc y tic le u ke mia 
( C L L)/s mall l y m p h oc ytic l y m p h o ma ( S L L) i ncl u di n g C L L / S L L wi t h a delet i on of t he s h ort ar m 
of  c hr om o s o me 1 7 ( del1 7 p), pati e nts wit h Wal de nstr ö m’s macr o gl o b uli ne mia, p atie nts wit h
mar gi nal z o ne l y m p h o ma ( M Z L) w h o re q uire s yste mic t hera p y a n d ha ve recei ve d at least o ne 
pri or a nti -C D 2 0 -base d t hera p y , a n d f or patie nts wit h c hr o nic graft vers us h ost disease (c G V H D) 
aft er fail ure of o ne or m ore li nes of s yste mic t hera p y.
F or t he m ost u p t o date a n d c o mpre he nsi ve n o ncli nical a n d cli nical i nf or mat i on re gar di n g 
i br uti ni b bac k gr o u n d, safety,  efficac y, a n d i n vitr o a n d i n vi v o precli nical acti vity a n d t o xic o l og y  
of  ibr uti ni b, r efer t o t he latest versio n of  t he i br uti ni b I n vesti gat or’s Br oc h ure a n d/ or t he 
a p plica ble r e gio n al la beli n g i nf or mati on.
1. 2.
C hr o nic L y m p h oc ytic Le u ke mi a a n d S m all L y m p h oc ytic L y m p h o m a
C L L is t he m ost c o m m o n f or m of a d ult le u ke mia i n t he de vel o pe d w orl d . T he esti mate d 2 0 1 0 
pre vale nce i n t he U nite d States ( U S) was a p pr o xi matel y 1 0 6, 0 0 0 i n di vi d uals (S E E R 2 0 1 0 ). T he 
me dia n a ge at prese ntati o n is t y p icall y bet wee n 6 5 a n d 6 8 years; a p o p ulat i on- base d st u d y  fo u n d 
t hat more t ha n half o f t he cases prese nte d at o ver 7 0 years of a ge ( Bre n ner 2 0 0 8 ). C L L is 
c haracterize d b y a n acc u m ulati o n of m on ocl o nal mat ure B cells ( C D 5 + / C D 2 3+ ) i n t he bl o o d, 
b o ne marr o w, a n d sec o n dar y  l y m p h or ga ns. T hese cells are c o nsta nt l y bei n g sti m ulate d b y t heir 
B C R, as well as b y  int eract i ons wi t h t heir micr oe n vir o n me nt (C hi orazzi 2 0 0 5 ). Acc or di n g t o t he 
W o rld Heal t h Or ga nizati on ( W H O), S L L , a disease wit h si milar pat h ol o gical fi n di n gs b ut 
wi t ho ut t he l y m p h oc y t osis, is c o nsi dere d t o be a ma nifestatio n of  t he sa me u n derl yi n g dis or der 
as C L L ( Ca m p o 2 0 1 1 ).
O nce dia g n ose d wit h C L L or S L L, patie nts ca n ha ve a varia ble c o urse — s ome n ot re q uiri n g 
treat me nt for m ore t ha n a deca de a n d ot hers re q uiri n g m ore ur ge nt treat me nt, par tic ularl y t h ose 
wi t h cli nicall y s y m pt o matic disease (Gri b be n 2 0 1 1 ). Acc or di n g t o t he I nter nati o nal W or ks h o p o n 
C hr o nic L y m p h oc y tic Le u ke mia (I W C L L) g ui deli nes, t he f oll o wi n g feat ures are i n dicat i ons f or 
t hera p y: pr o gressi ve marr o w fail ure ( ma nifeste d b y a ne mia or t hr o m b oc y t o p e nia), massi ve or 
pr o gressi ve s ple n o me gal y ( 6 c m or greater), massi ve l y m p h n o des ( 1 0 c m or greater i n t he 
l on gest di a meter), pr o gressi ve l y m p h oc yt osis wit h a ra pid l y m p h oc y te d o u bli n g ti me occ urri n g 
i n less tha n 6 m o nt hs, w orse ni n g a ut oi m m u ne c y t o pe nias resista nt t o c ortic oster oi ds or ot her 
sta n dar d treat me nt, a n d c o nst itut i on al  s y m pt o ms (Halle k 2 0 0 8 ).

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 7
1. 3.
St a n d ar d Tre at me nt a n d U n met Me dic al Nee d
T he past deca de has see n si g nifica nt a d va nce me nt i n t he treat me nt of C L L. A n u m ber of ne w 
a ge nts ha ve bee n e val uate d a n d a p pr o ve d f or t he treat me nt of patie nts wit h C L L, s uc h as 
ale mt uz u ma b, be n da m usti ne, ofat u m u ma b, a n d rit u xi ma b. C he m o -i m m u n ot hera p y re gi me ns 
c o ntai ni n g a n ucle osi de a nal o g a n d a n a nt i-C D 2 0 a ge nt ha ve mar ke dl y i m pr o ve d o utc o mes w he n 
use d as i nit ial t hera p y i n y o u n g ot her wise health y pati e nts re q uirin g treat m e nt.
T he c h o ice of treat me nt a n d its i nte nsity at a n y  p artic ular p oi nt i n t he ma na ge me nt of t his disease 
is lar gel y d e p e nde nt u p o n pati e nt a ge, c o mor bi di ties, a bilit y t o t olerate treat me nt, prese nce of 
p o or -ris k mol ec ular feat ures, c u m ulat i ve t o xicities, a n d i n sal va ge t hera p y, t he d urati o n of t he 
res p o nse t o pri or t hera p y. Hist ori call y, t he mai n fr o nt -li ne treat me nt f or C L L was c hl ora m b ucil . 
O ver t he past 2 deca des, h o we ver, ne wer a ge nts a n d c o m bi nati o ns of c he m ot hera p y ha ve bee n 
s h o w n t o be s u peri or t o c hl ora m b ucil, b ut t hese st u dies ha ve lar gel y e xcl u de d el derl y patie nts. 
Fl u dara bi ne, be n da m ust i ne, a n d ale mt uz u ma b as si n gle a ge nts ha ve s h o w n i m pr o ve d efficac y  
c o mpare d wi t h c hlora m b ucil  w he n e val uate d i n patie nts wit h a me dia n a ge of less t ha n 6 5 years 
(Rai  2 0 0 0; Hill me n 2 0 0 7 ; C hes o n 2 0 0 9 ; K na uf 2 0 0 9 ). H o we ver, i n t he o nl y P hase 3 st u d y 
c o mpari n g fl u dara bi ne wit h c hl ora m b ucil i n a ra n d o mize d fas hi o n i n C L L patient s 6 5 years or 
ol der ( Ei c h h orst 2 0 0 9 ), t here was n o be nefit i n pr o gressi on- free s ur vi val ( P F S) ( 1 8 vers us 
1 9 m o nt hs, res pecti vel y) or i n o verall s ur vi val ( O S) ( 4 6 vers us 6 4 m o nt hs, res pecti vel y).
T he a d dit i on of c ycl o p h os p ha mi de t o fl u dara bi ne f urt her i m pr o ve d res p o nse rates a n d P F S 
c o mpare d wi t h fl u dara bi ne al o ne, b ut at t he c ost of i ncrease d t o xicity (Fli n n 2 0 0 0 , O' Brie n 2 0 0 1 , 
Eic h h orst 2 0 0 6 ; Fli n n 2 0 0 7 ). I n a lar ge P hase 3 cli nical trial f or t he first -li ne treat me nt of C L L, 
t he a d ditio n of  rit u xi ma b, a n a nti-C D 2 0 m o n o cl o n al  a nti b o d y, t o flu dara bi ne a n d 
c yclo p h os p ha mi de i n t he fr o nt -li ne setti n g res ulte d i n si g nifica nt i m pr o ve me nt i n P F S a n d O S
c o mpare d wi t h fl u dara bi ne a nd c ycl o p h os p ha mi de al o ne, wi t h a hazar d ratio f or pr o gressi o n of  
0. 5 1 ( 9 5 % CI: 0. 3 9, 0. 6 7) f or patie nts less t ha n 7 0 years o f a ge ( N= 7 3 6) ( Halle k 2 0 1 0 ; 
Casa k 2 0 1 1 ). H o we ver, t he treat me nt effect i n pat ie nts 7 0 years or older ( N = 8 1) was decrease d, 
wi t h a hazar d rati o of 1. 1 7 ( 9 5 % CI: 0. 5 1, 2. 6 6). T his tre n d of di mi nis h e d efficac y ( P F S hazar d 
r atio > 1. 0 0) was als o see n i n patie nts 7 0 years or ol der i n a sec o n d -li ne st u d y c o mpari n g t he 
sa me c o m bi nati on re gi me ns (R o ba k 2 0 1 0 ). El derl y pati e nts e x perie nce d greater t o xicit y t ha n 
y o u n ger pati e nts i n ge neral a n d wit h ri t u xi ma b— p arti c ularl y c yt o pe nias (Casa k 2 0 1 1 ).
T h us, des pite t hese a d va nces, a d dit i on al  tr e at me nt o ptio ns are desira ble — es peciall y in t he 
elderl y  p o p ulat i on i n w hic h t olera nce t o c he m ot hera pe utic a ge nts ca n be a c halle n ge.
1. 4.
S u m m ar y of N o ncli nic al D at a
1. 4. 1.
P h ar m ac ol o g y
I br uti ni b was desi g ne d as a selecti ve a n d c o vale nt i n hi bit or of t he B T K (Pa n 2 0 0 7 ). I n vit r o, 
i br uti ni b is a p ote nt i n hi bit or of B T K acti vity (I C5 0 = 0. 3 9 n M) . T he irre versi ble bi n di n g o f 
i br uti ni b t o c ystei ne-4 8 1 i n t he acti ve site of B T K res ults i n s ustai ne d i n hi bit i on o f B T K cata l ytic 
acti vit y a n d e n ha nce d se lecti vity o ver ot her ki nases t hat d o n ot c o ntai n a c ystei ne at t his p ositi o n . 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 8
W he n a d de d directl y t o h u ma n w h o le bl o o d, i br uti ni b i n hi bits si g nal tra ns d ucti on fr om t he B C R 
a n d bl oc ks act i vati on of B -cells (I C 5 0 = 8 0 n M) as assa ye d b y a nti-I g M sti m ulati on fol l owe d b y 
C D 6 9 e x pressi o n ( H er m a n 2 0 1 1).
I br uti ni b arreste d cell gr o wt h a n d i n d uce d a p o pt osis i n h u ma n B -cell l y m p h o ma cell li nes 
i n vit r o a n d i n hi bit e d t u mor gr o wt h i n vi v o i n xe n o graft m o dels ( Her m a n 2 0 1 1). I br uti ni b als o 
i n hi bite d a d hesi on a n d mi grati o n o f M C L cells i n c o -c ult ure a n d re d uce d t u m or b ur de n i n l y m p h 
n o de a n d b o ne marr o w i n a m uri ne m o del of M C L disse mi nat i on a n d pr o gressi o n ( C ha n g 2 0 1 3a , 
C ha n g 2 0 1 3 b ).
F or m ore detaile d a n d c o m pre he nsi ve i nf or mat i on re gar di n g n o ncli nical p har mac o l og y , please 
refer t o t he c urre nt I B.
1. 4. 2.
S afet y P h ar m ac ol o g y a n d T o xic ol o g y
N o treat me nt -r elate d effects were o bser ve d i n t he ce ntral ner v o us s yste m  or res pirat or y s yste m in 
rats at a n y d ose teste d. F urt her, n o treat me nt -relate d c orrecte d Q T i nter val ( Q Tc) pr ol o n gati o n 
effect was o bser ve d at a n y teste d d ose i n a car di o vasc ular st u d y usi n g tele metr y-m o nit ore d d o gs . 
Base d o n data fr o m rat a n d d o g i ncl u di n g ge neral t o xicit y st u dies u p t o 1 3 wee ks d urati o n, t he 
greatest p ote ntial f or h u ma n t o xicit y wi t h i br uti ni b is pre dicte d t o be i n l y m p h oi d tiss ues 
(ly m p h o i d de pleti on) a n d t he gastr oi ntest i nal tract (s oft feces/ diarr hea with or wit h o ut 
i nfla m matio n) . A d dit i onal t o xicit y fi n di n gs see n i n o nl y o ne s pecies wit h n o o bser ve d h u ma n 
c orrelate i n cli nical st u dies t o date i ncl u de pa ncreatic aci nar cell atr o p h y  (rat), mi ni mall y 
decrease d tra bec ular a n d c ortical b o ne (rat) a n d c or neal d ystr o p h y  ( d o g). I n st u dies i n pre g na nt 
rats a n d ra b bits, ibr uti ni b a d mi nist r atio n was ass ociate d wit h malf or mat i ons (terat o ge nicit y)  at 
ibr uti ni b d oses t hat res ult i n a p pr o xi matel y 1 4 a n d 2 ti mes t he e x p os ure ( A U C) i n patient s 
a d mi nistere d t he d ose of 5 6 0 m g dail y, res pect i vel y. Fetal  loss a n d re d uce d fetal b o d y  wei g hts 
were al s o see n i n treate d pre g na nt a ni mals. Carci n o ge ni cit y st u dies ha ve n ot bee n c o n d ucte d 
wi t h i br uti ni b. I n vitr o a n d i n vi v o ge net ic t o xicity st u dies s h o we d t hat i br uti ni b is n ot ge n ot o xic . 
N o effects o n fertilit y or re pr o d ucti ve ca pacit ies were o bser ve d i n a st u d y in male a n d fe male 
rats.
F or t he m ost u p t o date a n d c o mpre he nsi ve i nf or mati o n re gar di n g n o ncli nical safet y  
p har mac o l og y  a n d t o xic o l og y , please refer t o t he c urre nt I B.
1. 5.
S u m m ar y of Cli nic al D at a
F or t he m ost u p t o date a n d c o mpre he nsi ve cli nical i nf or mat i on re gar di n g i br uti ni b, please refer 
t o t he c urre nt versi o n of t he I B.
1. 5. 1.
P h ar m ac o ki netics a n d Pr o d uct Met a b olis m
F o ll owi n g oral  a d mi nistratio n of  i br uti ni b at d oses ra n gi n g fr o m 4 2 0 t o 8 4 0 m g/ da y, e x p os ure t o 
i br uti ni b i ncrease d pr o p orti o nall y  wi t h s u bsta ntial i nter -s u bject varia bility . T h e m ea n ter mi nal
pl as ma eli mi nat i on half -life (t1/ 2) of i br uti ni b ra n ge d fr o m 4 t o 1 3 h o urs, wit h a me dia n ti me t o 
ma xi m u m plas ma c o nce ntrati o n ( T ma x ) of 2 h o urs. Des pite t he d o u bli n g i n mea n s yste mic 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 9
e x p os ure w he n d ose d wit h f o o d, t he fa v ora ble safet y pr ofile of i br uti ni b allo ws d os i n g wi t h or 
wi t ho ut f o o d . I br uti ni b is e xte nsi vel y meta b olize d pri maril y b y c yt oc hr ome P 4 5 0 ( C Y P) 3 A 4 . 
T he o n -tar get effects of t he mai n meta b o lite P CI -4 5 2 2 7 are n ot c o nsi dere d cli nicall y rele va nt . 
Stea d y -state e x p os ure of i br uti ni b a n d P CI-4 5 2 2 7 was less t ha n 2 -f ol d of first d ose e x p os ure
i m pl yi n g n o n-cli nicall y rele va nt acc u mulat i on . Less t ha n 1 % of i br uti ni b is e xcrete d i n t he uri ne. 
I br uti ni b e x p os ure is n ot altere d i n patie nts wit h creati ni ne cleara nce ( Cr Cl) > 3 0 m L/ mi n . 
P ati e nts wit h se vere re nal i m pair me nt or patie nts o n dial ysis ha ve n ot bee n st u die d. F o ll owi n g 
si n gle d ose a d mi nistrati o n, t he A U C of i br ut i ni b i ncrease d 2. 7-, 8. 2- a n d 9. 8-f ol d i n s u bjects wit h 
mil d ( C hil d - P u g h class A), m o derate ( C hil d-P u g h class B), a n d se vere ( C hil d-P u g h cl ass C) 
he pat ic i m pair me nt c o m pare d t o s u bjects wit h n or mal li ver f u ncti on . A hi g her pr o p orti o n of 
Gra de 3 or hi g her a d verse react i ons were re p orte d i n patie nts wit h B -cell mali g na ncies ( C L L, 
M C L a n d W M) wit h mil d he pat ic i m pair me nt base d o n N CI or ga n d ysf u ncti on w or ki n g gr o u p 
( N CI-O D W G) criteria f or he patic d ysf u nct i on c o m pare d t o patie nts wit h n or mal he pat ic 
f u ncti on.
F or t he m ost c o m pre he nsi ve i nf or mati o n re gar di n g p har mac o ki netics ( P K) a n d pr o d uct 
meta b o lis m, please refer t o t he c urre nt versi on of t he I B.
1. 5. 2.
S u m m ar y of Cli nic al S afet y
A br ief s u m mar y of safety data fr o m  mo n ot hera p y  st u dies is pr o vide d bel o w. F or t he most rece nt 
a n d t he m o re c o mpre he nsi ve safet y i nf or mati o n, please refer t o t he c urre nt versi o n of t he I B. 
A d dit i onal safety i nf or mati on ma y be a vaila ble f or a p pr o ve d i n dicat i ons i n re gi onal prescri bi n g 
la bels w here t he st u d y is c o n d ucte d (e g, U S PI, S m P C).
1. 5. 2. 1.
M o n ot her a p y St u di es
I nte grate d safet y data are s h o w n f or 1, 5 2 3 s u bjects wit h B -cell mali g na ncies treate d wit h 
i br uti ni b m on ot hera p y  in 1 7 st u dies t hat ha ve c o m plete d pri mar y a nal ysis or fi nal a nal ysis as of 
t he 3 1 J ul y 2 0 1 7 c ut off date f or t he versi o n 1 1 I n vesti gat or’s Br oc h ure u p date.
T he m ost f re q ue ntl y re p orte d treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) i n s u bjects recei vi n g 
i br uti ni b as m on ot hera p y  ( N = 1, 5 2 3 ):

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 0
M ost fre q ue ntl y re p orte d T E A Es 
1 5 % a
M ost fre q ue ntl y re p orte d Gra de 
3 or 4 T E A Es 3 % a
M ost fre q ue ntl y re p orte d 
Seri o us T E A Es 2 %
b
Diarr hea
Ne utr o pe nia
P ne u m o nia
Fati g ue
P ne u m o nia
Atrial fi brillati o n
Na usea
T hr o m b oc yt o pe nia
Fe brile ne utr o pe nia
C o u g h
A ne mia
P yre xia
P yre xia
H y perte nsi o n 
A ne mia
Diarr hea
Ne utr o pe nia 
Fati g ue
U p per r es pirat or y tract i nfecti o n
Atrial fi brillati o n
T hr o m b oc yt o pe nia
Oe de ma peri p heral
M uscle s pas m
a T a ble 5 of i br uti ni b I B; b T a ble 6 of i br uti ni b I B.
1. 5. 3.
Ris ks
1. 5. 3. 1.
Blee di n g -rel ate d E ve nts
T here ha ve bee n re p orts of he m orr ha gic e ve nts i n s u bjects treate d wit h i br uti ni b, b ot h wit h a n d 
wi t ho ut t hr o m b oc y t o p e nia. T he se i ncl u de mi n or he m orr ha gic e ve nts s uc h as c o nt usio n, e pista xis ,
a n d petec hiae; a n d maj or he m orr ha gic e ve nts, s o me fatal, i ncl u di n g gastr oi ntesti nal blee di n g, 
s u b d ural i ntracra nial he m orr ha ge , a n d he mat uria. Use of i br ut i ni b i n s u bjects re q uirin g ot her 
a nt ic oa g ula nts or me dicat i ons t hat i n hi bit platelet f u nct i on ma y i ncrease t he ris k of blee di n g. 
S u bjects wit h c o n ge nital blee di n g diat hesis ha ve n ot bee n st u die d . See Secti o n 5. 5. 3 f or g uida nce 
o n c o nc o mita nt use of a ntic oa g ula nts, a nti platelet t hera p y a n d / or s u p ple me nts. See Secti o n 5. 6
f or g uida nce o n i br ut i ni b ma na ge me nt wit h s ur geries or pr oce d ures.
1. 5. 3. 2.
C ar di ac Arr h yt h mi as a n d C ar di ac F ail ure
At rial fi brillati on, atrial fl utter, car diac fail ure a n d cases o f ve ntri c ular tac h yarr h yt hmia i ncl u di n g 
s o me fatal e ve nts, ha ve bee n re p orte d i n s u bjects treate d wit h i br uti ni b, partic ularl y i n s u bjects 
wi t h car dia c ris k fact ors, h y perte nsi o n, ac ute i nfecti o ns, a n d a pre vi o us hist or y  of car diac 
arr h yt h mia. P eri o di call y mo ni t or s u bjects cli nicall y for car diac arr h yt h mia. S u bjects w h o 
de vel o p arr h yt h mic s y m pt o m s (e g, palpi t atio ns, li g ht hea de d ness , s y nc o pe, c hest disc omf o rt or 
ne w o nset of d y s p nea) s h o uld be e val uate d cli nicall y , a n d if i n dicate d, ha ve a n E C G perf or me d. 
F or car diac arr h yt h mias w hic h persists, c o nsi der t he ris ks a n d be nefit s of i br uti ni b thera p y , a n d 
f oll ow t he pr ot oc ol d ose m o dificati o n g ui deli nes (see Secti o n 5. 2. 3 ).
1. 5. 3. 3.
R as h
Ras h has bee n c o m m o nl y re p orte d i n s u bjects treate d wit h eit her si n gle a ge nt i br uti ni b or i n 
c o m bi nat i on wi t h c he mot h era p y. M ost ras hes were mil d t o m o derate i n se verit y . Is olate d cases 
of  se vere c uta ne o us a d verse reacti ons ( S C A Rs) i ncl u di n g Ste ve ns -J o h ns o n s y n dr ome ( SJ S) ha ve 
bee n re p orte d i n s u bjects treate d wit h i br ut i ni b. S u bjects s h o ul d be cl osel y m o ni t or e d for si g ns 
a n d s y m pt o ms s u g gest i ve of S C A R i ncl u di n g SJ S. S u bjects r ecei vi n g i br ut i ni b s h o ul d be 
o bser ve d cl osel y  for ras hes a n d treate d s y m pt o maticall y, i ncl u di n g i nterr u pti o n of t he s us pecte d 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 1
a ge nt as a p pr o priate. I n a d diti on, h y perse nsit i vity- r elate d e ve nts i ncl u di n g er yt he ma, urticaria, 
a n d a n gi oe de ma ha ve bee n re p orte d.
1. 5. 3. 4.
N o n -mel a n o m a s ki n c a ncer
N o n -me la n oma s ki n ca ncers ha ve occ urre d i n s u bjects treate d wit h i br uti ni b . M o ni t or s u bjects 
f or t he a p peara nce of n o n-me la n oma s ki n ca ncer.
1. 5. 3. 5.
I nfecti o ns
Infecti o ns (i ncl u di n g se psis, bacterial, viral, or f u n gal i nfect i ons) were o bser ve d i n s u bjects 
treate d wit h i br uti ni b t hera p y. S o m e of t hese re p orte d i nfecti ons ha ve bee n ass ociate d wit h 
h os pi talizatio n a n d deat h . Alt h o u g h ca usalit y has n ot bee n esta blis he d, cases of pr o gressi ve 
m ult if oc al le u k oe nce p hal o pat h y ( P M L) a n d he pat itis B reacti vati on ha ve occ urre d i n s u bjects 
treate d wit h i br uti ni b. S u bjects s h o ul d be m o nit ore d f or s y m pt o ms (fe ver, c hills, wea k ness, 
c o nf usi o n , v o mit i n g a n d ja u n dice) a n d a p pr o priate t hera p y s h o uld be i nst itute d as i n dicate d.
1. 5. 3. 6.
C yt o pe ni as
Treat me nt -e mer ge nt Gra de 3 or 4 c yt o pe nias ( ne utr o pe nia, t hr o m b oc yt o pe nia, a n d a ne mia) were 
re p orte d i n s u bjects treate d wit h i br uti ni b. S u bjects s h o ul d be m o nit ore d f or fever, wea k ness, or
eas y br uisi n g a n d/ or blee di n g.
1. 5. 3. 7.
I nterstiti al L u n g Dise ase (I L D)
Cases of i nterstit ial l u n g disease (I L D) ha ve bee n re p orte d i n s u bjects treate d wit h ibr ut i ni b. 
M o ni t or s u bjects f or p ul m o nar y s y m pt o ms i n dicati ve of I L D. S h o ul d s y m pt o m s de vel o p, f oll ow 
t he pr ot oc ol d ose m o dificati on g ui deli nes (see Secti o n  5. 2. 3 ).
1. 5. 3. 8.
T u m or L ysis S y n dr o me
T here ha ve bee n re p orts of t u m or l ysis s y n dr o me ( T L S) e ve nts i n s u bjects treate d wit h
si n gle-a ge nt i br uti ni b or i n c o m bi nat i on wi t h c he m ot hera p y. S u bjects at ris k o f T L S are t h ose 
wi t h c o mor bi di ties a n d/ or ris k fact ors s uc h as hi g h t u m or b ur de n pri or t o treat me nt, i ncrease d 
uri c acid ( h y per uri ce mia), ele vate d lactate d e h y dr o ge nase ( L D H), b ul k y disease at baseli ne, a n d 
pre -e xist i n g ki d ne y a b n or malities.
1. 5. 3. 9.
Di arr he a
Di arr hea is t he most fre q ue nt l y re p orte d n o n-he mat ol o gi c A E wit h ibr ut i ni b m o n ot hera p y a n d 
c o m bi nat i on t hera p y . Ot her fre q ue nt l y re p orte d gastr oi ntesti nal e ve nts i ncl u de na usea, v omit i n g, 
a n d c o nst i pati on . T hese e ve nts are rarel y se vere . S h o ul d s y m pt o ms be se vere or pr ol o n ge d ,
f oll ow t he pr ot oc ol d ose m o dificati o n g ui deli nes (see Secti o n 5. 2. 3 ).
1. 5. 3. 1 0.
H y perte nsi o n
H y perte nsi o n has bee n c o m m o nl y  re p orte d i n s u bjects treate d wit h i br uti ni b. M o ni t or s u bjects 
f or ne w o nset of h y perte nsi on or h y perte nsi o n t hat is n ot a de q uatel y  c o ntr olle d after startin g 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 2
i br uti ni b. A d j ust e xisti n g a nti-h y perte nsi ve me dicati o ns a n d/ or i nit iate a nti-h y perte nsi ve 
treat me nt as a p pr o priate.
1. 5. 3. 1 1.
Le u k ost asis
T here were i s olate d cases of le u k ostasis re p orte d i n s u bjects treate d wit h i br uti ni b . A hi g h 
n u m ber of circ ulat i n g l y m p h oc ytes ( > 4 0 0, 0 0 0/ µ L) ma y c o nfer i ncrease d ris k . F or s u bject a n d 
i br uti ni b ma na ge me nt g ui da nce, refer t o Secti o n 5. 2. 3 .
1. 5. 3. 1 2.
L y m p h oc yt osis
U p o n i nit iati on of treat m e nt, a re versi ble i ncrease i n l y m p h oc yte c o u nts (ie, ≥5 0 % i ncrease fr o m 
baseli ne a n d a n a bs o l ute c o u nt > 5 0 0 0/ µ L), ofte n ass ociate d wit h re d ucti o n o f l y m p ha de n o pat h y, 
has bee n o bser ve d i n m o st s u bjects wit h C L L/s mall l y m p h oc ytic l y m p h o ma ( S L L) treate d wit h 
i br uti ni b. T his effect has als o bee n o bser ve d i n s o me s u bjects wit h M C L treate d wit h i br ut i ni b. 
T his o bser ve d l y m p h oc y t osis (i ncrease i n t he n u m ber of circ ulat i n g l y m p h oc ytes e g, 
> 4 0 0, 0 0 0/ µ L) is a p har mac o d y na mic effect a n d s h o ul d n ot be c o nsi dere d pr o gressi ve diseas e i n 
t he a bse nce of ot her cli nical fi n di n gs. I n b ot h disease t ypes, l y m p h oc y t osis ty p icall y occ urs 
d uri n g t he firs t fe w wee ks of i br ut i ni b t hera p y a n d t ypicall y  res ol ves wit hi n a me dia n of 
8. 0 wee ks i n s u bjects wit h M C L a n d 1 4 wee ks i n s u bjects wit h C L L/ S L L . T his 
p har mac o d y na mic effect was less pr o mi ne nt or n ot o bser ve d i n ot her i n dicat i ons.
F or s u bject a n d i br uti ni b ma na ge me nt g ui da nce, refer t o Secti o n 5. 2. 4 .
1. 5. 4.
P h ar m ac o d y n a mic Effect Le a di n g t o C h ar acteristic P atter n of Res p o nse
Precli nical st u dies ha ve re veale d a vital a n d m ult ifacete d r ole for B T K a n d t he B C R -si g nali n g 
pat h wa y  in B- cell le u ke m o ge nesis a n d l y m p h o ma g e nesis. T hese data s u g ge st t hat t he bl oc ka de 
of  t he B C R -si g nali n g pat h wa y b y i br uti ni b i n C L L res ults i n 3 ma j or effects: ( 1) direct i n d uct i on 
of  a p o pt osis, (2) i n hi bit i on of cell h o mi n g a n d mi grati o n t o c he m o ki nes wit h s u bse q ue nt 
a d hesi o n t o cell ular s u bstrates, a n d (3) i n hi bit i on of pr o liferati on ( H er ma n 2 0 1 1 ; 
P o na n der 2 0 1 2 ). O wi n g t o t he descri be d mec ha nis m o f act i on of B T K i n hi bit i on, a d mi nistrati o n 
of  i br uti ni b t o patie nts wit h ly m p h o pr oliferat i ve diseases has bee n ass ociate d wit h m obilizati o n 
of  t um o r cells fr om tiss ue t o perip heral bl o o d ( C ha n g 2 0 1 1 ; B ur ger 2 0 1 0 ; P oll yea 2 0 0 9 ).
T his effect be gi ns i n s o me cases wit hi n h o urs of t he first a d mi nistrati o n a n d t y p icall y reac hes 
pea k m a g nit u d e wit hi n t he first 3 mo nt hs of treat me nt . C o i nci de nt wit h t he i br uti ni b 
treat me nt -relate d l y m p h oc yt osis is a ra pid a n d s u bsta nti al decrease i n l y m p h n o de a n d/ or s plee n 
size ofte n o bser ve d wit h or wit h o ut a n i m pr o ve me nt i n he mat ol o gic para meters a n d/ or 
s y m pt o mat ic i m pr o ve me nt of disease-relate d s y m pt o ms. T his effect was n ote d i n C L L/ S L L 
pati e nts treate d o n b ot h P C Y C -0 4 7 5 3 a n d P C Y C - 1 1 0 2-C A ( Fi g ure 1 ).

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C -1 1 1 6 -C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 3
Fi g ure 1:
C h a n ges i n Peri p her al Bl o o d L y m p h oc yte C o u nts a n d B ur de n of 
L y m p h a de n o p at h y i n P atie nts wit h C L L/ S L L, St u d y P C Y C -1 1 0 2 -C A
A L C = a bs ol ute l y m p h oc yte c o u nt; R/ R = rela pse d/refract or y; S P D = s u m of pr o d ucts of l ym p h n o de di me nsi o n ; 
T N =treat me nt nai ve
T his p he n o me n o n is a p har mac o d y na mic effect of i br uti ni b, i n w hic h t he i n hi biti on of 
B T K -me diate d cell ular h o mi n g a n d a d hesi o n res ults i n a m o bilizat i on of C L L cells fr o m t he 
l y m p h n o de t o t he peri p heral bl o o d c o m part me nt . T his patter n of res p o nse ha d pre vi o usl y bee n 
n o te d wit h ot her a ge nts k n o w n t o i n hi bit B C R si g nali n g (Fr ie d ber g 2 0 0 8 ; F ur ma n 2 0 1 0 ). T his 
treat me nt -relate d l y m p h oc yt osis res ol ves o ver a varia ble p eri o d of  ti me ( me dia n 6 mo n t hs) wit h 
t he maj orit y of patient s meeti n g I W C L L 2 0 0 8 criteria f or res p o nse wit h c o nti n ue d i br uti ni b 
t hera p y (O’ Brie n 2 0 1 1 ). As s uc h, a n i ncrease i n t he n u m ber of circ ulat i n g l y m p h oc ytes i n t he 
p eri p h eral blo o d i n t he a bse nce of s y m pt o ms or ot her i n dicat ors of pr o gressi ve disease has n ot 
bee n c o nsi dere d a n i n dicat or of pr o gressi ve disease b y t he i n vesti gat ors i n cli nical st u dies wit h
i br uti ni b. T his is c o nsiste nt wit h t he rec o m me n dat i o n of c urre nt Natio n al C o mpre he nsi ve Ca ncer 
Net w or k ( N C C N) N H L 2 0 1 6 g ui deli ne a n d t he clarificat i on of t he I W C L L 2 0 0 8 criteria b y  its 
a ut h ors ( Halle k 2 0 1 2 ).
1. 6.
R ati o n ale f or Tri al
I br uti ni b has de m o nstrate d pr o misi n g act i vity i n st u dies e nr o lli n g ol der patie nts wit h treat me nt-
nai ve or rel a pse d/refract or y C L L a n d old er p ati e nts wit h S L L. T he pare nt st u d y , 
P C Y C -1 1 1 5 -C A, e val uates i br uti ni b i n tr e at me nt -nai ve el derl y pat ient s wit h C L L or S L L. T hi s 
o pe n -label e xte nsi o n st u d y  pr o vi des o pti o n s for c o nti n ue d treat me nt a n d f oll o w -u p of pati e nts 
ra n d omize d i n t he pare nt st u d y.
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 4
M o d el e d after t he desi g n o f t he pi v otal st u d y of i mati ni b, I RI S, i n c hr o nic p hase C M L 
(O’ Brie n 2 0 0 3 ), p atie nts i n P C Y C- 1 1 1 6-C A will be all o we d t o recei ve t he i n vesti gat or’s c h oice 
of  sec o n d-li ne t hera p y if cli nicall y i n dicate d a n d I R C P D has bee n c o nfir me d, i ncl u di n g a n 
o pti o n f or i br uti ni b f or rela pse d C L L/ S L L patie nts. Patie nts a ge d 6 5 or ol der w h o e x perie nce 
pr o gressi o n wi t hi n 1 2 m o nt hs of last d ose of c hl ora m b ucil ha ve a hi g her ris k of earl y deat h 
c o mpare d t o t h ose wi t h lo n ger re missi o ns ( Cat o vs k y  2 0 0 7). Patie nts w h o ha ve ac q uire d a 
d el et i on of t he s h ort c hr o m os o me of 1 7 ( del 1 7 p) d uri n g or f o ll owi n g treat m e nt wit h 
c hl ora m b ucil w o ul d als o n ot be c o nsi dere d a p pr o priate f or fl u dara bi ne or al k ylat i n g base d 
t hera p y. I n t hese hi g h-ris k p o p ulat i ons, t he use of i n vesti gati o nal a ge nts is j ust ifie d d ue t o t he 
pa uci t y of data t o s u p p ort safe a n d effecti ve c o m merciall y a vaila ble t hera pies i n t he rela pse d 
elderl y  or fr ail C L L patie nts, eit her wit h mo n ot hera p y  (Hill me n 2 0 0 7 , Ei c h h orst 2 0 0 9, 
K na uf 2 0 0 9 ) or wit h c o m bi nat i on t h era pies ( Casa k 2 0 1 1 , Fisc her 2 0 1 1 ). I n C L L patient s wit h d el 
1 7 p, effect i ve treat me nt o pti o ns are e ve n m ore li mite d; ale mt uz u ma b has de m o nstrate d efficac y, 
b ut t he safet y pr ofile wi t h se vere c yt o p e nias a nd i nfect i ous c o m plicat i ons has precl u de d its safe 
use i n t he el derl y p o p ulat i on ( L oza ns ki 2 0 0 4 ).
2.
S T U D Y O B J E C TI V E S

T o m o ni t or P F S

T o c o nti n ue treat me nt a n d safet y assess me nt of patie nts ra n d o mize d t o Ar m B ( i br uti ni b) i n 
St u d y  P C Y C - 1 1 1 5-C A (t he pare nt st u d y ) w h o ha ve n ot pr o gresse d at t he ti me of pare nt st u d y 
clos ure

T o f o ll ow pati e nts for l o n g -t er m o ut c o me

T o ca pt ure o verall res p o nse rate ( O R R), d urati o n of res p o nse ( D O R), P F S, a n d O S , a n d ti me 
t o ne xt t hera p y

T o f ulfill l o n g -ter m fol l ow- u p re q uire me nts of ra n d o mize d pat ient s after cl os ure of t he pare nt 
st u d y, i ncl u di n g O S
3.
S T U D Y D E SI G N
T his o pe n -label e xte nsi o n st u d y  pr o vides o n g oi n g treat m e nt a n d f oll ow- u p f or el d erl y pat ient s 
wi t h C L L or S L L w h o were pre vi o usl y e nr olle d i n t he pare nt st u d y , P C Y C - 1 1 1 5-C A . P atie nts 
w h o were ra n d o mize d i n t he pare nt st u d y are tra nsferre d t o t his e xte nsi o n st u d y w he n t he y
e x perie nce i n de pe n de nt re vie w c o m mittee (I R C)-c o nfir me d pr o gressi ve disease (P D ) or w he n 
t he pare nt stu d y is cl ose d b y t he S p o ns or , as descri be d i n Ta ble 1 .

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 5
T a ble 1 : 
P atie nt Tr a nsfer t o St u d y P C Y C- 1 1 1 6-C A a n d Assess me nts wit hi n 
P C Y C -1 1 1 6- C A
St at us at Tr a nsfer fr o m 
P are nt St u d y, P C Y C - 1 1 1 5-C A
Assess me nts After Tr a nsfer t o 
E xte nsi o n St u d y, P C Y C -1 1 1 6 -C A
P C Y C - 1 1 1 5-C A Ar m A or B Patie nts :  
I R C-c o nfir me d P D i n pare nt st u d y


Sc he d ule of assess me nts is base d o n ma na ge me nt decisi o n:
  N o t hera p y:  See A p pe n di x D
  Sec o n d -li ne i br uti ni b (if eli gi ble) ‡:  See A p pe n di x C
  Sec o n d -li ne n o n-i br uti ni b t hera p y:  See A p pe n di x D
P C Y C - 1 1 1 5-C A Ar m A Patie nts :  
C o m pleti o n of 1 2 c ycles of 
c hl ora m b ucil, a n d n o P D at cl os ure 
of pare nt st u d y
O R 
Disc o nti n uati o n of ra n d o mize d 
treat me nt f or a r eas o n ot her t ha n P D, 
a n d n o P D at cl os ure of t he pare nt 
st u d y


Bef ore P D, sc he d ule of assess me nts is i n A p pe n di x A ;
After P D, sc he d ule of assess me nts is base d o n ma na ge me nt decisi o n:
  N o t hera p y:  See A p pe n di x D
  Sec o n d -li ne i br uti ni b (if eli gi ble) ‡:  See A p pe n di x C
  Sec o n d -li ne n o n-i br uti ni b t hera p y:  See A p pe n di x D
P C Y C - 1 1 1 5-C A Ar m B Patie nts :  
O n g oi n g treat me nt wit h i br uti ni b, a n d 
n o P D at cl os ure of pare nt st u d y
O R
Disc o nti n uati o n of ra n d o mize d 
treat me nt f or a reas o n ot her t ha n P D, 
a n d n o P D at cl os ure of t he pare nt 
st u d y


Bef ore P D, sc he d ule of assess me nts is i n A p pe n di x B ; 
After P D, sc he d ule of assess me nts is as f oll o ws:
  N o t hera p y:  See A p pe n di x D
  Sec o n d -li ne n o n-i br uti ni b t hera p y:  See A p pe n di x D
Ar m A =c hl ora m b ucil i n P C Y C -1 1 1 5 -C A; Ar m B = i br uti ni b i n P C Y C-1 1 1 5 -C A; I R C =I n de pe n de nt Re vie w 
C o m mittee; n o n -i br uti ni b = alter nati ve a ntica ncer treat me nt ot her t ha n i br uti ni b; P D = pr o gressi ve disease
N ote : Alter nati ve a ntica ncer treat me nt is selecte d at t he i n vesti gat or’s discreti on . F or a patie nt ra n d o mize d t o 
c hl ora m b ucil i n t he pare nt st u d y, i br uti ni b is a n o pti o n f or sec o n d-li ne t hera p y, pr o vi de d t he patie nt meets t he criteria 
f or sec o n d-li ne i br uti ni b t hera p y (Secti o n 4. 2 )‡. F or a patie nt ra n d o mize d t o i br uti ni b i n t he pare nt st u d y, 
c hl ora m b ucil is a n o pti o n f or sec o n d -li ne t hera p y.
Treat me nt o pti o ns i n t his e xte nsi o n st u d y var y  de pe n di n g o n t he treat me nt t o w hic h t he patie nt 
was ra n d o mize d i n t he pare nt st u d y, t he disease -pr o gressi o n stat us at tra nsfer t o t he e xte nsi o n 
st u d y, a n d t he pla n ne d treat me nt i n t he e xte nsi on st u d y . C h o ice of sec o n d-li ne alter nati ve 
a nt ica ncer treat me nt is at t he cli nical j u d g me nt of t he i n vesti gat or. Treat me nt ca n be wit h 
i br uti ni b (for pati e nts ra n d o mize d t o c hl ora m b ucil i n t he pare nt st u d y w h o f ulfill t he criteria f or 
sec o n d-li ne i br uti ni b [Secti o n 4. 2 ]‡), c hl ora m b ucil (f or patie nts ra n d o mize d t o i br uti ni b i n t he 
pare nt st u d y ), or ot her t hera pies. I n a d diti on, a n y pati e nt ca n elect n ot t o u n der g o f urt her 
a nt ica ncer treat me nt.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 7
D osi n g i n t his st u d y is as f oll o ws:

P ati e nts c o nti n ui n g o n first -li ne i br uti ni b t hera p y e nter t his st u d y at t heir c urre nt t olerate d 
d ose . D o se a dj ust me nt , if re q uire d, is descri be d i n Secti o n 5. 2. 3 .

P ati e nts i nitiati n g sec o n d -li ne i br uti ni b t hera p y‡ start treat me nt at a d ose of 4 2 0 m g/ d a y. D ose 
re d uctio n , if r e q uire d is descri be d i n Sect i on 5. 2. 3 .

T he d ose (s) a n d treat me nt re gi me n(s) f or ot her alt er nat i ve a ntica ncer treat me nt   w hic h 
c o uld be c hl ora m b ucil, f or patie nts i nit iall y ra n d o mize d t o i br uti ni b
is selecte d b y t he 
i n vesti gat or i n li g ht of t he c urre nt sta n dar d of care.
P atie nts recei vi n g first -li ne or sec o n d -li ne i br uti ni b t hera p y ‡ i n t he e xte nsi on st u d y  will be 
f oll owe d f or safet y,  res p o nse (i ncl u di n g disease pr o gressi o n ), a n d s ur vi val. A ssess me nts i n 
s pecific s u b gr o u ps of  p atie nts are descri be d i n detail i n t he sc he d ules of assess me nts:
A p pe n di x A , assess me nts bef ore P D i n pat ient s ra n d omize d t o c hl ora m b ucil; A p pe n di x B , 
assess me nts bef ore P D i n patie nts ra n d o mize d t o i br uti ni b; A p pe n di x C , assess me nts after P D i n 
pa tie nts o n sec o n d -li ne i br uti ni b‡ ; a n d A p pe n di x D , assess me nts after P D i n patient s o n 
a nt ica ncer treat me nt ot her t ha n i br uti ni b (ie, n o n- i br uti ni b), or n o treat me nt .
U nli ke t he pare nt st u d y , i n t his e xte nsio n  st u d y, P D is esta blis he d by t he i n vesti gat or; t here is n o 
c o nfir mat i on of  P D b y a n I R C.
At  t he i n vesti gat or’s discreti on, pati e nts recei vin g sec o n d -li ne i br uti ni b t hera p y ‡ w h o ac hie ve a n d 
retai n M R D-ne gat i ve re missi on f or 6 c ycle s (i ncl u di n g 2 se q ue ntial M R D -ne gat i ve assess me nts 
at least 2 c ycles a part t hat i ncl u de at least o ne b o ne marr o w as pirate) ca n ha ve t heir i br uti ni b 
di sc o nti n ue d. If sec o n d-li ne i br utini b is disc o nti n ue d, t he s u bject will be f o ll ow e d f or M R D 
rec urre nce b y peri p heral bl o o d m o nit ori n g a p pr o xi matel y e ver y 6 c ycles; i br ut i ni b thera p y ma y
b e rei nit iate d i n t he e ve nt of rec urre nce of M R D p ositi ve stat us or cli nical pr o gressi o n.
F o ll owi n g i m ple me ntati o n of Pr ot oc ol  A me n d me nt 3, re-i nitiati o n of i br uti ni b t hera p y will n o 
l on ger be per mitt e d as part of t he P C Y C- 1 1 1 6-C A S t u d y. S uc h t hera p y  ca n o nl y be d o ne wit h 
c o m mercial dr u g s u p pl y or as part of t he se parate l o n g-t er m i br uti ni b e xte nsi o n st u d y if a s u bject 
meet s t he eli gi bilit y cri t eria.
3. 1.
Criteri a f or Tr a nsfer t o T his E xte nsi o n St u d y
P ati e nts w h o de m o nstrate I R C -c o nfir me d disease pr o gressi o n i n t he pare nt st u d y ( eit her o n 
ra n d omize d treat me nt or d uri n g f o ll ow- u p) will  c o m plete a n e n d-of -treat me nt visit u p t o 3 0 da y s 
after treat me nt disc o nt i n uati on a n d will t he n be tra nsferre d t o t he e xte nsi o n st u d y,
P C Y C - 1 1 1 6-C A.
If treat me nt is disc o nti n ue d i n t he a bse nce of I R C-c o nfir me d pr o gressi o n (ie , for a n A E, or 
wi t hdra wal  fr o m treat me nt b y t he patie nt or i n vesti gat or’s decisi on), pati e nts will re mai n i n t he 
pare nt st u d y  t o mo ni t or for fi rst pr o gressio n .

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 8
A n y pat ient  w h o wit hdra ws c o nse nt fr o m St u d y  P C YC- 1 1 1 5- C A will be i neli gi ble f or t he 
e xte nsi o n st u d y .
At  t he ti me of pare nt st u d y clos ure, all re mai ni n g patie nts will be tra nsferre d t o t he e xte nsi o n 
st u d y f or c o nti n ue d f oll ow - u p.
Sec o n d -li ne treat me nt, if cli nicall y i n dicate d, will be at t he i n vesti gat or’s discreti on . Ar m A 
pati e nts (ie, ra n d o mize d t o c hl ora m b ucil) w h o pr o gress a n d wis h t o i nitiate sec o n d-li ne treat me nt 
wi t h i br uti ni b i n t he e xte nsio n  st u d y m ust m eet all s pecific criteria i n S e cti o n 4. 2 ‡.
4.
S E L E C TI O N O F P A TI E N T S 
T his st u d y  is desi g ne d t o e nr oll patient s w h o were ra n d omize d i n t he pare nt S t u d y 
P C Y C - 1 1 1 5-C A.
4. 1.
Eli gi bilit y Criteri a
T o e nr oll i n St u d y  P C Y C-1 1 1 6- C A, pati e nts must meet all o f t he f o ll owi n g cri t eria:
1.
Ra n d o mize d i n t he pare nt st u d y , P C Y C-1 1 1 5- C A
2.
I nf or me d c o nse nt f or St u d y P C Y C-1 1 1 6- C A
3.
I R C-c o nfir me d P D i n t he pare nt st u d y or clos ure of t he pare nt st u d y
4. 2.
A d diti o n al Criteri a f or Recei vi n g Sec o n d- li ne Ibr uti ni b ‡
(N ote: s ec o n d-li ne tre at me nt wit h i br uti ni b will n o l o n ger be i niti ate d f oll o wi n g 
i m ple me nt ati o n of Pr ot oc ol A me n d me nt 3)
T o recei ve sec o n d -li ne ibr ut i ni b, p atie nts must m eet all of t he f oll owi n g cri t eria:
1.
I R C- c o nfir me d disease pr o gressi o n i n t he pare nt st u d y ( P C Y C- 1 1 1 5-C A), or f or patie nts 
w h o di d n ot pr o gress i n t he pare nt st u d y , i n vesti gat or-deter mi ne d disease pr o gressi o n i n t he 
e xte nsi o n st u d y ( P C Y C-1 1 1 6- C A)
2.
Recei ve d at least 3 c y cles of c hl ora m b ucil t hera p y
3.
D oc u m e nte d, pr ot oc ol- defi ne d reas o n f or c hl ora m b ucil disc o nti n uati on:

N o e vi de nce of  res p o nse i n ra dio gra p hicall y assesse d disease para meters at C ycle 5 
c o mpare d t o baseli ne; n o f urt her res p o nse ( defi ne d as fail ure t o reac h at least a P R, or a 
pl atea u of res p o nse wit h n o f urt her i m pr o ve me nt of disease para meters) after at least 
6 c ycles; c o uld n ot t ol erate treat me nt (a sit u atio n defi ne d b y t he rec urre nce of t o xicit y of  
at least Gra de 3 de s pite a p pr o priate d ose re d ucti o ns a n d o pti mal s y m pt o mat ic 
ma na ge me nt); or ma xi m u m treat me nt of 1 2 c y cles wit h c hlora m b ucil
4.
D e m o nstrates c o n ti n uatio n of  a de q uate or ga n f u ncti on, perf or ma nce stat us, a n d ot her 
criteria, as f oll ows:

Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) stat us of 0 - 2

A de q uate he mat ol o gic f u nct i on, defi ne d as a bs o l ute ne utr o p hil c o u nt ( A N C ) ≥0. 7 5 x 
1 0 9/ L (i n de pe n de nt of gr o wt h fact or s u p p ort i n t he prece di n g 7 da ys) a n d platelet c o u nt 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 9
≥3 0 x 1 0 9/ L (i n de pe n de nt of tra nsf usi on or gr o wt h fa ct o r s u p p ort i n t he prece di n g 
7 d a y s)

A de q uate he pat ic f u ncti o n, defi ne d as ser u m as partate tra nsa mi nase ( A S T) a n d ala ni ne 
tra nsa mi nase ( A L T) < 2. 5 x u p per li mit of n or m al ( U L N), a n d t otal bilir u bi n ≤1. 5 x U L N
( u nless d ue t o Gil bert's s y n dr ome)

A de q uate re na l f u ncti on, defi ne d as a n est i mate d gl omer ular filtrat i on rate ≥3 0 m L/ mi n 
usi n g t he C oc kcr oft -Ga ult e q uatio n

P ati e nts must ha ve rec o vere d fr o m ac ute t o xicit ies d ue t o prior c he m ot h era p y, 
r a diot h era p y, i n vesti gati onal dr u gs or e x peri me ntal treat me nts ( n o n -he mat ol o gic 
t o xicities ha ve res o l ve d t o a N CI C T C A E [versi o n 4. 0 3 ] Gra de of ≤2) pri or t o recei vi n g 
ne xt li ne i br uti ni b o n t hi s st u d y
5.
Meets at least 1 of t he I nter nati o nal W or ks h o p o n C hr o nic L y m p h oc y tic Le u ke mia 
(I W C L L) criteria f or acti ve disease re q uirin g treat me nt ( Halle k 2 0 0 8 ):

E vi de nce of pr o gressi ve marr o w fail ure as ma nifeste d b y  t he de vel o p me nt of, or 
w orse ni n g of, a ne mia ( he m o gl o bi n < 1 0 g/ d L), a n d/ o r t hr o m b oc yt o pe nia ( platelets 
< 1 0 0, 0 0 0/ L)

Massi ve ( ≥6 c m bel o w t he left c ostal mar gi n), pr o gressi ve, or s y m pt o mat ic 
s ple n o me gal y

Massi ve n o des (at least 1 0 c m l o n gest dia meter), pr o gressi ve, or s y m pt o matic 
l y m p ha de n o pat h y

Pr o gressi ve l y m p h oc y t osis wit h a n i ncrease of m ore t ha n 5 0 % o ver a 2-m o nt h peri o d or a 
l y m p h oc yte d o u bli n g ti me ( L D T) of < 6 m o nt hs . L D T ma y be o btai ne d b y li near 
re gressi o n e xtra p olati on of a bs o l ute l y m p h oc yte c o u nts o btai ne d at i nter vals of 2 wee ks 
o ver a n o bser vat i on peri o d of  2 t o 3 mo nt hs . I n patie nts wit h i nitial bl o o d l y m p h oc y t e 
c o u nts of < 3 0, 0 0 0/ L, L D T s h o ul d n ot be use d as a si n gle para meter t o defi ne i n dicat i on 
f or treat me nt . I n a d diti on, fact ors c o ntri b uti n g t o l y m p h oc yt osis or l y m p ha de n o pat h y 
ot her t ha n C L L (e g, i nfect i ons) s h o ul d be e xcl u de d.

A ut oi m m u ne he m o l ytic a ne mia a n d/ or i m m u ne t hr o m b oc yt o p e nia (see defi nit i ons bel o w) 
t hat is p o orl y res p o nsi ve t o c ortic oste r oids or ot her sta n dar d t hera p y .
(Defi nit i ons : A ut oi m m u ne he m o l ytic a ne mia is defi ne d b y at least 1 mar ker of he mol ys is 
[in direct bilir u bi n a b o ve t he U L N n ot d ue t o li ver disease, i ncrease d lactate 
de h y dr o ge nase [a b o ve U L N] wit h o ut alter nat i ve eti ol og y , or i ncrease d a bs olute 
r etic ulo c y t osis [a b o ve U L N] or b o ne m arr o w er yt hr o p oiesis i n t he a bse nce of blee di n g] 
A N D at least 1 mar ker of direct or i n direct a ut oi m m u ne mec ha nis m [ p osit i ve direct 
a nt i gl ob uli n f or I g G or C 3 d, c ol d a g gl ut i ni ns] [Di n g 2 0 0 7 ]. A ut oi m m u ne 
t hr o mb oc y t o pe nia is defi ne d b y platelets ≤1 0 0, 0 0 0/ L a n d i ncrease d me ga kar y oc ytes o n 
t he b o ne marr o w e xa mi nat i on.)

C o nst itut i onal s y m pt o m s, defi ne d as 1 or more of t he f o ll owi n g disease -relate d s y m pt o ms 
or si g ns, d oc u me nte d i n t he patie nt’s rec or d pri or t o ra n d o mizat i on:
o
U ni nte nti o nal wei g ht l oss > 1 0 % wit hi n 6 m o nt hs pri or t o S cree ni n g
o
Si g nifica nt fati g ue (i na bilit y t o w or k or perf or m us ual acti vities)
o
Fe vers > 1 0 0. 5° F or 3 8. 0° C f or 2 or m ore wee ks pri or t o S cree ni n g wit h o ut e vi de nce of 
i nfecti o n

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 0
o
Ni g ht s weats f or m ore t ha n 1 m o nt h pri or t o S cree ni n g wit h o ut e vi de nce of i nfecti o n
6.
O btai ne d t he S p o ns or ’s a p pr o val f or sec o n d-li ne i br utini b tr e at me nt .
T o recei ve sec o n d -li ne i br uti ni b, p atie nts m ust n ot meet a n y of t he f oll o wi n g criteri a:
1.
Di sease pr o gressio n i n v o l vi n g t he ce ntral ner v o us s yste m ( C N S ) or tra nsf or m at i on t o 
a n ot her hist ol o g y
2.
I nter ve ni n g c he m ot hera p y, i m m u n ot hera p y, or i n vestig ati o n al  a ge nt s pecificall y t o treat 
C L L if a d mi nistere d bef ore date of I R C c o nfir me d pr o gressi ve disease
3.
I n t he 4 wee ks bef ore d osi n g, ra diati on t hera p y, m ajor s ur ger y , or receipt of  a n 
i n vesti gati onal dr u g
4.
Re q ui re me nt f or treat me nt wit h a str o n g C Y P 3 A i n hi bit or
5.
U nc o ntr olle d s yste mic i nfecti o n or re q uire me nt f or i ntra ve n o us (I V) a nti bi otics
6.
N o nc o m plia nce o n t he pare nt st u d y
5.
T R E A T M E N T S
Bef ore i m ple me ntati o n of  A me n d me nt N o. 3:
C h o ice of sec o n d-li ne alter nati ve a ntica ncer treat me nt is at t he cli nical j u d g me nt of t he 
i n vesti gat or. S ec o n d-li ne treat me nt ca n i ncl u de i bruti ni b (for p ati e nts ra n d o mize d t o 
c hl ora m b ucil i n t he pare nt st u d y w h o fulfill  t he crit eria for sec o n d -li ne i br uti ni b [Secti o n 4. 2 ‡],
c hl ora m b ucil (f or patie nts ra n d o mize d t o i br uti ni b i n t he pare nt st u d y), or ot her t hera pies. I n 
a d ditio n, a n y patie nt ca n elect n ot t o u n der g o f urt her a ntica ncer treat me nt.
After i m ple me ntati o n of A me n d me nt N o. 3:
P ati e nts ra n d o mize d t o c hl ora m b ucil will be f o ll owe d u n til pr o gressi o n . F o ll owi n g pr o gressi o n, 
t hese s u bjects will e xit t he st u d y a n d t he i nitiati on of sec o n d-li ne treat me nt wit h i br uti ni b will
n ot be a vaila ble f or t hese patie nt s o n St u d y  P C Y C - 1 1 1 6-C A.
P ati e nts ra n d o mize d t o first-li ne i br uti ni b will  c o nti n ue t o recei ve i br ut i ni b u ntil pr o gressi o n.
I n or der t o mi ni mize or a v oi d treat me nt i nter ru pti o ns, patie nts o n sec o n d -li ne i br utini b o pti n g t o 
m o ve t o a not her l on g -t er m e xte nsio n  st u d y, ma y be allo we d t o c o nti n ue treat me nt wit hi n t his 
st u d y for a li mi te d ti me bef ore tra nsiti oni n g t o t he ot her st u d y.
5. 1.
I de ntific ati o n of Alter n ati ve A ntic a ncer Tre at me nts
5. 1. 1.
I br uti ni b
I br uti ni b is s u p plie d as har d gel at i n ca ps ules, eac h of w hic h c o ntai ns 1 4 0 m g of i br uti ni b. T he 
ca ps ules are pac ka ge d i n o pa q ue hi g h -de nsit y p ol yet h yle ne plast ic b ottl es wit h la bels beari n g t he 
a p pr o priate la bel te xt , as re q uire d b y g o ver ni n g re g ulat or y a ge ncies . T he dr u g pr o d uct is 
ma n ufact ure d f or P har mac yclics L L C , b y a c o ntract ma n ufact urer . All f or mulati o n e xci pie nts are 
c o mpe n dial a n d are c o m m o nl y  use d i n oral for m ul ati o ns.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 1
T he rec o m me n de d st ora ge c o n dit i on f or i br uti ni b ca ps ules is c o ntr olle d r o o m te m perat ure . 
F or mal I nter nati o nal C o nfere nce o n Har m o nizat i on (I C H) sta bilit y st u dies are o n g oi n g t o 
deter mi ne t he s hel f-life of t he pr o d uct . R efer t o t he p har mac y bi n der a n d st u d y dr u g la bel f or 
m o re detaile d i nf or mati on.
Refer t o t he i br uti ni b I B f or a d ditio nal i nf or mat i on re gar di n g t he dr u g pr o d uct.
5. 1. 2.
N o n -i br uti ni b T her a pies
S pecific a ge nt(s) a n d t he treat me nt re gi me n(s) are selecte d per t he cli nical j u d g me nt of t he 
i n vesti gat or. F or dr u g t hera pies, refer t o t he pac ka ge i nsert.
5. 1. 3.
N o Tre at me nt
A p at ient ca n elect n ot t o recei ve f urt her a nt ica ncer treat me nt.
5. 2.
I br uti ni b
5. 2. 1.
D os a ge a n d A d mi nistr ati o n
P ati e nts c o nti n ui n g o n first -li ne i br uti ni b t hera p y e nter t his st u d y at t heir c urre nt t olerate d d ose, 
w hile t h ose i nit iati n g sec o n d-li ne i br uti ni b t hera p y ‡ start treat me nt at a n oral d ose of 4 2 0 m g/ d a y
( 3 x 1 4 0 -m g ca ps ules).
I br uti ni b is a d mi nistere d orall y o nce dail y wit h 8 o u nces (a p pr o xi matel y  2 4 0 m L) of water . T he 
ca ps ules s h o ul d be s wall o we d i ntact a n d patie nts s h o ul d n ot atte m pt t o o pe n ca ps ules or diss o l ve 
t he m in water . Eac h d ose of i br uti ni b s h o uld be ta ke n at least 3 0 mi n utes bef ore eati n g or at least 
2 h o urs after a meal, at a p pr o xi matel y t he sa me ti me eac h da y . T he use of str o n g C Y P 3 A 
i n hi bit ors/i n d ucers a n d gra pefrui t a n d Se ville ora n ges ( d ue t o C Y P 3 A i n hi bit i on) s h o ul d be 
a v o i ded f or t he d urati o n of  t he st u d y (A p pe n di x G) .
If a d ose is n ot ta ke n at t he sc he d ule d ti me , it ca n be ta ke n as s o o n as p ossi ble o n t he sa me da y
wi t h a ret ur n t o t he n or mal sc he d ule t he f oll o wi n g da y. T he patie nt s h o ul d n ot ta ke e xtra 
ca ps ules t o ma ke u p t he misse d d ose.
T he first d ose will be deli vere d i n t he cli nic o n Da y 1, after w hic h s u bse q ue nt d osi n g is t ypicall y 
o n a n o ut patie nt basis . St u d y dr u g m a y not be s hi p pe d t o t he s u bject wit h o ut a p pr o val fr o m 
P C Y C a n d ma y  not be dis pe nse d t o a n y o n e ot her t ha n t he s u bject . I br uti ni b will be dis pe nse d t o 
pati e nts i n b ottles at eac h visit . U n use d i br uti ni b dis pe nse d d uri n g pre vi o us visits m ust be 
ret urne d t o t he site a n d dr u g acc o u nta bilit y rec or ds (Secti o n 1 1. 8 ) u p date d at eac h visit. Ret ur ne d 
ca ps ules m ust n ot be re-dis pe nse d t o a n y o ne.
D ose m o dificat i ons for t o xi cit y are descri be d bel ow i n Sect i on 5. 2. 3 .

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 2
5. 2. 2.
O ver d ose 
A n y d ose of st u d y  dr u g a d mi nistere d i n e xcess of t hat s pecifie d i n t his prot oc ol  is c o nsi dere d t o 
be a n o ver d ose . Si g ns a n d s y m pt o ms of a n o ver d ose t hat meet a n y S A E criteri o n m ust be 
re p orte d as a S A E i n t he a p pr o priate ti me fra me a n d d oc u me nte d as cli nical se q uelae t o a n 
o ver d ose.
T here i s n o s pecific e x perie nce i n t he ma na ge me nt of i br ut i ni b o ver d ose i n patient s. N o  
ma xi m u m t olerate d d ose ( M T D) was reac he d i n t he P hase 1 st u d y  in w hic h s u bjects recei ve d u p 
t o 1 2. 5 m g/ k g/ da y ( 1 4 0 0 m g/ da y). Heal t hy s u bjects were e x p ose d u p t o si n gle d ose of 1 6 8 0 m g. 
O ne healt h y s u bject e xperie nce d re versi ble Gra de 4 he pat ic e nz y me i ncreases ( A S T a n d A L T) 
after a d ose of 1 6 8 0 m g. S u bjects w h o i n geste d m ore t ha n t he rec o m me n de d d osa ge s h o ul d be 
clos el y  mo ni t ore d a n d gi ve n a p pr o priate s u p p ortive treat me nt.
Refer t o Secti o n 8. 3 f or furt her i nf or m at i on re gar di n g A E re p orti n g.
5. 2. 3.
D ose H ol d, Re d ucti o n, or Disc o nti n u ati o n
Treat me nt wit h i br uti ni b m ust be hel d f or a n y u n ma na gea ble, p ote ntiall y st u d y dr u g -r elate d 
t o xicit y t h at is Gra de 3 or hig her i n se verit y . Pl ease see S ectio n 5. 5. 3 f or g ui da nce f or 
ma na ge me nt of i br uti ni b i n patient s w h o re q uire a ntic oa g ula nt treat me nt.
St u d y  dr u g ma y be hel d f or a ma xi m u m of 2 8 c o nsec uti ve da ys f or t o xicit y . St u d y  treat me nt 
s h o uld be disc o nt i n ue d i n t he e ve nt of a t o xicity lasti n g > 2 8 da ys, u nless re vie we d a n d a p pr o ve d 
b y t he Me dical M o nit or.
A he mat ol o gi c A E gra di n g sc he me f or he mat ol o gic t o xicit y is i ncl u de d i n A p pe n di x I.
T he acti o ns i n Ta ble 3 , a n d Ta ble 4 s h o uld be ta ke n f or t he f oll o wi n g t o xicit ies:

Gra de 3 or greater ne utr o pe nia wit h i nfecti on or fe ver

Gra de 4 ne utr o pe nia ( A N C < 5 0 0/ µ L) f or > 7 da ys ( Ne utr o p hil gr o wt h fact ors are per mitte d 
per A merica n S ociet y of  Cli nical O n c olo g y  (A S C O ) g ui deli nes [ S m ith 2 0 0 6 ] a n d use m ust 
be rec or de d i n t he case re p ort f or m [ C R F ].)

Gra de 3 or 4 t hr o m b oc yt o p e nia ( platel ets < 5 0, 0 0 0/ µ L); or, i n patie nts wit h baseli ne 
t hr o mb oc y t o pe nia, a platelet decrease of 5 0 % -7 4 % fr o m baseli ne i n prese nce of blee di n g 

Gra de 4 t hr o m b oc yt o p e nia ( p latelets < 2 5, 0 0 0/ µ L); or, i n pati e nts wit h baseli ne 
t hr o mb oc y t o pe nia, decrease of ≥7 5 % f r o m baseli ne or < 2 0, 0 0 0/ µ L, w hic he ver is hi g her

Gra de 3 or greater n o n -he mat ol o gi cal t o xicit y ( N ote: Ta ble 4 rec o m me n dati o ns f or Gra de 3 
or hi g her car di a c fail ure a n d car diac arr h yt hmias)

Gra de 2 car diac fail ure ( Ta ble 4 )

A n y ot her Gra de 4 t o xicit y or u n m a na gea ble Gra de 3 t o xicit y
F or ot her A Es , i ncl u di n g gra de 2 A Es, t hat are dee me d per t he i n vest i gat or p ote ntiall y 
ma na gea ble b y d ose re d ucti o n, t hese ca n be ma na ge d wit h a o ne d ose le vel d ose re d ucti o n.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 3
T a ble 3 :
Dr u g Disc o nti n u ati o n Acti o ns f or I br uti ni b f or E ve nts n ot S pecifie d i n 
T a ble 4.
Occ urre nce a
Acti o n
1 st
H ol d i br uti ni b u ntil rec o ver y t o Gra de ≤ 1 or baseli ne; ma y 
r estart at ori gi nal d ose le vel b
2 n d
H ol d i br uti ni b u ntil rec o ver y t o Gra de ≤ 1 or baseli ne; restart 
at 1 d ose le vel l o wer ( 2 8 0 m g dail y)
3 r d
H ol d i br uti ni b u ntil rec o ver y t o Gra de ≤ 1 or baseli ne; restart 
at 1 d ose le vel l o wer ( 1 4 0 m g dail y)
4 t h
Disc o nti n ue i br uti ni b
a
1 st, 2n d, 3r d, or 4t h occ urre nce of t he s a me t o xicit y
b
W he n res u mi n g treat me nt, restart at t he sa me or l o wer d ose base d o n be nefit -ris k e val uati o n. If t he t o xicit y re occ urs, re d uce 
dail y d ose b y 1 4 0 m g.
T a ble 4:
I br uti ni b D ose M o dific ati o ns f or C ar di ac F ail ure or C ar di ac Arr h yt h mi as
E ve nts
Occ urre nce
Acti o n
Gr a de 2 c ar di ac f ail ure
First
H ol d st u d y dr u g u ntil rec o ver y t o Gr a de ≤ 1 or b aseli ne; 
rest art at 1 d ose le vel l o wer ( 2 c a ps ules [ie, 2 8 0 m g d ail y])
Sec o n d
H ol d st u d y dr u g u ntil rec o ver y t o Gr a de ≤ 1 or b aseli ne; 
rest art at 1 d ose le vel l o wer ( 1 c a ps ules [ie, 1 4 0 m g d ail y])
T hir d
Disc o nti n ue st u d y dr u g
Gr a de 3 c ar di ac arr h yt h mi as
First
H ol d st u d y dr u g u ntil rec o ver y t o Gr a de ≤ 1 or b aseli ne; 
rest art at 1 d ose le vel l o wer ( 2 c a ps ules [ie, 2 8 0 m g d ail y])
a
Sec o n d
Disc o nti n ue st u d y dr u g
Gr a de 3 or 4 c ar di ac f ail ure
Gr a de 4 c ar di ac arr h yt h mi as
First
Disc o nti n ue st u d y dr u g
a
E val uate t he be nefit -ris k bef ore res u mi n g treat me nt.
D ose c ha n ges m ust be rec or de d i n t he D osa ge A d mi nistrati o n C R F.
F or re q ui re d d ose mo dificat i on f or he patic i m pair me nt refer t o Secti o n 5. 2. 5 a n d f or c o nc o mita nt 
treat me nt wit h C Y P 3 A i n hi bit ors refer t o Secti o n 5. 5. 2. 1 .
5. 2. 4.
Tre at me nt -rel ate d L y m p h oc yt osis
Si milar t o ot her a ge nts tar geti n g B -cell rece pt or si g nali n g, tra nsie nt l y m p h oc yt osis is a 
p har mac o d y na mic effect of i br uti ni b, i n w hic h t he i n hi biti on o f B T K -me diate d cell ular h o mi n g 
a n d a d hesi o n res ults i n a m o bilizat i on of t u m or cells t o t he peri p heral bl o o d ( Ste ve ns o n 2 0 1 1 ).
U p o n i nit iati on of treat m e nt, a tra nsie nt p has e of increase i n l y m p h oc y te c o u nts (ie, ≥5 0 % 
i ncrease fr o m baseli ne a n d a b o ve a bs ol ute c o u nt 5, 0 0 0/ µ L), ofte n ass ociate d wit h re d ucti o n of 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 4
l y m p ha de n o pat h y, has bee n o bser ve d i n m ost patie nts ( 7 5 %) wit h rela pse d/refract or y C L L/ S L L 
treate d wit h i br uti ni b. T h is effect has als o bee n o bser ve d i n s ome pat ient s ( 3 3 %) wit h 
r ela pse d/refract or y ma nt le cell l y m p h oma ( M C L) treate d wit h i br uti ni b. T his o bser ve d tra nsie nt 
l y m p h oc yt osis is us uall y n ot ass ociate d wit h a n a d verse e ve nt a n d s h o ul d n ot be c o nsi dere d 
pr o gressi ve disease i n t he a bse nce of ot her cli nical fi n di n gs as per t he I WC L L g ui deli nes
(C hes o n 2 0 1 2 ). I n b ot h M C L a n d C L L , l y m p h oc yt osis t ypicall y occ urs d uri n g t he first fe w 
wee ks of i br uti ni b t hera p y a n d res ol ves wit hi n a me dia n of 8 wee ks i n t he M C L a n d 1 4 wee ks i n 
t he C L L/ S L L pati e nts.
A s u bsta ntial i ncrease i n t he n u m ber of circ ulat i n g l y m p h oc ytes (e g, > 4 0 0, 0 0 0/µ L) has bee n 
o bser ve d i n a s u bset of patie nts . T here ha ve bee n is olate d cases of le u k ostasis re p orte d i n 
pati e nts treate d wit h i br uti ni b.
A hi g h n u m ber of circ ulat i n g w hi t e blo o d cells ( > 4 0 0, 0 0 0/ µ L) ma y c o nfer i ncrease d ris k; t hese 
pati e nts s h o uld be cl osel y m o ni t or e d. A d mi nister s u p p orti ve care s uc h as h y drat i on a n d/ or 
le u k o p h oresis as i n dicate d . I br uti ni b ma y be te m p oraril y hel d, a n d Me dical M o nit or s h o ul d be 
c o ntacte d .
5. 2. 5.  
D ose M o dific ati o n f or He p atic I m p aire d S u bjects
I br uti ni b is meta b oliz e d i n t he li ver.

F or s u bjects w h o de vel o p mil d he pat ic i m pair me nt w hile o n st u d y  ( C hil d-P u g h cl ass A), t he 
rec o m me n de d d ose re d ucti o n f or i br uti ni b is t o a le vel of 2 80 m g dail y  (t w o ca ps ules).

F or s u bjects w h o de vel o p m o derate he patic i m pair me nt w hile o n st u d y ( C hil d-P u g h cl ass B), 
t he rec o m me n de d d ose re d ucti o n is t o a le vel o f 1 4 0 m g dail y  ( o ne ca ps ule).

S u bjects w h o de vel o p se vere he pat ic i m pair me nt ( C hil d-P u g h cl ass C) must h ol d st u d y  dr u g 
u nt il res ol ve d t o m o derate i m pair me nt ( C hil d-P u g h class B) or better.
M o ni t or s u bjects f or sig ns of  t o xicit y a nd f ol l ow d ose m o dificat i on g ui da nce as nee de d (refer t o 
A p pe n di x L ).
5. 2. 6.
W ar ni n gs , Prec a uti o ns, a n d A d verse Effects
5. 2. 6. 1.
W ar ni n gs a n d Prec a uti o ns
I br uti ni b is c o ntrai n dicate d i n s u bjects wit h cli nicall y si g nifica nt h y perse nsitivit y t o t he 
c o mp o u n d i ts elf or t o t he e xcipie nts i n i ts for m ulati o n . I br uti ni b has n ot bee n use d i n s u bjects 
wi t h biliar y o bstr uctio n, ac ute he pati tis, se vere li ver fail ure, or se verel y i m paire d re nal f u ncti on; 
t he use of i br uti ni b s h o uld be a v o i ded i n s u bjects wi t h t hese c o n diti ons . Pati e nts re q uirin g 
treat me nt wit h w arfari n will be e xcl u de d fr o m st u dies of i br uti ni b. T he use of str o n g C Y P 3 A 
i n hi bit ors or i n d ucers, gra pefr uit, a n d Se ville ora n ges s h o ul d be a v oi de d f or t he d urati o n of t he 
st u d y (A p pe n di x G ).

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 5
5. 3.
N o n -i br uti ni b T her a pies
T he d ose a n d d osi n g re gi me n, a d mi nistrati o n i nstr ucti o ns, a n d pr oce d ures f or h ol di n g a d ose, 
d ose re d ucti o n, a n d disc o nt i n uati on of  treat me nt are t o be per pac ka ge i nsert a n d cli nical 
j u d g me nt of t he i n vesti gat or.
Rele va nt war ni n gs, preca uti o ns, a n d a descri pti o n of p ossi ble a d verse effects are i n t he dr u g 
pr o d uct’s pac ka ge i nsert.
5. 4.
Tre at me nt C o m pli a nce
P ati e nt c o mplia nce wi t h t he i br uti ni b d osi n g re gi me n will be assesse d b y  t he site p har macist or 
desi g nee at eac h visit usi n g direct q uesti o ni n g, e xa mi nat i on of patie nt diaries, a n d ca ps ule 
c o u nts.
C o m plia nce wi t h t he i br uti ni b d osi n g re gi me n will be verifie d b y t he S p o ns or or desi g ne e a n d 
will be rec or de d i n t he st u d y  p har mac y bi n der. T he res p o nsi bilit ies of t he p har macist or desi g nee 
are as f o ll ows:

Mai ntai n rec or ds of pr o d uct deli ver y , i n ve nt or y, ret ur n, a n d destr ucti o n

Mai ntai n te m perat ure m o nit ori n g

Mai ntai n u p -t o-date acc o u nta bilit y of t he st u d y  dr u g i n t he st u d y dr u g acc o u nta bility l og ( or 
e q ui vale nt)

D oc u m e nt t he use of st u d y pr o d uct b y eac h patie nt

Ret ur n or destr o y  u n use d st u d y pr o d uct as per t he S p o ns or ’s i nstr ucti o ns
5. 5.
C o nc o mit a nt Me dic ati o ns D uri n g Ibr uti ni b T her a p y
5. 5. 1.
Per mitte d C o nc o mit a nt Me dic ati o ns
S u p p orti ve me dicat i ons i n acc or da nce wit h sta n dar d practice (s uc h as f or e mesis, diarr hea, etc. ) 
are per mitte d. Use of ne utr o p hil gr o wt h fact ors (fil grasti m a n d pe gfil grast i m) is per mitte d per 
i nstituti o nal  p olic y a n d i n acc or da nce wit h t he A S C O g uideli nes ( S m ith 2 0 0 6 ). Tra nsf usi o ns ma y 
be gi ve n i n acc or da nce wit h i nstit uti o nal p olic y.
P atie nts at Ris k f or T u m or L ysis S y n dr o me
P ati e nts wit h more t ha n 1 of  t h e fol l owi n g fact ors are c o nsi dere d t o be at i ncrease d ris k of t u m or 
l ysis s y n dr o me:

ser u m creati ni ne ≥ 1. 5 x U L N

W B C c o u nt ≥ 5 0 x 1 0 9/ L ( or 5 0, 0 0 0/ m m3)

uri c acid > U L N

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 6
S uc h patie nts s h o ul d be c o nsi dere d f or h y drati o n a n d treat m e nt wit h a uric acid l o weri n g a ge nt 
( xa nt hi ne o xi dase i n hi bit or all o p uri n ol or Ul ori c [fe b u x ostat] +/- ras b uricase) acc or di n g t o t he 
dr u g pr o d uct’s pac ka ge i nsert bef ore c o nti n ui n g treat me nt wit h st u d y  dr u g, as well as for 
fre q ue nt m o nit ori n g f or t u m or l ysis-ass ociate d sig ns a n d s y m pt o m s.
5. 5. 2.
C o nc o mit a nt Me dic ati o ns t o be Use d wit h C a uti o n
5. 5. 2. 1.
C Y P I n hi biti n g/I n d uci n g Dr u gs
I br uti ni b is meta b o lize d pri maril y b y C Y P 3 A4 . A v oi d c o -a d mi nistrati o n wit h str o n g or m o derate 
C Y P 3 A i n hi bit ors a n d c o nsi der alter nati ve a ge nts wit h less C Y P 3 A i n hi biti on .

If a str o n g C Y P 3 A i n hi bit or m ust be use d, re d uce i br uti ni b d ose t o 1 4 0 m g or wi t h h old 
treat me nt f or t he d urati o n of i n hi bit or use. S u bjects s h o ul d be m o nit ore d f or si g ns of i br uti ni b 
t o xicit y.

If a mo derate C Y P 3 A i n hi bit or m u st be use d, re d uce i br uti ni b t o 1 4 0 m g f or t he d uratio n of  
t he i n hi bit or use. F or s u bjects w h o are alrea d y o n m o derate C Y P 3 A i n hi bit or c o nc o mita nt l y 
wi t h ibr ut i ni b with o ut si g nifica nt t o xi cit y t he i n vestigat or m a y c o nsi der t he o verall ris k -
be nefit t o deter mi ne if a d ose re d u ctio n of  ibr ut i ni b is a p pr o priate. A v o i d gra pefr uit a n d 
Se ville or a n ges d uri n g i br ut i ni b t hera p y, as t hese c o ntai n m o derate i n hi bit ors of C Y P 3 A (see
Secti o n 5. 2. 1 ).

N o d ose a dj ust me nt  is re q uire d i n c om bi nat i on wi t h mil d i n hi bit ors.
A v o i d c o nc omit a nt use of str o n g C Y P 3 A i n d ucers (e g, car ba maze pi ne, rifa m pi n, p he n y t oin, a n d 
St. J o h n’s W ort) . C o nsi der a lter nat i ve a ge nts wit h less C Y P 3 A i n d ucti on.
A list of c o m m on C Y P 3 A i n hi bit ors a n d i n d ucers is pr o vi de d i n A p pe n di x G . F or f urt her 
i nf or mat i on, pl ease refer t o t he c urre nt versi o n o f t he I B a n d e xa m ples of i n hi bit ors, i n d ucers, 
a n d s u bstrates ca n be f o u n d at htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ mai n- ta ble/. T his 
we bsite is c o nti n uall y re vise d a n d s h o ul d be c hec ke d fre q ue n tly f or u p dates.
5. 5. 2. 2.
Dr u gs T h at M a y H a ve T heir Pl as m a C o nce ntr ati o ns Altere d b y Ib r uti ni b
I n vitr o st u dies i n dicate d t hat i br uti ni b is n ot a s u bstrate of P -gl yc o pr otei n ( P -g p), b ut is a mil d 
i n hi bit or. I br uti ni b is n ot e x pecte d t o ha ve s yste mic dr u g-dr u g i nteracti o ns wit h P -g p s u bstrates . 
H o we ver, it ca n n ot be e xcl u de d t hat i br uti ni b c o ul d i n hi bit i ntest i nal P-g p after a t hera pe utic 
d ose . T here i s n o cli nical data a vaila ble. T heref ore, t o a v oi d a p ote ntial i ntera ct i on i n t he GI 
tract, narr o w t hera pe utic ra n ge P- g p s u bstrates s uc h as di g o xi n s h o uld be ta ke n at l east 6 h o urs 
bef ore or after i br ut i ni b.
5. 5. 3.  
A nti pl atelet A ge nts a n d A ntic o a g ul a nts
Use i br ut i ni b with ca uti o n i n s u bjects re q uiri n g a ntic oa g ula nts or me dicati o n s t hat i n hi bit platelet 
f u ncti on a n d s u p ple me nts s uc h as fis h o il a n d vita mi n E pre parati o ns s h o ul d be a v oi de d d uri n g 
treat me nt wit h ibr ut i ni b. Blee di n g e ve nts of a n y gra de, i ncl u di n g br uisi n g a n d petec hiae, 
occ urre d i n pat ient s treate d wit h i br uti ni b a n d t he mec ha nis m for t he blee di n g e ve nts is n ot well 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 7
u n derst o o d . S u bjects wit h c o n ge nital blee di n g diat hesis ha ve n ot bee n st u die d . I br uti ni b s h o ul d 
be hel d at least 3 t o 7 da ys pre - a n d p ost -s ur ger y de pe n di n g u p o n t he t ype of s ur ger y  a n d t he ris k 
of  blee di n g (see Sect i on 5. 6 ).
S u bjects re q uiri n g t he i nit iati on of t hera pe utic a nt ic oa g ulati on t hera p y  (e g, atrial fi brillati on), 
c o nsi der t he ris ks a n d be ne fits of c o nt i n ui n g i br uti ni b t hera p y. If t hera pe utic a nt ic oa g ulat i on is 
cli nicall y i n dicate d, treat me nt wit h i br ut i ni b s h o ul d be hel d a n d n ot be restarte d u ntil t he s u bject 
is cli nicall y sta ble a n d has n o sig ns of  blee di n g. N o d ose re d ucti o n is re q uire d w h e n st u d y dr u g is 
restarte d. S u bjects s h o ul d be o bser ve d cl osel y f or si g ns a n d s y m pt o ms of blee di n g.
5. 5. 4.
Pr o hi bite d C o nc o mit a nt Me dic ati o ns
A n y c he mot h era p y, a ntica ncer i m m u n ot hera p y, or e x peri me ntal t hera p y is pr o hi bite d w hile t he 
pati e nt is recei vi n g i br uti ni b. L ocalize d, h or m o nal, or b o ne s pari n g treat me nt f or n o n - B-cell 
mali g na ncies ma y be c o nsi dere d wit h a p pr o val of t he Me dical Mo ni t or.
5. 6.
G ui deli nes f or I br uti ni b M a n a ge me nt wit h S ur geries or Pr oce d ures
I br uti ni b ma y i ncrease ris k of blee di n g wit h i n vasi ve pr oce d ures or s ur ger y. T he f o ll owi n g 
g ui da nce s h o ul d be a p plie d t o t he use of i br uti ni b i n t he perio perati ve peri o d f or patie n ts w h o 
re q uire s ur gical i nter ve ntio n or a n i n vasi ve pr oce d ure w hile recei vi n g i br uti ni b:
5. 6. 1.
Mi n or S ur gic al Pr oce d ures
F or mi n or pr oce d ures (s uc h as a ce ntral li ne place me nt, s ki n or nee dle bi o ps y, l u m bar p u nct ure 
[ ot her t ha n s h u nt reser v oir access], t h orace ntesis, or parace ntesis) i br uti ni b s h o uld be hel d f or at 
least 3 da ys prior t o t he pr oc e d ure a n d s h o ul d n ot be restarte d f or at least 3 da ys after t he 
pr oce d ure . F or b o ne marr o w bi o psies t hat are perf or me d w hile t he patie nt is o n i br uti ni b, it is n ot 
necessar y  t o h old i br uti ni b.
5. 6. 2.
M aj or S ur gic al Pr oce d ures
F or a n y  s ur ger y or i n vasi ve pr oce d ure re q uiri n g s ut ures or sta ples f or cl os ure, i br uti ni b s h o uld be 
hel d at least 7 da y s prior t o t he i nter ve nt i on (e xce pt f or e mer ge nc y pr oce d ures) a n d s h o ul d be 
hel d at least 7 da y s after t he pr oce d ure a n d restarte d at t he discret i on of t he i n vesti gat or w he n t he 
s ur gical site is reas o na bl y heale d wit h o ut ser osa n g ui ne o us drai na ge or t he nee d f or drai na ge 
t u bes.
6.
S T U D Y P R O C E D U R E S A N D A S S E S S M E N T S
Bef ore st u d y  e ntr y, t hr o u g h o ut t he st u d y, a n d at t he f oll ow- u p e val uat i ons, vari o us cli nical a n d 
di a g n ostic la b orat or y e val uat i ons are o utli ne d . T he p ur p ose of o btai ni n g t hese detaile d 
meas ure me nts is t o e ns ure a de q uate safet y a n d efficac y assess me nts. Cli nical e val uat i ons a n d 
la b orat or y assess me nts ma y be re peate d mor e f re q ue ntl y if cli nicall y i n dicate d.
E ver y  eff ort s h o ul d be ma de t o ha ve st u d y  assess me nt a n d pr oce d ures perf or me d at t he st u d y 
ce nter at w hic h t he patie nt was ra n d o mize d a n d is recei vi n g treat me nt.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 8
St u d y  assess me nts are briefl y descri be d bel o w a n d are descri be d i n detail i n t he sc he d ules of 
assess me nts i n t he a p pe n dices: A p pe n di x A , assess me nts bef ore P D i n patient s ra n d omize d t o 
c hl ora m b ucil; A p pe n di x B , assess me nts bef ore P D i n patient s ra n d omize d t o i br uti ni b; 
A p pe n di x C , assess me nts after P D i n pat ient s o n sec o n d-li ne i br uti ni b‡; a n d A p pe n di x D , 
assess me nts after P D i n patient s o n a ntica ncer treat me nt ot her t ha n i br uti ni b (ie, n o n- i br uti ni b), 
or n o treat me nt.
6. 1.
I nf or me d C o nse nt a n d Assess me nt of Eli gi bilit y
T he patie nt m ust first rea d, u n dersta n d, a n d si g n t he I nst itut i onal Re vie w B oar d (I R B)-/ Researc h 
Et hics B oar d ( R E B)-/I n de pe n de nt Et hics C o m mittee (I E C)-a p pr o ve d i nf or me d c o nse nt f or m 
(I C F) c o nfir mi n g his or her willi n g ness t o partici pate i n t his st u d y before a n y st u d y -s pecific 
pr oce d ures are perf or me d . T he p atie nt m u st als o gra nt per missi on t o use pr otecte d healt h 
i nf or mat i on per Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A) , if a p plica ble. I n 
a d ditio n, t he patie nt m ust si g n all a p pr o ve d I C F a me n d me nts per t he site I R B/ R E B /I E C’s 
g ui deli nes d uri n g t he c o urse of t he st u d y .
T he patie nt i nitiall y c o nse nts t o partici pati o n i n t his e xte nsio n  st u d y at e nr oll me nt i n t he pare nt 
st u d y. I nf or me d c o nse nt f or partici patio n i n t he e xte nsio n  st u d y will  a gai n be o btai ne d bef ore 
a n y e xte nsi o n- st u d y-s pecific pr oce d ures or assess me nts are perf or me d.
At  e ntr y int o t he e xte ns i on st u d y , all patie nts u n der g o a n eli gi bilit y visit . T he assess me nts at t he 
visit var y  de pe n di n g o n t he treat me nt t o w hic h t he patie nt was ra n d o mize d i n t he pare nt st u d y, 
t he disease-pr o gressi o n stat us at tra nsfer t o t he e xte nsi o n st u d y , a n d t he pla n ne d treat me nt i n t he 
e xte nsi o n st u d y . Assess me nts at t he eli gi bilit y visi t are descri be d i n A p pe n di x A , A p pe n di x B , 
A p pe n di x C , a n d A p pe n di x D.
6. 2.
R a n d o miz ati o n a n d Bli n di n g
T his is a n o pe n -la bel st u d y, a n d treat me nt assi g n me nt i n t he e xte nsi on st u d y  is n ot ra n d o mize d.
6. 3.
Assess me nts a n d Pr oce d ures b y Visit
St u d y -visi t assess me nts var y  de pe n di n g o n t he treat me nt t o w hic h t he patie nt was ra n d o mize d i n 
t he pare nt st u d y, t h e disease-pr o gressi o n stat us at tra nsfer t o t he e xte nsi o n st u d y , a n d t he pla n ne d 
treat me nt i n t he e xte nsi o n st u d y . Assess me nts i n t he vari o us patie nt-s u bsets are i n di vi d uall y 
liste d bel o w.
6. 3. 1.
P C Y C - 1 1 1 6-C A Assess me nts Bef ore P D i n Ar m A P atie nts (ie, i n p atie nts o n
c hl or a m b ucil i n p are nt st u d y)
P ati e nts ra n d o mize d t o c hl ora m b ucil i n t he pare nt st u d y  (ie, Ar m A of t he pare nt st u d y) w h o 
ha ve n ot e x perie nce d P D at t he ti me of pare nt -st u d y cl os ure are tra nsferre d t o t he e xte nsi o n 
st u d y a n d are assesse d as descri be d bel o w.
T he sc he d ule of assess me nts f or t hese patie nts is i n A p pe n di x A .

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 9
6. 3. 1. 1.
Eli gi bilit y Visit

I nf or me d c o nse nt

C o nfir mati o n o f eli gi bilit y f or P C Y C- 1 1 1 6-C A
6. 3. 1. 2.
D a y 1 of E ver y 4 t h M o nt h
U nt il 2 5 m o nt hs after t he start of treat me nt i n t he pare nt st u d y , t he f oll owi n g assess me nts occ ur 
e ver y 4 m o nt hs , o n Da y 1 of t h e mo nt h (ie, M o nt hs 1 3 , 1 7 , 2 1 , 2 5 , c o u nti n g fr o m C ycle 1 D a y 1 
i n t he pare nt st u d y); starti n g fr o m mo n t h 3 0 o n war ds , t he assess me nts t he n occ ur e ver y 6 m o nt hs 
u nt il t he patient  e x perie nces P D or t he st u d y is clos e d b y t he S p o ns or . Res p o nse assess me nts are 
t o be mai ntai ne d o n t he ori gi nal pare nt st u d y s c h e d ule.

C o nc o mita nt me dicat i ons ( o n g oi n g at t he e n d of t he c o nc o mita nt me dicati o ns re p orti n g 
p eri o d)

I de ntificati o n of alter nati ve a ntica ncer treat me nt i ncl u di n g start date a n d reas o n (f or patie nts 
di sc o nti n ui n g I P f or reas o ns ot her t ha n P D)

A d verse e ve nts ( o n g oi n g at t he e n d of t he A E re p orti n g peri o d)

Ot her mali g na nc y

P h ysical e xa mi nat i on

Vi t al si g ns

E C O G f u nct i onal stat us

H e m at olo g y

S er u m  c he mistr y

P ati e nt re p orte d o utc o mes ( P R O) assess me nts ( E Q- 5 D- 5 L, F A Ci T Fati g ue)

Di sease assess me nt b y disease -relate d s y m pt o ms a n d o verall res p o nse assess me nt
T he assess me nts bel o w will occ ur e ver y  1 2 mo n t hs u nt il t he pat ient  e x perie nces P D or t he st u d y 
is cl ose d b y t he S p o ns or.

Di sease assess me nt b y c o m p ute d t o m o gra p h y ( C T )/ma g net ic res o na nce i ma gi n g (M RI ) sca n

B o ne m arr o w bio ps y  a n d/ or as pir at e a n d M R D t o be perf or me d if i n dicate d

Pr e di cti ve Bio m ar kers
6. 3. 1. 3.
S us pecte d -P D V isit
T his visit occ urs as s o o n as p ossi ble after P D is s us pecte d:

P ati e nt -re p orte d o utc o mes assess me nts ( E Q- 5 D-5 L , F A CiT- Fat i g ue)

C o nc o mita nt me dicat i ons ( o n g oi n g at t he e n d of t he c o nc o mita nt me dicati o ns re p orti n g 
p eri o d )

A d verse e ve nts ( o n g oi n g at t he e nd of  t he A E re p ortin g peri o d )

Ot her m ali g na nc y

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 0

P h ysical e xa mi nat i on

Vi t al si g ns

E C O G f u nct i onal stat us

H e m at olo g y

C y t o ge netic, C L L fl u oresce nce i n sit u h y bri dizati on ( FI S H) pa nel

Di sease assess me nt b y C T/ M RI sca n, di sease-relate d s y m pt o ms, a n d o verall res p o nse 
assess me nt

B o ne m arr o w bio ps y  a n d/ or as pirate t o be perf or me d if i n dicate d

Pr e di cti ve bi o mar kers
If P D is c o nfir me d a n d a n i n dicati on f or treat me nt is prese nt per t he I W C L L g ui deli nes, sec o n d -
li ne treat me nt plan is deter mi ne d, a n d s u bse q ue nt assess me nts are as descri be d i n Sect i on 6. 3. 3
(if eli gi ble f or sec o n d -li ne i br uti ni b‡) or Secti o n 6 . 3. 4 (f or n o n-i br uti ni b t hera p y or n o treat m e nt ).
If P D is n ot c o nfir me d, s u bse q ue nt assess me nts are as descri be d i n Sect i on 6. 3. 1. 2 .
6. 3. 2.
P C Y C -1 1 1 6- C A Assess me nts Bef ore P D o r  e n d of i br uti ni b t her a p y f or ot her 
re a so ns i n Ar m B P atie nts (ie, i n p atie nts r a n d o mize d t o Ibr uti ni b i n p are nt 
st u d y)
P ati e nts ra n d o mize d t o i br uti ni b i n t he pare nt st u d y (ie, Ar m B of t he pare nt st u d y) w h o ha ve n ot 
e x perie nce d P D at t he ti me o f pare nt -st u d y clos ure are tra nsferre d t o t he e xte nsi on st u d y  for 
c o nti n ue d i br uti ni b t hera p y a n d are assesse d as descri be d bel o w.
T he sc he d ule of assess me nts f or t hese patie nts is i n A p pe n di x B .
6. 3. 2. 1.
Eli gi bilit y Visit

I nf or me d c o nse nt

C o nfir mati o n o f eli gi bilit y f or P C Y C-1 1 1 6- C A
6. 3. 2. 2.
D a y 1 of E ver y St u d y Visit
U nt il 27 c ycles after the start of treat me nt i n t he pare nt st u d y , t he f oll owi n g assess me nts occ ur 
o n Da y  1 of e ver y o d d-n u m bere d c ycle (ie, C ycles 1 3, 1 5, 1 7, 1 9, 2 1, 2 3, 2 5 , 2 7 c o u nti n g fr om 
C ycle 1 D a y 1 i n t he pare nt st u d y ); fr om C ycle 3 0 o n war ds, t he assess me nts t he n occ ur e ver y 
4 c ycles u nt il t he patient  e x perie nces P D or t he st u d y is close d b y  t he S p o ns or :

P ati e nt -re p orte d o utc o mes assess me nts ( E Q- 5 D-5 L , F A CiT- Fat i g ue)

C o nc o mita nt me dicat i ons

A d verse e ve nts 

Ot her mali g na ncies

P h ysical e xa mi nat i on (incl u di n g f oc use d oc ular q uesti o ns)

Vi t al si g ns

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 1

E C O G f u nct i onal stat us

H e m at olo g y

S er u m  c he mistr y

Di sease-relate d s y m pt o ms

O verall res p o nse assess me nt
Di s pe nse st u d y dr u g u p o n c o m plet i on of assess me nts.
6. 3. 2. 3.
D a y 1 of Desi g n ate d C ycles – Effic ac y Assess me nts
U nt il 25 c ycles after t he start of treat me nt i n t he pare nt st u d y, t he f oll owi n g assess me nts occ ur 
o n Da y  1 of e ver y 4t h c ycle (ie, C ycles 1 3, 1 7, 2 1, 2 5 c o u ntin g fr o m C ycle 1 D a y 1 i n t he pare nt 
st u d y); starti n g fr om C ycle 3 0 o n war ds, t he assess me nts t he n occ ur e ver y  1 2 c ycles u nt il t he 
pati e nt e x perie nces P D or t he st u d y is close d b y  t he S p o ns or :

Di sease assess me nt b y C T/ M RI sca n, disease-relate d s y m pt o ms, a n d o verall res p o nse 
assess me nt

Pr e di cti ve bi o mar kers

B o ne m arr o w bio ps y  a n d/ or as pirate a n d M R D t o be perf or m e d if i n dicate d
6. 3. 2. 4.
S us pecte d -P D Visit
T his visit occ urs as s o o n as p ossi ble after P D is s us pecte d : 

P ati e nt -re p orte d o utc o mes assess me nts ( E Q- 5 D-5 L , F A CiT- Fat i g ue)

P h ysical e xa mi nat i on (incl u di n g f oc use d oc ular q uesti o ns)

Vi t al si g ns

A d verse e ve nts ( o n g oi n g at t he e n d of t he A E re p orti n g peri o d)

C o nc o mita nt me dicat i ons ( o n g oi n g at t he e n d of t he c o nc o mita nt me dicati o ns re p orti n g 
p eri o d)

E C O G f u nct i onal stat us

H e m at olo g y

C y t o ge netic, C L L fl u oresce nce i n sit u h y bri dizati on ( FI S H) pa nel

Di sease assess ment  b y C T/ M RI sca n, di sease-relate d s y m pt o ms, a n d o verall res p o nse 
assess me nt

Pr e di cti ve Bio m ar kers

B o ne m arr o w bio ps y  a n d/ or as pirate t o be perf or me d if i n dicate d
If P D is c o nfir me d a n d t he I W C L L criteria are met f or active di sease re q uirin g treat m e nt , t he n 
t he sec o n d-li ne treat me nt pla n is deter mi ne d, a n d s u bse q ue nt assess me nts are as descri be d i n 
Secti o n 6. 3. 4 .

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 2
If P D is n ot c o nfir me d, s u bse q ue nt assess me nts are deter mi ne d b y w het her t he pati e nt is still 
recei vi n g i br uti ni b:

If t he patie nt is still recei vi n g i br uti ni b at t he ti me of t he S us pecte d -P D Visit, s u bse q ue nt 
assess me nts are as descri be d i n Sect i ons 6. 3. 2. 2 a n d 6. 3. 2. 3 . 

If t he patie nt is n o l o n ger recei vi n g i br uti ni b at t he ti me of t he S us pecte d -P D Visit
(e g, i br uti ni b was st o p pe d b y  t he i n vesti gat or w he n P D was s us pecte d), s u bse q ue nt 
assess me nts are as descri be d i n Sect i on 6. 3. 2. 6 .
6. 3. 2. 5.
E n d - of-Tre at me nt Visit
T he e n d-of -treat me nt visit occ urs wit hi n 3 0 da ys aft er t he e n d of ra n d o mize d i br uti ni b t hera p y. 
T he assess me nts are as f o ll ows:

P ati e nt -re p orte d o utc o mes assess me nts ( E Q- 5 D-5 L , F A CiT- Fat i g ue)

C o nc o mita nt me dicat i ons

A d verse e ve nts

Ot her mali g na ncies

P h ysical e xa mi nat i on (incl u di n g f oc use d oc ular q uesti o ns)

Vi t al si g ns

E C O G f u nct i onal stat us

H e m at olo g y

S er u m  c he mistr y

Di sease-relate d s y m pt o ms
6. 3. 2. 6.
Pre -P D F oll o w -u p Visits
U nt il 25 m o nt hs after t he start of treat me nt i n t he pare nt st u d y , pre-P D F oll o w -u p Visi ts occ ur 
e ver y 4 mo nt hs after t he E n d -of -Treat me nt Vi sit for pati e nts w h o ( 1) ha d n ot e x perie nce d P D 
a n d ( 2) ha d i br uti ni b t hera p y disc o nt i n ue d bef ore t he S us pecte d -P D Visit . Starti n g f r o m mo nt h 
3 0 o n war ds, t hese assess me nts t he n occ ur e ver y 6 m o nt hs u ntil P D or st u d y  clos ure (i br uti ni b 
t hera p y is n ot t o be restarte d i n t hese pat ient s). T he assess me nts are as f o ll ows:

P ati e nt -re p orte d o utc o mes assess me nts ( E Q- 5 D-5 L , F A CiT- Fat i g ue)

P h ysical e xa mi nat i on

Vi t al si g ns

C o nc o mita nt me dicat i ons ( o n g oi n g at t he e n d of t he c o nc o mita nt me dicati o ns re p orti n g 
p eri o d)

A d verse e ve nts ( o n g oi n g at t he e n d of t he A E re p orti n g peri o d)

Ot h er mali g na ncies

E C O G f u nct i onal stat us

H e m at olo g y

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 3

S er u m  c he mistr y

I de ntificati o n of alter nati ve a ntica ncer treat me nt i ncl u di n g start date, reas o n, d urati o n , a n d 
res p o nse (for pati e nts disc o nti n ui n g I P f or reas o ns ot her t ha n P D)

Di sease assess me nt b y disease -relate d s y m pt o ms a n d o verall res p o nse assess me nt
T he assess me nts bel o w occ ur e ver y  1 2 mo nt hs u ntil P D or stu d y clos ure:

Di sease assess me nt b y C T/ M RI sca n

Pr e di cti ve Bio m ar kers

B o ne m arr o w bio ps y  a n d/ or as pirate a n d M R D t o be perf or me d if i n dicate d
6. 3. 3.
P C Y C - 1 1 1 6-C A Assess me nts After Dise ase Pr o gressi o n – Sec o n d- li ne
Ibr uti ni b T her a p y ‡
P ati e nts w h o e x perie nce P D a n d t he n recei ve sec o n d-li ne t hera p y i br uti ni b thera p y are assesse d 
as descri be d bel o w.
T he sc he d ule of assess me nts f or t hese patie nts is i n A p pe n di x C .
6. 3. 3. 1.
Eli gi bilit y Visit

I nf or me d c o nse nt

C o nfir mati o n o f eli gi bilit y f or P C Y C- 1 1 1 6-C A 

C o nfir mati o n o f eli gi bilit y f or sec o n d-li ne i br uti ni b

P h ysical e xa mi nat i on (incl u di n g f oc use d oc ular q uesti o ns)

Vi t al si g ns

E C O G f u nct i onal stat us

H e m at olo g y

S er u m  c he mistr y

Me dical hist or y

C ollect a n d rec or d t he patie nt’s c o m p lete hist or y incl u di n g c o nc urre nt me dical si g ns a n d 
s y m pt o ms t hat occ urre d i n t he i nter ve ni n g peri o d bet wee n st o p pi n g first -li ne treat me nt i n t he 
pare nt st u d y  a n d start of sec o n d-li ne t hera p y.

Di sease assess me nt b y C T/ MRI sca n, di sease-relate d s y m pt o ms, a n d o verall res p o nse 
assess me nt (assess me nts perf or me d i n t he 8 wee ks bef ore t he start of sec o n d -li ne t hera p y ca n 
be use d)

B o ne m arr o w bi o ps y a n d/ or as pirate t o be perf or me d if i n dicate d
T he p h ysical e xa mi nat i on, vital s i g ns assess me nt, deter mi nati on of E C O G stat us, a n d 
ce ntral-la b orat or y he m at olo g y  a n d ser u m c he mistr y tests are n ot re q uire d at t he eli gi bility visit if 
t hese assess me nts ha ve bee n d o ne i n t he 7 da ys bef ore t he visit.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 4
6. 3. 3. 2.
D a y 1 of 1 st C ycle o n Ibr uti ni b ( m ust be c o m plete d wit hi n 1 4 d a ys of 
est a blis hi n g eli gi bilit y)

P ati e nt -re p orte d o utc o mes assess me nts ( E Q- 5 D-5 L , F A CiT- Fat i g ue)

C o nc o mita nt me dicat i ons

A d verse e ve nts

Ot her mali g na ncies

P h ysical e xa mi nat i on (incl u di n g f oc use d oc ular q uesti o ns)

Vi t al si g ns

E C O G f unct i onal stat us

H e m at olo g y

S er u m  c he mistr y

C y t o ge netic, C L L fl u oresce nce i n sit u h y bri dizati on ( FI S H ) pa nel

Pr e di cti ve bi o mar kers

Di s pe nse st u d y dr u g

St u d y  dr u g a d mi nistrati o n: T he first d ose of i br uti ni b will be ta ke n at t he i n vest i gati onal sit e 
o n Da y  1 of  C ycle 1 after all pr oce d ures are c o n d ucte d
6. 3. 3. 3.
D a y 1 of 2 n d T hr o u g h 6 t h C ycle o n Ibr uti ni b

P ati e nt -re p orte d o utc o mes assess me nts ( E Q- 5 D-5 L , F A CiT- Fat i g ue) o n C ycles 3 a n d 5.

C o nc o mita nt me dicat i ons

A d verse e ve nts

Ot her mali g na ncies

P h ysical e xa mi nat i on (incl u di n g f oc use d oc ular q uesti o ns)

Vi t al si g ns

E C O G f u nct i onal stat us

H e m at olo g y

S er u m  c he mistr y

Di s pe nse st u d y dr u g
T he f o ll owi n g will be perf or me d o n C ycle 5:

Di sease assess me nt b y C T/ M RI sca n, disease -relate d s y m pt o ms, a n d o verall res p o nse 
assess me nt

Pr e di cti ve bi o mar kers

B o ne m arr o w bio ps y  a n d/ or as pirate a n d M R D t o be perf or me d if i n dicate d

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 5
6. 3. 3. 4.
D a y 1 of C ycles fr o m 7 t h C ycle o n Ibr uti ni b t o St u d y Cl os ure
E ver y  o d d-n u m bere d c y cle of i br uti ni b t hera p y st artin g at t he 7 t h c ycle ( 7t h, 9t h, 1 1t h, etc., c ycle of
i br uti ni b) u nt il 27 c ycles after t he start of treat me nt, t he n e ver y 3 c ycles u nt il P D or st u d y cl os ure
starti n g fr om C ycle 3 0 , t he f oll owi n g assess me nts are perf or me d f or as lo n g as t he s u bject is 
ta ki n g i br uti ni b:

P ati e nt -re p orte d o utc o mes assess me nts ( E Q-5 D- 5 L , F A CiT- Fat i g ue)

C o nc o mita nt me dicat i ons

A d verse e ve nts 

Ot her mali g na ncies

P h ysical e xa mi nat i on (incl u di n g f oc use d oc ular q uesti o ns)

Vi t al si g ns

E C O G f u nct i onal stat us

H e m at olo g y

S er u m  c he mistr y

Di s pe nse st u d y dr u g
Als o, e ver y 4 t h c ycle of i br uti ni b u nt il 25 c ycles after t he start of treat me nt (ie, C ycles 1 3, 1 7, 2 1, 
2 5) , t he n starti n g fr om C ycle 3 0 o n war ds, e ver y 6 c ycles u nt il P D or st u d y cl os ure, t he foll o wi n g 
a d ditio nal  assess me nts are perf or me d:

Di sease assess me nt b y C T/ M RI sca n, disease-relate d s y m pt o ms, a n d o verall res p o nse 
assess me nt

Pr e di cti ve bi o mar kers

B o ne m arr o w bio ps y  a n d/ or as pirate t o be perf or me d as i n dicate d
6. 3. 3. 5.
S us pecte d -P D Visit
T his visit occ urs as s o o n as p ossi ble after P D is s us pecte d; disease stat us is assesse d as f o ll ows:

P ati e nt -re p orte d o utc o mes assess me nts ( E Q- 5 D-5 L , F A CiT- Fat i g ue)

P h ysical e xa mi nat i on (incl u di n g f oc use d oc ular q uesti o ns)

C o nc o mita nt me dicat i ons ( o n g oi n g at t he e n d of t he c o nc o mita nt me dicati o ns re p orti n g 
p eri o d)

A d verse e ve nts ( o n g oi n g at the e n d of t he A E re p orti n g peri o d)

Vi t al si g ns

E C O G f u nct i onal stat us

H e m at olo g y

C y t o ge netic, C L L fl u oresce nce i n sit u h y bri dizati on ( FI S H) pa nel

Di sease assess me nt b y C T/ M RI sca n, disease-relate d s y m pt o ms, a n d o verall res p o nse 
assess me nt

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 6

Pr e di cti ve Bi o m ar kers

B o ne m arr o w bio ps y  a n d/ or as pirate t o be perf or me d as i n dicate d
If P D is c o nfir me d a n d I W C L L crit eria are met for acti ve disease re q uiri n g treat me nt , t he n a 
ne xt -li ne treat me nt pla n is deter mi ne d, a n d s u bse q ue nt assess me nts are as descri be d i n 
Secti o n 6. 3. 4 .
If P D is n ot c o nfir me d, s u bse q ue nt assess me nts are deter mi ne d b y w het her patie nt is still 
recei vi n g i br uti ni b:

If t he patie nt is still recei vi n g i br uti ni b at t he ti me of t he S us pecte d -P D Visit, s u bse q ue nt 
assess me nts are as descri be d i n Sect i on s 6. 3. 3. 2 , 6. 3. 3. 3 , or 6. 3. 3. 4 ( de pe n di n g o n t he 
d urati o n of  pri or i br uti ni b t hera p y).

If t he s u bject is n o l o n ger recei vi n g i br uti ni b at t he ti me of t he S us pecte d -P D Visit 
(e g, i br uti ni b was st o p pe d b y  t he i n vesti gat or w he n P D was s us pecte d), s u bse q ue nt 
assess me nts are as descri be d i n Sect i on 6. 3. 3. 7 .
6. 3. 3. 6.
E n d - of-Tre at me nt Visit
T his visi t occ urs wit hi n 3 0 da ys of t he e n d of sec o n d-li ne i br uti ni b t hera p y. T he visit s h o ul d be 
perf or m e d bef ore i nit iati o n of  s u bse q ue nt a ntica ncer t hera p y. T he assess me nts are as f o ll ows:

P ati e nt -re p orte d o utc o mes assess me nts ( E Q- 5 D-5 L , F A CiT- Fat i g ue)

C o nc o mita nt me dicat i ons

A d verse e ve nts

Ot her mali g na ncies

P h ysical e xa mi nat i on (incl u di n g f oc use d oc ular q uesti o ns)

Vi t al si g ns

E C O G f u nct i onal stat us

H e m at olo g y

S er u m  c he mistr y

Di sease-relate d s y m pt o ms

Pr e di cti ve bi o mar kers
6. 3. 3. 7.
Pre -P D F oll o w -u p Visit s
U nt il 2 5 m o nt hs after t he start of treat me nt, t hese visit s occ ur e ver y  4 mo nt hs after t he E n d -of -
Treat me nt Visit f or patie nts w h o ( 1) ha d n ot e x perie nce d P D a n d ( 2) ha d i br uti ni b t hera p y 
di sc o nti n ue d bef ore t he S us pecte d -P D Visit . Fr o m  3 0 m o nt hs o n war ds, t hese assess me nts t he n 
occ ur e ver y  6 m o nt hs u nt il P D or st u d y cl os ure (i br utini b t hera p y is n ot t o be resta rte d i n t hese 
pati e nts) . T he assess me nts are as f o ll ows:

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 7

P ati e nt -re p orte d o utc o mes assess me nts ( E Q- 5 D-5 L , F A CiT- Fat i g ue)

P h ysical e xa mi nat i on

C o nc o mita nt me dicat i ons ( o n g oi n g at t he e n d of t he c o nc o mita nt me dicati o ns re p orti n g 
p eri o d)

A d verse e ve nts ( o n g o i n g at t he e n d of t he A E re p orti n g peri o d)

Ot her mali g na ncies

Vi t al si g ns

E C O G f u nct i onal stat us

H e m at olo g y

S er u m  c he mistr y

I de ntificati o n of alter nati ve a ntica ncer treat me nt i ncl u di n g d urati o n a n d res p o nse (for pati e nts 
di sc o nti n ui n g I P f or reas o ns ot her t ha n P D)

Di sease assess me nt b y C T/ M RI sca n, b o ne marr o w bio ps y a n d/or as pirate a n d M R D as 
a p pr o priate, disease-relate d s y m pt o ms, a n d o verall res p o nse assess me nt

Pr e di cti ve Bio m ar kers
6. 3. 4.
P C Y C - 1 1 1 6-C A Assess me nt s After Dise ase Pr o gressi o n – N o n -i br uti ni b 
S u bse q ue nt T her a p y or N o S u bse q ue nt T her a p y
F o ll owi n g i m ple me ntati o n of A me n d me nt 3, p at ient s w h o were ra n d o mize d t o a n d w h o 
s u bse q ue ntl y pr o gresse d o n c hl ora m b ucil will n ot be f o ll owe d a n d will e xit t he st u d y .
P atie nts w h o e x perie nce P D o n first-li ne i bru tini b a n d g o o n t o recei ve a n alter nati ve a ntica ncer 
treat me nt ot her t ha n i br uti ni b as s u bse q ue nt t hera p y or n o s u bse q ue nt t hera p y will be f o ll owe d 
per A p pe n di x D . U nt il i m ple me ntati o n of t he prese nt a me n d me nt, pat ient s w h o recei ved n o n-
i br uti ni b t hera p y were p ote nti all y eli gi ble t o recei ve s u bse q ue nt treat me nt wit h i br uti ni b if t he y 
met eli gi bilit y cr iteria o utli ne d i n Sect i on 4. 2 ‡. O nce t he Me di cal Mo ni t or a p pr o ved ne xt li ne 
i br uti ni b t hera p y, t he patie nt were assesse d f o ll owi n g t he sc he d ule d o utli ne d i n Sect i on 6. 3. 3
(a n d A p pe n di x C ) st artin g wit h t he eli gi bilit y visit ‡.
T he sc he d ule of assess me nts f or t hese pati e nts is i n A p pe n di x D .
6. 3. 4. 1.
Eli gi bilit y Visit

I nf or me d c o nse nt

C o nfir mati o n o f eli gi bilit y f or P C Y C- 1 1 1 6-C A
6. 3. 4. 2.
F oll o w -u p Visits
P ati e nts starti n g n o n-i br uti ni b s u bse q ue nt t hera p y will be f oll owe d ev er y  4 mo nt hs fr o m t he start 
of  s u bse q ue nt t hera p y wit h a n alter nati ve a ntica ncer treat me nt. Patie n ts decidi n g t o f ore g o 
s u bse q ue nt t hera p y will be f o ll owe d ev er y  4 mo nt hs fr o m t he date of decisi o n t o f ore g o 
s u bse q ue nt t hera p y.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 8
F ol l owi n g assess me nts are perf or me d at t he fre q ue nc y descri be d a b o ve :

S ur vi val stat us

I de ntificati o n of alter nat i ve a ntica ncer treat me nt i ncl u di n g start date, reas o n f or i nitiati n g 
t hera p y, d urati o n , a n d res p o nse

Ot her ma li g na ncies
Pr e di cti ve Bio m ar kers will  be c ollecte d e ver y 1 2 m o nt hs.
6. 4.
Descri pti o n of Assess me nts a n d Pr oce d ures
6. 4. 1.
C o nfir m ati o n of Eli gi bilit y
Perf or m  all necessar y pr oce d ures a n d e val uati o ns t o d oc u me nt t hat t he patie nt meets eac h 
eli gi bilit y crit erio n ( Sect i on 4. 1 ). I n a d diti on, f or patie nts w h o are bei n g c o nsi dere d f or sec o n d -
li ne i br uti ni b t hera p y, perf or m all necessar y  pr oce d ures a n d e val uati ons t o d oc u me nt t hat t he 
pati e nt meets t he a d dit i onal criteria f or sec o n d -li ne i br uti ni b (Sect i on 4. 2 )‡. Pl ease refer t o t he 
st u d y ma n ual for a m ore detaile d descri pt i on of t he pr oce d ures . Bl o o d sa m pl es f or he m at olo g y
a n d ser u m c he mistr y tests will be e val uate d b y a ce ntral la b orat or y  t o c o nfir m eli gi bility f or 
sec o n d-li ne i br uti ni b‡.
6. 4. 2.
Me dic al Hist or y
C ollect a n d rec or d t he patie nt ’s c om p lete hist or y incl u di n g c o nc urre nt me dical si g ns a n d
sy m pt o ms t hat occ urre d i n t he i nter ve ni n g peri o d bet wee n st o p pi n g first-li ne treat me nt i n t he 
pare nt st u d y a n d start of sec o n d-li ne i br uti ni b t her a p y ‡.
6. 4. 3.
A d verse E ve nts
T he acce pte d re g ulat or y  defi nitio n  of a n A E is i n Secti o n 8. 2 . I n t his l o n g-t er m e xte nsi on st u d y , 
A Es are rec or de d as f o ll ows:

A E data c o llecte d f or p atie nts o n first-li ne or sec o n d-li ne i br uti ni b wi t hi n A E re p orti n g 
p eri o d defi ne d i n S ect i on 8. 3. 1 . T hese e ve nts are rec or de d at t he st u d y  visits i de ntifie d i n t he 
sc he d ules of assess me nt (A p pe n di x B a n d A p pe n di x C ), w he n v ol unt eere d b y t he pat ient , 
a n d w he ne ver t he i n vesti gat or bec o mes a ware of a n e ve nt.

If A E is re p orte d as o n g oi n g at t he ti me of cl os ure of t he pare nt st u d y, AE data will c o nt i n ue 
t o be c ollecte d f or patie nt s ra n d o mize d t o c hl oram b ucil . T hese e ve nts are rec or de d at t he 
st u d y visits i de ntifie d i n t he S c he d ule of A ssess me nt (A p pe n di x A ).

A E data a re n ot c ollecte d f or patie nts o n sec o n d-li ne t hera p y with a n alter nat i ve a ntica ncer 
treat me nt ot her t ha n i br uti ni b.
E ve nts m ust be rec or de d fr o m t he ti me t he I C F is si g ne d (first-li ne i br uti ni b) or fr om start of 
eli gi bilit y assess me nts (sec o n d -li ne i br uti nib) u nt il 3 0 da ys after t he last d ose of st u d y dr u g. A 
la b orat or y a b n or malit y t hat is desi g nate d cli nicall y si g nifica nt b y  t he i n vestigat or will be 
rec or de d as a n A E . A Es of  s pecial i nterest (see Secti o n 8. 3. 4 f or details) will be re p orte d t o t he 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 9
S p o ns or wit hi n 2 4 h o urs of a ware ness a n d will re q uire e n ha nce d data c ollecti o n . A d dit i onal 
i m p orta nt re q uire me nts f or A E a n d S A E re p orti n g are e x plai ne d i n Sect i on 8. 3 .
6. 4. 4.
P h ysic al E x a mi n ati o n
P h ysical e xa mi nat i ons s h o ul d i ncl u de wei g ht, a n d e xa mi nat i on of t he s ki n, e yes ( wit h s pecific 
q uesti o ns f oc use d o n oc ular s y m pt o ms f or i br uti ni b patie nts o nl y), ears, n ose, t hr oat, l u n gs, 
heart, a b d o me n, e xtre mities, a n d l y m p hat ic s yste m. T he l y m p hat ic s yste m e xa mi nati on will 
i ncl u de bi-di me nsi o n al  meas ure me nts of palpa ble l y m p h n o des a n d meas ure me nt of s plee n a n d 
li ver sizes b y ce nti meters bel o w t he c ostal mar gi n o n t he res pect i ve si de.
T he e xa mi nat i on s h o ul d als o i ncl u de i n q uir y  of o c ular s y m pt o ms a n d pat ient s s h o ul d be referre d 
t o a n o p ht hal m ol ogist f or a f or mal e xa mi nat i on if a n y Gra de ≥2 s y m pt o ms are re p orte d.
6. 4. 5.
Vit al Si g ns
Vi t al si g ns will incl u de bl o o d press ure, heart rate, res pirat or y  rate, a n d b o d y t e mperat ure.
6. 4. 6.
E C O G Perf or m a nce St at us
T he E C O G perf or ma nce i n de x is pr o vi de d i n A p pe n di x H.
6. 4. 7.
C o nc o mit a nt Me dic ati o ns
D oc u m e nt all me dicatio ns f r o m t he ti me o f tra nsfer t o t he e xte nsi on st u d y t hr o u g h 3 0 da ys after 
t he last d ose. After a patie nt disc o nt i n ues st u d y treat me nt, recei pt of all s u bse q ue nt a ntica ncer 
t hera pies will be c ollecte d u ntil pat ient  deat h or cl os ure of t he st u d y.
6. 4. 8.
P atie nt -re p orte d O utc o mes
T w o P R O i nstr u me nts t he E Q-5 D- 5 L ( A p pe n di x J) a n d t he F A Ci T-fati g ue (A p pe n di x K) will  
be a d mi nistere d i n t his st u d y . T hese q uest i on naires are t o be c o m plete d b y  t he patient  prior t o 
a n y ot her st u d y pr oce d ures at t he desi g nate d visits.
6. 4. 8. 1.
E Q - 5 D- 5 L
T he E Q - 5 D- 5 L is a sta n dar dize d i nstr u me nt use d t o meas ure of healt h o utc o me 
(E ur o Q o l Gr o u p 1 9 9 0 ) a n d c o nsists of a 5-ite m q uesti o n naire a n d a “t her m o meter” vis ual 
a nal o g ue scale ra n gi n g fr o m 0 ( w orst i ma gi na ble healt h state) t o 1 0 0 ( best i ma gi na ble healt h 
state). T he sc ores f or t he 5 di me nsi o ns are use d t o c o m p ute a si n gle utilit y sc ore ra n gi n g fr om 
0 t o 1, re prese nti n g t he ge neral healt h stat us of t he i n di vi d ual . T he 5 di me nsi o ns e val uate d are 
m o bilit y,  self-care, us ual acti vities, pai n/ disc omf o rt, a n d a n xiety/ de pressi o n.
6. 4. 8. 2.
F A Ci T -F ati g ue
T he F A Ci T -F q uest i on naire is a meas ure of fat i g ue-relate d q uality of  life i n patient s wit h ca ncer 
a n d ot her c hr o nic diseases ( Yelle n 1 9 9 7 ). T he 1 3 -ite m F A Ci T-Fat i g ue Scale meas ures eac h ite m 
o n a 5 -p oi nt Li kert scale . T he F A Ci T -Fat i g ue Scale has bee n vali date d i n t he ge neral p o p ulati on, 
as well as i n pat ient s wit h ca ncer (Cella 2 0 0 2 ) or r he u mat oid art hri tis.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 0
6. 4. 9.
He m at ol o g y
H e m at olo g y  will be e val uate d b y a ce ntral la b orat or y a n d will incl u de a c o m plete bl o o d c o u nt 
( C B C) wit h w hit e blo o d cell differe nt ial. A n y missi n g ce ntral la b orat or y  blo o d s a m ples s h o uld 
be re dra w n as s o o n as p ossi ble . I n t he e ve nt t hat t he missi n g ce ntral la b orat or y sa m ple is 
u nrec o vera ble, l ocal la b orat or y  res ults will be c ollecte d, if a vaila ble, a n d e ntere d i n t he cli nical 
data base f or res p o nse or pr o gressi o n c o nfir mat i on.
6. 4. 1 0.
Ser u m C he mistr y
S er u m  c he mistr y will be e val uate d b y a ce ntral la b orat or y a n d will i ncl u de al b u mi n, al kali ne 
p h os p hatase, A L T, A S T, bl o o d urea nitr o ge n ( B U N), calci u m, creat i ni ne, gl uc ose, lactate 
de h y dr o ge nase ( L D H), p h os p hate, p otassi u m, s o di u m, t otal bilir u bi n, a n d uri c aci d. A n y missi n g 
ce ntral la b orat or y blo o d s a m ples s h o ul d be re dra w n as s o o n as p ossi ble.
6. 4. 1 1.
Dise ase Assess me nt
6. 4. 1 1. 1.
C o m p ute d T o m o gr a p h y ( C T ) Sc a ns
C T sca ns will be p erf or m e d as descri be d i n t he sc he d ules of assess me nt . M RI ma y be use d t o 
e val uate sites of disease t hat ca n n ot be a de q uatel y i ma ge d usi n g C T (i n cases w here M RI is 
desi ra ble, t he M RI must be o btai ne d at baseli ne a n d at all s u bse q ue nt re s p o nse e val uati ons) . 
If M RI i s re q uir e d for a n y  ot her reas o n, t his must first be disc usse d wit h t he st u d y’s Me dical 
M o ni t or.
6. 4. 1 1. 2.
B o ne M arr o w Bi o ps y a n d /or As pir ate
A b o ne marr o w as pirate a n d/or bi o ps y s h o ul d be o btai ne d t o c o nfir m C R, C R i or t o c o nfir m 
c yt o p e nic pr o gressio n a n d disti n g uis h a ut oi m m u ne a n d treat me nt -relate d c yt o p e nias 
(S ectio n 7. 5. 2 ). Marr o w c ollecte d t o c o nfir m C R s h o ul d ha ve M R D
assesse d b y flo w c y t o metr y 
o n t he as pirate . A n a d dit i onal t u be of b o ne marr o w as pirate will be c ollecte d f or bi o mar ker 
assess me nts a n d 2 sli des of t he as pirate s mear s u b mitte d.
6. 4. 1 1. 3.
Dise ase -rel ate d S y m pt o ms
Di sease-relate d s y m pt o msie, fati g ue, ni g ht s weats, fe ver, wei g ht l oss, s y m pt o ms of 
s ple n o me gal y (a b d o mi nal pai n/ disc o mf ort i ncl u di n g earl y satiet y), a n d a n ore xiawill  be 
assesse d a n d rec or de d.
6. 4. 1 1. 4.
O ver all Res p o nse Assess me nt
O verall res p o nse assess me nt will i ncl u de e val uat i on of p h ysica l e xa mi nati ons, rec or di n g of 
s y m pt o ms, he mat ol o gical e val uati o ns, a n d ra di o gra p hic e val uati ons per t he sc he d ule of 
assess me nts (see Secti o n 7 a n d A p pe n di x A, A p pe n di x B , a n d A p pe n di x C ). F or a n y s us pecte d 
case of disease pr o gressi o n, refer t o Secti o n 7. 1 .

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 1
6. 4. 1 2.
C yt o ge netic, C L L FI S H P a nel
As descri be d i n t he sc he d ules o f assess me nts, patie nts at s us pecte d P D a n d i n t he 8 wee ks bef ore
C ycle 1 D a y 1 of  sec o n d-li ne i br uti ni b t hera p y ‡ will ha ve a b o ne marr o w bi o ps y a n d/ or as pi rati on 
perf or m e d lo c all y  t o assess t he c yt o ge netic pr ofile b y usi n g t he sta n dar d C L L FI S H pr o bes t o 
detect a b n or malit ies i n c hr om o s o mes 1 3 q, 1 2, 1 1 q, a n d 1 7 p . If b o ne marr o w f or FI S H is n ot 
a vaila ble, a peri p heral bl o o d sa m ple i n a pat ient  wit h a pretreat me nt l y m p h oc yt osis 
( > 1 0, 0 0 0 cells/ µ L) ca n be s u bjecte d t o FI S H a nal ysis.
6. 4. 1 3.
E x pl or at or y I n vesti g ati o ns of Pr o g n ostic a n d Pre dicti ve Bi o m ar kers a n d 
Mec h a nis m of Tre at me nt Resist a nce
Bl o o d sa m ples will be c ollecte d as descri be d i n t he sc he d ules of assess me nts . T hese sa m ples will 
be pr ocesse d a n d mai ntai ne d f or d o w nstrea m testi n g t o e valuate p ot e ntial bi o mar kers relate d t o 
di sease res p o nse a n d t o i n vesti gate p ote ntial mec ha nis ms of treat me nt resista nce. T hese sa m ples 
ma y later be c haracterize d b y tec h n o l ogi es s uc h as ge ne e x pressi o n pr ofili n g, m utati o n al  a nal ysis 
b y se q ue nci n g, secrete d pr otei n anal ysis, a n d i ntracell ular si g nali n g pat h wa y  a nal ysis. I n hi biti on 
of  B T K a n d ot her relate d ki nases ma y als o be e x pl ore d. T hese eff orts ma y i de nt if y ge nes a n d 
pat h wa ys ass ociate d wit h pri mar y or later de vel o p me nt of resista nce t o i br uti ni b a n d p ote ntiall y 
ide nt if y bi o mar kers t hat c o ul d assist wit h f ut ure de vel o p me nt of t his c o m p o u n d.
6. 4. 1 4.
Alter n ati ve A ntic a ncer Tre at me nt
F or all patie nts i n pre-P D f o ll ow u p ( A p pe n di x A , A p pe n di x B a n d A p pe n di x C ) a n d 
A p pe n di x D , ide nt ificati o n of alter nati ve a ntica ncer treat me nt, i ncl u di n g start date, reas o n, 
d urati o n , a n d best o verall res p o nse ( B O R) will be rec or de d a n d assesse d at eac h visit acc or di n g 
t o t he visit sc he d ule of assess me nts.
F o ll owi n g i m ple me ntati o n of Pr ot oc ol A me n d me nt 3, f or patie nts ra n d o mize d t o c hl ora m b ucil ,
i de ntificati on of al ter nati ve a ntica ncer treat me nt will o nl y i ncl u de start date a n d reas o n.
7.
M AI N E F FI C A C Y E V A L U A TI O N S
Di sease e val uati ons i ncl u de t he f o ll owi n g: 

P h ysical e xa mi nat i on ( w hic h will f oc us o n t he pre se nce/a bse nce of size i ncrease/decrease i n 
l y m p h n o des, li ver, a n d s plee n)

Di sease-relate d s y m pt o ms

H e m at olo gi c para meters b y C B C perf or me d at a ce ntral la b orat or y

Ra di o gra p hic e val uat i on ( C T or M RI sca n of t he nec k, c hest, a b d o me n, a n d pel vis)

B o ne m arr o w as pir at e a n d/or bi o ps y as a p pr o priat e b y flo w c y t o metr y if t here is e vi de nce of 
C R i n t he ot her res p o nse para meters .
o
P atie nts w h o ac hie ve M R D-ne gati ve re missi o n i n t he b o ne marr o w m a y t he n be f oll ow e d 
b y peri p heral bl o o d M R D a p pr o xi matel y e ver y 6 m o nt hs .

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 2
o
P ati e nts w h o ha ve M R D -p osi ti ve stat us i n t he b o ne marr o w, ca n als o be f oll owe d wi t h 
p eri p heral  blo o d M R D assess me nts, h o we ver, o nce t he patie nt bec o mes M R D -ne gat i ve i n 
t he p eri p heral bl o o d, t his res ult s h o uld be s u bse q ue ntl y c o nfir me d wi t h a bo ne marr o w 
M R D assess me nt.
Efficac y assess me nts, f or t he p ur p ose of t he st u d y  res ult a nal yses, will be perf or me d b y t he 
i n vesti gat or. At  t he re q uest of Heal t h Aut h ori ties, t he data ma y be re vie we d b y a n I n de pe n de nt 
R e vie w C o m mittee (I R C) as well.
7. 1.
S us pecte d Dise ase Pr o gressi o n
T he sc he d ules of assess me nts are pr o vi de d i n A p pe n di x A , A p pe n di x B , a n d A p pe n di x C . A n y 
s us pecte d case of disease pr o gressi o n will pr o m pt  pr oce d ures perf or me d i n a S us pecte d-P D V isit 
(Secti o n 6. 3 ). Disease pr o gressi o n s h o ul d be c o nfir me d wit h a C T sca n ( or M RI, if C T is 
c o ntrai n dicate d) a n d s h o ul d be re p orte d t o t he S p o ns or wi t hi n 2 4 h o urs of di sc o ver y. If disease 
pr o gressi o n is s us pecte d base d o n t he res ults of a si n gle e xa mi nat i on (i ncl u di n g C T sca n) or a 
si n gle la b orat or y para meter, t his fi n di n g s h o ul d be c o nfir me d b y a s u bse q ue nt e val uati on at l east 
2 wee ks l ater.
St u d y  treat me nt a n d all st u d y-r elate d pr oce d ures a n d assess me nts as descri be d i n A p pe n di x A ,
A p pe n di x B , A p pe n di x C or A p pe n di x D 
s h o uld be c o nti n ue d u nt il disease pr o gressi o n is 
deter mi ne d b y t he i n vest i gat or. W he n disease pr o gressi o n has bee n deter mi ne d b y t he 
i n vesti gat or, t he c urre nt st u d y treat me nt s h o uld be di sc o nti n ue d.
If ne w a nt ica ncer t hera p y is i nitiate d prior t o pr o gressi ve disease, t he patie nt s h o ul d c o nt i n ue t o 
be f oll owe d f or di sease pr o gressio n as descri be d f or t he pre -P D f oll o w -u p p hase acc or di n g t o t he 
sc he d ule i n w hic h t he y are e nr olle d (Secti o n 6. 3 ).
Bl o o d tests perf or m e d l ocall y for deter mi nat i on of res p o nse or disease pr o gressi o n will nee d t o 
be re peate d b y  t he ce ntral la b orat or y for c o nfi r mat i o n of res ults.
7. 2.
G ui deli nes f or Dise ase E v al u ati o n
O bject i ve res p o nse will be cate g orize d as C R , C R wit h inc o m p lete b o ne marr o w rec over y ( C Ri), 
n P R , P R , sta ble disease, or P D — all base d u p o n I W C L L criteria ( Halle k 2 0 0 8 ). All res p o nses 
m u st be mai ntai ne d f or at least 2 m o nt hs t o be c o nsi dere d c o nfir me d . C Rs m ust be c o nfir me d b y 
b o ne marr o w bi o ps y a n d/or as pir at e. Res p o nse assess me nts will occ ur i n de pe n de nt of o n g oi n g 
t hera p y.
Detaile d defi nit i ons of all cate g ories o f res p o nse are i n A p pe n di x E . Res p o nse criteria a n d 
cr iteria f or disease pr o gressi o n are descri be d i n A p pe n di x F.
Gi ve n t he k n o w n mec ha nis m o f actio n of  B C R-i n hi biti n g a ge nts, i ncl u di n g i br uti ni b, a n d t he 
treat me nt -relate d l y m p h oc yt osis fre q ue ntl y o bser ve d d uri n g treat me nt wit h i br uti ni b, is olate d 
treat me nt -relate d l y m p h oc yt osis (i n a bse nce of ot her cli nical, C T, or la b orat or y e vide nce of 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 3
di sease pr o gressio n) will n ot be c o nsi dere d pr o gressi ve disease . T his a p pr oac h is s u p p orte d b y 
b ot h t he a ut h ors of t he I W C L L 2 0 0 8 g ui deli nes (Halle k 2 0 1 2 , C hes o n 2 0 1 2 ) a n d t he N C C N.
Ta ble 5 o utli nes w hat is re q uire d f or eac h para meter at baseli ne t o be e val ua ble t hr o u g h o ut t he 
st u dy.
T a ble 5:
E v al u a ble P ar a meter Re q uire me nts
P ar a meter
Re q uire me nts t o be E v al u a ble f or Res p o nse
Meas ura ble disease
L y m p h n o de > 1. 5 c m
S ple n o me gal y
E nlar ge d s plee n
He pat o me gal y
E nlar ge d li ver
L y m p h oc yte c o u nt
> 4, 0 0 0/ L
Platelets
< 1 0 0, 0 0 0/ L
A bs ol ute ne utr o p hil c o u nt
< 1, 5 0 0/ L
He m o gl o bi n
< 1 1. 0 g/ d L
7. 3.
S ust ai ne d He m at ol o gic al I m pr o ve me nt
I n all pat ient s a n d t he s u bset of patie nts wit h c y t o pe nia(s) at baseli ne ( H g b ≤1 1 g/ d L, 
pl at elets ≤1 0 0, 0 0 0 / μ L), ti me t o i m pr o ve me nt i n bl o o d c o u nts a n d perce nta ge of patie nts wi t h 
i m pr o ve me nt (s ustai ne d i m pr o ve me nt, defi ne d as i m pr o ve me nt i n c yt o pe nia b y a n i ncrease of 
H g b le vels fr o m baseli ne b y  ≥2 g/ d L, or a n i ncrease of platelet c o u nts fr o m baseli ne b y  ≥5 0 %, 
wi t h t he d uratio n of  im pr o ve me nt last i n g f or at least 5 6 d a y s wit ho ut bl o o d tra nsf usi o n or gr o wt h 
fact ors) will be assesse d .
7. 4.
Res ol uti o n of Pretre at me nt Dise ase -Rel ate d S y m pt o ms
Res o l uti on of pretreat me nt c o nstit uti o nal s y m pt o ms i ncl u di n g fat i g ue, wei g ht l oss, a n ore xia, 
fe vers, ni g ht s weats, or s y m pt o ms of s ple n o me gal y will be e val uate d.
7. 5.
Tre at me nt -Rel ate d Defi niti o ns
Defi nit i ons of meas ur a ble disease, treat me nt -relate d l y m p h oc yt osis, Ric hter’s tra nsf or mati on, 
M R D , a n d treat me nt fail ure ca n be f o u n d i n A p pe n di x E .
7. 5. 1.
C o m p ute d T o m o gr a p h y Sc a ns
Ra di ol o gi c al i ma gi n g b y C T wit h c o ntrast is re q uire d if attai na ble, a n d it m ust i ncl u de t he pel vis, 
a b d o me n, c hest, a n d nec k . P ati e nts w h o are i nt olera nt t o I V c o nt rast a ge nts will ha ve C T sca ns 
perf or m e d wit h or al c o ntrast. W he n p ossi ble, all patie nts s h o ul d ha ve ra di o gra p hic t u m or 
meas ure me nts perf or me d at t he partici pati n g st u d y ce nter or a n acce pta ble alter nate i ma gi n g 
facility usi n g a n i de ntical  i ma gi n g pr oto c ol  a n d si milar e q uip me nt . T he sa me i ma gi n g e q ui p me nt 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 4
s h o uld be utilize d f or all sca ns w he ne ver p ossi ble . T he sa me ra di o l ogi st s h o uld be assi g ne d t o 
rea d all t he sca ns f or a gi ve n patie nt t hr o u g h o ut t he st u d y.
C T sca ns of  t he nec k, c hest, a b d o me n, a n d pelvis will be perf or me d at ti mes s pecifie d i n t he 
sc he d ules of assess me nts. I n t he e ve nt disease pr o gressi on is s us pecte d base d o n p h ysical 
e xa mi nat i on or a la b orat or y  test, a C T sca n m ust be perf or me d t o c o nfir m disease pr o gressi o n.
U p t o 6 meas ura ble l y m p h n o des (tar get lesi o ns), clearl y  meas ura ble i n 2 per pe n dic ular 
di me nsi o ns, will be f o ll owe d f or eac h pat ient . Meas ura ble sites of disease s h o ul d be c h ose n s uc h 
t hat t he y are re prese ntati ve of t he patie nt’s disease. I n a d diti o n, selecti on of tar get lesi o ns s h o uld 
be fr om as dis parate re gi o ns of t he b o d y as p ossi ble. If a d diti onal lesio n s are prese nt b ut are n ot 
i ncl u de d i n t he tar get lesi on assess me nt, t he y  ca n be a d de d as n o ntar get lesi o ns f oll owe d 
t hr o u g h o ut t he st u d y.
T he l o n gest di a meter of t he s plee n a nd li ver will be assesse d at S cree ni n g a n d all s u bse q ue nt 
res p o nse e val uati ons.
L y m p h n o des a n d s plee n will be e val uate d r a dio gra p hicall y , a n d ra dio gra p hic fi n di n gs will 
o verri de p h ysical e xa mi nat i on assess me nt of t he sa me lesi o n.
Sca ns will be rea d b y  a n in de pe n de nt l ocal ra di o l ogi st, a n d res ults will be i nter prete d b y t he 
i n vesti gat or.
7. 5. 2.
B o ne M arr o w As pir ate a n d /or Bi o ps y a n d Mi ni m al Resi d u al Dise ase
If t he patie nt’s p h ysical e xa mi nati on fi n di n gs, la b orat or y e val uati ons, a n d ra di o gra p hic 
e val uat i ons s u g gest t hat C R has bee n ac hie ve d, a b o ne marr o w as pirate a n d/or bi o ps y s h o ul d be 
o btai ne d t o c o nfir m t he C R or n P R . I n rare cases w here pr o gressi o n is o nl y s h o w n i n 
1 para meter, a b o ne marr o w as pirate a n d/or bi o ps y ca n be perf or me d t o c o nfir m c y t o pe nic 
pr o gressi o n a n d dist i n g uis h a ut oi m m u ne a n d treat me nt-relate d c yt o p e nias.
P eri p heral  blo o d a n d b o ne marr o w as pirate or bi o ps y wit h fl ow c y t o m etr y assess me nt(s) f or 
M R D s h o ul d be d o ne if t here is e vi de nce of C R i n all o f t he res p o nse para meters . M R D is 
defi ne d as < 1 C L L cell per 1 0, 0 0 0 le u k oc y t es. F oll o wi n g t he attai n me nt of a n M R D -ne gat i ve 
C R c o nfir me d b y b o ne marr o w as pirate, patie nts s h o ul d be f o ll owe d wi t h p erip h er al  blo o d M R D 
a nal yses a p pr o xi matel y e ver y 6 m o nt hs . Pati e nts w h o ha ve M R D -p osi tive stat us i n t he b o ne
marr o w, ca n als o be f o ll owe d wi t h p erip h er al  blo o d M R D assess me nts e ver y 4 t o 6 c ycles, 
h o we ver, o nce t he pati e nt bec o mes M R D -ne gat i ve i n t he peri p heral bl o o d, t his res ult s h o ul d be 
s u bse q ue ntl y c o nfir me d wit h a b o ne marr o w M R D assess me nt.
8.
A S S E S S M E N T O F S A F E T Y
I n t his lo n g- t er m e xte nsi on st u d y , A Es are rec or de d as f o ll ows:

A E data c ollecte d f or patie nts o n first -li ne or sec o n d-li ne i br uti ni b withi n A E re p orti n g 
p eri o d defi ne d i n Sect i on 8. 3. 1 . All A Es are rec or de d at t he st u d y visits i de ntifie d i n t he 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 5
sc he d ules of assess me nt f or i br uti ni b (A p pe n di x B a n d A p pe n di x C ), w he n v ol unt eere d b y 
t he patie nt, a n d w he ne ver t he i n vest i gat or bec o mes a ware of an e ve nt.

If A E re p orte d as o n g oi n g at t he ti me of clos ure of t he pare nt st u d y , A E data will c o nti n ue t o 
be c o llecte d f or patie nt s ra n d o mize d t o c hl oram b ucil . All A Es are rec or de d at t he st u d y  visits 
i de ntifie d i n t he sc he d ule of assess me nt (A p pe n di x A ).

A E data are n ot c ollecte d f or patie nts o n sec o n d -li ne t hera p y with a n alter nat i ve a ntica ncer 
treat me nt ot her t ha n i br uti ni b.
8. 1.
S afet y M o nit ori n g Pl a n
A P h ar m a c o vigila nce C o m mittee will c o m par e A Es i n t he st u d y  wit h safet y data fr o m t he e ntire 
cli nical trial data base f or i br uti ni b. All e nr olle d patie nts will be e val uate d cli nicall y  a nd usi n g 
sta n dar d la b orat or y testi n g d uri n g t heir partici pati o n i n t his st u d y.
S af et y assess me nts will c o nsist of m o nit ori n g a n d rec or di n g A Es a n d S A Es; meas ure me nts of 
pr ot oc ol -s pecifie d he mat ol o g y, cli nical c he mistr y, a n d ot her la b orat or y varia bles; meas ure me nt 
of  pr ot oc ol-s pecifie d vital si g ns; a n d ot her pr ot oc ol-s pecifie d tests t hat are dee me d crit ical t o t he 
safet y e val uat i on of t he st u d y  dr u g(s).
8. 2.
Defi niti o ns
8. 2. 1.
A d verse E ve nts
A n A E i s a n y u nt o war d me dical occ urre nce i n a patie nt a d mi nistere d a p har mace ut ical pr o d uct 
a n d w hic h d oes n ot necessaril y ha ve a ca usal relat i o ns hi p with t hi s treat me nt . A n A E ca n 
t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a cli nicall y si g nifica nt a b n or mal 
la b orat or y fi n di n g, f or e xa m ple), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a n 
i n vesti gati onal st u d y  dr u g, w het her or n ot c o nsi dere d relate d t o t he st u d y dr ug ( I C H-E 2 A 1 9 9 5 ).
F or t he p ur p oses of t his cli nical st u d y , A Es i ncl u de e ve nts w hic h are eit her ne w or re prese nt 
detecta ble e xacer bati o ns of pre -e xist i n g c o n diti ons.
Di sease pr o gressio n is n ot a n A E ; rat her it ma y be t he ca use of a n A E . A E s t hat occ ur d ue t o 
di sease pr o gressio n m ust be re p orte d as all ot her treat me nt -e mer ge nt A E s.
T he ter m  “disease pr o gressi o n” s h o ul d n ot be re p orte d as a n A E ter m. As a n e xa m ple, 
" w orse ni n g of C L L/ S L L" or t he cli nica l dia g n osis t hat is ass ociate d wit h disease pr o gressi o n 
s h o uld be re p orte d.
A E s ma y incl u de, b ut are n ot li mite d t o:

S u bject i ve or o bjecti ve s y m pt o ms s p o nta ne o usl y offere d b y t he patient  a n d/ or o bser ve d b y 
t he i n vesti gat or or st u d y  staff i ncl u di n g la b orat or y a b n or malities of cli nical si g nifica nce.

A n y A Es e x peri e nce d b y t he patie nt t hr o u g h t he c o m plet i on of fi nal st u d y  pr oce d ures.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 6

A Es n ot pre vi o usl y o bser ve d i n t he patie nt t hat e mer ge d uri n g t he pr ot oc ol -s pecifie d A E 
re p orti n g peri o d, i ncl u di n g si g ns or s y m pt o ms ass ociate d wit h C L L/ S L L t hat were n ot 
prese nt bef ore t he A E re p orti n g peri o d (see Secti o n 8. 3. 1 ).

C o m plicat i ons t hat occ ur as a res ult of pr ot oc ol -ma n date d i nter ve nt i ons ( e g, i n vasi ve 
pr oce d ures s uc h as bi o psies).

T he f o ll owi n g are N O T c o nsi dere d A Es:

Pre -e xisti n g c o n dit i o n:  A pre -e xist i n g c o n diti on ( d oc u me nte d o n t he me dical hist or y C R F) 
is n ot c o nsi dere d a n A E u nless t he se verit y,  fre q ue nc y, or c haracter of t he e ve nt w orse ns 
d uri n g t he st u d y  p erio d.

Pre -pl a n ne d or electi ve h os pit aliz ati o n:   A h os pitalizat i on pla n ne d be f ore si g ni n g t he I C F
is n ot c o nsi dere d a n S A E, b ut rat her a t hera pe utic i nter ve nt i on . H o we ver, if d uri n g t he 
pre -pla n ne d h os pitalizat i on a n e ve nt occ urs, w hic h pr ol o n gs t he h os pitalizat i on or m eets a n y 
ot her S A E criteria, t he e ve nt will be c o nsi dere d a n S A E . S ur geri es or i nter ve nti o ns t hat were 
u n der c o nsi derat i on, b ut n ot perf or me d bef ore e nr oll me nt i n t he st u d y , will n ot be c o nsi dere d 
serio us if t he y are perf or me d after e nr oll me nt i n t he st u d y  for a c o n di tio n t hat has n ot 
c ha n ge d fr o m its baseli ne le vel. El ecti ve h os pitalizati o ns f or s ocial reas o ns, s olel y f or t he 
a d mi nistrati o n of c he m ot hera p y, or d ue t o lo n g tra vel dista nces are als o n ot S A Es.

Di a g n ostic testi n g a n d pr oce d ures:   Testi n g a n d pr oce d ures s h o ul d n ot t o be re p orte d as 
A Es or S A Es, b ut rat her t he ca use f or t he test or pr oce d ure s h o ul d be re p orte d.
8. 2. 2.
Seri o us A d verse E ve nt
N ote:  T he ter ms “ se vere” a n d “seri o us” are n ot s y n o n y m o us. Se verit y ( or i nte nsit y) r efers t o t he 
gra de of a n A E (see bel o w) . “ Seri o us” is a re g ulat or y defi nitio n .
A S A E (e x perie nce) or reacti o n is a n y u nt o war d me dical occ urre nce t hat at a n y  d ose:

Res ults i n deat h (ie, t he A E act uall y  ca uses or lea ds t o deat h).

Is life-t hreate ni n g. Life -t hreate ni n g is defi ne d as a n A E i n w hic h t he patie nt was at ris k of 
deat h at t he ti me of t he e v e nt . It d oes n ot refer t o a n e ve nt w hic h h y p ot heticall y mi g ht ha ve 
ca use d deat h if it were m ore se vere . If either t he i n vesti gat or or t he S p o ns or belie ves t hat a n 
A E m eets t he defi nit i on of life -t hreate ni n g, it will be c o nsi dere d life-t hreate ni n g.

Re q ui r es i n-pat ient  h os pitalizati on > 2 4 h o urs or pr ol o n gati o n o f e xist i n g h os pi talizati on.

Res ults i n persiste nt or si g nifica nt disa bilit y/ i nca pacity (ie, t he A E res ults i n s u bsta nt ial 
di sr u pti on of t he patie nt’s a bilit y t o c o n d uct n or mal life f u nct i ons).

Is a c on ge nital a n o ma l y/ birt h-d ef ect .

Is a n i m p orta nt me dical e ve nt t hat ma y n ot res ult i n deat h, be i m me diatel y life-t hreate ni n g or 
re q uire h os pitalizatio n, b ut m a y be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he e ve nt ma y je o par dize t he pati e nt or patie nt ma y re q uire i nter ve nti on t o pre ve nt 
o ne of t he ot her o utc o mes liste d i n t his defi nit i on . E xa m ples of s uc h e ve nts are i nte nsi ve 
treat me nt i n a n e mer ge nc y de partme nt  or at h o me f or aller gic br o nc h os pas m, bl o o d 
d y scrasias, or c o n v ulsi on t ha t d oes n ot res ult i n h os pitalizati o n; or de vel o p me nt of dr u g 
de pe n de nc y  or dr u g a b use.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 7
Gi ve n t hat t he i n vesti gat or’s pers pecti ve ma y be i nf or me d b y ha vi n g act uall y o bser ve d t he e ve nt, 
a n d t he S p o ns or is li kel y t o ha ve br oa der k n o wle d ge of t he dr u g a n d its effects t o i nf or m its 
e val uat i on of t he si g nifica nce of t he e ve nt, if eit her t he S p o ns or or t he i n vesti gat or belie ves t hat 
t he e ve nt is seri o us, t he e ve nt will be c o nsi dere d seri o us.
8. 2. 3.
Se verit y
Defi nit i ons f o u n d i n t he C o m m o n Ter mi n o l og y Cri t eri a for A d verse E ve nts versi o n 4. 0 3
(C T C A E v 4. 0 3 ) will be use d f or gra di n g t he se verit y (i nte nsity) of n o n he mat ol o gic A Es . Refer t o 
A p pe n di x I f or t he gra di n g of he mat ol o gic A Es . T he C T C A E v 4. 0 3 di s pla ys Gra des 1 t hr o u g h 5 
wi t h u ni q ue cli nical descri pti ons of se verit y f or eac h refere nce d A E. S h o ul d a pat ient e x perie nce 
a n y A E n ot liste d i n t he C T C A E v 4. 0 3 , t he f oll owi n g gra di n g s yste m s h o ul d be use d t o assess 
se verity:

Gra de 1 ( Mil d A E) – e x perie nces w hic h are us uall y tra nsie nt, re q uiri n g n o s pecial treat me nt, 
a n d n ot i nterferi n g wit h t he patie nt’s dail y act i vities

Gra de 2 ( M o derate A E) – e x perie nces w hic h i ntr o d uce s o me le vel of i nc o n ve nie nce or 
c o ncer n t o t he patie nt, a n d w hic h ma y i nterfere wit h dail y act i vities, b ut are us uall y 
a meliorate d b y  si m ple t hera pe utic me as ures

Gra de 3 ( Se vere A E) – e x perie nces w hic h are u nacce pta ble or i nt olera ble, si g nifica nt l y 
i nterr u pt t he patie nt’s us ual dail y acti vit y, a n d re q uire s yste mic dr u g t hera p y or ot her 
treat me nt

Gra de 4 ( Life -t hreate ni n g or disa bli n g A E) – e x perie nces w hic h ca use t he patie nt t o be i n 
i m mi ne nt da n ger of deat h

Gra de 5 ( Deat h relate d t o A E) – e x perie nces w hic h res ult i n patie nt deat h
8. 2. 4.
C a us alit y
T he i n vesti gat or is t o assess t he ca usal relati o n (ie, w het her t here is a reas o na ble p ossi bility t hat 
t he st u d y dr u g ca use d t he e ve nt) usin g t he f o ll owi n g defi nit i ons:
N ot Rel ate d:
A n ot her ca use of t he A E is m ore pla usi ble; a te m p oral se q ue nce ca n n ot 
be esta blis he d wit h t he o nset of t he A E a n d a d mi nistrati o n of t he 
i n vesti gati onal pr o d uct; or, a ca usal relati o ns hi p is c o nsi dere d 
bi o l ogicall y i m pla usi ble.
U nli kel y:
T he c urre nt k n o wle d ge or i nf or mati o n a b o ut t he A E i n dicates t hat a 
r elat i ons hi p t o t he i n vest i gati onal pr o d uct is u nli kel y.
P ossi bl y Relate d:
T here i s a cli nicall y pla usi ble ti me se q ue nce bet wee n o nset of t he A E 
a n d a d mi nistrati o n of  t he i n vesti gati onal pr o d uct, b ut t he A E c o ul d als o 
be attri b ute d t o c o nc urre nt or u n derl yi n g disease, or t he use of ot her 
dr u gs or pr oce d ures . P ossi bl y relate d s h o ul d be use d w he n t he 
i n vesti gati onal pr o d uct is o ne of se veral bi o l ogicall y  pla usi ble A E 
ca uses.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 8
Relate d:
T he A E is clearl y relate d t o use of t he i n vest i gati onal pr o d uct.
8. 2. 5.
U ne x pecte d A d verse E ve nts
A n “ u ne x pecte d” A E is a n A E t hat is n ot liste d i n t he I B/ pac ka ge i nsert or is n ot liste d at t he 
s pecificity or se verit y t hat has bee n o bser ve d . F or e xa m ple, he patic necr osis w o ul d be 
“ u ne x pecte d” ( b y  virt u e of greater se verity)  if t he I B referre d o nl y t o ele vate d he patic e nz y mes 
or he patit is. Si milarl y, cere bral t hr o m b oe m b o lism a n d cere bral vasc ulit is w o ul d be “ u ne x pecte d” 
( b y virt ue of greater s pecificit y)  if t he I B/ pac ka ge i nsert liste d o nl y cere bral vasc ular acci de nts. 
“ U ne x pecte d” als o refers t o A Es t hat are m e nt i one d i n t he I n vest i gat or's Br oc h ure as occ urri n g 
wi t h a class of dr u gs or as a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he d r u g, b ut are 
n ot s pecificall y  me nt i one d as occ urri n g wit h t he st u d y  dr u g u n der i n vesti gati on.
8. 3.
D oc u me nti n g a n d Re p orti n g of A d verse a n d Seri o us A d verse E ve nts b y 
I n vesti g at ors
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all A Es a n d S A Es t hat are o bser ve d or re p orte d 
d uri n g t he st u d y , as o utli ne d i n t he pri or secti o ns, are rec or de d o n t he C R F. All A Es o n g oi n g at 
t he ti me o f clos ure of t he pare nt st u d y  must be f oll o we d u p t o res ol uti on i n t he e xte nsi on st u d y . 
All S A Es als o m ust be re p orte d o n t he S A E W or ks heet (see Secti o n 8. 3. 3 ).
8. 3. 1.
A d verse E ve nt Re p orti n g Peri o d
F or patie nts ra n d omize d t o i br uti ni b i n t he pare nt st u d y a n d c o nti n ui n g o n i br uti ni b the r a p y i n 
P C Y C - 1 1 1 6-C A , A E s will c o nt i n ue t o be re p orte d u nt il 3 0 da ys f o ll owi n g t he l ast d ose of 
i br uti ni b.
F or patie n ts w h o were ori gi nall y  ra n d o mize d t o c hl ora m b ucil i n t he pare nt st u d y a n d cr oss o ver 
t o t he sec o n d-li ne i br uti ni b t hera p y i n P C Y C - 1 1 1 6-C A , A Es will be re p orte d fr o m t he ti me t he 
pati e nts start eli gi bilit y pr oce d ures t o c o m me nce sec o n d -li ne i br uti ni b thera p y u ntil 3 0 da ys 
f oll owi n g t he last d ose of i br uti ni b.
P ati e nts w h o were ori gi nall y ra n d o mize d t o c hl ora m b ucil i n t he pare nt st u d y a n d ha ve n ot 
cr osse d o ver t o sec o n d- li ne i br uti ni b with A Es o n g oi n g at t he ti me o f clos ure of t he pare nt st u d y  
will c o nt i n ue t o ha ve t hose A Es m o nit ore d u ntil res ol ut i on.
If a n S A E is prese nt at t he E n d-of -St u d y Visi t, t he S A E s h o uld be f ol l owe d t o res ol ut i on or u n til 
t he i n vesti gat or assesses t he patie nt as sta ble, or t he patie nt is l ost t o f o ll ow- u p or wi t hdra ws 
c o nse nt . Res ol uti o n/sta ble mea ns t he patie nt has ret ur ne d t o baseli ne state of healt h or t he 
i n vesti gat or d oes n ot e x pect a n y f urt her i m pr o ve me nt or w orse ni n g of t he e ve nt.
A n y S A E t hat occ urs m ore t ha n 3 0 da ys after t he last d ose of t he st u d y  dr u g a n d is dee me d 
r elate d t o i br uti ni b m u st be re p orte d t o t he S p o ns or. Res ol ut i on i nf or mati on after 3 0 da ys s h o ul d 
be pr o vi de d.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 9
Pr o gressi ve disease s h o ul d n ot be re p orte d as a n e ve nt ter m, b ut i nstea d s y m pt o ms/cli nical si g ns 
of  disease pr o gressio n ma y  be re p orte d. All deat hs s h o ul d be re p orte d wit h t he pri mar y ca use of 
deat h as t he A E ter m, as deat h is t y p icall y t he o utc o me of t he e ve nt, n ot t he e ve nt itself. A ut o ps y  
a n d p ost mort e m  re p orts must be f or war de d t o t he S p o ns or, or desi g nee, as o utli ne d a b o ve, if 
all o we d per l ocal re g ulat or y g ui deli nes. If a deat h occ urs wit hi n 3 0 da ys after t he last d ose of 
st u d y dr u g, t he deat h m ust be re p orte d t o t he S p o ns or as a n S A E.
8. 3. 2.
Assess me nt of A d verse E ve nts
In vest i gat ors will assess t he occ urre nce of A Es i ncl u di n g S A Es as descri be d i n t he sc he d ules of 
assess me nts f or i br uti ni b (A p pe n di x B a n d A p pe n di x C ), rec or di n g e ve nts w he n v ol unt eere d b y 
t he pati e nt , disc o vere d b y st u d y pers o n nel d uri n g q uesti o ni n g, detecte d t hr o u g h p h ysical 
e xa mi nat i on, cli nicall y si g nifica nt la b orat or y  test, or ot her mea ns. E ve nts will be rec or de d i n t he
pati e nt ’s me dical rec or d a n d o n t he A E C R F a n d, w he n a p plica ble, o n t he S A E W or ks heet.
Eac h rec or de d A E or S A E will be descri be d b y it s d uratio n (i e, start a n d e n d dates), se verit y,  
re g ulat or y s erio us ness cri teria (if ap plica ble), s us pecte d relat i ons hi p t o t he i n vest i gati onal 
pr o d uct, a n d a n y  acti ons ta ke n.
8. 3. 3.
E x pe dite d Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts
All S A Es (i nit ial a n d f oll ow- u p i nf or m at i on) will be re p orte d o n t he S A E W or ks heet a n d fa xe d 
t o P har mac yclics Dr u g Safety,  or desig nee, wi t hi n 2 4 h o urs of t he disc o ver y of t he e ve nt or 
i nf or mat i on . P har mac yclics ma y re q uest f o ll ow- u p a n d ot her a d dit i onal i nf or mat i on fr om t he 
i n vesti gat or (e g, h os pital a d missi on/ disc har ge n otes a n d la b orat or y  res ults). T he c o nt act 
i nf or mat i on ( p h o ne, fa x a n d e mail) f or t he dr u g safet y  ca n be f o u n d o n t he S A E W or ks heet f or m 
a n d i nstr ucti o ns.
All deat hs s h o ul d be re p orte d wit h t he pri mar y  ca use of deat h as t he A E ter m, as deat h is 
t ypicall y  t he o utc o me of t he e ve nt, n ot t he e ve nt itself. T he pri mar y  ca use of deat h o n t he 
a ut o ps y re p ort or t he A E / S A E most pr o xi mal t o deat h s h o ul d be t he ter m re p orte d . A ut o ps y  a n d 
p ost m ort e m  re p orts must be f or war de d t o P har mac yclics Dr u g Safet y,  or desig nee, as o utli ne d 
a b o ve.
If st u d y dr u g is disc ont i n ue d beca use of a n S A E, t his i nf or mati on m u st be i ncl u de d i n t he S A E 
re p ort.
8. 3. 4.
E ve nts of S peci al I nterest
S pecific A E s, or gr o u ps of A E s, will be f oll owe d as part of sta n dar d safet y m o nit ori n g act i vities 
b y t he S p o ns or . T hese e ve nts will be re p orte d t o t h e S p o ns or wit hi n 2 4 h o urs of a ware ness 
f oll owi n g t he pr oce d ure descri be d a b o ve f or S A Es ( Secti o n 8. 3. 3 ) a n d will re q uire e n ha nce d data 
c ollect i on . H o we ver, a n E ve nt of S pecial I nterest will be c o nsi dere d a n S A E o nl y if it meets 1 of  
t he crit eria for S A Es . All E ve nts of S pecial I nterest will be s u b mitt e d wit ho ut a seri o us cri t erio n 
selecte d if n o ot her seri o us criteri o n is met.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 0
8. 3. 4. 1.
M aj or He m orr h a ge
Maj or h e m orr ha ge is defi ne d as a n y of t he f oll o wi n g: 

A n y treat me nt -e mer ge nt he morr ha gic A Es of Gra de 3 or hi g her *.

A n y treat me nt -e mer ge nt serio us a d vers e e ve nts of blee di n g of a n y gra de

A n y treat me nt -e mer ge nt ce ntral ner v o us s yste m he m orr ha ge/ he mat o ma of a n y gra de
* All he m orr ha gic e ve nts re q uiri n g tra nsf usi o n of re d bl o o d cells s h o ul d be re p orte d as Gra de 3 
or hi g her A E per C T C A E v 4. 0 3.
E ve nts meet i n g t he defi nit i on of maj or he m orr ha ge will be ca pt ure d as a n e ve nt of s pecial 
i nterest acc or di n g t o Secti o n 8. 3. 4 a b o ve.
8. 3. 5.
Pre g n a nc y
D ue t o t he i ncl usi o nar y a ges of t his st u d y, it is n ot e x pecte d t hat fe male st u d y patient s will ha ve 
t he a bilit y t o bec o me pre g na nt.
Bef ore st u d y  e nr oll me nt, male pat ient s m ust be willi n g t o use a n effecti ve barri er met h o d of 
c o ntrace pti o n d uri n g t he st u d y a n d for 3 m o nt hs f oll o wi n g t he l ast d ose of st u d y dr u g if se x uall y 
acti ve wit h a fe male of c hil d beari n g p ote ntial . A patie nt m ust i m me diatel y i nf or m t he 
i n vesti gat or if t he patie nt’s part ner bec ome s pre g na nt fr om t he ti me of c o nse nt t o 3 m o nt hs after 
t he last d ose of i br uti ni b. T he i n vesti gat or s h o ul d c o u nsel t he patient , disc ussi n g a n y ris ks of 
c o nti n ui n g t he pre g na nc y a n d a n y p ossi ble effects o n t he fet us . 
Alt h o u g h pre g na nc y  itself is n ot re gar de d as a n A E, t he o utc o me will nee d t o be d oc u me nte d. 
Re p ort a n y  pre g na nc y t hat occurs i n a patie nt’s part ner fr o m t he ti me of c o nse nt t o 3 0 da ys after 
t he last d ose of i br uti ni b. Rec or d a n y  occ urre nce of pre g na nc y o n t he Pre g na nc y Re p ort F or m 
Part I a n d fa x t o P har mac yclics Dr u g Safet y,  or desi g nee, wit hi n 2 4 h o urs of lear ni n g of t he 
e ve nt . Wit h c o nse nt t he pre g na nt fe male will be f oll o we d f or o utc o me, w hic h is defi ne d as 
elect i ve ter mi nati o n of t he pre g na nc y, miscarria ge, or deli ver y of t he fet us. F or pre g na ncies wit h 
a n o utc o me of li ve birt h, t he ne w b or n i nfa nt will be f oll owe d u nt il 30 da ys ol d b y c o m p leti n g t he 
Pre g na nc y Re p ort F or m Part II . A n y c o n ge nital a n o mal y/ birt h defect n ote d i n t he i nfa nt m ust be 
re p orte d as a n S A E.
8. 3. 6.
E ye -Rel ate d A d verse E ve nts
Ne w or w o rse ni n g e ye-relate d s y m pt o ms t hat are Gra de 2 or hi g her, or a s y m pt o m t hat was 
Gra de 2 or hi g her at baseli ne w orse ns, s h o ul d be e val uate d b y a n o p ht hal m o l ogist w h ose 
fi n di n gs s h o ul d be re p orte d o n t he o p ht hal m o l ogic e C R F .
8. 3. 7.
Ot her M ali g n a ncies
A ll ne w m alig na nt t u m ors i ncl u di n g s oli d t u m ors, s ki n mali g na ncies a n d he mat ol o gic 
mali g na ncies are t o be re p orte d f or t he d urati o n of st u d y treat me nt a n d d uri n g a n y pr ot oc ol -

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 1
s pecifie d f oll ow- u p peri o ds i ncl u di n g p ost -pr o gressi o n f o ll ow- u p f or o verall s ur vi val i n all
pati e nt s.
8. 4.
Re p orti n g of Seri o us A d verse E ve nts b y S p o ns or
Re g ulat or y  Aut h ori ties, I R Bs/ R E Bs/I E Cs, a n d i n vesti gat ors will be n otifie d of S A Es i n 
acc or da nce wit h a p plica ble re q uire me nts (e g, G o o d Cli nical Pract ices [ G C Ps], I C H g ui deli nes, 
nat i onal re g ulat i ons, a n d l ocal re q uire me nts).
T he P har mac yclics P har mac o vi gila nce C o m mittee will re vie w a n d e val uate acc u m ulat i n g safety 
data fr o m  t he e ntire cli nical tri al data base f or i br uti ni b at a p pr o priate i nter vals (e g, q uarterl y) t o 
i de ntif y ne w safet y si g nals or i ncrease d fre q ue nc y of e ve nts . T his will i ncl u de a n a g gre gate 
re vie w a n d c o m paris o n t o a c o ntr ol gr o u p of S A Es fr om pre vi o us st u dies t hat were dee me d as 
“ n ot s us pecte d” of bei n g ass ociate d wit h use of i bruti ni b beca use t he y  were li kel y t o ha ve bee n 
ma nifestati o ns of u n derl yi n g disease or t hat c o m m o nl y  occ ur i n t he patie nt p o p ulat i on.
8. 5.
S peci al Re p orti n g Sit u ati o ns
S peci al re p orti n g sit uat i ons o n a S p o ns or st u d y  ma y re q uire e x pe dite d re p orti n g a n d/ or safety 
e val uat i on w hic h i ncl u de, b ut are n ot li mite d t o:

O ver d ose of a n y st u d y  dr u g

S us pecte d a b use/ mis use of a st u d y  dr u g

I na d verte nt or acci de ntal e x p os ure t o a st u d y dr u g

Me dicat i on err or i n v o l vi n g a pr o d uct ( wit h or wit h o ut s u bject e x p os ure t o t he st u d y dr u g 
(e g, na me c o nf usio n )
Occ urre nce of a n y s pecial re p orti n g sit uati ons s h o ul d be rec or de d i n t he e C R F . If a n y s pecial 
re p orti n g sit uati on meets t he criteria of a n A E, it s h o ul d be rec or de d o n t he A Es e C R F . If t he A E 
is c o nsi dere d seri o us, it s h o ul d be rec or de d o n t he A Es e C R F as seri o us a n d s h o ul d be re porte d 
o n t he Seri o us A d verse E ve nt Re p ort F or m . T he Seri o us A d verse E ve nt Re p ort F or m s h o ul d be 
se nt via e mail or fa x t o P har mac yclics Dr u g Safet y or desi g nee wit hi n 2 4 h o urs of a ware ness.
9.
WI T H D R A W A L O F P A TI E N T F R O M T R E A T M E N T O R S T U D Y
I n vesti gat ors are e nc o ura ge d t o kee p a patie nt e x perie nci n g cli nical be nefit o n st u d y treat me nt 
u nless si g nifica nt t o xicit y p uts t he pati e nt at ris k or r o uti ne n o nc o m p lia nce p uts t he st u d y 
o utc o m es at ris k.
9. 1.
Disc o nti n u ati o n of Tre at me nt
T reat me nt will be disc o nti n ue d i n t he e ve nt of a n y of t he f oll owi n g ci rc u msta nces:

P r o gressi ve disease 

U nacce pta ble t o xicit y: a n i nterc urre nt ill ness or a d verse e ve nt t hat pre ve nts f urt her i br uti ni b 
a d mi nistrati o n 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 2

Wit h dra wal o f c o nse nt f or treat me nt b y patie nt

I n vesti gat or decisi on (s uc h as c hr o nic n o nc o m p lia nce, si g nifica nt pr ot oc ol de viati on, or t he 
best i nterest of t he patie nt)

C o m plet i on of treat m e nt per Pr ot oc ol A me n d me nt 3

St u d y  ter mi nati on b y S p o ns or

P ati e nt b e c o mes pre g na nt
All patie nt s, re gar dless of reas o n f or disc o nti n uati on of st u d y  treat me nt will u n der g o a n 
E n d -of -Treat m e nt Visit a n d be f ollo w e d f or pr o gressi o n  a n d s ur vi val.
T he I n vesti gat or s h o ul d n otif y  t he S p o ns or wit hi n 2 4 h o urs if a pat ient disc o nt i n ues i br uti ni b 
thera p y d ue t o disease pr o gressi o n a n d s h o ul d pr o vi de d oc u me ntati o n of disease pr o gressi o n f or 
re vie w b y t he S p o ns or’s Me dical M o nit or. If a patie nt s h o ws si g ns of disease pr o gressi o n o n 
p h ysical e xa mi nat i on or l a b orat or y assess me nt, t he pati e nt ma y c o nt i n ue st u d y tr e at me nt u ntil 
di sease pr o gressio n is c o nfir me d . T hese pat ient s s h o uld st a y  in t he st u d y  t o be f oll owe d f or 
s ur vi val.
9. 2.
Wit h dr a w al fr o m t he St u d y
Wit h dra wal fr o m t he st u d y (i ncl u di n g all f oll ow- u p re q uire me nts) will occ ur u n der t he f o ll owi n g 
circ u msta nces:

Wit h dra wal o f c o nse nt f or f o ll ow- u p b y t he patie nt

L ost t o f oll o w - u p

C o m plet i on of st u d y  u n der Pr ot oc ol Ame n d me nt 3

St u d y  ter mi nati on b y S p o ns or

Deat h
I n case a patie nt is l ost t o f oll o w-u p, e ver y p ossi ble eff ort m ust be ma de b y t he st u d y  sit e 
pers o n nel t o c o nt act t he patie nt a n d deter mi ne t he reas o n f or disc o nt i n uati on . T he m eas ures 
ta ke n t o f oll ow- u p m ust be d oc u m e nte d i n t he patie nt’s rec or ds.
W he n a pat ient  wit hdra ws bef ore c o m plet i n g t he st u d y, t he reas o n f or wit h dra wal m ust be 
d oc u m e nte d i n t he s o urce d oc u me nts.
1 0.
S T A TI S TI C A L C O N SI D E R A TI O N S
T his sect i on o utli nes t he ge neral statist ical a nal ysis a p pr oac hes i nte n de d f or t he safety a n d 
efficac y a nal yses f or t he st u d y. Detaile d a nal yses will be descri be d i n t he fi nal statist ical a nal ysis 
pl a n ( S A P).
Data fr o m S t u d y P C Y C- 1 1 1 5-C A a n d S t u d y P C Y C-1 1 1 6 -C A will be c o m bi ne d at t he s u bject 
le vel f or safety a n d efficac y a nal yses.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 3
1 0. 1.
E n d p oi nts

P F S o n first -li ne t hera p y 

Pr o gressi o n Free S ur vi val after i nit iati o n of s u bse q ue nt a ntica ncer t hera p y ( P F S 2)

O verall s ur vi val

Ti m e t o ne xt treat me nt 

O R R a n d D O R

S af et y as meas ure d b y all AEs a n d S A Es

Di sease o utc o me fol l owi n g cessat i on of i br uti ni b thera p y aft er attai n me nt of mi ni mal 
resid ual disease ( M R D)- ne gat i ve re missi on i n t h ose patie nts recei vi n g i br uti ni b as sec o n d-
li ne t hera p y
1 0. 2.
R a n d o miz ati o n 
T his st u d y  is a n e xte nsi on st u d y  of P C Y C-1 1 1 5- C A a n d i ncl u des o nl y a q ualifie d s u bset of t he 
s u bjects fr om t he P C Y C-1 1 1 5 -C A S t u d y. It is a n o pe n-la bel, n o n-ra n d omize d st u d y.
1 0. 3.
S a m ple -Size C o nsi der ati o ns
As t hi s is a n e xte nsi on st u d y , n o f or mal p o wer calc ulat i ons were perf or me d . T he sa m ple size will 
be t he n u m ber of pat ient s w h o are tra nsferre d t o t his st u d y after I R C-c o nfir me d disease 
pr o gressi o n i n t he pare nt st u d y  or clos ure of t he pare nt st u d y . Acc urac y of est i mati on f or eac h 
efficac y e nd p oi nt will de pe n d o n t he n u m ber of a vaila ble pat ient s i n a rele va nt s u b gr o u p defi ne d 
b y li ne of t hera p y.
1 0. 4.
Pl a n ne d A n al ysis
T his e xte nsi o n st u d y will re mai n o pe n a n d st u d y foll o w -u p will c o nt i n ue a p pr o xi matel y 1 0 years 
fro m  ra n d o mizatio n of  t he first patie nt i n t he pare nt P C Y C - 1 1 1 5-C A S t u d y. Efficac y a n d safet y 
a nal ysis f or t he st u d y e n d p oi nts will be perf or me d p eri o di call y as a p pr o priate.
1 0. 5.
A n al ysis P o p ul ati o ns
1 0. 5. 1.
I nte nt-t o-Tre at P o p ul ati o n
T he i nte nt -t o-treat (I T T) p o p ulat i on is defi ne d as all ra n d omize d pat ient s i n St u d y 
P C Y C - 1 1 1 5-C A . All efficac y  a nal yses will be perf or me d base d o n t he I T T p o p ulat i on u nless 
ot her wi se s pecifie d, a n d patient s will be a nal yze d as ra n d omize d f or t he a nal yses relate d t o first -
li ne t hera p y a n d O S.
1 0. 5. 2.
S afet y P o p ul ati o n
T he safet y p o p ul at i on f or first-li ne t hera p y i ncl u des all patie nts w h o recei ve d at least 1 d ose of 
st u d y dr u g i n St u d y P C Y C- 1 1 1 5-C A, ei t her c hl ora m b ucil or i br uti ni b.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 4
1 0. 6.
C o ntr ol f or Bi as
T he P C Y C - 1 1 1 5-C A ra n d o mizat i on c o de will b e c o ntr olle d t hr o u g h a ce ntralize d pr oce d ure a n d 
will n ot be k n o w n t o pers o n nel direct l y i n v ol ve d with st u d y  c o n d uct or data a nal ysis i n b ot h 
S t u d y P C Y C- 1 1 1 5-C A a n d St u d y  P C Y C -1 1 1 6- C A u ntil t he P C Y C -1 1 1 5- C A data base p orti o n is 
l oc ke d a n d u n bli n de d . S u bse q u e nt t o s p o ns or u n bli n di n g , st u d y will be f ull y o pe n -lab el .
1 0. 7.
Effic ac y A n al yses
1 0. 7. 1.
Pr o gressi o n -free S ur vi v al
P F S o n first -li ne t hera p y is defi ne d as t he ti me fr o m t he date of ra n d omizat i on t o disease 
pr o gressi o n deter mi ne d b y t he i n vesti gat or or deat h fr o m a n y ca use, w hic he ver occ urs first . 
P F S o n first -li ne t hera p y will be a nal yze d i n t he I T T p o p ulati on . Pati e nts w h o d o n ot pr o gress i n 
t he pare nt st u d y a n d d o n ot e nr oll i n St u d y  P C Y C - 1 1 1 6-C A will be ce ns ore d at t he last di sease
assess me nt perf or me d b y i n vest i gat or i n St u d y P C Y C -1 1 1 5 -C A .
P F S 2 will be a nal yze d f or I T T patie nts . It is defi ne d as t he ti me i nter val bet wee n t he date of 
ra n d omizat i on a n d date of e ve nt, w hic h is defi ne d as pr o gressi ve disease as assesse d b y 
i n vesti gat or t hat  occ urs aft er t he ne xt li ne of s u bse q ue nt a nt ica ncer t hera p y (i nclu di n g cr oss -o ver 
t o i br uti ni b), deat h fr o m a n y ca use, or t he start of a sec o n d s u bse q ue nt a ntica ncer t hera p y if n o 
pr o gressi ve disease is rec or de d . T h ose w h o d o n ot recei ve s u bse q ue nt t hera p y or d o n ot 
e x perie nce t he e ve nt as s pecifie d a b o ve are ce ns ore d at t he last disease assess me nt wit h o ut 
sec o n d disease pr o gressi o n.
T he a nal ysis f or P F S o n first -li ne t hera p y will f oll o w t he pri mar y met h o d descri be d i n t he 
P C Y C - 1 1 1 5-C A pr ot oc ol  a n d t he S A P, e xce pt t hat a stratifie d l o g -ra n k test will be p urel y 
descri pt i ve. T he est i mate of t he hazar d rati o a n d its c orres p o n di n g 9 5 % CI will be c om p ute d 
usi n g a C o x pr o p or tio nal  hazar d m o d el  stratifie d b y t he ra n d o mizati on stratificat i on fact ors ( Rai 
sta ge a n d E C O G perf or ma nce sc ore) . Me dia n P F S 2 a n d its 9 5 % c o nfi de nce i nter val ( CI) will be 
esti mate d usi n g t he Ka pla n- Meier met h o d.
1 0. 7. 2.
O ver all Res p o nse R ate
O R R is defi ne d as t he cr u de pr o p orti o n of patie nts w h o ac hie ve a C R, C Ri , n P R, or P R as 
deter mi ne d b y t he i n vesti gat or. Patie nts w h o ac hie ve a P R wit h l y m p h oc yt osis will n ot be 
i ncl u de d i n t he O R R. P ati e nts wit h no p ost -d ose disease assess me nt will be c o nsi dere d - n o n-
res p o n ders. T he O R R is esti mate d wit h a n e xact 9 5 % c o nfi de nce i nter val. A nal ysis detail will b e 
defi ne d i n t he statist ical a nal ysis pla n.
1 0. 7. 3.
D ur ati o n of Res p o nse
T o a de q uatel y reflect t he d urati o n o f ti me d uri n g w hic h patient s are e x perie nci n g t u m or 
re d uctio n a n d si g nifica nt be nefit i n ter ms of disease c o ntr ol, D O R will be c o m p ute d f or t he 
res p o n ders s u bset base d o n t he res p o nse criteria (Secti o n 1 0. 7. 2 ), a n d will i ncl u de d urati o n w he n 
a res p o n der ac hie ve s a P R wit h ly m p h oc y t osis. He nce, D O R est i mate d b y t he Ka pla n -Meier 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 5
met h o d is defi ne d as t he i nter val bet wee n t he date of i nit ial d oc u me ntati o n of a res p o nse, 
i ncl u di n g P R wit h l y m p h oc yt osis, a n d t he date of first d oc u me nte d e vi de nce of pr o gressi ve 
di sease, deat h, or date of ce ns ori n g if a p plica ble. N o n -res p o n ders are e xcl u de d fr o m t he a nal ysis 
f or D O R . S u bjects w h o are pr o gressi o n -free a n d ali ve or ha ve u n k n o w n s ur vi val stat us will be 
ce ns ore d at t he last disease assess me nt . A nal ysis detail will be defi ne d i n t he statistical a nal ysis 
pl a n.
1 0. 7. 4.
Dise ase O utc o me F oll o wi n g M R D- Ne g ati ve C R
At  t he i n vesti gat or’s discreti on, pati e nts recei vi n g sec o n d-li ne i br uti ni b t hera p y w h o ac hie ve a n d 
retai n M R D-ne gat i ve C R f or 6 c ycles ca n ha ve t heir i br uti ni b disc o nt i n ue d. If sec o n d-li ne 
i br uti ni b is disc o nti nue d, t he pati e nt will be f o ll owe d f or M R D rec urre nce . A 6 -m o nt h 
M R D -ne gat i ve C R rate per t he sa me e val ua ble s u b gr o u p defi ne d f or O R R ( Secti o n 1 0. 7. 3 ) a n d 
t he rec urre nce rate base d o n a s u bset of patie nts w h o ac hie ve a 6-m o nt h M R D -ne gat i ve C R will 
be calc ulate d.
M R D -ne gat i ve s u bjects w h o e x perie nce c o nfir me d M R D-p osi tive rela pse a n d/ or cli nical disease 
pr o gressi o n b y  I WC L L cri teria ma y restart i br uti ni b t hera p y.
1 0. 7. 5.
O ver all S ur vi v al
O S is defi ne d as t he ti me fr om ra n d omizat i on t o deat h d ue t o a n y  ca use. Pati e nts w h o are k n o w n 
t o be ali ve or w h ose s ur vi val stat us is u n k n o w n will be ce ns ore d at t he last date t he patie nt is 
k n o w n t o be ali ve . P ati e nts w h o are lost t o f o ll ow- u p wit h o ut a n y  p ost baseli ne 
assess me nts/ visits will be ce ns ore d at t he date of ra n d o mizat i on . S ur vi val rate at la n d mar k p oi nts 
will be s u m marize d b y  first-li ne treat me nt ar m usi n g Ka pla n-Meier est i mates.
1 0. 8.
S afet y A n al yses
S af et y a nal yses will be prese nte d i n acc or da nce wit h t he treat me nt act uall y recei ve d b y patient s.
N o n -he mat ol o gi cal AEs re p orte d b y  t he i n vestigat or will  be gra de d acc or di n g t he c urre nt versi o n 
of  t he N CI C T C A E v 4. 0 3 . He mat ol o gic t o xicit y will  be assesse d b y t he I W C L L 2 0 0 8 criteria f or 
gra di n g he mat ol o gic t o xicit y i n C L L st u di es. Ver bati m descri pti o ns of A Es will be c o de d t o a 
preferre d ter m a n d ma p pe d t o S yste m Or ga n Class usi n g t he c urre nt versi o n of t he Me dical 
Di ct i onar y  for Re g ulat or y  Act i vities ( Me d D R A). A Es t hat starte d after t he first d ose of st u d y  
dr u g a n d u p t o 3 0 da ys after t he last d ose of st u d y dr u g or i nit iati on of s u bse q ue nt t hera p y , w hic h 
occ urs earlier, are c o nsi dere d treat me nt e mer ge nt . All treat me nt -e mer ge nt A Es will be ta b ulate d 
usi n g sta n dar d met h o ds.
All la b orat or y val ues will be c o n verte d t o sta n dar d i nter nati onal u nits ( SI u nits) . He mat ol o gic 
t o xicit y will be gra de d acc or di n g t o t he I W C L L criteria (Halle k 2 0 0 8 ). All ot her gra da ble 
la b orat or y para meters will be gra de d usi n g t he N CI C T C A E . Sta n dar d met h o ds f or s u m marizi n g 
la b orat or y varia bles will be use d, i ncl u di n g t he use of s u m mar y  st atistics a n d s hift ta bles.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 6
1 1.
S T U D Y A D MI NI S T R A TI O N A N D I N V E S TI G A T O R O B LI G A TI O N S
1 1. 1.
Re g ul at or y a n d Et hic al C o m pli a nce 
T his cli nical st u d y  was desi g ne d a n d will be i m ple me nte d i n acc or da nce wit h t he pr ot oc ol, t he 
I C H Har m o nize d Tri partite G ui deli nes f or G o o d Cli nical Pract ices, wit h a p plica ble l ocal 
re g ulat i ons (i ncl u di n g U S C o de of Fe deral Re g ulati o ns [ C F R] Ti tle 2 1 a n d E ur o pea n Directi ve 
2 0 0 1/ 2 0/ E C), a n d wit h t he et hical pri nci ples lai d d o w n i n t he Declarat i on of Helsi n ki.
1 1. 2.
I nstit uti o n al Re vie w B o ar d (I R B), Rese arc h Et hics B o ar d ( R E B) a n d I n de pe n de nt 
Et hics C o m mittee (I E C) A p pr o v al
T he i n vesti gat or will s u b mit t his pr ot oc ol, t he I C F, I B, a n d a n y ot her rele va nt s u p p orti n g 
i nf or mat i on (e g, all a d vert isi n g materials or materials gi ve n t o t he patie nt d uri n g t he st u d y) t o t he 
a p pr o priate I R B/ R E B/I E C f or re vie w a n d a p pr o val bef ore st u d y  init iati on . A me n d me nts t o t he 
pr ot oc ol  a n d I C F must al s o be a p pr o ve d b y t he I R B/ R E B/I E C bef ore t he i m ple me ntati o n of 
c ha n ges i n t his st u d y.
T he i n vesti gat or is res p o nsi ble f or pr o vi di n g t he I R B/ R E B/I E C wit h a n y re q uire d i nf or mati on 
bef ore or d uri n g t he st u d y, s uc h as S A E e x pe dite d re p orts or st u d y pr o gress re p orts.
T he I R B/ R E B/I E C m ust c o m pl y wit h c urre nt U nite d States ( U S) re g ulat i ons ( § 2 1 C F R 5 6) as 
well as c o u ntr y -s pecific nati onal re g ulat i ons a n d/ or l ocal la ws.
T he f o ll owi n g d oc u m e nts mus t be pr o vide d t o P har m ac yclics or its a ut h orize d re prese ntati ve 
bef ore e nteri n g patie nts i n t his st u d y : ( 1) a c o p y of t he I R B/ R E B/I E C letter t hat gra nts f or mal 
a p pr o val; a n d ( 2) a c o p y of t he I R B/ R E B/I E C-a p pr o ve d I C F.
1 1. 3.
I nf or me d C o nse nt 
T he I C F a n d pr ocess m ust c o m pl y wit h t he U S re g ulat i ons ( § 2 1 C F R Part 5 0) as well as c o u ntr y  
s pecific nati onal re g ulat i ons a n d/ or l ocal la ws . T he I C F will d oc u me nt t he st u d y -s pecific 
i nf or mat i on t he i n vesti gat or or hi s/ her desi g nee pr o vi des t o t he patie nt a n d t he patie nt’s 
agree m e nt t o partici pate.
T he i n vesti gat or or desi g nee ( desi g nee m ust be liste d o n t he Dele gat i on of A ut h orit y l og), 
m ust
e x plai n i n ter ms u n dersta n da ble t o t he patie nt t he p ur p ose a n d nat ure of t he st u d y , st u d y 
pr oce d ures, a ntici pate d be nefits, p ote ntial r is ks, p ossi ble A Es, a n d a n y disc o mf ort partici pat i on 
i n t he st u d y ma y e nt ail. T his pr ocess m ust be d oc u me nte d i n t he patie nt’s s o urce rec or d . Eac h 
pati e nt must pr o vi de a si g ne d a n d date d I C F bef ore a n y  st u d y-r elate d ( n o nsta n dar d of care) 
acti vit ies are perf or me d. T he ori gi nal a n d a n y  a me n de d si g ne d a n d date d c o nse nt f or ms m ust 
r e mai n i n eac h pat ient ’s st u d y file at t he st u d y site a n d be a vaila ble f or verificati o n b y st u d y 
m o nit ors at a n y  ti me. A c o p y  of eac h si g ne d c o nse nt f or m must be gi ve n t o t he patie nt at t he ti me 
t hat it is si g ne d b y t he patient .

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 7
1 1. 4.
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce
S p o ns or s hall i m ple me nt a n d mai ntai n q ualit y c o ntr ol a n d q uality ass ura nce pr oce d ures t o e ns ure 
t hat t he st u d y is c o n d ucte d a n d data are ge nerate d, d oc u me nte d a n d re p orte d i n c om p lia nce with 
t he pr ot oc ol, G C P, a n d a p plica ble re g ulat or y re q uire me nts. T hi s st u d y s hall be c o n d ucte d i n 
acc or da nce wit h t he pr o visi o ns of t he Declarat i on of Helsi n ki ( Oct o ber 2 0 0 8) a n d all re visi o ns 
t here of, a n d i n acc or da nce wit h F D A re g ulati o ns ( 2 1 C F R Parts 1 1, 5 0, 5 4, 5 6, a n d 3 1 2, 
S u b part D – Res p o nsi bilit ies of S p o ns ors a n d I n vesti gat ors) a n d wit h t he I C H g ui deli nes o n G C P 
(I C H E 6).
1 1. 5.
Pr otecte d P atie nt He alt h I nf or m ati o n A ut h oriz ati o n
I nf or mat i on o n m ai ntai ni n g patie nt c o nfid e nti alit y in acc or da nce t o i n di vi d ual l ocal a n d nat i onal 
pati e nt pri vac y re g ulat i ons m u st be pr o vide d t o eac h patie nt as part of t he i nf or me d c o nse nt 
pr ocess (refer t o Secti o n 1 1. 3 ), eit her as part of t he I C F or as a se parate si g ne d d oc u me nt (f or 
e xa m ple, i n t he U S, a site-s pecific HI P A A c o nse nt ma y be use d) . T he i n vesti gat or or desi g nee 
m ust
e x plai n t o eac h patie nt t ha t f or t he e val uati on of st u d y  res ults, t he patie nt’s pr otecte d healt h 
i nf or mat i on o btai ne d d uri n g t he st u d y  ma y be s hare d wit h P har mac yclics a n d its desi g nees, 
re g ulat or y a ge ncies, a n d I R Bs/ R E Bs/I E Cs. As t he st u d y  Sp o ns or , P har mac yclics will n ot use t he 
pa tie nt’s pr otecte d healt h i nf or mat i on or discl ose it  t o a t hir d part y wit ho ut a p plica ble pat ient  
a ut h orizat i on . It is t he i n vesti gat or’s or desi g nee’s res p o nsi bility t o o btai n writte n per missi o n t o 
use pr otecte d healt h i nf or mati o n fr o m eac h patie nt . If a patie nt wit hdra ws per missi o n t o use 
pr otecte d healt h i nf or mati on, i t is t he i n vesti gat or’s res p o nsi bility t o o btai n t he wit h dra wal 
re q uest i n writi n g fr o m t he patie nt a n d t o e ns ure t hat n o f urt her data will be c ollecte d fr o m t he 
pati e nt . A n y data c ollecte d o n t he patie nt bef ore wit h dra wal will be use d i n t he a nal ysis o f st u d y 
res ults.
D uri n g t he re vie w of s o urce d oc u me nts b y  t h e mo ni t ors or a u dit ors, t he c o nfi de ntiality of  t he 
pati e nt will be res pecte d wit h strict a d here nce t o pr ofessi o nal sta n dar ds a n d re g ulat i ons.
1 1. 6.
St u d y Files a n d Rec or d Rete nti o n
T he i n vesti gat or m ust
kee p a rec or d t hat lists all pati e nts c o nsi dere d f or e nr oll me nt (i ncl u di n g 
t hose w h o di d n ot u n der g o scree ni n g) i n t he st u d y . F or t h ose patie nts s u bse q ue nt l y e xcl u de d 
fr om e nr oll me nt, t he reas o n(s) f or e xcl usi o n is t o be rec or de d.
T he i n vesti gat or/st u d y staff m ust mai ntai n a de q uate a n d acc urate rec or ds t o e na ble t he c o n d uct 
of  t he st u d y t o be f ull y d oc u me nte d a n d t he st u d y data t o be s u bse q ue ntl y verifie d . Esse nt ial 
d oc u m e nt atio n i ncl u des, b ut i s n ot li mite d t o, t he I B, si g ne d pr ot oc ols a n d a me n d me nts, 
I R B/ R E B/I E C a p pr o val letters ( date d), si g ne d F or m F D A 1 5 7 2 a n d Fi na ncial Discl os ures, 
sig ne d I C Fs (i ncl u di n g pat ient  c o nfi de ntiality i nf or mati on), dr u g di s pe nsi n g a n d acc o u nta bility 
rec or ds, s hi p pin g rec or ds of i n vest i gati onal pr o d uct a n d st u d y -relate d materials, si g ne d 
( ele ctr o nicall y), date d a n d c o mplete d C R Fs, a n d d oc u me ntati o n of C R F c orrecti o ns, S A E f or ms 
tra ns mitte d t o P har mac yclics a n d n otificati on of S A Es a n d relate d re p orts, s o urce 
d oc u m e nt atio n, n or m al la b orat or y val ues, dec o di n g pr oce d ures f or bli n de d st u dies, c urric ula 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 8
vit a e for st u d y  staff, a n d all rele va nt c orres p o n de nce a n d ot her d oc u me nts pertai ni n g t o t he 
c o n d uct of t he st u d y.
All esse ntial d oc u me ntati o n will be retai ne d b y t he i n vestig at or f or at least 2 years after t he date 
t he last mar keti n g a p plicat i on is a p pr o ve d f or t he dr u g f or t he i n dicati o n f or w hic h it is bei n g 
i n vesti gate d a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g a p plicati ons; or, if n o 
a p plicat i on is t o be file d or if t he a p plicati o n is n ot a p pr o ve d f or s uc h i n dicati o n, u ntil 2 years 
aft er for m al disc o nt i n uati on of cli nical de vel o p me nt of t he dr u g.
T he i n vesti gat or m ust n otif y P har mac yclics a n d o btai n writte n a p pr o val fr o m P har m ac yclics 
bef ore destr o yi n g a n y cli nical st u d y d o c u me nts or i ma ges ( e g, sca n, ra di o gra p h, E C G traci n g) at 
a n y ti me. S h o ul d a n i n vesti gat or wis h t o assi g n t he st u d y  rec or ds t o a n ot her part y or mo ve t he m  
t o a n ot her l ocati o n, a d va nce writte n n otice will be gi ve n t o P har mac yclics. P har mac yc lics will 
i nf or m t he i n vesti gat or of  t he date t hat st u d y rec or ds ma y be destr o ye d or ret ur ne d t o 
P har mac yclics.
P har mac yclics m ust be n otifie d i n a d va nce of, a n d P har mac yclics m ust pr o vi de e x press writte n 
a p pr o val of, a n y c ha n ge i n t he mai nte na nce of t he fore g oi n g d oc u m e nts if t he i n vesti gat or wis hes 
t o mo ve st u d y  rec or ds t o a n ot her l ocati o n or assi g n res p o nsi bility f or rec or d rete ntio n t o a n ot her 
part y . If t he i n vesti gat or ca n n ot g uara ntee t he arc hi vi n g re q uire me nts set f ort h herei n at his or her 
st u d y site for all  s uc h d oc u me nts, s pecial arra n ge me nts must be ma de bet wee n t he i n vesti gat or
a n d P har mac yclics t o st ore s uc h d oc u me nts i n seale d c o ntai ners a wa y fr o m t he st u d y site s o t hat 
t he y ca n be ret ur ne d seale d t o t he i n vesti gat or f or a u dit p ur p oses.
1 1. 7.
C ase Re p ort F or ms a n d Rec or d M ai nte n a nce
C R Fs will be use d t o c ollect t he cli nical st u d y  data a n d must be c o m plete d f or eac h e nr o lle d 
pati e nt wit h all re q uire d st u d y data acc uratel y rec or de d s uc h t hat t he i nf or mati on mat c hes t he 
data c o ntai ne d i n me dical rec or ds ( e g, p h ysicia ns’ n otes, n urses’ n otes, cli nic c harts a n d ot her 
st u d y-s pecific s o urce d oc u me nts). A ut h orize d st u d y site pers o n nel ( ie, liste d o n t he Dele gati on of 
A ut h ori t y lo g) will  c o mplete C R Fs desi g ne d f or t his st u d y  acc or di n g t o t he c o m pleti on 
g ui deli n es t hat will be pr o vi de d. T he i n vesti gat or will e ns ure t hat t he C R Fs are acc urate, 
c o mplete, l e gi ble, a n d c o mplete d wi t hi n 5 da ys of eac h patie nt’s visit. At  all ti mes, t he 
i n vesti gat or has fi nal res p o nsi bilit y f or t he acc urac y a nd a ut he nt icity of all cli nical data.
T he C R Fs e xists wit hi n a n electr o nic data ca pt ure ( E D C) s yste m wit h c o ntr olle d access ma na ge d 
b y P har mac yclics or its a ut h orize d re prese ntati ve f or t his st u d y . St u d y  staff will be a p pr o priatel y 
trai ne d i n t he use of C R Fs a n d a p plicati on of electr o nic si g nat ures bef ore t he start of t he st u d y 
a n d bef ore bei n g gi ve n access t o t he E D C s yst e m. Ori gi nal  data a n d a n y c ha n ges of data will be 
rec or de d usi n g t he E D C s yst e m, wit h all c han ges trac ke d b y  t he s yste m a n d rec or de d i n a n 
ele ctr o nic a u dit tr ail. T he i n vesti gat or attests t hat t he i nf or mat i on c o ntai ne d i n t he C R Fs is tr ue 
b y pr o vi di n g electr o nic si g nat ure wit hi n t he E D C s yste m . After data base l oc k, t he i n vesti gat or
will recei ve a c o p y of t he patie nt data (e g, pa per, C D, or ot her a p pr o priate me dia) f or arc hi vi n g 
at t he st u d y sit e.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 9
1 1. 8.
I n vesti g ati o n al St u d y Dr u g Acc o u nt a bilit y
I br uti ni b a n d a n y P h ar mac yclics-s u p plie d c o m parat or m ust be ke pt i n a l oc ke d li mite d access 
r o o m. T he st u d y  dr u g m ust n ot be use d o utsi de t he c o nte xt of t he pr ot oc ol . U n der n o 
circ u msta nces s h o uld t he i n vesti gat or or ot her site pers o n nel s u p pl y i br uti ni b t o ot her 
i n vesti gat ors, patie nts, or cli nics or all o w s u p plies t o be use d ot her t ha n as directe d b y t his 
pr ot oc ol wi t ho ut pri or a ut h ori zat i on fr o m P har mac yclics.
Acc o u nta bilit y rec or ds f or i br uti ni b a n d a n y P h ar mac yclics-s u p plie d c o mparat or m ust be 
mai ntai ne d a n d rea dil y a vaila ble f or re g ular i ns pecti o ns b y re prese ntati ves of P har mac yclics a n d 
are o pe n t o ins pect i ons b y re g ulat or y  a ut h orities at a n y time.
A n I n vest i gati onal Dr u g Acc o u nta bilit y L o g m ust be use d f or dr u g acc o u nta bilit y.
F or a d di tio nal  details o n i n vesti gati onal st u d y  dr u g ma na ge me nt, please r efer t o t he P har mac y 
Ma n ual.
1 1. 9.
St u d y M o nit ori n g/ A u dit Re q uire me nts
Re prese ntati ves of P har mac yclics or its desi g nee will m o nit or t hi s st u d y u ntil c o mplet i on . 
M o ni t ori n g will be c o n d ucte d t hr o u g h pers o nal visits with t he i n vesti gat or a n d site staff, re m ote 
m o nit ori n g, as well as a n y a p pr o priate c o m m u nicati o ns b y  mail, fa x, e mail, or t ele p h o ne. T he 
p ur p ose of m o nit ori n g is t o e ns ure t hat t he st u d y  is c o n d ucte d i n c om p lia nce with t he pr ot oc ol, 
sta n dar d o perati n g pr oce d ures ( S O Ps), a n d ot her writte n i nstr ucti o ns a n d re g ulat or y g uideli nes, 
a n d t o e ns ure t he q ualit y a n d i nte grit y of t he data. T his st u d y  is als o patie nt t o re vie ws or a u dits.
T o ass ure t he acc urac y  of data c ollecte d i n t he C R Fs, it is ma n dat or y t hat t he mo ni t or/a u dit or 
ha ve access t o all ori gi nal s o urce d oc u m e nts, i nclu di n g all electr o ni c me dical rec or ds ( E M R) at 
reas o na ble ti mes a n d u p o n reas o na ble n otice. D uri n g t he re vie w of s o urce d oc u me nts, e ver y 
eff ort will be ma de t o mai ntai n t he a n o n y mit y a n d c o nfi de nt iality of  all patient s d uri n g t his 
cli nical st u d y. H o we ver, beca use o f t he e x peri me ntal nat ure of t his treat me nt, t he i n vesti gat or
a grees t o all o w t he I R B/ R E B/I E C, re prese ntati ves of P har mac yclics, its desi g nate d a ge nts a n d 
a ut h orize d e m plo y ees of t he a p pr o priate Re g ulat or y A ut h orit y t o i ns pect the facilit ies use d i n 
t his st u d y a n d, f or p ur p oses of verificati o n, all o w direct access t o t he h os pital or cli nic rec or ds of 
all patie nts e nr olle d i nt o t his st u d y. A state me nt t o t his effect will be i ncl u de d i n t he i nf or me d 
c o nse nt a n d per missi o n f or m a ut hori zi n g t he use of pr otecte d healt h i nf or mati o n.
P har mac yclics or its a ut h orize d re prese ntati ve ma y perf or m a n a u dit at a n y  ti me d uri n g or after 
c o mplet i on of t his st u d y . All st u d y -relate d d oc u me ntatio n m ust be m a de a vaila ble t o t he 
desi g nate d a u dit or . I n a d dit i on, a re prese ntati ve of t he F D A or ot her Re g ulat or y  A ge ncies ma y 
c h o ose t o i ns pect a st u d y sit e at a n y ti me bef ore, d uri n g, or after c o m pleti on of t he cli nical st u d y . 
I n t he e ve nt of s uc h a n i ns pecti on, P har mac yclics will be a vaila ble t o assist i n t h e pre paratio n . 
All perti ne nt st u d y  data s h o uld be ma de a vaila ble as re q ueste d t o t he Re g ulat or y  Aut h ori t y for 
verificati o n, a u dit, or i ns pect i on p ur p oses.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 0
1 1. 1 0.
I n vesti g at or Res p o nsi bilities
A c o m p lete list of i n vesti gat or res p o nsi bilities is o utli ne d i n t he cli nical trial researc h a gree me nt 
a n d t he State me nt of I n vest i gat or F or m F D A 1 5 7 2, b ot h of w hic h are si g ne d b y t he i n vesti gat or
bef ore c o m me nce me nt of t he st u d y . I n s u m mar y, t he i n vesti gat or will c o n d uct t he st u d y 
acc or di n g t o t he c urre nt pr ot oc ol; will rea d a n d u n dersta n d t he I B; will o btai n I R B/ R E B/I E C 
a p pr o val t o c o n d uct t he st u d y; will o btai n i nf or me d c o nse nt fr o m eac h st u d y partici pa nt; will 
mai ntai n a n d s u p pl y t o t he S p o ns or or desi g nee, a u di t ors a n d re g ulat or y a ge ncies a de q uate a n d 
acc urate rec or ds of st u d y acti vity a n d dr u g acc o u nta bilit y f or st u d y-relate d mo ni t orin g, a u di ts, 
I R B/ R E B/I E C re vie ws a n d re g ulat or y ins pecti o ns; will  re p ort S A Es t o t he S p o ns or or desi g nee 
a n d I R B/ R E B/I E C acc or di n g t o t he s pecifics o utli ne d i n t his pr ot oc o l; will pers o nall y c o n d uct or 
s u per vise t he st u d y; a n d will e ns ure t hat c ollea g ues partici pat i n g i n t he st u d y are i nf or me d a b o ut 
t heir o bli gati ons i n meet i n g t he a b o ve c o m mitme nts.
1 1. 1 1.
S p o ns or Res p o nsi bilities
A c o m p lete list of t he S p o ns or res p o nsi bilities is o utli ne d i n t he cli nical trial researc h a gree me nt 
a n d i n t he la ws a n d re g ulat i on of t he c o u ntr y  in w hic h t he researc h is c o n d ucte d . I n s u m mar y, t he 
S p o ns or will select q ualifie d i n vesti gat ors, pr o vi de t he m with t he i nf or mat i on t he y  nee d t o 
pr o perl y c o n d uc t t he st u d y, e ns ure a de q uate m o nitori n g of t he st u d y , c o n d uct t he st u d y in 
acc or da nce wit h t he ge neral i n vest i gati onal pla n a n d pr ot oc ols a n d pr o m pt l y i nf or m 
i n vesti gat ors, health a n d re g ulat or y  a ge ncies/a ut h orities as a p pr o priate of si g nifica nt ne w a d verse 
effects or ris ks wit h res pect t o t he dr u g.
1 1. 1 2.
Fi n a nci al Discl os ure
A se parate fi na ncial a gree me nt will be ma de bet wee n eac h p rinci pal  i n vesti gat or a n d 
P har mac yclics or its a ut h orize d re prese ntati ve bef ore t he st u d y dr u g is deli vere d.
F or t hi s st u d y, eac h i nvesti gat or a n d s u b- i n vesti gat or (as desi g nate d o n t he F or m F D A 1 5 7 2) will 
pr o vi de a si g ne d Fi na ncial Discl os ure F or m i n acc or da nce wit h § 2 1 C F R 5 4 . Eac h i n vesti gat or
will n otif y  P har mac yclics or its a ut h orize d re prese ntati ve of a n y rele va nt c ha n ges d uri n g t he 
c o n d uct of t he st u d y a n d f or 1 ye ar after t he st u d y has bee n c o mplete d.
1 1. 1 3.
Li a bilit y a n d Cli nic al Tri al I ns ur a nce
I n t he e ve nt of a si de effect or i nj ur y, a p pr o priate me dical care as deter mi ne d b y t he 
i n vesti gat or/ desi g nee will be pr o vi de d.
T he I C F will i ncl u de a descri pti on of tr e at me nt i n t he e ve nt of a st u d y r elate d i nj ur y a n d 
ha n dli n g of t he c osts ass ociate d t here wit h, i nc or p orati n g c o u ntr y-s pecific nati o nal re g ulati ons 
a n d/ or l ocal la ws. Fi na ncial c o m pe nsat i on f or lost wa ges, di sa bilit y or disc omf o rt d ue t o t he 
st u d y is n ot a vaila ble.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 1
Cli nical trial i ns ura nce has bee n u n derta ke n acc or di n g t o t he la ws of t he c o u ntries w here t he 
st u d y will be c o n d ucte d. A n i ns ura nce certificate will be ma de a vaila ble t o t he partici pati n g sites 
at t he ti me of st u d y init iat i on.
1 1. 1 4.
Pr ot oc ol A me n d me nts
P har mac yclics will i nit iate a n y c ha n ge t o t he pr ot oc ol in a pr ot oc ol a me n d me nt d oc u me nt . T he 
a me n d me nt will be s u b mitte d t o t he re g ulat or y a ut h orities a n d/ or I R B/ R E B/I E C t o get her wit h, if 
a p plica ble, a re vise d m o del I C F. Wr itte n d oc u me ntati o n of  re g ulat or y a ut h orities, I R B/ R E B/I E C 
a n d re q uire d site a p pr o val, as a p plica ble, m ust be recei ve d b y P har mac yclics bef ore t he 
a me n d me nt ma y ta ke effect at eac h site. A d dit i onall y , u n der t hi s circ u msta nce, i nf or mati on o n 
t he i ncrease d ris k a n d/ or c ha n ge i n sc o pe m ust be pr o vi de d t o patie nts alrea d y  acti vel y 
parti ci pat i n g i n t he st u d y, a n d t he y m ust rea d, u n dersta n d a n d si g n a n y re vise d I C F c o nfir mi n g 
willi n g ness t o re mai n i n t he tri al.
N o ot her si g nifica nt or c o nsiste nt c ha n ge i n t he st u d y pr oce d ures, e xce pt t o eli mi nate a n 
i m me diate hazar d, s hall be effecte d wi t ho ut t he m ut ual a gree me nt of t he i n vesti gat or a n d 
P har mac yclics.
1 1. 1 5.
P u blic ati o n of St u d y Res ults
P har mac yclics ma y use t he res ul ts of t his cli nical st u d y in re gistrati o n d oc u m e nts for Re g ul at or y 
A ut h ori ties i n t he U S or a br oa d. T he res ults ma y als o be use d f or pa pers, a bstracts, p osters, or 
ot her m at erial prese nte d at scie nt ific meet i n gs or p u blis he d i n pr ofessi onal j our nals or a s part of 
a n aca de mic t hesis b y a n i n vesti gat or. I n all cases, t o a v oi d discl os ures t hat c o ul d je o par dize 
pr o pri et ar y rig hts a n d t o e ns ure acc urac y  of t he data, P har mac yclics reser ves t he ri g ht t o pre vie w 
all ma n uscri pts a n d a bstracts relate d t o t his st u d y , allo wi n g P har mac yclics s ufficie nt ti me t o 
ma ke a p pr o priate c o m me nts bef ore s u b missi o n f or p u blicati o n.
I n most cases, t he i n vesti gat ors at t he sites wit h t he hi g hest accr uals of eli gi ble patie nts s hall be 
liste d as lea d a ut h ors o n ma n uscri pts a n d re p orts of st u d y res ults. T he Me dical M o nit or, st u d y  
di rect or a n d/ or lea d statisticia n ma y als o be i ncl u de d i n t he list of a ut h ors . T hi s c ust o m ca n be 
a djuste d u p o n m ut u al  a gree me nt of t he a ut h ors a n d P har mac yclics.
1 1. 1 6.
St u d y Disc o nti n u ati o n
T he S p o ns or reser ves t he rig ht t o ter mi nate t he st u d y  at a n y time . S h o ul d t his be necessar y, b ot h 
t he S p o ns or a n d t he i n vesti gat or will arra n ge disc o nt i n uati on pr oce d ures . I n ter mi nati n g t he 
st u d y, t he S p o ns or a n d t he i n vesti gat or will ass ure t hat a de q uate c o nsi derat i on is gi ve n to t he 
pr otecti o n of  t he patie nts’ i nterests.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 2
1 2.
R E F E R E N C E S
Bre n ner H, G o n d os A, P ulte D . Tre n ds i n l o n g -t er m s ur vi val of patie nts wit h c hro nic l y m p h oc ytic le u ke mia 
fr o m t he 1 9 8 0s t o t he earl y 21st ce ntur y . Bl o o d 2 0 0 8; 1 1 1( 1 0): 4 9 1 6 - 4 9 2 1.
B ur ger J A, O' Brie n S, F o wler N, et al. T he Br ut o n's t yr osi ne ki nase i n hi bit or, P CI -3 2 7 6 5, is well t olerate d 
a n d de m o nstrate d pr o misi n g cli nical acti vit y i n c hr o nic l y m p h oc ytic le u ke mia ( C L L) a n d s mall 
l y m p h oc ytic l y m p h o ma ( S L L): A n u p date o n o n g oi n g P hase 1 st u dies. Bl o o d 2 0 1 0; 1 1 6: A bstract 5 7.
C a m p o E, S wer dl o w S H, Harris N L, et al. T he 2 0 0 8 W H O 
classificati o n of l y m p h oi d ne o plas ms a n d 
be y o n d: e v ol vi n g c o nce pts a n d practical a p plicati o ns . Bl o o d 2 0 1 1; 1 1 7: 5 0 1 9 -5 0 3 2.
Casa k SJ, Le mer y SJ, S he n Y L, et al. U. S. F o o d a n d Dr u g A d mi nistrati o n a p pr o val: Rit u xi ma b i n 
c o m bi nati o n wit h fl u dara bi ne a n d c ycl o p h os p ha mi de f or t he treat me nt of patie nts wit h c hr o nic l y m p h oc ytic 
le u ke mia. T he O nc ol o gist 2 0 1 1; 1 6: 9 7 -1 0 4.
Cat o vs k y D, Ric har ds S, Mat utes E, et al. Assess me nt of fl u dara bi ne pl us c ycl o p h os p ha mi de f or patie nts 
wit h c hr o nic l y m p h oc ytic le u kae mia (t he L R F C L L 4 Trial): a ra n d o mize d c o ntr olle d trial. La ncet 
2 0 0 7; 3 7 0: 2 3 0 - 3 9.
Cella D, Lai J, C ha n g C, et al . Fati g ue i n ca ncer patie nts c o m pare d wit h fati g ue i n t he ge neral U nite d States 
p o p ulati o n . Ca ncer 2 0 0 2; 9 4: 5 2 8 -3 8.
C hil d C G, T urc otte J G. “ S ur ger y a n d p ortal h y perte nsi o n”. I n C hil d C G. T he li ver a n d p ortal h y perte nsi o n. 
P hila del p hia: Sa u n ders . 1 9 6 4. p p. 5 0- 6 4.
C ha n g B Y, Fra ncesc o M, De R o oij M F, et al. E gress of C D 1 9 + C D 5 + cells i nt o peri p heral bl o o d f oll o wi n g 
treat me nt wit h t h e Br ut o n t yr osi ne ki nase i n hi bit or i br uti ni b i n ma nt le cell l y m p h o ma patie nts. Bl o o d. 
2 0 1 3a; 1 2 2: 2 4 1 2 - 2 4.
C ha n g B Y, Fra ncesc o M, Ste g ger da S, et al. I br uti ni b I n hi bits Mali g na nt Cell A d hesi o n a n d Mi grati o n a n d 
Re d uces T u m or B ur de n i n L y m p h N o de a n d B o ne Marr o w 
i n a M uri ne 
M o del of Ma ntle 
C ell 
Disse mi nati o n a n d Pr o gressi o n. 2 0 1 3 b A A C R: A bstract 9 2 3. 
C ha n g B Y, Ma ga dala 
P, H ua n g, M M, et al. E gress of C D 1 9 + C D 5 + cells i nt o t he Peri p heral Bl o o d 
f oll o wi n g Tr e at me nt wit h Br ut o n T yr osi ne Ki nase I n hi bit or, P CI -3 2 7 6 5, i n Ma ntle 
Cell L y m p h o ma 
Patie nts, Bl o o d 2 0 1 1; 1 1 8: A bstract 9 5 4.
C hes o n B D, B yr d J C, Rai K R, et al. N o vel tar gete d a ge nts a n d t he nee d t o ref i ne cli nical e n d p oi nts i n 
c hr o nic l y m p h oc ytic le u ke mia . J Cli n O nc ol 2 0 1 2; 2 3: 2 8 2 0- 2 2.
C hes o n B D, R u m mel MJ . Be n da m usti ne: re birt h of a n ol d dr u g. J Cli n O nc ol 2 0 0 9; 2 7: 1 4 9 2– 1 5 0 1.
C hi orazzi N, Rai K R, Ferrari ni M. C hr o nic l y m p h oc ytic le u ke mia . N E n gl J Me d 2 0 0 5; 3 5 2: 8 0 4 – 8 1 5.
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E), Versi o n 4. 0 3. P u blis he d J u ne 1 4, 2 0 1 0
Di n g W, 
Z e nt C S. Dia g n osis a n d ma na ge me nt of a ut oi m m u ne c o m plicati o ns of c hr o nic l y m p h oc ytic 
le u ke mia/ s mall l y m p h oc ytic l y m p h o ma. Cli n A d v He mat ol O nc ol. 2 0 0 7; 5: 2 5 7- 6 1.
Eic h h orst B F, B usc h R, H o pfi n ger G, et al. Fl u dara bi ne pl us c ycl o p h os p ha mi de vers us fl u dara bi ne al o ne 
i n first-li ne t hera p y of y o u n ger patie nts wit h c hr o nic l y m p h oc ytic le u ke mia. Bl o o d 2 0 0 6; 1 0 7: 8 8 5– 8 9 1.
Eic h h orst B F, B usc h R, Stil ge n ba uer S, et al. First -li ne t h era p y wit h fl u dara bi ne c o mpare d wit h 
c hl ora m b ucil d oes n ot r es ult i n a ma j or be nefit f or el derl y patie nts wit h a d va nce d c hr o nic l y m p h oc ytic 
le u ke mia. Bl o o d 2 0 0 9; 1 1 4: 3 3 8 2 – 3 3 9 1.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 3
E ur o Q ol Gr o u p. E ur o Q ol -A ne w facilit y f or t he meas ure me nt of healt h -r elate d q ualit y of lif e. Hea lt h 
P olic y. 1 9 9 0; 1 6: 1 9 9 – 2 0 8.
Fisc her K, Cra m ber P, B usc h R, et al. Be n da m usti ne c o m bi ne d wit h rit u xi ma b i n patie nts wit h rela pse d 
a n d/ or r efract or y c hr o nic l y m p h oc ytic le u ke mia: a m ultice nter p hase II trial of t he G e r ma n C hr o nic 
L y m p h oc ytic Le u ke m ia St u d y Gr o u p. J Cli n O nc ol. 2 0 1 1; 2 9: 3 5 5 9-6 6.
Fli n n I W, Ne u ber g D S, Gre ver M R, et al. P hase III trial of fl u dara bi ne pl us c ycl o p h os p ha mi de c o mpare d 
wit h fl u dara bi ne f or patie nts wit h pre vi o usl y u ntreate d c hr o nic l y m p h oc ytic le u ke mia: U S I nter gr o u p Trial
E 2 9 9 7. J Cli n O nc ol 2 0 0 7; 2 5: 7 9 3 – 7 9 8.
Fli n n I W, B yr d J C, M orris o n C, et al. Fl u dara bi ne a n d c ycl o p h os p ha mi de wit h fil grasti m s u p p ort i n patie nts 
wit h pre vi o usl y u ntreate d i n d ole nt l y m p h oi d mali g na ncies. Bl o o d. 2 0 0 0; 9 6: 7 1 -5.
Frie d ber g J W, S har ma n J, Sc hae f er-C utill o J, et al. F osta mati ni b dis o di u m ( F os D), a n oral i n hi bit or of S y k, 
is well-t olerate d a n d has si g nifica nt cli nical acti vit y i n diff use lar ge B-cell l y m p h o ma ( D L B C L) a n d c hr o nic 
l y m p h oc ytic le u ke mia ( S L L/ C L L). Bl o o d. 2 0 0 8; 1 1 2( 1 1). A bstract 3.
F ur m a n R R, B yr d J C, Br o w n J R, et al. C A L -1 0 1, a n is of or m -selecti ve i n hi bit or of p h os p hati d yli n osit ol 3-
ki nase P 1 1 0, de m o nstrates cli nical acti vit y a n d p har mac o d y na mic ef f ects i n patie nts wit h r ela pse d or  
r efract or y c hr o nic l y m p h oc ytic le u ke mia. Bl o o d. 2 0 1 0; 1 1 6 ( 2 1). A bstract 5 5 a n d oral prese ntati o n at: 
A mer ican S ociet y of He mat ol o g y A n n ual Meeti n g; Dece m ber 4 -7, 2 0 1 0; Orla n d o, F L.
Gri b be n J G, O’ Brie n S. U p date of t hera p y of c hr o nic l y m p h oc ytic le u ke mia . J Cli n O nc ol 2 0 1 1: 2 9: 5 4 4–
5 5 0.
Halle k M. Si g nali n g t h e en d of c hr o nic l y m p h oc ytic le u ke mia: ne w fr o ntli ne treat me nt strate gies. Bl o o d. 
2 0 1 3; 1 2 2: 3 7 2 3 - 3 4.
Halle k M, C hes o n B D, Cat o vs k y D, et al. Res p o nse assess me nt i n c hr o nic l y m p h oc ytic le u ke mia treate d 
wit h n o vel a ge nts ca usi n g a n i ncrease of p e ri p heral bl o o d ly m p h oc ytes. Bl o o d 2 0 1 2 (letter; p u blis he d 4 
J u ne 2 0 1 2). htt p:// bl o o dj o ur na l.he mat ol o g yli brar y. or g/c o nte nt/ 1 1 1/ 1 2/ 5 4 4 6/re pl y # bl o o dj o ur nal _el _ 6 9 2 0. 
Accesse d 2 3 A u g ust 2 0 1 2
Halle k M, Fisc her K, Fi n gerle -R o ws o n G, et al. A d diti o n of rit u xi ma b t o fl u dara bi ne a nd c ycl o p h os p ha mi de 
i n patie nts wit h c hr o nic l y m p h oc ytic le u kae mia: A ra n d o mise d, o pe n-la bel, p hase 3 trial. La ncet 2 0 1 0; 3 7 6: 
1 1 6 4 – 1 1 7 4.
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 oc ytic 
le u ke mia: a re p ort fr o m t he I nter nati o nal W or ks h o p 
o n C hr o nic L y m p h oc ytic L e u ke mia u p dati n g t he 
Nati o nal Ca ncer I nstit ute -W or ki n g Gr o u p 1 9 9 6 g ui deli ne. Bl o o d 2 0 0 8; 1 1 1: 5 4 4 6 – 5 4 5 6.
Her ma n S E, G or d o n A L, Hertlei n E, et al. Br ut o n t yr osi ne ki nase re prese nts a pr o misi n g t hera pe utic tar get 
f or treat me nt of c hr o nic l y m p h oc ytic le u ke mia a n d is effecti vel y tar gete d b y P CI -3 2 7 6 5. Bl o o d. 2 0 1 1; 
1 1 7: 6 2 8 7 -6 2 9 6.
Hill me n P, S k ot nic ki A B, R o ba k T, et al . Ale mt uz u ma b c o m pare d wit h c hl ora m b ucil as first -li ne t hera p y 
f or c hr o nic l y m p h oc ytic le u ke mia. J Cli n O nc ol 2 0 0 7; 2 5: 5 6 1 6– 5 6 2 3.
I nter nati o nal C o nfere nce o n Har m o nisati o n 
(I C H) of Tec h nical Re q uire me nts f or Re gistrati o n of 
P har mace uticals f or H u ma n Us e: I C H Har m o nise d Tri partite G ui deli ne: G ui da nce f or G o o d Cli nical 
Practice (I C H - E6) ( R 1). J u ne 1 9 9 6 . 
I nter nati o nal C o nfere nce 
o n Har m o nizati o n 
(I C H) G ui deli ne 
f or I n d ustr y: Cli nical 
Safet y Data 
Ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g (I C H -E 2 A). Marc h 1 9 9 5.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 4
I n vesti gat or's Br oc h ure. I br uti ni b. P har mac yclics L L C; Ja nsse n Researc h & De vel o p me nt, L L C. 
K na uf W U, Lissic h k o v T, Al da o u d A, et al. P hase III ra n d o mize d st u d y of be n da m usti ne c o mpare d wit h 
c hl ora m b ucil i n pre vi o usl y u ntreate d patie nts wit h c hr o nic l y m p h oc ytic le u ke mia. J Cli n O nc ol. 2 0 0 9;2 7: 
4 3 7 8- 8 4.
L oza ns ki G, Heere ma N A, Fli n n I W, et al. Ale mt uz u ma b is a n effecti ve t hera p y f or c hr o nic l y m p h oc ytic 
le u ke mia wit h p 5 3 m utati o ns a n d deleti o ns. Bl o o d . 2 0 0 4; 1 0 3: 3 2 7 8 - 8 1.
Nati o nal C o m pre he nsi ve Ca ncer Net w or k ( N C C N). N C C N Cli nical Practice G ui d eli nes i n O nc ol o g y 
( N C C N G ui deli nes) N o n-H o d g ki n’s L y m p h o mas. Versi o n 3 . 2 0 16 . N C C N. or g
O' Brie n S M, Ka ntarjia n H M, C ortes J, et al. Res ults of t he fl u dara bi ne a n d c ycl o p h os p ha mi de c o m bi nati o n 
re gi me n i n c hr o nic l y m p h oc ytic le u ke mia. J Cli n O nc ol. 2 0 0 1; 1 9: 1 4 14- 2 0.
O’ Brie n S G, G uil h ot F, Lars o n R A, et al. I mati ni b c o m pare d wit h i nterfer o n a n d l o w-d ose c ytara bi ne f or 
ne wl y dia g n ose d c hr o nic -p hase c hr o nic m yel oi d le u ke mia . Ne w E n gl J Me d 2 0 0 3; 3 4 8( 1 1): 9 9 4 – 1 0 0 4.
O' Brie n S, B ur ger J A, Bl u m K A, et al. T he Br ut o n's t yr osi ne ki nase ( B T K) i n hi bit or P CI -3 2 7 6 5 i n d uces 
d ura ble r es p o nses i n rela pse d or r efract or y ( R/ R) c hr o nic l y m p h oc ytic le u ke mia/s mall l y m p h oc ytic 
l y m p h o ma ( C L L/ S L L): F oll o w-u p of a P hase I b/II st u d y . Bl o o d 2 0 1 1; 1 1 8: A bstract 9 8 3.
O ke n, M M, Creec h, R H, T o r me y, D C, et al. T o xicit y a n d r es p o nse criteria of t he easter n c o o perati ve 
o nc ol o g y gr o u p. A m J Cli n O nc ol 1 9 8 2; 5: 6 4 9 - 6 5 5.
Pa n Z, Sc heere ns H, Li SJ, et al . Disc o ver y of selecti ve irre versi ble i n hi bit ors f or Br ut o n's t yr osi ne ki nase . 
C he m Me d C he m 2 0 0 7; 2: 5 8 – 6 1.
P oll yea D A, S mit h S, F o wler N, et al. A P hase I D ose Escalati o n St u d y of t he B T K I n hi bit or P CI -3 2 7 6 5 i n 
Rela pse d a n d Refract or y B -cell N o n -H o d g ki n L y m p h o ma a n d Us e of a N o vel Fl u or esce nt Pr o be 
P har mac o d y na mic Assa y. Bl o o d ( A S H A n n ual Meeti n g A bst racts) 2 0 0 9; 1 1 4( 2 2): 3 7 1 3.
P o na n der S, C he n S S, B u g g y J, et al. T he Br ut o n t yr osi ne ki nase i n hi bit or P CI -3 2 7 6 5 t h warts c hr o nic 
l y m p h oc ytic le u ke mia cell s ur vi val a n d tiss ue h o mi n g i n vitr o a n d i n vi v o. Bl o o d 2 0 1 2; 1 1 9: 1 1 8 2– 1 1 8 9.
P u g h R N, M urra y -L y o n I M, Da ws o n L, et al. “ Tra nsecti o n of t he oes o p ha g us f or blee di n g oes o p ha geal 
varices”. T he Britis h j o ur nal of s ur ger y. 1 9 7 3; 6 0: 6 4 6 -9. 
Rai K R, Peters o n B, A p pel ba u m F R, et al. Fl u dara bi ne c o m pare d wit h c hl ora m b ucil as pri mar y t hera p y f or 
c hr o nic l y m p h oc ytic le u ke mia. N E n gl J Me d 2 0 0 0; 3 4 3: 1 7 5 0 – 1 7 5 7.
R o ba k T, D m osz y ns ka A, S olal -Seli g n y P, et al. Rit u xi ma b pl us fl u dara bi ne pr ol o n gs pr o gressi o n -free 
s ur vi val c o m pare d wit h fl u dara bi ne a n d c ycl o p h os p ha mi de al o ne i n pre vi o usl y treate d c hr o nic l y m p h oc ytic 
le u ke mia. J Cli n O nc ol 2 0 1 0; 2 8: 1 7 5 6– 1 7 6 5.
S mit h TJ, K hatc heressia n J, L y ma n G H, et al . 2 0 0 6 u p date of rec o m me n dati o ns f or t he use of w hite bl o o d 
cell gr o wt h fact ors: A n e vi de nce-base d cli nical practice g ui deli ne 2 0 0 6; 2 4: 3 1 8 7 - 3 2 0 5.
Ste ve ns o n F K, Kr ys o v S, Da vies A J, et al. B- cell r ece pt or si g nali n g i n c hr o nic l y m p h oc ytic le u ke mia. 
Bl o o d 2 0 1 1; 1 1 8: 4 3 1 3 - 4 3 2 0.
S ur veilla nce E pi de mi ol o g y a n d E n d Res ults ( S E E R), N CI, U S Nati o nal I nstit utes of H e alt h, F ast Stats; 
Statistics Stratifie d b y Ca ncer Site, 2 0 1 0.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 5
Yelle n S B, Cell a D F, We bster K, et al. Meas uri n g fati g ue a n d ot her a ne mia -r elate d s y m pt o ms wit h t he 
F u ncti o nal Assess me nt of Ca ncer T hera p y ( F A C T) meas ure me nt s yste m. J Pai n S y m pt o m Ma na ge. 
1 9 9 7; 1 3: 6 3 - 7 4.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 6
1 3.
A P P E N DI C E S

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 8
c.
B o ne marr o w bi o ps y a n d/or  as pirate s ho ul d be perf or me d t o c o nfir m c o m plete res p o nse (C R ) or n P R , w he n a p pr o priate, t o e val uate c yt o pe nia. Marr o w 
c ollecte d t o c o nfir m C R s h o ul d ha ve mi ni mal resi d ual disease (M R D)
assessed b y fl o w c yt o metr y o n t he as pirate; patie nts c o nfir me d as M R D -ne gati ve i n 
t he marr o w s h o ul d be f oll o we d a p pr o xi matel y e ver y 6 m o nt hs f or M R D b y peri p heral fl o w c yt o metr y (Secti o n 6. 4. 1 1. 2 ). Patie nts w h o ha ve M R D -p ositi ve 
stat us i n t he b o ne marr o w, ca n als o be f oll o we d wit h peri p heral bl o o d M R D assess me nts e ver y 4 t o 6 m o nt hs , h o we ver, o nce t he patie nt bec o mes M R D -
ne gati ve i n t he peri p heral bl o o d, t his res ult s h o ul d be s u bse q ue ntl y c o nfir me d wit h a b o ne marr o w M R D assess me nt.
d.
T o be c o m plete d bef ore a n y ot her pr oce d ures or p h ysicia n i nteracti o ns; i ncl u des E Q - 5 D- 5 La n d F A Ci T -Fati g ue i nstr u me nts
e.
O nl y a d verse e ve nts a n d c o nc o mita nt m e dicati o ns o n g oi n g at t he e n d of A E/c o nc o mita nt me dicati o ns re p orti n g peri o d will be f oll o we d -u p t o res ol uti o n.
f.
Patie nts disc o nti n ui n g I P f or reas o ns ot her t ha n P D m ust be m o nit ore d f or alter nati ve a nti -ca ncer treat me nt i ncl u di n g start date a n d reas o n.
g.
E ver y 1 2 m o nt hs or earlier if P D is s us pecte d.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 8 0
b.
U n til 25 c ycles after t he start of treat me nt i n t he pare nt st u d y, t he f oll o wi n g assess me nts occ ur o n Da y 1 of e ver y 4 t h c ycle (ie, C ycles 1 3 , 1 7, 2 1, 2 5, 
c o u nti n g fr o m C ycle 1 D a y 1 i n t he pare nt st u d y ); fr o m C ycle 3 0 o n war d s, t he assess me nts t he n occ ur e very 1 2 c ycles (e ver y 1 2 m o nt hs f or p r e-P D f oll o w -
u p) u ntil t he patie n t e x perie nces P D or t he st u d y is cl ose d b y the S p o ns or .
c.
A d verse e ve nts are rec or de d at desi g nate d st u d y visits, w he n v ol u nteere d b y t he patie nt, a n d w he ne ver t he i n vesti gat or bec o mes a ware of a n e ve nt . A ll ne w 
mali g na nt t u m ors i ncl u di n g s oli d t u m ors, s ki n mali g na ncies a n d he mat ol o gic mali g na ncies are t o be re p orte d f o r t h e d urati o n of st u d y treat me nt a n d d uri n g 
a n y pr ot oc ol-s pecifie d f oll o w-u p peri o ds i ncl u di n g p ost -pr o gressi o n f oll o w -u p f or o verall s ur vi val.
d.
If P D is c o nfir me d a n d t he I W C L L treat me nt g ui deli nes i n dicate t hat ne w a ntica ncer t hera p y is i n dicate d, sec o n d-li ne treat me nt pla n is esta blis he d a n d 
s u bse q ue nt assess me nts are as descri be d i n A p pe n di x D . If P D is n ot c o nfir me d, s u bse q ue nt assess me nts are deter mi ne d b y w het her patie nt is still recei vi n g
i br uti ni b: 

If t h e patie nt is still recei vi n g i br uti ni b at t he ti me of t he S us pecte d -P D Visit, s u bse q ue nt assess me nts are descri be d u n der “ Desi g nate d C ycles / D a y 1”

If t h e patie nt is n o l o n ger recei vi n g i br uti ni b at t he ti me of t he S us pecte d -P D Visit, s u bse q ue nt assess me nts are descri be d u n der “ Pre -P D F oll o w - u p 
Visits.” i br uti ni b is n ot t o be restarte d i n t hese patie nts.
e.
Visit t hat f oll o ws t he e n d of ra n d o mize d i br uti ni b t hera p y
f.
T his visit pr o vi des f oll o w-u p f or patie nts i n w h o m P D is n ot c o nfir me d b ut w h o were n o l o n ger recei vi n g i br uti ni b at t he ti me of t he S us pecte d -P D Visit
(e g, i br uti ni b was st o p pe d b y t he i n vesti gat or w he n P D was s us pecte d) . U n til 25 m o nt hs after t he start of treat me nt i n t he pare nt st u d y, pr e-P D F oll o w - u p 
Visits occ ur e ver y  4 m o nt hs after t he E n d-of -Treat me nt Visit f or patie nts w h o ( 1) ha d n ot e x perie nce d P D a n d ( 2) ha d i br uti ni b t h e r a p y disc o nti n ue d bef ore 
t he S us pecte d-P D Visit . Starti n g fr o m m o nt h 3 0 o n war ds, t hese assess me nts t he n occ ur e ver y 6 m o nt hs u ntil P D or st u d y cl os ure (i br uti ni b t hera p y is n ot t o 
be restarte d i n t hese patie n ts).
g.
B o ne marr o w bi o ps y a n d/or  as pirate s ho ul d be perf or me d t o c o nfir m c o m plete res p o nse ( C R) or n P R , w he n a p pr o priate, t o e val uate c yt o pe nia. Marr o w 
c ollecte d t o c o nfir m C R s h o ul d ha ve mi ni mal resi d ual disease ( M R D) assesse d b y fl o w c yt o metr y o n t he as pirate; patie nts c o nfir me d as M R D -ne gati ve i n 
t he marr o w s h o ul d be f oll o we d a p pr o xi matel y e ver y 6 c ycles f or M R D b y peri p heral fl o w c yt o metr y (see Secti o n 6. 4. 1 1. 2 ). Patie nts w h o ha ve M R D -
p ositi ve stat us i n t he b o ne marr o w, ca n als o be f oll o we d wit h p eri p heral bl o o d M R D assess me nts e ver y 4 t o 6 c y cles, h o we ver, once t he patie nt bec o mes 
M R D -ne gati ve i n t he peri p heral bl o o d, t his res ult s h o ul d be s u bse q ue ntl y c o nfir me d wit h a b o ne marr o w M R D assess me nt.
h.
T o be c o m plete d bef ore a n y ot her pr oce d ures or p h ys icia n i nteracti o ns; i ncl u des E Q - 5 D- 5 L a n d F A Ci T -Fati g ue i nstr u me nts .
i.
I ncl u des f oc use d oc ular q uesti o ns ( n ot re q uire d f or pre-P D) .
j.
Patie nts disc o nti n ui n g I P f or reas o ns ot her t ha n P D m ust be m o nit ore d f or alter nati ve a nti -ca ncer treat me nt i ncl u di n g start date, reas o n, d ur ati o n, a n d 
res p o nse.
k.
O nl y a d verse e ve nts a n d c o nc o mita nt me dicati o ns o n g oi n g at t he e n d of A E/c o nc o mita nt me dicati o ns re p orti n g peri o d will be f oll o we d -u p t o res ol uti o n.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 8 3
n.
T he first d ose of i br uti ni b o n Da y 1 of C ycle 1 will be ta ke n at t he i n vesti gati o nal site after all pr oce d ures are c o n d ucte d .
o.
Patie nts disc o nti n ui n g I P f or reas o ns ot her t ha n P D m ust be m o nit ore d f or alter nati ve a nti -ca ncer treat me nt i ncl u di n g d urati o n a n d res p o nse .
p.
O nl y a d verse e ve nts a n d c o nc o mita nt me dicati o ns o n g oi n g at t he e n d of A E/c o nc o mita nt me dicati o ns re p orti n g peri o d will be f oll o we d -u p t o res ol uti o n.
After i m ple me ntati o n of Pr ot oc ol A me n d me nt 3 , t he patie nts w h o e x perie nce d P D a n d recei ve d sec o n d-li ne i br uti ni b t hera p y will e xit t he st u d y. T hese patie nts 
m a y  be ca n di dates f or a n ot her l o n g-ter m e xte nsi o n st u d y (ie, ot her t ha n St u d y P C Y C- 1 1 1 6-C A) ma de a vaila ble f or acti ve patie nts w h o c h o ose t o c o nti n ue o n 
i br uti ni b o n a cli nical pr ot oc ol w he n access t o c o m mercial i br uti ni b is n ot feasi ble.
I n or der t o mi ni mize or a v oi d treat me nt i nterr u pti o ns, t he patie nts o n sec o n d-li ne i br uti ni b o pti n g t o m o ve t o a n ot her l o n g-ter m e xte nsi o n st u d y, ma y be all o we d 
t o c o nti n ue treat me nt wit hi n t his st u d y f or a li mite d ti me bef ore tra nsiti o ni n g t o the ot her st u d y.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 8 5
A p pe n di x E.
Defi niti o ns of Res p o nse (H alle k 2 0 0 8 )
C o m plete Res p o nse ( C R)
All o f t he fol l owi n g are re q uire d f or a C R:

N o si g nifica nt l y m p ha de n o pat h y  ( > 1. 5 c m) b y C T or palpa ble o n e xa mi nat i on (if n ot 
sca n na ble)

N o he pat os ple n o me g al y b y C T

N o c o nstit uti o nal s y m pt o ms , defi ne d as: n o fe ver > 3 8º C f or ≥ 2 wee ks wit h o ut e vi de nce of 
i nfecti on, n o u ni nte nt i onal ≥1 0 % b o d y  wei g ht loss wi t hi n last 6 mo nt hs, n o ni g ht s weats f or 
> 1 m o nt h wi t ho ut e vi de nce of i nfect i on, a n d n o fati g ue ( E C O G perf or ma nce sc ore ≥ 2) 
i nterferi n g wit h w or k or us ual acti vities

A N C > 1 5 0 0/ L , plat elets > 1 0 0, 0 0 0/ L , a n d he m o gl o bi n > 1 1. 0 g/ d L

L y m p h oc y te c o u nt < 4. 0 x 1 0 9/ L
Marr o w as pirate
a n d/ or bi o ps y m ust be perf or me d after all ot her criteria meet t he defi nit i on o f 
C R . T o defi ne a C R, t he marr o w sa m ple m ust be at least n or m ocell ular f or a ge, wit h < 3 0 % of 
n ucleate d cells bei n g l y m p h oc y t es. B- l y m p h oi d n o d ules s h o ul d be a bse nt. I n a d diti on, i n pat ient s 
w h o meet t he C R criteria, M R D b y fl o w c yt o met r y s h o ul d be perf or me d t o e val uate M R D stat us.
C o m plete Res p o nse wit h a n I nc o m plete M arr o w Rec o ver y ( C Ri)
C Ri  is defi ne d as a C R wit h a n i nc om p lete rec o ver y o f t he patie nt’s b o ne marr o w. B o ne marr o w 
m ust be h y p ocell ular . Patie nts w h o ha ve a C Ri f ulfill criteria f or a C R, b ut c o nti n ue t o ha ve 
persiste nt a ne mia, t hr o m b oc y t o p e nia, or ne utr o pe nia d ue t o dr u g t o xi cit y in t he b o ne marr o w a n d 
n ot d ue t o a n y  evi de nce of C L L.
N o d ul ar P arti al Res p o nse ( n P R)
N o d ul ar partial res p o nse ( n P R) is a res p o nse w here patie nts meet criteria f or a C R, b ut t he b o ne 
marr o w bi o ps y  s h o ws t hat t here are still B-l y m p h oi d n o d ules prese nt. T hese n o d ules are resi d ual 
di sease a n d t herefore t he pati e nt is ter me d a n n P R.
P arti al Res p o nse ( P R)
At  least t w o of t he Cate g or y A para meters must be met; wi t h o ne e xce pti on: s u bjects w h o o nl y  
ha ve a b n or m al l y m p h n o des at baseli ne. F or t his e xce pti on, s u bjects will o nl y  nee d t o meet t he 
l y m p h n o de res p o nse criteria. 

≥ 5 0 % decrease 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, b y C T or, if o nl y o ne
meas ura ble l y m p h n o de at baseli ne, a ≥ 5 0 % decrease i n t he l o n gest dia meter of t he si n gle 
l y m p h n o de b y C T A N D n o i ncrease i n a n y  ot her l y m p h n o de b y C T. N ote: I n a s mall l y m p h 
n o de < 2 c m, a n i ncrease o f < 2 5 % i s n ot c o nsi dere d t o be si g nifica nt. 

N o ne w e nlar ge d l y m p h n o des b y C T or p h ysical e xa mi nat i on 

≥ 5 0 % decrease i n t he e nlar ge me nt of s plee n a n d/ or li ver size fr o m baseli ne or n or malizat i on 
b y C T 

If a b n or mal at baseli ne, a ≥ 5 0 % dr o p i n l y m p h oc yte c o u nt fr o m baseli ne or ≤ 4. 0 x 1 0 9/ L 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 8 6
Pl us a res p o nse i n at least o ne of  t h e fol l owi n g cri t eria i n de pe n de nt of gr o wt h fact or s u p p ort or 
tra nsf usi on * If all criteria are n or mal at baseli ne, t he y m ust re mai n n or mal t o be c o nsi dere d a 
P R: 

A N C > 1 5 0 0/ μ L, or ≥ 5 0 % i m pr o ve me nt o ver baseli ne 

Pl at elets > 1 0 0, 0 0 0/ μ L, or ≥ 5 0 % i m pr o ve me nt o ver baseli ne 

H e m o gl o bi n > 1 1. 0 g/ d L , or ≥ 5 0 % i m pr o ve me nt o ver baseli ne 
* N ote: F or a criteri o n t o be c o nsi dere d a res p o nse, it m ust ha ve bee n e val ua ble at baseli ne.
P R wit h L y m p h oc yt osis
If a b n or mal l y m p h oc yte c o u nt at baseli ne a n d res p o nse criteria ( ≥ 5 0 % dr o p i n l y m p h oc y te c o u nt 
fr om baseli ne or ≤ 4. 0 x 1 0 9/ L) has n ot bee n met a n d patie nt res p o n ds i n o nl y o ne ot her 
Cate g or y . A para meter bel o w, t he n t he res p o nse is c o nsi dere d P R L. 

≥ 5 0 % decrease 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 b y C T or, if o nl y o ne meas ura ble 
l y m p h n o de at baseli ne, a ≥ 5 0 % decrease i n t he l o n gest dia meter of t he si n gle l y m p h n o de 
b y C T A N D n o i ncrease i n a n y  ot her l y m p h n o de b y C T. N ote: I n a s mall l y m p h n o de 
< 2 c m, a n i ncrease of < 2 5 % is n ot c o nsi dere d t o be si g ni fica nt.

N o ne w e nlar ge d l y m p h n o des b y C T or p h ysical e xa mi nat i on.

≥ 5 0 % decrease i n t he e nlar ge me nt of li ver a n d/or s plee n size fr o m  baseli ne or n or malizati on 
b y C T.
Pl us a res p o nse i n at least o ne of  t h e fol l owi n g cri t eria i n de pe n de nt of gr o wt h fact or s u p p ort or 
tra nsf usi on. * If all criteria are n or mal at baseli ne, t he y  must r e m ai n n or mal t o be c o nsidere d a 
P R: 

A N C > 1 5 0 0/ μ L or ≥ 5 0 % i m pr o ve me nt o ver baseli ne 

Pl at elets > 1 0 0, 0 0 0/ μ L or ≥ 5 0 % i m pr o ve me nt o ver baseli ne 

H e m o gl o bi n > 1 1. 0 g/ d L , or ≥ 5 0 % i m pr o ve m e nt o ver baseli ne 
* N ote: F or a criteri o n t o be c o nsi dere d a res p o nse, it m ust ha ve bee n e val ua ble at baseli ne .
St a ble Dise ase
N ot meet i n g criteria f or C R, C Ri, n P R, P R, P R wit h l y m p h oc yt osis, or pr o gressi ve disease
Pr o gressi ve Dise ase
At  least O N E of  fol l owi n g:

Ne w e nlar ge d n o des > 1. 5 c m, ne w he pat o me gal y , or ne w s ple n o me gal y

≥ 5 0 % i ncrease fr o m na dir i n e xist i n g l y m p h n o de ( m ust reac h > 1. 5 c m i n t he l o n gest 
di a meter) or ≥ 5 0 % i ncrease fr o m na dir i n s u m of pr o d uct of dia meters of m ult i ple n o des

≥ 5 0 % i ncrease fr o m na dir i n e nlar ge me nt of li ver or s plee n

≥5 0 % i ncrease fr o m t he na dir c o u nt if c o nfir me d b y ce ntral la b o n ≥2 seri al assess me nts if 
t he A L C is ≥3 0, 0 0 0/ µ L a n d l y m p h oc y te d o u bli n g ti me is ra pi d, u nless c o nsi dere d treat me nt 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 8 7
r elate d l y m p h oc yt osi s Ne w c y t o pe nia ( he mo gl o bi n or pl at elets) attri b uta ble t o C L L. T he 
pr o gressi o n of a n y c y t o pe nia ( u nrelate d t o a ut oi m m u ne c yt o pe nia or blee di n g), as 
d oc u m e nte d b y a decrease of he m o gl o bi n le vels fro m  baseli ne b y m o re t ha n 2 g/d L or t o 
< 1 0. 0 g/ d L, or b y a decrease o f pl at elet c o u nts fr o m baseli ne b y m o re t ha n 5 0 % or t o 
< 1 0 0 , 0 0 0/L i n t he prese nce of acti ve C L L defi nes di sease pr o gressio n . W he n a p plica ble, a
marr o w bi o ps y  s h o uld d e m o n strate a n i nfiltrate of cl o nal C L L cells.

U ne q ui v ocal pr o gressi o n f or n o n- tar get lesi ons

Tra nsf or mat i on t o a m ore a g gressi ve hist ol o g y  (e g, Ric hter's 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 esta blis he d b y l y m p h n o de bi o ps y.
S us pecte d pr o gressi ve disease m ust be c o nfir me d b y a serial e xa mi nat i on at l east 2 weeks later.
Me as ur a ble Dise ase
P ati e nts must ha ve at l east 1 meas ura ble site of disease t o partici pate i n t h e pare nt st u d y. 
Meas ura ble sites of disease are defi ne d as l y m p h n o des or l y m p h n o de masses . Eac h m eas ura ble 
sit e of disease m ust be greater t ha n 1. 5 c m i n its lo n gest di a meter . Meas ure me nt m ust be 
deter mi ne d b y i ma gi n g e val uati o n.
P ati e nts ma y ha ve a pre vio usl y  irra diate d area fr o m a mali g na nc y pri or t o de vel o p me nt of C L L. 
T u m or lesi o n s t hat are sit uate d i n a pre vi o usl y irra diate d area mi g ht or mi g ht not be c o nsi dere d 
meas ura ble . If t here are t u m or lesi ons i n pre vi o usl y irra diate d areas a n d pr o gressi o n has 
occ urre d, t hese lesi o ns will be c o nsi dere d meas ura ble . If t u mor l esio ns i n pre vi o usl y  irra diate d 
areas are prese nt a n d ha ve bee n sta ble, t he n t hese l esio n s are n ot c o nsi dere d meas ura ble. If t u mor 
lesio ns i n pre vi o usl y  irra diate d areas pr o gress d uri n g t he st u d y, t he n disease pr o gressi o n will be 
c o nsi dere d t o ha ve occ urre d, if pr o gressi o n is c o nfir me d b y t he i n vesti gat or.
All ot her sites of disease will be c o nsi dere d assessa ble . Assessa ble disease i ncl u des o bject i ve 
e vi de nce of disease t hat is i de ntifie d b y r a diol o gi c al  ima gi n g, p h ysical e xa mi nat i on, or ot her 
pr oce d ures, as a p pr o priate, i ncl u di n g peri p heral bl o o d c o u nts.
Tre at me nt -rel at ed L y m p h oc yt osis
T reat me nt-relate d l y m p h oc yt osis is defi ne d as a n ele vati on i n bl o o d l y m p h oc y te c o u nt of ≥5 0 % 
c o mpare d wi t h baseli ne t hat occ urs i n t he setti n g of u ne q ui v ocal i m pr o ve me nt i n at least 1 ot her 
di sease-relate d para meter i ncl u di n g l y m p h n o de size, s plee n size, he mat ol o gic para meters 
( he m o gl obi n a n d platelet c o u nt), or disease -relate d s y m pt o ms. Treat m e nt -relate d l y m p h oc yt osis 
is is olate d l y m p h oc yt osis occ urri n g w he n n o ot her criteria f or pr ogressi ve disease are met . I n t his 
parti c ular st u d y, it will n ot be c o nsi dere d pr o gressi ve disease. T his is s u p p orte d b y  t h e most 
rece nt versi on of t he N C C N N H L 2 0 1 6 g ui deli nes.
Ric hter’s Tr a nsf or m ati o n
Ri c hter's s y n dr o me is l y m p h o mat o us tra nsf or m at i on t o a m o re a g gressi ve hist ol o g y i n a patient  
wi t h C L L or S L L a n d is m ost ofte n c haracterize d b y t he de velo p m e nt of  hi g h-gra de N H L or 
H o d g ki n’s disease . S y m pt o ms of Ric hter’s tra nsf or mat i on ca n i ncl u de ne w or pr o gressi ve 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 8 8
l y m p ha de n o pat h y or or ga n o me gal y, fe ver, loss of wei g ht a n d m uscle m ass, a n d ot her healt h 
pr o bl e ms. Ri c hter's tra nsf or matio n ca n be s u g geste d b y  a C T/ P E T sca n, b ut must be c o nfir me d 
wi t h a bio ps y (ie, l y m p h n o de) de m o nstrati n g t he hist ol o gic tra nsf or mat i on.
Mi ni m al Resi d u al Dise ase
( M R D)
M R D is de fi ne d as < 1 C L L cell per 1 0, 0 0 0 le u k oc y tes, as assesse d b y flo w c y t o metr y of a b o ne 
marr o w as pirate a n d/or bi o ps y or peri p heral bl o o d sa m ple . Patie nts w h o ac hie ve a c o m plete 
res p o nse ( C R) s h o ul d be e val uate d f or era diati on of disease cells as deter mi ne d b y flo w 
c yt o metr y o n t he b o ne marr o w as pirati on w he n a vaila ble . Pati e nts w h o ac hie ve M R D -ne gati ve 
re missi o n i n t he b o ne marr o w ma y t he n be f ollo we d b y  peri p heral blo o d M R D a p pr o xi matel y 
e ver y 6 c ycles de pe n di n g o n t heir visit sc he d ule . Pati e nts w h o ha ve M R D-p osi tive stat us i n t he 
b o ne marr o w, ca n als o be f o ll owe d wi t h p erip heral bl o o d M R D assess me nts, h o we ver, o nce t he 
pati e nt bec o mes M R D-ne gat i ve i n t he peri p heral bl o o d, t his res ult s h o ul d be s u bse q ue ntl y 
c o nfir me d wit h a m arr o w M R D assess me nt .

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 8 9
A p pe n di x F.
Criteri a f or Res p o nse C ate g ories
P ar a meter
C R
P R
P D
Gr o u p A
L y m p ha de n o pat h y a
N o ne; ≤1. 5c m
Decrease ≥5 0 %
i ncrease ≥5 0 %
He pat o me gal y
N o ne
Decrease ≥5 0 %
i ncrease ≥5 0 % or ne w 
he pat o me gal y
S ple n o me gal y
N o ne
Decrease ≥5 0 %
i ncrease ≥5 0 % or ne w 
s ple n o me gal y
Bl o o d l y m p h oc ytes
< 4 0 0 0/ µ L
Decrease ≥5 0 % fr o m 
baseli ne
i ncrease ≥5 0 % o ver 
baseli ne c
Marr o w
b
N or m ocell ular, 
< 3 0 % l y m p h oc ytes, 
n o B l y m p h oi d n o d ules. 
H y p ocell ular defi nes C Ri
Gr o u p B
Platelet c o u nt
> 1 0 0, 0 0 0/ µ L
> 1 0 0, 0 0 0/ µ L or i ncrease 
≥5 0 % o ver baseli ne
Decrease of ≥5 0 % fr o m 
baseli ne sec o n dar y t o 
C L L
He m o gl o bi n
> 1 1 g/ d L
> 1 1 g/ d L or i ncrease 
≥5 0 % o ver baseli ne
Decrease of > 2 g/ d L fr o m 
baseli ne sec o n dar y t o 
C L L
Ne utr o p hils
> 1 5 0 0/ µ L
> 1 5 0 0/ µ L or i ncrease 
≥5 0 % o ver baseli ne
N/ A
a S u m of t he pr o d ucts of m u lti ple l y m p h n o des (as e val uate d b y C T sca ns) or t he l o n gest dia meter of o ne 
tar get l y m p h n o de
b T his para meter is n ot rele va nt f or t he P D cate g or y u nless c o nfir mi n g c yt o pe nic pr o gressi o n.
c S u bjects wit h treat me nt -r elate d l y m p h oc yt osis s h o ul d re mai n o n st u d y treat me nt i n t he a bse nce of ot her 
criteria f or pr o gressi ve disease (see S e cti o n 7. 2 ). F or s u bjects wit h o ut treat me nt -r elate d l y m p h oc yt osis, 
P D b y l y m p h oc yte c o u nt ca n be c o nsi dere d base d o n ≥5 0 % i ncrease fr o m t he na dir c o u nt if c o nfir me d 
b y ce ntral la b o n ≥2 serial assess me n ts if t he A L C is ≥3 0, 0 0 0 / µ L a n d l y m p h oc yte d o u bli n g ti me is 
ra pi d.
N ote: Gr o u p A defi nes t he t u m or l oa d a n d Gr o u p B defi nes t he f u ncti o n of t he he mat o p oietic s yste m .
C R: all of t he criteria nee d t o be met a n d s u bjects ha ve t o lac k disease relate d c o nstit ut i o nal s y m pt o ms. 
B o ne ma rr o w a n d as pirate is re q uire d t o c o nfir m C R.
P R: At least t w o of t he Gr o u p A para meters m ust be met; wit h t w o e xce pti o ns: 1) s u bjects w h o o nl y ha ve 
a b n or ma l l y m p h n o des at baseli ne, or 2) s u bjects w h o ha ve o nl y a b n or mal l y m p h n o de a nd a b n or mal 
l y m p h oc yte c o u nt ( A L C) at baseli ne. F or t hese t w o e xce pti o ns, s u bjects will o nl y nee d t o meet t he l y m p h 
n o de res p o nse criteria. 
I n a d diti o n t o t he Gr o u p A criteria, all s u bjects m ust als o ha ve a res p o nse i n at least o ne of t he Gr o u p B 
criteria.
S D: t he a bse nce of P D a n d t he fail ure t o ac hie ve a res p o nse.
P D: at least 1 of t he a b o ve criteria fr o m Gr o u p A or B are met or de vel o p me nt of tra nsf or mati o n t o a 
m or e a g gressi ve hist ol o g y.
Cr oss refere nce:  Halle k 2 0 0 8 , Halle k 2 0 1 2 , Halle k 2 0 1 3

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 9 0
A p pe n di x G.
I n hi bit ors a n d I n d ucers of C Y P 3 A
I n hi bit ors a n d i n d ucers of C Y P 3 A are defi ne d as f oll o ws. Refer t o Secti o n 5. 5. 2. 1 o n i nstr ucti o ns f or 
c o nc o mita nt use of C Y P 3 A i n hi bit ors or i n d ucers wit h i br uti ni b. F urt her i nf or m ati o n ca n be f o u n d at t he 
f oll o wi n g we bsite: htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ mai n-ta ble/.
I n hi bit ors of C Y P 3 A
I n d ucers of C Y P 3 A
Str o n g i n hi bit ors:
car ba maze pi ne
i n di na vir
efa vire nz
nelfi na vir
ne vira pi ne
rit o na vir
bar bit urates
clarit hr o m yci n
gl uc oc ortic oi ds
itrac o naz ole
m o dafi nil
ket oc o naz ole
o xcar barze pi ne
nefaz o d o ne
p he n o bar bital
sa q ui na vir
p he n y t oi n
s u b o x o ne
pi o glitaz o ne
telit hr o m yci n
rifa b uti n
c o bicistat
rifa m pi n
b oce pre vir
St. J o h n’s W ort
mi befra dil
tr o glitaz o ne
tela pre vir
tr olea n d o m yci n
p osac o naz ole a
M o der ate i n hi bit ors:
a pre pita nt
a m pre na vir
a mi o dar o ne
ataza na vir
ci pr ofl o xaci n
criz oti ni b
dar u na vir
dr o ne dar o ne
er yt hr o m yci n
diltiaze m
fl uc o naz ole
f osa m pre na vir
gra pefr uit j uice
Se ville ora n ge j uice
vera pa mil
v oric o naz ole b
i mati ni b
We a k i n hi bit ors:
ci meti di ne
fl u v o xa mi ne
All ot her i n hi bit ors:
c hl ora m p he nic ol
dela viri di ne
diet h yl -dit hi ocar ba mate
gest o de ne
mife prist o ne
n orfl o xaci n
n orfl u o xeti ne
star fr uit
a
Base d o n P B P K si m ulati o ns, u p t o 9. 7- f ol d i ncrease i n A U C a n d 6. 2 -f ol d i ncrease i n C ma x c o ul d be o bser ve d . If 
i br uti ni b nee ds t o be a d mi nistere d wit h p osac o naz ole, 1 4 0 m g i br uti ni b will be d ose d.
b
B ase d o n i nter nal data, 1 4 0 m g i br uti ni b d ose d wit h v oric o naz ole pr o d uces i br uti ni b e x p os ures si milar t o 5 6 0 
m g i br uti ni b d ose d al o ne. T heref ore, f or t his st u d y, if i br uti ni b nee ds t o be a d mi nistere d wit h v oric o naz ole, 1 4 0 
m g i br uti ni b will be d ose d.

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 9 1
A p pe n di x H.
E C O G St at us Sc ores
St at us
E aster n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or m a nce St at us
a
0
F ull y  acti ve, a ble t o carr y o n all pre-disease perf or ma nce wit h o ut restricti o n.
1
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a li g ht or se de ntar y 
nat ure, e g, li g ht h o use w or k, office w or k.
2
A m b ulat or y a n d ca pa ble of all self -care, b ut u na ble t o carr y o ut a n y w or k acti vities . U p a n d a b o ut m ore t ha n 
5 0 % of wa ki n g h o urs.
3
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs.
4
C o m pletel y disa ble d . Ca n n ot carr y o n a n y self -care. T otall y c o nfi ne d t o be d or c hair.
5
Dea d.
a
O ke n, M M, Creec h, R H, T or me y, D C, et al . T o xicit y a n d res p o nse criteria of t he easter n c o o perati ve o nc ol o g y gr o u p. 
A m J Cli n O nc ol 1 9 8 2; 5: 6 4 9 - 6 5 5.
S o urce : htt p:// w w w.ec o g. or g/ ge neral/ perf _stat ht ml ; accesse d 0 4 Ja n uar y 2 0 0 8

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 9 2
A p pe n di x I.
H e m at ol o gic A d verse E ve nt Gr a di n g Sc he me ( H alle k 2 0 0 8 )
A n e val uat i on of t he he mat ol o gic t o xicit y i n patients wi t h a d va nce d C L L/ S L L m ust c o nsi der t he 
hi g h fre q ue nc y of marr o w i n v o l ve me nt a n d pre vi ous e x p os ure t o c he m ot hera p y  wit h c o nse q ue nt 
me d ullar y  c o mpr o mise at t he i nitiati o n of  t hera p y. T he sta n dar d he mat ol o gic gra di n g s yste m f or 
s oli d t u m ors ca n n ot, t heref ore, be direct l y a p plie d. A s u bsta ntial pr o p orti o n of pat ient s w o uld be 
c o nsi dere d t o ha ve Gra de 2 t o 4 he mat ol o gic t o xicit y  b efore a n y  t hera p y is gi ve n. T heref ore, t he 
f oll owi n g m o difie d sc he ma will be use d t o q ua ntitate he mat ol o gic deteri orati o n i n pat ient s wit h 
C L L/ S L L.
He m at ol o gic Gr a di n g Sc he me
Decre ase i n Pl atelets or H g b ( N a dir) fr o m 
Pre -tre at me nt V al ue, %
A N C/ μ L ( n a dir) c
T o xicit y Gr a de
0 - 1 0 % a
≥ 2 0 0 0
0
1 1 - 2 4 % a, b
≥ 1 5 0 0 a n d < 2 0 0 0
1
2 5 - 4 9 % a, b
≥ 1 0 0 0 a n d < 1 5 0 0
2
5 0 - 7 4 % a, b
≥ 5 0 0 a n d < 1 0 0 0
3
7 5 % a, b
< 5 0 0
4
a.
If at a n y le vel of decrease, t he platelet c o u nt falls bel o w 2 0 x 1 0 9/ L, t o xicit y will be c o nsi dere d Gra de 4. If t he 
baseli ne platelet c o u nt is < 2 0 x 1 0 9/ L, platelet t o xicit y ca n n ot be e val uate d.
b.
Baseli ne a n d s u bse q ue nt H g b val ues m ust be deter mi ne d t he da y of a n y  gi ve n tra nsf usi o n.
c.
If t he A N C was < 1 0 0 0/ µ L bef ore t hera p y, t he patie nt is n ot e val ua ble f or t o xicit y refera ble t o t he A N C

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 9 3
A p pe n di x J.
E Q - 5 D- 5 L
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 9 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 9 5
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 9 6
A p pe n di x K.
F A Ci T - F ati g ue
 
  
  
 
 
     
 
  
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
  
 
  
 
 
 
 
  
  
 
 
  
    
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
  
 
 
  
 
 
 
  
 
 
   
 
 
 
  
  
 
 
 
  
 
 
 
  
  
    
 
 
      
 
   
 
 
 
 
 
 
 
  
  
  
    
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

I M B R U VI C A® (i br uti ni b)
Pr ot oc ol P C Y C - 1 1 1 6-C A , A me n d me nt 4
1 0 Oct 2 0 2 2
FI N A L
P har mac yclics L L C
Pr o prietar y a n d C o nfi de ntial
Pa ge 9 7
A p pe n di x L.
C hil d -P u g h  Sc ore f or S u bjects wit h Li ver I m p air me nt*
( * C hil d- P u g h Sc ore t o be use d o nly i n s u bjects wit h c hr o nic liver dise ase)
Me as ure
1 p oi nt
2 p oi nts
3 p oi nts
T otal bilir u bi n, μ m ol/ L ( m g/ d L)
< 3 4 ( < 2)
3 4- 5 0 ( 2 -3)
> 5 0 ( > 3)
Ser u m al b u mi n, g/ L ( g/ d L)
> 3 5 ( > 3. 5)
2 8- 3 5 ( 2. 8 -3. 5)
< 2 8 ( < 2. 8)
P T/I N R
< 1. 7
1. 7 1- 2. 3 0
> 2. 3 0
Ascites
N o ne
Mil d
M o derate t o Se vere
He patic e nce p hal o pat h y
N o ne
Gra de I -II ( or s u p presse d 
wit h me dicati o n)
Gra de III -I V 
( or refract or y)
P oi nts
Cl ass
5 - 6
A
7 - 9
B
1 0- 1 5
C
S o urce: 
1.
C hil d C G, T urc otte J G. “ S ur ger y a n d p ortal h y perte nsi o n”. I n C hil d C G. T he li ver a n d p ortal h y perte nsi o n. 
P hila del p hia: Sa u n ders . 1 9 6 4. p p. 5 0- 6 4. 
2.
P u g h R N, M urra y -L y o n I M, Da ws o n L, et al. “ Tra nsecti o n of t he oes o p ha g us f or blee di n g oes o p ha geal 
varices” . T he Britis h j o ur nal of s ur ger y, 1 9 7 3; 6 0: 6 4 6 - 9.
‡ N ote: sec o n d -li ne i br uti ni b is n ot a p plic a ble after i m ple me nt ati o n of Pr ot oc ol A me n d me nt 3.

 
 
Pr ot oc ol/ Pr ot oc ol A me n d me nt A p pr o v al F or m 
F or m N o.: F O R M- 0 3 4 5. 2 
Effecti ve D ate:  2 5 J a n 2 0 1 9 
G o ver ni n g D oc:  WI- 0 1 3 9 
P a ge:  1  of 2 
C o nfi de nti al  
T his i nf or mati o n is c o nfi de ntial t o P har mac yclics, a n A b b Vie C o m pa n y  T he user is res p o nsi ble f or usi n g t he a p pr o priate re visi o n of t his d oc u me nt  
Pr ot oc ol/ Pr ot oc ol A me n d m e nt A p pr o v al F or m 
D ate circ ul ate d f or re vie w :  1 6- Se p- 2 0 2 2  
 
P ur p ose :  Pr ot oc ol A m e n d me nt  
 
St u d y N u m ber :  P C Y C-1 1 1 6 -C A 
Pr ot oc ol Versi o n d ate ( D D M M M Y Y Y Y):  3 0 Oct o ber 2 0 2 2 
  Ori gi n al 
  A me n d me nt – Versi o n # 4 
Pr ot oc ol Title:  A n O p e n-la bel E xte nsi o n St u d y i n Patie nts 6 5 Years or Ol der wit h C hr o nic L y m p h oc ytic Le u ke mia ( C L L) or S mall 
L y m p h oc ytic L y m p h o ma ( S L L) W h o Partici pate d i n St u d y P C Y C- 1 1 1 5- C A (I br uti ni b vers us C hl ora m b ucil)  
Ple ase i n dic ate t h at y o u h a ve re vie we d a n d a p pr o ve t he d oc u me nt liste d a b o ve b y si g ni n g a n d d ati n g bel o w.  
A p pr o v al Si g n at ures 
N a me 
Si g n at ure 
A p pr o v al D ate 
Cli nic al Scie nce 
 N A 
 
 
 
 
Cli nic al O per ati o ns  
 N A 
 
 
 
 
Dr u g S afety & P h ar m ac ovi gil a nce 
 N A 
 
 
 
 
Bi o metrics  
 N A 
 
 
 
 
1 0/ 1 0/ 2 2
 
 
 
 

 
 
Pr ot oc ol/ Pr ot oc ol A me n d me nt A p pr o v al F or m 
F or m N o.: F O R M- 0 3 4 5. 2 
Effecti ve D ate:  2 5 J a n 2 0 1 9 
G o ver ni n g D oc:  WI- 0 1 3 9 
P a ge:  2  of 2 
C o nfi de nti al  
T his i nf or mati o n is c o nfi de ntial t o P har mac yclics, a n A b b Vie C o m pa n y  T he user is res p o nsi ble f or usi n g t he a p pr o priate re visi o n of t his d oc u me nt  
A p pr o v al Si g n at ures 
N a me 
Si g n at ure 
A p pr o v al D ate 
Re g ul at ory Aff airs  
 N A 
 
  
 
 
Rese arc h  
 N A 
 
      
 
 
Cli nic al P h ar m ac ol o gy  
 N A 
 
      
 
 
P R C C h air m a n  
 N A 
 
      
 
 
 
 
 
 
 

 
 
Pr ot oc ol/ Pr ot oc ol A me n d me nt A p pr o v al F or m 
F or m N o.: F O R M- 0 3 4 5. 2 
Effecti ve D ate:  2 5 J a n 2 0 1 9 
G o ver ni n g D oc:  WI- 0 1 3 9 
P a ge:  1  of 1 
C o nfi de nti al  
T his i nf or mati o n is c o nfi de ntial t o P har mac yclics, a n A b b Vie C o m pa n y  T he user is res p o nsi ble f or usi n g t he a p pr o priate re visi o n of t his d oc u me nt  
D oc u me nt Hist or y 
D C R 
Re v 
C h a n ge Descri pti o n 
9 8 4 8 
0 
Ne w F or m. 
1 0 4 6 3 
1 
A d diti o n of Pr ot oc ol date a n d versi o n. 
2 1 4 1 1 
2 
Ref or mat si g nat ure ta ble t o ma ke r o o m f or D oc u Si g n electr o nic si g nat ure c o nfir mati o ns.