A Phase 2 Study to Evaluate the Efficacy and Tolerability of Debio 1562 in Combination With Rituximab in Patients With Relapsed and/or Refractory Diffuse Large B-Cell Lymphoma and Other Forms of Non-Hodgkin's Lymphoma
Phase: PHASE2
Conditions: Diffuse Large B-Cell Lymphoma, B-cell Non-Hodgkin's Lymphoma
Sponsor: Debiopharm International SA

Offici al Titl e:   
A P h as e 2 St u dy t o E v al u at e t h e Effic acy a n d T ol er a bilit y of D e bi o 1 5 6 2 i n  
C o m bi n ati o n wit h Rit uxi m a b i n P ati e nts wit h R el a ps e d a n d/ or R efr act ory  
Diff us e L ar g e B -C ell Ly m p h o m a a n d Ot h er F or ms of N o n -H o d gki n ’s Ly m p h o m a 
N C T N u m b er:   
N C T 0 2 5 6 4 7 4 4  
D oc u m e nt  D at e :  
Pr ot oc ol V ersi o n 7: 1 1  M a y 2 0 2 0 

C LI NI C A L S T U D Y P R O T O C O L  
 
St u d y Title:  
A P hase 2 St u d y t o E val uate t he Efficac y a n d T olera bilit y of De bi o 1 5 6 2  i n 
C o m bi nati o n wit h Rit u xi ma b i n Patie nts wit h Rela pse d a n d/ or Refract or y 
Diff use Lar ge 
B -Cell L y m p h o ma a n d 
Ot her F or ms of 
N o n -H o d g ki n’s 
L y m p h o ma  
St u d y N u m ber:  
De bi o 1 5 6 2 -2 0 1  
St u d y P h ase:  
2  
Pr o d uct N a me:  
De bi o 1 5 6 2   
I N D N u m ber: 
1 0 9, 5 1 7  
E u dr a C T N u m ber:  
2 0 1 5 -0 0 4 0 6 1 -8 7  
Cli nic altri al. g o v  N C T 
N u m ber : 
N C T 0 2 5 6 4 7 4 4  
I n dic ati o n: 
Diff use Lar ge B -Cell L y m p h o ma , B-cell N o n -H o d g ki n’s L y m p h o ma  
I n vesti g at ors: 
M ultice nter  
S p o ns or:  
De bi o p har m I nter nati o nal S. A.    
F or u m ”a près -d e mai n”  Case P ostale 5 9 1 1 , C he mi n Messi d or 5 -7  , 1 0 0 2 
La us a n ne , S witzerla n d  
C o ntact: 
, M D 
Title: 
 
T ele p h o ne: 
 
E -mail:
    
     
C urre nt versi o n:   
Pre vi o us versi o ns:  
7, date d 2 4  A pril 2 0 2 0, i nte grati n g a me n d me nts 1 -6  
6, date d 2 1  Fe br uar y 2 0 2 0, i nte grati n g a me n d me nts 1 -5  
5, date d 1 9 Dece m ber 2 0 1 8, i nte grati n g a me n d me nts 1 -4  
4, date d 2 3  Fe br uar y 2 0 1 8 , i nte grati n g a me n d me nts 1-3  
3, date d 2 3 J u ne 2 0 1 7, i nte grati n g a me n d me nt 1 -2  
2, date d 2 9 Fe br uar y 2 0 1 6, i nte grati n g a me n d me nt 1  
1, date d 2 Se pte m ber 2 0 1 5, i nitial pr ot oc ol  
C o nfi de nti alit y St ate me nt  
T his d oc u me nt is t he pr o priet ar y a n d c o nfi de nti al pr o pert y of  
De bi o p h ar m I nter n ati o n al S. A.
V V- T M F- 5 1 6 1 9 | Pa ge 1/ 1 1 2

Pr ot oc ol  
Pa ge 2  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
La us a n ne ( S witzerla n d)  
S P O N S O R S I G N A T U R E P A G E 
C o m pa n y/ S p o ns or si g nat or y  
, M D 
De bi o p har m I nter nati o nal S. A.  
F or u m  ”a près -d e mai n”  Case P ostale 5 9 1 1  
C he mi n Messi d or 5 -7 , 1 0 0 2 La usa n ne 
S witzerla n d  
T el.: 
 
E -mail
 
Date  
V V- T M F- 5 1 6 1 9 | Pa ge 2/ 1 1 2
1 1- M A Y- 2 0 2 0

Pr ot oc ol  
 
Pa ge 3  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
I N V E S TI G A T O R’ S A G R E EM E N T  
 
I ha ve recei ve d a n d rea d t he I n v esti gati o nal Br oc h ure f or De bi o 1 5 6 2 . I ha v e rea d pr ot oc ol 
De bi o  1 5 6 2 -2 0 1  a n d a gree t o c o n d uct t he st u d y as o utli ne d  a n d i n c o nf or ma nce wit h G o o d Cli nical 
Practices ( G C Ps) a n d a p plica ble re g ulat or y re q uire me nts .  I a gree t o mai ntai n t he c o nfi de ntialit y 
of all i nf or mati o n recei ve d or de vel o pe d i n c o n necti o n wit h t his pr ot oc ol.  
 
 
Pri nte d Na me of I n v esti gat or   
 
 
 
 
 
 
 
Si g nat ure of I n vesti gat or   
 
 
 
 
 
 
 
Date  
 
V V- T M F- 5 1 6 1 9 | Pa ge 3/ 1 1 2

Pr ot oc ol  
 
Pa ge 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
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 O F T E R M S  
A b bre vi ati o n or S peci alist 
Ter m  
E x pl a n ati o n  
A D A  
A nti -dr u g a nti b o d y  
A D C  
A nti b o d y  dr u g c o nj u gate  
A D C C  
A nti b o d y -d e pe n de nt cell me diate d c yt ot o xicit y  
A E  
A d verse e ve nt  
A L B  
Al b u mi n  
A L K -P  
Al kali ne p h os p hatase  
A L T  / S G P T 
Ala ni ne a mi n otra nsferas e / Ser u m gl uta mic p yr u vic 
tra nsa mi nase 
A N C  
A bs ol ute ne utr o p hil c o u nt  
a P T T 
Acti vate d partial t hr o m b o plasti n ti me  
A S T  / S G O T 
As partate a mi n otra nsferase / Ser u m gl uta mic o x al oacetic 
tra nsa mi nase  
A U C  
Area u n d er t he ti me -c o nce ntrati o n c ur ve  
-h C G  
beta -h u ma n c h ori o nic g o na d otr o pi n  
BI D  
T wice dail y  
B U N  
Bl o o d urea nitr o ge n  
C ma x  
Ma xi m u m plas ma dr u g c o nce ntrati o n  
C 7 D 1  
C ycle 7  D a y 1  
Ca  
Calci u m  
C D C  
C o m ple me nt -de pe n de nt c yt ot o xicit y  
C F R  
C o de of Fe d eral Re g ul ati o ns  
CI  
C o nfi de nce i nter val  
CI O M S  
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces  
CI P  
Ca ncer I m a gi n g Pr o gra m  
Cl  
C hl ori de  
C L  
Cleara nce  
C L L  
C hr o nic L y m p h oc ytic Le u ke mia  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C R  
C o m plete res p o nse/re missi o n  
C R O  
C o ntract Researc h Or ga nizati o n  
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  
V V- T M F- 5 1 6 1 9 | Pa ge 4/ 1 1 2

Pr ot oc ol  
 
Pa ge 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
A b bre vi ati o n or S peci alist 
Ter m  
E x pl a n ati o n  
C T E P  
Ca ncer T hera p y E val uati o n Pr o gra m  
D C P  
Di visi o n of Ca ncer Pre v e nti o n  
D D  
Dr u g Dicti o nar y  
D L B C L  
Diff use Lar ge B -Cell L y m p h o ma  
D M E  
D ose m o dif yi n g e ve nt  
D o R  
D urati o n of res p o ns e  
E C G  
Electr 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 C R F 
Electr o nic case re p ort f or m  
E O T  
E n d of treat me nt  
F A C T -G  
F u ncti o nal Assess me nt of Ca ncer T hera p y -Ge neral  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
FI H  
First -i n-h u ma n  
F L  
F ollic ular L y m p h o ma  
F N A  
Fi ne Nee dle As pir ati o n  
G C P  
G o o d Cli nical Practice  
G -C S F  
Gra n ul oc yte c ol o n y -sti m ulati n g fact or 
G V H D  
Graft vers us h ost  disease  
H Bs A g  
He patitis B s urface a nti ge n  
H B V  
He patitis B vir us  
Hct  
He mat ocrit  
H D -A S C T  
Hi g h d ose c he m ot hera p y wit h a ut ol o g o us ste m cell 
tra ns pla ntati o n 
H g b  
He m o gl o bi n  
HI V  
H u ma n I m m u n o deficie nc y Vir us  
H R Q o L  
Healt h -relate d q ualit y of life 
I B 
I n v esti gat or’s Br oc h ure 
I C F 
I nf or me d c o ns e 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 D E 
I n v esti gati o nal De vice E x e m pti o n 
I D M C 
I n d e pe n de nt Data M o nit ori n g C o m mittee  
I E C 
I n d e pe n de nt Et hics C o m mittee 
V V- T M F- 5 1 6 1 9 | Pa ge 5/ 1 1 2

Pr ot oc ol  
 
Pa ge 6  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
A b bre vi ati o n or S peci alist 
Ter m  
E x pl a n ati o n  
I g A 
I m m u n o gl o b uli n A 
I g G 
I m m u n o gl o b uli n G 
I g M 
I m m u n o gl o b uli n M 
I M 
I ntr a m usc ular 
I M P 
I n v esti gati o nal Me dici nal Pr o d uct  
I N D 
I n v esti gati o nal Ne w Dr u g  
I N R 
I nter nati o nal N or m alize d Rati o  
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
I ntr a ve n o us 
I W R S 
I nteracti ve We b Res p o nse S yste m 
K  
P otassi u m  
L D H  
Lactate d e h y dr o ge n ase  
m A b  
M o n ocl o nal a nti b o d y  
M A L T  
M uc osa -ass o ciate d l y m p h oi d tiss ue  
M C L  
Ma ntle Cell L y m p h o ma  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
MI D  
Mi ni mal I m p orta nt Differe nce  
M RI  
Ma g n etic Res o na nce I ma gi n g  
m R N A  
messe n ger Ri b o n ucleic aci d  
M T D  
Ma xi m u m t olerate d d ose  
M Z L  
Mar gi nal Z o ne L y m p h o ma  
Na  
S o di u m  
N A or N/ A  
N ot a vaila ble  
N CI  
Nati o nal Ca ncer I nstit ute 
N H L  
N o n -H o d g ki n L y m p h o m a  
N K  
Nat ural killer  
O R R  
O bjecti ve res p o ns e rat e  
O S  
O verall s ur vi val  
P C R  
P ol y m eras e c hai n reacti o n  
P D  
Pr o gressi ve disease  
P E T  
P ositr o n e missi o n testi n g  
V V- T M F- 5 1 6 1 9 | Pa ge 6/ 1 1 2

Pr ot oc ol  
 
Pa ge 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
A b bre vi ati o n or S peci alist 
Ter m  
E x pl a n ati o n  
P F S  
Pr o gressi o n -free s ur vi val 
P K  
P har mac o ki netics  
P M L  
Pr o gressi ve m ultif ocal le u k oe nce p h al o pat h y  
P O  
B y m o ut h  
P R  
Partial res p o nse/re missi o n  
Pr n  
As nee de d  
P T  
Pr ot hr o m bi n ti me  
Q 3 W  
O nce e v er y t hree wee ks  
Q 4 h  
E ver y f o ur h o urs  
Q 6 h  
E ver y si x h o urs  
Q W  
O nce e v er y wee k  
R B C  
Re d bl o o d cell  
R -C H O P  
Rit u xi ma b -C ycl o p h os p ha mi de, d o x or u bici n H y dr oc hl ori de, 
vi ncristi ne ( O nc o vi n), a n d Pre d nis o ne  
R/ R  
Rela 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 A S  
Statistical A nal ysis S oft ware  
S C  
S u bc uta ne o us  
S CI D  
Se vere c o m bi ne d i m m u n o deficie nt  
S D  
Sta ble disease  
S O C  
S yste m Or ga n Class  
S P D  
S u m of t he pr o d uct of t he dia meters  
S R C  
Safet y R e vie w C o m mittee  
S T D 1 0 
Se verel y t o xic d ose t o 1 0 % of a ni mals  
S U S A R  
S us pecte d U ne x pecte d S eri o us A d verse Reacti o n  
t1/ 2 
Ter mi nal half -life 
T/ C  
Rati o  of Me dia n T u m or V ol u me f or Treate d a n d C o ntr ol 
gr o u ps  
T E A Es  
Treat me nt e mer ge nt a d verse e ve nts  
T L S  
T u m or L ysis S y n dr o me  
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
V S S  
V ol u me of distri b uti o n at stea d y st ate  
V V- T M F- 5 1 6 1 9 | Pa ge 7/ 1 1 2

Pr ot oc ol  
 
Pa ge 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
A b bre vi ati o n or S peci alist 
Ter m  
E x pl a n ati o n  
W B C  
W hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n  
V V- T M F- 5 1 6 1 9 | Pa ge 8/ 1 1 2

Pr ot oc ol  
 
Pa ge 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
P R O T O C O L S Y N O P SI S  
Title of St u d y : A P hase 2 St u d y t o E val uate t he Efficac y a n d T olera bilit y of De bi o 1 5 6 2  i n 
C o m bi nati o n wit h Rit u xi ma b i n Patie nts wit h Rel a pse d a n d/or Refract or y Diff use Lar ge B -Cell 
L y m p h o ma a n d Ot her F or ms of N o n -H o d g ki n’s  L y m p h o ma  
St u d y ce nter(s): A p pr o xi matel y 5 5 ce nters gl o ball y 
St u die d peri o d ( m o nt hs): A p pr o xi matel y 4 8  
m o nt hs (i ncl u di n g f oll o w -u p)  
P h ase of de vel o p me nt: P hase 2  
P ur p ose/r ati o n ale: De bi o 1 5 6 2  is a n a nti b o d y dr u g  c o nj u gat e ( A D C) c o nsisti n g of t he h u ma nize d 
a nti-C D 3 7 a nti b o d y, K 7 1 5 3 A, c o nj u gate d via a sta ble t hi oet her -bas e d li n ker t o t he c yt ot o xic 
ma yta nsi n oi d D M 1. O nce release d wit hi n t he tar get cell, D M 1 acts as a n a nti -mit otic a ge nt t hat 
i n hi bits t u b uli n p ol y meri zati o n a n d microt u b ule asse m bl y. Cells treate d wit h ma yta nsi n oi ds arrest 
i n t he G 2/ M p hase of t he cell c ycle, a n d e ve nt uall y die b y a p o pt osis (Re millar d  1 9 7 5 ). De bi o 1 5 6 2  
bi n ds wit h hi g h affi nit y a n d s pecifi cit y t o t h e le u k oc yt e a nti ge n C D 3 7, f o u n d o n t he s urface of 
mali g na nt h u ma n B l y m p h oc yt es, a n d t o s o me e xte nt, n or mal B cells ( M o ore  1 9 8 7 , Barre na  2 0 0 5 , 
Dec kert, 2 0 1 3 ). 
N o ncli nical st u dies d e m o nstrate d t hat De bi o 1 5 6 2  has p ote nt c yt ot o xic acti vit y a gai nst C D 3 7 -
p ositi ve l y m p h o ma cell li nes i n vitr o a n d a nti -t u m or acti vit y i n a variet y of m o use t u m or x e n o graft 
m o dels of N o n -H o d g ki n’s L y m p h o ma ( N H L).  
I n a first-i n-h u ma n ( FI H) P hase 1 st u d y, treat me nt wit h si n gle a ge nt De bi o 1 5 6 2  was s h o w n t o 
elicit o bjecti ve res p o nses, i ncl u di n g a c o m plete res p o nse, i n patie nts wit h rela pse d/refract or y  ( R/ R) 
N H L ( Stat his  2 0 1 4 ). I n t he FI H, si n gl e a ge nt st u d y, t he m ost c o m m o n a d verse e ve nts ( A Es ) were: 
ne utr o pe nia, t hr o m b oc yt o pe nia, fati g ue, p yre xia, na usea , a n d diarr hea.  T he d ose of 1. 4 m g/ k g wit h 
gra n ul oc yte gr o wt h fact or s u p p ort was d eter mi ne d t o be t he ma xi m u m t olerate d d ose ( M T D ) after 
re vie wi n g t he data f or 4 9 patie nts acr oss 8 d os e le vels. A d diti o nall y, a d ose of 1. 0 m g/ k g was 
deter mi ne d t o be t he M T D wit h o ut pr o p h yla xis of gra n ul oc yte gr o wt h fact or  i n t his st u d y. 
Rit u xi ma b is a C D 2 0 -directe d, 
m o n ocl o nal a nti b o d y t hat i n d uces a n ti b o d y-de p e n de nt cell 
me diate d c yt ot o xicit y ( A D C C), c o m ple me nt -de pe n de nt c yt ot o xicit y ( C D C) , a n d a p o pt osis. 
Rit u xi ma b , i n c o m bi nati o n wit h ot her a ge nts, is c urre ntl y a p pr o ve d f or t he treat me nt of n e wl y 
dia g n ose d or R/ R B -cell N H L, i ncl u di n g 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 ( C L L). Precli nical st u dies i n dicate t hat t he a nti-t u m or acti vit y of De bi o 
1 5 6 2  is e n ha nce d w he n c o m bi ne d wit h rit u xi ma b.  
I n t his P hase  2 st u d y, we pr o p ose t o i n vesti gat e t he safet y a n d a nti-t u m or acti vit y of De bi o 1 5 6 2  
i n c o m bi nati o n wit h rit u xi ma b f or t he treat me nt of patie nts wit h R/R D L B C L a n d ot her f or ms of 
B -cell N H L . 
O bjecti ves:  
 Pri m ar y  
T he pri mar y o bjecti ve s of t he st u d y are t o:  
1)  D eter mi ne t he safet y a n d t olera bilit y of t he pr o p ose d De bi o 1 5 6 2  d ose re gi me ns i n 
c o m bi nati o n wit h  rit u xi ma b  
2)  D eter mi ne t he a nti-t u m or acti vit y of t he pr o p ose d De bi o 1 5 6 2  d ose re gi me ns i n 
c o m bi nati o n wit h rit u xi ma b   
 Sec o n d ar y  
V V- T M F- 5 1 6 1 9 | Pa ge 9/ 1 1 2

Pr ot oc ol  
 
Pa ge 1 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
Sec o n dar y o bjecti ves  are t o : 
1)  C haracterize t he p har mac o ki netics ( P K ) of De bi o 1 5 6 2  i n c o m bi nati o n wit h rit u xi ma b    
2)  D eter mi ne ti me t o e ve nt o utc o mes (pr o gressi o n -free s ur vi val [P F S ], ti me t o res p o ns e, 
d urati o n of res p o ns e [D o R ], a n d o verall s ur vi val [O S ]) 
3)  Assess t he i m m u n o ge nicit y of De bi o 1 5 6 2 (a nti -dr u g a nti b o d y [ A D A]) w he n a d mi nistere d 
i n c o m bi nati o n wit h rit u xi ma b   
 E x pl or at or y  
E x pl orat or y o bjecti ves are t o : 
1)  C orrelat e t h e e xte nt of C D 3 7 a n d C D 2 0 a nti ge n e x pressi o n i n t u m or sa m ples wit h a nti -
t u m or acti vit y of t he De bi o 1 5 6 2  a n d rit u xi ma b  c o m bi nati o n   
 
 
 
 
 
 
 
 
5)  Assess h ealt h-relate d q ualit y of life ( H R Q oL)  
T he st u d y o bjecti ves,  a n d c orres p o n di n g st u d y e n d p oi nts are f ull y d efi ne d i n t he  b o d y of t h e  
pr ot oc ol.  
N u m ber of p atie nts ( pl a n ne d):  It is esti mate d t hat a p pr o xi matel y 75  p atie nts will be e nr olle d 
i nt o t he st u d y, w hic h c o nsists of t hree parts: 
 P art 1 (S afet y r u n -i n): A p pr o xi matel y 1 5 pati e nts wit h a di a g n osis of R /R D L B C L, 
F ollic ular 
L y m p h o m a  ( F L), 
Mar gi nal Z o ne L y m p h o ma  ( M Z L)/ M u c osa-ass o ciate d 
l y m p h oi d tiss ue ( M A L T), Ma ntle Cell L y m p h o ma ( M C L) or ot her N H L s u bt y pes wit h t he 
S p o ns or’s a p pr o val  will be e nr olle d. 
 P art 2 (I niti al assess me nt of s afet y a n d effic ac y of o nce e ver y t hree wee ks [ Q 3 W ] a n d 
o nce e ver y wee k [ Q W ] d osi n g re gi me ns) : A p pr o xi matel y 3 0  patie nts, wit h a dia g n osis 
of rela pse d D L B C L as defi ne d bel o w will be e nr olle d .  
 P art 3 ( E x p a nsi o n ): A p pr o xi matel y 3 0 patie nts wit h a dia g n osis of rela pse d D L B C L will 
be e nr olle d  
T he esti mate d d urati o n of t he st u d y is a p pr o xi matel y 4 8 m o nt hs f or patie nt accr ual, d osi n g, a n d 
f oll o w u p. 
St u d y Desi g n O ver vie w:  T his is a n o pe n la bel, m ultice nter , a da pti ve P h ase 2 cli nical st u d y. F or 
eac h patie nt, t he st u d y will i ncl u de a scree ni n g peri o d, a treat me nt peri o d, a n d a f oll o w -u p peri o d.  
T he st u d y c o nsists of t hree parts:  
 S afet y r u n-i n ( Part 1)  
 I nitial assess me nt of safet y a n d efficac y of Q 3 W a n d Q W d osi n g re gi me ns ( Part 2) 
 E x pa nsi o n ( Part 3) 
 
 
 
V V- T M F- 5 1 6 1 9 | Pa ge 1 0/ 1 1 2

Pr ot oc ol  
 
Pa ge 1 1  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
S afety R u n -In ( P art 1)  
Patie nts wit h D L B C L, F L, M C L, M Z L/ M A L T or ot her N H L s u bt y pes ( wit h S p o ns or’s a p pr o val) 
will be  eli gi ble f or e nr oll me nt i n t he safet y r u n -i n part of t he st u d y. D uri n g t he s afet y r u n -i n, at 
least si x D L B C L a n d si x F L N H L p atie nts will be e nr olle d. 
Patie nts will be gi ve n  De bi o 1 5 6 2 a n d rit u xi ma b o n t he sa me da y (i.e., Da y 1) Q 3 W i ntra ve n o usl y 
(I V). De bi o 1 5 6 2 will be gi ve n at a d ose of 0. 7 m g/ k g, f oll o we d b y 3 7 5 m g/ m 2 of rit u xi ma b. 
F oll o wi n g re vie w  of safet y a n d P K data b y a Safet y Re vie w C o m mittee ( S R C - c o m prise d of t he 
S p o ns or’s Me dical Direct or a n d I n vesti gat ors fr o m partici pati n g sites) o nce t he last patie nt of t he 
safet y r u n-i n has c o m plet e d 1 c ycl e of treat me nt, t he S R C will ma ke a rec o m me n dati o n t o eit her 
st o p t he st u d y f or u nacce pta ble safet y, or t o c o nti n ue t he Q 3 W d osi n g sc he d ule wit h t he 0. 7 m g/ k g 
d ose of De bi o  1 5 6 2 or a n alter nate hi g her ( 1. 0 m g/ k g) or l o wer d ose of De bi o  1 5 6 2 .  
T his part of t he st u d y h as bee n c o m plete d a n d t he S R C rec o m me n de d c o nti n uati o n of t he st u d y.  
I niti al Assess m e nt of S afety a n d Effic acy of Q 3 W a n d Q W D osi n g Re gi m e ns  ( P art 2) 
D uri n g P art 2  of t he st u d y , o nl y patie nts  wit h rel a pse d D L B C L will be  e nr olle d  i nt o t w o parallel 
co h orts  acc or di n g t o t he d osi n g  re gi me n of De bi o 1 5 6 2 : co h ort A  (2 1 -da y treat me nt c ycle wit h a 
Q 3 W d osi n g sc he d ule) a n d co h ort B  (2 1 -da y treat me nt c ycle wit h a Q W  d osi n g sc he d ul e). 
Patie nt s i n co h ort A  will recei v e De bi o 1 5 6 2 a n d rit u xi ma b I V o n t he sa me da y ( Da y 1) o n a Q 3 W 
d osi n g sc he d ule. De bi o 1 5 6 2 will be gi ve n at a d ose of 0. 7 m g/ k g ( u nless rec o m me n de d ot her wise 
b y t he S R C), f oll o we d b y 3 7 5 m g/ m 2 of rit u xi ma b.  
C o h ort B  will e x pl ore a Q W d osi n g sc he d ule of De bi o 1 5 6 2: 0. 4, 0. 2, a n d 0. 2 m g/ k g of 
De bi o  1 5 6 2  will be a d mi nistere d I V t o patie nts o n Da y 1, Da y 8 a n d Da y 1 5 of a 2 1 -da y tr eat me nt 
c ycle, res pecti vel y. Rit u xi ma b will be a d mi nistere d I V at a d ose of 3 7 5 m g/ m 2 o n Da y 1 of eac h 
treat me nt c ycle (f oll o wi n g De bi o 1 5 6 2 a d mi nistrati o n).  After a me n d me nt # 6, patie nts recei vi n g 
t he Q W re gi me n were all o we d t o s witc h t o t he Q 3 W re gi me n 
A n  I n de p e n de nt Data M o nit ori n g C o m mittee (I D M C - c o m prise d of i n de pe n de nt e x perts i n t he 
fiel d of h e mat ol o g y, o nc ol o g y, a n d bi ostatistics)  will perf or m re g ular re vie w s of c u m ulati ve safet y, 
efficac y, a n d P K data  i n b ot h co h ort s A a n d B  (Secti o n  4. 1. 3. 2 ). 
I n s u m mar y: for co h ort A, a f utilit y a n al ysis will be perf or me d after 1 0 patie nts are e val ua ble f or 
efficac y ( i.e., p atie nts s h o ul d ha ve p erf or me d at least o n e p ost bas eli ne o bjecti ve res p o ns e 
assess me nt - u nless t her e is e arlier cle ar evi de nce of P r o gressive D ise as e [ P D]). A d diti o nall y, t he 
t otalit y of t he safet y d ata f or t his d ose re gi me n will be re vie we d b y t he I D M C w h o ca n rec o m me n d 
t o ter mi nate or m o dif y t h e d osi n g re gi me n i n case of u nacce pta ble safet y. If f utilit y is met a n d/ or 
t he safet y pr ofile is u nacce pta ble (as deter mi ne d b y t h e I D M C ), t he e nr oll me nt of t his c o h ort will 
be st o p pe d.  Ot her wise, a n  a d diti o nal 5 patie nts will be e nr olle d a n d a s u bse q ue nt f utilit y a n al ysis 
will be perf or me d after 1 5  patie nts are e val ua ble f or efficac y. Si milarl y, t he c u m ulati ve safet y data 
f or t his d ose re gi me n will be re vie we d b y t h e I D M C. If f utilit y  is met a n d/ or the safet y pr ofile is 
u nacce pta ble , t his c o h ort will be st o p pe d. Ot her wise, a rec o m me n d ati o n ma y  be ma de b y t he 
I D M C t o c o nti n ue wit h t he e x pa nsi o n (st u d y Part 3) usi n g  t he sa me d osi n g re gi me n as d escri be d  
i n co h ort A.  
F or co h ort B , t here will be n o f utility a n al ysis, h o we ver a n i nte ns e safet y o versi g ht b y t he I D M C 
will be perf or me d . At mi ni m u m, t he I D M C will c o n d uct data re vi e ws at t h e f oll o wi n g p oi nts: 
V V- T M F- 5 1 6 1 9 | Pa ge 1 1/ 1 1 2

Pr ot oc ol  
 
Pa ge 1 2  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1)  A n i nitial re vie w of safet y d ata o n ce t he t hir d p atie nt has c o m plete d  o ne c ycle of treat me nt.  
2)  A s u bse q ue nt re vie w of safet y, a vaila bl e P K a n d efficac y data o n ce t he si xt h patie nt has  
c o m plete d 2 c ycles of treat me nt, wit h a rec o m me n dati o n t o:  
a. St o p t his c o h ort i n case of u nacce pta ble s afet y  
b.  E nr oll 6 m ore patie nts i n or der t o o btai n m ore d ata, or  
c. E x pl ore a ne w Q W d osi n g sc h e d ule ( w hic h will n ot e x cee d t he t otal c u m ulati ve 
Q 3 W d ose of 1. 0 m g/ k g)  
3)  I n cas e t he I D M C rec o m me n ds t o e nr oll 6 m ore p atie nts, a re vie w of s afet y, a vaila ble P K 
a n d efficac y d ata o nce t h e t welft h patie nt has c o m plete d 2 c ycles of tre at m e nt. T he I D M C 
will t he n ma ke a rec o m me n dati o n t o:  
a. St o p t his c o h ort i n case of u nacce pta ble s afet y  
b.  E x pl ore a ne w Q W d osi n g sc h e d ule ( w hic h will n ot e x cee d t he t otal c u m ulati ve 
Q 3 W d ose of 1. 0 m g/ k g)  
c. C o nti n ue wit h e nr oll me nt of patie nts i n co h ort B i n t h e e x pa nsi o n part (st u d y 
Part  3), de pe n di n g o n e v al uati o n o f t he t otalit y of data i n b ot h co h ort s A a n d B  
Assi g n me nt of patie nts t o c o h ort s A a n d B will be d o ne t hr o u g h a ce ntral all ocati o n s yst e m 
(I nteracti ve We b  Res p o nse S yste m [I W R S]) as f oll o ws:  
 1: 1 ra n d o mizati o n w he n b ot h c o h orts are o p e n f or recr uit me nt  
 A ut o matic all ocati o n t o c o h ort A w he n e nr oll me nt t o C o h ort B is pa use d d uri n g I D M C 
re vie w f or 6 patie nts of c o h ort B  
 
E x p a nsi o n ( P art 3)  
Part 3 of t h e st u d y will e nr oll a d diti o nal patie nts wit h rela pse d D L B C L t o f urt her assess safet y, 
efficac y a n d P K of t he  selecte d d osi n g s c he d ule (s) i n vesti gat e d i n Part 2 of t he st u d y (i.e., si x 2 1 -
da y c ycles of Q 3 W a n d/ or Q W  De bi o 1 5 6 2 d osi n g ), as rec o m me n de d b y t h e I D M C.  
I n t his part of t he st u d y , t he I D M C will c o nti n ue t o re vie w safet y, efficac y a n d P K data a vaila ble 
after e ver y 1 0 p atie nts  are e nr olle d a n d treate d f or at least 2 c ycles.  (Secti o n  4. 1. 3. 2 ). 
A sc he matic o ver vie w of t he st u d y desi g n is s h o w n i n  Fi g ure  1  bel o w.  
I n t his st u d y, t h e anti -t u m or acti vit y will be assesse d f oll o wi n g t he rec o m me n dati o ns fr o m t he 
I nter nati o nal C o nfere n ce o n Mali g n a nt L y m p h o mas I ma gi n g W or ki n g Gr o u p 2 0 1 4 (A p pe n di x  I) 
a n d A Es  will be gra d e d usi n g  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 .  
V V- T M F- 5 1 6 1 9 | Pa ge 1 2/ 1 1 2

Pr ot oc ol  
 
Pa ge 1 3  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
Fi g ure  1 :  
Sc h e m atic O ver vi e w of t he St u d y Desi g n  
  
T he st u d y d esi g n a n d met h o d ol o g y are detail e d i n t he f ull pr ot oc ol. 
M ai n Criteri a f or  St u d y Eli gi bilit y ( Refer t o Secti o n  3  f or a c o m plete list of eli gi bilit y 
criteri a):  
Di a g n osis a n d all o w a ble pri or t her a p y a n d dise ase me as ur a bilit y:  
1)  F or t he safet y r u n -i n, patie nts m ust ha ve hist o pat h ol o gicall y c o nfir me d dia g n osis of 
rela pse d a n d/ or refract or y D L B C L, F L, M Z L/ M A L T, M C L, or ot her S p o ns or a p pr o ve d 
N H L s u bt y pes acc or di n g t o t he W orl d Healt h Or ga nizati o n ( W H O) classificati o n 2 0 0 8 f or 
w hic h sta n dar d meas ures d o n ot e xist or are n o l o n ger effecti ve.  
2)  F or P art 2 a n d P art 3 of t he st u d y, patie nts m ust ha ve hist o pat h ol o gicall y a n d cli nicall y 
c o nfir me d dia g n osis of rela pse d D L B C L. Patie nts will be c o nsi dere d t o ha ve a rela pse d 
disease if t he y s h o we d a d urati o n of res p o nse of at least 2 4 wee ks after t heir first li ne of 
t hera py . T he f oll o wi n g p atie nts wit h rela pse d D L B C L will be e nr olle d:  
i. Patie nts w h o recei ve d o nl y o n e li ne of pre vi o us t hera p y a n d ac hie ve d eit her 
c o m plete res p o nse ( C R) or partial res p o nse ( P R) f or at least 2 4 wee ks (fr o m 
t he last da y of t he last c ycle) after t heir first li ne of t hera p y, b ut w h o are n ot 
eli gi ble f or 
hi g h 
d os e c he m ot hera p y 
wit h a ut ol o g o us st e m cell 
tra ns pla ntati o n ( H D-A S C T)  
ii. Patie nts w h o recei ve d m ore t ha n o n e li ne of pre vi o us t hera p y (i ncl u di n g 
H D -A S C T), a n d ha v e ac hie ve d a  d urati o n of res p o nse ( C R or P R) of at least 
8 wee ks (fr o m t he last da y of t he l ast c ycle)  after t heir last li ne of t hera p y  
3)  All p atie nts i n t he st u d y m ust ha ve : 
V V- T M F- 5 1 6 1 9 | Pa ge 1 3/ 1 1 2

Pr ot oc ol  
 
Pa ge 1 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
a. Recei ve d  n o m ore t h a n si x pri or treat me nt re gi me ns.  Pri or treat me nt wit h a n a nti -
C D 2 0 a ge nt, eit her al o ne or i n c o m bi nati o n, is all o we d.  
b.  E val ua ble  or m eas ura ble disease i n acc or da nce wit h t he I nter nati o nal 
W or ki n g 
Gr o u p G ui deli n es f or L y m p h o ma ( C hes o n  2 0 1 4 ).  
M ai n Eli gi bility Criteri a f or All P atie nts:  
1)  A d ult patie nts wit h E aster n C o o perati ve O nc ol o g y Gr o u p  (E C O G ) Perf or ma nce Stat us  
0 -2  
2)  Patie nts m ust ha ve a de q u ate bl o o d c o u nts  a n d or ga n f u ncti o n   
3)  Patie nts m ust ha ve a vaila ble a pat h ol o g y -i nf or me d fres h or arc hi ve d t u m or tiss ue bi o ps y  
reflecti n g t he c urre nt D L B C L diseas e . If t he tiss ue bi o ps y is ol der t h a n 1 8 m o nt h s fr o m 
t he scree ni n g visit a n d a fres h o ne ca n n ot be a v aila ble , patie nts s h o ul d pr o vi de fi ne 
nee dle as pir ati o n ( F N A) sa m ples.  
4)  Patie nts w h o ha ve recei ve d pri or all o ge neic ste m cell tra ns pla ntati o n  will be e x cl u de d  
fr o m t he safet y r u n-i n part  of t he st u d y; h o we ver t he y m a y be all o we d t o e nr oll i n  Part 
2 a n d Part 3  of t he st u d y  if t heir graft vers us h ost disease ( G V H D) is c o ntr olle d a n d t he 
S p o ns or a p pr o ves.  
5)  Patie nts wit h ≥ Gra de 2 p eri p heral ne ur o pat h y will be e x cl u de d.  
6)  Patie nts wit h acti ve he p atitis A, B or C i nfecti o n or ot her u n c o ntr olle d i nterc urre nt 
ill ness will be  e x cl u de d. 
7)  W o me n of c hil d beari n g p ote ntial  w h o are pre g na nt or breast f ee di n g will be e x cl u de d.  
8)  Patie nts w h o ha ve recei v e d  pri or ot her a nti-C D 3 7 -tar geti n g t hera p y will be e x cl u de d . 
I n vesti g ati o n al pr o d uct, d os a ge, a n d m o de of a d mi nistr ati o n: De bi o 1 5 6 2  a n d rit u xi ma b will 
be a d mi nistere d I V . D uri n g t he s afet y r u n -i n Part 1 a n d i n co h ort A  of Part 2 , De bi o 1 5 6 2  will be 
gi ve n  o n  Da y 1  of a 2 1 -d a y c ycle  at a d ose of 0. 7  m g/ k g . Patie nts i n co h ort B of Part 2 will recei ve 
De bi o 1 5 6 2 at d oses of 0. 4, 0. 2 a n d 0. 2 m g/ k g at Da y  1, Da y 8 a n d Da y 1 5  of a 2 1 -d a y c ycle , 
res pecti vel y. D uri n g t he e ntire st u d y, 3 7 5 m g/ m 2 of  rit u xi ma b will be a d mi nistere d o n  Da y 1  of 
eac h 2 1 -d a y c ycl e .  
I n a n eff ort t o mi ni mize t he ris k of C or o na vir us  Disease 2 0 1 9  (C O VI D -1 9 ) i nfecti o n f or p atie nts 
partici pati n g i n t he st u d y , t he S p o ns or deci de d t hat i n t he i nterest of patie nt  safet y it is best t o all o w 
t o s witc h patie nts w h o are o n t he Q W  De bi o 1 5 6 2 d osi n g re gi me n t o t he Q 3 W. T he s witc h fr o m 
t he Q W t o Q 3 W re gi me n is n ot e x pecte d t o res ult i n a n y detri me ntal effect o n safet y or efficac y 
f or t hese p atie nts, base d o n rece nt a nal ysis of preli mi nar y st u d y d ata.If a s witc h t o t he Q 3 W 
re gi me n is c o nsi dere d b y t h e treati n g p h ysicia n t o be i n t he b est i nterest of a gi ve n p atie nt t o 
miti gate t he C O VI D -1 9 ris k, t he f oll o wi n g s h o ul d be o bser ve d:  
- t he patie nt m ust ter mi n ate his/ her o n g oi n g wee kl y a d mi nistrati o n c ycl e b ef ore s witc hi n g t o t he 
Q 3 W re gi me n. F or i nsta nce, if t he p atie nt recei ve d his/ her first wee kl y a d mi nistrati o n of 0. 4 m g/ k g 
( D 1), h e/s he s h o ul d c o nti n ue t o recei ve wee kl y treat me nt u ntil t he e n d of t hat c ycle. O nl y t he n, 
t he patie nt ca n start t he Q 3 W d osi n g re gi me n ( 0. 7 m g/ k g);  
- p atie nts w h o s witc h s h o ul d c o nti n ue t o recei ve t h e Q 3 W re gi me n f or t he re m ai nder  of t he st u d y.  
V V- T M F- 5 1 6 1 9 | Pa ge 1 4/ 1 1 2

Pr ot oc ol  
 
Pa ge 1 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
T his will re d uce t he n u m ber of visits t o t he  h os pital. T heref ore, re d uci n g t h e e x p os ure of patie nts 
t o a p ote ntial ris k of c o nta mi nati o n, w hile e ns uri n g a d e q uate treat me nt. T he meas ure ta ke n will 
als o re d uce t he b ur de n at t he trial si tes d uri n g t he pa n de mic.  
T re at me nt  a n d st u d y d ur ati o n : Patie nts will recei ve st u d y treat me nt f or si x 2 1-da y c ycles , or 
u ntil t he y de vel o p u nacce pta ble t o xicit y, wit h dra w c o nse nt, or t h e S p o ns or ter mi nates t he st u d y. 
Per missi o n t o pr ol o n g t he st u d y treat me nt c o ul d be e x ce pti o nall y gra nte d b y St u d y S p o ns or if 
patie nts are deri vi n g be nefit fr o m t he st u d y treat me nt a n d after c o m plete prese ntati o n of t he 
i n di vi d ual case b y t he St u d y I n vesti gat or, partic ul arl y t he me dical justificati o n f or e xte n di n g t he 
treat me nt a n d t h e re-assess me nt of t he ris k/ be nefit bala nce. T he S p o ns or ’s decisi o n will c o nsi der 
t he a vaila bilit y of t h e I n v esti gati o nal M e dici nal Pr o d uct (I M P) at t he ti me of t he re q uest. A re p ort 
of t he disc ussi o ns wit h t h e S p o ns or m ust be file d i n t he s o urce d o c u me ntati o n.   
Patie nts w h o dis pla y i nt olera bilit y t o t he c o m bi nati o n re gi me n ma y be eli gi ble t o c o nti n ue 
treat me nt wit h si n gle a ge nt De bi o 1 5 6 2 . 
Patie nts w h o disc o nti n ue t he st u d y treat me nt f or reas o ns ot her t ha n P D (i ncl u di n g treat me nt 
c o m pleti o n) will be f oll o we d b y ra di o gra p hic s ca n, e ver y 1 2 wee ks (±  4  wee ks)  fr o m t he ti me of 
t heir last o n-st u d y t u m or assess me nt u ntil P D , start of a n y n e w a nti -ca n cer t hera p y, or deat h .  
F or patie nts w h o are e x ce pti o nall y gra nte d c o nti n ue d  st u d y treat me nt after c o m pleti o n of 6 c ycles, 
re peat ra di o gra p hic t u m or res p o nse assess me nts ca n be perf or me d as per l ocal i nstit uti o nal care 
practice. I deall y, re p eat assess me nts s h o ul d c o nti n ue at 6 -wee k ( ±  1 wee k) i nter vals a n d s h o ul d 
n ot be l o n ger t ha n 1 2 -wee ks ( ±  4 wee ks).  Peri o di c t u m or ass ess me nt will be c o n d uct e d usi n g t he 
sa me i ma gi n g m o dalit y of pri or c ycles of treat me nt u ntil P D, start of a n y n e w a nti -ca ncer t hera p y, 
or deat h.  
All patie nts will be c o ntacte d e v er y 1 2 wee ks (±  4 wee ks)  fr o m t he ti me of t he 3 0-da y safet y 
f oll o w-u p visit u ntil o ne year fr o m last patie nt’s first st u d y treat me nt.  
St atistic al met h o ds:  All statistical a nal ys es will be perf or me d usi n g t he m ost rece ntl y release d 
a n d a vaila bl e Statistical A nal ysis S oft ware  (S A S ) statistical s oft ware, u nless ot her wise n ote d. F or 
cate g orical varia bl es, t he n u m ber a n d perce nt of eac h cate g or y wit hi n a para met er will be 
calc ulate d. F or c o nti n u o us varia bles, t he sa m ple size ( n), mea n, me di a n, a n d sta n dar d d e viati o n, 
as well as t he mi ni m u m a n d ma xi m u m val ues, will be prese nte d. Missi n g data will n ot be i m p ute d 
u nless ot her wise state d. T here will be a s u m mar y of patie nt dis p ositi o n , patie nt de m o gra p hics,  a n d 
baseli ne c haracteristics. P K para meters will be c o m p ute d a n d prese nt e d i n ta ble s a n d listi n gs.  
Plas ma c o nce ntrati o ns will be prese nte d i n g ra p hs f or eac h patie nt a n d b y c o h orts. Lat est versi o n 
of S A S or Wi n N o nli n will be use d f or t he P K a n al ys es.  
N o f or mal i nteri m a nal ysis f or efficac y will be perf or me d; h o we v er, f utilit y a nal yses will be 
c o n d ucte d after 1 0 p atie nts a n d, if dee me d necessar y, 1 5 patie nts i n co h ort A are e val u a ble f or 
efficac y ( i.e., p atie nts s h o ul d ha ve p erf or me d at least o n e p ost bas eli ne o bjecti ve res p o ns e 
assess me nt - u nless t here is e arlier cle ar evi de nce of P D ), as well as c u m ulati ve after e nr oll me nt 
of e ver y 1 0 e val ua bl e patie nts f or efficac y (if d ee me d necessar y) i n st u d y Part 3. At eac h a n al ysis, 
f utilit y will be e val uat e d usi n g a Ba yesia n a p pr oac h wit h a n o n-i nf or mati ve c o nj u gate pri or. T he 
decisi o n r ule wi ll be t o rec o m me n d st o p pi n g f or f utilit y if t here is s ufficie ntl y l o w pr o ba bilit y 
( 2 0 % or less) t hat O bjecti ve Res p o nse Rate ( O R R ) e x cee ds t he pre -s pecifi e d ( hist orical) c o ntr ol 
res p o nse of 4 0 %.  T he pri mar y a nal ysis will be c o n d ucte d after all e nr olle d pat ie nts reac he d t heir 
3 r d o n -treat me nt sc he d ule d res p o nse assess me nt or ha ve disc o nti n ue d fr o m treat me nt. T he fi nal 
a nal ysis will be tri g gere d o ne year after t he last accr ue d patie nt’s first d ose d ate. I n t he e x ce pti o nal 
V V- T M F- 5 1 6 1 9 | Pa ge 1 5/ 1 1 2

Pr ot oc ol  
 
Pa ge 1 6  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
case t hat after t he fi nal a nal ysis a p atie nt(s) mi g ht c o nti n ue t o recei ve st u d y treat me nt u n der t he 
pr ot oc ol, a n y s u bse q ue nt data ge n erat e d fr o m t his patie nt(s) will be s u m marize d i n a n a d de n d u m 
re p ort t o be iss ue d after t he last treat me nt of t he last patie nt.  
A statistical a n al ysis pl a n ( S A P) will f ull y d escri be t he pl a n ne d a nal yses f or t his st u d y , i ncl u di n g 
se nsiti vit y a nal ysis relat e d t o patie nts w h o mi g ht s witc h d ose re gi me n d uri n g t h e C O VI D -1 9 
pa n de mic . 
 
 
 
 
 
 
 
 
 
V V- T M F- 5 1 6 1 9 | Pa ge 1 6/ 1 1 2

Pr ot oc ol  
 
Pa ge 1 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
T A B L E O F C O N T E N T S  
S P O N S O R SI G N A T U R E P A G E  ....................................................................................................2  
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 O F T E R M S  ....................................................4  
P R O T O C O L S Y N O P SI S  ................................................................................................................9  
A R TI C L E I.  LI S T O F FI G U R E S  ...............................................................................................2 3  
1.  
I N T R O D U C TI O N ......................................................................................................2 4  
1. 1.  
Tar get Bac k gr o u n d  .....................................................................................................2 4  
1. 2.  
De bi o  1 5 6 2  ..................................................................................................................2 4  
1. 2. 1.  
Mec ha nis m of Acti o n  .................................................................................................2 6  
1. 3.  
N o n -H o d g ki n L y m p h o m a ( N H L): M e dical N ee d  ......................................................2 6  
1. 4.  
N o n -Cli nical St u dies of De bi o 1 5 6 2  ...........................................................................2 7  
1. 4. 1.  
P har mac ol o g y  .............................................................................................................2 7  
1. 4. 2.  
P har mac o ki netics  ........................................................................................................2 8  
1. 4. 2. 1.  
S i n gle D ose P har m ac o ki netics of De bi o 1 5 6 2 i n C D-1 Mice  ....................................2 8  
1. 4. 3.  
T o xic ol o g y  ..................................................................................................................2 9  
1. 5.  
Cli nical St u dies of De bi o 1 5 6 2  ...................................................................................2 9  
1. 5. 1.  
First -i n-H u ma n P has e 1 St u d y  ....................................................................................2 9  
1. 6.  
Rati o nale f or De bi o 1 5 6 2 d osi n g re gi me ns  ................................................................3 0  
1. 7.  
Rati o nale f or t he St u d y Pla n  .......................................................................................3 1  
1. 8.  
Cli nical P har mac ol o g y  ................................................................................................3 2  
1. 9.  
Ris k Mi ni mizati o n Meas ures  ......................................................................................3 3  
1. 1 0.  
A me n d me nt Hist or y  ....................................................................................................3 4  
1. 1 0. 1.  
A m e n d me nt 1  ..............................................................................................................3 4  
1. 1 0. 2.  
A me n d me nt 2  ..............................................................................................................3 5  
1. 1 0. 3.  
A me n d me nt 3  ..............................................................................................................3 5  
1. 1 0. 4.  
A me n d me nt 4  ..............................................................................................................3 6  
1. 1 0. 5.  
A me n d me nt 5  ..............................................................................................................3 6  
1. 1 0. 6.  
A me n d me nt 6  ..............................................................................................................3 7  
2.  
S T U D Y O BJ E C TI V E S A N D  E N D P OI N T S  ..............................................................3 9  
2. 1.  
O bjecti ves  ...................................................................................................................3 9  
2. 1. 1.  
Pri mar y O bj ecti ves  .....................................................................................................3 9  
2. 1. 2.  
Sec o n dar y O bj ecti ves  .................................................................................................3 9  
V V- T M F- 5 1 6 1 9 | Pa ge 1 7/ 1 1 2

Pr ot oc ol  
 
Pa ge 1 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
2. 1. 3.  
E x pl orat or y O bjecti ves  ...............................................................................................3 9  
2. 2.  
E n d p oi nts  ....................................................................................................................3 9  
2. 2. 1.  
Pri mar y E n d p oi nts  ......................................................................................................3 9  
2. 2. 2.  
Sec o n dar y E n d p oi nts  ..................................................................................................3 9  
2. 2. 3.  
E x pl orat or y E n d p oi nts  ................................................................................................4 0  
3.  
S T U D Y P O P U L A TI O N  .............................................................................................4 1  
3. 1.  
Criteria f or Selecti o n of Patie nt P o p ulati o n  ................................................................4 1  
4.  
I N V E S TI G A TI O N A L P L A N .....................................................................................4 4  
4. 1.  
St u d y Desi g n  ...............................................................................................................4 4  
4. 1. 1.  
O ver vie w  .....................................................................................................................4 4  
4. 1. 2.  
Re place me nt of Patie nts  .............................................................................................4 7  
4. 1. 3.  
Safet y R e vie w C o m mittee ( S R C) a n d I n de p e n de nt Data M o nit ori n g 
C o m mittee (I D M C)  ....................................................................................................4 7  
4. 1. 3. 1.  
Safet y R e vie w C o m mittee ( S R C)  ...............................................................................4 7  
4. 1. 3. 2.  
I n d e pe n de nt Data M o nit ori n g C o m mittee (I D M C) ....................................................4 7  
5.  
S T U D Y T R E A T M E N T  ..............................................................................................5 0  
5. 1.  
Descri pti o n of St u d y Treat me nt  ..................................................................................5 0  
5. 2.  
De bi o 1 5 6 2 Pac ka gi n g a n d La b eli n g  ..........................................................................5 0  
5. 3.  
St ora ge, Ha n dli n g, a n d Acc o u nta bilit y  .......................................................................5 0  
5. 4.  
St u d y Treat me nt C o m plia nce  .....................................................................................5 0  
5. 5.  
Assi g n me nt of Patie nt N u m ber  ...................................................................................5 1  
5. 6.  
Bli n di n g  ......................................................................................................................5 1  
5. 7.  
Dr u g Pre parati o n a n d A d mi nistrati o n  .........................................................................5 1  
5. 7. 1.  
Pre - a n d P ost -I nf usi o n Pr o p h yla xis ...........................................................................5 1  
5. 7. 2.  
De bi o 1 5 6 2 Pre parati o n  ..............................................................................................5 2  
5. 7. 3.  
Rit u xi ma b Pre parati o n  ................................................................................................5 2  
5. 7. 4.  
A d mi nistrati o n  ............................................................................................................5 2  
5. 7. 4. 1.  
De bi o 1 5 6 2  ..................................................................................................................5 2  
5. 7. 4. 2.  
Rit u xi ma b  ...................................................................................................................5 3  
5. 7. 4. 3.  
P ost -i nf usi o n m o nit ori n g peri o d .................................................................................5 3  
5. 7. 4. 4.  
Cli nic Visit D urati o n  ...................................................................................................5 3  
5. 7. 5.  
Ma na ge me nt of P ote ntial I nf usi o n -relat e d Reacti o ns .................................................5 4  
5. 8.  
T o xicit y Ma n a ge me nt G ui deli nes  ...............................................................................5 6  
V V- T M F- 5 1 6 1 9 | Pa ge 1 8/ 1 1 2

Pr ot oc ol  
 
Pa ge 1 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
5. 8. 1.  
M o nit ori n g a n d Ma n a ge me nt of T u m or L ysis S y n dr o me ( T L S)  ...............................5 7  
5. 8. 2.  
M o nit ori n g a n d Ma n a ge me nt of C yt o pe nias  ..............................................................5 7  
5. 8. 3.  
M o nit ori n g a n d Ma n a ge me nt of Rit u xi ma b -ass ociate d B o wel O bstr ucti o n 
a n d B o wel Perf orati o n  ................................................................................................5 8  
5. 8. 4.  
M o nit ori n g a n d Ma n a ge me nt of Rit u xi ma b -i n d uce d Pr o gressi ve M ultif ocal 
Le u k o e nce p hal o pat h y ( P M L)  .....................................................................................5 8  
5. 8. 5.  
M o nit ori n g a n d Ma n a ge me nt of Rit u xi ma b -i n d uce d Re nal T o xicit y ........................5 8  
5. 8. 6.  
M o nit ori n g of Rit u xi ma b -i n d uce d Car di o vas c ular T oxicit y  ......................................5 8  
5. 8. 7.  
M o nit ori n g of Rit u xi ma b -i n d uce d Seri o us I nfecti o ns ................................................5 8  
5. 8. 7. 1.  
M o nit ori n g a n d Ma n a ge me nt of Rit u xi ma b -i n d uce d H B V Reacti vati o n ...................5 9  
5. 8. 8.  
M o nit ori n g of Rit u xi ma b -i n d uce d Se vere M uc o c uta ne o us Reacti o ns .......................5 9  
5. 9.  
De bi o 1 5 6 2 a n d Rit u xi ma b D ose M o dificati o ns  ........................................................5 9  
5. 9. 1.  
Dela y or S ki p D osi n g of St u d y Treat me nt  .................................................................5 9  
5. 9. 2.  
D ose M o dif yi n g E v e nts ( D M E) ..................................................................................6 0  
5. 9. 2. 1  A d verse E v e nts Re q uiri n g Per ma n e nt St u d y Treat me nt Disc o nti n u ati o n  ........................6 0  
5. 9. 2. 2 A d verse E v e nts Re q uiri n g D ose Re d ucti o n  .......................................................................6 0  
5. 1 0.  
Re m o val of Patie nts fr o m t he St u d y  ...........................................................................6 1  
5. 1 0. 1.  
Disc o nti n uati o n fr o m St u d y Treat me nt  ......................................................................6 1  
5. 1 0. 2.  
Disc o nti n uati o n fr o m t he St u d y  ..................................................................................6 2  
5. 1 1.  
Peri o d of O bser vati o n  .................................................................................................6 3  
5. 1 2.  
C o nc o mita nt Me dicati o ns a n d Pr oce d ures  .................................................................6 3  
5. 1 2. 1.  
A nti ne o plastic T hera p y  ...............................................................................................6 3  
5. 1 2. 2.  
He mat o p oietic Gr o wt h  Fact ors  ...................................................................................6 3  
5. 1 2. 3.  
Bis p h os p h o nates  .........................................................................................................6 3  
5. 1 2. 4.  
A ntic oa g ula nts  ............................................................................................................6 3  
5. 1 2. 5.  
A n ti virals ....................................................................................................................6 3  
5. 1 2. 6.  
I m m u nizati o ns ............................................................................................................6 4  
5. 1 2. 7.  
Ot her C o nc o mita nt  Me dicati o ns  .................................................................................6 4  
5. 1 3.  
O ver d ose a n d Me dicati o n Err or  ..................................................................................6 4  
6.  
P H A R M A C O KI N E TI C 
 .......................................6 5  
6. 1.  
P K Assess me nts  ..........................................................................................................6 5  
6. 1. 1.  
U nsc he d ule d Visits  .....................................................................................................6 5  
6. 2.  
I m m u n o ge nicit y Assess me nts ....................................................................................6 5  
V V- T M F- 5 1 6 1 9 | Pa ge 1 9/ 1 1 2

Pr ot oc ol  
 
Pa ge 2 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
6. 2. 1.  
U nsc he d ule d Visits  .....................................................................................................6 6  
 
 
 
 
7.  
T R A N S L A TI O N A L R E S E A R C H S T U DI E S  ............................................................6 7  
8.  
S T U D Y P R O C E D U R E S  ............................................................................................6 8  
8. 1.  
I nf or me d C o nse nt  .......................................................................................................6 8  
8. 2.  
I n cl usi o n a n d E x cl usi o n Criteria ................................................................................6 8  
8. 3.  
C o nfir mati o n of Disease Dia g n osis  ............................................................................6 8  
8. 4.  
De m o gra p hic/ Me di cal Hist or y  ...................................................................................6 8  
8. 5.  
Pri or a nti -ca ncer treat me nt f or L y m p h o ma  ................................................................6 8  
8. 6.  
Vital Si g ns  ..................................................................................................................6 8  
8. 7.  
P h ysical E x a mi nati o n, Wei g ht a n d Hei g ht  .................................................................6 8  
8. 8.  
Assess me nt of Healt h -rel ate d Q ualit y of Life ............................................................6 9  
8. 9.  
Electr ocar di o gra m ( E C G)  ...........................................................................................6 9  
8. 1 0 . 
La b orat or y Ass ess me nts  .............................................................................................6 9  
8. 1 0. 1.  
He mat ol o g y  .................................................................................................................6 9  
8. 1 0. 2.  
Ser u m C he mistr y  ........................................................................................................6 9  
8. 1 0. 3.  
Ur i nal ysis ....................................................................................................................7 0  
8. 1 0. 4.  
C oa g ulati o n  .................................................................................................................7 0  
8. 1 0. 5.  
Viral Ser ol o g y  .............................................................................................................7 0  
8. 1 1.  
Pre g n a nc y Scree n  ........................................................................................................7 0  
8. 1 2.  
B -s y m pt o m assess me nt ...............................................................................................7 1  
8. 1 3.  
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma n ce Stat us  ........................................7 1  
8. 1 4.  
Ra di ol o gic I ma gi n g a n d T u m or Res p o nse Assess me nt ..............................................7 1  
8. 1 5.  
B o ne Marr o w Ass ess me nt  ..........................................................................................7 1  
8. 1 6.  
T u m or Bi o ps y  .............................................................................................................7 2  
 
 
9.  
A S S E S S M E N T O F S A F E T Y  .....................................................................................7 3  
9. 1.  
Rec or di n g A d verse E ve nts a n d Seri o us A d verse E ve nts  ...........................................7 3  
9. 1. 1.  
Defi niti o n of A d verse E v e nts  .....................................................................................7 3  
9. 1. 1. 1.  
A d verse E v e nt ( A E)  ....................................................................................................7 3  
9. 1. 1. 2.  
Seri o us A d verse E v e nt ( S A E)  ....................................................................................7 4  
9. 2.  
Rec or di n g A d verse E ve nts  .........................................................................................7 6  
V V- T M F- 5 1 6 1 9 | Pa ge 2 0/ 1 1 2

Pr ot oc ol  
 
Pa ge 2 1  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
9. 2. 1.  
Re p orti n g Seri o us A d verse E ve nts  .............................................................................7 6  
9. 2. 2.  
Re p orti n g a Pre g na nc y  ................................................................................................7 7  
1 0.  
S T A TI S TI C S  ..............................................................................................................7 8  
 
 
1 0. 2.  
A nal ysis P o p ulati o ns  ..................................................................................................7 9  
1 0. 3.  
P har mac o ki netic ( P K) A nal yses  .................................................................................7 9  
1 0. 4.  
Safet y A nal yses  ..........................................................................................................7 9  
1 0. 5.  
A nti -T u m or Acti vit y  ...................................................................................................8 0  
1 0. 6.  
A nal ysis a n d St o p pi n g R ules  ......................................................................................8 0  
1 0. 6. 1.  
F utilit y A nal yses  .........................................................................................................8 0  
 
 
1 0. 6. 3.  
St o p pi n g R ules f or Safet y  ...........................................................................................8 1  
1 0. 7.  
Statistical A nal ysis of F A C T -L y m  .............................................................................8 1  
1 1.  
A D MI NI S T R A TI V E C O N SI D E R A TI O N S  ..............................................................8 2  
1 1. 1.  
I n v esti gat ors a n d St u d y A d mi nistrati ve Str uct ure ......................................................8 2  
1 1. 2.  
I nstit uti o nal Re vie w B oar d (I R B) or I n d e pe n de nt Et hics C o m mittee (I E C) 
A p pr o val  .....................................................................................................................8 2  
1 1. 3.  
Et hical C o n d uct of t he St u d y  ......................................................................................8 2  
1 1. 4.  
Patie nt I nf or mati o n a n d C o nse nt  ................................................................................8 2  
1 1. 5.  
Patie nt C o nfi de ntialit y  ................................................................................................8 3  
1 1. 6.  
St u d y M o nit ori n g  ........................................................................................................8 3  
1 1. 7.  
Case  Re p ort F or ms a n d St u d y Re p orts  .......................................................................8 4  
1 1. 8.  
Pr ot oc ol De viati o ns  ....................................................................................................8 4  
1 1. 9.  
Pr ot oc ol A me n d me nts  ................................................................................................8 4  
1 1. 1 0.  
E n d of St u d y  ...............................................................................................................8 4  
1 1. 1 1.  
St u d y Ter mi nati o n  ......................................................................................................8 4  
1 1. 1 1. 1.  
St u d y Ter mi nati o n  ......................................................................................................8 4  
1 1. 1 1. 2.  
Site Ter mi nati o n  .........................................................................................................8 5  
1 1. 1 2.  
S o urce D oc u m e ntati o n  ................................................................................................8 5  
1 1. 1 3.  
Q ualit y C o ntr ol a n d Ass ura nce  ...................................................................................8 5  
1 1. 1 4.  
S p o ns or A u dits a n d I ns p ecti o ns b y Re g ul at or y A ge n cies  ..........................................8 5  
1 1. 1 5.  
Rec or d Rete nti o n  ........................................................................................................8 6  
1 1. 1 6.  
P u blicati o n a n d Discl os ure P olic y  ..............................................................................8 6  
V V- T M F- 5 1 6 1 9 | Pa ge 2 1/ 1 1 2

Pr ot oc ol  
 
Pa ge 2 2  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1 2.  
LI S T O F R E F E R E N C E S  ............................................................................................8 7  
1 3.  
A P P E N DI C E S  ............................................................................................................8 9  
A P P E N DI X  A.  S C H E D U L E O F E V E N T S O F S A F E T Y R U N -I N F O R Q 3 W 
D O SI N G ( S T U D Y P A R T 1 ) ......................................................................................8 9  
A P P E N DI X  B.  S C H E D U L E O F E V E N T S O F C O H O R T A F O R Q 3 W D O SI N G 
( S T U D Y P A R T 2 A N D 3)  .........................................................................................9 2  
A P P E N DI X  C.  S C H E D U L E O F E V E N T S O F C O H O R T B F O R Q W D O SI N G 
( S T U D Y P A R T 2 A N D 3) .........................................................................................9 6  
A P P E N DI X  D.  P H A R M A C O KI N E TI C A N D I M M U N O G E NI CI T Y A S S E SS M E N T 
O F S A F E T Y R U N -I N F O R Q 3 W D O SI N G ( S T U D Y P A R T 1)  ............................1 0 0  
A P P E N DI X  E.  P H A R M A C O KI N E TI C A N D I M M U N O G E NI CI T Y A S S E SS M E N T 
O F C O H O R T A F O R Q 3 W D O SI N G ( S T U D Y P A R T 2  A N D 3)  .........................1 0 1  
A P P E N DI X  F.  P H A R M A C O KI N E TI C A N D I M M U N O G E NI CI T Y A S S E SS M E N T S 
O F C O H O R T B F O R Q W D O SI N G ( S T U D Y P A R T 2 A N D 3)  ............................1 0 2  
 
 
 
A P P E N DI X  H.  E A S T E R N C O O P E R A TI V E O N C O L O G Y G R O U P ( E C O G ) 
P E R F O R M A N C E S T A T U S S C A L E  .......................................................................1 0 4  
A P P E N DI X  I. R E S P O N S E A S S E S S M E N T S  O F H O D G KI N A N D N O N -H O D G KI N 
L Y M P H O M A: T H E L U G A N O  C L A S SI FI C A TI O N ( C H E S O N 2 0 1 4)  .................1 0 5  
A P P E N DI X  J. B O D Y S U R F A C E A R E A C A L C U L A TI O N  ...................................................1 0 9  
A P P E N DI X  K.  A N N A R B O R C L A S SI FI C A TI O N A N D T H E C O T S W O L D  
M O DI FI C A TI O N S  ...................................................................................................1 1 0  
 
V V- T M F- 5 1 6 1 9 | Pa ge 2 2/ 1 1 2

Pr ot oc ol  
 
Pa ge 2 3  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
LI S T O F T A B L E S  
Ta ble  1:  
Pr o d uct Descri pti o n  ....................................................................................................2 5  
Ta ble  4:  
Ma na ge me nt G ui deli nes f or P ote ntial I nf usi o n -rel ate d Reacti o ns .............................5 5  
Ta ble  5:  
De bi o 1 5 6 2 a n d Rit u xi ma b T o xicities  ........................................................................5 6  
Ta ble  6:  
A d verse E v e nts Re q uiri n g Per ma n e nt Disc o nti n uati o n of Rit u xi ma b  .......................6 0  
Ta ble  7:  
A d verse E v e nt Se verit y  ..............................................................................................7 5  
Ta ble  8:  
A d verse E v e nt Relate d ness  .........................................................................................7 5  
LI S T O F FI G U R E S  
Fi g ure  1:  
Sc he matic O ver vi e w of t he St u d y Desi g n  ..................................................................1 3  
Fi g ure  2:  
C he mical Str uct ure of De bi o 1 5 6 2  .............................................................................2 5  
Fi g ure  3:  
Sc he matic Re pres e ntati o n of De bi o 1 5 6 2  ...................................................................2 6  
Fi g ure  4:  
I n viv o A nti -T u m or Acti vit y of De bi o 1 5 6 2 i n C o m bi nati o n wit h Rit u xi ma b  ...........2 8  
Fi g ure 5:  
Sc he matic O ver vi e w of t he St u d y Desi g n  ..................................................................4 6  
 
 
V V- T M F- 5 1 6 1 9 | Pa ge 2 3/ 1 1 2

Pr ot oc ol  
 
Pa ge 2 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1.   
I N T R O D U C TI O N 
De bi o 1 5 6 2  is a n A D C  c o nsisti n g of t he h u ma nize d a nti -C D 3 7 a nti b o d y, K 7 1 5 3 A , c o nj u gate d via 
a t hi oet her-base d li n ker t o t he c yt ot o xic ma yt a nsi n oi d, D M 1  (Dec kert, 2 0 1 3 ). T he A D C  is sta ble 
i n bl o o d s uc h t hat t he c yt ot o xic p ote nc y of D M 1 is rest ore d o nl y after De bi o 1 5 6 2  is b o u n d t o its 
cell s urface t ar get t he n i nter nalize d a n d releas e d fr o m t he c o nj u gate wit hi n t he cell.   O nce release d 
wit hi n t he tar get cell, D M 1 acts as a n a nti -mit otic a ge nt t hat i n hi bits t u b uli n p ol y merizati o n a n d 
micr ot u b ule a sse m bl y.  C ells treate d wit h ma yt a nsi n oi ds arrest i n t he G 2/ M p hase of t he cell c ycl e, 
a n d e ve nt uall y die b y a p o pt osis ( Re millar d  1 9 7 5 ).  De bi o 1 5 6 2  bi n ds wit h hi g h affi nit y a n d hi g h 
s pecificit y t o t he le u k oc yte a nti ge n, C D 3 7.  The selecti ve e x pressi o n of C D 3 7 o n t he s urface of B -
cell deri ve d l y m p h oc ytes a n d mali g na nt cells ma kes C D 3 7 a s uita ble tar get f or a ma yta nsi n oi d 
A D C  as a p ote ntial treat me nt f or patie nts wit h B -cell deri ve d mali g n a ncies s uc h as N H L  a n d C L L. 
1. 1.   
T ar get B ac k gr o u n d  
T he tar get a nti ge n f or De bi o 1 5 6 2  is t he le u k oc yt e a nti ge n C D 3 7, als o k n o w n as G P 5 2-4 0, 
tetras pa ni n-2 6, or T S P A N 2 6.   C D 3 7 is a hea vil y gl yc os yl ate d tra ns me m bra ne pr otei n of  t he 
tetras pa ni n s u perfa mil y wit h a m olec ular wei g ht  of a p pr o xi matel y 4 0 -5 0 k D ( Maec k er  1 9 9 7 ).  
N or mal tiss ue e x pressi o n is hi g hl y restricte d, wit h str o n g e x pressi o n li mite d t o B -cells d uri n g t he 
pre -B t o peri p heral B -cell sta ges (Li n k  1 9 8 6 , Barre na  2 0 0 5 ) a n d o nl y wea k e x pressi o n o n T-cells, 
m yel oi d cells a n d gra n ul oc ytes ( Li n k  1 9 8 6 , Sc h wartz -Al biez  1 9 8 8 ).  C D 3 7 is a bse nt o n ot her 
he mat o p oietic cells i ncl u di n g he mat o p oietic st e m cells, pr o -B -cells a n d n or mal plas ma cells ( Li n k  
1 9 8 6 ).  T h ere is als o n o e x pressi o n of C D 3 7 i n  n o n -l y m p h oi d tiss ue (Li n k  1 9 8 6 ).  I n c o ntrast, t he 
C D 3 7 a nti ge n is hi g hl y e x presse d o n B -cell N H L i ncl u di n g D L B C L, F L, M C L , as well as C L L 
(M o ore  1 9 8 7 , Barre n a  2 0 0 5 ).  T his patter n of restricte d e x pressi o n i n n or mal tiss ue b ut hi g h 
e x pressi o n i n mali g na nt tiss ue s u g gests t hat C D 3 7 re pres e nts a pr o misi n g t hera pe utic tar get f or B -
cell mali g na n cies.  
I m m u n o hist oc he mical (I H C) st u dies c o n d ucte d at I m m u n o Ge n, I nc. (I m m u n o Ge n) usi n g h u ma n 
t u m or tiss ue micr oarra ys ha ve de m o nstrate d C D 3 7 e x pressi o n i n t he maj orit y of N H L c ores 
i ncl u di n g F L, M A L T, D L B C L, M C L a n d  B ur kitt’s l y m p h o ma.  As e x pecte d, n o n -s pecific stai ni ng 
was o bser ve d i n T -cell l y m p h o ma a n d m ulti ple m yel o ma c ores.  T hese data are c o nsiste nt wit h 
pre vi o usl y p u blis he d st u dies, w hic h de m o nstrate d t hat C D 3 7 is wi del y e x presse d o n B -cell 
mali g na n cies s uc h as N H L a n d B -cell C L L ( Li n k  1 9 8 6 , M o ore  1 9 8 7 , Sc h wartz -Al biez  1 9 8 8 , 
Barre na  2 0 0 5 ). 
1. 2.   
De bi o 1 5 6 2  
De bi o 1 5 6 2  is s y nt hesize d b y c o nj u gati n g t he ma yt a nsi n oi d D M 1 t o t he h uma nize d m o n ocl o nal 
a nti b o d y K 7 1 5 3 A , usi n g  t he heter o bif u ncti o nal cr ossli n ki n g a ge nt S M C C.  T he n o me nclat ure a n d 
str uct ure of De bi o 1 5 6 2  are s h o w n i n Ta ble  1  b el o w.  
V V- T M F- 5 1 6 1 9 | Pa ge 2 4/ 1 1 2

Pr ot oc ol  
 
Pa ge 2 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
T a ble  1 :  
Pr o d uct Descri pti o n  
C he mical Na me(s):  
K 7 1 5 3 A h u ma nize d m o n ocl o nal a nti b o d y t etraa mi de wit h 
N 2' -[ 3-[[ 1-[( 4-car b o x yc ycl o he x yl) met h yl] -2, 5 -di o x o -3 -
p yrr oli di n yl]t hi o] -1 -o x o pr o p yl] -N 2' -d eacet yl m a yt a nsi ne  
Ge neric Na me:  
N ot assi g ne d  
 
C A S Re gistr y N u m ber:   
1 6 0 7 8 2 4 -6 4 -5  
 
I n v esti gati o nal C o de N u m ber: N ot assi g ne d  
 
S y n o n y ms:  
De bi o 1 5 6 2  
N 2' -deacet yl -N 2' -( 3-merca pt o -1 -o x o pr o p yl) -Ma yt a nsi ne -
C o nj u gate d H u ma nize d M o n ocl o nal A nti b o d y ( K 7 1 5 3 A)  
Ma yta nsi n oi d -C o nj u gate d H u ma nize d M o n ocl o nal 
A nti b o d y a gai nst C D 3 7  
 h u C D 3 7 -3 -D M 1  
h u C D 3 7 -3 -D M 1 c o nj u gate  
h u C D 3 7 -3 -S M C C -D M 1  
h u C D 3 7 -3 -M C C -D M 1  
A nti b o d y S y n o n y ms:   
K 7 1 5 3 A  
h u C D 3 7 -3  
 
T he c he mical str uct ure of De bi o 1 5 6 2  is s h o w n i n Fi g ure  2 .  O n a vera ge, t here are 3. 5 m olec ules 
of D M 1 li n ke d vi a dis ulfi de b o n ds t o eac h a nti b o d y m olec ule pr o vi di n g a sta ble c o nj u gate.  A 
sc he matic re prese ntati o n of D M 1 b o u n d t o t h e h u ma nize d C D 3 7 -3 a nti b o d y ( K 7 1 5 3 A) is s h o w n 
i n Fi g ure  3 . 
Fi g ure  2 :  
C he mic al Str uct ure  of De bi o 1 5 6 2  
M e O
Cl
N
O
O
N
H
O
O
M e O
H O
3- 4
O
N
O
O
S
N
H N
O
O
O
K 7 1 5 3 A
 
D M 1 is ~ 1. 8 % wei g ht b y m o n ocl o nal a nti b o d y  
V V- T M F- 5 1 6 1 9 | Pa ge 2 5/ 1 1 2

Pr ot oc ol  
 
Pa ge 2 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
a n d 
M C L. A g gressi ve l y m p h o mas a re ofte n c ura ble wit h i nte nsi ve c he m ot hera p y re gi me ns, 
w hereas i n d ole nt l y m p h o mas are us uall y i nc ura ble i n a d va nce d cli nical sta ges.  
A nti -ca ncer treat me nt f or t his di vers e diseas e is d e pe n de nt o n t he s pecific s u bt y pe a n d st a ge b ut 
ma y i ncl u de ra diati o n, c h e m ot hera p y, bi ol o gic t h era p y, c h e m ot hera p y pl us ra diati o n or ste m cell 
tra ns pla ntati o n.  T he i ntr o d ucti o n of t he C D 2 0-directe d Ma b rit u xi ma b has ha d a si g nifica nt effect 
o n patie nt o utc o mes.  Rit u xi ma b i n d uces A D C C, C D C a n d a p o pt osis.  Rit u xi ma b is c urre nt l y 
a p pr o ve d f or t he treat me nt of ne wl y dia g n os e d or R/ R B -cell N H L, i ncl u di n g t he treat me nt of 
ne wl y dia g n os e d D L B C L i n c o m bi nati o n wit h c he m ot hera p y, as well as C L L .  C o m bi nati o n 
re gi me ns c o nt ai ni n g rit u xi ma b a n d c he m ot hera pe utic a ge nts h a ve b ee n s h o w n t o i ncrease o verall 
res p o nse rates a n d t he rat e of c o m plete re missi o ns as well as t o dela y ti me t o pr o gressi o n ( Le o nar d  
2 0 0 8 , C hes o n  2 0 0 8 ). H o we ver, p atie nts ma y s h o w pri mar y a n d sec o n d ar y resista nce.  T he fi ve-
year s ur vi val rat e of N H L patie nts has rise n fr o m 4 7 % ( 1 9 7 5 -1 9 7 7) t o a p pr o xi matel y 7 1 % ( 2 0 0 4 -
2 0 1 0) ( Le u k e mia, L y m p h o ma, 
M yel o m a Facts  2 0 1 5 ); t hese s ur vi v al statistics hi ghli g ht t he 
c o nti n ue d nee d f or i m pr o ve d t hera p e utic strate gies.  
1. 4.   
N o n -C li nic al St u dies of De bi o 1 5 6 2  
A brief s u m mar y of De bi o 1 5 6 2 n o ncli nical data is pr o vi de d here.  A d diti o nal i nf or mati o n ca n b e 
f o u n d i n t he De bi o 1 5 6 2  I n v esti gat or’s Br oc h ure  (I B). 
1. 4. 1.   
P h ar m a c ol o g y  
De bi o 1 5 6 2  bi n di n g affi nity a n d c a p acity  
De bi o 1 5 6 2  has bee n s h o w n t o bi n d wit h hi g h affi nit y a n d s pecificit y t o B -cells (a p p are nt K D : ~ 0. 2  
–  0. 5  n M) wit h n o e vi de nce of n o n -s p ecific bi n di n g at c o n ce ntrati o ns as hi g h as 1 0 0 n M.  Fl o w 
c yt o metr y e x peri me nts usi n g a fl u oresce ntl y l a belle d C D 3 7 a nti b o d y s h o w t hat t he n u m ber of 
a nti ge n bi n di n g sites o n B -cells is at least a n or der of ma g nit u de hi g h er t h a n t hat of ot h er cell t y pes 
i n n or mal peri p heral bl o o d.   
De bi o 1 5 6 2  m o de of acti o n   
T he c yt ot o xi c acti vit y of De bi o 1 5 6 2  is me diate d b y t he selecti ve bi n di n g of t he A D C  t o t he C D 3 7 
a nti ge n.  Cell deat h is i n d uce d b y se v eral mec h a nis ms , i ncl u di n g cell c ycle arrest, i n d ucti o n of 
a p o pt osis a n d effect or -m e diate d c yt ot o xicit y (A D C C a n d C D C) .  
I n viv o a nti -t u m or activity of si n gle a g e nt De bi o 1 5 6 2  i n severe c o m bi ne d i m m u n o deficie nt 
(S CI D ) mice xe n o gr aft m o dels   
T he a nti -t u m or acti vit y of De bi o 1 5 6 2  has bee n d e m o nstrate d i n s e veral N H L x e n o graft m o d els 
usi n g S CI D mice.  A si n gle I V d ose ( 1 0  m g/ k g) was ac ti ve (rati o of me dia n t u m or v ol u me f or 
treate d a n d co ntr ol gr o u ps [ T/ C] = 1 6 %) i n fe male S CI D mice beari n g est a blis he d D o H H 2 ( F L) 
t u m ors wit h 4/ 9 a ni mals s h o wi n g partial re gressi o n, 2/ 9 c o m plete re gressi o n a n d 1/ 9 re mai ni n g 
t u m or free b y t he e n d of t he st u d y.  I n a D L B C L m o use m o del ( S U -D H L -4 ), De bi o 1 5 6 2  
de m o nstrate d d os e -de p e n de nt a nti -t u m or acti vit y wit h T/ C val ues of 2 4% , 2%  a n d 0 % at d oses of 
2. 5, 5 a n d 1 0 m g/ k g, res p ecti vel y.  I n a d diti o n, at t he 1 0 m g/ k g d ose , De bi o 1 5 6 2  i n d uce d c o mplete 
re gressi o ns a n d t u m or free s ur vi v ors i n all of t he mice ( 8/ 8).  I n a J V M-3 ( B -C L L) m o del, De bi o 
1 5 6 2  de m o nstrate d a nti -t u m or acti vit y wit h T/ C val ues of 1 6%  a n d 2 6 % at d oses of 5 a n d 1 0 
m g/ k g, res p ecti vel y.   A cti vit y was als o o bser ve d i n mice beari n g  BJ A B ( B L) xe n o graft t u m ors.   
V V- T M F- 5 1 6 1 9 | Pa ge 2 7/ 1 1 2

Pr ot oc ol  
 
Pa ge 2 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
I n vitr o cyt ot o xic activity of De bi o 1 5 6 2  i n c o m bi n ati o n wit h rit u xi m a b  
De bi o 1 5 6 2  i n c o m bi nati o n wit h rit u xi ma b de m o nstrate d s y ner gistic pr o-a p o pt otic acti vit y i n a 
pa nel of cell li nes re prese ntati ve of di verse N H L s u bt y pes, i ncl u di n g acti vate d B-cell-li ke a n d 
ger mi nal ce nter B -cell– li ke D L B C L, C L L a n d M C L.  
I n viv o a nti -t u m or activity of De bi o 1 5 6 2  i n c o m bi n ati o n wit h rit u xi m a b   
De bi o 1 5 6 2  i n c o m bi nati o n wit h rit u xi ma b de m o nstrate d s y n er gistic a nti-t u m or acti vit y i n 
x e n o gra ft m o dels of N H L esta blis he d fr o m  
 or  
 cells (Fi g ure  4 ).  I n b ot h 
m o dels  t he c o m bi nati o n of De bi o 1 5 6 2  a n d rit u xi ma b was c o m pare d wit h sta n dar d-of -care (R -
C H O P.  I n t he  
 m o del, the a nti -t u m or acti vit y of De bi o 1 5 6 2  (
 m g/ k g) i n c o m bi nati o n 
wit h rit u xi ma b (
 m g/ k g) was c o m para ble t o t hat of R -C H O P  wit h e xte n de d , c o m plete t u m or 
re gressi o ns i n all mice.  I n a d diti o n, t he c o m bi nati o n re gi me n was   
 f ol d m ore acti ve t ha n 
si n gle a ge nt De bi o 1 5 6 2  or r it u xi ma b at t he sa me d ose  (Fi g ure  4 ).  I n t he  
 m o del, t he 
De bi o 1 5 6 2  (
 m g/ k g) a n d rit u xi ma b ( 1 0 m g/ k g) c o m bi nati o n was m ore acti ve t ha n R -C H O P , 
wit h  
%  perce nt of t he  a ni mals ac hie v i n g a c o m pl ete res p o nse a n d re mai ni n g t u m or free f or t h e 
d urati o n of t he st u d y  c o m pare d t o  o nl y   
% i n t he R -C H O P gr o u p .  Si milarl y, t he c o m bi nati o n 
re gi me n was m or e p ote nt ( T/ C =  %) t ha n eit her De bi o 1 5 6 2  ( T/ C =  
%) or rit u xi ma b ( T/ C  =  
%) al o ne  (Fi g ure  4 ). 
 
 
 
1. 4. 2.   
P h ar m a c o ki netics  
N o ncli nical st u dies wit h De bi o 1 5 6 2  n o n -cr oss reacti ve ( m o use) s pecies were c o n d ucte d t o defi ne 
P K para meters a n d t o d eter mi ne t he sta bilit y of t h e li n ker a n d i m pact of c o nj u gati o n o n a nti b o d y 
cleara nce.   T he st u dies are s u m marize d here a n d f urt her detaile d i n t he De bi o 1 5 6 2  I B.  
1. 4. 2. 1.  
Si n gle D os e P h ar m a c o ki netics of De bi o 1 5 6 2  i n C D-1 Mice  
De bi o 1 5 6 2  s h o w e d bi p h asic P K  dis p ositi o n u p o n si n gle I V a d mi nistrati o n i n C D -1 mice wit h a 
distri b uti o n p hase of ~
 h o urs a n d mea n eli mi nati o n half -life of De bi o 1 5 6 2  of a b o ut  
 d a ys f or 
V V- T M F- 5 1 6 1 9 | Pa ge 2 8/ 1 1 2

Pr ot oc ol  
 
Pa ge 2 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
c o nj u gate a n d  
 da ys f or t he K 7 1 5 3 A a nti b o d y c o m p o ne nt.  T hese res ults i n dicate t hat De bi o 1 5 6 2  
is sta ble i n circ ulati o n of t he m o use.  
1. 4. 3.   
T o xic ol o g y  
D ue t o lac k of C D 3 7 se q ue nce h o m ol o g y a n d/ or De bi o 1 5 6 2  bi n di n g i n a ni mal s pecies, 
I m m u n o Ge n ge n erate d a m o use 
 m o del e x pressi n g t he h u ma n C D 3 7 a nti ge n.   
A nal ysis of C D 3 7 distri b uti o n a n d e x pressi o n le vels de m o nstrate d si milar tiss ue distri b uti o n b ut 
l o wer e x pressi o n t ha n t h at o bser ve d i n h u ma n cells.  De bi o 1 5 6 2  gi ve n at d oses k n o w n t o de pl ete 
h u ma n B cells 
 
 
T w o G o o d La b orat or y Practice st u dies e v al uate d t he n o n-tar gete d t o xicit y 
 of 
De bi o 1 5 6 2  i n 
 mice.  
 De bi o 1 5 6 2  ( d oses 
 
) ca use d re v ersi ble a n d n o n -re versi ble c h a n ges i ncl u di n g 
 
 
   
   
 
   
 
   
  
   
   
 
  
T he maj orit y of De bi o 1 5 6 2 -relate d alterati o ns de m o nstrate d a si g nifica nt rest orati o n t o war ds 
n or mal   
.  U n der t he c o n diti o ns of t hese st u dies, t he S T D1 0 f or De bi o 1 5 6 2  was 
deter mi ne d 
 (see De bi o 1 5 6 2 I B ).  
1. 5.   
Cli n ic al St u dies of De bi o 1 5 6 2  
1. 5. 1.   
First -i n-H u m a n P h ase 1 St u d y  
S afety  
D uri n g t he escalati o n p hase of t he FI H st u d y wit h De bi o 1 5 6 2  (I M G N 03 0 1 , N C T 0 1 5 3 4 7 1 5 ), 
i nf usi o n reacti o ns a n d earl y o nset ne utr o pe nia were o bser ve d a n d t his res ulte d i n t he 
i m ple me ntati o n of peri -i nf usi o nal a n d pre-d ose ster oi d pr o p h yla xis at t he 0. 4 m g/k g d ose  t o 
s uccessf ull y miti gate t h ese occ urre nces.  I n s u bse q ue nt d ose escalati o ns, later o nset G ra de 4 
ne utr o pe nia a n d G rad e 3 fe brile ne utr o pe nia re q uire d t he i m ple me ntati o n of gra n ul o c yt e gr o wt h 
fact or pr o p h yla xis, per i nstit uti o nal practice.  O verall, t he m ost c o m m o n treat me nt e mer ge nt A Es 
(T E A Es), i.e., o cc urri n g i n m ore  t ha n 1 0 % of patie nts, i ncl u de ne utr o pe nia, fe v er, fati g u e, 
t hr o m b oc yt o pe ni a, na us ea, diarr hea, h y p o kale mia, ast he nia, as partate a mi n otra nsferas e ( A S T ) 
i ncreas e d, d ys p n o ea, al a ni ne a mi n otra nsferas e ( A L T ) i ncreas e d, peri p heral oe d e ma, fe brile 
ne utr o pe nia, d ecreas e d a p petite, m uscle wea k n ess, a n d a n e mia.  Gra de 3 or greater T E A Es , 
re gar dl ess of relati o ns hi p t o De bi o 1 5 6 2 , t hat ha ve bee n re p orte d b y m ore t h a n o ne patie nt i ncl u de 
ne utr o pe nia , fe brile ne utr o pe nia, le u k o pe nia, t hr o m b oc yt o pe ni a, a ne mia, A L T i ncreased , diarr hea, 
h y p o natr ae mia, l e u k o pe nia, l y m p h o p h e nia, a n d p ne u m o nia .  O ne patie nt s uffere d G ra de 3 
m y ocar dial i nf arcti o n  a n d Gra d e 5 car diac arrest  t hat was c o nsi dere d t o be u nrelat e d t o st u d y 
treat me nt.   
V V- T M F- 5 1 6 1 9 | Pa ge 2 9/ 1 1 2

Pr ot oc ol  
 
Pa ge 3 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
A nti -t u m or activity  
Of t he f ort y -ni ne patie nts e val uate d, fo ur  P R a n d o ne C R  ha ve bee n re p orte d i n patie nts wit h 
D L B C L  or F L .  Res p o nses ha ve bee n o bser ve d i n patie nts wit h t hree or greater pri or li nes of 
t hera p y i ncl u di n g a ut ol o g o us ste m cell tra ns pla nt rela pses.  
1. 6.   
R ati o n ale f or  De bi o 1 5 6 2 d osi n g re gi me ns  
T he M T D  of De bi o 1 5 6 2  i n t he FI H si n gle a ge nt st u d y I M G N0 3 0 1 was 1. 4 m g/ k g  I V Q 3 W wit h 
gra n ul oc yte gr o wt h fact or s u p p ort a n d 1. 0 m g/ k g I V Q 3 W wit h o ut pr o p h yla xis of gra n ul oc yte  
gr o wt h fact or . 
T he selecte d  d os e of De bi o 1 5 6 2  i n c o m bi nati o n wit h rit u xi ma b i n t he safet y r u n-i n (st u d y Part 1) 
of t his st u d y will be 0. 7  m g/ k g  I V Q 3 W  (i n a 2 1-da y treat me nt c ycle) , wit h t he d ose cal c ulate d 
usi n g t otal b o d y wei g ht.  T his d ose le vel was dee me d t olera ble i n t he FI H st u d y wit h o ut t he use of 
gr o wt h fact or s u p p ort . 
I n Part 2 of t his st u d y, t he sa me 0. 7 m g/ k g I V Q 3 W  De bi o 1 5 6 2 d osi n g re gi me n  i n c o m bi nati o n 
wit h rit u xi ma b will be f urt her ass ess e d i n co h ort A. I n parallel, a n e w  Q W De bi o 1 5 6 2 d osi n g 
sc he d ule will be e x pl ore d  i n co h ort B . I n t his c o h ort, De bi o 1 5 6 2 will be a d mi nistere d at a d ose of 
0. 4 m g/ k g o n Da y 1, 0. 2 m g/ k g o n Da y 8 a n d 0. 2 m g/ k g o n Da y 1 5  (i n a 2 1-da y treat me nt c ycle) . 
T his a d diti o nal wee kl y d osi n g re gi me n is ai me d t o ma xi mize t he s y ner gistic effects of t he 
c o m bi nati o n of De bi o 1 5 6 2 a n d rit u xi ma b t hat was o bser ve d i n pri or n o n -cli nical st u dies, w hic h 
i n t ur n ma y tra nslat e i nt o a greater effi cac y of t he c o m bi nati o n treat me nt i n h u ma ns w hile 
mai ntai ni n g or i m pr o vi n g t he safet y pr ofile of t he st u d y treat me nt. T his h y p ot hesis is base d o n t he 
pre -cli nical m o dels s h o wi n g i m p r o ve d De bi o 1 5 6 2 i nter nalizati o n w he n c o m bi ne d wit h rit u xi ma b, 
a n d t he preli mi nar y p h ar mac o ki netic c h aracterizati o n of De bi o 1 5 6 2 t hat h a ve s h o w n a relati vel y 
s h ort half-life of De bi o 1 5 6 2 c o m pare d wit h rit u xi ma b. A nal yses of a v aila ble P K data fr o m t he 
c o mplete d FI H si n gl e a ge nt p hase 1 trial a n d t he c o m plete d safet y r u n -i n of t his c urre ntl y o n g oi n g 
P hase 2 st u d y s u g gest t hat a Q W a d mi nistrati o n of De bi o 1 5 6 2 w o ul d pr ol o n g t he e x p os ure of 
De bi o 1 5 6 2 t o t he C D 3 7 a nti ge n, a n d i m pr o ve t he s y ner gistic effect wi t h rit u xi ma b. 
T he S p o ns or has c o n d ucte d se veral m o deli n g si m ulati o ns of De bi o 1 5 6 2 plas ma c o nce ntr ati o n 
vers us ti me, w hic h s u g gest a l o wer pea k c o n ce ntrati o n ( C ma x ) a n d a n e xte n de d dr u g e x p os ure wit h 
t he Q W re gi me n c o m pare d t o t he Q 3 W re gi me n, w hic h ma y res ult i n a s ustai ne d tar get rece pt or 
occ u pa n c y ( C D 3 7). A d diti o nall y, preli mi nar y P K m o delli n g a n d si m ulati o n a nal ys es s u g gest t hat 
t he Cma x  of De bi o 1 5 6 2 ma y b e ass o ciate d wit h t he o nset of n e utr o pe nia, w hic h has b ee n s h o w n t o 
be t he m ost c o m m o n a d verse rea cti o ns i n t he cli ni cal setti n g s o far.  
T he pr o p ose d Q W d osi n g s c he d ule of De bi o 1 5 6 2 will li kel y re d uce t he p ea k c o n ce ntrati o n w hile 
mai ntai n t he o verall e x p os ure. 
Wit h o ut e x cee di n g t he M T D, t his c o ul d be ac hie ve d wit h t he 
a d mi nistrati o n of 0. 4 m g/ k g at t he b e gi n ni n g of t h e treat me nt c ycle, f ol l o w e d b y t w o c o nsec uti ve 
d oses of 0. 2 m g/ k g eac h, t he sec o n d a n d t hir d wee k res pecti vel y. T he t otal c u m ulati ve d ose of 0. 8 
m g/ k g per c ycle is b el o w t he M T D defi ne d i n t he si n gle a ge nt FI H st u d y 0 3 0 1( 1. 0 m g/ k g). 
T heref ore, t h e wee kl y re gi me n is h y p ot hesize d t o li mit t he ris k of ne utr o pe nia w hile mai ntai ni n g 
t he e x p os ure of De bi o 1 5 6 2 t o mali g na nt B-cells via t he C D 3 7 a nti ge ns. A d diti o nal i nf or mati o n 
ca n be f o u n d i n t he I B.  
V V- T M F- 5 1 6 1 9 | Pa ge 3 0/ 1 1 2

Pr ot oc ol  
 
Pa ge 3 1  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
Rit u xi ma b will be gi ve n at 3 7 5 m g/ m 2 I V Q 3 W  (i n a 2 1-da y treat me nt c ycl e)  t hr o u g h o ut the st u d y , 
c o nsiste nt wit h d osi n g of rit u xi ma b wit h c o nc urre nt c he m ot hera p y i n N H L , (Rit u x a n ®  (rit u xi ma b) 
P ac ka ge Ins ert  2 0 1 4 ).   
Fr o m t he data t h us far, t he t o xicit y pr ofiles of De bi o 1 5 6 2  a n d rit u xi ma b are ge nerall y n o n -
o verla p pi n g, alt h o u g h ne utr o pe nia , i nf usi o n reacti o ns a n d fe ver h a ve  b ee n o bser ve d wit h b ot h 
De bi o 1 5 6 2  m o n ot hera p y a n d si n gle a ge nt rit u xi ma b, wit h  ne utr o pe nia bei n g a  d ose li miti n g e ve nt 
f or De bi o 1 5 6 2 .     
1. 7.   
R ati o n ale f or t he St u d y Pl a n  
T his is a n o pe n la bel, P hase 2, cli nical st u d y t hat c o nsists of t hree parts: 1) S afet y r u n -i n, 2)  Initial 
assess me nt of safet y a n d effi cac y of Q 3 W a n d Q W d osi n g re gi me ns  a n d 3) E x pa nsi o n . F or eac h 
patie nt, t he st u d y will i ncl u de a scree ni n g peri o d, a treat me nt peri o d, a n d a f oll o w -u p peri o d.  T he 
st u d y is desi g ne d t o deter mi ne t he safet y, t olera bilit y a n d a nti -t u m or acti vit y of De bi o 1 5 6 2  i n 
c o m bi nati o n wit h rit u xi ma b.  T he P K of De bi o 1 5 6 2  a n d rit u xi ma b as well as t he i m m u n o ge nicit y 
of  De bi o 1 5 6 2  will be e v al uate d.  
Base d o n t he br oa d e x pressi o n of C D 3 7 i n B -cell N H L a n d t he i nitial a nti -t u m or acti vit y see n wit h 
De bi o 1 5 6 2  i n D L B C L, t his trial will i nitiall y i ncl u de a br oa d ra n ge of B-cell N H L s u bt y p es , i n a n 
eff ort t o see k si g n als of safet y a n d acti vit y f or t he c o m bi nati o n of De bi o 1 5 6 2  wit h rit u xi ma b . 
Patie nts wit h D L B C L, F L, 
M C L, or 
M Z L/ M A L T or ot her N H L s u bt y p es ( wit h S p o ns or’s 
a p pr o val) are eli gi ble f or e nr oll me nt i n t he safet y r u n -i n.  At least si x D L B C L a n d si x F L N H L 
patie nts will be e nr olle d  i n t his part of t he st u d y . T E A Es occ urri n g d uri n g C ycle 1 i n patie nts 
e nr olle d i nt o t he safet y r u n -i n will be re vie we d a n d ta ke n i nt o c o nsi derati o n w he n c o nfir mi n g t h e 
s uita bilit y of t h e c o m bi n ati o n treat me nt  f or c o nti n uati o n wit h  t he s ec o n d part of t he st u d y.  T his 
part of t he st u d y has bee n c o m plete d a n d t he S R C rec o m me n de d c o nti n uati o n of t he st u d y.  
I n Part  2 a n d Part 3  of t he st u d y , e nr oll me nt will be  f oc use d o n patie nts wit h rela pse d D L B C L, f or 
t he f oll o wi n g reas o ns: 
1.  D L B C L patie nts re prese nt t he lar gest gr o u p of N H L  p atie nts  (a b o ut 4 0 % of all N H L  
cases), wit h a si g nifica nt u n met me dical nee d.  
2.  D L B C L patie nts s h o we d  t he hi g hest res p o ns e rat e c o m pare d t o patie nts  wit h ot her N H L  
s u bt y pes i n a cli nical st u d y wit h a n ot her a nti C D 3 7 A D C, A G S 6 7 E (Sa was, 2 0 1 7 ). 
3.  Rela pse d D L B C L p atie nts c o ul d be nefit m ore t ha n refract or y p atie nts fr o m t he treat me nt 
wit h De bi o 1 5 6 2 : efficac y dat a o btai ne d s o far i n dicates t hat res p o nse rate i n rela pse d 
D L B C L  patie nts  is e nc o ura gi n g (a p pr o xi matel y 4 3 %) .   
4.  F oc us i n g o n rela pse d D L B C L patie nts will i m pr o ve t he h o m o ge n eit y of t he st u d y 
p o p ulati o n  a n d facilitate data i nter pretati o n . 
5.  T he pri mar y m ec h a nis m of acti o n of De bi o 1 5 6 2 (a nti-C D 3 7 a nti b o d y li n ke d wit h t he 
t u b uli n-disr u pti n g pa yl o a d a ge nt D M 1) is well s uite d f or t he m ore a g gressi ve,  ra pi dl y 
di vi di n g N H Ls , s uc h as rela pse d D L B C L . 
V V- T M F- 5 1 6 1 9 | Pa ge 3 1/ 1 1 2

Pr ot oc ol  
 
Pa ge 3 2  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1. 8.   
Cli nic al P h ar m ac ol o g y  
De bi o 1 5 6 2 c o n ce ntrati o ns i n plas ma were o btai ne d b y usi n g a v ali date d e nz y m e-li n ke d 
i m m u n os or be nt assa y li ga n d bi n di n g ass a y.  
De bi o 1 5 6 2  P K para meters fr o m t he FI H  st u d y 0 3 0 1 were deter mi ne d f or C ycl e 1 f or eac h patie nt.  
I n m ost cas es, tma x  c oi nci de d wit h t he e n d of i nf usi o n, as e x pecte d. O verall res ults were fairl y 
c o nsiste nt acr oss c ycles, s u g gesti n g t hat t h e P K of De bi o 1 5 6 2 d oes n ot c h a n ge u p o n re peat d osi n g. 
O n a vera ge, C ma x  a n d A U C 0 -i nf i ncrease d wit h a n i ncrease i n d ose. Greater t ha n pr o p orti o nal 
i ncreas es occ urre d at d oses of 0. 8 m g/ k g a n d a b o v e w he n c o m pare d t o t he 0. 1 t o 0. 7 m g/ k g d oses, 
m ost li kel y d u e t o a n i ncrease i n t he mea n cleara n ce ( C L) i n t he l o wer d os e ra n ge.  
 
 
  
 T hes e 
c ha n ges i n ter mi nal eli mi nati o n rate are c o nsiste nt wit h tar get me diate d dr u g dis p ositi o n at l o w 
d oses, 
wit h sat urati o n of t his 
mec ha nis m occ urri n g at hi g h er d oses. 
 
 i n eac h gr o u p, t he v al ues f or Vss were c o nsiste nt wit h 
plas ma v ol u me
 
 
  T h ere was n o a p pare nt acc u m ulati o n of De bi o 1 5 6 2  i n re p eate d d osi n g.  
V V- T M F- 5 1 6 1 9 | Pa ge 3 2/ 1 1 2

Pr ot oc ol  
 
Pa ge 3 3  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1. 9.   
Ris k Mi ni miz ati o n Me as ures  
Base d o n t he c urre ntl y a vaila ble i nf or mati o n,  t he m ost c o m m o nl y re p orte d se v ere a d verse 
reacti o ns were he mat ol o gical e ve nts, i ncl u di n g ne u tr o pe nia, fe brile ne utr o pe nia, le u k o pe nia, a n d 
t hr o m b oc yt o pe ni a. Fe brile ne utr o pe nia is t he o nl y e x pect e d Seri o us A d verse Reacti o n of De bi o 
1 5 6 2. I n t his cli nical trial, s pecific meas ures are i m ple me nte d t o mi ni mize a n d m o nit or t his ris k 
a n d ot her i de ntifie d ris ks d uri n g tr eat me nt wit h De bi o 1 5 6 2 a n d rit u xi ma b . 
F or t h e ma na ge me nt of occ urri n g c yt o p e nia or pre v e nti n g t he re-e mer ge n ce of s eri o us o n es 
i ncl u di n g fe brile ne utr o p e nia, s pecific treat me nt m o dificati o n g ui deli nes are pr o vi de d i n Se cti o n 
5. 8. 2  of t his pr ot oc ol . T h e safet y m eas ures i ncl u de d ose re d u cti o n, use of b o ne marr o w s u p p orti ve 
meas ures, a n d disc o nti n uati o n of st u d y treat me nt. I n a d diti o n t o r o uti ne A E re p orti n g, vital si g ns 
a n d he mat ol o g y assess me nts i ncl u di n g W hite Bl o o d Cell ( W B C ) c o u nt a n d differe ntial cell 
c o u nti n g are pla n ne d al o n g t he treat me nt c ycl e , a n d m ore fre q u e nt f or c ycl es 1 a n d 2.  
T o mi ni mize t he ris k of seri o us i nfecti o ns, patie nts prese nti n g wit h acti ve he patitis or h u ma n 
i m m u n o deficie nc y vir us (HI V ) i nf ecti o n, or ha vi n g recei ve d atte n u ate d vacci nati o n wit hi n 3 0 da ys 
pri or t o first st u d y treat me nt  are e x cl u de d f or partici pati o n . As patie nts will recei ve rit u xi ma b i n 
a d diti o n t o De bi o 1 5 6 2 , t he y are re q uire d t o recei v e a nti viral treat me nt per i nstit uti o nal g ui deli nes.  
T o mi ni mize t he ris k of e mer ge nce of seri o us i nf usi o n-relate d reacti o n or t o miti gate its p ote ntial 
se verit y i n cas e of occ urre nce, t he st u dy pr ot oc ol defi nes t he pre - a n d p ost -i nf usi o n pr o p h yla xis 
(Secti o n 5. 7. 1 ) as well as s pecific g ui deli ne t o ma na ge seri o us i nf usi o n-rel ate d reacti o ns (Secti o n 
5. 7. 5 ).  Patie nts w h o ha ve ha d a pri or a na p h ylactic or  ot her seri o us i nf usi o n -relate d reacti o ns are 
e x cl u de d fr o m t he st u d y. As a n a d diti o nal preca uti o nar y meas ure, p atie nts will re mai n i n t he cli nic 
u n der m o nit ori n g f or f o ur h o urs after c o m pleti o n of t he rit u xi ma b i nf usi o n d uri n g t he first c ycle. 
Patie nts recei vi n g De bi o 1 5 6 2 o nl y, i.e., o n Da y 8 a n d Da y 1 5 f or t h e Q W d osi n g sc h e d ule  or d u e 
V V- T M F- 5 1 6 1 9 | Pa ge 3 3/ 1 1 2

Pr ot oc ol  
 
Pa ge 3 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
t o rit u xi ma b i nt olera bilit y, will als o re mai n i n t h e cli nic u n der m o nit ori n g f or o ne h o ur f or all 
c ycles. I n a d diti o n, trai ne d me dical p ers o n nel, a p pr o priate pr o p h ylactic me dicati o n a n d ot her 
res o urces is ma n dat or y t o ha ve a vaila bl e at partici p ati ng sites bef ore st arti n g t o i nf usi o n i n case of 
a na p h yla xis.  
T o mi ni mize t he ris k of t u m or l ysis s y n dr o me (T L S ), patie nts wit h hi g h t u m or b ur de n a n d/ or hi g h 
circ ulati n g l y m p h oc yte c o u nts s h o ul d be a de q u atel y h y drat e d pri or t o t he i nf usi o n. Ser u m 
c he mistr y assess me nts will be c o n d ucte d at eac h visit, i ncl u di n g at Da y 2 a n d Da y 3 after t he first 
t w o c ycles.   
As p ne u m o nitis has bee n re p ort e d  wit h t he use of A D Cs, i ncl u di n g o n e fatal case i n a patie nt 
recei vi n g treat me nt wit h De bi o 1 5 6 2, des pite t he a bs e nce of a cas u al d ose a n d te m p oral 
relati o ns hi p wit h De bi o 1 5 6 2, t he c urre nt pr ot oc ol e x cl u des t he e nr oll me nt of patie nts wit h c urre nt 
dia g n osis of i nterstitial l u n g diseas e or wit h cli nical hist or y of s e vere pare nc h y mal l u n g dis or ders.  
I n a n eff ort t o mi ni mize t he ris k of C or o na vir us Disease 2 0 1 9 ( C O VI D -1 9 ) i nfecti o n f or p atie nts 
partici pati n g i n t he st u d y , t he s p o ns or deci de d t hat i n t he i nterest of patie nt safet y it is best t o all o w 
t o s witc h patie nts w h o are o n t he Q W  De bi o 1 5 6 2 d osi n g re gi me n t o t he Q 3 W. T he s witc h fr o m 
t he Q W t o Q 3 W re gi me n is n ot e x pecte d t o res ult i n a n y detri me ntal effect o n safet y or efficac y 
f or t hese patie nts, b ase d o n rece nt a nal ysis of preli mi nar y st u d y data. 
T his will re d uce  t he n u m ber of vi sits t o t he h os pital. T heref ore, re d uci n g t h e e x p os ure of patie nts 
t o a p ote ntial ris k of c o nta mi nati o n, w hile e ns uri n g a d e q uate treat me nt. T he meas ure ta ke n will 
als o re d uce t he b ur de n at t he trial sites d uri n g t he pa n de mic.  
As of A pril 1 4 , 2 0 2 0, t hree p atie nts are o n treat me nt  wit h  Q W d ose re gi me n . All were gra nte d 
p er missi o n t o s witc h t o t he Q 3 W  re gi me n b y St u d y S p o ns or  i n t he best i nterest of t he patie nts. 
St u d y e nr oll me nt has b ee n c o m plete d. I n a d diti o n t o t he s pecific ris k mi ni mizati o n meas ures, safet y 
will be cl osel y e val u ate d t hr o u g h o ut t he st u d y u ntil t he 3 0 -da y safet y f oll o w -u p visit. T he safet y 
assess me nts i ncl u de A E re p orti n g, la b orat or y assess me nts, electr ocar di o gra m ( E C G ), p h ysical 
e x a ms, a n d vital si g ns. A n I D M C will m o nit or t he safet y data re g ularl y t hr o u g h o ut t he st u d y, a n d 
pr o vi de rec o m me n dati o ns at t he pre -d efi ne d ti me p oi nt base d o n t he data (s ee Secti o n 4. 1. 3. 2 ).   
1. 1 0.   
A me n d me nt Hist o r y 
1. 1 0. 1.   
A me n d me nt 1  
T he reas o n s f or a m e n di n g t he pr ot o c ol are as f oll o ws:     
1.  T he d oc u me nt was e dite d t o clarif y pr ot oc ol pr oce d ures, i m pr o ve i nter nal c o nsiste nc y a n d, 
c o nse q ue ntl y, rea da bilit y a n d u n dersta n di n g.  
2.  S o me of t he details w ere re m o ve d fr o m t he s y n o p sis as t he y are detaile d i n t he mai n b o d y 
of t he pr ot oc ol, t here b y re d uci n g d u plicati o n a n d ris k of err or.  
3.  T he Safet y Re vi e w C o m mittee c o m p ositi o n a n d f u ncti o n is descri be d i n t he s y n o psis as it 
is refere nce d earl y i n t he d oc u me nt. 
4.  T he f oll o wi n g s ecti o ns o f t he pr ot oc ol were re vise d a n d e dite d f or clarifi cati o n p ur p oses: 
a. T he rati o nale f or t he starti n g d oses of De bi o 1 5 6 2  (f or merl y I M G N 5 2 9) a n d 
rit u xi ma b 
V V- T M F- 5 1 6 1 9 | Pa ge 3 4/ 1 1 2

Pr ot oc ol  
 
Pa ge 3 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
b.  T he rati o nale f or t he st u d y pla n  
c. T he St u d y Desi g n  
d.  St u d y Dr u g A d mi nistrati o n  
e. Ma na ge me nt g ui deli nes f or i nf usi o n reacti o n 
f. P K Assess me nts  
g.  E C G pr oce d ures  
h.  Ra di ol o gic i ma gi n g a n d t u m or res p o nse ass ess me nt g ui deli nes  
5.  T he o bjecti ves a n d e n d p oi nts were e dite d f or clarit y a n d o ne of t he e x pl orat or y o bjecti ves 
was e x pa n de d 
; 
t he c orres p o n di n g e n d p oi nt was re vise d acc or di n gl y. 
6.  Re visi o ns were ma de t o t he I ncl usi o n a n d E xcl usi o n Criteria.  
7.  T he T o xicit y Ma n a ge me nt G ui deli nes, i ncl u di n g t he secti o ns of t he pr ot oc ol descri bi n g 
d ose m o dificati o ns a n d A E assess me nts, were re vise d t o i m pr o ve i nter nal c o nsiste nc y a n d 
t o defi ne “ D os e M o dif yi n g E ve nts ”. 
8.  T he g ui deli nes f or patie nt disc o nti n uati o n a n d c ollecti o n of s u bse q ue nt  a nti-ca ncer t hera p y 
were  re vise d. 
9.  T he he mat ol o g y a n d ser u m c he mistr y assess me nts wer e str ea mli ne d.  
1 0.  T he secti o n of t he pr ot oc ol detaili n g t he st u d y acti vities was delete d e ntirel y.  
1 1.  T he secti o n of t he pr ot oc ol descri bi n g rec or ds ret e nti o n was strea mli ne d.  
1 2.  M issi n g refere n ces w ere a d de d t o t he pr ot oc ol. 
1 3.  T he Sc he d ule of E v e nts was  re vise d. 
1 4.  T he  A n n Ar b or Sta gi n g Criteria ( wit h C ots w ol d M o dificati o ns) were a d de d t o t he pr ot oc ol.  
1. 1 0. 2.   
A me n d me nt 2  
T he pr ot oc ol was a me n de d f or a d mi nistrati ve reas o ns as t he o w ners hi p of I M G N 5 2 9 was 
tra nsferre d fr o m I m m u n o Ge n I nc. t o D e bi o p har m I nter nati o nal S. A.  
As a res ult, t he f oll o wi n g c ha n ges w ere m a de:  
 T he S p o ns or na me a n d a d dress were  u p date d  
 T he c o ntact me di cal direct or’s na me a n d a d dress were u p d ate d  
 Pr o d uct i de ntifier was c h a n ge d fr o m I M G N 5 2 9 t o De bi o 1 5 6 2 t hr o u g h o ut t he d oc u me nt  
 St u d y n u m b er was c ha n ge d fr o m 0 3 0 2 t o De bi o 1 5 6 2 -2 0 1 t hr o u g h o ut t he d oc u me nt  
1. 1 0. 3.   
A me n d me nt 3  
T he reas o ns f or a m e n di n g t he pr ot o c ol are as f oll o ws : 
 T o c o nfi ne t he p atie nt p o p ulati o n t o t h ose wit h rela pse d D L B C L i n st u d y P art 2 (co h ort s 
A a n d  B) a n d st u d y P art 3, t o ha ve a m ore h o m o ge ne o us p o p ulati o n f or dat a a nal ysis.  
V V- T M F- 5 1 6 1 9 | Pa ge 3 5/ 1 1 2

Pr ot oc ol  
 
Pa ge 3 6  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 T o a d d a n ar m t o i n vesti gate a ne w Q W  De bi o 1 5 6 2 d osi n g sc he d ule (co h ort B) w hile 
mai ntai ni n g t he c urre nt Q 3 W De bi o 1 5 6 2 d osi n g ar m  (co h ort A) , wit h o ut i ncreasi n g t he 
c u m ulati ve De bi o  1 5 6 2 d ose c ur rentl y all o we d i n t he pr ot oc ol ( i.e., 0. 7 m g/ k g –  1. 0 m g/ k g  
Q 3 W ). 
 T o c ha n ge t he fi x e d st u d y desi g n t o a n a d a pti ve desi g n i n or der t o utilize t he ge n erat e d data 
t o esta blis h a d osi n g re gi me n ass ociate d wit h o pti mal be nefit-ris k. 
 T o a d d bl o o d sa m pli n g ti me p oi nts t o i m pr o ve e val uati o n of P K dis p ositi o n . 
 
 
 T o a d d H R Q o L assess me nt .  
1. 1 0. 4.   
A me n d me nt 4  
T he mai n reas o n f or a m e n di n g t he pr ot oc ol was  t o reflect t he f oll o wi n g c ha n ges re q ueste d b y 
re g ulat or y healt h a ut h orities d uri n g t he re vie w pr ocess of t he pre vi o us pr ot oc ol .  
 T o u p date eli gi bilit y criteria t o e x cl u de patie nts c urre ntl y prese nti n g i nterstitial l u n g 
disease, diff use pare n c h y m al l u n g disease, or wit h a past hist or y of se v ere/ Gra de 3 
pare nc h y m al l u n g dis or d er  
 T o  e xte n d t he peri o d of m o nit ori n g t o 4 h o urs after c o m pleti o n of t he rit u xi ma b i nf usi o n 
f or t he first c ycl e 
 T o i ntr o d uce a ne w secti o n of ris k mi ni mizati o n meas ures f or t h e e x pecte d seri o us 
a d verse reacti o ns  
I n a d diti o n, Secti o n 5. 9  was re vise d f or clarificati o n p ur p oses.  S o me mi n or c ha n ges are als o 
i ncl u de d i n ot her secti o ns of t he pr ot oc ol f or clarificati o n a n d t o i m pr o ve c o nsiste nc y. 
 
1. 1 0. 5.   
A me n d me nt 5  
T he mai n reas o n f or a me n di n g t he pr ot oc ol is t o a d dress t he p ote ntial f or e x ce pti o nal i n di vi d ual 
patie nts’ st u d y treat me nt pr ol o n gati o n be y o n d 6 c ycles , pr o vi de d t he p atie nt is be nefitti n g fr o m 
t he st u d y treat me nt a n d after disc ussi n g a n d a gree me nt wit h t he St u d y S p o ns or.  
F urt her m ore, t his pr ot oc ol a me n d me nt als o a d dresses t he f oll o wi n g:  
 T o clarif y st u d y treat me nt d urati o n a n d t he c o n diti o ns u n der w hic h treat me nt d urati o n 
ma y b e pr ol o n ge d f or p atie nts w h o e x ce pti o nall y c o nti n ue st u d y treat me nt be y o n d 6 
c ycles ( Secti o n  4. 1. 1 ) 
 T o clarif y t h e fre q ue n c y a n d i ma gi n g 
m o d alit y of ra di ol o gic t u m or res p o nse 
assess me nts f or patie nts w h o e x ce pti o nall y c o nti n ue st u d y treat me nt be y o n d 6 c ycles 
( Secti o n 8. 1 4 ) 
 T o clarif y last ti me p oi nt of P K, I m m u n o ge nicit y 
 Assess me nts 
at C ycle 7 Da y 1 ( C 7 D 1), i nstea d of E n d of Treat me nt ( E O T) visit a n d wit h n o a d diti o nal 
sa m ples ta ke n at 3 0-da y f oll o w -u p visit f or patie nts w h o e x ce pti o nall y c o nti n ue wit h 
treat me nt be y o n d 6 c ycles ( Secti o ns 6. 1 ; Secti o n 6. 2 ; Secti o n 6. 3 ; A p pe n di x  E , 
A p pe n di x  F  
)  
V V- T M F- 5 1 6 1 9 | Pa ge 3 6/ 1 1 2

Pr ot oc ol  
 
Pa ge 3 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 T o clarif y last ti me p oi nt of assess me nts of H R Q o L at C 7 D 1: i nstea d of E O T visit a n d 
wit h n o a d diti o nal H R Q o L assess me nt t o be c o m plete d at 3 0 -da y f oll o w -u p visit f or 
patie nts w h o e x ce pti o na ll y c o nti n ue wit h treat me nt be y o n d 6 c ycles ( Secti o n 8. 8 ) 
 T o clarif y t hat pri mar y a nal ysis will be c o n d u cte d after all e nr olle d patie nts reac h t h eir 
3r d o n -treat me nt sc he d ul e d res p o ns e assess me nt or ha ve disc o nti n ue d fr o m treat me nt. 
T he fi nal a n al ysis will be tri g gere d o ne year after t he last accr ue d patie nt’s first d ose 
date.  I n t he e x ce pti o nal case t hat after t he fi nal a nal ysis a patie nt(s) mi g ht c o nti n ue t o 
recei v e st u d y treat me nt u n der t he pr ot oc ol, a n y s u bse q ue nt data ge nerate d fr o m t his 
patie nt(s) will be s u m marize d i n a n a d de n d u m re p ort t o be iss ue d after t h e last treat me nt 
of t he last patie nt ( Secti o n 1 0 ). 
 A P P E N DI C E S A -C: Sc h e d ule of e v e nts were re vise d f or clarificati o n p ur p oses.  
 
 Clarificati o n was ma de re gar di n g t he s e parate t u bes use d f or bl o o d dra w f or P K 
assess me nt a n d f or a nti -dr u g a n ti b o dies ( A D A).  
 
 Clarificati o n t hat t he p ote ntial i m m u n o ge nicit y a gai nst rit u xi ma b will be assesse d.  
 
 S o me mi n or c ha n ges are als o i ncl u de d i n ot her secti o ns of t he pr ot oc ol t o i m pr o ve 
clarit y a n d c o nsiste nc y.  
 
Base d o n t h e c ha n ges a b o ve, t his a me n d me nt is  c o nsi dere d s u bsta ntial, re q uiri n g a p pr o val b y 
Et hics C o m mittees a n d Re g ul at or y A ut h orities bef ore i m ple me ntati o n.  
 
1. 1 0. 6.   
A me n d me nt 6  
I n a n eff ort t o mi ni mize t he ris k of C O VI D-1 9 i nfecti o n f or patie nts partici pati n g i n t he st u d y , 
t he S p o ns or deci de d t hat i n t he  i nterest of patie nt s afet y it is best t o all o w t o s witc h patie nts w h o 
are o n t he Q W  De bi o 1 5 6 2 d osi n g re gi me n t o t he Q 3 W. T he s witc h fr o m t he Q W t o Q 3 W 
re gi me n is n ot e x pecte d t o res ult i n a n y d etri me ntal effect o n safet y or effi cac y f or t h ese patie nts, 
b ase d o n rece nt a nal ysis of preli mi nar y st u d y data.  
If a s witc h t o t he Q 3 W re gi me n is c o nsi dere d b y t he treati n g p h ysi cia n t o b e i n t he b est i nterest of 
a gi v e n patie nt t o miti gat e t he C O VI D -1 9 ris k, t he f oll o wi n g s h o ul d be o bs er ve d : 
 t he patie nt m ust ter mi nat e his/ her o n g oi n g wee kl y a d mi nistrati o n c ycle b ef ore s witc hi n g 
t o t he Q 3 W re gi me n. F or i nsta nce, if t he patie nt recei ve d his/ her first wee kl y a d mi nistrati o n 
of 0. 4 m g/ k g ( D 1), he/s he s h o ul d c o nti n ue t o recei ve wee kl y treat me nt u nti l t he e n d of t hat 
c ycle. O nl y t he n, t he pati e nt ca n start t he Q 3 W d osi n g re gi me n ( 0. 7 m g/ k g). p atie nts w h o 
s witc h s h o ul d c o nti n ue t o recei v e t he Q 3 W re gi m e n f or t he re mai nder  of t he st u d y.  
 T his will re d uce t he n u m ber of visits t o t he h os pital. T heref ore, r e d u ci n g t he e x p os ure of 
patie nts t o a p ote ntial ris k of c o nta mi nati o n, w hile e ns uri n g a de q u ate treat me nt. T he 
meas ure ta ke n will als o r e d uce t he b ur de n at t he trial sites d uri n g t he pa n d e mic.  
As of A pril 1 4, 2 0 2 0, patie nts w h o are o n treat me nt wit h Q W d ose  re gi me n were gra nte d 
per missi o n t o s witc h t o t he Q 3 W re gi me n b y  t he S p o ns or i n t he ir best i nterest.  St u d y e nr oll me nt 
has bee n c o m plet e d.  
V V- T M F- 5 1 6 1 9 | Pa ge 3 7/ 1 1 2

Pr ot oc ol  
 
Pa ge 3 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
A p ote ntial s witc h of o n g oi n g patie nts recei vi n g Q W re gi me n t o a Q 3 W is n ot a ntici pate d t o i m pact 
t he pri mar y a n al ysis. N o net heless, a se nsiti vit y a nal ysis  will be perf or me d t o i de ntif y a n y p ote ntial 
i m pact. 
C o nsi deri n g t hat C O VI D -1 9 prese nts a n i m mi ne nt p ote ntial ris k f or t he patie nts, t his c ha n ge was 
alrea d y i m ple me nt e d as a n Ur ge nt Safet y M eas ure, of i m me diate effect. I n or der t o c o m pl y wit h 
rele va nt re g ulati o ns, this  s u bsta ntial pr ot oc ol a me n d me nt is bei n g s u b mitte d t o all rele va nt 
Re g ulat or y A ge nci es a n d Et hic C o m mittees , f oll o wi n g l ocal re g ulati o ns. 
As access t o st u d y sites b y st u d y/s p o ns or m o nit ors c o ul d be diffic ult or i m p ossi ble d uri n g t he 
C O VI D -1 9 pa n de mic, re m ote m o nit ori n g will be all o we d, if p ossi ble, a n d acc or di n g t o l ocal 
re q uire me nts. 
S o me mi n or e dits are als o i ncl u de d i n A p pe n di x  E a n d A p pe n di x  F t o i m pr o ve t he clarit y a n d 
c o nsiste nc y of  P K a n d A D A  assess me nt s i n t he pr ot oc ol. 
V V- T M F- 5 1 6 1 9 | Pa ge 3 8/ 1 1 2

Pr ot oc ol  
 
Pa ge 3 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
2.   
S T U D Y  O B J E C TI V E S A N D E N D P OI N T S  
2. 1.   
O bjecti ves  
2. 1. 1.   
Pri m ar y O bjecti ve s 
 Deter mi ne t he safet y a n d t olera bilit y of t he pr o p ose d De bi o 1 5 6 2  d ose re gi me ns  i n 
c o m bi nati o n wit h rit u xi ma b  
 Deter mi ne t he a nti-t u m or acti vit y of t he pr o p ose d De bi o 1 5 6 2 d ose re gi me ns  i n 
c o m bi nati o n wit h rit u xi ma b  
2. 1. 2.   
Sec o n d ar y O bjecti ves  
 C haracterize t he P K  of De bi o 1 5 6 2  i n c o m bi nati o n wit h rit u xi ma b   
 Deter mi ne ti me t o e ve nt o utc o mes [P F S, ti me t o res p o nse, D o R, a n d O S ] 
 Assess t he i m m u n o ge nicit y of De bi o 1 5 6 2  ( A D A) w he n a d mi nistere d i n c o m bi nati o n 
wit h rit u xi ma b. 
2. 1. 3.   
E x pl or at or y O bjecti ves  
 C orrelate t he e xte nt of C D 3 7 a n d C D 2 0 a nti ge n e x pressi o n i n t u m or sa m ples wit h a nti -
t u m or acti vit y of t he De bi o 1 5 6 2 a n d rit u xi ma b c o m bi nati o n.  
 
 
 
 
 
 
 
 
 
 
 Assess H R Q o L.  
2. 2.   
E n d p oi nts  
2. 2. 1.   
Pri m ar y E n d p oi nts  
 T E A Es, cli nicall y  si g nifi ca nt c ha n ges i n cli nical la b orat or y test res ults, E C G a n d vital 
si g n meas ure me nts  
 N u m ber of patie nts wit h cli nical res p o nses  ( O R R) as assesse d b y t he L u ga n o 
Classificati o n of res p o ns e assess me nts ( A p pe n di x  I) 
2. 2. 2.   
Sec o n d ar y E n d p oi nts  
 P K para m eters  (e v al uate d as d ee me d a p pr o priate b ut n ot li mite d t o) : Cma x , A U C0 -t, 
A U C i nf, ter mi nal half-life (t½ ), CL , Vss, Tma x , f or b ot h De bi o 1 5 6 2  a n d rit u xi ma b  
 Calc ul ati o n of ti me t o e ve nt para met ers : 
V V- T M F- 5 1 6 1 9 | Pa ge 3 9/ 1 1 2

Pr ot oc ol  
 
Pa ge 4 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 P F S  a n d O S  
 Ti me t o res p o nse  a n d d urati o n of res p o nse  
 I m m u n o ge nicit y of De bi o 1 5 6 2 : p rese nce of h u m a n A D A  
2. 2. 3.   
E x pl or at or y E n d p oi nts  
 E x pressi o n le vels of C D 3 7 , C D 2 0 b y I H C (pr otei n)  a n d/ or m R N A detecti o n  a n d 
c orrel ati o n of t hese meas ures t o cli nical res p o ns e criteria.  
 
 
  
 
 
 
 
 
 
 
 
 H R Q o L will be assesse d t hr o u g h a nal ysis of patie nt re p orte d F u n cti o nal Assess me nt 
of Ca ncer T hera p y -L y m p h o ma ( F A C T -L y m) sc ores. 
 
V V- T M F- 5 1 6 1 9 | Pa ge 4 0/ 1 1 2

Pr ot oc ol  
 
Pa ge 4 1  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
3.   
S T U D Y P O P U L A TI O N  
3. 1.   
Criteri a f or Selecti o n of P atie nt P o p ul ati o n  
I ncl usi o n Criteri a  
1)  F or Par t 1 of t he st u d y, patie nts m ust ha ve hist o pat h ol o gicall y c o nfir me d dia g n osis of R/ R 
D L B C L, F L, M Z L/ M A L T, M C L, or ot her S p o ns or a p pr o ve d N H L s u bt y pes acc or di n g t o t he 
W H O classificati o n 2 0 0 8 f or w hic h sta n dar d meas ures d o n ot e xist or are n o l o n ger effecti ve.   
2)  F or P art 2 a n d P art 3 of t he st u d y, p atie nts m ust ha ve hist o pat h ol o gicall y a n d cli nicall y 
c o nfir me d di a g n osis of rela pse d D L B C L . Patie nts will be c o nsi dere d t o ha ve a rela pse d 
disease if t he y s h o w e d a d urati o n of res p o ns e of at least 2 4 wee ks after t heir first li ne of 
t hera p y. T he f oll o wi n g p atie nts wit h rela pse d D L B C L will be e nr olle d: 
i. Patie nts w h o recei ve d o nl y o n e li ne of pre vi o us t hera p y a n d ac hie ve d eit her 
c o m plete res p o nse ( C R) or partial res p o nse  ( P R) f or at least 2 4 wee ks (fr o m 
t he last da y of t he last c ycl e) after t heir first li ne of t hera p y, b ut are n ot 
eli gi ble f or 
hi g h 
d os e c he m ot hera p y 
wit h a ut ol o g o us st e m cell 
tra ns pla ntati o n ( H D-A S C T)  
ii. Patie nts w h o recei ve d m ore t ha n o n e li ne of pre vi o us t hera p y (i ncl u di n g 
H D -A S C T), a n d ha v e ac hie ve d a d urati o n of res p o nse ( C R or P R) of at least 
8 wee ks (fr o m t he last da y of t he l ast c ycle) after t heir last li ne of t hera p y.  
3)  Patie nts m ust ha ve recei ve d n o m ore t ha n si x pri or treat me nt re gi me ns.  Pri or treat me nt 
wit h a n a nti -C D 2 0 a ge nt, eit her al o ne or i n c o m bi nati o n, is all o we d.  
4)  Patie nts m ust be ≥ 1 8 years.  
5)  Patie nts m ust ha ve E C O G Perf or ma nce Stat us 0 - 2.  
6)  Patie nts m ust meet t he f oll o wi n g la b orat or y crite ria: 
 A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1. 0 x 1 0 9/ L ( 1 0 0 0/ m m3) 
 Platelet c o u nt ≥ 5 0 x 1 0 9/ L ( 5 0, 0 0 0/ m m3; patie nts m ust n ot ha ve bee n tra nsf use d 
wit hi n 1 0  da ys  pre vi o us of bl o o d dra w n  f or la b orat or y assess me nt) 
 Patie nts recei vi n g t hera pe utic a ntic oa g ul ati o n a re eli gi ble pr o vi de d t heir 
a ntic oa g ulati o n para m eters are wit hi n ra n ge (e. g. I nter nati o nal N or malize d Rati o 
[I N R] 2 -3 o n C o u ma di n if a p plica ble) a n d t he y ha ve n o hist or y of ≥ Gra de 2 
blee di n g w hile o n a ntic o a g ul ati o n t hera p y  
 F or p atie nts receivi n g t her a pe utic d oses of a ntic o a g ul ati o n: Platelet c o u nt ≥ 1 0 0 
x 1 0 9/ L ( 1 0 0, 0 0 0/ m m3; m ust n ot ha ve bee n tra nsf use d wit hi n pre vi o us 1 0 da ys)  
 He m o gl o bi n ≥ 8. 0 g/ d L ( ma y h a ve bee n tra nsf use d)  
 Ser u m creati ni ne ≤ 2. 0 x u p per li mit of n or mal ( U L N) or 2 4 -h o ur creati n i ne 
cleara nce of ≥ 6 0 m L/ mi n ute  
 A S T ≤ 2. 5 x U L N; A L T ≤ 2. 5 x U L N a n d  
V V- T M F- 5 1 6 1 9 | Pa ge 4 1/ 1 1 2

Pr ot oc ol  
 
Pa ge 4 2  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 T otal bilir u bi n ≤ 1. 5 x U L N; patie nts wit h d o c u me nte d dia g n osis of Gil bert 
s y n dr o me are eli gi ble if t otal bilir u bi n ≤ 3. 0 x U L N . 
7)  Patie nts m ust ha ve e val ua ble or me as ura ble disease i n acc or da nce wit h t he I nter n ati o nal 
W or ki n g Gr o u p G ui deli n es f or L y m p h o ma ( C hes o n 2 0 1 4 ). 
8)  Patie nts w h o are He patitis B s urface a nti ge n ( H Bs A g ) + ( m ust be p ol y merase c hai n 
reacti o n [P C R ] ne gati ve) w h o are ta ki n g a nti virals are all o we d t o e nr oll.  
9)  Male patie nts a n d fe mal e patie nts  of c hil d beari n g p ote ntial partici pati n g i n t his st u d y m ust 
a gree t o use t w o hi g hl y effecti ve met h o ds of c o ntrace pti o n t hr o u g h o ut t h e st u d y a n d f or at 
least 1 2 wee ks after t he last d ose of De bi o 1 5 6 2 a n d 1 2 m o nt hs after t he last d ose of 
rit u xi ma b.  E x a m ples of acce pta ble birt h c o ntr ol met h o ds i ncl u de b ut are n ot li mite d t o t he 
f oll o wi n g met h o ds: (e. g., oral, pare nteral, or i m pla nta ble h or m o nal c o ntrace pti ve; t u bal 
li gati o n; i ntra-uteri ne  d e vice; barri er c o ntrace pti ve wit h s per mici de; part ner’s late x 
c o n d o m or vasect o m y).  
1 0)  Patie nts m ust be willi n g t o pr o vi de i nf or me d c o nse nt a n d be willi n g t o c o m pl y wit h t he 
st u d y pr ot oc ol. 
1 1)  Patie nts m ust ha ve a vaila ble a pat h ol o g y -i nf or m e d fres h or arc hi v e d t u m or tiss ue bi o ps y 
reflecti n g t he c urre nt D L B C L disease. If t he tiss ue bi o ps y is ol der t ha n 1 8 m o nt h s fr o m t he 
scree ni n g visit a n d a fres h o ne ca n n ot be a vaila ble , patie nts s h o ul d pr o vi de fi ne nee dle 
as pirati o n ( F N A) sa m ples.  
E xcl usi o n Criteri a  
1)  Patie nts wit h a dia g n osis of C L L or S mall L y m p h oc ytic L y m p h o ma . 
2)  F or Part  2 a n d Part 3  of t he st u d y , patie nts wit h pri mar y refract or y D L B C L ( defi ne d as 
pr o gressi o n of diseas e wit hi n 2 4 wee ks  after fi rst li ne of treat me nt). 
3)  F or Part 2 a n d Part 3 of t h e st u d y , patie nts t hat are eli gi ble t o u n der g o first ti me H D-A S C T . 
4)  F or Part 2 a n d Part 3 of t he st u d y , patie nts wit h R/ R F L, M Z L/ M A L T, M C L, or a n y ot h er 
N H L s u bt y p es acc or di n g t o t he W H O classificati o n  
5)  T he  f oll o wi n g e x cl usi o ns, wit h re gar d t o pri or t h era p y a p pl y: 
 N ot rec o vere d fr o m pri or c he m ot hera p y or ra diati o n  as per I n vesti gat or’s j u d g me nt .  
 A nti -C D 2 0 
m o n ocl o nal a nti b o d y t hera p y 
wit hi n 1 4 da ys of starti n g st u d y 
treat me nt. 
 Pri or t hera p y wit h ot her a nti-C D 3 7 -tar geti n g t hera p y. 
 Ra di oi m m u n ot hera p y wit hi n t w o m o nt hs pri or t o starti n g st u d y treat me nt.  
 S mall m olec ule a nti -ca n cer t hera pe utic a ge nt, a n d all i n vesti gati o nal a ge nts wit hi n 
5 x t 1/ 2 or 1 4 da ys w hic he ver is s h orter.  
 All o ge n eic ste m cell tra ns pla ntati o n i n t he s afet y r u n -i n peri o d. I n Part 2 a n d Part 
3 of t he st u d y, patie nts w h o ha ve ha d a n all o ge neic ste m cell tra ns pla nt ma y be 
eli gi ble if t heir G V H D is c o ntr olle d, after i n vesti gat or/ S p o ns or disc ussi o n.   
V V- T M F- 5 1 6 1 9 | Pa ge 4 2/ 1 1 2

Pr ot oc ol  
 
Pa ge 4 3  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 C hr o nic, s yste mic tr eat m e nt wit h c ortic ost er oi ds u nless t he d ose has bee n sta ble f or 
> 7 da ys a n d is e q ui val e nt t o ≤ 1 0 m g of pre d nis o n e per da y.   
 Patie nts w h o ha ve n ot rec o vere d fr o m pri or s ur ger y.  Patie nts m ust ha v e rec o vere d 
or sta bilize d fr o m t he si d e effects of a n y m aj or or mi n or s ur gical pr oce d ures pri or 
t o st u d y treat me nt.  
6)  Patie nts w h o ha v e ha d a pri or a n a p h yl actic or ot h er se v ere i nf usi o n reacti o n s uc h t hat t he 
patie nt is u na ble t o t olerate a nti b o d y a d mi nistrati o n.  
7)  Patie nts w h o ha ve k n o w n ce ntral ner v o us s yste m, me ni n geal, or e pi d ural dis ease i ncl u di n g 
brai n metastases.  
8)  Patie nts w h o ha ve recei v e d or are t o recei ve vacci nati o n wit h li ve vir uses wit hi n 3 0 da ys 
of C ycl e 1 Da y 1.  
9)  I m paire d car diac f u ncti o n or cli nicall y si g nifica nt car diac disease s u c h as: 
 Ne w Y or k Heart Ass ociati o n Class III or I V car diac disease, i ncl u di n g pree xisti n g 
cli nicall y si g nifi ca nt 
v e ntric ular arr h yt h mia, c o n gesti ve 
h eart fail ure, 
or 
car di o m y o pat h y;  
 U nsta ble a n gi na pect oris ≤ 6 m o nt hs pri or t o starti n g st u d y treat me nt;  
 Ac ute m y oc ar dial i nfarcti o n ≤ 6 m o nt hs pri or t o starti n g st u d y treat me nt; or  
 Ot her cli nicall y si g nifica nt heart diseas e e. g., ≥ gra de 3 h y p erte nsi o n, hist or y of 
la bile h y p erte nsi o n, or hist or y of p o or c o m pli a nce wit h a n a nti h y perte nsi ve 
re gi me n. 
1 0)  Patie nts wit h ≥ Gra de 2 peri p heral ne ur o pat h y.  
1 1)  Patie nts wit h acti ve he patitis A, B or C i nfecti o n.  
1 2)  U nc o ntr olle d i nterc urre nt ill ness, i ncl u di n g b ut n ot li mite d t o, o n g oi n g or acti ve i nfecti o n, 
ps yc hiatric ill ness t hat 
w o ul d li mit c o m plia nce 
wit h st u d y re q uire me nts, acti v e 
a ut oi m m u ne disease re q uiri n g i m m u n os u p pressi ve t hera p y, se v ere i m m u ne deficie nc y. 
1 3)  K n o w n dia g n osis of HI V i nfecti o n.  
1 4)  Patie nts wit h a c o nc urre nt pri mar y mali g na nc y t hat re q uires treat me nt or t hat w o ul d 
c o nf o u n d t he diseas e res p o nse i nter pretati o n f or t he disea se u n d er st u d y. 
1 5)  W o me n of c hil d beari n g p ote ntial  w h o are pre g na nt or breast f ee di n g.  
1 6)  Patie nts c urre ntl y pres e nti n g i nterstitial l u n g disease , diff use pare nc h y m al l u n g diseas e, or 
wit h a past hist or y of se v ere/ Gra de 3 p are n c h y m al l u n g dis or ders . 
 
V V- T M F- 5 1 6 1 9 | Pa ge 4 3/ 1 1 2

Pr ot oc ol  
 
Pa ge 4 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
4.   
I N V E S TI G A TI O N A L P L A N 
4. 1.   
St u d y Desi g n  
4. 1. 1.   
O ver vie w  
T his is a n o pe n la bel, m ultice nter, a da pti ve P hase 2 cli nical st u d y of De bi o 1 5 6 2 i n c o m bi nati o n 
wit h rit u xi ma b i n patie nts wit h D L B C L a n d ot her s u bt y pes of  B -cell N H L.   
F or eac h partici p ati n g patie nt, t he st u d y will i ncl u de a scree ni n g peri o d, a treat me nt peri o d, a n d a 
f oll o w-u p peri o d.  
T he st u d y c o nsists of t hree parts: 
 
S afety R u n -In ( P art 1)  
Patie nts wit h D L B C L, F L, M C L, M Z L/ M A L T or ot her N H L s u bt y pes ( wit h S p o ns or’s a p pr o val) 
will be  eli gi ble f or e nr oll me nt i n t he  safet y r u n-in part of t he st u d y. D uri n g t he s afet y r u n -i n, at 
least si x D L B C L a n d si x F L N H L p atie nts will be e nr olle d.  
Patie nts will be gi ve n De bi o 1 5 6 2 a n d rit u xi ma b I V o n t he sa me da y (i.e., Da y 1) Q 3 W. De bi o 
1 5 6 2 will be gi ve n at a d ose of 0. 7 m g/ k g, f oll o we d b y 3 7 5 m g/ m 2 of rit u xi ma b.  
F oll o wi n g re vie w of safet y a n d P K d ata b y a S R C (c o m prise d of t h e S p o ns or’s Me dical Direct or 
a n d I n vesti gat ors fr o m p artici pati n g sites) o nce t h e last patie nt of t he s afet y r u n -i n has c o m plete d 
1 c ycl e of tr eat me nt, t he S R C will ma ke a rec o m me n dati o n t o eit her st o p t he st u d y f or u n acce pta ble 
safet y, or c o nti n ue t h e Q 3 W d osi n g sc he d ule wit h t he 0. 7 m g/ k g d ose of De bi o 1 5 6 2 or a n alter nate 
hi g her ( 1. 0 m g/ k g) or l o wer d ose of De bi o 1 5 6 2  (Secti o n 4. 1. 3. 1 ). 
T his part of t he st u d y h as bee n c o m plete d a n d t he S R C rec o m me n de d c o nti n uati o n of t he st u d y.  
I niti al Assess m e nt of S afety a n d Effic acy of Q 3 W a n d Q W D osi n g Re gi m e ns ( P art 2) 
D uri n g Part 2 of t he st u d y, o nl y patie nts  wit h rel a pse d D L B C L will be e nr olle d i nt o t w o parallel 
c o h orts acc or di n g t o t he d osi n g re gi me n of De bi o 1 5 6 2 : co h ort A ( 2 1 -da y treat me nt c ycle wit h a 
Q 3 W d osi n g sc he d ule) a n d co h ort B ( 2 1-da y c ycl e treat me nt c ycles wit h a Q W d osi n g sc he d ule).  
Patie nt s i n co h ort A  will recei v e De bi o 1 5 6 2 a n d rit u xi ma b I V o n t he sa me da y ( Da y 1) o n a Q 3 W 
d osi n g sc he d ule. De bi o 1 5 6 2 will be gi ve n at a d ose of 0. 7 m g/ k g ( u nless rec o m me n de d ot her wise 
b y t he S R C), f oll o we d b y 3 7 5 m g/ m 2 of rit u xi ma b.  
C o h ort B  will e x pl ore a Q W d osi n g sc he d ule of De bi o 1 5 6 2: 0. 4, 0. 2, a n d 0. 2 m g/ k g of 
De bi o  1 5 6 2  will be a d mi nistere d I V t o patie nts o n Da y 1, Da y 8 a n d Da y 1 5 of a 2 1 -da y treat me nt 
c ycle, res pecti vel y. Rit u xi ma b will be a d mi nistere d I V at a d ose of 3 7 5 m g/ m 2 o n Da y 1 of eac h 
treat me nt c ycl e (f oll o wi n g De bi o 1 5 6 2 a d mi nistrati o n).  After a me n d me nt # 6 ( Secti o n 1. 1 0. 6), 
patie nts recei vi n g a Q W re gi me n were all o we d t o s witc h t o Q 3 W re gi me n.  
A n I D M C (c o m prise d of i n de pe n d e nt e x perts i n t he fiel d of he m at ol o g y, o nc ol o g y, P K  a n d 
bi ostatistics)  will perf or m re g ular re vie ws of c u m ulati ve safet y, efficac y, a n d P K data i n b ot h 
co h ort s A a n d B ( Secti o n  4. 1. 3. 2 ). 
V V- T M F- 5 1 6 1 9 | Pa ge 4 4/ 1 1 2

Pr ot oc ol  
 
Pa ge 4 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
I n s u m mar y: f or co h ort A, a f utilit y a n al ysis will be perf or me d after 1 0 patie nts are e val ua ble f or 
efficac y ( i.e., p atie nts s h o ul d ha ve p erf or me d at least o n e p ost bas eli ne o bjecti ve res p ons e 
assess me nt - u nless t her e is e arlier cle ar evi de nce of P D ). A d diti o nall y, t h e t otalit y of t he safet y 
data f or t his d ose re gi me n will be re vie we d b y t he I D M C w h o ca n rec o m me n d t o ter mi nate or 
m o dif y t h e d osi n g re gi m e n i n case of u nacce pt a ble safet y. If f utilit y is met a n d/ or safet y pr ofile is 
u nacce pta ble as d eter mi n e d b y t h e I D M C, t his c o h ort will be st o p p e d. Ot h er wise, a n a d diti o nal 5 
patie nts will be e nr olle d a n d a s u bse q ue nt f utilit y a nal ysis will be perf or me d after 1 5 e val ua ble 
patie nts f or efficac y.  Si milarl y, t h e c u m ulati ve s afet y d ata f or t his d ose re gi me n will be re vie we d 
b y t he I D M C. If f utilit y is met a n d/ or safet y pr ofile is u nacce pta ble, t his c o h ort will be st o p pe d. 
Ot her wise, de p e n di n g o n t he e val uati o n o f t he t otalit y of d ata i n b ot h co h orts  ( A a n d B), a 
rec o m me n dati o n ma y be ma de b y t he I D M C t o c o nti n ue wit h t he e x pa nsi o n (st u d y Part 3) usi n g 
t he sa me d osi n g re gi me n as i n co h ort A.  
F or c o h ort B, t he re will be n o f utilit y a nal ysis, h o we ver a n i nte nse safet y o versite b y I D M C will 
be perf or me d . At mi ni m u m, I D M C will c o n d uct re vie ws at t he f oll o wi n g ti me p oi nts: 
1)  A n i nitial re vie w of safet y d ata o nce t he first 3 p atie nts ha ve recei ve d at least o n e c ycl e of 
treat me nt  
2)  A s u bse q ue nt re vie w of safet y,  a vaila ble  P K a n d effi cac y data  after 6 patie nts w ill ha ve 
c o m plete d 2 c ycles of treat me nt, wit h a  rec o m me n dati o n t o:  
a. St o p t his c o h ort i n case of u nacce pta ble s afet y  
b.  E nr oll 6 m ore patie nts i n or der t o o btai n m ore d ata, or  
c. E x pl ore a ne w Q W d osi n g sc h e d ule ( w hic h will n ot e x cee d t he t otal c u m ulati ve 
Q 3 W d ose of 1. 0 m g/ k g)  
3)  Re vie w of safet y, a v aila ble P K a n d efficac y data after 1 2 p atie nts will ha ve c o m plete d 2 
c ycles of tr eat me nt i n cas e data of a n a d diti o nal 6 patie nts are d ee me d n ecessar y (see p oi nt 
2 b a b o ve). T h e I D M C will t he n ma ke a rec o m me n dati o n t o:  
a. St o p t his c o h ort i n case of u nacce pta ble s afet y  
b.  E x pl ore a ne w Q W d osi n g sc h e d ule ( w hic h will n ot e x cee d t he t otal c u m ulati ve 
Q 3 W d ose of 1. 0 m g/ k g)    
c. C o nti n ue wit h e nr oll me n t of patie nts i n co h ort B i n t he e x pa nsi o n part (st u d y 
Part  3), de pe n di n g o n e v al uati o n o f t he t otalit y of data i n b ot h co h ort A a n d B  
If t he I D M C rec o m me n d t o e x pl ore a differe nt d ose, o nl y o ne ne w d ose re gi me n will be 
i n vesti gate d. I n s u c h case, t he t hr ee I D M C re vie ws des cri be d a b o ve will occ ur f or t his n e w 
re gi me n. 
Assi g n me nt of p atie nts t o c o h ort s A a n d B will be d o ne t hr o u g h a n  IW R S as f oll o ws:  
 1: 1 ra n d o mizati o n  w h e n b ot h co h orts are o p e n f or recr uit me nt  
 A ut o matic all ocati o n t o c o h ort A d uri n g I D M C re vie w of co h ort B  
Base d o n e val u ati o n of t he t otalit y of data a v aila bl e fr o m t he safet y r u n -i n Part 1 a n d Part 2 of t he 
st u d y, t he I D M C will ma ke a rec o m me n d ati o n o n c onti n uati o n wit h e n r oll me nt of patie nts i n eit her 
c o h ort A, co h ort B or b ot h c o h orts.  
V V- T M F- 5 1 6 1 9 | Pa ge 4 5/ 1 1 2

Pr ot oc ol  
 
Pa ge 4 6  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 
E x p a nsi o n ( P art 3)  
Part 3 of t he st u d y will e nr oll a d diti o nal rela pse d D L B C L p atie nts t o f urt her assess safet y, efficac y 
a n d P K of t he select e d d osi n g sc h e d ule (s) i n vesti gate d i n Part 2 of t he st u d y (i.e., si x 2 1-da y c ycles 
of Q 3 W a n d/ or Q W De bi o 1 5 6 2 d osi n g), as rec o m me n de d b y t he I D M C.  
I n t his st u d y p art, t he I D M C will c o nti n ue t o re vie w safet y, efficac y a n d P K data a vaila ble after 
e ver y 1 0 patie nts e nr olle d a n d treate d  f or at least 2 c ycles (Secti o n  4. 1. 3. 2 ).  
A sc he matic o ver vie w of t he st u d y desi g n is pr o vi de d i n Fi g ure 5  b el o w.  
I n t his st u d y, t he anti -t u m or acti vit y will be assesse d b y t he L u ga n o Classificati o n (A p pe n di x  I) 
a n d A Es will be gra d e d usi n g  C T C A E versi o n 4. 0 3  
Fi g ure 5 :  
Sc h e m atic O ver vi e w of t he St u d y Desi g n  
 
St u dy tre at m e nt d ur ati o n  
Patie nts will recei ve st u d y tr eat me nt f or si x 2 1 -da y c ycles, or u ntil t he y de vel o p u nacce pta bl e 
t o xicit y, wit h dra w c o ns e nt, or t he S p o ns or ter mi nates t he st u d y. Permissi o n t o pr ol o n g t he st u d y 
treat me nt c o ul d b e e x ce pti o nall y gra nte d b y St u d y S p o ns or  if patie nts are deri vi n g be n efit fr o m 
t he st u d y tr eat me nt a n d after c o m plete pres e ntati o n of t he i n di vi d ual case b y t he St u d y 
I n v esti gat or, p artic ularl y t he me dical j ustificati o n f or e xte n di n g t h e treat me nt a n d t he re-
assess me nt of t he ris k/ be nefit b ala nce. T he S p o ns or’s decisi o n will c o nsi der t he a vaila bilit y of 
i nvesti gati o nal me dici nal pr o d uct (I M P) at t he ti me of t he re q uest. A  re p ort of t he disc ussi o ns wit h 
t he S p o ns or m ust be file d i n t he s o urce d oc u m e ntati o n.  
Patie nts w h o dis pla y i nt olera bilit y t o t he c o m bi nati o n re gi me n ma y be eli gi ble t o c o nti n ue 
treat me nt wit h si n gle a ge nt De bi o 1 5 6 2 . 
V V- T M F- 5 1 6 1 9 | Pa ge 4 6/ 1 1 2

Pr ot oc ol  
 
Pa ge 4 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
4. 1. 2.   
Re pl ace me nt of P atie nts  
Patie nts w h o will n ot be e val ua ble f or safet y ma y  be re place d if  t he y: 
 Wit h dre w c o nse nt bef ore at least o ne c ycl e of st u d y treat me nt is c o m plete d  
 Are  disc o nti n ue d d ue t o h y perse nsiti vit y reacti o n o n Da y  1 of C ycle 1  
 D isc o nti n ue bef ore t he e n d of C ycl e 1 d ue t o: 
o  A Es u nrelate d t o st u d y treat me nt  
o  De vel o p me nt of ra pi d disease pr o gressi o n  
o  Deat h, u nrel ate d t o st u d y treat me nt  
4. 1. 3.   
S afet y  Re vie w C o m mittee  ( S R C) a n d I n de pe n de nt D at a M o nit ori n g 
C o m mittee (I D M C ) 
4. 1. 3. 1.  
S afet y Re vie w C o m mittee ( S R C)  
T he S R C , c o m prise d of t he S p o ns or’s Me dical Direct or  a n d I n v esti gat ors fr o m partici pati n g sites , 
is res p o nsi ble f or safet y data re vie w d uri n g t he c o urse of t he safet y ru n -i n ( Part 1).  D uri n g t he 
safet y ru n -i n, t he S R C  will meet e ver y 2 -4 wee ks b y t elec o nfere nce t o re vie w patie nt safet y 
u p dates.   
S afety Revie w F oll o wi n g t he S afety R u n -i n - P art 1 :  O nce t h e last pati e nt i n t he safet y  r u n-i n 
has c o m plete d o ne c ycle of st u d y treat me nt, e nr oll me nt will be p a use d a n d a n S R C meeti n g will 
be c o n v e ne d t o re vie w all a vaila ble safet y a n d P K data.  T he S R C will deter mi ne w het her t he 
De bi o 1 5 6 2 d ose of 0. 7 m g/ k g s h o ul d be e val uat e d i n t he ne xt  part o f t he st u d y, or w het h er a n 
alter nati ve d ose s h o ul d b e e val uat e d.  D uri n g t he safet y r u n -i n, t he S R C will re vie w t he a v aila ble 
safet y a n d P K data a n d ma y deci de t o escalate t he De bi o 1 5 6 2 starti n g d ose fr o m 0. 7 m g/ k g t o 1. 0 
m g/ k g, w hic h is o ne d ose le vel l o wer t ha n t he M T D defi ne d i n t he m o n ot hera p y st u d y, wit h 
gra n ul oc yte gr o wt h fact or s u p p ort.  If t he S R C deter mi nes at a n y ti me t hat t he d ose s h o ul d be 
re d uce d f or safet y reas o ns, a l o wer d ose of De bi o 1 5 6 2 will be e x pl ore d. 
4. 1. 3. 2.  
 I n de pe n de nt D at a M o nit ori n g C o m mittee (I D M C) 
T he I D M C , c o m prise d of i n de pe n de nt e x perts i n t he fiel d of he m at ol o g y, o nc ol o g y , a n d 
bi ostatistics , will be  res p o nsi ble f or t he re vie w of safet y, efficac y a nd P K data d uri n g t he c o urse 
of P art 2 a n d P art 3 of t h e st u d y.  
A t m ulti ple  ti me p oi nt s d uri n g t h e se st u d y p arts , a vaila ble safet y, (preli mi nar y ) P K  a n d a nti-t u m or 
acti vit y  data will be pr o vi de d f or re vi e w b y t he I D M C: 
F or  co h ort A  ( Part 2) : 
1.  O nce 1 0 patie nts are  e v al ua ble f or efficac y ( i.e., patie nts s h o ul d ha ve perf or me d at least 
o ne p ost baseli ne o bjecti ve res p o ns e ass ess me nt - u nless t here is e arlier cl e ar evi d e nce of 
P D ). E nr oll me nt i n t his c o h ort will c o nti n ue d uri n g t he  I D M C re vie w. 
2.  O nce 1 5  patie nt s are e v al ua ble f or efficac y ( i.e., patie nts s h o ul d ha ve perf or me d at least 
o ne p ost baseli ne o bjecti ve res p o ns e ass ess me nt - u nless t here is e arlier cl e ar evi d e nce of 
P D ). E nr oll me nt i n t his co h ort will c o nti n ue d uri n g t he I D M C re vie w. 
V V- T M F- 5 1 6 1 9 | Pa ge 4 7/ 1 1 2

Pr ot oc ol  
 
Pa ge 4 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
F or c o h ort B  ( Part 2) : 
1.  O nce t he 3 r d patie nt has c o m plete d o ne c ycle of treat me nt . E nr oll me nt i n t his co h ort will  
c o nti n ue d uri n g t h e I D M C safet y re vie w. 
2.  O nce t he 6 t h pat ie nt has c o m plete d t w o c ycl es of treat me nt . E nr oll me nt i n t his co h ort will 
be pa use d  d uri n g t he I D M C safet y re vie w. 
3.  O nce t he 1 2 t h patie nt has c o m plete d t w o c ycl es of treat me nt . E nr oll me nt i n t his co h ort will 
c o nti n ue d uri n g t h e I D M C safet y re vie w. 
F or a ny c o h ort ( P art 3 ): 
A fter e ver y 1 0 p atie nts h a ve c o m plete d t w o c ycl es of treat me nt a n d are e val ua ble f or efficac y ( i.e., 
patie nts s h o ul d ha ve perf or me d at least o ne p ost baseli ne o bjecti ve res p o nse assess me nt - u nless 
t here is e arlier cle ar evi de nce of P D). E nr oll me nt will c o nti n ue d uri n g t he I D M C safet y re vi e w. 
Cli nical safet y , efficac y a n d P K data t hat will be pr o vi de d f or S R C  a n d I D M C  re vie w will i ncl u de, 
b ut are n ot li mite d t o t he f oll o wi n g: A Es , la b orat or y d ata, E C G res ults, d ose m o dificati o ns,  a 
s u m mar y of seri o us a d verse e ve nts (S A Es ), t u m or assess me nts, o verall t u m or res p o nse  a n d D o R . 
Base d o n t heir e x pertise a n d  e x perie nce i n treati n g D L B C L patie nts, t he I D M C me m bers will 
esta blis h all t he criteria n ecessar y t o ta ke t he decisi o n of st o p pi n g or c o nti n ui n g t he st u d y.  
I D M C S afety, E ffic acy a n d P K  Revie w  - P art 2  
C o h ort A : O nce t he first 1 0  patie nt s e val ua ble f or efficac y (i.e., p atie nts s h o ul d ha ve perf or me d 
at least o n e p ost b aseli ne o bjecti ve res p o nse assess me nt - u nless t here is e arlier cle ar evi de nce of 
P D ) d uri n g P art 2 of t he st u d y are a vaila ble f or f utilit y a n al ysis , t he I D M C will re vie w t he t otalit y 
of t he  s afet y data f or t he Q 3 W d osi n g re gi me n a n d ca n rec o m me n d t o ter mi nate or m o dif y t he 
d osi n g re gi me n i n cas e of u nacce pta ble safet y. If f utilit y is met a n d/ or safet y pr ofile is u nacce pt a ble 
as deter mi ne d b y t he I D M C, t his c o h ort will be st o p pe d. Ot her wise, a n a d diti o nal 5 patie nts will 
be e nr olle d a n d a s u bse q ue nt f utilit y a nal ysis will be perf or me d after 1 5 e val ua ble p atie nts f or 
efficac y. Si milarl y, t he c u m ulati ve safet y dat a f or t his d ose re gi me n will be re vie we d b y t h e I D M C. 
If f utilit y is met a n d/ or safet y pr ofile is u nacce pta ble, t his c o h ort will b e st o p pe d. Ot her wise, 
de pe n di n g o n t he e v al uati o n o f t he t otalit y of d ata i n b ot h co h orts ( A a n d B), a rec o m me n dati o n 
ma y be m a de b y t he I D M C t o c o nti n ue wit h t h e e x pa nsi o n (st u d y P art 3) usi n g  t he s a me d osi n g 
re gi me n as i n co h ort A.  
C o h ort B : A n i nitial I D M C re vie w of safet y dat a will be perf or me d o nce t he first 3 patie nts ha ve 
recei v e d at least o ne c ycl e of treat me nt. A s u bs e q ue nt re vie w of safet y, a v aila ble P K a n d efficac y 
data will be perf or me d  b y t h e I D M C o nce 6 p atie nts will ha ve c o m plete d 2 c ycles of treat me nt, 
a n d a rec o m me n dati o n will be ma de t o eit her:  
1.  St o p t he co h ort  i n case of u nacce pta ble safet y 
2.  E nr oll 6 m ore patie n ts i n or der t o o btai n m ore d ata 
3.  E x pl ore a n alter nati ve Q W d osi n g  re gi me n 
I n case t he I D M C dee ms it necessar y t o e nr oll 6 m ore patie nts ( p oi nt 2 a b o ve), t he I D M C will 
re vie w s afet y, a vaila ble P K a n d efficac y data a gai n o nce  1 2 p atie nts ha ve  c o m plete d 2 c ycl es of 
treat me nt, a n d will deci d e  w het her  t o: 
1.  St o p t he co h ort, i n case of u nacce pta ble s afet y 
V V- T M F- 5 1 6 1 9 | Pa ge 4 8/ 1 1 2

Pr ot oc ol  
 
Pa ge 4 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
2.  E x pl ore a n alter nati ve Q W d osi n g re gi me n  
3.  C o nti n ue wit h t he e x pa nsi o n  ( Part 3 of t he st u d y)  
T he I D M C ma y rec o m m e n d de viati o n fr o m t he pl a n ne d patie nt n u m ber s f oll o wi n g re vie w of t he 
c um ulati ve  safet y, effi cac y a n d P K dat a. If t h e I D M C rec o m me n d t o e x pl ore a differe nt d ose, o nl y 
o ne ne w d ose re gi me n will be i n vesti gate d. I n s uc h case, t he t hree I D M C re vie ws descri be d a b o v e 
will occ ur f or t his ne w re gi me n.  
Base d o n e v al uati o n of t h e t otalit y of dat a a v aila ble fr o m t h e safet y r u n -i n, Part 1 a n d Part 2 of t he 
st u d y, t he I D M C will ma ke a rec o m me n d ati o n o n c o nti n uati o n wit h e nr oll me nt of patie nts i n eit her 
c o h ort A, c o h ort B or b ot h c o h orts.  
 
I D M C S afety , Effic acy a n d P K Revie w - P art 3  
T he I D M C  will c o nti n ue t o re vie w safet y, efficac y a n d P K data a v aila ble after e v er y 1 0 patie nts  
are e nr olle d a n d tr eate d f or at least 2 c ycl es. 
In ge neral, i f t he S R C or t he I D M C  d eter mi ne at a n y ti me t h at t he d ose s h o ul d be re d u ce d f or 
safet y reas o ns, a l o wer d ose of De bi o 1 5 6 2 will b e e x pl ore d.  
 
V V- T M F- 5 1 6 1 9 | Pa ge 4 9/ 1 1 2

Pr ot oc ol  
 
Pa ge 5 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
5.   
S T U D Y T R E A T M E N T  
5. 1.   
Descri pti o n of St u d y Tre at me nt  
T he i n vesti gati o nal st u d y dr u g, De bi o 1 5 6 2 , will be pr o vi de d b y t he S p o ns or i n 2 0 m L glass vials 
eac h c o ntai ni n g 5 m L of a pr otei n c o nce ntrati o n of 8 . 0 m g/ m L De bi o 1 5 6 2  
 
  
Rit u xi ma b will be s u p plie d as a c o m merciall y a vaila ble f or m ulati o n.  Please refer t o t he rit u xi ma b 
prescri bi n g i nf or mati o n.  
5. 2.   
De bi o 1 5 6 2  P ac k a gi n g a n d L a beli n g  
T he De bi o 1 5 6 2  c o ntai ner 
 
  T he la bel  
 will i ncl u de t he necessar y i nf or mati o n 
as re q uire d b y t h e c o u ntr y i n w hic h it is bei n g use d.   
5. 3.   
St or a ge, H a n dli n g, a n d Acc o u nt a bilit y  
S pecific details re gar di n g st ora ge a n d ha n dli n g  of De bi o 1 5 6 2  a n d rit u xi ma b ca n be f o u n d i n t he 
P har mac y Ma n u al.  
A d diti o nall y, p leas e refer t o t he rit u xi ma b prescri bi n g i nf or mati o n re gar di n g t he pr o per st ora ge 
a n d ha n dli n g of t his dr u g.  
Acc o u nta bilit y a n d s hi p pi n g d oc u me nts f or all dr u gs s u p plie d b y t h e S p o ns or m ust be mai ntai ne d  
b y t he Pri nci pal I n vesti gat or or desi g nee (e. g., t he st u d y p har macist).  T he I n vesti gat or or desi g n ee 
m ust mai ntai n a n acc urate rec or d of t he recei pt a n d dis pe nsi n g of 
De bi o 1 5 6 2  i n a dr u g 
acc o u nta bilit y l o g. T hes e rec or ds m ust al wa ys b e a vaila ble f or i ns p ecti o n, a n d a c o p y will be 
s u p plie d t o t he S p o ns or, o n re q uest. I nf or m ati o n rec or de d o n t hese acc o u nta bilit y a n d s hi p pi n g 
d oc u me nts will i ncl u de q ua ntities recei ve d, dates a n d a m o u nt dis pe nse d , t he rec or der’s i nitials, 
patie nt n u m ber t o w h o m t he dr u g was a d mi nistere d, l ot n u m ber of dr u g a d mi nistere d, a n d dr u g 
l ost, da ma ge d , or destr o ye d.  
U p o n c o m pleti o n of t he st u d y, all De bi o 1 5 6 2  dis patc he d t o a site m ust be acc o u nte d f or a n d 
u n use d s u p plies destr o ye d acc or di n g t o t he site’s Sta n dar d O perati n g Pr oce d ures u p o n S p o ns or 
a p pr o val . If t h e site ca n n ot destr o y o nsite, ret ur n of u n use d s u p plies t o t he S p o ns or ca n be arra n ge d. 
T he ori gi nal dr u g rec o n ciliati o n rec or ds s hall be mai ntai ne d at t h e site a n d a c o p y c ollecte d a n d 
se nt t o t he S p o ns or o nce a re prese ntati ve of t he c o m pa n y has c o nfir me d t h e dr u g acc o u nta bilit y. 
T he p har mac y s hall mai ntai n acc urate rec or ds of all st u d y dr u gs t hat ha ve b ee n recei ve d, st ore d, 
dis pe nse d, destr o ye d, a n d use d. T he electr o nic Case Re p ort F or m ( e C R F) s hall als o rec or d d etails 
of st u d y dr u g a d mi nistrati o n  s uc h as date a n d ti me of a d mi nistrati o n . 
Dr u g acc o u nta bilit y will be m o nit ore d re g ularl y.  
5. 4.   
St u d y Tre at me nt C o m pli a nce  
De bi o 1 5 6 2  a n d rit u xi ma b s u p plie d f or t he st u d y ma y n ot be use d f or a n y p ur p ose ot her t ha n t he 
st u d y or a d mi nistere d ot her t ha n as d escri be d i n t his pr ot oc ol.   
V V- T M F- 5 1 6 1 9 | Pa ge 5 0/ 1 1 2

Pr ot oc ol  
 
Pa ge 5 1  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
S o urce d oc u me nts  m ust ca pt ure t he d ates w he n dr u g is dis pe nse d a n d t h e i nitials of t he  p ers o n 
pre pari n g t he d ose as well as t he v ol u mes a n d d oses dis pe nse d, patie nt n u m ber, l ot n u m ber, a n d 
e x pirati o n date if a vaila ble of t he dr u g a d mi nistere d.  
U n der n o circ u msta nces is t he I n vesti gat or all o we d t o releas e De bi o 1 5 6 2  s u p plies t o a n y p h ysi cia n 
n ot na me d as part of t he st u d y (e. g. , n ot na me d i n t he F D A F or m 1 5 7 2)  or t o a d mi nister t hese 
s u p plies t o a patie nt n ot e nr olle d i n t his st u d y.  If i n vesti gati o nal s u p plies are t o be dis pe nse d fr o m 
a n y facilit y ot her t ha n t hat s u per vise d directl y b y t he Pr i nci pal I n v esti gat or (i.e., h os pital 
p har mac y, satellite p h ar mac y), it is t h e res p o nsi bilit y of t he Pri nci pal I n vesti gat or t o e ns ure t h at 
all De bi o 1 5 6 2  is mai ntai ne d i n t he ma n ner descri be d i n t he P har mac y M a n ual. 
F or De bi o 1 5 6 2 , t w o differe nt dr u g l ots ca n n ot b e mi x e d i n a si n gle d ose a d mi nistrati o n.  
5. 5.   
Assi g n me nt of P atie nt N u m ber  
Patie nt n u m bers are assi g ne d i n se q ue ntial or der as patie nts si g n i nf or me d c o nse nt t o partici pate.  
Patie nts w h o ha v e c o ns e nte d t o t he st u d y a n d w h o ha ve recei v e d at least o ne d o s e of st u d y 
treat me nt will be c o nsi dere d e nr olle d.   
Patie nts w h o are iss ue d a patie nt n u m ber, b ut w h o d o n ot s uccessf ull y c o m plete t he scree ni n g 
pr ocess a n d w h o d o n ot recei ve a d ose of  st u d y treat me nt will be c o nsi dere d a scree n fail ure . 
A patie nt n u m ber  t hat has bee n iss ue d f or a gi ve n p atie nt w h o  faile d scree ni n g will n ot be re -iss ue d 
f or a n ot her patie nt , b ut  ca n be re-iss ue d t o t he sa me patie nt if he/s he is re-scree ne d f or t he st u d y 
at a later d ate.  
5. 6.   
Bli n di n g  
N ot a p plica ble as t his is a n o pe n -la bel st ud y.  
5. 7.   
Dr u g Pre p ar ati o n a n d A d mi nistr ati o n   
De bi o 1 5 6 2 is a n e x peri me ntal a ntica ncer dr u g, a n d as wit h ot her p ote nti all y t o xic c o m p o u n ds, 
ca uti o n s h o ul d be e x ercise d w he n ha n dli n g t his c o m p o u n d. It is rec o m m e n de d t hat gl o v es a n d 
pr otecti ve gar me nts be w or n d u ri n g pre parati o n. Si milar preca uti o ns s h o ul d be ta ke n w he n 
ha n dli n g rit u xi ma b.  Refer t o t he P har mac y 
M a n ual a n d rit u xi ma b pac ka ge i nsert f or m ore 
i nf or mati o n. 
 
F or l o gistical reas o ns (s u c h as h oli da ys, wee ke n ds, etc.), c h a n ges of ± 3 d a ys i n t he start of a n y 
c ycle of st u d y treat me nt are per mitte d.  Si milarl y , intra -c ycl e a d mi nistrati o ns o n Da y 8 a n d Da y 1 5 
i n C o h ort  B patie nt ca n h a ve a wi n d o w  of -1 da y t o + 3 da ys  f or l o gistical reas o ns; h o we ver, e ver y 
t w o a d mi nistrati o ns nee d t o ha ve a mi ni mal i nter v al of 5 da ys . 
5. 7. 1.   
Pre - a n d P ost -I nf usi o n Pr o p h yl a xis 
Pri or t o recei vi n g treat me nt wit h De bi o 1 5 6 2  a n d rit u xi ma b, patie nts will be gi ve n de x a met has o ne 
I V at 8  m g ( or e q ui vale nt) , aceta mi n o p he n P O or I V 3 2 5 –  6 5 0 m g, a n d a n a nti hista mi ne  (e. g. 2 5-
5 0 m g di p he n h y dra mi n e or e q ui vale nt) a p pr o xi matel y 3 0 -6 0 mi n utes pri or t o t he De bi o 1 5 6 2  
i nf usi o n.  Patie nts will be i nstr ucte d t o ta ke oral de x a met has o ne at 8  m g/ da y o n D a ys 2 a n d 3,  
f oll o wi n g t h e i nf usi o n. If a n y patie nt re q uires m ore i nte nsi ve treat me nt t o pre v e nt i nf usi o n 
reacti o n, i n vesti gat ors m a y m o dif y t he re gi me n acc or di n gl y.  
V V- T M F- 5 1 6 1 9 | Pa ge 5 1/ 1 1 2

Pr ot oc ol  
 
Pa ge 5 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 Da y 1 i n C ycl es 1 a n d 3 d uri n g safet y r u n -i n ( Part 1) 
 Da y 1 i n C ycl es 1 a n d 2 i n c o h orts A a n d B ( Part 2 a n d Part 3)  
5. 7. 5.   
M a n a ge me nt of P ote nti al I nf usi o n -rel ate d  Re acti o ns  
Des pite pre -i nf usi o n pr o p h yla xis, s o me patie nts recei vi n g De bi o 1 5 6 2  or rit u xi ma b ha ve 
e x perie nce d i nf usi o n -related  reacti o ns. 
Mil d t o m o derate i nf usi o n -relate d reacti o ns c o nsisti n g of c hills a n d ri g ors h a ve b ee n e x perie nce d 
b y s o me p atie nts recei vi n g De bi o 1 5 6 2 . 
Se vere i nf usi o n reacti o ns ha ve bee n re p orte d b y s o me patie nts recei vi n g rit u xi ma b.  I nf usi o n 
reacti o ns c o nsisti n g of fe ver, c hills/ri g ors, n a usea, pr urit us, a n gi oe de ma, h y p ote nsi o n, h ea d ac he, 
br o nc h os pas m, urticaria, ras h, v o miti n g, m yal gia, dizzi ness, or h y perte nsi o n ma y t y picall y occ ur 
wit hi n 3 0 t o 1 2 0 mi n utes of be gi n ni n g t he first rit u xi ma b i nf usi o n a n d res ol ve wit h sl o wi n g or 
i nterr u pti o n of t he i nf usi o n a n d wit h s u p p orti ve care ( di p he n h y dra mi ne, aceta mi n o p he n, a n d 
i ntra ve n o us sali ne). T he i nci de nce of i nf usi o n reacti o ns is hi g hest d uri n g t he first i nf usi o n a n d 
decrease d wit h eac h s u bse q ue nt i nf usi o n. As s uc h, all patie nts will recei v e pre -i nf usi o n 
pr o p h yla xis.   A d diti o nall y , patie nts will b e pr o vi de d oral ster oi ds t o be ta ke n o n Da ys 2 a n d 3 of 
eac h c ycle.  
S o me patie nts treate d wit h I V i nf usi o ns of t hera pe utic dr u gs h a ve e x perie nce d c o nc urre nt i nf usi o n -
relate d reacti o ns (refer t o C T C A E Versi o n 4. 0 3).  T he si g ns  a n d s y m pt o ms ma y var y a n d i ncl u de 
f or e x a m ple, hea d ac h e, fe ver, facial fl us hi n g, pr urit us, m yal gia, na us ea, c h est ti g ht ness, d ys p nea, 
v o miti n g, er yt h e ma, a b d o mi nal disc o mf ort, dia p h oresis, s hi vers, li g ht hea de d ness,  h y p ote nsi o n, 
pal pitati o ns, a n d s o m n ole nc e.  A na p h yl a xis mi g ht occ ur at a n y ti me d uri n g a n i nf usi o n.  Bef ore 
a n y i nf usi o n is starte d, a p pr o priate me dical pers o n nel, me dicati o n (e. g. e pi ne p hri ne, i n hale d beta 
a g o nists, a nti hista mi nes, a n d c ortic oster oi ds), a n d ot her re q uire d res o urces t o treat a na p h yl a xis 
m ust be rea dil y a vail a ble.  I n ge neral, I n v esti gat ors s h o ul d 
ma na ge ac ute aller gic or 
h y perse nsiti vit y reacti o ns acc or di n g t o I nstit uti o nal practices. Ge neral , s u g geste d g ui deli nes f or 
t he ma na ge me nt of ac ute i nf usi o n-relate d reacti o ns a n d f or su bse q ue nt retreat me nt are pr o vi de d 
i n Ta ble  4 .  Dela ye d i nf usi o n -relate d reacti o ns ma y o cc ur; t heref ore patie nts s h o ul d be a d vise d t o 
see k i m me diate m edical treat me nt if s y m pt o ms n e wl y de vel o p a n d/ or rec ur after disc har ge fr o m 
cli nic. 
Patie nts w h o e x perie nce a  >  Gra de 2  i nf usi o n-relate d reacti o n d uri n g or i m me diatel y f oll o wi n g 
a d mi nistrati o n of De bi o 1 5 6 2  s h o ul d ha ve bl o o d dra w n wit hi n t hree h o urs of t h e  o nset of t h e 
reacti o n  a n d o ne wee k later f or d eter mi nati o n of dr u g c o nce ntrati o n ( P K) a n d a nti b o dies t o De bi o 
1 5 6 2  ( A D A) ( Secti o ns 6. 1. 1  a n d 6. 2. 1 ). 
 
V V- T M F- 5 1 6 1 9 | Pa ge 5 4/ 1 1 2

Pr ot oc ol  
 
Pa ge 5 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
T a ble  4 :  
M a n a ge me nt G ui deli nes f or P ote nti al I nf usi o n -rel ate d Re a cti o ns  
I nf usi o n Re a cti o n C T C A E 
v 4. 0 3 Se verit y Gr a de  
M a n a ge me nt  
Gra de 1: Mil d, tra nsie nt reacti o n  
  Mai ntai n i nf usi o n rate u nless pr o gressi o n of s y m pt o ms t o ≥ Gra de 2; if 
s y m pt o ms w orse n, refer t o g ui deli nes bel o w 
  Pr o met hazi ne 1 5 0 m g  b y m o ut h  (P O ) per da y ( e ver y 4 h o urs [ Q 4 h ]) as 
nee de d ( pr n ) f or na usea  ( or e q ui vale nt) 
  Di p he n h y dra mi ne 2 5 -5 0 m g P O or I V pr n  ( or e q ui vale nt) 
  Met h yl pre d nis ol o ne 1 2 5 m g ( or e q ui vale nt) I V pr n  
Gra de 2: M o derate  
  I nterr u pt i nf usi o n a n d disc o n nect i nf usi o n t u bi n g fr o m patie nt 
  Pr o met hazi ne 1 5 0 m g P O per da y ( Q 4 h) pr n f or na usea ( or e q ui vale nt)  
  Di p he n h y dra mi ne 2 5 -5 0 m g P O or I V pr n ( or e q ui vale nt)  
  Aceta mi n o p he n 6 5 0 m g P O pr n ( or e q ui vale nt)  
  Met h yl pre d nis ol o ne 1 2 5 m g ( or e q ui vale nt) I V pr n  
  After rec o ver y fr o m s y m pt o ms, res u me t he i nf usi o n at 5 0 % of t he 
pre vi o us rate a n d if n o f urt her s y m pt o ms a p pear, gra d uall y i ncrease rate 
of i nf usi o n ( d o n ot s ur pass ma xi m u m i nf usi o n rate all o we d per pr ot oc ol) 
u ntil i nf usi o n is c o m plete d.  
  F or s u bse q ue nt d osi n g i n f ut ure c ycles,  patie nts s h o ul d be pre -me dicate d 
wit h De xa met has o ne 8 m g P O t wice dail y (BI D ) ( or e q ui vale nt) t he da y 
pri or t o dr u g a d mi nistrati o n a n d 
Aceta mi n o p he n 6 5 0 
m g P O ( or 
e q ui vale nt) a n d Di p he n h y dr a mi ne 2 5 -5 0 
m g P O 3 0 -6 0 
mi n utes ( or 
e q ui vale nt) pri or t o d osi n g.  
Gra de 3: Se vere, pr ol o n ge d 
reacti o n n ot ra pi dl y res p o nsi ve t o 
s y m pt o matic me dicati o n a n d/ or 
brief i nterr u pti o n of i nf usi o n; 
rec urre nce of s y m pt o ms 
f oll o wi n g i nitial i m pr o ve me nt; 
h os pitalizati o n i n dicate d f or 
cli nical se q uelae  
  St o p i nf usi o n a n d disc o n nect i nf usi o n t u bi n g fr o m patie nt 
  A d mi nister Di p he n h y dra mi ne ( 2 5 -5 0 m g) I V ( or e q ui vale nt)  
  A d mi nister n or mal sali ne, e pi ne p hri ne ( 0. 2 -0. 5 m L of a 1: 1 0 0 0 dil uti o n 
[ 0. 2-0. 5  
m g] s u bc uta ne o usl y [ S C] 
or i ntra m usc ularl y [I M]) ( or 
e q ui vale nt) a n d br o nc h o dilat ors ( ne b u lize d al b uter ol, 2. 5-5 m g i n 3 m L of 
sali ne) as me dicall y i n dicate d 
  C o nsi der I V ster oi ds ( met h yl pre d nis ol o ne ( or e q ui vale nt) u p t o 0. 5 m g/ k g 
e ver y 6 h o urs [ Q 6 h]) t o pre ve nt rec urre nt or o n g oi n g reacti o ns  
  A d vise patie nt t o see k e mer ge nc y treat me nt a n d n otif y i n vesti gat or/cli nic 
if t he i nf usi o n-relate d s y m pt o ms rec ur after disc har ge fr o m cli nic. 
  Re p ort as a n S A E  
  I n vesti gat ors s h o ul d c o nfer wit h t he s p o ns or re gar di n g retreat me nt of t he 
patie nt. If t he i n vesti gat or a n d s p o ns or a gree t hat t he patie nt c o ul d be r e-
c halle n ge d, t he n pr o p h yla xis f or a n i nf usi o n -relate d reacti o n s h o ul d occ ur 
i n all s u bse q ue nt c ycles. F or t his, patie nts s h o ul d be pre-me dicate d wit h 
De xa met has o ne 8 m g P O BI D t he da y pri or dr u g a d mi nistrati o n a n d 
Aceta mi n o p he n 6 5 0 m g P O a n d Di p he n h y dra mi ne 2 5 -5 0 m g P O 3 0 -6 0 
mi n utes pri or t o d osi n g.  
Gra de 4: Life -t hreate ni n g 
c o nse q ue nces, ur ge nt 
i nter ve nti o n i n dicate d  
  I m me diatel y st o p i nf usi o n a n d disc o n nect i nf usi o n t u bi n g fr o m patie nt 
  P er ma ne ntl y disc o nti n ue st u d y me dicati o n treat me nt  
  A d mi nister Di p he n h y dra mi ne 5 0 m g I V ( or e q ui vale nt)  
  A d mi nister n or mal sali ne, e pi ne p hri ne ( 0. 2 -0. 5 m L of a 1: 1 0 0 0 dil uti o n 
( 0. 2-0. 5 m g) S C or I M ( or e q ui vale nt)  
  A d mi nister br o nc h o dilat ors ( ne b ulize d al b uter ol, 2. 5 -5 m g i n 3 m L of 
sali ne) as me dicall y i n dicate d 
  A d mi ni ster I V ster oi ds ( met h yl pre d nis ol o ne u p t o 0. 5 m g/ k g Q 6 h) ( or 
e q ui vale nt) t o pre ve nt rec urre nt or o n g oi n g reacti o ns  
  Re p ort as a seri o us a d verse e ve nt  
  Re m o ve patie nt fr o m st u d y.  
V V- T M F- 5 1 6 1 9 | Pa ge 5 5/ 1 1 2

Pr ot oc ol  
 
Pa ge 5 6  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
5. 8.   
T o xicit y  M a n a ge me nt G ui deli nes  
D ose m o dificati o ns s h o ul d occ ur base d o n t he e mer gi n g safet y pr ofile of De bi o 1 5 6 2  a n d t he 
k n o w n safet y ris ks of rit u xi ma b.  
Fre q u e nt A Es o bser ve d i n patie nts recei vi n g si n gle a ge nt De bi o 1 5 6 2  i ncl u de d Gra de 3/ 4 
ne utr o pe nia, fe brile ne utr o pe nia , t hr o m b oc yt o pe nia, fe ver a n d i nf usi o n reacti o n.  T he c o m plete 
safet y ris k pr ofile of De bi o 1 5 6 2 is detaile d i n t he De bi o 1 5 6 2 I B .   
F or details o n t he m ost c o m m o n l y-re p orte d t o xicities ass ociate d wit h rit u xi ma b please refer t o t he 
rit u xi ma b la bel. 
Ta ble  5  s h o ul d b e use d as a g ui de t o hel p i n vesti gat ors assess st u d y treat me nt relate d t o xicities.   
P ote ntial o verla p pi n g t o xicities i ncl u de fe ver, i nf usi o n -relate d reacti o n, a n d dela ye d-o nset 
ne utr o pe nia.  I n vesti gat ors s h o ul d re d uce or disc o nti n ue De bi o 1 5 6 2  f or Gra de 3-4 n o n -
he mat ol o gic t o xicities base d o n cli nical j u d g me nt , a n d s h o ul d ma na ge rit u xi ma b i n d uce d t o xicit y 
per la bel ( Secti o n  5. 9 ).   
T a ble  5 :  
De bi o 1 5 6 2  a n d Rit u xi m a b T o xicities  
A E  
De bi o 1 5 6 2  
( ≥ 1 0 % of p atie nts i n 
m o n ot her a p y)  
Rit u xi m a b  
( per l a bel) 
Fe ver  
● 
● 
I nf usi o n relate d reacti o n 
● 
● 
Ne utr o pe nia  
Dela ye d o nset  Ne utr o pe nia  
● 
 
● 
A ne mia  
● 
 
Ast he nia  
● 
 
A S T/ A L T i ncrease  
● 
 
Decrease d a p petite  
● 
 
Diarr hea  
● 
 
D ys p n oea  
● 
 
Fati g ue  
● 
 
Fe brile ne utr o pe nia  
● 
 
H y p o kalae mia  
● 
 
M uscle wea k ness  
● 
 
Na usea  
● 
 
Oe de ma –  peri p heral  
● 
 
T hr o m b oc yt o pe nia  
● 
 
B o wel o bstr ucti o n a n d perf orati o n  
 
● 
Car diac arr h yt h mias  
 
● 
V V- T M F- 5 1 6 1 9 | Pa ge 5 6/ 1 1 2

Pr ot oc ol  
 
Pa ge 5 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
A E  
De bi o 1 5 6 2  
( ≥ 1 0 % of p atie nts i n 
m o n ot her a p y)  
Rit u xi m a b  
( per l a bel) 
C hills  
 
● 
I nfecti o n 
 
● 
I nterstitial p ne u m o nitis 
 
● 
L y m p h o pe nia  
 
● 
M uc oc uta ne o us reacti o ns  
 
● 
Pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y  
 
● 
Reacti vati o n of he patitis B  
 
● 
Re nal t o xicit y  
 
● 
Se vere i nf usi o n relate d reacti o n  
 
● 
T u m or L ysis S y n dr o me  
 
● 
5. 8. 1.   
M o nit ori n g a n d M a n a ge me nt of T u m or L ysis S y n dr o me ( T L S)  
Ac ute re nal fail ure, h y p er kale mia, h y p ocal ce mia, h y p er uri ce mia, or h y p er p h os p hate mia fr o m 
t u m or l ysis, ca n occ ur wit hi n 1 2 - 2 4 h o urs after t he first i nf usi o n wit h rit u xi ma b a n d ma y  be fatal.   
Si g ns of T L S ha v e als o b ee n o bs er ve d i n patie nts recei vi n g De bi o 1 5 6 2 .  Patie nts wit h hi g h t u m or 
b ur de n a n d/ or hi g h circ ulati n g l y m p h o c yte c o u nts ( > 2 5 × 1 0 9/ L) are at greater ris k f or T L S a n d 
s h o ul d be a de q uatel y h y drate d be gi n ni n g 1 2 - 2 4 h o urs pri or t o t he i nf usi o n of De bi o 1 5 6 2  (e. g. 
2  L wit hi n 1 2 - 2 4 h o urs pri or t o i nf usi o n –  r o u g hl y 1 7 0 cc e v er y t w o h o urs).  
A n y p atie nt e x perie nci n g T L S or at ris k f or T L S s h o ul d be ma na ge d acc or di n g t o i nstit uti o nal 
practice.   
5. 8. 2.   
M o nit ori n g a n d M a n a ge me nt of C yt o pe ni as  
C yt o pe nias ( ne utr o pe ni a a n d t hr o m b oc yt o pe ni a) ha ve b ee n o bs er ve d i n patie nts treat e d wit h  
rit u xi ma b as well as De bi o 1 5 6 2 .  I n patie nts recei vi n g rit u xi ma b m o n ot hera p y at 3 7 5 m g/ m 2 I V 
wee kl y f or r ela pse d or refract or y l o w -gra d e or f ollic ular N H L , Gra de 3 -4 n e utr o pe nia occ urre d i n 
6 % a n d gra de 3 -4 t hr o m b oc yt o p e nia occ urre d i n 2 %  (Rit u x a n ®  (rit u xi ma b) P ac ka ge Insert  2 0 1 4 ).  
I n N H L p atie nts w h o recei ve d De bi o 1 5 6 2  m o n ot hera p y  at t he d ose of 0. 7 m g/ k g , G ra d e 3 
ne utr o pe nia  was t he hi g h est gra de re p orte d .  
Patie nts e x perie nci n g se v ere c yt o p e nia s h o ul d f oll o w t he rec o m me n d ati o ns of d ose -m o dificati o n 
a n d a d diti o nal c orrecti ve/ pre ve nti ve meas ures (s uc h as gra n ul oc yte c ol o n y -sti m ulati n g fact or [ G-
C S F]) prese nt i n t his pr ot oc ol  (Secti o n 5. 9 ). T he t y pe of G -C S F  s u p p ort will be deter mi ne d b y t he 
st u d y p h ysicia n, as well as t he cli nical j u d ge me nt t o deci de t he d urati o n of s uc h treat me nt .  
If a patie nt d e vel o ps Gra de 4 t hr o m b oc yt o pe ni a lasti n g > 7 da ys, st u d y treat me nt s h o ul d b e 
ter mi nate d a n d t he t o xicit y s h o ul d be f oll o we d u ntil  res ol uti o n or sta bilizati o n (Secti o n  5. 9. 2 ).   
V V- T M F- 5 1 6 1 9 | Pa ge 5 7/ 1 1 2

Pr ot oc ol  
 
Pa ge 5 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
5. 8. 3.   
M o nit ori n g 
a n d  
M a n a ge me nt 
of 
Rit u xi m a b -ass oci ate d 
B o wel 
O bstr ucti o n a n d B o wel  Perf or ati o n  
Patie nts recei vi n g rit u xi ma b s h o ul d be c o nti n uall y m o nit ore d f or si g ns or s y m pt o ms of b o wel 
o bstr ucti o n a n d b o wel perf orati o n. Perf orati o ns ha ve bee n s h o w n t o occ ur at hi g her fre q ue n c y i n 
patie nts w h o ha ve recei v e d ra diati o n t hera p y. Si g ns a n d s y m pt o ms of b o wel o bstr ucti o n i ncl u de 
i nter mitte nt a b d o mi nal pai n, na usea, v o miti n g, diarr hea, c o nsti pati o n, a n d a b d o mi nal diste nsi o n.  
Si g ns a n d s y m pt o ms of b o wel  perf orati o n i ncl u de fe ver, na us ea, v o miti n g, he mate m esis, c hills, 
a n d se vere st o mac h pai n. Patie nts are a d vise d t o n otif y t heir treati n g p h ysici a n i m me diatel y if t he y 
e x perie nce a n y of t he si g ns or s y m pt o ms descri be d a b o ve.  If a p ositi ve dia g n osis of gastr oi ntesti nal 
perf orati o n is ma de, rit u xi ma b sh o ul d be i m me diatel y disc o nti n ue d a n d t he patie nt s h o ul d be 
treate d as p er i nstit uti o nal g ui deli nes.  
5. 8. 4.   
M o nit ori n g a n d 
M a n a ge me nt of Rit u xi m a b -i n d uce d Pr o gressi ve 
M ultif oc al Le u k oe nce p h al o p at h y ( P M L)  
J o h n C u n ni n g ha m vir us i nfecti o n res ulti n g i n P M L a n d deat h ca n occ ur i n patie nts recei vi n g 
rit u xi ma b a n d it has bee n s h o w n t o occ ur m ore fre q ue ntl y i n patie nts w h o recei ve d rit u xi ma b i n 
c o m bi nati o n wit h c he m ot hera p y or as part of a he mat o p oietic ste m cell tra ns pla nt.  M ost cases of 
P M L were dia g n os e d wit hi n 1 2 m o nt hs of t heir last i nf usi o n of rit u xi ma b.  C o nsi der t he dia g n osis 
of P M L i n a n y patie nt prese nti n g wit h ne w -o ns et ne ur ol o gi c ma nifestati o ns.   E val uati o n of P M L 
i ncl u des, b ut is n ot li mite d t o, c o ns ultati o n wit h a ne ur ol o gist, brai n ma g n etic res o na nce i ma gi n g  
(M RI ), a n d l u m bar p u n ct ure.  If a p ositi ve dia g n osis of P M L is m a de, rit u xi ma b s h o ul d be 
disc o nti n ue d.  
5. 8. 5.   
M o nit ori n g a n d M a n a ge me nt of Rit u xi m a b -i n d uce d Re n al T o xicit y 
Se vere, i n cl u di n g fatal, re na l t o xicit y has b ee n s h o w n t o  occ ur after  rit u xi ma b a d mi nistrati o n i n 
patie nts wit h N H L.  Re n al t o xicit y h as occ urre d i n patie nts w h o e x perie n ce T L S .  Patie nts s h o ul d 
be m o nit ore d cl osel y f or si g ns of re nal fail ure , i ncl u di n g b ut n ot li mite d t o wea k ness, s hort ness of 
breat h , c o nf usi o n, met allic taste i n m o ut h , fl ui d rete nti o n, n a usea, fla n k pai n, seiz ures, a n d 
decrease d uri n e o ut p ut .  Rit u xi ma b s h o ul d be disc o nti n ue d i n patie nts e x perie nci n g risi n g ser u m 
creati ni ne or oli g uria.   Patie nts e x perie nci n g re nal fail ure s h o ul d be m a na ge d acc or di n g t o 
i nstit uti o nal g ui deli nes. 
5. 8. 6.   
M o nit ori n g of Rit u xi m a b -i n d uce d C ar di o v asc ul ar T o xicit y 
Car diac t o xicit y h as bee n re p orte d i n patie nts recei vi n g rit u xi ma b.  Car diac m o nit ori n g s h o ul d be 
perf or me d d uri n g a n d aft er all i nf usi o ns of rit u xi ma b f or patie nts w h o de v el o p cli nicall y si g nifica nt 
arr h yt h mias.  Rit u xi ma b s h o ul d be disc o nti n ue d i n patie nts e x perie nci n g seri o us or life-t hreate ni n g 
car diac arr h yt h mias.  P atie nts e x perie nci n g car diac t o xicit y s h o ul d be ma na ge d acc or di n g t o  
i nstit uti o nal g ui deli nes. 
5. 8. 7.   
M o nit ori n g of Rit u xi m a b -i n d uce d Seri o us I nfecti o ns  
Seri o us, s o meti mes fatal bacterial, f u n gal, or viral ( ne w or reacti vate d) i nfecti o ns ha ve bee n s h o w n 
t o occ ur i n patie nts recei vi n g rit u xi ma b, d uri n g t hera p y a n d u p t o o ne year f oll o wi n g t he 
c o m pleti o n of rit u xi ma b -base d t hera p y.   Re p orte d ne w or reacti vate d viral i nfecti o ns i ncl u d e 
c yt o me gal o vir us, her pes si m ple x vir us, par v o vir us B 1 9, varicella z oster vir us, West Nile vir us, 
V V- T M F- 5 1 6 1 9 | Pa ge 5 8/ 1 1 2

Pr ot oc ol  
 
Pa ge 5 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
a n d he patitis B vir us ( H B V) a n d he patitis C  vir us .  P atie nts s h o ul d be m o nit ore d f or si g ns a n d 
s y m pt o ms of i nfecti o ns.  Rit u xi ma b s h o ul d be disc o nti n ue d i n patie nts e x perie nci n g seri o us 
i nfecti o ns; patie nts s h o ul d recei v e a nti-i nfecti ve t hera p y as p er i nstit uti o nal g ui deli nes. 
5. 8. 7. 1.  
M o nit ori n g a n d M a n a ge me nt of Rit u xi m a b -i n d uce d H B V Re acti v ati o n  
H B V reacti vati o n wit h f ul mi na nt he patitis, he patic fail ure, a n d d eat h has b ee n s h o w n t o occ ur i n 
patie nts wit h he mat ol o gi c mali g na n cies w h o recei ve d  rit u xi ma b.  T he me dia n ti me t o dia g n osis of 
he patitis was a p pr o xi matel y f o ur m o nt hs f oll o wi n g t h e first d ose of rit u xi ma b a n d a p pr o xi matel y 
o ne m o nt h after t h e last d ose.  K n o w n H B V carrier s ca n partici pate i n  t his st u d y pr o vi de d t he y are 
H Bs A g P C R ne gati ve a n d are recei vi n g a nti viral t hera p y.   R it u xi ma b s h o ul d be disc o nti n ue d i n 
patie nts w h o de v el o p viral he p atitis ; patie nts s h o ul d recei ve a p pr opriate treat me nt i ncl u di n g 
a nti viral t hera p y as p er i nstit uti o nal g ui deli nes .  
5. 8. 8.   
M o nit ori n g of Rit u xi m a b -i n d uce d Se vere M uc o c ut a ne o us Re acti o ns  
M uc oc uta ne o us reacti o ns, s o me wit h fatal o utc o me, ha ve bee n s h o w n t o occ ur i n patie nts treate d 
wit h rit u xi ma b.  T hese reacti o ns i ncl u de para ne o plastic pe m p hi g us, Ste ve ns -J o h ns o n s y n dr o me, 
lic he n oi d der matitis, vesic ul o b ull o us der matitis, a n d t o xic e pi der mal necr ol ysis.  T he o nset of 
t hese reacti o ns h as varie d fr o m 1 t o 1 3 wee ks f oll o wi n g rit u xi ma b e x p os ure.  Rit u xi ma b s h o ul d 
be disc o nti n ue d i n patie nts e x perie nci n g se v ere m uc oc uta ne o us reacti o ns.  
5. 9.   
De bi o 1 5 6 2 a n d Rit u xi m a b D ose M o dific ati o ns  
5. 9. 1.   
Del a y or S ki p D osi n g of St u d y Tre at me nt  
I n or der f or a patie nt t o recei ve a n y st u d y treat me nt ( De bi o 1 5 6 2 al o ne or De bi o 1 5 6 2 a n d 
rit u xi ma b), t he f oll o wi n g re-treat me nt criteria m ust be met. 
 A N C m ust be ≥ 1. 0 x 1 0 9/ L ( 1 0 0 0/ m m3) 
 Platelet c o u nt m ust be ≥ 5 0 x 1 0 9/ L ( 5 0, 0 0 0/ m m3) 
 All n o n -he mat ol o gic t o xicities m ust be ≤ Gra d e 2 (e x ce pt al o pecia) or ret ur ne d t o 
baseli ne  
C o h ort A a n d B : If t he retreat me nt criteria are n ot met o n Da y 1 of a gi ve n c ycle, t he patie nt 
s h o ul d be re-e val uat e d wit hi n 4 8 -7 2 h o urs, a n d d osi n g s h o ul d be dela ye d u n til t he criteria are met. 
If t he retr eat me nt criteri a are met wit hi n 1 4 da ys, st u d y treat me nt s h o ul d res u me at pla n ne d or 
re d uce d d ose (see Secti o n 5. 9. 2 ), a n d t he st u d y p h ysicia n ma y o pt f or t he r o uti ne a d mi nistrati o n 
of sec o n dar y pr o p h yla xis wit h G -C S F d uri n g f oll o wi n g c ycles.  
If t he retr eat me nt criteri a are met wit hi n 1 4-2 1 d a ys, st u d y treat me nt s h o ul d res u me at pl a n ne d or 
re d uce d d ose (see Secti o n 5. 9. 2 ), a n d sec o n dar y pr o p h yla xis wit h G -C S F s h o ul d be a d mi nistere d 
if t he dela y was d u e t o u n met he mat ol o gical para meters.  
If d osi n g is dela ye d f or > 2 1 da ys d ue t o u n met retreat me nt criteria, b ot h st u d y treat me nts s h o ul d 
be disc o nti n ue d (see Secti o n 5. 9. 2 ).    
C o h ort B: If t he retr eat me nt criteria are n ot met o n Da y 8 or Da y 1 5 of a gi ve n c ycle, d osi n g of 
De bi o 1 5 6 2 s h o ul d be s ki p pe d o n t hat visit, sec o n dar y pr o p h yla xis wit h G -C S F will be i n dicate d 
V V- T M F- 5 1 6 1 9 | Pa ge 5 9/ 1 1 2

Pr ot oc ol  
 
Pa ge 6 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
a n d t he retr eat me nt criteria will be re -e val uate d at t he ne xt visit w he n i nf usi o n is pla n ne d  t o 
occ ur. If t he retreat me nt criteria are n ot met o n D a y 1 of t he ne xt c ycle, t h e r ules descri be d a b o v e 
f or t he dela y o n Da y 1 of a n y gi v e n c ycl e will a p pl y. 
5. 9. 2.   
D ose M o dif yi n g E ve nts ( D M E) 
D ose M o dif yi n g E ve nts ( D M Es) are defi ne d as a n y a d v erse e ve nts t hat re q uire d ose re d ucti o n or 
disc o nti n uati o n  of t he st u d y treat me nt.   
 
5. 9 . 2. 1  A d verse E ve nts Re q uiri n g Per m a ne nt St u d y Tre at me nt Disc o nti n u ati o n  
B ot h De bi o 1 5 6 2 a n d rit u xi ma b s h o ul d be per ma ne ntl y disc o nti n ue d i n t he case of t he f oll o wi n g 
treat me nt-relate d e v e nts : 
 ≥ Gra de 3 car diac e v e nt  
 ≥ Gra de 3 c uta ne o us reacti o ns relate d t o rit u xi ma b treat me nt  
 Ot her n o n -he m at ol o gic e ve nts of Gra d e 4 se verit y  
 Gra de 4 t hr o m b o c yt o p e nia lasti n g > 7 d a ys  
 ≥ Gra de 3 n e ur o pat h y    
 D ose dela y > 2 1 da ys d u e t o u n met retreat me nt  criteria 
Rit u xi ma b s h o ul d be per ma ne ntl y disc o nti n ue d i n patie nts e x perie nci n g t he A Es liste d i n  Ta ble  6 . 
T a ble  6 :  
A d verse E ve nts Re q uiri n g Per m a ne nt Disc o nti n u ati o n of Rit u xi m a b  
Se verit y Gr a de  
( C T C A E v 4. 0 3 Gr a de) 
A d verse E ve nt  
A n y Gra de  
B o wel Perf orati o n  
Gra de ≥ 3  
Car dia c Arr h yt h mias 
A n y Gra de  
H y perse nsiti vit y a n d/ or Aller gic Reacti o ns t o rit u xi ma b  
Gra de ≥ 3  
I nfecti o ns 
Gra de ≥ 3  
M uc oc uta ne o us Reacti o ns  
A n y Gra de  
Pr o gressi ve M ultif ocal Le u k oe nce p hal o pat h y  ( P M L) 
Gra de ≥ 3  
Re nal Fail ure  
A n y Gra de  
Viral He patitis  
 
5. 9 . 2. 2 A d verse E ve nts Re q uiri n g D ose Re d ucti o n 
Rit u xi ma b d ose re d ucti o ns are n ot all o we d.  If patie nts d o n ot t olerate treat me nt wit h rit u xi ma b, 
t he y ma y c o nti n ue o n De bi o 1 5 6 2 al o ne. 
 
F or C o h ort A , d ose re d u cti o n of De bi o 1 5 6 2 will occ ur as f oll o ws:  
V V- T M F- 5 1 6 1 9 | Pa ge 6 0/ 1 1 2

Pr ot oc ol  
 
Pa ge 6 1  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 0. 7  m g / k g  0. 4 m g/ k g  
 
F or C o h ort B , d ose re d u cti o n of De bi o 1 5 6 2 will occ ur as f oll o ws:  
 0. 4  m g/ k g  0. 2 m g/ k g  
 0. 2  m g/ k g  0. 1 m g/ k g  
 
D ose of De bi o 1 5 6 2 s h o ul d be re d uce d i n patie nts e x perie nci n g t h e A Es bel o w:  
Sec o n d occ urre nce of h e m at ol o gic eve nts : 
 Gra de 4 n e utr o pe nia l asti n g ≥ 7 da ys  
 Gra de 3 t hr o m b o c yt o p e nia ass ociate d wit h blee di n g  t hat re q uires tr a nsf usi o n 
 Gra de 4 t hr o m b o c yt o p e nia  lasti n g < 7 d a ys 
 ≥ Gra de 3 fe brile n e utr o p e nia  
N o n -he m at ol o gic eve nts : 
 
Gra de 3 n a usea, v o miti n g or di arr h ea , lasti n g m ore t ha n 4 8 h o urs , d es pite t he use of 
o pti mal s u p p orti ve care  
 
Ot her n o n -he m at ol o gic t o xicities ≥ Gra de 3 e x ce pt f or t he f oll o wi n g:  
o  A Es relate d t o u n derl yi n g diseas e  
o  Is olat e d, as y m pt o matic Gra de 3 l a b orat or y bi o c he mistr y a b n or malities t hat 
last f or ≤ 7 da ys or ha v e n ot bee n o pti mall y ma na ge d  
Ot her eve nts : 
 
T w o d ose dela y s ( o n t h e first da y of t w o c o ns ec uti ve c ycles) d ue t o u n met retreat me nt 
criteria  
 
D ose of De bi o 1 5 6 2 ca n be re d uce d f or o nl y o n ce f or a gi ve n patie nt, a n d it ca n n ot be re -
escalate d.  If a p atie nt ca n n ot t olerate treat me nt wit h De bi o 1 5 6 2, b ot h De bi o 1 5 6 2 a n d rit u xi ma b 
s h o ul d be disc o nti n ue d.   
5. 1 0.   
Re m o v al of P at ie nts fr o m t he St u d y  
T he pati e nt is free t o wit h dra w c o nse nt a n d disc o nti n ue partici pati o n i n t he st u d y at a n y ti me 
wit h o ut prej u dice t o f urt her treat me nt .  P atie nts ma y b e disc o nti n ue d fr o m st u d y treat me nt , a n d 
c o nti n ue t o be f oll o we d p er pr ot oc ol,  or t he y m a y be re m o ve d fr o m t he st u d y alt o get h er.  
5. 1 0. 1.   
Disc o nti n u ati o n fr o m St u d y Tre at me nt  
Patie nts ma y be wit h dra w n fr o m st u d y treat me nt at a n y ti me at t heir o w n re q uest, or t he y ma y b e 
wit h dra w n at t he discreti o n of t he I n v esti gat or or S p o ns or  f or s afet y or n o n-c o m plia nce t o t h e 
pr ot oc ol.  
Reas o ns f or per ma ne nt disc o nti n uati o n of b ot h st u d y dr u gs  ma y i n cl u de t he f oll o wi n g: 
 Ra di ol o gical P D  
 
Cli nical pr o gressi o n  
 
Wit h dra wal of c o nse nt  t o st u d y treat me nt, b ut a grees t o t he pr ot oc ol-defi ne d f oll o w u p  
V V- T M F- 5 1 6 1 9 | Pa ge 6 1/ 1 1 2

Pr ot oc ol  
 
Pa ge 6 2  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 A E  
 I n v esti gat or decisi o n  
 St u d y t er mi nate d b y S p o ns or  
 Maj or pr ot oc ol de viati o n or n o n -c o m plia nce  
 Patie nt bec o mes pre g n a nt  
 Deat h  
 Ot her  
De pe n di n g o n t he diseas e state a n d t he t u m or res p o nse, p atie nts w h o per ma ne ntl y disc o nti n ue 
st u d y tr eat me nt will e nter i nt o t he res p o nse a n d s ur vi val f oll o w-u p p orti o n of t he st u d y : p atie nts 
w h o ha d disc o nti n ue d st u d y tr eat me nt d u e t o P D will be f oll o we d -u p f or s ur vi val e ver y 1 2 wee ks 
( ± 4 wee ks) f or u p t o o ne year fr o m t he last patie nt’s first d ose ( C ycl e 1 Da y 1); Patie nts w h o 
disc o nti n ue d t he treat me nt f or reas o ns ot her t ha n P D (i ncl u di n g treat me nt c o m pleti o n) will be 
f oll o we d b y ra di o gra p hic assess me nt e ver y 1 2 wee ks ( ± 4 wee ks) fr o m t he ti me of t he patie nt’s 
last o n-st u d y t u m or assess me nt u ntil d oc u me ntati o n of P D or be gi n ni n g of s u bse q ue nt a nti -ca n cer  
t hera p y (re gi me n a n d start date t o be rec or de d i n t h e E D C). After t he res p o nse f oll o w-u p, patie nts 
will e nter i nt o t he s ur vi val f oll o w -u p. Patie nts will n ot be re q uire d t o visit t he cli nic f or s ur vi val 
f oll o w-u p.  
 
5. 1 0. 2.   
Disc o nti n u ati o n fr o m t he St u d y  
Reas o ns f o r patie nt disc o nti n uati o n fr o m t he st u d y are as f oll o ws: 
 Wit h dra wal of c o nse nt t o st u d y treat me nt a n d f oll o w u p  
o  If a patie nt wit h dra ws fr o m t he st u d y, a n d als o wit h dra ws c o nse nt f or discl os ure of 
f ut ure i nf or m ati o n, n o f urt her st u d y-s pecific e val u ati o ns s ho ul d be perf or m e d, a n d 
n o a d diti o nal data s h o ul d be c ollecte d.  T he S p o ns or ma y retai n a n d c o nti n ue t o use 
a n y d ata c ollecte d bef ore eac h wit h dra wal of c o ns e nt.  
 L ost t o F oll o w -u p  
o  If a patie nt d oes n ot ret ur n f or a sc h e d ule d visit, e ver y eff ort s h o ul d be ma de t o 
c o ntact t he p atie nt.  All atte m pts t o c o ntact t he p atie nt a n d i nf or mati o n recei ve d 
d uri n g c o ntact atte m pts m ust be d oc u me nte d i n t h e patie nt’s me dical rec or d.  E ver y 
eff ort s h o ul d be ma d e t o d oc u me nt patie nt o utc o me.  
 
T he st u d y was  ter mi nate d b y t he S p o ns or 
 I n v esti gat or Decisi o n 
 Deat h  
 Ot her  
V V- T M F- 5 1 6 1 9 | Pa ge 6 2/ 1 1 2

Pr ot oc ol  
 
Pa ge 6 3  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
5. 1 1.   
Peri o d of O bser v ati o n  
F or p ur p os es of t his st u d y, t he p eri o d of safet y o bser vati o n e xte n ds fr o m t h e ti me t he patie nt si g ns 
t he st u d y c o ns e nt u ntil t he fi nal safet y f oll o w-u p visit.  
5. 1 2.   
C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures  
All c o nc o mita nt me dicati o ns a n d s u p p orti ve t hera p y ta ke n wit hi n f o ur wee ks bef ore  C ycle 1, Da y 
1 u ntil t he e n d of t he peri o d of safet y o bs er vati o n m ust be rec or de d o n t he a p pr o priate e C R F.  T he 
i de ntit y of all 
me dicati o ns, d osa ge, a n d r o ute of a d mi nistrati o n, fre q ue nc y, d urati o n of 
a d mi nistrati o n, a n d i n dicati o n f or use will be rec or de d i n t he a p pr o priate secti o ns of t he e C R F.  
5. 1 2. 1.   
A nti ne o pl astic T her a p y  
Ot her c he m ot hera p y, i n vesti gati o nal a ge nts , or bi ol o gic t hera p y will n ot be per mit te d d uri n g t he 
st u d y treat me nt. 
Palliati ve ra di ot hera p y f or l ocal peri p heral met astases n ot bei n g us e d o n  tar get lesi o ns is all o w e d.  
H o we ver, t he nee d f or s uc h t hera p y ma y be a n i n dicati o n of disease pr o gressi o n a n d s h o ul d be 
disc usse d wit h t he S p o ns or pr i or t o i m ple me ntati o n.  Ra di ot hera p y f or ce ntral metastases (e. g. 
verte bral, me diasti nal) will n ot be all o we d; t he n ee d f or s uc h ra di ot hera p y w hile o n t hera p y will 
be see n as a n i n dicati o n of disease pr o gressi o n a n d t he patie nt s h o ul d b e wit h dra w n fr o m t he ra p y. 
5. 1 2. 2.   
He m at o p oietic Gr o wt h  F act ors  
Patie nts recei vi n g rec o m bi na nt er yt hr o p oieti n or dar be p oieti n alfa pri or t o st u d y start ma y c o nti n ue 
t o recei ve pre-tr eat me nt d oses.  T h e use of er yt hr o p oietic gr o wt h fact ors ma y be i m ple me nte d at 
t he discreti o n of t he treati n g p h ysicia n or I n v esti gat or.  T he use of gra n ul oc yte gr o wt h fact ors ma y 
be i m ple me nte d as s pecifie d i n Secti o n  5. 8. 2 . 
5. 1 2. 3.   
Bis p h os p h o n ates  
Bis p h os p h o nates are per mitte d if a patie nt was recei vi n g o n g oi n g bis p h os p h o nate t hera p y at ti me 
of scree ni n g a n d will c o nti n ue o n a sta ble re gi me n t hr o u g h o ut pr ot oc ol t hera p y .  T he nee d t o start 
bis p h os p h o nates w hile o n t hera p y will be see n as a n i n dicati o n of diseas e pr o gressi o n a n d t he 
patie nt s h o ul d be wit h dra w n fr o m t hera p y.  
5. 1 2. 4.   
A ntic o a g ul a nts  
T hera p e utic d oses of a ntic oa g ulati o n t hera p y are per mitte d , as l o n g as pl atelets ≥ 10 0 x 1 0 9/ L 
( 1 0 0, 0 0 0/ m m3) at baseli ne a n d t h e patie nt d o es n ot ha ve a hist or y of ≥ Gra de 2 blee di n g w hile 
ta ki n g a ntic o a g ulati o n t hera p y a n d t h e patie nt has n ot bee n tra nsf use d wit hi n pre vi o us 1 0 da ys . 
Pr o p h ylactic use of l o w d ose a ntic oa g ula nts f or mai nte n a nce of li ne pate nc y is als o all o we d.  
5. 1 2. 5.   
A nti vir als  
W hile bei n g treate d wit h rit u xi ma b,  p atie nts are t o recei ve a nti viral pr o p h yl a xis t hr o u g h o ut t he 
st u d y p er i nstit uti o nal g ui deli nes .  T y p e a n d d osi n g of s uc h will be i m ple me nte d at t he discreti o n 
of t he tre ati n g p h ysicia n or i n vesti gat or.    
V V- T M F- 5 1 6 1 9 | Pa ge 6 3/ 1 1 2

Pr ot oc ol  
 
Pa ge 6 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
5. 1 2. 6.   
I m m u niz ati o ns 
Vacci n ati o n wit h li ve vir uses (e. g., measles, m u m ps, r u bella, or p oli o) is pr o hi bite d .  Vacci nati o ns 
wit h n o n -li ve or ga nis ms (e. g., fl u or teta n us) ma y n ot be effecti ve w hile recei vi n g rit u xi ma b.  
5. 1 2. 7.   
Ot her C o nc o mit a nt  Me dic ati o ns  
Me dicati o ns f or t he tr eat me nt of A Es  or ca ncer s y m pt o ms , e. g. p ac k e d re d bl o o d cells a n d pai n 
me dicati o ns , are all o we d.  Pr o p h yl actic use of ster oi ds a n d/ or a nti hista mi nes are re q uire d f or 
pri mar y pr o p h yl a xis a gai nst i nf usi o n reacti o n .  Si milarl y, t he use of pr o p h yl actic a nti bi otics are 
per mitte d  if nee de d t o miti gate ris k of i nfecti o n.  A d diti o nal me dicati o ns ( n ot a d dresse d a b o v e) 
use d t o treat u n derl yi n g me dical c o n diti o ns at st u d y e ntr y i ncl u di n g a nti -e metics a n d a nti -
diarr heals w ill be all o we d t o c o nti n ue. A nti b o d y -ma yt a nsi ne c o nj u gates wit h n o nclea va ble 
t hi oet her-li n ke d D M 1 as t he c yt ot o xic a ge nt s uc h as De bi o 1 5 6 2 are n ot e x pecte d t o ha ve a 
p ote ntial f or dr u g -dr u g i nteracti o n wit h a n y of t he maj or h u ma n C Y Ps (see I B f or a d diti o n al 
i nf or mati o n). 
5. 1 3.   
O ver d ose a n d Me dic ati o n Err or  
O ver d ose –  T h ere is n o k n o w n treat me nt/a nti d ote a vaila ble f or De bi o 1 5 6 2  or rit u xi ma b .  
S u p p orti ve meas ures s h o ul d be i nstit ute d if a n i nsta nce arises i n w hic h a patie nt s uffers a n 
o ver d ose of st u d y dr u g.  
Me dicati o n Err or –  A n y mista ke ma de i n pres cri bi n g, dis pe nsi n g, a d mi nisteri n g a n d/ or use of 
De bi o 1 5 6 2  or rit u xi ma b m ust be re p orte d t o t he s p o ns or i m me diatel y a n d rec or de d o n t he e C R F.  
 
V V- T M F- 5 1 6 1 9 | Pa ge 6 4/ 1 1 2

Pr ot oc ol  
 
Pa ge 6 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
6.   
P H A R M A C O KI N E TI C 
 
6. 1.   
P K Assess me nts  
Bl o o d sa m ples f or P K meas ure me nts will be c ollecte d fr o m all patie nts (A p pe n di x  D , A p pe n di x  E , 
A p pe n di x  F ). Details of sa m ple pre parati o n a n d s hi p pi n g are pr o vi de d i n t h e La b o rat or y Ma n ual. 
De bi o 1 5 6 2 P K –  Patie nt plas ma sa m ples will be a nal yz e d t o meas ure c o nj u gate, t otal a nti b o d y 
a n d/ or na ke d a nti b o d y, free D M 1 a n d b o u n d D M 1; a d diti o nal meta b olites ma y b e e val u ate d.  
Rit u xi ma b P K - t otal rit u xi ma b will be meas ure d. 
Bl o o d sa m ples f or De bi o 1 5 6 2 a n d rit u xi ma b P K meas ure me nts i n Part 1 a n d Part 2 of t he st u d y 
will be c ollecte d as d escri be d i n A p pe n di x  D , A p pe n di x  E , A p pe n di x  F . 
I n part 3 of t he st u d y, if t he Q 3 W re gi me n is c o nti n ue d, t he P K sa m pli n g sc he d ule will be t he s a me 
t o t hat i n t he C o h ort A of Part 2; if t he Q W re gi m e n is c o nti n ue d, t he P K s a m pli n g sc h e d ule will 
be t he sa m e t o t h at i n t he C o h ort B of Part 2. H o we ver, t he I D M C ma y rec o m me n d s o me c ha n ges 
i n t he sa m pli n g sc he m e f oll o wi n g re vie w of trial d ata.  
At t he en d of treat me nt ( E O T) a n d 3 0-d a y safet y foll o w -u p visit, bl o o d dra ws  will be t a ke n f or P K 
assess me nt a n d f or a nti -dr u g a nti b o dies ( A D A). 
I n p atie nts w h o e x ce pti o nall y c o nti n ue t he st u d y treat me nt be y o n d C ycle 6, t he last P K sa m ple 
will be ta ke n at C 7 D 1 at pre -d os e bl o o d dra w i nstea d of at t he E O T visit . F or p atie nts alrea d y 
be y o n d C 7 D 1 after ame n d me nt # 5 , t he last P K sa m ple will be ta ke n  at D1 of t he  ne xt p ossi ble  
s u bse q ue nt c ycle at pre-d ose bl o o d dra w i nstea d of at t he E O T visit . N o a d diti o nal sa m ples will 
be  ta ke n at 3 0-d a y f oll o w -u p visit.  
6. 1. 1.   
U nsc he d ule d Visits  
A n y p atie nt w h o e x perie nces a ≥ Gra de 2 i nf usi o n-relate d reacti o n d uri n g t he a d mi nistrati o n of 
De bi o 1 5 6 2 will ha ve bl o o d dra w n wit hi n t hree h o urs of t he o nset of t he reacti o n a n d o ne wee k 
later f or deter mi nati o n of dr u g c o nce ntrati o n t o De bi o 1 5 6 2. 
P K sa m ples ma y als o b e o btai ne d  at a n y ti me d u ri n g t he treat me nt peri o d f or assess me nt of 
treat me nt-relate d A Es, if dee me d a p pr o priate b y t h e I n vesti gat or a n d S p o ns or. 
6. 2.   
I m m u n o ge nicit y Assess me nts 
T he p ote ntial i m m u n o ge nicit y a gai nst De bi o 1 5 6 2  or D M 1  or rit u xi ma b will be assesse d i n pre -
d ose plas ma sa m ples  at Da y 1 a n d at a n y ti me p oi nt f or t he ot her da ys of  P K e val uati o n i n all 
c ycles as o utli ne d i n Secti o n  6. 1 , a n d at a n y ti me p oi nt  f or sa m ples ta ke n at t he E O T  a n d 3 0-d a y 
safet y f oll o w-u p visit  (A p pe n di x  D , A p pe n di x  E , a n d A p pe n di x  F ).   
I n patie nts w h o e x ce pti o nall y c o nti n ue t he st u d y treat me nt be y o n d C ycl e 6, t he last sa m ple f or 
A D As will be ta ke n at C 7 D 1 at pre -d ose bl o o d dra w, i nstea d of at t he E O T visit . F or patie nts 
alrea d y b e y o n d C 7 D 1 after a me n d me nt # 5, t h e last A D A  sa m ple will be t a ke n at D 1 of t he n e xt 
p ossi ble s u bse q ue nt c ycle at pre-d ose bl o o d dra w i nstea d of at t he E O T visit . N o  a d diti o nal 
sa m ples will be ta ke n at t he 3 0-da y f oll o w -u p visit.  
V V- T M F- 5 1 6 1 9 | Pa ge 6 5/ 1 1 2

Pr ot oc ol  
 
Pa ge 6 6  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
T he st u d y will e v al uate t he p ote ntial i m pact of i m m u n o ge nicit y o n P K, safet y, a n d a nti -t u m or 
acti vit y of De bi o 1 5 6 2  a n d t otal  K 7 1 5 3 A  a nti b o d y.  I n case of n o n -p er pr ot oc ol rit u xi ma b e x p os ure 
or safet y fi n di n gs , t he p ote ntial i m pact of i m m u n o ge ni cit y o n rit u xi ma b P K c o ul d be assesse d.  
Details of sa m ple pre parati o n a n d s hi p pi n g are pr o vi de d i n t he La b orat or y Ma n ual.  
6. 2. 1.   
U nsc he d ule d Visits  
A n y p atie nt w h o e x perie nces a ≥ Gra de 2 i nf usi o n -relate d reacti o n d uri n g t he a d mi nistrati o n of 
De bi o 1 5 6 2 will ha ve bl o o d dra w n wit hi n t hree h o ur s of t he o nset of t he reacti o n a n d o ne wee k 
later f or deter mi nati o n of A D A f or mati o n. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
V V- T M F- 5 1 6 1 9 | Pa ge 6 6/ 1 1 2

Pr ot oc ol  
 
Pa ge 6 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
7.   
T R A N S L A TI O N A L R E S E A R C H S T U DI E S  
  
 
 
 
 
 
 
 
 
 
T he e x pl orat or y e val uati o ns will be re p orte d se p aratel y.  
 
V V- T M F- 5 1 6 1 9 | Pa ge 6 7/ 1 1 2

Pr ot oc ol  
 
Pa ge 6 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
8.   
S T U D Y P R O C E D U R E S  
T he sc he d ule of cli nical 
 st u d y assess me nts a n d pr oce d ures is detaile d i n t he 
Sc he d ule s of E ve nts  (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 t he sc hed ule of P K a n d 
i m m u n o ge nicit y assess m e nts are d etaile d i n A p pe n di x  D , A p pe n di x  E , a n d A p pe n di x  F . 
8. 1.   
I nf or me d Co nse nt  
Eac h patie nt m ust pr o vi de writte n i nf or me d c o nse nt bef ore a n y st u d y -re q uire d pr oce d ures are 
c o n d ucte d, u nless t h ose pr oce d ures are perf or me d as part of t he patie nt’s sta n dar d care.   
8. 2.   
I ncl usi o n a n d E xcl usi o n Criteri a 
T he i ncl usi o n a n d e x cl usi o n crite ria will be assess e d d uri n g scree ni n g a n d a gai n  o n C ycle 1 Da y 
1  pri or t o d osi n g .   
8. 3.   
C o nfir m ati o n of Dise ase Di a g n osis  
At scree ni n g, dise ase dia g n osis, t he sta ge at ori gi nal dia g n osis, a n d c urre nt disease stat us will be 
c o nfir me d i n acc or da nce wit h t he A n n Ar b or sta gi n g criteria ( A p pe n di x  K , Ar mita ge  2 0 0 5 ). 
8. 4.   
De m o gr a p hic/ Me dic al Hist or y  
T he a ge, race, a n d ge n der of t he patie nt are t o be rec or de d d uri n g scree ni n g.  
D uri n g t he Scree ni n g peri o d, a c o m plete me dical hist or y f or all me dicall y releva nt c o n diti o ns will 
be c o m pile d f or eac h p atie nt.   
8. 5.   
Pri or a nti -c a ncer tre at me nt f or L y m p h o m a  
All pri or a nti -ca ncer t h era p ies f or t he treat me nt of l y m p h o ma m ust be rec or de d i n t he E D C: 
gr o u pi n g if p ossi ble t he i n di vi d ual a ge nts bel o n gi n g t o t he sa m e treat m e nt re gi me n (e. g. R -C H O P, 
R -I C E, R-Ge m o x, etc), t he mai nte na nce t hera p y if a n y, wit h i n dicati o n of t he starti n g a n d e n d -
dates, t he best res p o nse ac hie ve d, a n d t he pri mar y reas o n f or disc o nti n uati o n if a p plica ble. T he 
e n d-date of t he last treat me nt re gi me n a n d t he date of t he s u bse q ue nt disease pr o gressi o n m ust be 
a vaila ble. If a p plica ble, t he h i g h-d os e t hera p y a n d t he b o ne marr o w tra ns pla ntati o n s h o ul d be 
descri be d as part of t h e s a me re gi me nt. Reas o n f or patie nts’ i neli gi bilit y f or H A -A S C T s h o ul d be 
rec or de d as w ell. 
8. 6.   
Vit al Si g ns  
Vital si g ns i ncl u di n g bl o o d press ure, heart rat e, te m perat ure, a n d res pirat or y rate will be meas ure d 
at t he ti mes s pecifie d i n t he Sc he d ule of E ve nts  (A p pe n di x  A , A p pe n di x  B  a n d A p pe n di x  C ). 
8. 7.   
P h ysic al E x a mi n ati o n , Wei g ht a n d Hei g ht 
P h ysical e x a mi nati o n, hei g ht (scree ni n g o nl y) a n d wei g ht m ust be perf or me d as i n dicat e d i n t he 
Sc he d ule of 
E ve nts  (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 c o m plete p h ysical 
e x a mi nati o n  i ncl u di n g assess me nts of ge neral a p p eara n ce, s ki n, hea d (e yes, ears, n ose, a n d t hr oat), 
nec k, l u n gs, heart, a b d o me n, bac k, l y m p h n o d es, e xtre mities, a n d ne ur ol o gical s ys t e m will be 
V V- T M F- 5 1 6 1 9 | Pa ge 6 8/ 1 1 2

Pr ot oc ol  
 
Pa ge 6 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
c o m plete d at s cree ni n g  a n d E O T .  Directe d p h ysical e x a mi nati o ns will be c o m plete d at a d diti o nal 
ti me p oi nts as s pecifie d i n t he Sc he d ule of E ve nts.  
8. 8.   
Assess me nt of He alt h -rel ate d Q u alit y of Life  
I n Part 2 a n d Part 3 of t he st u d y, H R Q o L will be assesse d at Da y 1 of eac h c ycl e  ( bef ore De bi o 
1 5 6 2 i nf usi o n) , at t he E O T visit a n d at t he 3 0 -da y s afet y foll o w -u p visit  (A p pe n di x  B  a n d 
A p pe n di x  C ). T he F A C T -L y m i nstr u me nt will be use d a n d will be self -a d mi nistere d via pe n a n d 
pa per. T he F A C T -L y m is a sta n dar diz e d meas ure of H R Q o L s pecific t o patie nts wit h  N H L . It is 
c o m prise d of t h e F u n cti o nal Assess me nt of Ca ncer T hera p y -Ge neral versi o n 4 ( 2 7 ite ms), s c ore d 
i n f o ur d o mai ns ( P h ysical w ell-bei n g:  7 ite ms; S ocial/ Fa mil y  well -bei n g:  7 ite ms;  E m oti o nal  well -
bei n g:  6 ite ms; F u n cti o nal well -bei n g:  7 ite ms), a n d t he F A C T -L y m p h o ma S u bscale , reflecti n g 
L y m p h o ma s pecific c o n cer ns ( 1 5 ite ms).  
I n p atie nts w h o e x ce pti o nall y c o nti n ue t he st u d y treat me nt be y o n d C ycle 6, t he last H R Q o L 
assess me nt will be  perf or me d at C 7 D 1 bef ore i nf usi o n i nstea d of at E O T visit, a n d n o a d diti o nal 
H R Q o L assess me nt will be c o m plete d at t he 3 0 -d a y f oll o w -u p visit.  
8. 9.   
Electr oc ar di o gr a m ( E C G)  
A sta n dar d 1 2 -lea d E C G will be perf or me d as o utli ne d i n t he Sc he d ules of E ve nts ( A p pe n di x  A , 
A p pe n di x  B  a n d A p pe n di x  C ).  
8. 1 0.   
L a b or at or y Assess me nts  
L a b orat or y assess me nts  will be perf or me d as o utli ne d i n t he Sc he d ule s of E ve nts (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 as cli nicall y i n dicate d.    
N ote t hat pri or t o eac h a d mi nistrati o n of De bi o 1 5 6 2 , la b orat or y res ults m ust be re vie we d t o 
e val uate f or p ote ntial t o xicit y.   
Cli nical la b orat or y tests will i ncl u de t he f oll o wi n g:  
8. 1 0. 1.   
He m at ol o g y  
 He mat ocrit ( Hct)  
 Re d bl o o d cell ( R B C) c o u nt  
 He m o gl o bi n ( H g b)  
 W B C c o u nt wit h differe ntial  
 Platelet c o u nt  
 
8. 1 0. 2.   
Ser u m C he mistr y  
 Al b u mi n  ( A L B) 
 Lactate d e h y dr o ge n ase ( L D H)  
 Al kali ne p h os p hatase ( A L K -P)   
 Ma g n esi u m  
 A L T; S G P T  
 P h os p h or us  
 A S T; S G O T  
 P otassi u m ( K)  
V V- T M F- 5 1 6 1 9 | Pa ge 6 9/ 1 1 2

Pr ot oc ol  
 
Pa ge 7 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 Bl o o d urea nitr o ge n ( B U N)   
 S o di u m ( Na)  
 Calci u m ( Ca)  
 T otal bilir u bi n  
 C hl ori de ( Cl)  
 T otal pr otei n  
 Creati ni ne  
 Uric aci d  
 Gl uc ose  
 I m m u n o gl o b uli n le vels (I g G, I g A, I g M) 
8. 1 0. 3.   
Uri n al ysis  
 A p peara nce, s p ecific gra vit y a n d p H  
 Se mi -q ua ntitati ve di pstic k e val uati o n of gl uc ose, pr otei n, bilir u bi n, ket o nes, le u k oc yt es 
a n d bl o o d  
 Micr osc o pic e x a mi nati o n of se di me nt t o be perf or me d if uri nal ysis is p ositi ve f or 
W B C, pr otei ns or bl o o d  
8. 1 0. 4.   
C o a g ul ati o n  
 Pr ot hr o m bi n ti me ( P T) or I N R  
 Acti vate d  partial t hr o m b o plasti n ti me (a P T T)  
8. 1 0. 5.   
Vir al Ser ol o g y  
Patie nts will be teste d d uri n g scree ni n g f or H Bs A g.  
8. 1 1.   
Pre g n a nc y Scree n  
All fe male patie nts of c hil d -beari n g p ote ntial will c o m plete a ser u m beta -h u ma n c h ori o nic 
g o na d otr o pi n ( -h C G) or uri ne pre g n a nc y t est (as I nstit uti o nal or C o u ntr y re q uire me nts dictate)  
d uri n g scree ni n g a n d at ti me p oi nts s pecifie d i n t he Sc he d ule s of E ve nts ( A p pe n di x  A , A p pe n d i x B  
a n d A p pe n di x  C ).  T he S p o ns o r will n otif y i n v esti gat ors w here c o u ntr y-s pecific pre g na nc y testi n g 
re q uire me nts are re q uest e d b y t h e Nati o nal Healt h A ut h orit y.  If t h e test is perf or me d wit hi n t hree 
da ys pri or t o start of st u d y tr eat me nt, it nee d n ot b e re p eate d o n Da y 1 of C ycl e 1.   T h e pre g na nc y  
test res ult m ust be ne gati ve f or t he patie nt t o be e nr olle d a n d t o recei ve t he st u d y dr u g.  
If a fe male p atie nt bec o m es pre g n a nt w hile partici p ati n g i n t his st u d y, t h e I n v esti gat or a n d S p o ns or 
m ust be i nf or me d i m me diatel y a n d t he patie nt will b e wit h dra w n fr o m st u d y treat me nt  if t he 
pre g na nc y is c o nfir me d  (Secti o n 9. 2. 2 ). 
Fe male patie nts w h o are n ot of c hil d beari n g p ote ntial  are defi ne d t h ose meet i n g at least o ne of t he 
f oll o wi n g criteria: 
1.  Ha ve u n der g o ne a d oc u me nte d h ysterect o m y a n d/ or bilateral o o p h orect o m y;  
2.  Ha ve me dicall y -c o nfir m e d o varia n fail ure;  
3.  Ac hie ve d  p ost me n o pa us al stat us, defi ne d as f oll o ws: cessati o n of re g ular me nses f or at 
least 1 2 c o nsec uti ve m o nt hs wit h n o alter nati ve pat h ol o gical or p h ysi ol o gical ca use; 
V V- T M F- 5 1 6 1 9 | Pa ge 7 0/ 1 1 2

Pr ot oc ol  
 
Pa ge 7 1  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
stat us ma y be c o nfir me d b y ha vi n g a s er u m f ollicl e sti m ulati n g h or m o ne le vel wit hi n t he 
la b orat or y’s refere n ce ra n ge f or p ost me n o pa us al w o me n. 
8. 1 2.   
B -s y m pt o m assess me nt 
B -s y m pto ms ( u ne x plai ne d fe vers [ b o d y te m perat ure of > 3 8° C elsi us ], dre nc hi n g ni g ht s weats 
a n d/ or wei g ht l oss greater t ha n 1 0 % of b o d y wei g ht) will be d oc u me nte d at ti me p oi nts s pecifie d 
i n t he Sc he d ule of E ve nts (A p pe n di x  A , A p pe n di x  B  a n d A p pe n di x  C ).   
8. 1 3.   
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us  
E C O G perf or ma n ce stat us ( A p pe n di x  H ) will be assesse d d uri n g scree ni n g a n d at ot her ti mes 
s pecifie d i n t he Sc h e d ule of E ve nts (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 assess me nt 
is n ot necessar y o n Da y 1 of C ycl e 1 if t he scree ni n g assess me nt was o bt ai ne d wit hi n t hree da ys 
pri or t o Da y 1.  
8. 1 4.   
R a di ol o gic I m a gi n g  a n d T u m or Res p o nse Assess me nt  
T u m or res p o nse assess m e nt will be base d o n t he 5 -p oi nt scale p er t he L u ga n o classificati o n of 
res p o nse ass ess me nts of H o d g ki n a n d N H L  (C hes o n 2 0 1 4 ). 
R a di o gra p hic t u m or e val uati o n b y c o m p ute d t o m o gra p h y ( C T ) or p ositr o n -e missi o n t o m o gra p h y 
(P E T )-C T  sca n of c h est, nec k, a b d o me n, a n d p el vis will be p erf or me d wit hi n 2 8 da ys pri or t o first 
d ose  of st u d y treat me nt .  T he a nat o mical re gi o ns t o be assesse d ra di o gra p hi call y p ost b aseli ne will 
be deter mi ne d i n di vi d uall y b y e xte nt of disease. T h o u g h less preferre d, a M RI is acce pta bl e.  
Patie nts wit h F D G -a vi d disease will be f oll o we d b y [1 8F] -F D G -P E T sca n.  R e peat ass ess me nts  will 
be perf or me d e ver y 6 wee ks  ±  1 wee k , be gi n ni n g at C ycl e 1, Da y 1 a n d will n ot s hift as a res ult  of 
dela ys i n st u d y treat me nt . 
W he ne ver p ossi ble, t he sa me ra di o gra p hic sca n assess me nt use d at scree ni n g (e. g., P E T -C T) 
s h o ul d be use d at all s u bse q ue nt ra di o gra p hic e v al uati o ns.   
Res p o nse F oll o w -u p:  Patie nts w h o ha ve disc o nti n ue d st u d y treat me nt f or reas o ns ot her t ha n P D 
will be f oll o we d b y ra di o gra p hic ass ess me nt  e ver y 1 2 wee ks ( ±  4  wee ks) , b e gi n ni n g fr o m t he ti me 
of t he patie nt’s last o n -st u d y t u m or assess me nt, u ntil d oc u me ntati o n of P D, or be gi n ni n g  
s u bse q ue nt a nti-ca n cer t hera p y or  d eat h . 
F or patie nts w h o are e x ce pti o nall y gra nt e d c o nti n u e d st u d y treat me nt after c o m pleti o n of 6 c ycles, 
re peat ra di o gra p hic t u m or res p o nse assess me nts ca n be perf or me d as per l ocal i nstit uti o nal care 
practice. I deall y, re p eat assess me nts s h o ul d c o nti n ue at 6 -wee k ( ±  1 wee k) i nter vals a n d s h o ul d 
n ot be l o n ger t h a n 1 2 -wee ks ( ± 4 wee ks).  Peri o di c t u m or assess me nt will be c o n d uct e d usi n g t he 
sa me i ma gi n g m o dalit y of pri or c ycles of treat me nt u ntil P D, start of a n y n e w a nti-ca ncer t hera p y, 
or deat h.  
8. 1 5.   
B o ne M arr o w Assess me nt  
If a p plica ble, a b o n e marr o w assess me nt will be perf or me d wit hi n t hree m o nt hs pri or t o t he first 
d ose. A re peat b o ne marr o w bi o ps y or as pirat e will be re q uire d f or p atie nts wit h b o ne marr o w 
i nfiltrati o n at baseli ne w h o ha ve a C R  b y i ma gi n g a n d p h ysical e x a mi nati o n  a n d will, i n case 
p ossi ble a n d dee me d acce pta ble b y t he In vesti gat or , be perf or me d e ver y 6 wee ks as cli nicall y 
V V- T M F- 5 1 6 1 9 | Pa ge 7 1/ 1 1 2

Pr ot oc ol  
 
Pa ge 7 2  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
i n dicate d. I n or der t o better u n dersta n d t he effect of De bi o 1 5 6 2  o n W B C s, b o ne marr o w 
bi o psies/as pirates ma y als o be re q ueste d  f or t h ose patie nts w h o e x perie nce G ra de 4 c yt o p e nias. 
8. 1 6.   
T u m or Bi o ps y   
Patie nts m ust pr o vi de a fres h or arc hi ve d t u m or bi o ps y sa m ple reflecti n g t h eir D L B CL disease. If 
t he tiss ue bi o ps y is ol der t ha n 1 8 m o nt hs a n d a fres h o ne ca n n ot be a v aila ble, patie nt s h o ul d pr o vi de 
F N A s a m ples as d escri be d i n t he la b ma n ual. De -i de ntifie d pat h ol o g y re p orts s h o ul d be i ncl u de d 
wit h sa m ple s hi p me nt t o t he S p o ns or or desi g n ee . A d de n d u ms t o pat h ol o g y re p orts s h o ul d be 
s hare d wit h t he S p o ns or or desi g n ee as s o o n as t h e y are a vaila bl e.  If a pati e nt has a t u m or bi o ps y 
o btai ne d a n y ti me w hile o n st u d y, sli des ma y b e re q ueste d t o be se nt t o t he S p o ns or f or f urt her 
 testi n g or testi n g f or t he pres e nce of D e bi o 1 5 6 2 or D M -1 i n t he sa m ple ; t he 
pat h ol o g y re p ort f or s u c h a sa m ple s h o ul d als o b e s hare d wit h t he S p o ns or. If t here is n o me dical 
ur ge nc y, t he ti mi n g of t he bi o ps y or s ur gical o perati o n relati ve t o t he a d mi nistrati o n of De bi o 1 5 6 2 
a n d t he nat ure of t he sa m ple t o be gi ve n t o t he S p o ns or s h o ul d be c o or di nate d wit h t he S p o ns or, 
i n or der t o e n a ble o bser vati o n of t he dr u g a n d/ or its c o m p o ne nts i n t he t u m or. Pat h ol o g y re p orts 
perf or me d o n ol der bi o psies of t he patie nt s h o ul d be s hare d wit h t he S p o ns or or desi g nee w he n 
a vaila ble.  
Details of sa m ple pre p arati o n a n d s hi p pi n g of t u m or bi o psies are des cri be d i n t he La b orat or y 
Ma n ual.  
 
  
 
 
 
 
V V- T M F- 5 1 6 1 9 | Pa ge 7 2/ 1 1 2

Pr ot oc ol  
 
Pa ge 7 3  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
9.   
A S S E S S M E N T O F S A F E T Y  
9. 1.   
Rec or di n g A d verse E ve nts a n d Seri o us A d verse E ve nts  
A Es (i ncl u di n g S A Es) will be d oc u me nte d o n t he A E e C R F a n d m o nit ore d c o nti n u o usl y 
t hr o u g h o ut t he st u d y fr o m t he ti me i nf or me d c o nse nt is o btai ne d u ntil 3 0 da ys after t he patie nt’s 
last st u d y treat me nt or u ntil t he e ve nt has res ol ve d or sta bilize d or a n o utc o me has bee n reac he d, 
w hic he ver c o mes first.  
F or patie nts w h o disc o nti n ue st u d y tr eat me nt d ue t o a st u d y -rel ate d A E, t he re p orti n g ti me-pe ri o d 
ma y be e xte n de d. T hese patie nts m ust be f oll o we d at least o nce a wee k f or f o ur wee ks, a n d 
s u bse q ue ntl y at 4-wee k i nter vals u ntil res ol uti o n or sta bilizati o n of t he A E  or la b orat or y 
a b n or malit y, w hi c he ver c o mes first ( Secti o n  5. 1 0. 1 ). 
If t he I n vesti gat or c o nsi d ers it necess ar y t o re p ort a n A E c o nsi dere d st u d y dr u g relate d i n a patie nt 
occ urri n g aft er t he e n d of st u d y, he or s he s h o ul d c o ntact t he S p o ns or t o deter mi ne h o w t he A E 
s h o ul d be d oc u me nte d a n d re p orte d. 
9. 1. 1.   
Defi niti o n of A d verse E ve nts  
9. 1. 1. 1.  
A d verse E ve nt ( A E)  
A n A E is a n y n o xi o us, pat h ol o gic, or u ni nte n d e d c ha n ge i n a nat o mical, p h ysi ol o gic, or meta b olic 
f u ncti o n as i n dicat e d b y p h ysical si g ns, s y m pt o ms, or la b orat or y c h a n ges occ urri n g i n a n y p h ase 
of a cli nical st u d y, w het h er or n ot c o nsi dere d st u d y dr u g -relate d.  T his i ncl u des a n e x acer bati o n of 
a pre-e xisti n g c o n diti o n. A Es i ncl u de:  
 W orse ni n g (c ha n ge i n nat ure, se verit y, or fre q ue n c y) of c o n diti o ns prese nt at t he o nset 
of t he st u d y  
 I nterc urre nt ill nesses 
 Dr u g i nteracti o ns  
 E ve nts relate d t o or p ossi bl y rel ate d t o c o nc o mita nt me dicati o ns  
 A b n or mal la b orat or y v al ues (t his i ncl u des si g nifi ca nt s hifts fr o m baseli ne wit hi n t he 
ra n ge of n or mal t hat t he I n vesti gat or c o nsi ders t o be cli nicall y i m p orta nt) 
 Cli nicall y si g nifica nt a b n or malities i n p h ysical e xa mi nati o n, vital si g ns, a n d wei g ht  
N ote t hat P D  s h o ul d n ot be re p ort e d as a n A E. 
T hr o u g h o ut t h e st u d y, t he I n vesti gat or m ust rec or d all A Es w hic h o c c ur i n a patie nt fr o m t he ti me 
t hat i nf or me d c o nse nt is o btai ne d u ntil 3 0 da ys after last st u d y treat me nt o n t h e A E C R F, re gar dless 
of t he se verit y or relati o ns hi p t o st u d y dr u g. T he I n v esti gat or s h o ul d treat patie nts wit h A Es 
a p pr o priatel y a n d o bs er ve t he m at s uita ble i nter vals u ntil t he e ve nts sta bilize or res ol ve. A Es ma y 
be disc o vere d t hr o u g h o bser vati o n or e x a mi nati o n of t he patie nt, q u esti o ni n g of t he p atie nt, 
c o m plai nt b y t he patie nt, or b y a b n or mal cli nical la b orat or y v al ues.  
I n a d diti o n, A Es ma y als o i ncl u de la b orat or y val u es t hat bec o me si g nifica ntl y o ut of ra n ge.  S uc h 
a b n or mal la b orat or y v al u es or test res ults c o nstit ute A Es if t he y i n d u ce cli ni cal si g ns or s y m pt o ms, 
i.e., are c o nsi dere d cli nicall y si g nifica nt (e. g., a cli nicall y si g nifica nt A E res ulti n g i n st u d y 
V V- T M F- 5 1 6 1 9 | Pa ge 7 3/ 1 1 2

Pr ot oc ol  
 
Pa ge 7 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
disc o nti n uati o n c o nstit utes i n a n d of itself a n  S A E ), or re q uire t hera p y (e. g., a n y h e mat ol o gi c 
a b n or malit y t hat re q uires tra nsf usi o n or gra n ul o c yt e gr o wt h fact or  treat me nt); a n d s h o ul d be 
rec or de d o n t he A E e C R F u n der t he si g ns, s y m pt o ms or dia g n osis ass ociate d wit h t he m. F or 
a b n or mal la b orat or y v al ues t hat q ualif y as a D M E, patie nts m ust ha ve a n e v al uati o n wit hi n 4 8 -7 2 
h o urs, a n d t he n f oll o we d u ntil ret ur n t o baseli ne or sta bilizati o n, w hic he ver c o mes first . 
A n A E will be c o nsi dere d t o be a T E A E  if it be gi ns or w orse ns o n or after t he first d ose of De bi o 
1 5 6 2 or rit u xi ma b, w hic he ver occ urs first, a n d bef ore t he 3 0 -da y f oll o wi n g t he last d ose of De bi o 
1 5 6 2 or rit u xi ma b, w hic he ver occ urs last . 
9. 1. 1. 2.  
 Seri o us A d verse E ve nt ( S A E)  
A S A E is a n y A E o cc urri n g at a n y d ose t hat res ults i n a n y of t he f oll o wi n g o utc o mes:  
 Deat h  
 Is life-t hreate ni n g 
 Re q uires i n patie nt h os pitalizati o n  
 Re q uires pr ol o n gati o n of e xisti n g h os pitalizati o n  
 A persiste nt or si g nifica nt disa bilit y or i nca p acit y or s u bsta ntial disr u pti o n of t he a bilit y 
t o c o n d uct n or mal life f u ncti o ns 
 A c o n ge nital a n o mal y or birt h defect  
 I m p ort a nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life-t hreat e ni n g, or re q uire 
h os pitalizati o n ma y b e 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 gme nt, t he y ma y je o par dize t he p atie nt a n d ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o m es liste d i n t his defi niti o n.  E xa m ples of s u c h 
me dical e ve nts i ncl u de aller gic br o nc h os p as m re q uiri n g i nte nsi ve treat me nt i n a n 
e mer ge n c y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n 
i n patie nt h os pitalizati o n. 
N ote t hat h os pitalizati o n is defi ne d as a d missi o n t o treat a cli nical A E .  T he f oll o wi n g e v e nts w o ul d 
n ot be c o nsi dere d h os pitalizati o ns f or S A E re p orti n g p ur p o ses: 2 3-h o ur h ol d f or o bser vati o n, 
a d missi o n t o a h os pice facilit y or n ursi n g h o m e, res pite care, o ut patie nt s ur ger y, s ocial a d missi o n 
(e. g. a patie nt w h o h as n o w here t o sle e p) or a d missi o n n ot ass ociate d wit h a preci pitati n g cli nical 
A E  (e. g. electi ve or pre -pla n ne d s ur ger y, or i n -p atie nt a d mi nistrati o n of s u bse q ue nt c he m ot hera p y, 
etc.).  
All A Es will be e v al uate d acc or di n g t o  versi o n 4. 0 3  of N CI C T C A E.  If t h e A E is n ot liste d i n t he 
C T C A E versi o n 4. 0 3 , it s h o ul d be gra de d f or se v erit y base d o n t he descri pti o n gi ve n  i n Ta bl e  7 .
V V- T M F- 5 1 6 1 9 | Pa ge 7 4/ 1 1 2

Pr ot oc ol  
 
 Pa ge 7 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
T a ble  7 :  
A d verse E ve nt Se verit y  
Se verit y  
Defi niti o n  
Gra de 1 ( Mil d)  
N o li mitati o n o f us ual acti vities. 
Gra de 2 ( M o derate)  
S o me li mitati o n of us ual acti vities.  
Gra de 3 ( Se vere)  
I na bilit y t o carr y o ut us ual acti vities. 
Gra de 4 ( Life -t hreate ni n g or disa bli n g ) 
I m me diate ris k of deat h. 
Gra de 5 ( Fatal)  
Res ulti n g i n deat h  
 
Relati o ns hi p of  a n A E or S A E t o st u d y me dicati o n is t o be deter mi ne d b y t he I n vesti gat or bas e d 
o n t he defi niti o ns i n  Ta ble 8 .  Relati o ns hi p s h o ul d be attri b ute d n ot o nl y t o t he c o m bi nati o n 
re gi me n, b ut als o t o eac h dr u g wit hi n t he c o m bi nati o n re gi me n. 
T a ble  8 :  
A d verse E ve nt Rel ate d ness  
Rel ati o ns hi p t o P r o d uct(s)   
Defi niti o n  
N ot Relate d  
N o relati o ns hi p bet wee n t he e ve nt , i ncl u di n g la b orat or y test a b n or malit y 
a n d t he a d mi nistrati o n of st u d y dr u g .  T here is n o te m p oral relati o ns hi p 
a n d t here is u na m bi g u o us e vi de nce s u p p orti n g a n ot her ca use .   
U nli kel y Relate d  
A cli nical e ve nt , i ncl u di n g la b orat or y test a b n or malit y, wit h a te m p oral 
relati o ns hi p t o st u d y dr u g a d mi nistrati o n 
w hic h ma kes a 
ca usal 
relati o ns hi p i m pr o ba ble, a n d i n 
w hic h ot her dr u gs/c hemicals or 
u n derl yi n g disease pr o vi de pla usi ble e x pla nati o ns .    
P ossi bl y Relate d  
A cli nical e ve nt , i ncl u di n g la b orat or y test a b n or malit y wit h a reas o na ble 
ti me se q ue nce t o a d mi nistrati o n of st u d y dr u g, b ut w hic h c o ul d als o be 
e x plai ne d b y c o nc urre nt disease or ot her dr u gs  or c he micals. 
Pr o ba bl y Relate d  
A cli nical e ve nt , i ncl u di n g la b orat or y test a b n or malit y, wit h a reas o na ble 
ti me se q ue nce t o a d mi nistrati o n of st u d y dr u g, u nli kel y t o be attri b ute d 
t o c o nc urre nt disease or ot her dr u gs or c he micals a n d w hic h f oll o ws a 
cli nicall y reas o na ble res p o nse o n  wit h dra wal ( de -c halle n ge).   R e-
c halle n ge  i nf or mati o n is n ot re q uire d t o f ulfill t his defi niti o n.  T he 
ass ociati o n of t he cli nical e ve nt/la b orat or y a b n or malit y m ust als o ha ve 
s o me bi ol o gic pla usi bilit y, at least o n t he oretical gr o u n ds. 
Defi nitel y Relate d   
A cli nical e ve nt , i ncl u di n g la b orat or y test a b n or malit y, occ urri n g i n a 
pla usi ble ti me relati o ns hi p t o a d mi nistrati o n of st u d y dr u g, a n d w hic h 
ca n n ot be e x plai ne d b y c o nc urre nt disease or ot her dr u gs or c he micals.   
T he res p o nse t o wit h dra wal  of t he dr u g ( de -c halle n ge) s h o ul d be 
cli nicall y pla usi ble.   T he e ve nt m ust be defi niti ve p har mac ol o gicall y or 
p he n o me n ol o gicall y, usi n g a satisfact or y re -c halle n ge pr oce d ure if 
necessar y . 
N CI G ui deli nes f or I n vesti gat ors: A d verse E ve nt Re p orti n g Re q uire me nts f or D C T D ( C T E P a n d CI P) 
a n d D C P I N Ds a n d I D Es (effecti ve Se pte m ber 1 6, 2 0 1 3): 
ht t p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns/ d ocs/ae g ui deli nes. p df 
V V- T M F- 5 1 6 1 9 | Pa ge 7 5/ 1 1 2

Pr ot oc ol  
 
 Pa ge 7 6  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
9. 2.   
Rec or di n g A d verse E ve nts  
9. 2. 1.   
Re p orti n g Seri o us A d verse E ve nts  
A n y S A E, re gar dless of relati o ns hi p t o st u d y m e dicati o n, w hic h o cc urs i n a patie nt fr o m t he ti me 
i nf or me d c o nse nt is o btai ne d  u ntil 3 0 da ys after t h e last st u d y treat me nt, s h o ul d be rec or de d b y t h e 
cli nical site o n a n S A E R e p ort f or m.  T his re p orti n g re q uire me nt als o i ncl u des S A Es t hat are 
attri b ute d t o a st u d y pr oce d ure p erf or me d d uri n g t he scree ni n g peri o d (fr o m t he ti me of c o ns e nt 
u ntil t he ti me of first d ose of st u d y treat me nt).  T he S A E m ust be c o m pletel y des cri be d o n t he 
patie nt’s eC R F, i ncl u di n g t he j u d g m e nt of t he I n v e sti gat or as t o t he relati o ns hi p of t he S A E t o t he 
st u d y tr eat me nt (De bi o 1 5 6 2  a n d rit u xi ma b) .  T he I n v esti gat or will pr o m ptl y s u p pl y all 
i nf or mati o n i de ntifie d a n d re q uest e d b y t h e S p o ns or ( or C o ntract R esearc h O r ga nizati o n [ C R O]) 
re gar di n g t he S A E.  
T he I n v esti gat or m ust re p ort t he S A E t o t he S p o n s or’s Me dical Direct or  or desi g nee.  T h e S A E 
Re p ort  f or m m ust be c o m plete d a n d s u b mitte d wit hi n 2 4 h o urs of t he I n vesti gat or’s lear ni n g of 
t he e ve nt t o t he c o ntact p ers o ns liste d i n t he St u d y Ma n ual pr o vi de d t o eac h site a n d mai ntai ne d i n 
t he I n v esti gat or st u d y files.  A n y f oll o w -u p i nf or m ati o n m ust als o be c o m plete d o n a n S A E Re p ort 
f or m a n d s u b mitte d t o t he sa me c o ntacts. 
W he n re p orti n g S A Es, t h e f oll o wi n g a d diti o nal p oi nts s h o ul d be n ote d:  
 T he u n derl yi n g dia g n os is or s y n dr o me s h o ul d be re p orte d as t he pri mar y S A E ter m, 
rat her t ha n t h e si g ns or s y m pt o ms (si g ns a n d s y m pt o ms ma y b e d escri be d i n t h e 
narrati ve).  
 Pr o gressi o n of disease s h o ul d n ot be re p orte d as a n S A E; a n y seri o us me dical 
e ve nt/c o n diti o n t hat res ults f r o m pr o gressi o n of u n derl yi n g diseas e s h o ul d be re p orte d 
as t he S A E. 
 Deat h s h o ul d n ot be re p orte d as a n S A E, b ut rat her as a n o utc o me of a s p ecific S A E, 
u nless t he e ve nt prece di n g t he deat h is u n k n o w n.  I n t hese e x ce pti o nal cases, deat h ma y 
be use d as a n e ve nt ter m.  If a n a ut o ps y was perf or me d, t he a ut o ps y re p ort s h o ul d be 
pr o vi de d.  
It is t h e res p o nsi bilit y of t he S p o ns or t o e ns ure t hat eac h I n vesti gat or recei ves a c o p y of a n y 
C o u ncil f or I nt er nati o nal Or ga nizati o ns of Me dical Scie nces ( CI O M S) or Me d Watc h re p ort t hat 
has bee n s u b mitte d t o t he a p pr o pri ate nati o nal re g ulat or y a ge nci es as n otificati o n of a s us pecte d 
u ne x pecte d seri o us a d v erse reacti o n ( S U S A R ).  T he I n v esti gat or ( or S p o ns or or S p o ns or’s 
re pres e ntati ve if s o desi g nat e d) m ust pr o m ptl y re p ort all S U S A Rs t o t he  I nstit uti o nal Re vie w 
B oar d (I R B)/I n de p e n de nt Et hics C o m mittee  (I E C) f or re vie w i n acc or da nce wit h nati o nal 
re g ulati o ns.  I R B/I E C n otificati o n of t he S U S A R ma y t a ke t h e f or m of a s u b missi o n of a c o p y of 
t he CI O M S/ Me d Watc h re p ort or ot her f or mat acce pte d b y t he I R B/I E C.  A c o p y of t he 
CI O M S/ Me d Watc h re p ort a n d n otificati o n t o I R B/I E C s h o ul d be retai ne d i n t he site’s st u d y files.  
I n a d diti o n t o CI O M S/ Me d Watc h re p orts, t he S p o ns or will als o n otif y t he I n vesti gat ors a n d 
I R Bs/I E Cs of all deat hs t hat occ ur d uri n g t he st u d y, irres p ecti ve of relati o ns hi p t o st u d y 
me dicati o n , t hr o u g h a n n ual u p dates t o t he De bi o 1 5 6 2 I B. 
Disease pr o gressi o n a n d/ or pr o gressi o n of t he disease u n der st u d y are a nti ci pate d occ urre n ces i n 
o nc ol o g y dr u g d e vel o p m e nt, a n d as s uc h , are c o nsi dere d e x pecte d as per t he c urre nt I B f or t he 
V V- T M F- 5 1 6 1 9 | Pa ge 7 6/ 1 1 2

Pr ot oc ol  
 
 Pa ge 7 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
c o m p o u n d.  If a patie nt e x pires fr o m pr o gressi o n of disease a n d/ or fr o m t he disease u n der st u d y 
d uri n g t he p eri o d of o bli gati o n t o re p ort S A Es , disease pr o gressi o n a n d/ or pr o gressi o n of t he 
disease u n der st u d y wit h a fat al o utc o me d o n ot nee d t o be re p orte d as S A Es .  T he a p plica ble 
pr ot oc ol eC R F pa ge(s) p ertai ni n g t o d eat h s h o ul d be a p pr o priatel y c o m plet e d h o we ver, as diseas e 
pr o gressi o n.  
9. 2. 2.   
Re p orti n g a Pre g n a nc y  
Pre g n a nc y a n d lactati o n are e x cl usi o n crit eria.  T he S p o ns or m ust be n otifie d i n t he e ve nt of a 
pre g na nc y , re p orte d b y a patie nt or patie nt’s p art ner, d uri n g t he c o urse of t he st u d y a n d t hr o u g h 
3 0 da ys after t he p atie nt’s last d ose of De bi o 1 5 6 2 .  Pre g na n c y is n ot t o be re p orte d as a n A E. 
H o we ver, S A Es  ass o ciate d wit h or res ulti n g fr o m t he pre g n a nc y s h o ul d be rec or de d, a n d t he 
pre g na nc y re p orti n g f or m s h o ul d be us e d t o re p ort t he pre g n a nc y.  T he pre g n a nc y will b e f oll o we d 
t hr o u g h d eli ver y or fi n al o utc o me. 
V V- T M F- 5 1 6 1 9 | Pa ge 7 7/ 1 1 2

Pr ot oc ol  
 
 Pa ge 7 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1 0.   
S T A TI S TI C S  
All statistical a nal yses  will be perf or me d usi n g t he m ost rece ntl y release d a n d a vaila ble S A S 
statistical s oft ware, u nless ot her wise n ote d.  F or cate g orical v aria bl es, t he n u m ber a n d p erce nt of 
eac h cate g or y wit hi n a para meter will be cal c ulate d.  F or c o nti n u o us varia bl es, t he sam ple size ( n), 
mea n, me dia n, a n d sta n dar d de viati o n, as well as t he mi ni m u m a n d ma xi m u m val ues, will be 
prese nte d.  Missi n g data will n ot be i m p ute d u nless ot her wise state d.   T here will be a  s u m mar y of 
patie nt dis p ositi o n , patie nt de m o gra p hics , a n d b aseli n e c haracteristics.  P K para m eters will be 
c o m p ute d a n d prese nte d i n ta bles a n d listi n gs.  Plas ma c o nce ntrati o ns will be prese nte d i n gra p hs 
f or eac h patie nt a n d b y c o h orts.  Lat est versi o n of S A S or Wi n N o nli n will be use d f or t he P K 
a nal ys es.  
A  S A P  will f ul l y des cri be t he pla n ne d a nal ys es f or t his st u d y, i ncl u di n g se nsiti vit y a nal ysis relat e d 
t o patie nts w h o mi g ht s witc h d ose re gi me n d uri n g t he C O VI D-1 9 pa n de mic . A nal ys es will be 
perf or me d t he safet y p o p ulati o n, t he efficac y e v al ua ble p o p ulati o n or t he P K p op ulati o n .  All 
a nal ys es f or a nti-t u m or acti vit y will use t he first d ose date as t he start ti me.   
 
T he pri mar y e n d p oi nts of t his st u d y are:  
- 
T E A Es , cli nicall y-si g nifica nt c ha n ges i n cli nical l a b orat or y test r es ults, E C G , a n d vital 
si g n meas ure me nts; 
- 
O R R  defi ne d as t he pr o p orti o n of s u bjects wit h a best o verall res p o ns e of P R or C R as 
assesse d b y t he 2 0 1 4 L u ga n o classificati o n of res p o nse assess me nts of N H L.  
T he pri mar y a n al ysis will be c o n d ucte d after all e nr olle d patie nts ha ve reac h e d t heir 3 r d o n -
treatme nt sc he d ul e d res p o nse assess me nt or h a ve disc o nti n ue d fr o m treat me nt. T he fi nal a nal ysis 
will be tri g gere d o ne year after t he last accr ue d p atie nt’s first d ose d ate. I n t he e x ce pti o nal cas e 
t hat after t he fi n al a nal ysis a patie nt(s) mi g ht c o nti n ue t o recei v e st u d y treat me nt u n der t he 
pr ot oc ol, a n y s u bse q ue nt data ge n erat e d fr o m t his patie nt(s) will be s u m marize d i n a n a d de n d u m 
re p ort t o be iss ue d after t he last treat me nt of t he last patie nt. 
As t he recr uit me nt c o nti n ue d bet wee n c o m pleti o n of t he safet y r u n -i n part of t he i m ple me ntati o n 
of t he pr ot oc ol a me n d me nt # 3 ( w he n c o h ort B of Q W was i ntr o d uce d), a n u m ber of N H L patie nts 
ha ve recei ve d De bi o 1 5 6 2 0. 7 m g/ k g Q 3 W i n c o m bi nati o n wit h rit u xi ma b. Patie nts prese nti n g wit h 
rela pse d D L B C L as per c urren t i ncl usi on criteria will be a nal yze d t o get her wit h t he patie nts 
e nr olle d i n c o h ort A. All ot her patie nts (i.e. refract or y D L B C L, or ot her f or ms of N H L) e nr olle d 
i n t his peri o d will be a nal yz e d se paratel y.  
 
 
 
 
 
 
 
 
V V- T M F- 5 1 6 1 9 | Pa ge 7 8/ 1 1 2

Pr ot oc ol  
 
 Pa ge 7 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
 
 
1 0. 2.   
A n al ysis P o p ul ati o ns  
T he f oll o wi n g a nal ysis p o p ulati o ns will be c o nsi dere d:  
- 
Scree ne d P o p ul ati o n:  
All s u bjects scree n e d will be part of t he scree ne d p o p ulati o n.  
- 
S afet y P o p ul ati o n:  
All s u bjects w h o recei ve at least o n e d os e De bi o 1 5 6 2 will be p art of t he safet y p o p ulati o n. 
Re p orti n g i n t he safet y p o p ulati o n will be d o ne a gai nst t he act ual treat me nt recei v e d.  
- 
Effic ac y E v al u a ble P o p ul ati o n:  
All s u bjects w h o recei ve d at least o ne d ose of De bi o 1 5 6 2 a n d rit u xi ma b, a n d ha d b ot h 
baseli ne a n d p ost -baseli ne e val ua ble diseas e will be part of t he efficac y e val ua bl e 
p o p ulati o n. Re p orti n g i n t he efficac y e val ua bl e p o p ulati o n will be d o ne a g ai nst t he 
assi g ne d treat me nt.  
- 
P K P o p ul ati o n:  
All s u bjects w h o recei ve o ne d ose of st u d y dr u g a n d ha ve at least o ne P K c o nce ntrati o n 
res ult a vaila ble ( De bi o 1 5 6 2 or rit u xi ma b c o nce ntrati o n, i ncl u di n g v al ue bel o w li mit of 
q ua ntificati o n). Re p orti n g i n t he P K  p o p ul ati o n will be d o ne a gai nst t he act ual treat me nt 
recei v e d. 
1 0. 3.   
P h ar m ac o ki netic ( P K)  A n al yses  
P K para meters  t hat will be e val uate d i ncl u de, b ut are n ot li mite d t o:  C ma x , Tma x , Ter mi nal half-life 
(t1/ 2), Vss, CL , A U C0 -t, A U Ci nf. T hese will be deri ve d fr o m plas ma c o nce ntrati o ns of De bi o 1 5 6 2 , 
t otal a n d/ or na ke d h u ma nize d C D 3 7 m A b (K 7 1 5 3 A ), D M 1 (free a n d b o u n d), as well as p ote ntial 
cata b olites , a n d t otal rit u xi ma b, usi n g t he act ual s a m pli n g ti mes. C o nce ntrati o n data a n d all P K 
para meter s will be liste d per patie nt a n d s u m marize d descri pti vel y per d ose. If a p pr o priate, no n -
c o m part me ntal ( M o del i n de pe n de nt) met h o ds will be use d t o c o m p ute t he P K para m eters usi n g 
t he latest versi o n of S A S or P h oe ni x Wi n N o nli n s oft ware.  
T he  P K dis p ositi o n o f De bi o 1 5 6 2 (a n d rit u xi ma b, if dee me d a p pr o priate) will als o be descri be d 
t hro u g h a p o p ulati o n P K a p pr oac h usi n g N O N M E M (I C O N S ol uti o ns). T his e val uati o n will be 
re p orte d se p aratel y. 
I n di vi d ual plas ma c o n ce ntrati o n vers us act ual ti me pr ofiles f or eac h patie nt a n d treat me nt, as well 
as t he mea n ( +/ - st a n dar d de viati o n) plas m a c o n ce ntrati o n vers us s c he d ule d ti me pr ofiles f or eac h 
d ose le vel, will be pres e nte d gra p hicall y o n n or m al a n d se mi -l o g scale.  
1 0. 4.   
S afet y A n al yses  
A Es , c onc o mita nt me dicati o n , a n d res ults fr o m p h ysical e x a mi nati o n will be liste d.  
A Es  will als o be c o de d wit h t he Me dical Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A ; versi o n 
1 9 . 0 or later) a n d s u m marize d per S yste m O r ga n C lass ( S O C) a n d preferre d ter m . 
V V- T M F- 5 1 6 1 9 | Pa ge 7 9/ 1 1 2

Pr ot oc ol  
 
 Pa ge 8 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
C o nc o mi ta nt me dicati o ns will be c o d e d usi n g t he W H O  Dr u g Dicti o nar y ( W H O -D D; J u ne 1, 2 0 1 2 
or later versi o n). A dicti o nar y listi n g of all u ni q ue c o nc o mita nt me dicati o ns use d i n t he st u d y will 
be pr o vi de d.  
All he mat ol o g y, bl o o d c he mistr y, vital si g ns, a n d E C G res ul ts will be liste d per patie nt f or eac h 
assess me nt a n d descri pti ve statistics will be ta b ulate d f or select criteria.   C ha n ges fr o m baseli ne i n 
he mat ol o g y, bl o o d c he mistr y, vital si g ns, a n d E C G res ults will be s u m marize d b y treat me nt. S hifts 
i n he mat ol o g y a nd bl o o d c he mistr y fr o m Baseli ne val ues will be s u m marize d.   Plas ma will als o 
be e val u ate d f or t he pres e nce of h u m oral res p o ns es a gai nst t he h u ma nize d a nti C D 3 7 a nti b o d y 
c o m p o ne nt or a gai nst t he D M 1 c o m p o ne nt ( A D A).  
1 0. 5.   
A nti -T u m or Acti vit y  
O R R –  T he best o veral l res p o nse will be deter mi ne d b y t h e I n vesti gat or f or eac h e val ua ble p atie nt 
as C R, P R, sta ble disease (S D ), or rel a pse d diseas e/ P D. T he O R R will be ta b ulate d b y d os e c o h ort 
assi g ne d as well as t he d ose at w hi c h t he res p o nse occ urre d al o n g wit h t he 8 0 % a n d  t he 9 5 % 
c o nfi de nce i nter val ( CI). T o meet t he defi niti o n of res p o nse -e v al ua ble, patie nts m ust ha ve 
u n der g o ne ra di o gra p hi c assess me nt at bas eli ne, recei ve d at least o n e d os e of De bi o 1 5 6 2  a n d 
rit u xi ma b, a n d m ust ha ve ha d at least o ne p ost -d os e t u m or assess me nt.  
O S –  O verall s ur vi val will be a nal yze d usi n g t he Ka pla n -Mei er met h o d.  Me dia n O S  a n d 9 5 % CI  
(if feasi ble) will be prese nte d . T he O S rate at o n e year al o n g wit h t he 9 5 % CI will be esti mate d 
a n d prese nt e d. 
D o R –  T he D o R will be esti mate d f or all e v al ua ble patie nts w h o ac hie ve a n o bjecti ve res p o nse 
( P R or C R).  Me dia n d urati o n a n d ass ociate d 9 5 % CIs will be prese nte d.  
P F S –  P F S will be a nal yz e d usi n g t he Ka pla n -Mei er met h o d.  Me dia n P F S  a n d 9 5 % CI (if feasi ble) 
a n d t he rate of P F S at si x m o nt hs  a n d at 1 year a n d t heir 9 5 % CI will be esti mate d a n d prese nt e d . 
1 0. 6.   
A n al ysis  a n d S t o p pi n g R ules  
1 0. 6. 1.   
F utilit y A n al yses  
N o f or mal i nteri m a nal ysis f or efficac y will be perf or me d; h o we v er, f utilit y a nal yses will be 
c o n d ucte d after 1 0 p atie nts a n d, if dee me d necessar y, 1 5 patie nts i n co h ort A are e val u a ble f or 
efficac y ( i.e., p atie nts s h o ul d ha ve p erf or me d at least o n e p ost bas eli ne o bjecti ve res p o ns e 
assess me nt - u nless t here is e arlier cle ar  evi de nce of P D ), as well as c u m ulati ve after e nr oll me nt 
of e ver y 1 0 e val ua bl e patie nts f or efficac y (if d ee me d necessar y) i n st u d y Part 3. At eac h a n al ysis, 
f utilit y will be e val uate d usi n g a Ba yesia n a p pr oac h wit h a n o n-i nf or mati ve c o nj u gate pri or. 
 
 
 
 
 
 
 
                      
 
V V- T M F- 5 1 6 1 9 | Pa ge 8 0/ 1 1 2

Pr ot oc ol  
 
 Pa ge 8 1  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1 0. 6. 3.   
St o p pi n g R ules f or S afet y  
T here are n o f or mal i nteri m a nal ys es f or s afet y pla n ne d f or t his st u d y. H o we ver, s a fet y will be 
re vie we d re g ularl y d uri n g t he st u d y b y t he S R C a n d I D M C (Secti o n  4. 1. 3 ). 
T he S R C a n d I D M C ca n rec o m me n d t o ter mi nate or m o dif y a n y d osi n g re gi me n t o g uar d patie nt’s 
safet y. T he S R C a n d I D M C will m o nit or all safet y as pects wit h s peci al f oc us o n ne utr o pe ni a, 
fe brile ne utr o p e nia, he p atic da ma ge, p ne u m o nitis a n d ne ur o pat h y.  
1 0. 7.   
St atis tic al A n al ysis of F A C T-L y m  
Healt h -relate d q ualit y of life will be e val uate d base d o n t he F A C T-L y m. Please refer t o sc ori n g 
ma n ual ( w w w.facit. or g ) f or i nstr ucti o n f or c o m p uti n g o verall sc ore a n d s u bscale sc ores. 
O verall sc ore a n d s u bscale sc ore will be pres e nte d b y visits, f or eac h c o h ort a n d o verall (i n de x 
sc ore a n d c ha n ge fr o m baseli ne). I n a d diti o n, c o u nt a n d perce nta ge of s u bjects wit h/ wit h o ut 
cli nicall y mea ni n gf ul mi ni mall y i m p orta nt differe nces fr o m baseli ne will be  re p orte d b y visits, f or 
eac h c o h ort a n d o verall.  
V V- T M F- 5 1 6 1 9 | Pa ge 8 1/ 1 1 2

Pr ot oc ol  
 
 Pa ge 8 2  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1 1.   
A D MI NI S T R A TI V E C O N SI D E R A TI O N S  
1 1. 1.   
I n vesti g at ors a n d St u d y A d mi nistr ati ve Str uct ure 
Bef ore i nitiati o n of t he st u d y, t he I n v esti gat ors m ust pr o vi de t he S p o ns or wit h a c o m plete d F or m 
F D A 1 5 7 2. St u d y m e dicati o ns ma y b e a d mi nistere d o nl y u n der t he s u per visi o n of t he I n vesti gat ors 
liste d o n t his f or m. C urric ul u m vitae m ust be pr o vi de d f or t he I n vesti gat ors a n d s u b-i n vesti gat ors 
liste d o n F or m F D A 1 5 7 2. 
T he I n vesti gat or s h o ul d e ns ure t hat all pers o ns assisti n g wit h t he  st u d y are a de q uatel y i nf or me d 
a b o ut t he pr ot oc ol, a n y a me n d me nts t o t he pr ot oc ol, t he st u d y treat me nts, a n d t heir st u d y relat e d 
d uties a n d f u ncti o ns. T he I n vesti gat or m ust mai ntai n a list of s u b -i n vesti gat ors a n d ot her 
a p pr o priatel y q u alifie d p ers o ns t o w h o m he or s he has dele gate d si g nifica nt st u d y rel ate d d uties.  
Desi g n ate d res p o nsi bilities are t o be rec or de d o n a Dele gati o n of Res p o nsi bilit y L o g ( or e q ui vale nt 
d oc u me nt) t hat is si g ne d b y t he Pri nci pal I n v esti gat or a n d desi g nees.   It is t he Pri nci pal 
I n vesti gat or’s res p o nsi bilit y t o e ns ure t h at t he L o g is mai ntai ne d a n d re m ai ns c urre nt t hr o u g h o ut 
t he st u d y. 
1 1. 2.   
I nstit uti o n al Re vie w B o ar d (I R B) or I n de pe n de nt Et hics C o m mittee 
(I E C) A p pr o v al 
Bef ore i nitiati o n of t he st u d y, t he I n vesti gat or m ust pr o vi de t he S p o n s or wit h a c o p y of t he writte n 
I R B/I E C a p pr o val of t he pr ot oc ol a n d t he I nf or me d C o nse nt F or m (I C F). T his a p pr o val m ust refer 
t o t he I C F a n d t o t he st u d y title, st u d y n u m ber, a n d versi o n a n d date of iss ue of t he st u d y pr ot oc ol, 
as gi ve n b y t he S p o ns or o n t he c o ver pa ge of t he pr ot oc ol.  
Stat us re p orts m ust be s u b mitte d t o t he I R B/I E C at least o nce per year or as per i nstit uti o nal 
g ui deli nes.  T he I R B/I E C m ust be n otifie d of c o m pleti o n of t he st u d y a n d a fi nal re p ort m ust be 
pr o vi de d t o t he I R B/I E C.  A c o p y o f t hese re p orts will be se nt t o t he st u d y cli nical m o nit or or 
desi g nee .  T he I n vesti gat ors m ust mai ntai n a n acc urate a n d c o m plete rec or d of all s u b missi o ns 
ma de t o t he I R B/I E C, i ncl u di n g a list of all re p orts a n d d oc u me nts s u b mitte d.  A Es w hic h are 
re p orted t o t he U S F D A or ot her Re g ul at or y a ge ncies ( E x pe dite d Safet y Re p orts) m ust be 
s u b mitte d pr o m ptl y t o t h e I R B/I E C as per i nstit uti o nal g ui deli nes.  
1 1. 3.   
Et hic al C o n d uct of t he St u d y  
T he pr oce d ures set o ut i n t his st u d y pr ot oc ol, pertai ni n g t o t he c o n d uct, e val ua ti o n, a n d 
d oc u me ntati o n of t his st u d y, are desi g n e d t o e ns ure t hat t he S p o ns or a n d I n vesti gat ors a bi de b y 
G C P as descri be d i n t he 2 1 C o de of Fe deral Re g ulati o ns ( C F R ) Parts 5 0, 5 6, a n d 3 1 2 a n d t h e 
I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) G C P G ui delines.  C o m plia nce wit h t hese 
re g ulati o ns a n d g ui deli nes als o c o nstit utes c o m plia nce wit h t he et hical pri nci ples descri be d i n t he 
Declarati o n of Helsi n k i. 
1 1. 4.   
P atie nt I nf or m ati o n a n d C o nse nt 
Bef ore e nr olli n g i n t he cli nical st u d y, t he patie nt m ust c o nse nt t o par tici pate after t h e nat ure, sc o p e, 
a n d p ossi ble c o nse q u e nces of t he cli nical st u d y h a ve bee n e x plai ne d i n a f or m u n dersta n d a ble t o 
hi m or her.  A n I C F t hat i ncl u des i nf or mati o n a b o ut t he st u d y will be pre pare d a n d gi v e n t o t he 
V V- T M F- 5 1 6 1 9 | Pa ge 8 2/ 1 1 2

Pr ot oc ol  
 
 Pa ge 8 3  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
patie nt, or t h e patie nt’s le ga ll y a ut h orize d re prese ntati ve(s).  T his d oc u me nt will c o ntai n all 
rele va nt re g ul at or y a ut h orit y a n d I C H-re q uire d ele me nts.  T he I C F m ust be i n a la n g ua ge 
u n dersta n da ble t o t he patie nt or t he patie nt’s le gall y a ut h orize d re prese ntati ve(s) a n d m ust s pecif y 
w h o i nf or me d t he patie nt or t he patie nt’s le gall y a ut h orize d re prese nt ati ve.  
After rea di n g t he i nf or me d c o nse nt d oc u me nt, t he patie nt or t he patie nt’s le gall y a ut h orize d 
re pres e ntati ve(s) m ust gi ve c o nse nt i n writi n g.  If t he patie nt or t he p atie nt’s le gally a ut h orize d 
re pres e ntati ve(s) is u na ble t o rea d, oral pres e ntati o n a n d e x pla nati o n of t he writte n I C F a n d 
i nf or mati o n t o be s u p plie d m ust ta ke place i n t he prese nce of a n i m partial wit ness.  C o nse nt m ust 
be c o nfir me d at t he ti me of c o nse nt orall y a n d b y t he pers o nall y d ate d si g n at ure of t he patie nt or 
b y t he patie nt’s le gall y a ut h orize d re pres e ntati ve(s).   T he wit ness a n d t he pers o n c o n d u cti n g t h e 
i nf or me d c o ns e nt disc ussi o ns m ust als o si g n a n d pers o nall y d ate t h e I C F.  It s h o ul d als o b e 
rec or de d a n d d ate d i n t he s o urce d oc u m e nt t hat c o nse nt was gi ve n. 
A c o p y of t he si g ne d a n d date d I C F(s) m ust be gi ve n t o t he patie nt or t he patie nt’s le gall y a ut h orize d 
re pres e ntati ve(s).  T h e ori gi nal si g n e d a n d d ate d I C F will be retai ne d b y t h e I n vesti gat or.   Patie nt  
c o nfi de ntialit y will be m ai ntai ne d as o utli ne d i n Secti o n  1 1. 5 . 
T he I n v esti gat or will n ot u n derta ke a n y meas ures s pecificall y re q uire d s olel y f or t h e cli nical st u d y 
u ntil vali d c o nse nt has bee n o btai ne d.  
A m o del of t he I C F t o be use d i n t his st u d y will be pr o vi de d t o t he sites se paratel y fr o m t his 
pr ot oc ol.   
1 1. 5.   
P atie nt  C o nfi de nti alit y  
Patie nt na mes will n ot be s u p plie d t o t he S p o ns or.   If t he p atie nt na me a p pears o n a n y d oc u me nts , 
it m ust be o bliterate d bef ore a c o p y of t he d o c u me nt is s u p plie d t o t he S p o ns or. If a patie nt’s n a me 
or ot her patie nt d etails were  hi d de n i n a p h ysi cal m a n ner b ef ore a d o c u me nt was sca n n e d , it s h o ul d 
be verifi e d  t hat t he n a me a n d all ot her details are i n visi ble i n t he electr o nic d oc u me nt bef ore it is 
s u p plie d t o t he S p o ns or. St u d y fi n di n gs st or e d o n a c o m p uter will be st ore d i n acc or da n ce wit h 
l ocal data pr otecti o n la ws.  Patie nt sca ns, bl o o d, a n d tiss ue sa m ples se nt t o o utsi de la b orat ories 
a n d/ or C R Os (e. g., tiss ue a nal ysis la b orat or y) are i de ntifie d b y st u d y patie nt n u m ber o nl y t o e ns ure 
mai nte na nce of c o nfi de ntialit y.   T h e patie nt I C F will state t hat p u blicati o ns res ulti n g fr o m t his 
st u d y will n ot refer t o patie nt na me or i ncl u de a n y ot her i nf or mati o n t hat mi g ht discl ose t he i de ntit y 
of t he patie nt.   T he patie nts will be t ol d t hat t he S p o ns or, re prese nt ati ves of t he S p o ns or, t he 
I R B/I E C, or re g ul at or y a ut h orities ma y i ns pect t heir me dical rec or ds t o verif y t he inf or mati o n 
c ollecte d, a n d t h at all pers o nal i nf or mati o n ma de a vaila ble f or i ns pecti o n will be ha n dle d i n 
strictest c o nfi de nce a n d i n acc or da n ce wit h l ocal data pr otecti o n la ws. T he I n v esti gat or will 
mai ntai n a p ers o nal pati e nt i de ntificati o n list ( patie nt n u m bers wit h t he c orres p o n di n g p atie nt 
na mes) t hat will o nl y b e ke pt at site t o e na ble rec or ds t o be i de ntifie d. 
1 1. 6.   
St u d y M o nit ori n g  
M o nit ori n g pr oce d ures t h at c o m pl y wit h c urre nt G C P g ui deli nes will be f oll o we d.  O n -site re vie w 
of t he eC R Fs f or c o m plete ness a n d clarit y, cr oss -c h ec ki n g 
wit h s o urce d oc u me nts, a n d 
clarificati o n of a d mi nistrati ve matters will be perf or me d.  
T he st u d y will be m o nit ore d b y t h e S p o ns or or its desi g nee.   O n -site m o nit ori n g  will be p erf or me d 
b y a re prese nt ati ve of t he S p o ns or ( Cli nical  St u d y M o nit or) w h o will re vie w t he eC R Fs a n d s o urce 
V V- T M F- 5 1 6 1 9 | Pa ge 8 3/ 1 1 2

Pr ot oc ol  
 
 Pa ge 8 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
d oc u me nts.  T h e site m o nit or will e ns ure t hat t he i n vesti gati o n is c o n d ucte d acc or di n g t o pr ot oc ol 
desi g n a n d re g ulat or y re q uire me nts b y fre q u e nt site visits a n d c o m m u nicati o ns ( e. g. l etter, 
tele p h o ne, email,  a n d facsi mile).  
D uri n g t h e C O VI D -1 9 pa n de mic, re m ote d ata m o nit ori n g mi g ht b e i m ple me nte d , if feasi ble at t he 
site le vel a n d all o we d b y l ocal re g ulati o ns. 
1 1. 7.   
C ase Re p ort F or ms a n d St u d y Re p orts  
e C R Fs  are pr o vi de d f or eac h patie nt.   All f or ms m ust be fil le d o ut b y a ut h orize d st u d y pers o n nel.  
All c orrecti o ns t o t he ori gi nal eC R F e ntr y m ust i n dicate t he reas o n f or c ha n ge.  T he I n vesti gat or is 
re q uire d t o e-si g n t he eC R F after all d ata ha v e bee n ca pt ure d f or eac h p atie nt.  If c orrecti o ns are 
ma de aft er re vi e w a n d si g nat ur e b y t he I n vesti gat or, he or s he m ust be ma de a ware of t he c ha n ges, 
a n d his or her a ware ness d oc u me nte d b y re -si g ni n g t he eC R F.  
1 1. 8.   
Pr ot oc ol De vi ati o ns  
T he I n vesti gat or will c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol.   
A n y de p art ures fr o m t he pr ot oc ol m ust be f ull y d oc u me nte d as a pr ot oc ol de viati o n.  Pr ot oc ol 
de viati o ns will be re vie we d b y t he s p o ns or a n d ma y be re q uire d t o be s u b mitte d t o t he I R B/I E C as 
per i nstit uti o nal g ui deli nes.  
1 1. 9.   
Pr ot oc ol A me n d me nts  
A n y c h a n ge t o t he pr ot oc ol  will be rec or de d i n a writte n a me n d me nt.  T he si g ne d a me n d m e nt will  
be attac h e d t o t his Pr ot oc ol.  A me n d me nt t o  t he pr ot oc ol ma y re q uire re g ul at or y s u b missi o ns (e. g . 
I R B/I E C) i n acc or da n ce wit h l ocal re g ul ati o ns.  If t his st u d y is a re g ul at or y c o m mit me nt , c ha n ges  
t o t he pr ot oc ol will be i m ple me nte d wit h a p pr o val fr o m t h e  a p plica ble re g ulat or y a ut h orities.  I n 
s o me cases, a n a me n d me nt ma y re q uire a c ha n ge t o t he I C F. 
1 1. 1 0.  
E n d of St u d y  
T he E n d of St u d y will b e defi ne d as t he latter of t he c o m pleti o n of t he Safet y  f oll o w-u p visit f or 
t he last patie nt re mai ni n g o n treat me nt or o ne year fr o m t he last accr ue d p atie nt’s first visit.  
1 1. 1 1.  
St u d y Ter mi n ati o n  
1 1. 1 1. 1.  
St u d y Ter mi n ati o n  
If t he S p o ns or, a n I n v esti gat or, or S t u d y Cli nical M o nit or disc o vers c o n diti o ns arisi n g d uri n g t he 
stu d y t hat i n dicate t hat t he cli nical i n vesti gati o n s h o ul d be halte d d ue t o a n u nacce pt a ble patie nt 
ris k, t he st u d y m ust be ter mi nate d after a p pr o pri ate c o ns ultati o n bet wee n t he S p o ns or a n d t he 
I n v esti gat ors.  I n a d diti o n, a decisi o n o n t he p art of t he S p o nsor  t o s us pe n d or disc o nti n ue 
de vel o p me nt of t he test material ma y be ma de at a n y ti me.  
Wit hi n 1 5 da ys of pre m at ure cl os ur e, 
t he S p o ns or m ust n otif y t he c o m pete nt a ut h orities a n d 
I R B/I E C of a n y me m ber state w here t he st u d y is bei n g c o n d u cte d, pr o vi di n g t he reas o ns f or st u d y 
cl os ure.  
V V- T M F- 5 1 6 1 9 | Pa ge 8 4/ 1 1 2

Pr ot oc ol  
 
 Pa ge 8 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1 1. 1 1. 2.  
Site Ter mi n ati o n  
A s pecific site ma y be t er mi nate d se p arate fr o m t he ge neral st u d y f or, b ut n ot li mite d t o, t he 
f oll o wi n g c o n diti o ns: 
 T he disc o ver y of a n u ne x pecte d, si g nifica nt, or u nacce pta bl e ris k t o t he patie nts 
e nr olle d at t he site 
 Fail ure of t he I n vesti gat or t o e nter patie nts at a n acce pta bl e rate  
 I ns ufficie nt a d here n ce b y t he I n v esti gat or t o pr ot o c ol re q uire m e nts 
 I ns ufficie nt, i nc o m plete, a n d/ or u n eval ua bl e data  
1 1. 1 2.  
S o urce D oc u me nt ati o n  
S o urce data are defi n e d as t he ori gi nal d oc u me nts, data, a n d rec or ds.  T his i ncl u des, b ut is n ot 
li mite d t o t he f oll o wi n g:  h os pital rec or ds, cli nic a n d office c h arts, st u d y-s pecific s o urce d oc u me nt 
w or ks heets, p h o ne l o gs, la b re q uisiti o ns a n d re p orts, i ma ges, l ocal la b orat or y re p orts (if 
a p plica ble), electr o nic d ata/i nf or mati o n s o urces a n d a n y ot her d oc u m e ntati o n re gar di n g t he 
patie nts.   
1 1. 1 3.  
Q u alit y C o ntr ol a n d Ass ur a nce  
Cli nical sites will be m o nit ore d b y t h e S p o ns or or its desi g nee t o e ns ure t he acc urac y of  dat a 
a gai nst s o urce d oc u me nts. Data will be ca pt ure d usi n g vali date d s yste ms.  Trai ni n g will occ ur at 
a n I n vesti gat or meeti n g or at t he site i nitiati o n visit or b ot h, a n d i nstr ucti o n ma n uals (e. g., 
la b orat or y ma n uals a n d p har mac y m a n uals) will b e pr o vi de d t o ai d c o nsiste nc y i n data c ollecti o n 
a n d re p orti n g acr oss sites.  
All re q uire d data will be e ntere d i nt o a data bas e i n acc or da nce wit h C F R 2 1 Part 1 1 c o m plia nce.  
T he data base will i ncl u de a n a u dit trail t o d oc u me nt a n y e vi de nce of data pr ocessi n g or acti vit y o n 
eac h data fiel d b y eac h user.  Users will be gi ve n restricte d access b ase d o n t heir r ole i n t he st u d y 
t hr o u g h a pass w or d pr otecte d e n vir o n me nt.  All missi n g data will be e x plai ne d. 
Data e ntere d i n t he s yst e m m ust be verifia ble a gai nst s o urce d oc u me nts a n d will be re vie we d 
ma n uall y f or v ali dit y a n d c o m plete ness a gai nst t he s o urce d oc u me nts b y a cli nical m o nit or fr o m 
t he S p o ns or or its desi g nee.  If necessar y, t he st u d y site will be c o ntact e d f or c orrecti o ns or 
clarificati o ns.  D uri n g t he C O VI D -1 9 pa n d e mic, re m ote data m o nit ori n g mi g ht be i m ple me nte d, if 
feasi ble at t he site le vel a n d all o we d b y l ocal re g ulati o ns. 
1 1. 1 4.  
S p o ns or A u dits a n d I ns pecti o ns b y Re g ul at or y A ge ncies  
F or t he p ur p ose of e ns uri n g c o m plia nce wit h t he cli nical trial pr ot oc ol, G C P a n d ot her a p plica bl e 
re g ulat or y re q uir e me nts, t he I n vesti gat or s h o ul d p er mit a u diti n g b y or o n t he be h alf of t he s p o ns or 
a n d i ns pecti o n b y re g ulat or y a ut h orities.  
T he I n vesti gat o r a grees t o all o w t he a u dit ors/i ns pect ors t o ha ve direct access t o his/ her st u d y 
rec or ds f or re vie w, bei n g u n derst o o d t hat t hese pers o n nel will n ot discl ose a n y p ers o nal i de ntit y 
or pers o nal me dical i nf or mati o n.  T he I n v esti gat or will ma ke e ver y eff ort t o hel p wit h t he 
perf or ma n ce of t he a u dits a n d i ns pecti o ns, gi vi n g access t o all necessar y facilities, data, a n d 
d oc u me nts.  
V V- T M F- 5 1 6 1 9 | Pa ge 8 5/ 1 1 2

Pr ot oc ol  
 
 Pa ge 8 6  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
As s o o n as t he I n vesti gat or is n otifie d of a pla n ne d i ns pecti o n b y t he a ut h orities, he /s he will i nf or m 
t he S p o ns or a n d a ut h orize t he S po ns or t o partici pate i n t his i ns pecti o n.   T he c o nfi de ntialit y of t he 
data verifi e d a n d t he pr ot ecti o n of t he patie nts s h o ul d be res pecte d d uri n g t hese i ns pecti o ns.  
A n y res ult a n d i nf or mati o n arisi n g fr o m t he i ns pecti o ns b y t he re g ulat or y a ut h orities will b e 
i m me diatel y c o m m u nicat e d b y t h e I n vesti gat or t o t he S p o ns or. 
T he I n vesti gat or s h all ta ke a p pr o pri ate meas ures re q uire d b y t he S p o ns or t o ta ke c orrecti ve acti o ns 
f or all pr o ble ms f o u n d d uri n g t he a u dit or i ns pecti o ns. 
1 1. 1 5.  
Rec or d Rete nti o n  
T he I n vesti gat or m us t mai ntai n c o nfi de ntial st u d y d o c u me ntati o n a n d pre ve nt acci de nt al or 
pre mat ure d estr ucti o n of t h ose d oc u me nts.  St u d y d oc u m e nts s h o ul d be retai ne d f or at least 1 0 
years aft er t he c o m pleti o n or disc o nti n uati o n of a cli nical trial.  H o we ver, a p plica ble re g u lat or y 
re q uire me nts will be ta k e n i nt o acc o u nt i n t he e ve nt t hat a l o n ger peri o d is re q uire d.   
T he I n vesti gat or m ust n otif y t he s p o ns or pri or t o destr o yi n g a n y st u d y esse ntial d oc u me nts 
f oll o wi n g t he cli nical trial c o m pleti o n or disc o nti n uati o n. 
If t he I nvesti gat or's p ers o nal sit uati o n is s uc h t hat arc hi vi n g ca n n o l o n ger b e e ns ure d b y hi m/ her,  
t he I n v esti gat or s hall i nf or m t he S p o ns or a n d t he rele va nt rec or ds s hall be tra nsferre d t o a m ut uall y 
a gree d u p o n d esi g nee.  
1 1. 1 6.  
P u blic ati o n a n d Discl os ure P olic y  
T he i n f or m ati o n o btai ne d d uri n g t he c o n d u ct of t his cli nical st u d y is c o nfi de ntial, a n d discl os ure 
t o t hir d parties ot her t ha n t h ose n ote d b el o w is pr o hi bite d.  All i nf or m ati o n c o ncer ni n g t h e pr o d uct 
as well as a n y m atter c o n cer ni n g t he o perati o n of t he S p o ns or,  s uc h as cli ni cal i n dicati o ns f or t he 
dr u g, its f or m ula, met h o ds of ma n ufact ure a n d ot her scie ntific data rel ati n g t o it, t hat ha ve bee n 
pr o vi de d b y t he S p o ns or a n d are u n p u blis he d, are c o nfi de ntial a n d m ust re mai n t he s ole pr o pert y 
of t he S p o ns or.  T he I n vesti gat or will a gree t o use t he i nf or mati o n o nl y f or t he p ur p oses of carr yi n g 
o ut t his st u d y a n d f or n o ot her p ur p ose u nless pri or writte n p er missi o n fr o m t he S p o ns or is 
o btai ne d.  
I nf or mati o n o btai ne d d uri n g t he c o n d u ct of t his st u d y will be use d b y t he Sp o ns or  i n c o n necti o n 
wit h t he de vel o p me nt of De bi o 1 5 6 2 .  T he st u d y I n v esti gat or is o bli ge d t o pr o vi de t he S p o ns or 
wit h c o m plete test res ults a n d all data d e vel o pe d i n t his st u d y.  T he S p o ns or has f ull o w ners hi p of 
t he ori gi nal e C R Fs c o m plete d as part of the st u d y.  T his i nf or mati o n ma y be discl ose d t o ot her 
p h ysicia ns w h o are c o n d u cti n g si milar st u dies a n d t o t he F D A as dee m e d necessar y b y t h e S p o ns or.  
Patie nt -s pecific i nf or mati o n ma y be pr o vi de d t o ot her a p pr o priate me dical p ers o n nel relate d t o t he 
care of t hat patie nt o nl y wit h patie nt's pri or c o nse nt.  
T he I n vesti gat or a n d a n y ot her pers o n nel ass ociat e d wit h t his st u d y will n ot p u blis h t he res ults of 
t he st u d y, i n w h ole or i n part, at a n y ti me, u nless t he y ha v e c o ns ulte d wit h t he S p o ns or, pr o vi de d 
t he Sp o ns or  a c o p y of t h e draft d o c u me nt i nte n de d f or p u blicati o n, a n d o btai ne d t he S p o ns or’s 
writte n c o nse nt f or s u c h p u blicati o n.  All i nf or mati o n o btai ne d d uri n g t he c o n d uct of t his st u d y 
will be re gar de d as c o nfi de ntial.  T he S p o ns or  will use t he i nf or mati o n f or re gistrati o n p ur p oses 
a n d f or t he ge neral de vel o p me nt of t he dr u g.  
V V- T M F- 5 1 6 1 9 | Pa ge 8 6/ 1 1 2

Pr ot oc ol  
 
 Pa ge 8 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1 2.   
LI S T O F R E F E R E N C E S  
Ar mita ge J O, Sta gi n g N o n -H o d g ki n L y m p h o ma. C A: A C a ncer J o ur n al f or Cli nici a ns . 5 5; 6: 3 6 8-
3 7 6. 2 0 0 5.  
Barre na S, Al mei da J, Y u nta M, et al. A berra nt e x pressi o n of tetras pa ni n m olec ules i n B-cell 
c hr o nic l y m p h o pr oliferati ve dis or ders a n d its c orrelati o n wit h n or mal B -cell mat urati o n. Le uke mi a  
1 9( 8): 1 3 7 6 -8 3, 2 0 0 5.  
Bec k wit h  K A, B yr d J C, M ut h usa m y N. Tetras p a ni ns as t hera pe utic tar gets i n he mat o l o gical 
mali g na n c y: a c o n cise re vie w. Fr o nt iers i n P hysi ol o gy 2 3; 6:  9 1 , 2 0 1 5.  
Bec k wit h K A, Friss ora F W, Stefa n o vs ki M R, et al. T he C D 3 7-tar gete d a nti b o d y-dr u g c o nj u gat e 
I M G N 5 2 9 is hi g hl y acti v e a gai nst h u ma n C L L a n d i n a n o vel C D 3 7 tra ns ge nic m uri ne le u ke mia 
m o del . Le uke mi a 2 8( 7): 1 5 0 1 -1 5 1 0 , 2 0 1 4. 
Blattler W A a n d C hari R VJ. Dr u gs t o E n ha n ce t he T hera p e utic P ote nc y of A ntica ncer A nti b o dies: 
A nti b o d y Dr u g C o nj u gates as T u m or Acti vate d Pr o dr u gs.  A meric a n C a ncer S ociety  3 1 7 -3 1 8, 
2 0 0 1.  
Bl u m  R H a n d Ka hlert T.  Ma yt a nsi ne: A P hase I St u d y of a n A nsa Macr oli de w it h A ntit u m or 
Acti vit y.  C a ncer Tre at m e nt Re p orts  6 2( 3): 4 3 5 -4 3 8. 1 9 7 8.  
Ca ba nillas F, R o dri g uez V, Hall S W, et al.  P hase I St u d y of M a yt a nsi ne Usi n g a 3-Da y Sc h e d ule.  
C a ncer Tre at me nt Re p orts  6 2( 3): 4 2 5 -4 3 8 , 1 9 7 8.  
C ha b ner B A, Le vi ne A S, J o h ns o n B L et al.  I niti al Cli nical Trials of Ma yta nsi ne, a n A ntit u m or 
Pla nt Al kal oi d.  C a ncer Tre at me nt Re p orts  6 2( 3): 4 2 9 -4 3 3. 1 9 7 8.  
C hes o n B D, Fis her RI , Barri n gt o n S F  et al. Rec o m me n dati o ns f or I niti al e val uati o n, Sta gi n g a n d 
Res p o nse Assess me nt of H o d g ki n a n d N o n -H o d g ki n L y m p h o ma: T he L u ga n o Classificati o n . 
Jo ur n al  Cli n ic al O nc ol o gy  3 2 (2 7 ): 3 0 5 9 -3 0 6 7 , 2 0 1 4 .   
C hes o n B D a n d Le o nar d J P.  M o n ocl o nal A nti b o d y T hera p y f or B -Cell N o n -H o d g ki n  L y m p h o ma. 
N e w E n gl a n d  Jo ur n al of  Me d ici ne 3 5 9: 6 1 3 -6 2 6, 2 0 0 8.  
Cra wf or d C, Casert a C, R oila F, He mat o p oietic gr o wt h fact ors: E S M O Cli nical Practice 
G ui deli nes f or t he a p plicati o ns, A n n als of O nc ol o gy  2 1 ( S u p pl. 5): 2 4 8 -2 5 1, 2 0 1 0.  
Dec kert J, Par k P U, C hic klas S, Yi Y, et al. A n o vel a nti -C D 3 7 a nti b o d y -dr u g c o nj u gate wit h 
m ulti ple a nti -t u m or mec ha nis ms f or t he treat me nt of B-cell mali g n a ncies . Bl o o d 1 2 2( 2 0): 3 5 0 0 -
3 5 1 0 , 2 0 1 3. 
Ea ga n R T, I n gle J N, R u bi n J, et al. Earl y Cli nical St u d y of a n I nter mitte nt Sc he d ule f or Ma yt a nsi ne 
(N S C -1 5 3 8 5 8): Brief C o m m u nicati o n. Jo ur n al of t he  N at i o n al C a ncer I nstit ute 6 0( 1): 9 3 -9 6 , 
1 9 7 8.  
Iss ell B F a n d Cr o o ke S T. Ma yta nsi n e. C a ncer Tre at me nt Revie w  5: 1 9 9 -2 0 7, 1 9 7 8.  
K u pc ha n S M, K o m o da Y, C o urt W A, et al. Ma yta nsi ne, a N o vel A ntile u ke mic A nsa Macr oli de 
fr o m Ma yte n us o vat us. J o ur n al of t he A meric a n C a ncer S ociety 9 4: 4, 1 9 7 2.  
La p al o m bella  R , Ye h Y Y, Wa n g L, et al. Tetras pa ni n C D 3 7 directl y m e diates tra ns d ucti o n of 
s ur vi val a n d a p o pt otic si g nals. C a ncer Ce ll 2 1( 5): 6 9 4 -7 0 8 , 2 0 1 2. 
V V- T M F- 5 1 6 1 9 | Pa ge 8 7/ 1 1 2

Pr ot oc ol  
 
 Pa ge 8 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
Le o n ar d  J P, Marti n P, R ua n J, et al.  Ne w m o n ocl o nal a nti b o dies f or n o n -H o d g ki n  l y m p h o ma. 
A n n als of O nc ol o gy  1 9 ( 4): 6 0 -6 2, 2 0 0 8.  
Le u k e mia, L y m p h o m a, M yel o ma Facts 2 0 1 4 -2 0 1 5 .  Le uke mi a a n d Ly m p h o m a S ociety . p g 1 5 , 
2 0 1 5  
Li n k M P, Bi n dl J, Mee ker T C, et al. A u ni q ue a nti ge n o n mat ure B cells defi ne d b y a m o n ocl o nal 
a nti b o d y. Jo ur n al of  I m m u n olo gy  1 3 7( 9): 3 0 1 3 -3 0 1 8, 1 9 8 6.  
Maec ker H T, T o d d S C a n d Le v y S. T he tetras pa ni n s u perfa mil y: m olec ul ar facilitat ors. F A S E B 
Jo ur n al  1 1: 4 2 8 -4 4 2, 1 9 9 7.  
M o ore, K., C o o per, S. A. a n d J o nes, D. B. Use of t he m o n ocl o nal a nti b o d y W R 1 7, i de ntif yi n g t he 
C D 3 7 g p 4 0 -4 5 K d a nti ge n c o m ple x, i n t he dia g n osis of B -l y m p h oi d mali g na n c y. Jo ur n al of  
P at h ol o gy  1 5 2: 1 3 -2 1, 1 9 8 7.  
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 eric a n Jo ur n al  Cli n ic al O nc ol o gy  5( 6): 6 4 9 -6 5 5 , 1 9 8 2. 
Nati o nal C o m pre he nsi ve Ca ncer Net w or k G ui deli nes i n O nc ol o g y. N o n -H o d gki n  Ly m p h o m as.  
Versi o n 3. 2 0 1 1, Ma y 1 8, 2 0 1 1.   
Ra o P N, Freireic h EJ, S mit h M L et al. Cell C ycl e P hase -s pecifi c C yt ot o xicit y of t he A ntit u m or 
A ge nt Ma yta nsi ne. C a ncer Res e arc h 3 9: 3 1 5 2 -3 1 5 5, 1 9 7 9.  
Re millar d S, Re b h u n LI, H o wie G A et al.  A nti mit otic Acti vit y of t he P ote nt T u m or I n hibit or 
Ma yta nsi n e.  Scie nce  1 8 9: 1 0 0 2 -1 0 0 5, 1 9 7 5.  
Rit u x a n ®  (rit u xi ma b) P ac ka ge Ins ert. Ge n e ntec h, I n c. 2 0 1 4 . 
Sa was A, Sa v a ge KJ, Perez R P, et al. A P hase I St u d y of t he A nti -C D 3 7 A nti b o d y Dr u g C o nj u gate 
A G S 6 7 E i n A d va nce d L y m p h oi d Mali g n a ncies. I nteri m Res ults. He mat ol o gical O nc ol o g y 3 5( 2) : 
4 9, 2 0 1 7  
Sc h wartz -Al biez R, D ör ke n B, H of ma n n W, et al. T he B cell-ass ociate d C D 3 7 a nti ge n ( g p 4 0 -5 2). 
Str uct ure a n d s u bcell ular e x pressi o n of a n e xte nsi vel y gl yc os yl ate d gl yc o pr otei n. Jo ur n al of  
I m m u n olo gy . 1 4 0( 3): 9 0 5 -9 1 4, 1 9 8 8.  
S mit h TJ, B o hl ke K, L y ma n G H, et al. Rec o m me n dati o ns f or t he Use of W B C Gr o wt h Fact ors: 
A merica n S oci et y of Cli nical O nc ol o g y Cli nical Practice G ui d eli ne U p date, J o ur n al of Cli nic al 
O nc ol o gy 3 3  (2 8 ): 3 1 9 9 -3 2 1 4 , 2 0 15 . 
Stat his  A, Free d m a n A S, Fli n n I W et al. A P hase I St u d y of I M G N 5 2 9, a n A nti b o d y-Dr u g 
C o nj u gate ( A D C) Tar geti n g C D 3 7, i n A d ult Patie nts wit h Rela pse d or R efract or y B -Cell N o n -
H o d g ki n’s L y m p h o ma ( N H L) . A S H meeti n g a bstr act 6 2 4, 2 0 1 4.  
S E E R  Ca ncer Statistics Facts h ee ts: 
N o n-H o d g ki n L y m p h o ma. 
Nati o nal Ca ncer I nstit ute. 
Bet hes d a, M D, htt p://seer.ca ncer. g o v/statfacts/ ht ml/ n hl. ht ml . Accesse d 1 3 J a n uar y 2 0 1 5 
 
V V- T M F- 5 1 6 1 9 | Pa ge 8 8/ 1 1 2

Pr ot oc ol  
 
 Pa ge 8 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
1 3.   
A P P E N DI C E S  
A P P E N DI X  A.  S C H E D U L E O F E V E N T S  O F S A F E T Y R U N -IN F O R Q 3 W  D O SI N G (S T U D Y P A R T 1)   
Acti vit y  
Scree ni n g  
C ycles  1 a n d 3  
C ycle 2  
C ycles 
≥ 4  
E O T j 
3 0 -d a y 
F oll o w -u p f, n  
 
≤2 8 d a ys 
pri o r t o  
1 st d ose  
D a y 1 k   
D a y 2   
D a y 3  
D a y 8  
± 1 d a y  
D a y 1 5  
± 1 d a y  
D a y 1 k  
D a y 8  
± 1 d a y  
D a y 1 5  
± 1 d a y  
D a y 1 k  
 
( 3 0-4 2 D a ys)  
I nf or me d C o nse nt 
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De m o gra p h y  
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C o nfir m diseas e dia g n osis, sta ge 
at dia g n osis a n d c urre nt sta ge  
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Me dical Hist or y  
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Re vie w a n d D oc u me nt 
I ncl usi o n/ E xcl usi o n Criteria 
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C o nfir m patie nt c o nti n ues t o 
satisf y I/ E Criteria 
 
C 1 
o nl y  
  
  
  
  
  
  
  
  
 
 
P h ysical e xa mi n ati o n a 
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Vital Si g ns b 
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Wei g ht  
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Hei g ht  
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B -s y m pt o ms 
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E C O G perf or ma nce stat us  
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Pre g na nc y test ( uri n e or ser u m)   
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He mat ol o g y  a n d C he mistr y c 
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V V- T M F- 5 1 6 1 9 | Pa ge 8 9/ 1 1 2

Pr ot oc ol  
 
 Pa ge 9 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
Acti vit y  
Scree ni n g  
C ycles 1 a n d 3  
C ycle 2  
C ycles 
≥ 4  
E O T j 
3 0 -d a y 
F oll o w -u p f, n 
 
≤2 8 d a ys 
pri o r t o 1 st 
d os e  
D a y 
1 k  
D a y 2   
D a y 3  
D a y 8  
± 1 d a y  
D a y 1 5  
± 1 d a y  
D a y 
1 k  
D a y 8  
± 1 d a y  
D a y 1 5  
± 1 d a y  
D a y 1 k   
  
( 3 0-4 2 D a ys)  
C oa g ulati o n c 
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Uri nal ysis c  
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Viral Ser ol o g y ( H Bs A g)  
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Ra di ol o gic t u m or  
assess me nts d  
●  
 
E ver y 6 wee ks  ( ± 1 wee k) fr o m C ycle 1 Da y 1 ( n o sc he d ule s hift d ue t o d ose 
dela ys) edela ys)  e  
●f 
 ●f 
Bi o ps y t u m or tiss ueg 
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B o ne Marr o w Assess me nt h  
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E ver y 6 wee ks ( ± 1 wee k) fr o m C y cle 1, Da y 1 as Cli nicall y I n dicate d  
 
 
E C G ( 1 2 -lea d)i 
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O n Da y 1 of C ycl es 2 a n d 4  t o 
c oi n ci d e wit h P K dra ws ( ± 1 h o ur)  
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P har mac o ki netic a n d 
I m m u n o ge nicit y Assess me nts 
See A p pe n di x  D  
A E a n d S A E e val u ati o n  l 
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C o nc o mita nt Me dicati o n
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De bi o 1 5 6 2  I nf usi o n 
  
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Rit u xi ma b I nf usi o n  
  
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a)  Directe d p h ysical e xa mi nati o n is acce pta ble w hile o n st u d y treat me nt  a n d at t he 3 0 -da y safet y F oll o w -u p Visit . C o m plete e xa mi nati o n is re q uire d at scree ni n g 
a n d E O T . P h ysical e xa mi nati o ns ma y be perf or me d u p t o 3 da ys pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 of all C ycles.  
b)  De bi o 1 5 6 2  - v ital si g ns ( bl o o d press ure, heart rate, te m perat ure, a n d res pirat or y rate) will be meas ure d i m me diatel y bef ore eac h a d mi nistrati o n, e ver y 3 0 mi n 
 5 mi n d uri n g t he i nf usi o n  (if a p plica ble), a n d i m me diatel y after i nf usi o n. Rit u xi m a b  - vital si g ns will be meas ure d i m me diatel y bef ore eac h  a d mi nistrati o n, 
e ver y 6 0 mi n  5 mi n d uri n g t he i nf usi o n a n d i m me diatel y after i nf usi o n . F or all c ycles, p atie nts m ust re mai n  i n t he cli ni c f or safet y o bser vati o n f or o ne  h o ur 
f oll o wi n g c o m pleti o n of t heir rit u xi ma b i nf usi o n. 
c)  La b orat or y assess me nts ma y be  perf or me d u p t o 3 da ys pri or t o st u d y dr u g  a d mi nistrati o n  i n all c ycles. All dra ws o n D a y 1 of treat me nt s h o ul d be pre -d ose . 
I n t he e ve nt of se vere t o xicit y, re peat la b orat or y tests s h o ul d be perf or me d wit hi n 4 8 h o urs, a n d t he n f oll o we d at least t wi ce wee kl y  u ntil re-treat me nt criteria 
are met.  
Ser u m C he mistr y - A L B, A L K -P, A L T, A S T, B U N, Ca, Cl, Creati ni ne, Gl uc ose, L D H, Ma g nesi u m, P h os p h or us, K, Na, T otal bilir u bi n, T otal pr otei n, Uric 
aci d, I m m u n o gl o b uli n le vels (I g G, I g A, I g M ) .  
V V- T M F- 5 1 6 1 9 | Pa ge 9 0/ 1 1 2

Pr ot oc ol  
 
 Pa ge 9 1  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
He m at ol o g y - Hct, H g b, Platelet c o u nt, R B C c o u nt,  W B C c o u nt wit h differe ntial . 
Uri n al ysis - A p peara nce, s p ecific gra vit y a n d p H, Se mi -q ua ntitati ve di pstic k e val uati o n of gl uc ose, pr otei n, bilir u bi n, ket o nes, le u k oc ytes a n d bl o o d, 
Micr osc o pic e xa mi nati o n of s e di me nt t o  be perf or me d if uri nal ysis is p ositi ve f or W B C, pr otei ns or bl o o d .  
C o a g ul ati o n tests:  T/I N R a n d a P T T   
d)  Ra di o gra p hic t u m or e val uati o n b y C T or P E T -C T sca n of c hest, nec k, a b d o me n a n d pel vis will be perf or me d wit hi n 2 8 da ys pri or t o first d ose of st u d y 
treat me nt.  T he a nat o mical re gi o ns t o be assesse d ra di o gra p hicall y p ost baseli ne will be deter mi ne d b y i n di vi d ual patie nts’ e xte nt of disease. W he ne ver 
p ossi ble, t he sa me ra di o gra p hi c sca n assess me nt use d at scre e ni n g (e. g., P E T -C T) s h o ul d be use d at all s u bse q ue nt ra di o gra p hic e val uati o ns.   
e)  P ost -baseli ne disease assess me nts will be perf or me d e ver y 6 wee ks fr o m C ycle 1, Da y 1 a n d will n ot s hift d ue t o d ose dela ys.  F or patie nts w h o are e xce pti o nall y 
gra nte d c o nti n ue d st u d y treat me nt after c o m pleti o n of 6 c ycles , re peat ra di o gra p hic t u m or res p o nse assess me nts ca n be perf or me d as per l ocal i nstit uti o nal 
care practice. I deall y, re peat assess me nts s h o ul d c o nti n ue at 6 -wee k ( ± 1 wee k) i nter vals a n d s h o ul d n ot be l o n ger t ha n 1 2 -wee ks ( ±  4 wee ks). P eri o dic t u m or 
assess me nt will be c o n d ucte d usi n g t he sa me i ma gi n g m o dalit y of pri or c ycles of treat me nt u ntil P D, start of a n y ne w a nti -ca ncer t hera p y, or deat h.  
f) 
P atie nts disc o nti n ui n g De bi o 1 5 6 2  f or reas o ns ot her t ha n P D will  ha ve s u bse q ue nt c li nic visits f or ra di o gra p hic assess me nt e ver y 1 2 wee ks ( ±  4  wee ks) fr o m 
t he ti me of t heir last o n -st u d y t u m or assess me nt u ntil P D or starti n g a s u bse q ue nt a nti-ca ncer t hera p y. F or patie nts w h o disc o nti n ue f or P D, n o ra di o gra p hic 
sca ns will be re q uire d at t he E O T visit or t he f oll o w-u p  visits . All patie nts will be f oll o we d f or s ur vi val e ver y 1 2 wee ks ( ± 4 wee ks)  fr o m t he ti me of t he 3 0-
da y safet y F oll o w -u p visit,  f or u p t o o ne year fr o m t he last patie nt’s first d ose ( C ycle 1 Da y 1). P atie nts will n ot be re q uire d t o visit t he cli nic f or s ur vi val 
f oll o w-u p . 
g)  P atie nts m ust ha ve a vaila ble a pat h ol o g y -i nf or me d t u m or bi o ps y sa m ple re prese ntati ve of t he c urre nt disease, 
.  
h)  If a p plica ble, a b o ne marr o w bi o ps y or as pirate will be perf or me d wit hi n 3 m o nt hs pri or t o first d ose.  A re peat b o ne marr o w bi o ps y or as pirate  will be re q uire d 
f or patie nts wit h b o ne marr o w i nfiltrati o n at baseli ne w h o ha ve a C R b y i ma gi n g a n d p h ysi cal e xa mi nati o n, a n d will, i n c ase p ossi ble a n d dee me d acce pta ble 
b y t he I n vesti gat or, be perf or me d e ver y 6 wee ks  as cli nicall y i n dicate d .  I n or der t o better u n dersta n d t he effect of D e bi o 1 5 6 2  o n W B Cs , b o ne marr o w 
bi o psies/as pirates ma y als o be re q ueste d f or t h ose patie nts w h o e x perie nce gra de 4 c yt o pe nias . 
i) 
T he scree ni n g  E C G will  be perf or me d wit hi n 1 4  da ys pri or t o first treat me nt.  I n C ycles 1 a n d 3, E C G s will be perf or me d  wit hi n t hree h o urs pri or t o d ose, at 
t he e n d of t he De bi o 1 5 6 2  i nf usi o n (t o c oi nci de wit h C ma x a n d P K bl o o d dra w) a n d  2 4  4  h o urs after i nf usi o n .  A n E C G will be perf or me d o n D a y 1 of 
C ycles 2 a n d 4  (i ncl usi ve) t o c oi nci de wit h t he pre-d ose P K bl o o d dra w . A n E C G at t he 3 0 -da y F oll o w -u p  visit is n ot re q uire d u nless cli nicall y i n dicate d  or if 
t he E O T assess me nt was miss e d . 
j) 
E O T  v isit s h o ul d occ ur wit hi n 7 da ys of t he decisi o n t o disc o nti n ue st u d y treat me nt.  
k)  C ycle 1 Da y 1 assess me nts ( E C O G, wei g ht, B S y m pt o ms a n d pre g na nc y test) d o n ot ne e d t o be re peate d if t he y are c ollecte d wit h i n 3 da ys of st u d y dr u g 
a d mi nistrati o n.  F or all ot her c ycles, t he Da y 1 wi n d o w is ± 3 da ys .  
l) 
T he peri o d of safet y o bser vati o n e xte n ds fr o m t he ti me of c o nse nt u ntil 3 0 da y s after t he patie nt’s last st u d y treat me nt or u ntil t he A Es has res ol ve d or sta bilize d 
or a n o utc o me has bee n reac he d, w hic he ver c o mes first.  
m)  C o nc o mita nt me dicati o ns s h o ul d be c ollecte d be gi n ni n g fr o m 4 wee ks pri or t o C ycle 1, D a y 1 u ntil t he e n d of t he peri o d of safet y o bser vati o n . 
n)  I n t he e ve nt t hat a patie nt is u na ble t o ret ur n t o t he cli nic f or a f oll o w-u p visit, tele p h o ne c o ntact wit h t he patie nt t o assess A Es , c o nc o mita nt me dicati o ns, a nti-
ca ncer treat me nts will be c o n d ucte d.  
V V- T M F- 5 1 6 1 9 | Pa ge 9 1/ 1 1 2

Pr ot oc ol  
 
 Pa ge 9 2  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
A P P E N DI X  B.  S C H E D U L E O F E V E N T S O F  C O H O R T A F O R Q 3 W D O SI N G ( S T U D Y P A R T 2  A N D 3 ) 
Acti vit y  
Scree ni n g  
C ycles 1 a n d 2  
C ycles 3 -6  q   
E O T  l 
3 0 -d a y  
F oll o w -u p  g, p 
 
≤2 8 d a ys 
pri o r t o  
1 st d ose  
D a y 1 m   
D a y 2   
D a y 3  
D a y 8  
± 1 d a y  
D a y 1 5  
± 1 d a y  
D a y 1 m  
 
( 3 0-4 2 D a ys)  
I nf or me d C o nse nt 
● 
 
 
 
 
 
 
 
 
De m o gra p h y  
● 
 
 
 
 
 
 
 
 
C o nfir m diseas e dia g n osis, 
sta ge at dia g n osis a n d c urre nt 
sta ge 
● 
 
 
 
 
 
 
 
 
Me dical Hist or y  
● 
 
 
 
 
 
 
 
 
Re vie w a n d D oc u me nt 
I ncl usi o n/ E xcl usi o n Criteria 
● 
 
 
 
 
 
 
 
 
C o nfir m patie nt c o nti n ues t o 
satisf y I/ E Criteria 
  
C 1 o nl y   
 
 
 
 
 
 
 
P h ysical e xa mi n ati o n  a 
● 
●  
 
 
 
 
● 
● 
● 
Vital Si g ns  b 
● 
●  
 
 
● 
●  
● 
● 
● 
Healt h -relate d Q ualit y of Life 
c 
 
●  
 
 
 
 
● 
● 
● 
Wei g ht  
● 
●  
 
 
 
 
● 
● 
● 
Hei g ht  
● 
 
 
 
 
 
 
 
 
B -s y m pt o ms 
● 
●  
 
 
 
 
● 
● 
● 
E C O G perf or ma nce stat us  
● 
●  
 
 
 
 
● 
● 
● 
Pre g na nc y test ( uri n e or 
ser u m) 
● 
●  
 
 
 
 
● 
● 
● 
He mat ol o g y  a n d C he mistr y d  
● 
●  
●  
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● 
 
V V- T M F- 5 1 6 1 9 | Pa ge 9 2/ 1 1 2

Pr ot oc ol  
 
 Pa ge 9 3  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
Acti vit y  
Scree ni n g  
C ycles 1 a n d 2  
C ycles 3 -6   q   
E O T  l 
3 0 -d a y 
F oll o w -u p  g,  p  
 
≤2 8 d a ys 
pri o r t o 1 st 
d os e  
D a y 1 m   
D a y 2   
D a y 3  
D a y 8  
± 1 d a y  
D a y 1 5  
± 1 d a y  
D a y 1 m  
  
( 3 0-4 2 D a ys)  
C oa g ulati o n  d 
● 
●  
  
 
 
 
● 
● 
● 
Uri nal ysis  d  
● 
● 
  
 
 
 
● 
● 
● 
Viral Ser ol o g y ( H Bs A g)  
● 
 
  
 
 
 
 
 
 
Ra di ol o gic t u m or  
A ssess me nts e 
● 
 
E ver y 6 wee ks ( ± 1 wee k) fr o m C ycle 1, Da y 1 ( n o sc he d ule s hift d ue t o d ose 
dela ys)  f 
●g 
●g 
Bi o ps y t u m or tiss ue h 
● 
 
  
 
 
 
 
 
 
B o ne Marr o w Assess me nt  i  
● 
  
E ver y 6 wee ks ( ± 1 wee k) fr o m C ycle 1, Da y 1 as Cli nicall y I n dicate d   
 
 
E C G ( 1 2 -lea d) k 
● 
● 
●  
 
 
 
● 
● 
● 
P har mac o ki netic a n d 
I m m u n o ge nicit y Assess me nts 
See A p pe n di x  E  
A E a n d S A E e val u ati o n  n 
● 
●  
● 
● 
● 
● 
● 
● 
● 
C o nc o mita nt Me dicati o n  o 
● 
●  
● 
● 
● 
● 
● 
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● 
De bi o 1 5 6 2 I nf usi o n  
 
●  
  
 
 
 
● 
 
 
Rit u xi ma b I nf usi o n  
 
●  
  
 
 
 
● 
 
 
a)  Directe d p h ysical e xa mi nati o n is acce pta ble w hile o n st u d y treat me nt a n d at t he 3 0 -da y safet y F oll o w -u p Visit. C o m plete e xa mi nati o n is re q uire d at scree ni n g 
a n d E O T . P h ysical e xa mi nati o ns ma y be perf or me d u p t o 3 da ys pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 of all C ycles.  
b)  De bi o 1 5 6 2  - vital si g ns ( bl o o d press ure, heart rate, te m perat ure, a n d res pirat or y rate) will be meas ure d i m me diatel y bef ore eac h a d mi nist rati o n, e ver y 3 0 mi n 
 5 mi n d uri n g t he i nf usi o n (if a p plica ble), a n d i m me diatel y after i nf usi o n.  Rit u xi m a b  - vital si g ns will be meas ure d i m me diatel y bef ore eac h a d mi nistrati o n, 
e ver y 6 0 mi n  5 mi n d uri n g t he i nf usi o n a n d i m me diatel y after i nf usi o n.  P atie nts will re mai n i n t he cli nic u n der m o nit ori n g f or f o ur h o urs after c o m pleti o n 
of t he rit u xi ma b  i nf usi o n f or t he first c ycle. P ost-a d mi nistrati o n safet y m o nit ori n g c o ul d p ote ntiall y be s h orte ne d (i.e. < 4 h o urs b ut at least 1 h o ur) f oll o wi n g 
s u bse q ue nt a d mi nistrati o n of rit u xi ma b, base d o n t he j u d ge me nt of t he i n vesti gat or. P atie nts recei vi n g De bi o 1 5 6 2 o nl y will als o re mai n i n t he cli ni c u n der 
m o nit ori n g f or o ne h o ur.  
c)  H R Q o L assess me nt at Da y 1 of eac h c ycle will be perf or me d pri or t o De bi o 1 5 6 2 i nf usi o n.  I n patie nts w h o e xce pti o nall y c o nti n ue t he st u d y treat me nt be y o n d 
C 6, t he last H R Q o L assess me nt  will be perf or me d at C 7 D 1 bef ore t he i nf usi o n a n d n o a d diti o nal H R Q o L assess me nt will be c o m plete d at 3 0 -da y foll o w u p 
V V- T M F- 5 1 6 1 9 | Pa ge 9 3/ 1 1 2

Pr ot oc ol  
 
 Pa ge 9 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
visit.  
d)  La b orat or y assess me nts ma y b e perf or me d u p t o 3 da ys pri or t o st u d y dr u g  a d mi nistrati o n  i n all c ycles. If t he scree ni n g la b orat or y assess me nts are perf or me d 
wit hi n 3 da ys pri or dr u g a d mi nistrati o n o n Da y 1 of C ycle 1, n o assess me nts nee d t o be re peate d o n Da y 1 of C ycle 1. All dra ws o n da ys of treat me nt s h o ul d 
be pre -d ose. I n t he e ve nt of se vere t o xicit y, r e peat la b orat or y tests s h o ul d be perf or me d wit hi n 4 8 h o urs, a n d t he n f oll o we d at least t wice wee kl y u ntil 
retreat me nt criteria are met.  
Ser u m C he mistr y - A L B, A L K -P, A L T, A S T, B U N, Ca, Cl, Creati ni ne, Gl uc ose, L D H, Ma g nesi u m, P h os p h or us,  K, Na, T otal bilir u bi n, T otal pr otei n, Uric 
aci d, I m m u n o gl o b uli n le vels (I g G, I g A, I g M ).  
He m at ol o g y - Hct, H g b, Platelet c o u nt, R B C c o u nt, W B C c o u nt wit h differe ntial.  
Uri n al ysis - A p peara nce, s p ecific gra vit y a n d p H, Se mi -q ua ntitati ve di pstic k e val uati o n of gl uc ose, pr otei n, bilir u bi n, ket o nes, le u k oc ytes a n d bl o o d, 
Micr osc o pic e xa mi nati o n of s e di me nt t o be perf or me d if uri nal ysis is p ositi ve f or W B C, pr otei ns or bl o o d.  
C o a g ul ati o n tests:  T/I N R a n d a P T T .  
If dee me d necessar y b y t he I n vesti gat or a n a d diti o nal he mat ol o gical assess me nt ca n be perf or me d o n Da y 1 5 of C ycles 3 -6.   
e)  Ra di o gra p hic t u m or e val uati o n b y C T or P E T -C T sca n of c hest, nec k, a b d o me n a n d pel vis will be perf or me d wit hi n 2 8 da ys pri or t o first d ose of st u d y 
treat me nt.  T he a nat o mical re gi o ns t o be assesse d ra di o gra p hicall y p ost baseli ne will be deter mi ne d b y i n di vi d ual patie nts’ exte nt of disease. W he ne ver 
p ossi ble, t he sa me ra di o gra p hi c sca n assess me nt use d at scre e ni n g (e. g., P E T -C T) s h o ul d be use d at all s u bse q ue nt ra di o gra p hic e val uati o ns.  
f) 
P ost -baseli ne disease assess me nts will be perf or me d e ver y 6 wee ks fr o m C ycle 1, Da y 1 a n d will n ot s hift d ue t o d ose dela ys.  F or patie nts w h o are e xce pti o nall y 
gra nte d c o nti n ue d s t u d y treat me nt after c o m pleti o n of 6 c ycles, re peat ra di o gra p hic t u m or res p o nse assess me nts ca n be perf or me d as per l ocal i nstit uti o nal 
care practice. I deall y, re peat assess me nts s h o ul d c o nti n ue at 6 -wee k ( ± 1 wee k) i nter vals a n d s h o ul d n ot be l o n ger t ha n 1 2 -wee ks ( ± 4 wee ks). P eri o dic t u m or 
assess me nt will be c o n d ucte d usi n g t he sa me i ma gi n g m o dalit y of pri or c ycles of treat me nt u ntil P D, start of a n y ne w a nti -ca ncer t hera p y, or deat h.  
g)  P atie nts disc o nti n ui n g De bi o 1 5 6 2 f or reas o ns ot her t ha n P D will ha ve s u bse q ue nt cli nic visits f or ra di o gra p hic assess me nt e ver y 1 2 wee ks ( ± 4 wee ks) fr o m 
t he ti me of t heir last o n-st u d y t u m or assess me nt u ntil P D or starti n g a s u bse q ue nt a nti -ca ncer t hera p y. F or patie nts w h o disc o nti n ue f or P D, n o ra di o gra p hic 
sca ns will be re q uire d at t he E O T visit or t he f oll o w -u p visits. All patie nts will be f oll o we d f or s ur vi val e ver y 1 2 wee ks ( ± 4 wee ks) fr o m t he ti me of t he 3 0 -
da y safet y F oll o w -u p visit, f or u p t o o ne year fr o m t he last patie nt’s first d ose ( C ycle 1 Da y 1) . P atie nts will  n ot be re q uire d t o visit t he cli nic f or s ur vi val 
f oll o w-u p.  
h)  P atie nts m ust ha ve a vaila ble a pat h ol o g y -i nf or me d t u m or bi o ps y sa m ple re prese ntati ve of t he c urre nt disease, 
.  
i) 
If a p plica ble, a b o ne marr o w bi o ps y or as pirate will be perf or me d wit hi n 3 m o nt hs pri or t o first d ose.  A re peat b o ne marr o w bi o ps y or as pirate will be re q uire d 
f or patie nts wit h b o ne marr o w i nfiltrati o n at baseli ne w h o ha ve a C R b y i ma gi n g a n d p h ysi cal e xa mi nati o n, a n d will, i n c ase p ossi ble a n d dee me d acce pta ble 
b y  t he I n vesti gat or, be perf or me d e ver y 6 wee ks as cli nicall y i n dicate d.  I n or der t o better u n dersta n d t he effect of D e bi o 1 5 6 2 o n W B Cs, b o ne marr o w 
bi o psies/as pirates ma y als o be re q ueste d f or t h ose patie nts w h o e x perie nce gra de 4 c yt o pe nias.  
 
 
  
k)  T he scree ni n g E C G will be perf or me d wit hi n 1 4 da ys pri or t o first treat me nt. I n C ycles 1 a n d  2 , E C Gs will be perf or me d wit hi n t hree h o urs pri or t o d ose, at 
t he e n d of t he De bi o 1 5 6 2 i nf usi o n (t o c oi nci de wit h C ma x a n d P K bl o o d dra w) a n d 2 4  4 h o urs after i nf usi o n.  A n E C G will be perf or me d o n D a y 1 of 
C ycles 3 -6  t o c oi nci de wit h t he pre-d ose P K bl o o d dra w . A n E C G at t he 3 0-da y F oll o w -u p  visit is n ot re q uire d u nl ess cli nicall y i n dicate d or if t he E O T 
assess me nt was misse d.  
l) 
E O T  visit s h o ul d occ ur wit hi n 7 da ys of t he decisi o n t o disc o nti n ue st u d y treat me nt.  
m)  C ycle 1 Da y 1 assess me nts ( E C O G, wei g ht,  B S y m pt o ms a n d pre g na nc y test) d o n ot ne e d t o be re peate d if t he y are c ollecte d wit hi n 3 da ys of st u d y dr u g 
a d mi nistrati o n.  F or all ot her c ycles, t he Da y 1 wi n d o w is ± 3 da ys.  
n)  T he peri o d of safet y o bser vati o n e xte n ds fr o m t he ti me of c o nse nt u ntil 3 0 da y s after t he patie nt’s last st u d y treat me nt or u ntil t he A Es has res ol ve d or sta bilize d 
or a n o utc o me has bee n reac he d, w hic he ver c o mes first.  
V V- T M F- 5 1 6 1 9 | Pa ge 9 4/ 1 1 2

Pr ot oc ol  
 
 Pa ge 9 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7 , 2 4 A pril  2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1 -6  
 
La us a n ne ( S witzerla n d)  
o)  C o nc o mita nt me dicati o ns s h o ul d be c ollecte d be gi n ni n g fr o m 4 wee ks pri or t o C ycle 1, D a y 1 u ntil t he e n d of t he p eri o d of safet y o bser vati o n . 
p)  I n t he e ve nt t hat a patie nt is u na ble t o ret ur n t o t he cli nic f or a f oll o w-u p visit, tele p h o ne c o ntact wit h t he patie nt t o assess A Es , c o nc o mita nt me dicati o ns, a n d 
a nti -ca ncer treat me nts will be c o n d ucte d . 
q)  P er missi o n t o pr ol o n g t he st u d y treat me nt c o ul d be e xce pti o nall y gra nte d b y St u d y S p o ns or  if patie nts are deri vi n g be nefit fr o m t he st u d y treat me nt a n d after 
c o m plete prese ntati o n of t he i n di vi d ual case b y t he St u d y I n vesti gat or, partic ularl y t he me dical j ustificati o n f or e xte n di n g t he treat me nt a n d t he re -assess me nt 
of t he ris k /be nefit bala nce. T he  S p o ns or ’s decisi o n will c o nsi der t he a vaila bilit y of I M P at t he ti me of re q uest . A re p ort of t he disc ussi o ns wit h t he S p o ns or 
m ust be file d i n t he s o urce d oc u me ntati o n.  
 
V V- T M F- 5 1 6 1 9 | Pa ge 9 5/ 1 1 2

Pr ot oc ol  
 
 Pa ge 9 6  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7, 2 4 A pril  2 0 2 0   
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne ( S witzerla n d)  
 
 
A P P E N DI X  C.  S C H E D U L E O F E V E N T S  O F C O H O R T B  F O R Q W  D O SI N G (S T U D Y P A R T 2  A N D 3 )  
Acti vit y  
Scree ni n g  
C ycles 1 a n d 2  
C ycles 3 -6  q  
E O T  l 
3 0 -d a y 
F oll o w -u p  g, p 
 
≤2 8 d a ys 
pri o r t o  
1 st d ose  
D a y 1  m   
D a y 2   
D a y 3  
D a y 8  
(-1 t o + 3 
d a ys)  
D a y 1 5  
(-1 t o + 3 
d a ys)  
D a y 1  m  
D a y 8  
(-1 t o + 3 
da ys)  
D a y 1 5  
(-1 t o + 3 
da ys)  
 
( 3 0-4 2 D a ys)  
I nf or me d C o nse nt 
● 
 
  
  
 
 
  
  
  
 
 
De m o gra p h y  
● 
 
  
  
 
 
  
  
  
 
 
C o nfir m diseas e dia g n osis, 
sta ge at dia g n osis a n d c urre nt 
sta ge 
● 
 
  
  
 
 
  
  
  
 
 
Me dical Hist or y  
● 
 
  
  
 
 
  
  
  
 
 
Re vie w a n d D oc u me nt 
I ncl usi o n/ E xcl usi o n Criteria 
● 
 
  
  
 
 
  
  
  
 
 
C o nfir m patie nt c o nti n ues t o 
satisf y I/ E Criteria 
  
C 1 o nl y   
  
  
 
 
  
  
  
 
 
P h ysical e xa mi n ati o n  a 
● 
●  
  
  
●  
●  
●  
●  
●  
●  
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Vital Si g ns  b 
● 
●  
  
  
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●  
●  
● 
Healt h -relate d Q ualit y of Life 
c 
 
●  
  
  
 
  
●  
  
  
●  
● 
Wei g ht  
● 
●  
  
  
●  
●  
●  
●  
●  
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● 
Hei g ht  
● 
 
  
  
 
 
  
  
  
 
 
B -s y m pt o ms 
● 
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E C O G perf or ma nce stat us   
● 
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●  
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Pre g na nc y test ( uri n e or 
ser u m) 
● 
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●  
  
  
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He mat ol o g y  a n d C he mistr y d  
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V V- T M F- 5 1 6 1 9 | Pa ge 9 6/ 1 1 2

Pr ot oc ol  
 
 Pa ge 9 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7, 2 4 A pril  2 0 2 0   
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne ( S witzerla n d)  
 
Acti vit y  
Scree ni n g  
C ycles 1 a n d 2  
C ycles  3 -6   q  
E O T  l 
3 0 -d a y 
F oll o w -u p  g, p 
 
≤2 8 d a ys 
pri o r t o  
1 st d ose  
D a y 1  m   
D a y 2   
D a y 3  
D a y 8  
(-1 t o + 3 
d a ys)  
D a y 1 5  
(-1 t o + 3 
d a ys)  
D a y 1  m  
D a y 8  
(-1 t o + 3 
da ys)  
D a y 1 5  
(-1 t o + 3 
da ys)  
 
( 3 0-4 2 D a ys)  
C oa g ulati o n  d 
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Uri nal ysis  d 
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Viral Ser ol o g y ( H Bs A g)  
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Ra di ol o gic t u m or assess me nts  
e 
● 
 
E ver y 6 wee ks ( ± 1 wee k) fr o m C ycle 1, Da y 1 ( n o sc he d ule s hift d ue t o d ose 
dela ys)  f 
●g  
●g 
Bi o ps y t u m or tiss ue h 
● 
 
  
  
 
 
  
  
  
 
 
B o ne Marr o w Assess me nt  i  
● 
 
E ver y 6 wee ks ( ± 1 wee k) fr o m C ycle 1, Da y 1 as Cli nicall y I n dicate d  
 
 
E C G ( 1 2 -lea d) k 
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P har mac o ki netic a n d 
I m m u n o ge nicit y Assess me nts 
See A p pe n di x  F  
A E a n d S A E e val u ati o n  n 
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C o nc o mita nt Me dicati o n o 
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De bi o 1 5 6 2 I nf usi o n  
 
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Rit u xi ma b I nf usi o n  
 
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a)  Directe d p h ysical e xa mi nati o n is acce pta ble w hile o n st u d y treat me nt a n d at t he 3 0 -da y safet y F oll o w -u p Visit. C o m plete e xa mi nati o n is re q uire d at scree ni n g 
a n d E O T . P h ysical e xa mi nati o ns ma y be perf or me d u p t o 3 da ys pri or t o st u d y dr u g a d mi nistrati o n o n Da y 1 of all C ycles.  
b)  De bi o 1 5 6 2  - vital si g ns ( bl o o d press ure, heart rate, te m perat ure, a n d res pirat or y rate) will be meas ure d i m me diatel y bef ore eac h a d mi nist rati o n, e ver y 3 0 mi n 
 5 mi n d uri n g t he i nf usi o n (if a p plica ble), a n d i m me diatel y after i nf usi o n. Rit u xi m a b  - vital si g ns will be meas ure d i m me diatel y bef ore eac h a d mi nistrati o n, 
e ver y 6 0 mi n  5 mi n d uri n g t he i nf usi o n a n d i m me diatel y after i nf usi o n. P atie nts will re mai n i n t h e cli nic u n der m o nit ori n g f or f o ur h o urs after c o m pleti o n 
of t he rit u xi ma b i nf usi o n f or t he first c ycle.  P ost -a d mi nistrati o n safet y m o nit ori n g c o ul d p ote ntiall y be s h orte ne d (i.e. < 4 h o urs b ut at least 1 h o ur) f oll o wi n g 
s u bse q ue nt a d mi nistrati o n of rit u xi ma b, base d o n t he j u d ge me nt of t he i n vesti gat or. P atie nts recei vi n g De bi o 1 5 6 2 o nl y, i.e., o n Da y 8 a n d Da y 1 5 of eac h 
c ycle or d ue t o rit u xi ma b i nt olera bilit y, will als o re mai n i n t he cli nic u n der m o nit ori n g f or o ne h o ur.  
c)  H R Q o L assess me nt at Da y 1 of eac h c ycle will be perf or me d pri or t o De bi o 1 5 6 2 i nf usi o n. I n patie nts w h o e xce pti o nall y c o nti n ue t he st u d y treat me nt be y o n d 
C 6, t he last H R Q o L assess me nt will be perf or me d at C 7 D 1 bef ore t he i nf usi o n, a n d n o a d diti o nal H R Q o L a ssess me nt will be c o m plete d at t he 3 0-da y f oll o w -
V V- T M F- 5 1 6 1 9 | Pa ge 9 7/ 1 1 2

Pr ot oc ol  
 
 Pa ge 9 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7, 2 4 A pril  2 0 2 0   
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne ( S witzerla n d)  
 
u p visit.  
d)  La b orat or y assess me nts ma y b e perf or me d u p t o 3 da ys pri or t o st u d y dr u g  a d mi nistrati o n  i n all c ycles. If t he scree ni n g la b orat or y assess me nts are perf or me d 
wit hi n 3 da ys pri or dr u g a d mi nistrati o n  o n Da y 1 of C ycle 1, n o assess me nts nee d t o be re peate d o n Da y 1 of C ycle 1. All dra ws o n Da y 1 of treat me nt s h o ul d 
be pre -d ose. I n t he e ve nt of se vere t o xicit y, re peat la b orat or y tests s h o ul d be perf or me d wit hi n 4 8 h o urs, a n d t he n f oll o we d at leas t t wice wee kl y u ntil 
retreat me nt criteria are met.  
Ser u m C he mistr y - A L B, A L K -P, A L T, A S T, B U N, Ca, Cl, Creati ni ne, Gl uc ose, L D H, Ma g nesi u m, P h os p h or us, K, Na, T otal bilir u bi n, T otal pr otei n, Uric 
aci d, I m m u n o gl o b uli n le vels (I g G, I g A, I g M ).  
He m at ol o g y - Hct, H g b, Platelet c o u nt, R B C c o u nt, W B C c o u nt wit h differe ntial.  
Uri n al ysis - A p peara nce, s p ecific gra vit y a n d p H, Se mi -q ua ntitati ve di pstic k e val uati o n of gl uc ose, pr otei n, bilir u bi n, ket o nes, le u k oc ytes a n d bl o o d, 
Micr osc o pic e xa mi nati o n of s e di me nt t o be perf or me d if uri nal ysis is p ositi ve f or W B C, pr otei ns or bl o o d.  
C o a g ul ati o n tests:  T/I N R a n d a P T T  
e)  Ra di o gra p hic t u m or e val uati o n b y C T or P E T -C T sca n of c hest, nec k, a b d o me n a n d pel vis will be perf or me d wit hi n 2 8 da ys pri or t o first d ose of st u d y 
treat me nt.  T he a nat o mical re gi o ns t o be assesse d ra di o gra p hicall y p ost baseli ne will be deter mi ne d b y i n di vi d ual patie nts’ e xte nt of dis ease. W he ne ver 
p ossi ble, t he sa me ra di o gra p hi c sca n assess me nt use d at scre e ni n g (e. g., P E T -C T) s h o ul d be use d at all s u bse q ue nt ra di o gra p hic e val uati o ns.  
f) 
P ost -baseli ne disease assess me nts will be perf or me d e ver y 6 wee ks fr o m C ycle 1, Da y 1 a n d will n ot s hift d ue t o d ose dela ys . F or patie nts w h o are e xce pti o nall y 
gra nte d c o nti n ue d st u d y treat me nt after c o m pleti o n of 6 c ycles , re peat ra di o gra p hic t u m or res p o nse assess me nts ca n be perf or me d as per l ocal i nstit uti o nal 
care practice. I deall y, re peat assess me nts s h o ul d c o nti n ue at 6 -wee k ( ± 1 wee k) i nter vals a n d s h o ul d n ot be l o n ger t ha n 1 2 -wee ks ( ± 4 wee ks).  P eri o dic t u m or 
assess me nt will be c o n d ucte d usi n g t he sa me i ma gi n g m o dalit y of pri or c ycles of treat me nt u ntil P D, start of a n y ne w a nti -ca ncer t hera p y, or deat h.  
g)  P atie nts disc o nti n ui n g De bi o 1 5 6 2 f or reas o ns ot her t ha n P D will ha ve s u bse q ue nt cli nic visits f or ra di o gra p hic assess me nt e ver y 1 2 wee ks ( ±  4 wee ks) fr o m 
t he ti me of t heir last o n-st u d y t u m or assess me nt u ntil P D, or  starti n g a s u bse q ue nt a nti-ca ncer t hera p y. F or patie nts w h o disc o nti n ue f or P D, n o ra di o gra p hic 
sca ns will be re q uire d at t he E O T or f oll o w-u p visits. All patie nts will be f oll o we d f or s ur vi val e ver y 1 2 wee ks ( ±  4 wee ks) fr o m t he ti me of t he 3 0 -da y safet y  
foll o w -u p visit, f or u p t o o ne year fr o m t he last patie nt’s first d ose ( C ycle 1 Da y 1) . P atie nts will n ot be re q uire d t o visit t he cli nic f or s ur vi val f oll o w -u p.  
h)  P atie nts m ust ha ve a vaila ble a pat h ol o g y -i nf or me d t u m or bi o ps y sa m ple re prese ntati ve of t he curre nt disease, 
.  
i) 
If a p plica ble a b o ne marr o w bi o ps y or as pirate will be perf or me d wit hi n 3 m o nt hs pri or t o first d ose.  A re peat b o ne marr o w bi o ps y or as pirat e will be re q uire d 
f or patie nts wit h b o ne marr o w i nfiltrati o n at baseli ne wh o ha ve a C R b y i ma gi n g a n d p h ysi cal e xa mi nati o n, a n d will, i n c ase p ossi ble a n d dee me d acce pta ble 
b y t he I n vesti gat or, be perf or me d e ver y 6 wee ks as cli nicall y i n dicate d.  I n or der t o better u n dersta n d t he effect of D e bi o 1 5 6 2 o n W B Cs, b o ne marr o w 
bi o psie s/as pirates ma y als o be re q ueste d f or t h ose patie nts w h o e x perie nce gra de 4 c yt o pe nias.  
 
 
  
k)  T he scree ni n g E C G will be perf or me d wit hi n 1 4 da ys pri or t o first treat me nt. O n Da y 1 of C ycles 1 a n d 2 , E C Gs will be perf or me d wit hi n t hree h o urs pri or t o 
d ose, at t he e n d of t he De bi o 1 5 6 2 i nf usi o n (t o c oi nci de wit h C ma x  a n d P K bl o o d dra w) a n d 2 4  4 h o urs after i nf usi o n. O n Da y 8 a n d 1 5 of C ycles 1 a n d 2, 
E C Gs will be perf or me d wit hi n t hree h o urs pri or t o d ose a n d at t he e n d of t he De bi o 1 5 6 2 i nf usi o n (t o c oi nci de wit h C
ma x  a n d P K bl o o d dra w). A n E C G will 
be perf or me d o n Da y 1 of C ycles 3 -6  t o coi nci de wit h t he pre -d ose P K bl o o d dra w . A n E C G at t he 3 0-da y F oll o w -u p  visit is n ot re q uire d u nless cli nicall y 
i n dicate d or if t he E O T assess me nt was misse d. 
l) 
E O T  visit s h o ul d occ ur wit hi n 7 da ys of t he decisi o n t o disc o nti n ue st u d y treat me nt.  
m)  C ycle 1 Da y  1 assess me nts ( E C O G, wei g ht, B S y m pt o ms a n d pre g na nc y test) d o n ot ne e d t o be re peate d if t he y are c ollecte d wit hi n 3 da ys of  st u d y dr u g 
a d mi nistrati o n.  F or all ot her c ycles, t he Da y 1 wi n d o w is ± 3 da ys.  
V V- T M F- 5 1 6 1 9 | Pa ge 9 8/ 1 1 2

Pr ot oc ol  
 
 Pa ge 9 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7, 2 4 A pril  2 0 2 0   
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne ( S witzerla n d)  
 
n)  T he peri o d of safet y o bser vati o n e xte n ds fr o m t he  ti me of c o nse nt u ntil 3 0 da ys after t he patie nt’s last st u d y treat me nt or u ntil t he A E(s) has res ol ve d or 
sta bilize d or a n o utc o me has bee n reac he d, w hic he ver c o mes first . 
o)  C o nc o mita nt me dicati o ns s h o ul d be c ollecte d be gi n ni n g fr o m 4 wee ks pri or t o C ycle 1, D a y 1 u ntil t he e n d of t he peri o d of safet y o bser vati o n . 
p)  I n t he e ve nt t hat a patie nt is u na ble t o ret ur n t o t he cli nic f or a f oll o w-u p visit, tele p h o ne c o ntact wit h t he patie nt t o assess A Es, c o nc o mita nt me dicati o ns, a n d 
a nti -ca ncer treat me nts will be c o n d ucte d.  
q)  P er missi o n t o pr ol o n g t he st u d y treat me nt c o ul d be e xce pti o nall y gra nte d b y St u d y S p o ns or if patie nts are deri vi n g be nefit fr o m t he st u d y treat me nt a n d after 
c o m plete prese ntati o n of t he i n di vi d ual case b y t he St u d y I n vesti gat or, partic ularl y t he  me dical j ustificati o n f or e xte n di n g t he treat me nt a n d t he re -assess me nt 
of t he ris k /be nefit bala nce. T he  S p o ns or ’s decisi o n will c o nsi der t he a vaila bilit y of I M P at t he ti me of re q uest. A re p ort of t he disc ussi o n s wit h t he S p o ns or 
m ust be file d i n t he s o u rce d oc u me ntati o n. 
 
V V- T M F- 5 1 6 1 9 | Pa ge 9 9/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 0 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7, 2 4 A pril 2 0 2 0   
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne ( S witzerla n d)  
 
A P P E N DI X  D.  P H A R M A C O KI N E TI C A N D I M M U N O G E NI CI T Y A S S E S S M E N T O F  S A F E T Y R U N -I N 
F O R Q 3 W D O SI N G ( S T U D Y P A R T 1)  
Acti vit y  
C ycles 1 a n d 3  
C ycles  
2 a n d 4 -8  
E O T  
3 0 -D a y  
F oll o w -u p  
D a y 1   
D a y 2   
D a y 3   
D a y 8   
D a y 1 5   
D a y 1  
 
 
Bl o o d sa m ples f or P K  
• Pre-d ose  
• 5’ after 
E OI D 1 5 6 2  
• 5’ after 
E OI R T X  
• 2 44 h 
after E OI 
D 1 5 6 2  
• 4 84 h 
after E OI 
D 1 5 6 2  
● 
● 
• Pre-d ose  
• 5’ after E OI 
R T X * 
● 
● 
Bl o o d sa m ples f or i m m u n o ge nicit y ( A D A) 
assess me nt  
• Pre-d ose   
 
 
 
 
• Pre-d ose   
● 
● 
U nsc he d ule d P K a n d i m m u n o ge nicit y ( A D A) 
sa m ples 
As cli nicall y i n dicate d d uri n g acti ve st u d y treat me nt a 
 
 
D 1 5 6 2: De bi o 1 5 6 2; E OI:  E n d Of I nf usi o n; E O O P:  E n d Of O bser vati o nal P eri o d; R T X:  Rit u xi ma b.  ●:  A n y ti me d uri n g t he visit  
 
* I n t he e ve nt t hat rit u xi ma b is disc o nti n ue d, a p ost-d ose bl o o d dra w will be ta ke n f oll o wi n g c o m pleti o n of t he De bi o 1 5 6 2 i nf usi o n.   
a) P atie nts w h o e x perie nce a ≥ Gra de 2 i nf usi o n reacti o n d uri n g or i m me diatel y f oll o wi n g a d mi nistrati o n of De bi o 1 5 6 2 will ha ve bl o o d dra w n f or deter mi nati o n 
of dr u g c o nce ntrati o n a n d a nti b o dies t o De bi o 1 5 6 2 ( A D A).  T w o sa m ples s h o ul d be o btai ne d: ( 1) wit hi n t hree h o urs of t he o nse t of t he reacti o n; a n d ( 2) o ne wee k 
later. 
V V- T M F- 5 1 6 1 9 | Pa ge 1 0 0/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 0 1  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7, 2 4 A pril 2 0 2 0   
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne ( S witzerla n d)  
 
A P P E N DI X  E.  P H A R M A C O KI N E TI C A N D I M M U N O G E NI CI T Y A S S E S S M E N T O F  C O H O R T A F O R 
Q 3 W D O SI N G ( S T U D Y P A R T 2  A N D 3 ) 
Acti vit y  
C ycles 1 a n d 2  
C ycles 3 -6   b  
 
E O T   b  
3 0 -D a y  
F oll o w -u p  b  
D a y 1   
D a y 2   
D a y 3   
D a y 8   
D a y 1 5  
D a y 1  
 
 
 
Bl o o d sa m ples f or De bi o 1 5 6 2  
• Pre-d ose  
• 5’ after 
E OI 
D 1 5 6 2  
• 2 h after 
S OI R T X  
• 5’ after 
E OI R T X  
• E O O P  
• 2 44 h 
after E OI 
D 1 5 6 2  
• 4 84 h 
after E OI 
D 1 5 6 2  
● 
● 
• Pre-d ose  
• 5’ after E OI 
D 1 5 6 2  
• 5’ after E OI R T X 
 
 
 
Bl o o d sa m ples f or rit u xi ma b  
• Pre-d ose  
• E OI 
R T X  
• 2 44 h 
after E OI 
D 1 5 6 2  
• 4 84 h 
after E OI 
D 1 5 6 2  
● 
● 
• Pre-d ose  
• 5’ after E OI R T X 
 
●  
●  
Bl o o d  sa m ples f or i m m u n o ge nicit y ( A D A) 
assess me nt  
• Pre-d ose   
 
 
 
  
• Pre-d ose  
 
●  
● 
U nsc he d ule d P K a n d i m m u n o ge nicit y 
( A D A) s a m ples 
As cli nicall y i n dicate d d uri n g acti ve st u d y treat me nt a 
 
 
 
D 1 5 6 2: De bi o 1 5 6 2; E OI:  E n d Of I nf usi o n; E O O P:  E n d Of O bser vati o nal P eri o d; R T X:  Rit u xi ma b; S OI:  Start Of I nf usi o n , ●:  A n y ti me d uri n g t he visit  
a) P atie nts w h o e x perie nce a ≥ Gra de 2 i nf usi o n reacti o n d uri n g or i m me diatel y f oll o wi n g a d mi nistrati o n of De bi o 1 5 6 2 will ha ve bl o o d dra w n f or deter mi nati o n  
of dr u g c o nce ntrati o n a n d a nti b o dies t o De bi o 1 5 6 2 ( A D A).  T w o sa m ples s h o ul d be o btai ne d: ( 1) wit hi n t hree h o urs of t he o nse t of t he reacti o n; a n d ( 2) o ne wee k 
later. 
b) I n patie nts w h o e xce pti o nall y c o nti n ue t he st u d y treat me nt be y o n d C 6, t he last P K sa m ple a n d t he sa m ple f or i m m u n o ge nicit y ( A D A) assess me nt will be ta ke n 
at C 7 D 1 at pre -d ose bl o o d dra w i nstea d of at t he E O T visit. F or patie nts alrea d y be y o n d C 7 D 1 after A me n d me nt 5, t he l ast P K sa m ple w ill be ta ke n at D 1 of t he 
ne xt p ossi ble s u bse q ue nt c ycl e at pre -d ose bl o o d dra w i nste a d of at t he E O T visit. N o a d diti o nal sa m ples will be ta ke n at t he 3 0 -da y f oll o w -u p visit. 
V V- T M F- 5 1 6 1 9 | Pa ge 1 0 1/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 0 2  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7, 2 4 A pril 2 0 2 0   
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne ( S witzerla n d)  
 
A P P E N DI X  F.  P H A R M A C O KI N E TI C A N D I M M U N O G E NI CI T Y A S S E S S M E N T S O F  C O H O R T B 
F O R Q W D O SI N G ( S T U D Y  P A R T 2  A N D 3 )  
Acti vit y  
C ycles 1 a n d 2  
C ycle 3  
C ycles 4 -6    b   
E O T  b  
3 0 -D a y  
F oll o w -u p  b  
D a y 1   
D a y 2   
D a y 3   
D a y 8  
D a y 
1 5  
D a y 1   
D a y 8   
D a y 1 5   
D a y 1   
D a y 8   
D a y 1 5  
  
 
Bl o o d sa m ples f or De bi o 
1 5 6 2  
• Pre-d ose  
• 5’ after 
E OI D 1 5 6 2  
• 2 h after 
S OI R T X  
• 5’ after 
E OI R T X  
• E O O P 
• 
2 4 4 h 
after 
E OI 
D 1 5 6 2  
• 4 84 h 
after 
E OI 
D 1 5 6 2  
• Pre-
d ose  
• 5’ 
after 
E OI 
D 1 5 6 2  
• 
E O O P  
• Pre-
d ose  
• 5’ 
after 
E OI 
D 1 5 6 2  
• 
E O O P  
• Pre-
d ose  
• 5’ after 
E OI 
D 1 5 6 2  
• 5’ after 
E OI 
R T X  
 
• Pre-
d ose  
• 5’ 
after 
E OI 
D 1 5 6 2  
 
• Pre -
d ose  
• 5’ after 
E OI 
D 1 5 6 2  
 
• Pre-
d ose  
• 5’ after 
E OI 
D 1 5 6 2  
 
• Pre-
d ose  
• 5’ after 
E OI 
D 1 5 6 2  
 
• Pre-
d ose  
• 5’ after 
E OI 
D 1 5 6 2  
 
  
 
Bl o o d sa m ples f or 
rit u xi ma b 
• Pre-d ose  
• E OI R T X 
• 
2 4 4 h 
after 
E OI 
D 1 5 6 2  
• 4 84 h 
after 
E OI 
D 1 5 6 2  
●  
● 
• Pre-
d ose  
• E OI 
R T X  
●  
● 
• Pre-
d ose  
• E OI 
R T X  
●  
●  
●   
●  
Bl o o d sa m ples f or 
i m m u n o ge nicit y  ( A D A) 
assess me nt  
●  
  
  
  
  
● 
  
 
● 
  
 
●   
●  
U nsc he d ule d P K a n d 
i m m u n o ge nicit y ( A D A) 
sa m ples 
As cli nicall y i n dicate d d uri n g acti ve st u d y treat me nt a 
  
 
D 1 5 6 2: De bi o 1 5 6 2; E OI:  E n d Of I nf usi o n; E O O P:  E n d Of O bser vati o nal P eri o d; R T X:  Rit u xi ma b; S OI:  Start Of I nf usi o n , ●:  A n y ti me d uri n g t he visit  
a) P atie nts w h o e x perie nce a ≥ Gra de 2 i nf usi o n reacti o n d uri n g or i m me diatel y f oll o wi n g a d mi nistrati o n of De bi o 1 5 6 2 will ha ve bl o o d dra w n f or deter mi nati o n 
of dr u g c o nce ntrati o n a n d a nti b o dies t o De bi o 1 5 6 2 ( A D A).  T w o sa m ples s h o ul d be o btai ne d: ( 1) wit hi n t hree h o urs of t he o nse t of t he reacti o n; a n d ( 2) o ne wee k 
later.  
b) I n patie nts w h o  e xce pti o nall y c o nti n ue t he st u d y treat me nt be y o n d C 6, t he last P K sa m ple a n d t he sa m ple f or i m m u n o ge nicit y ( A D A) assess me nt will be ta ke n 
at C 7 D 1 at pre -d ose bl o o d dra w  i nstea d of at t he E O T visit. F or patie nts alrea d y be y o n d C 7 D 1 after A me n d me nt 5, t he last P K sa m ple will be ta ke n  at D 1 of t he 
s u bse q ue nt c ycle at pre -d ose bl o o d dra w i nstea d of at t he E O T visit . N o a d diti o nal sa m ple will be ta ke n at t he 3 0 -da y f oll o w -u p.
V V- T M F- 5 1 6 1 9 | Pa ge 1 0 2/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 0 3  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7, 2 4 A pril 2 0 2 0   
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne ( S witzerla n d)  
 
 
V V- T M F- 5 1 6 1 9 | Pa ge 1 0 3/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 0 4  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
Versi o n 7, 2 4 A pril 2 0 2 0   
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne ( S witzerla n d)  
 
A P P E N DI X  H.  E A S T E R N C O O P E R A TI V E O N C O L O G Y G R O U P ( E C O G ) P E R F O R M A N C E S T A T U S 
S C A L E  
(O ke n  1 9 8 2 ) 
G R A D E   
S C A L E  
0   
F ull y acti ve, a bl e t o carr y o ut all pre -diseas e perf or ma nce wit h o ut restricti o n. ( Kar n ofs k y 9 0 -1 0 0)  
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 s e d e ntar y nat ure, 
e. g., li g ht h o use w or k, office w or k.  ( Kar n ofs k y 7 0 -8 0)  
2   
A m b ulat or y a n d ca pa bl e of all self -care b ut u n a ble t o carr y o ut 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.  ( Kar n ofs k y 5 0 -6 0)  
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.  ( Kar n ofs k y 3 0 -4 0)  
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 b e d or c hair.  ( Kar n ofs k y 1 0 -2 0)  
 
 
V V- T M F- 5 1 6 1 9 | Pa ge 1 0 4/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 0 5  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
 
Versi o n 7, 2 4 A pril 2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne  ( S witzerla n d) 
 
A P P E N DI X  I. R E S P O N S E A S S E S S M E N T S  O F H O D G KI N A N D N O N -H O D G KI N L Y M P H O M A: T H E 
L U G A N O C L A S SI FI C A TI O N (C H E S O N 2 0 1 4 ) 
 
Res p o nse a n d Site  
P E T -C T Sc a n  
C T -b ase d Res p o nse  
C o m plete Res p o nse  
C o m plete met a b olic res p o nse  
C o m plete r a di ol o gic res p o nse ( all of t he 
f oll o wi n g) 
L y m p h n o des a n d e xtral y m p hatic 
sites 
 
 
 
 
 
 
 
 
 
 
Sc ore 1, 2, or 3 wit h or wit h o ut a resi d ual m ass 
o n 5 P S †  
 
I n Wal de yer’s ri n g or e xtra n o dal sites wit h hi g h 
p h ysi ol o gic u pta ke or wit h acti vati o n wit hi n 
s plee n or marr o w (e. g., wit h c he m ot hera p y or 
m yel oi d c ol o n y -sti m ulati n g fact ors), u pt a ke 
ma y b e greater t ha n  n or mal me diasti n u m a n d/ or 
li ver.  C o m plete meta b olic res p o nse ma y be 
i nferre d if u pta ke at sites of i nitial i n v ol ve me nt 
is n o great t ha n s urr o u n di ng n or mal tiss ue e v e n 
if t he tiss ue has hi g h p h ysi ol o gic u pta ke. 
Tar get n o des/ n o dal mass es m ust re gress t o  
≤ 1. 5 c m i n L Di  
N o e xtral y m p hatic sites of disease  
 
 
 
 
 
 
 
N o n -meas ure d lesi o ns  
N/ A  
A bse nt  
Or ga n e nlar ge me nt  
N/ A  
Re gress t o n or mal  
Ne w lesi o ns  
N o ne  
N o ne  
B o ne marr o w  
N o e vi de nce of F D G -a vi d disease i n marr o w   
N or mal b y m or p h ol o g y; if i n deter mi nate, 
 
P arti al Res p o nse  
P arti al met a b olic res p o nse  
P arti al re missi o n ( all of t he f oll o wi n g)  
L y m p h n o des a n d e xtral y m p hatic 
sites 
 
 
Sc ore 4 or  5 † wit h re d uce d u pta ke c o m pare d wit h 
baseli ne a n d resi d ual m ass(es) of a n y size .  At 
i nteri m, t hese fi n di n gs s u g gest res p o n di n g 
disease . 
≥ 5 0 % decreas e i n S P D of u p t o 6 tar get 
meas ura ble n o d es a n d e xtra n o dal sites  
V V- T M F- 5 1 6 1 9 | Pa ge 1 0 5/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 0 6  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
 
Versi o n 7, 2 4 A pril 2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne  ( S witzerla n d) 
 
 
 
 
 
 
 
At e n d of treat me nt, t hese fi n di n gs i n dicate 
resi d ual disease. 
 
 
 
W he n a lesi o n is t o o s mall t o meas ure o n 
C T, assi g n 5 m m X 5 m m as t he defa ult 
val ue  
W he n n o l o n ger visi ble, assi g n 0 X 0 m m  
F or a n o de > 5 m m X 5 m m, b ut s maller 
t ha n n or mal, use act ual meas ure me nt f or 
calc ulati o n  
N o n -meas ure d lesi o ns 
N/ A  
A bse nt/ n or mal, re gresse d, b ut n o i ncrease  
Or ga n e nlar ge me nt  
 
N/ A  
S plee n m ust ha ve re gresse d b y ≥ 5 0 % i n 
le n gt h be y o n d n or mal 
Ne w lesi o ns  
N o ne  
N o ne  
B o ne marr o w  
Resi d ual u pta ke hi g her t ha n u pta ke i n n or mal 
marr o w b ut re d u ce d c o m pare d wit h 
b aseli ne 
( diff use u pta ke c o m p ati ble wit h reacti ve c h a n ges 
fr o m c he m ot hera p y all o we d).  If t here are 
persiste nt f ocal c h a n ges i n t he marr o w i n t he 
c o nte xt of a n o dal res p o nse, c o nsi derati o n s h o ul d 
be gi v e n t o f urt her e val uati o n wit h M RI or bi o ps y 
or a n i nte r val sca n. 
N/ A  
N o res p o nse or st a ble dise ase   
N o met a b olic res p o nse  
St a ble dise ase  
Tar get n o des/ n o dal mass es, 
e xtra n o dal lesi o ns  
 
Sc ore 4 or 5 wit h n o si g nifica nt c ha n ge i n F D G 
u pta ke fr o m b aseli ne at i nteri m or e n d of 
treat me nt 
< 5 0 % d ecreas e fr o m baseli ne i n S P D of 
u p t o 6 d o mi na nt, meas ura ble n o des a n d 
e xtra n o dal 
sites;  
n o 
criteria 
f or 
pr o gressi ve disease are met  
N o n -meas ure d lesi o ns  
N/ A  
N o i ncreas e c o nsiste nt wit h pr o gressi o n  
Or ga n e nlar ge me nt  
N/ A  
N o i ncreas e c o nsiste nt wit h pr o gressi o n  
Ne w lesi o ns 
N o ne  
N o ne  
B o ne marr o w  
N o c ha n ge fr o m baseli ne  
N/ A  
Pr o g ressi ve dise ase  
 
Pr o g ressi ve met a b olic dise ase  
 
Pr o g ressi ve dise ase re q uires at le ast 1 of 
t he f oll o wi n g 
V V- T M F- 5 1 6 1 9 | Pa ge 1 0 6/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 0 7  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
 
Versi o n 7, 2 4 A pril 2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne  ( S witzerla n d) 
 
I n di vi d ual tar get n o des/ n o dal 
masses  
Sc ore 4 or 5 wit h a n i ncreas e i n i nte nsit y of 
u pta ke fr o m baseli ne a n d/ or  
P P D pr o gressi o n  
E xtra n o dal lesi o ns  
Ne w F D G -a vi d f oci c o nsiste nt wit h l y m p h o ma at 
i nteri m or e n d-of -treat me nt assess me nt 
A n 
i n di vi d ual 
n o de/lesi o n  
m ust 
be 
a b n or mal wit h:  
L Di > 1. 5 c m a n d  
I n crease b y > 5 0 % fr o m P P D na dir a n d 
A n i ncreas e i n L Di or S Di fr o m na dir  
0. 5 c m f or lesi o ns ≤ 2 c m  
1. 0 c m f or lesi o ns > 2 c m  
I n t he setti n g of s pl e n o me gal y, t he s ple ni c 
le n gt h m ust i ncrease b y > 5 0 % of t he 
e xte nt of its pri or i ncreas e be y o n d 
baseli ne (e. g., a 1 5 -c m s plee n 
m ust 
i ncreas e t o > 1 6 c m).  If n o pri or 
s ple n o me gal y, m ust i ncrease b y at least 2 
c m fr o m baseli ne  
Ne w or rec urre nt s ple n o me gal y  
N o n -meas ure d lesi o ns  
N o ne  
Ne w or clear pr o gressi o n of pree xisti n g 
n o n -meas ure d lesi o ns  
Ne w lesi o ns  
 
Ne w F D G -a vi d f oci c o nsiste nt wit h l y m p h o ma 
rat her t ha n a n ot her eti ol o g y (e. g., i nfecti o n, 
i nfla m mati o n).  If u ncertai n re gar di n g eti ol o g y of 
ne w lesi o ns, bi o ps y or i nter val sca n ma y b e 
c o nsi dere d  
Re gr o wt h of pre vi o usl y res ol ve d lesi o ns  
A ne w n o de > 1. 5 c m i n a n y a xis  
A ne w e xtra n o dal site > 1. 0 c m i n a n y a xis; 
if < 1. 0 c m i n a n y a xis, its prese n ce m ust 
be u ne q ui v ocal a n d m ust be attri b uta ble 
t o l y m p h o m a 
Assessa ble diseas e of a n y size 
u ne q ui v ocall y attri b uta bl e t o l y m p h o ma  
B o ne marr o w  
 
Ne w or rec urre nt F D G -a vi d f oci  
Ne w or rec urre nt i n v ol ve me nt  
A b bre viati o ns: 5 P S, 5 -p oi nt scale; C T, c o m p ute d t o m o gra p h y; F D G, fl u or o de o x y gl u c ose; 
 L Di, l o n gest 
tra ns verse di a meter of a l esi o n; M RI, ma g netic res o na nce i ma gi n g; N/ A: n ot a p plica ble; P E T, p ositr o n e missi o n t o m o gra p h y; P P D, 
V V- T M F- 5 1 6 1 9 | Pa ge 1 0 7/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 0 8  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
 
Versi o n 7, 2 4 A pril 2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-6  
 
La us a n ne  ( S witzerla n d) 
 
 
 
 
cr oss pr o d uct of t he L Di a n d per pe n dic ular di a meter; S Di, s h ortest a xis per pe n dic ular t o t he L Di; S P D, s u m of t he pr o d uct of t he 
per pe n dic ular dia meters f or m ulti ple lesi o ns.  
* A sc ore of 3 i n m a n y patie nts i n dicates a g o o d pr o g n osis wit h sta n dar d treat me nt, es p eciall y if at t he ti me of a n i nteri m sca n. 
H o we ver, i n trials i n v ol vi n g P E T w here de -escalati o n is i n vesti gate d, it ma y b e prefera ble t o c o nsi der a sc ore of 3 as i n a de q uate 
res p o nse (t o a v oi d u n d ertreat me nt). Meas ure d d o mi na nt lesi o ns: U p t o si x of t he lar gest d o mi na nt n o d es, n o dal masses, a n d e xtra n o dal 
lesi o ns selecte d t o be clearl y meas ura ble i n t w o dia meters. N o des s h o ul d prefera bl y b e fr o m dis parat e re gi o ns of t he b o d y a n d s h o ul d 
i ncl u de, w here a p plica ble, me diasti nal a n d retr o perit o neal areas. N o n-n o d al lesi o ns i ncl u de t h ose i n s oli d or ga ns (e .g ., li ver, s plee n, 
ki d ne ys, l u n gs), GI i n v ol ve me nt, c uta ne o us l esi o ns, or t h ose n ote d o n pal p ati o n. N o n -meas ure d lesi o ns: A n y disease n ot selecte d as 
meas ure d, d o mi na nt dise ase a n d tr ul y ass essa ble disease s h o ul d b e c o nsi d ere d n ot m eas ure d. T hes e sites i ncl u de a n y n o d es, n o dal 
masses, a n d e xtra n o dal sites n ot selecte d as d o mi na nt or meas ura ble or t h at d o n ot meet t he re q uire me nts f or meas ura bilit y b u t are 
still c o nsi dere d a b n or mal, as w ell as tr ul y assessa ble disease, w hic h is a n y site of s us pecte d disease t hat w o ul d be diffic ult  t o f oll o w  
q ua ntitati vel y wit h  meas ure me nt, i ncl u di n g ple ural eff usi o ns, as cites, b o n e lesi o ns, le pt o me ni n geal disease, a b d o mi nal mass e s, a n d 
ot her lesi o ns t hat ca n n ot be c o nfir me d a n d f oll o we d b y i m a gi n g. I n Wal de yer’s ri n g or i n e xtra n o dal sites (e. g., GI tract, li v er, b o ne 
marr o w), F D G u pta ke m a y be greater t ha n i n t he me diasti n u m wit h  c o m plete meta b olic res p o nse, b ut  s h o ul d be n o hi g her t ha n 
s urr o u n di n g n or mal p h ysi ol o gic u pta ke (e. g., wit h  marr o w acti vati o n as a res ult of c he m ot hera p y or m yel oi d gr o wt h fact ors). 
† P E T 5 P S: 1, n o u pta ke a b o ve bac k gr o u n d; 2, u pta ke ≤ me diasti n u m; 3, u pta ke > me di asti n u m b ut ≤ li ver; 4, u pta ke m o deratel y >  
li ver; 5, u pta ke mar k e dl y hi g her t h a n li ver an d/ or ne w l esi o ns; X ne w areas of u pta ke u nli kel y t o be relate d t o l y m p h o m a.  
 
V V- T M F- 5 1 6 1 9 | Pa ge 1 0 8/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 0 9  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
 
Versi o n 7, 2 4 A pril 2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-5  
 
La us a n ne ( S witzer la n d) 
 
A P P E N DI X  J.  B O D Y S U R F A C E A R E A C A L C U L A TI O N  
I n or der t o pre p are t he c orrect rit u xi ma b d ose f or a d mi nistrati o n t o eac h pati e nt, t he b o d y s urface 
area m ust be calc ulat e d usi n g t he f oll o wi n g f or m ula or e q ui vale nt:  
B o d y S urface Area  ( m2) = ([ Hei g ht { c m } x Wei g ht { k g }] / 3 6 0 0) ½ 
T he val ue calc ulate d will t he n be use d t o d eter mi ne t he q u a ntit y of c h e m ot hera pe utic dr u g t o b e 
place d i nt o t he i nf usi o n b a g.  T he wei g ht us e d f or calc ulati o n of B S A s h o ul d be o btai ne d pri or t o 
first treat me nt a n d t hereafter s h o ul d o nl y b e m o difie d f or si g nifica nt ( ≥ 1 0 %) c h a n ges i n b o d y 
wei g ht n ot i nfl ue n ce d b y wei g ht gai n or l oss attri b ute d t o fl ui d rete nti o n (e x ce pti o ns ma y be ma de 
f or i nstit uti o nal p olicies).   
 
 
 
V V- T M F- 5 1 6 1 9 | Pa ge 1 0 9/ 1 1 2

Pr ot oc ol  
 
 Pa ge 1 1 0  of 1 1 0  
St u d y  De bi o 1 5 6 2 -2 0 1  
 
Versi o n 7, 2 4 A pril 2 0 2 0  
C o p yri g ht De bi o p har m I nter nati o nal S. A.  
I nte grati n g a me n d m e nts 1-5  
 
La us a n ne ( S witzer la n d) 
 
A P P E N DI X  K.  A N N A R B O R C L A S SI FI C A TI O N A N D T H E 
C O T S W O L D  M O DI FI C A TI O N S   
St a ge  
Fe at ures  
I 
I n v ol ve m e nt of a si n gle l y m p h n o de re gi o n or l y m p h oi d str uct ure 
(e. g., s plee n, t h y m us, Wal de yer’s ri n g) 
II 
I n v ol ve m e nt of t w o or m ore l y m p h n o de re gi o ns o n t he sa me si de 
of t he dia p hra g m  
III 
I n v ol ve m e nt of l y m p h re gi o ns or str uct ures o n b ot h si des of t he 
dia p hra g m  
I V 
I n v ol ve m e nt of e xtra n o d al site(s) be y o n d t hat desi g nat e d E 
F or all sta ges:  
A  
B  
 
N o s y m pt o ms  
Fe ver ( > 3 8 °C), dre nc hi n g s weats, wei g ht l oss ( 1 0 % b o d y wei g ht 
o ver 6 m o nt hs)  
F or Sta ges I t o III 
E  
 
I n v ol ve m e nt of a si n gle, e xtra n o dal site c o nti g u o us or pr o xi mal t o 
k n o w n n o dal site  
C ots w o l d m o dificati o ns 
 Massi ve 
me diasti nal disease has bee n defi ne d b y t he 
C ots w ol d 
meeti n g as a t h oraci c rati o of 
m a xi m u m  
tra ns verse mass dia meter greater t ha n or e q ual t o 3 3 % of 
t he i nter nal tra ns verse t h oracic dia meter meas ure d at t he 
T 5/ 6 i nter verte bral disc le vel o n c hest r a di o gra p h y.  
 T he n u m ber of a nat o mic re gi o ns i n v ol ve d s h o ul d be 
i n dicate d b y a s u bscri pt (e. g., II 3) 
 Sta ge III m a y b e s u b di vi de d i nt o: III 1, wit h or wit h o ut 
sple n ic, hilar, celiac, or p ortal n o des; III 2, wit h para-a ortic, 
iliac, mese nteric n o des 
 Sta gi n g s h o ul d be i de ntifie d as cli nical sta ge ( C S) or 
pat h ol o gic sta ge ( P S)  
 A  
ne w  
cat e g or y  
of  
res p o nse  
t o  
t hera p y, 
u nc o nfir me d/ u ncertai n c o m plete re missi o n ( C R) ca n b e 
i ntr o d uce d 
beca us e 
of 
t he 
p ersiste nt 
ra di ol o gic 
a b n or malities of u ncertai n si g nifica n ce  
Ar mita ge  2 0 0 5  
  
V V- T M F- 5 1 6 1 9 | Pa ge 1 1 0/ 1 1 2