Clinical trial NCT01724346
Conditions: Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Keywords: CLL SLL
Sponsor: Pharmacyclics LLC.
Start date: 2013-12-03; Completion date: 2023-08-18
Enrollment: 269 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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)

Detailed description:

Arms: arm 1: Participants who received chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) Days 1 and 15 of 28-day cycle up to 12 cycles in Study 1115. In Study 1116, participants had the option to crossover to next-line ibrutinib 420 mg/day after disease progression (PD). arm 2: Participants who received ibrutinib 420 mg daily in Study 1115 received ibrutinib orally once daily. Participants continuing in first-line ibrutinib therapy entered Study 1116 at the ibrutinib dose tolerated in Study 1115.
Interventions: intervention 1: Ibrutinib intervention 2: Next-line ibrutinib
Intervention descriptions: intervention 1: Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily intervention 2: Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily

Protocol documents:
Prot_000.pdf: 


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. 
 
 
 
 
 

SAP_001.pdf: 
Ibrutinib
PCYC-1116-CA – Statistical Analysis Plan
Version 1.0 – 13 June 2023
1
Statistical Analysis Plan for Study PCYC-1116-CA
An Open-label Extension Study in Patients 65 Years 
or Older with Chronic Lymphocytic Leukemia (CLL) 
or Small Lymphocytic Leukemia (SLL) Who 
Participated in Study PCYC-1115-CA (Ibrutinib vs 
Chlorambucil)
Date: 13 June 2023
Version 1.0
 
NCT01724346


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PCYC-1116-CA – Statistical Analysis Plan
Version 1.0 – 13 June 2023
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Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Objectives and Design ................................................5
2.1
Study Objectives .................................................................................... 5
2.2
Study Design Overview.......................................................................... 6
2.3
Treatment Assignment and Blinding....................................................... 7
2.4
Sample Size Determination .................................................................... 8
3.0
Endpoints...............................................................................8
3.1
Primary Efficacy Endpoint(s) ................................................................. 8
3.2
Secondary Efficacy Endpoint(s) ............................................................. 9
3.2.1
Key Secondary Efficacy Endpoints......................................................... 9
3.2.2
Supportive Secondary Efficacy Endpoints .............................................. 9
3.3
Additional Efficacy Endpoints................................................................ 9
3.4
Safety Endpoint(s).................................................................................. 9
3.5
Other Endpoint(s)................................................................................... 9
4.0
Analysis Populations .............................................................9
5.0
Subject Disposition..............................................................10
6.0
Study Treatment Duration and Dosing..............................10
7.0
Subject Characteristics .......................................................11
7.1
Demographics and Baseline Characteristics.......................................... 11
7.2
Prior and Concomitant Medications...................................................... 11
7.3
Protocol Deviations .............................................................................. 12
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints ............................12
9.0
Efficacy Analyses.................................................................13
9.1
General Considerations......................................................................... 13
9.2
Handling of Missing Data..................................................................... 13
9.3
Primary Efficacy Endpoint(s) and Analyses.......................................... 14
9.3.1
Primary Efficacy Endpoint(s) ............................................................... 14
9.3.2
Main Analysis of Primary Efficacy Endpoint(s).................................... 14
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint(s)........................................................................................... 15
 


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9.4
Secondary Efficacy Endpoints and Analyses ........................................ 16
9.4.1
Key Secondary Efficacy Endpoint(s).................................................... 16
9.4.2
Main Analyses of Key Secondary Efficacy Endpoint(s)........................ 17
9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints ............................................................................... 20
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses....................... 20
9.5
Additional Efficacy Endpoints and Analyses ........................................ 21
9.6
Efficacy Subgroup Analyses................................................................. 22
10.0
Safety Analyses....................................................................23
10.1
General Considerations......................................................................... 23
10.2
Adverse Events..................................................................................... 23
10.2.1
Treatment-Emergent Adverse Events.................................................... 23
10.2.2
Adverse Event Overview...................................................................... 23
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 24
10.2.4
Deaths, Serious Adverse Events, and Adverse Events Leading to 
Study Treatment Discontinuation.......................................................... 25
10.2.5
Adverse Events of Special Interest........................................................ 25
10.3
Analysis of Laboratory Data................................................................. 26
10.4
Analysis of Vital Signs......................................................................... 26
11.0
Other Analyses ....................................................................26
12.0
Interim Analyses..................................................................27
13.0
Overall Type-I Error Control.............................................27
14.0
Version History ...................................................................27
14.1
Changes to Planned Analyses in the Protocol........................................ 27
15.0
References............................................................................28
List of Tables
Table 1.
Handling of Intercurrent Events............................................................ 12
Table 2.
Summary of the Estimand Attributes Corresponding to the 
Primary Efficacy Objectives................................................................. 15
Table 3.
Summary of the Estimand Attributes Corresponding to the Key 
Secondary Efficacy Objectives ............................................................. 18
 


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Table 4.
Summary of the Estimand Attributes Corresponding to the 
Supportive Secondary Efficacy Objective............................................. 20
Table 5.
Subgroup Definition for Efficacy Analysis ........................................... 22
Table 6.
SAP Version History Summary ............................................................ 27
List of Figures
Figure 1.
Study Schematic..................................................................................... 7
List of Appendices
Appendix A.
List of SAP Signatories ........................................................................ 29
Appendix B.
Definition of Adverse Events of Special Interest................................... 30
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for the Ibrutinib 
Study PCYC-1116-CA "An Open-label Extension Study in Patients 65 Years or Older 
with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL) 
Who Participated in Study PCYC-1115-CA (Ibrutinib vs Chlorambucil)."
The final analysis for Study PCYC-1116-CA intends to summarize the long-term efficacy 
and safety outcomes of ibrutinib in subjects 65 years or older with CLL or SLL across the 
overall follow-up period starting from initiation of the parent study PCYC-1115-CA to 
closure of the extension study PCYC-1116-CA. 
To avoid the patient selection bias in assessing long-term outcomes, all 269 randomized 
subjects in the intent-to-treat (ITT) population of the parent study will be analyzed 
including those who did not roll-over to the extension study due to death or any other 
reasons. The SAP will not be updated in case of administrative changes or amendments to 
the protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC 27513) or later under the Windows SAS server.
This SAP includes changes to analyses described in the protocol. Details are outlined in 
Section 14.1.
2.0
Study Objectives and Design
2.1
Study Objectives
●
To monitor progression-free survival (PFS)
●
To continue treatment and safety assessment of patients randomized to Arm B 
(ibrutinib) in Study PCYC-1115-CA (the parent study) who have not 
progressed at the time of parent study closure
●
To follow patients for long-term outcome
 


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●
To capture overall response rate (ORR), duration of response (DOR), PFS, 
overall survival (OS), and time to next therapy (TTNT)
●
To fulfill long-term follow-up requirements of randomized patients after 
closure of the parent study, including OS
2.2
Study Design Overview
Study PCYC-1116-CA is an open-label, multicenter, extension study of PCYC-1115-CA 
(parent study) which was initiated concurrently with the parent study. Subjects were 
transferred to this study after Independent Review Committee (IRC) confirmation of 
disease progression (PD) in the parent study or at closure of the parent study by Sponsor.
When rollover to Study PCYC-1116-CA occurred, subjects in the chlorambucil arm had 
either completed or discontinued the first-line chlorambucil treatment and were to be 
continuing pre-PD response follow-up or were starting post-PD follow-up for subsequent 
therapy and overall survival; subjects in the ibrutinib arm were to be continuing first-line 
ibrutinib treatment and/or pre-PD response follow-up, or starting post-PD follow-up, 
whichever was applicable based on the treatment and response status at the end of 
participation of the parent study.
The study schematic is shown in Figure 1.
 


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Figure 1.
Study Schematic
The response and progression were evaluated by the investigator and IRC in accordance 
with the IWCLL guidelines including clarifications2-5 from the parent study 
PCYC-1115-CA and by investigator assessment in the extension study PCYC-1116-CA.
The PCYC-1116-CA study will be closed when approximately 10 years elapsed from the 
first subject randomized in PCYC-1115-CA. Due to the nature of an extension study, the 
final analysis for the PCYC-1116-CA clinical study report (CSR) will be based on the 
pooled clinical database of the parent study and extension study.
2.3
Treatment Assignment and Blinding
Subjects were randomized to ibrutinib or chlorambucil, in a 1:1 ratio at the beginning of 
the parent study. Randomization of treatment assignment was blocked by geographic 
region (US versus non-US) and was be stratified by: 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 


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●
Eastern Cooperative Oncology Group (ECOG) performance status (0, 1 
versus 2)
●
Presence of advanced-stage disease (Rai stage <3 versus 3-4)
When transferring to the extension study, subjects were to continue the ongoing treatment 
(if any) from the parent study or initiate subsequent therapy after PD at the discretion of 
the investigator in the extension study. Crossover to next-line ibrutinib as a subsequent 
therapy was an option for patients enrolled in the chlorambucil arm only.
Both the parent and extension studies were open label. Neither the subjects nor the 
investigators were blinded to treatment. However, in the parent study, the Sponsor's staff 
overseeing the conduct of the study and IRC had been blind to treatment assignment when 
reviewing or evaluating the efficacy data until the study was closed and its clinical 
database was locked for analysis. No blinding was performed in the extension study.
2.4
Sample Size Determination
The sample size for the parent study was calculated based on the primary endpoint, PFS, 
in the parent study (reference to protocol and SAP for study PCYC-1115-CA). No sample 
size and power calculations were conducted for the extension study PCYC-1116-CA.
The long-term efficacy and safety outcomes for the first-line treatments will be 
summarized descriptively by arms side-by-side based on the pooled clinical database of 
parent and extension studies. No hypothesis testing will be performed.
3.0
Endpoints
All primary and secondary endpoints are for first line treatment, unless otherwise 
specified. PFS, OS, ORR, and minimal residual disease (MRD)-negativity under next-line 
ibrutinib treatment will be summarized as additional efficacy endpoints.
3.1
Primary Efficacy Endpoint(s)
●
Progression Free Survival (PFS)
 


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3.2
Secondary Efficacy Endpoint(s)
3.2.1
Key Secondary Efficacy Endpoints
●
Progression Free Survival after initiation of subsequent anticancer therapy 
(PFS2)
●
Overall Survival (OS)
●
Time to next treatment (TTNT)
●
Overall Response Rate (ORR)
●
Rate of MRD Negativity
3.2.2
Supportive Secondary Efficacy Endpoints
●
Duration of Response (DOR)
3.3
Additional Efficacy Endpoints
●
Progression Free Survival (PFS) after next-line Ibrutinib
●
Overall Survival (OS) after next-line Ibrutinib
●
Overall Response Rate (ORR) after next-line Ibrutinib
●
Rate of MRD Negativity after next-line Ibrutinib
3.4
Safety Endpoint(s)
Safety as measured by TEAEs, laboratory and vital sign measurements.
3.5
Other Endpoint(s)
No other endpoints will be evaluated for this study.
4.0
Analysis Populations
The following population sets will be used for the analyses:
 


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The Intent-to-Treat (ITT) Population as defined in the parent study, PCYC-1115-CA, 
includes the 269 randomized subjects and will be used for all efficacy and disposition 
summaries for the first-line therapy, unless otherwise specified. Subjects will be analyzed 
as randomized.
The safety population includes all subjects in the ITT population who received at least 1 
dose of either chlorambucil or ibrutinib as the first-line therapy in the parent study, 
PCYC-1115-CA. Subjects in the safety population will be analyzed according to the 
actual treatment received and will be used to summarize the safety (including dosing) for 
the first-line therapy.
The crossover analysis set includes all chlorambucil-arm subjects who received at least 1 
dose of ibrutinib as the next-line study treatment. This analysis set will be used for all 
efficacy and safety summaries of the next-line ibrutinib.
5.0
Subject Disposition
Subject disposition for each study treatment and for study participation will be tabulated.
The overall time on study will be summarized using Kaplan-Meier method with reversed 
censoring to overall survival (i.e., subjects who died will be censored at death date). The 
reason for subjects who did not roll over to PCYC-1116-CA study will be summarized 
separately.
6.0
Study Treatment Duration and Dosing
Exposure to first-line ibrutinib and chlorambucil will be summarized separately for 
treatment duration and dosing information (e.g., total cumulative dose administered, total 
number of doses received, average dose level per administration, and relative dose 
intensity). A similar summary will be provided for the next-line ibrutinib.
 


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7.0
Subject Characteristics
Categorical variables will be summarized with the number and percentage of subjects. 
Continuous variables will be summarized with descriptive statistics (number of non-
missing observations, mean and standard deviation, median, minimum, and maximum).
7.1
Demographics and Baseline Characteristics
All demographics and baseline characteristics were summarized for the ITT population by 
treatment arm in the PCYC-1115-CA CSR and will not be repeated for the 
PCYC-1116CA CSR.
7.2
Prior and Concomitant Medications
Medications will be coded to preferred term and Anatomical Therapeutic Chemical (ATC) 
class according to World Health Organization (WHO) Drug dictionary.
Prior medications are defined as medications that started prior to the first dose date of any 
study drug from Study PCYC-1115-CA. Concomitant medications for the first-line study 
treatment are defined as medications that were taken at any time from the first dose date 
of the first-line study drug through the last dose date of first-line study drug. Concomitant 
medications for the next-line are defined as medications that were taken at any time from 
the first dose date of the next-line study drug through the last dose date of next-line study 
drug.
Concomitant medications will be summarized by therapeutic class and preferred term and 
by treatment arm for all subjects in the safety population. The following concomitant 
medications of special interest will be summarized separately: transfusion and growth 
factors, CYP3A inhibitors and inducers, anticoagulants and/or antiplatelets.
Subsequent CLL/SLL antineoplastic agents taken after the first dosing date of the first-
line treatment will be summarized by the regimen type.
 


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7.3
Protocol Deviations
Subjects with important protocol deviations (IPDs) will be identified by the study 
management team prior to the analysis and will be presented for each treatment arm.
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
The following methods noted in Table 1 will be used to address potential intercurrent 
events for the primary analysis of the primary and key secondary efficacy endpoints 
(defined in Section 9.0):
Table 1.
Handling of Intercurrent Events
Intercurrent 
Events
Handling Strategies
Applied Endpoints
Premature 
discontinuation of 
study drug
Treatment policy strategy
Valid assessments and/or 
follow-up will be used 
regardless of the study drug 
discontinuation.
PFS, PFS2, OS, time to next treatment, ORR, 
DOR, MRD-negativity rate
Use of subsequent 
anti-cancer therapy
Treatment policy strategy
Valid assessments and/or 
follow-up will be used 
regardless of use of 
subsequent anti-cancer 
therapy.
PFS, OS, DOR
While on treatment strategy
Disease assessments at or 
prior to initiation of 
subsequent antineoplastic 
therapy will be used.
ORR, MRD negativity rate
Composite strategy
Initiating the second 
subsequent therapy will be 
considered as a PFS2 event.
PFS2
 


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Intercurrent 
Events
Handling Strategies
Applied Endpoints
Discontinuation of 
study before 
observing an event
Hypothetical strategy
Censoring subjects at the last 
adequate follow-up (last 
adequate disease assessment 
for PFS, PFS2 and DOR; last 
known alive date for OS and 
time to next treatment)
PFS, PFS2, OS, time to next treatment, DOR
Discontinuation of 
study without any 
valid assessments
Composite strategy
Discontinuation of study
without any valid assessment 
due to any cause will be 
considered as non-responders.
ORR, MRD negativity rate
DOR = duration of response; PFS = progression free survival; MRD = Minimal Residual Disease; ORR = overall 
response rate; OS = overall survival
9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted on the ITT population, unless otherwise specified. 
The extension study was not powered for hypothesis testing. The same between-arm 
comparisons as for the primary analysis of the parent study will be repeated with the 
longer-term data in purpose of presenting the relative efficacy benefit descriptively. All p-
values are nominal.
Because the response and PD were evaluated by investigator only in the extension study 
(PCYC-1116-CA), the efficacy endpoints based on response assessments (e.g., PFS, 
PFS2, ORR, DOR) will be analyzed using the investigator assessments. The outcomes 
based on IRC assessments are available in the CSR for PCYC-1115-CA.
9.2
Handling of Missing Data
Missing efficacy data will not be imputed, unless otherwise specified. For binary 
endpoints, subjects who had no baseline and/or post-baseline disease assessment will be 
 


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considered as non-responders. For time-to-event endpoints, subjects without any event 
will be censored on their last adequate assessment for the endpoint. In addition, sensitivity 
analysis will be performed for the primary endpoint if there is any PFS event that occurred 
after 2 consecutive missing assessments. Details are specified for each individual endpoint
in Section 9.3 and Section 9.4.
9.3
Primary Efficacy Endpoint(s) and Analyses
9.3.1
Primary Efficacy Endpoint(s)
Analysis of the primary endpoint of PFS was conducted on the ITT Population based on 
treatment as randomized. PFS is defined as the time from the date of randomization to the 
date of disease progression determined by the investigator or date of death from any 
cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy 
prior to PD or death.
For subjects with baseline and postbaseline response assessments but without 
investigator-assessed PD and who were not known to have died at the time of the analysis, 
PFS will be censored at the date of the last adequate disease assessment by the 
investigator, where adequate disease assessment is defined as physical examination and 
CBC, or CBC and CT scan within 56 days of each other. For subjects without baseline 
and/or post-baseline assessments, PFS will be censored on the date of randomization.
9.3.2
Main Analysis of Primary Efficacy Endpoint(s)
The attributes of the estimand corresponding to the primary efficacy objective are
summarized in Table 2.
 


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Table 2.
Summary of the Estimand Attributes Corresponding to the 
Primary Efficacy Objectives
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical Summary
PFS
Ibrutinib or 
Chlorambucil
PFS by 
investigator 
assessment
ITT 
population
Valid assessments 
will be used 
regardless of study 
drug discontinuation
or use of subsequent 
anti-cancer therapy.
Subjects who did not 
experience a PFS 
event as of the 
analysis will be 
censored at the last 
adequate disease 
assessment date, or 
randomization date if 
no baseline or no 
post-baseline 
assessment is 
available.
Distribution of PFS 
will be estimated by 
Kaplan-Meier (KM)
method for each 
treatment arm. 
Median PFS and 
landmark estimates 
with 95% confidence 
interval (CI) will be 
provided. The hazard 
ratio (ibrutinib/ 
chlorambucil) and its 
95% CI will be 
calculated based on a 
Cox proportional 
hazard model 
stratified by the two 
randomization 
stratification factors. 
A nominal p-value 
will also be calculated 
by the stratified log-
rank test.
9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint(s)
Sensitivity analyses of the primary efficacy endpoint of PFS will include: 
Sensitivity Analysis 1: Unstratified PFS Analysis
An unstratified log rank test will be performed to compare the first-line treatment effect of 
ibrutinib vs chlorambucil and the hazard ratio (ibrutinib/chlorambucil) along with its 95% 
CI based on an unstratified Cox model will be provided.
 


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Sensitivity Analysis 2: Censoring PFS Event after 2 or more consecutive missing 
assessments
Disease progression or death documented immediately after missing two or more 
consecutive scheduled disease assessments are to be censored at the last adequate disease 
assessment prior to the consecutive missing assessments in the same stratified analysis as 
for the primary endpoint.
Supplementary Analysis: Use of subsequent antineoplastic therapy prior to documented 
PD or death
A supplementary analysis will be performed for the use of subsequent antineoplastic 
therapy prior to the first documentation of disease progression or death due to any cause: 
subjects will be censored at the last adequate assessment prior to the use of new 
antineoplastic therapy.
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Key Secondary Efficacy Endpoint(s)
The key secondary endpoints are listed as follows:
●
Progression Free Survival after initiation of subsequent anticancer therapy 
(PFS2): PFS2 is defined as the time from the date of randomization to the 
earliest occurrence of the following three types of events:
○
PD per investigator response assessment after initiation of the first 
subsequent anti-cancer therapy
○
Initiation of second subsequent anti-cancer therapy
○
Death due to any cause, regardless of administration of subsequent 
anticancer therapy.
●
Subjects who did not experience a PFS2 event will be censored at the last 
adequate disease assessment or the last follow-up for subsequent anti-cancer 
therapy, whichever occurs later.
 


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PCYC-1116-CA – Statistical Analysis Plan
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●
Overall survival (OS): OS is defined as the time from randomization to death 
due to any cause. Subjects who are not known to have died at study closure will 
be censored at the last date the subject is known to be alive. Subjects who are 
lost to follow-up without any post baseline assessments/visits will be censored 
at the date of randomization. All data for subjects on Ibrutinib and 
Chlorambucil arms collected by the case report form (CRF) will be used for the 
OS analysis.
●
Time to next treatment: Time from randomization to initiation of any 
subsequent treatment for CLL. Subjects who have not started any subsequent 
treatment for CLL at the time of the analysis will be censored at the last known 
alive date.
●
Overall Response Rate (ORR): ORR is defined as the proportion of subjects 
who achieve a CR, CRi, nPR, or PR as determined by the investigator at or 
prior to initiation of subsequent antineoplastic therapy. Subjects with no post-
baseline disease assessment will be considered non-responders.
●
Rate of MRD-negativity: Proportion of subjects who achieved MRD-negative 
response defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow 
cytometry of a bone marrow aspirate and/or peripheral blood sample per central 
laboratory at or prior to initiation of subsequent antineoplastic therapy. Subjects 
with no post-baseline MRD samples will be considered non-responders.
9.4.2
Main Analyses of Key Secondary Efficacy Endpoint(s)
The attributes of the estimands corresponding to the key secondary efficacy objectives are 
summarized in Table 3.
 


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Table 3.
Summary of the Estimand Attributes Corresponding to the Key 
Secondary Efficacy Objectives
Estimand
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
PFS2
Ibrutinib or 
Chlorambucil
PFS after 
initiation of 
subsequent 
anticancer 
therapy
ITT 
population
Valid assessments will be 
used regardless of study 
drug discontinuation.
Subjects who did not 
experience a PFS2 event 
will be censored at the 
last adequate disease 
assessment or the last 
follow-up for subsequent 
anti-cancer therapy, 
whichever occurs later.
Same as 
primary 
endpoint.
OS
Ibrutinib or 
Chlorambucil
Overall 
Survival
ITT 
population 
Valid assessments will be 
used regardless of study 
drug discontinuation or 
use of subsequent anti-
cancer therapy.
Subjects who are not 
known to be dead will be 
censored at the last known 
alive date
Same as 
primary 
endpoint.
TTNT
Ibrutinib or 
Chlorambucil
Time to next 
treatment
ITT 
population
Valid assessments will be 
used regardless of study 
drug discontinuation.
Subjects who are not 
known to have any 
subsequent therapy will 
be censored at the last
known alive date.
Same as 
primary 
endpoint.
 


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Estimand
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
ORR
Ibrutinib or 
Chlorambucil
Overall 
Response 
Rate
ITT 
population
Valid assessments prior to
initiation of subsequent 
antineoplastic therapy will 
be used regardless of 
study drug 
discontinuation.
Discontinuation of study 
without any valid 
assessment due to any 
cause will be considered 
as non-responders.
Proportion of 
responders.
Rate ratio and 
95% CI
Cochran-
Mantel-
Haenszel chi-
square test 
stratified by
the two 
randomization 
stratification 
factors.
MRD-
negativity 
rate
Ibrutinib or 
Chlorambucil
MRD-
negativity 
rate
ITT 
population
Valid assessments prior to
initiation of subsequent 
antineoplastic therapy will 
be used regardless of 
study drug 
discontinuation.
Discontinuation of study 
without any valid
assessment due to any 
cause will be considered 
as non-responders.
Proportion for 
MRD-
negativity 
Note for Limitation of OS Analysis
According to protocol amendment 3 which was implemented at 60 months median follow 
up, post PD follow up for Chlorambucil arm was terminated. Subjects in the 
Chlorambucil arm were to exit study after PD and those who crossed over to next-line 
ibrutinib had opportunity to rollover to another long-term ibrutinib study. Therefore, the 
estimate of hazard ratio and log rank test will be impacted and can mainly be used for 
descriptive purposes. The limitation will be noted in footnote of all related tables and 
figures, and the landmark estimates for Chlorambucil arm will be limited up to 60 months, 
while ibrutinib arm will have all meaningful landmark estimates up to study closure 
(approximately 10 years).
 


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9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints
No additional analysis will be performed for the key secondary endpoints.
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses
●
The supportive secondary endpoints are listed below:
○
Duration of Response (DOR): Duration of response will be calculated for 
the subjects achieving a response (CR, CRi, nPR, PR) per investigator 
assessment and is defined as time from the date of initial response 
including PR with lymphocytosis to the date of disease progression or the 
date of death from any cause, whichever occurs first. For subjects without 
documented PD or death, DOR will be censored at the date of last adequate 
disease assessment.
●
The attributes of the estimand corresponding to the supportive secondary 
efficacy objective are summarized in Table 4.
Table 4.
Summary of the Estimand Attributes Corresponding to the 
Supportive Secondary Efficacy Objective
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical 
Summary
DOR
Ibrutinib or 
Chlorambucil
Duration of 
Response
ITT subjects 
achieving 
response (PR 
or better)
prior to 
initiation of 
subsequent 
antineoplastic 
therapy
Valid assessments will 
be used regardless of 
study drug 
discontinuation or use 
of subsequent anti-
cancer therapy to 
identify PD or death 
event.
Subjects who are not 
known to have PD or 
death will be censored
at the last adequate 
disease assessment.
KM estimates 
and 95% CI
 


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9.5
Additional Efficacy Endpoints and Analyses
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.6
Efficacy Subgroup Analyses
Subgroup analysis for PFS may be performed using the prognostic variables at screening 
or baseline listed in Table 5. The hazard ratio with its 95% CI will be calculated based on 
unstratified Cox regression model for each subgroup and presented by a forest plot.
Table 5.
Subgroup Definition for Efficacy Analysis
Subgroup
Definition of Subgroup
Age
< 70, ≥ 70
Gender
Male, Female
Race
White, Non-White
Geographic Region
US, Non-US
Histological Diagnosis
CLL, SLL
Baseline Rai Stage as recorded in IWRS
Stage 0-II, III-IV
Baseline ECOG as recorded in IWRS
0-1, 2
Bulky Disease
LDi < 5cm, ≥ 5cm
Elevated LDH at Baseline
No (≤ ULN), Yes (> ULN)
Cytopenia at Baseline
Yes, No
Chromosome 11q Deletion
Yes, No
Serum β2- microglobulin
≤ 3.5mg/L, > 3.5 mg/L
IGHV
Unmutated, Mutated
IWRS = Interactive Web Response System; ECOG = Eastern Cooperative Oncology Group; LDi = longest diameter; 
LDH = lactic acid dehydrogenase; ULN = upper limit of normal; Cytopenia = yes, if platelet count ≤ 100,000/uL, Hgb ≤ 
11g/dL, or ANC ≤ 1500/uL is observed; IGHV = immunoglobulin heavy chain variable region
 


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10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Safety Population. Safety summaries will be 
presented in accordance with the treatment actually received by subjects. Statistical tests 
will not be performed for the safety analysis.
Safety summaries will be based on laboratory test results, vital sign measurements, the 
incidence and severity of adverse events.
10.2
Adverse Events
Adverse events will be summarized and presented using MedDRA. Non-hematological 
AEs reported by the investigator will be graded according to NCI-CTCAE version 4.03. 
Hematologic toxicity will be assessed by the IWCLL 2008 guidelines.
Verbatim descriptions of AEs will be coded to a preferred term and mapped to the 
appropriate System Organ Class using the current version of Medical Dictionary for 
Regulatory Activities (MedDRA).
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) for the first-line therapy are defined as any 
AE related or possibly related to the first-line study treatment by investigator or any AE 
with an onset date that is on or after the first dose date of the first-line study treatment and 
no more than 30 days after the last dose of the first-line study treatment or initiation of 
subsequent anti-cancer therapy (including next-line therapy), whichever occurs earlier.
Treatment-emergent adverse events (TEAEs) for the next-line ibrutinib treatment are 
defined as any AE related or possibly related to the next-line ibrutinib by investigator or 
any AE with an onset date that is on or after the first dose date of the next-line ibrutinib 
treatment and no more than 30 days after the last dose of the next-line ibrutinib treatment 
 


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or initiation of other anti-cancer therapy subsequent to the next-line ibrutinib study 
treatment, which occurs earlier.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized for the first-line therapy and the next-line ibrutinib treatment separately.
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study treatment according to investigator
●
Any treatment-emergent AE leading to discontinuation of study treatment
●
Any treatment-emergent AE leading to dose reduction(s) of study treatment
●
Any serious treatment-emergent AE
●
Any serious treatment-emergent AE related to study treatment according to 
investigator
●
Any treatment-emergent AE leading to death
●
Any major hemorrhage
The overview of AEs will be provided for the first-line therapy and the next-line ibrutinib 
treatment respectively.
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by system organ class (SOC)
and/or preferred term (PT) for the first-line therapy and the next-line ibrutinib treatment
respectively. Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise. In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to study 
treatment will be reported.
 


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10.2.4
Deaths, Serious Adverse Events, and Adverse Events 
Leading to Study Treatment Discontinuation
Treatment-emergent serious adverse events (SAEs), TEAEs leading to discontinuation of 
study treatment, and TEAEs leading to death will be summarized by SOC and/or PT for 
the first-line therapy and the next-line ibrutinib treatment respectively. A listing of all 
deaths during the entire study period will also be provided.
10.2.5
Adverse Events of Special Interest
Adverse events of special interest listed below will be summarized for the first-line
therapy and may also be summarized for the next-line ibrutinib treatment as data 
warranted. All but atrial fibrillation are grouping terms (definition in Appendix B) and 
will be summarized by PT in tables respectively. Atrial fibrillation is based on single 
preferred term and will be included in the TEAE by SOC and/or PT summary tables
specified in Section 10.2.3.
●
hemorrhage
●
major hemorrhage
●
other malignancies (treatment emergent and during entire study period 
separately)
●
hypertension
●
other cardiac arrhythmia (excluding atrial fibrillation)
●
ventricular tachyarrhythmia
●
ischemic stroke
●
cardiac failure
●
sepsis
●
interstitial lung disease (ILD)
●
atrial fibrillation 
 


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10.3
Analysis of Laboratory Data
All laboratory values will be converted to SI units and classified as normal, low, or high 
based on normal ranges. Hematologic parameters will be assessed by the IWCLL 
guidelines for grading hematologic toxicity in CLL studies. All other gradable laboratory 
parameters will be graded using the NCI CTCAE v4.03 or higher.
Unless otherwise specified, only baseline and post-baseline lab values collected on or 
after the first dose date of the first-line study treatment and within 30 days after the last 
dose of the first-line study treatment or initiation of subsequent anti-cancer therapy 
(including next-line therapy), whichever occurs earlier, will be included in the analysis.
For selected hematology and chemistry laboratory parameters, a summary of worst post-
baseline toxicity grade will be provided. Only subjects whose grades worsened post-dose 
are counted in the numerator of percentage calculation while denominator is the safety 
population in each treatment arm.
Abnormalities in uric acid and liver function will also be summarized. Shifts tables will 
be created for creatinine clearance.
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, and heart rate will be 
summarized.
Over-time summary statistics (mean, standard deviation, median and range) of vital signs 
will be tabulated.
11.0
Other Analyses
Subjects impacted by the ongoing COVID-19 pandemic may be summarized in data 
tables and/or listings as data warranted.
 


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12.0
Interim Analyses
●
No interim analysis was planned.
13.0
Overall Type-I Error Control
No hypothesis testing will be performed for this study. Efficacy endpoints will be 
analyzed in the same method as for PCYC-1115-CA primary analysis for presenting long-
term efficacy outcomes. Nominal 2-sided p-values will be calculated without adjustment 
of multiplicity.
14.0
Version History
Table 6.
SAP Version History Summary
Version
Date
Summary
1.0
13 June 2023
Initial version
14.1
Changes to Planned Analyses in the Protocol
The endpoint "Disease outcome following cessation of ibrutinib therapy after attainment 
of minimal residual disease (MRD)-negative remission in those subjects receiving 
ibrutinib as second-line therapy" prespecified in the protocol will not be analyzed. The 
decision was made because only two subjects achieved MRD negativity in peripheral 
blood on next-line ibrutinib with up to 9-year study follow-up and none of them stopped 
ibrutinib treatment after attainment of MRD negativity.
The MRD negativity rate for first-line treatment and the next-line ibrutinib will be 
summarized respectively.
 


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15.0
References
1.
Bhattacharya S, Fyfe G, Robert J, et al. Role of sensitivity analyses in assessing 
progression-free survival in late-stage oncology trials. J Clin Oncol. 
2009;27(35):5958-64.
2.
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine 
clinical end points in chronic lymphocytic leukemia. J Clin Oncol.
2012;30(23):2820-2. 
3.
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and 
treatment of chronic lymphocytic leukemia: a report from the International 
Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute-Working Group 1996 guidelines. Blood. 2008; 111(12):5446-56.
4.
Hallek M, Cheson BD, Catovsky D, et al. Response assessment in chronic 
lymphocytic leukemia treated with novel agents causing an increase of peripheral 
blood lymphocytes. Blood. 2012 (letter; published 4 June 2012). Available from: 
http://bloodjournal.hematologylibrary.org/content/111/12/5446/reply#bloodjournal
_el_6920. Accessed 23 August 2012.
5.
Hallek M, Cheson BD, Catovsky D, et al. E-Letter regarding "Guidelines for the 
diagnosis and treatment of chronic lymphocytic leukemia: a report from the 
International Workshop on Chronic Lymphocytic Leukemia updating the National 
Cancer Institute–Working Group 1996 guidelines": Clarification of iwCLL criteria 
for a partial response to therapy. Blood. Nov 13 2013.
6.
ICH E9 (R1) Addendum on estimands and sensitivity analysis in clinical trials to 
the guideline on statistical principles for clinical trials, November 2019.
7.
DSS Estimand Excellence Working Group. Guidance Document on Estimand 
Implementation in Study Protocol and Statistical Analysis Plan Version 1.0. 17 
October 2022
 


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Appendix A.
List of SAP Signatories
Name
Title
Role/Functional Area
Manager, Statistics
Author
Project Director, Biostatistics
Clinical Statistics
Executive Director, Biostatistics
Clinical Statistics
Associate Director, Statistical Programming
Statistical Programming
Senior Medical Director, Clinical Development 
Oncology
Medical/Scientific Monitor
Senior Director, Regulatory Affairs
Regulatory
Senior Medical Director, PST Lead-Oncology
Safety
 


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Appendix B.
Definition of Adverse Events of Special Interest
Adverse Events of Special Interest (AESI) will be identified using the following search 
criteria:
Area of Safety Interest
Search Criteria
Hemorrhage
Hemorrhage SMQ excluding laboratory terms
Major Hemorrhage
Subset of hemorrhagic events which were ≥ Grade 3, serious, or 
CNS hemorrhage/hematomas.
Other malignancy
Other malignancies are identified by medical monitor and safety 
scientist review of preferred terms under the system organ class 
"Neoplasms benign, malignant and unspecified (incl cysts and 
polyps)" in MedDRA coding.
Hypertension
Hypertension SMQ narrow search
Other cardiac arrhythmia (excluding 
atrial fibrillation)
Cardiac arrhythmia SMQ (broad and narrow search) excluding 
preferred term of "atrial fibrillation"
ventricular tachyarrhythmia
Ventricular tachyarrhythmia SMQ narrow search
ischemic stroke
Ischemic Stroke SMQ narrow search
cardiac failure
cardiac failure SMQ narrow search
Sepsis
preferred terms containing "sepsis," "septic," "bacteremia,"
"fungaemia" or "viraemia" and excluding the preferred term 
"septic screen" and those containing "aseptic"
Interstitial Lung Disease (ILD)
ILD SMQ narrow search
Atrial Fibrillation
Preferred Term in MedDRA coding.