Conditions: Diffuse Large B-Cell Lymphoma B-cell Non-Hodgkin's Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 100
Healthy volunteers: no

Brief summary:
The primary purpose of the study was to determine the safety and tolerability, anti-tumor activity of the proposed Debio 1562 dose regimens in combination with rituximab.

Detailed description:

Arms:
arm 1: Participants with a diagnosis of relapsed and/or refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL), and with non-Hodgkin's lymphoma (NHL) including follicular lymphoma (FL), marginal zone lymphoma/mucosa-associated lymphoid tissue (MZL/MALT), mantle cell lymphoma (MCL) or other NHL with the Sponsor's approval received Debio 1562 0.7 mg/kg, intravenous (IV) infusion followed by rituximab 375 mg/m\^2 IV infusion, once on Day 1 of 21-day cycles until the study discontinuation criteria were met (until they develop disease progression, death, unacceptable toxicity, withdraw consent, start new anti-lymphoma treatment or the Sponsor terminates the study). arm 2: Participants with R/R DLBCL received Debio 1562 0.7 mg/kg, IV infusion followed by rituximab 375 mg/m\^2 IV infusion, once on Day 1 of 21-day cycles until the study discontinuation criteria were met (until they develop disease progression, death, unacceptable toxicity, withdraw consent, start new anti-lymphoma treatment or the Sponsor terminates the study). arm 3: Participants with R/R, FL, MZL/MALT, MCL or other NHL with the Sponsor's approval received Debio 1562 0.7 mg/kg, IV infusion followed by rituximab 375 mg/m\^2 IV infusion, once on Day 1 of 21-day cycles until the study discontinuation criteria were met (until they develop disease progression, death, unacceptable toxicity, withdraw consent, start new anti-lymphoma treatment or the Sponsor terminates the study). arm 4: Participants with relapsed DLBCL received Debio 1562 0.7 mg/kg, IV infusion followed by rituximab 375 mg/m\^2 IV infusion, once on Day 1 of a 21-day cycle for at least 6 cycles and/or until the study discontinuation criteria were met (until they develop disease progression, death, unacceptable toxicity, withdraw consent, start new anti-lymphoma treatment or the Sponsor terminates the study). arm 5: Participants with relapsed DLBCL received Debio 1562 0.4 mg/kg IV infusion followed by rituximab 375 mg/m\^2 IV infusion on Day 1, then Debio 1562 0.2 mg/kg IV infusion on Days 8 and 15 of a 21-day cycle for at least 6 cycles and/or until the study discontinuation criteria were met (until they develop disease progression, death, unacceptable toxicity, withdraw consent, start new anti-lymphoma treatment or the Sponsor terminates the study).

Interventions: intervention 1: Debio 1562 intervention 2: Rituximab
Intervention descriptions: intervention 1: Administered as IV Infusion. intervention 2: Administered as IV Infusion.

Protocol document:
Prot_000.pdf: 
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) 
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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 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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●  
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● 
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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  
 
●  
  
 
 
 
● 
 
 
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 
● 
●  
  
  
●  
●  
●  
●  
●  
●  
● 
Vital Si g ns  b 
● 
●  
  
  
●  
●  
●  
●  
●  
●  
● 
Healt h -relate d Q ualit y of Life 
c 
 
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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 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 
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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 
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B o ne Marr o w Assess me nt  i  
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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





SAP_001.pdf: 
Official Title: 
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 
NCT Number: 
NCT02564744 
Document Date: 
SAP Version: 3.1: 07 May 2021 


 
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Statistical Analysis Plan 
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Debiopharm International S.A. 
 
 
 
 
Statistical Analysis Plan 
 
Study Title: 
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 
Investigational Product: Debio 1562 
 
Study Number: Debio 1562-201 
 
 
SPONSOR: 
Debiopharm International S.A. 
Forum “après-demain” 
5-7 chemin Messidor, P.O. Box 5911 
CH-1002 Lausanne, Switzerland 
 
Version 3.1 dated 2021-05-07 
 
The information in this statistical analysis plan is confidential. It is provided to personnel directly 
involved in the trial. No information can be provided to a third party without written authorization from 
Debiopharm International S.A. Further reproduction of this document, in whole or in part, is not 
permitted. 
 
 
 
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TRIAL SUMMARY 
Study Number: 
Debio 1562-201 
Study Title: 
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 
Study Phase: 
2 
Design: 
The clinical trial consists of three parts: a safety run-in 
(part 1), initial assessment of safety and efficacy of every 
three-week (Q3W) and every week (QW) dosing 
regimens of Debio 1562 (part 2) and an expansion (part 
3). Please refer to Section 4.1 for the full description of 
the study design. 
Protocol Version and Date: 
Amendment 6, dated of 2020-04-24 
Statistical Analysis Plan 
Version and Date: 
Version 3.1, dated of 2021-05-07 
Sponsor (Debiopharm International S.A., Lausanne, Switzerland) 
- 
: 
, MD 
- 
: 
 
- Study Biostatistician: 
, PhD 
 
 
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SIGNATURE PAGE 
SAP SIGNATURES 
Author 
(Electronically signed) 
 
 
Approval 
(Electronically signed) 
 
  
 
 
(Electronically signed) 
 
 
 
(Electronically signed) 
 
Study Biostatistician 
 
(Electronically signed) 
 
 
 
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REVISION HISTORY 
Version Date 
Changes 
1.3 
2017-05-12 
Statistical analysis plan compliant with protocol amendment 1. 
First and only version signed by Immunogen and provided by PPD 
Biostatistics department. 
2.0 
2018-10-13 
Implementation of changes to be compliant with protocol 
amendment 2 and amendment 3: 
- 
Change of clinical trial sponsor (Immunogen to Debiopharm 
International S.A.); 
- 
Change in investigational product name from IMGN529 to 
Debio 1562; 
- 
Use of Debiopharm International S.A. statistical analysis plan 
template; 
- 
Timing of statistical analysis; 
- 
Updates in sample size calculation; 
- 
Clarifications of PFS definition and sensitivity analyses; 
- 
Section on futility boundaries as part of the adaptive design; 
- 
Adding analysis of Health-related Quality of Life; 
- 
Adding additional exploratory endpoints analysis; 
- 
Revision of the section on pharmacokinetics; 
- 
Re-structuring the sections of the document. 
3.0 
2021-03-10 
Implementation of changes to be compliant with protocol 
amendment 6: 
- 
Revision of the section on sample size calculation; 
- 
Revision of the section on pharmacokinetics; 
- 
Update of the schedule of assessments (appendices); 
- 
Addition of sensitivity analyses on efficacy endpoints to take 
into account the possibility for a subject to switch from QW 
regimen to a Q3W regimen due to the COVID-19 pandemic. 
 
 
 
 
- 
Addition of the per protocol population  
3.1 
2021-05-07 
Minor Formating changes: update TOC, and few hyperlink. 
 
 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITIONS ..................................................................... 9 
1 
INTRODUCTION .......................................................................................................... 13 
2 
STUDY OBJECTIVES .................................................................................................... 13 
2.1 
PRIMARY OBJECTIVE(S) ..................................................................................................... 13 
2.2 
SECONDARY OBJECTIVES.................................................................................................... 13 
2.3 
EXPLORATORY OBJECTIVES ................................................................................................. 13 
3 
STUDY ENDPOINTS ..................................................................................................... 14 
3.1 
PRIMARY ENDPOINT(S) ..................................................................................................... 14 
3.2 
SECONDARY ENDPOINTS .................................................................................................... 14 
3.3 
EXPLORATORY ENDPOINTS ................................................................................................. 14 
4 
STUDY DESIGN AND TREATMENT ............................................................................... 15 
4.1 
STUDY DESIGN ................................................................................................................ 15 
4.1.1 
Part 1: Safety run-in and Phase 2 .......................................................................... 15 
4.1.2 
Part 2: Initial assessment of safety and efficacy of Q3W and QW dosing regimens of 
Debio 1562 ......................................................................................................................... 16 
4.1.3 
Part 3: Expansion .................................................................................................. 16 
4.2 
SAFETY REVIEW COMMITTEE AND INDEPENDENT DATA MONITORING COMMITTEE ............................ 17 
4.2.1 
Safety Review Committee ...................................................................................... 17 
4.2.2 
Independent Data Monitoring Committee ............................................................... 17 
4.3 
STUDY TREATMENTS ......................................................................................................... 18 
4.4 
OVERALL END-OF-STUDY ................................................................................................... 18 
4.5 
STUDY PROCEDURES ......................................................................................................... 18 
5 
RANDOMIZATION AND BLINDING .............................................................................. 18 
 
 
 
 
 
 
 
 
 
7 
ANALYSIS POPULATIONS ........................................................................................... 19 
7.1 
SCREENED POPULATION ..................................................................................................... 19 
7.2 
ALL TREATED / SAFETY POPULATION ..................................................................................... 19 
7.3 
EFFICACY EVALUABLE POPULATION ....................................................................................... 19 
7.4 
PER PROTOCOL POPULATION ............................................................................................... 20 
7.5 
PK POPULATION .............................................................................................................. 20 
8 
DATA HANDLING ......................................................................................................... 20 
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8.1 
MISSING DATA ................................................................................................................ 20 
8.2 
CODING ......................................................................................................................... 20 
8.3 
HANDLING OF VALUES BELOW (OR ABOVE) A THRESHOLD .......................................................... 20 
8.4 
HANDLING OF UNSCHEDULED ASSESSMENTS OR RETESTS ........................................................... 20 
9 
GENERAL STATISTICAL CONSIDERATIONS ................................................................ 21 
9.1 
GENERAL CONVENTIONS .................................................................................................... 21 
 
 
 
 
9.3 
MULTI-CENTRE STUDIES .................................................................................................... 23 
9.4 
TIMING OF ANALYSES ........................................................................................................ 23 
10 STATISTICAL ANALYSIS METHODS ............................................................................ 23 
10.1 
DISPOSITION OF PATIENTS, DEMOGRAPHIC AND BASELINE DATA.................................................. 23 
10.1.1 
Screen Failures and Eligibility Criteria ..................................................................... 23 
10.1.2 
Subject Disposition ................................................................................................ 23 
10.1.3 
Protocol Deviations ............................................................................................... 24 
10.1.4 
Demographic and Baseline Characteristics .............................................................. 24 
10.1.5 
Medical History ..................................................................................................... 24 
10.1.6 
Disease Characteristics and Prior Therapy .............................................................. 25 
10.1.6.1 
Current Cancer Diagnosis .............................................................................................. 25 
10.1.6.2 
Prior Cancer Systemic Treatments .................................................................................. 25 
10.1.7 
Prior and Concomitant Medications/Procedures ....................................................... 26 
10.1.8 
Eastern Cooperative Oncology Group Performance Status ....................................... 26 
10.1.9 
Bone Marrow Assessment ...................................................................................... 26 
10.1.10 
Tumor Biopsy .................................................................................................... 26 
10.1.11 
Transfusion Log ................................................................................................ 27 
10.2 
EFFICACY ANALYSES ......................................................................................................... 27 
10.2.1 
Multiple Comparisons/Multiplicity ........................................................................... 27 
10.2.2 
Radiologic Tumor Assessment ................................................................................ 27 
10.2.3 
Primary Efficacy Analysis ....................................................................................... 28 
10.2.4 
Secondary Efficacy Analyses .................................................................................. 29 
10.2.4.1 
Progression Free Survival .............................................................................................. 29 
10.2.4.2 
Duration of Response .................................................................................................... 30 
10.2.4.3 
Time to Response ......................................................................................................... 30 
10.2.4.4 
Overall Survival ............................................................................................................ 31 
 
 
 
10.3 
SAFETY ANALYSES ............................................................................................................ 42 
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10.3.1 
Adverse Events ..................................................................................................... 42 
10.3.2 
Deaths and Other Significant Adverse Events .......................................................... 44 
10.3.3 
Clinical Laboratory Evaluations ............................................................................... 44 
10.3.3.1 
Hematology ................................................................................................................. 44 
10.3.3.2 
Serum chemistry .......................................................................................................... 45 
10.3.3.3 
Urinalysis and Pregnancy Test ....................................................................................... 45 
10.3.3.4 
Liver Function Test ....................................................................................................... 45 
10.3.3.5 
Vital Signs .................................................................................................................... 46 
10.3.4 
Other Safety Measures .......................................................................................... 46 
10.3.4.1 
Physical Examination..................................................................................................... 46 
10.3.4.2 
Electrocardiogram ......................................................................................................... 47 
10.3.4.3 
B-Symptoms ................................................................................................................ 47 
10.4 
EXTENT OF EXPOSURE ....................................................................................................... 48 
10.5 
PHARMACOKINETICS ......................................................................................................... 49 
 
 
 
10.7 
OTHER ANALYSES ............................................................................................................ 51 
10.7.1.1 
Health-Related Quality of Life ........................................................................................ 51 
10.8 
INTERIM ANALYSES........................................................................................................... 51 
 
 
10.8.1.2 
Stopping Rules for Safety .............................................................................................. 51 
11 SUMMARY OF CHANGES TO THE PROTOCOL .............................................................. 51 
12 REFERENCES ............................................................................................................... 52 
13 APPENDICES ............................................................................................................... 54 
APPENDIX A. 
SCHEDULE OF EVENTS OF SAFETY RUN-IN FOR Q3W DOSING (PART 1)
 
54 
APPENDIX B. 
SCHEDULE OF EVENTS OF COHORT A FOR Q3W DOSING (PART 2 AND 3)
 
57 
APPENDIX C. 
SCHEDULE OF EVENTS OF COHORT B FOR QW DOSING (PART 2) ............ 61 
APPENDIX D. 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENT OF SAFETY 
RUN-IN FOR Q3W DOSING (PART 1) ................................................................................. 65 
APPENDIX E. 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENT OF COHORT A 
FOR Q3W DOSING (PART 2) .............................................................................................. 66 
APPENDIX F. 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENT OF COHORT B 
FOR QW DOSING (PART 2) ................................................................................................ 67 
 
 
 
APPENDIX H. 
RESPONSE ASSESSMENT OF HODGKIN AND NON-HODGKIN 
LYMPHOMA: THE LUGANO CLASSIFICATION (CHESON, 2014) ......................................... 70 
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APPENDIX I. 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
STATUS SCALE (OKEN, 1982) ............................................................................................. 75 
APPENDIX J. 
IMPUTATION ALGORITHM FOR PARTIAL AND MISSING DATES .............. 76 
APPENDIX K. 
CRITERIA OF PROTOCOL DEVIATIONS THAT CAN LEAD TO EXCLUSION 
FROM THE PER-PROTOCOL POPULATION .......................................................................... 78 
INCLUSION CRITERIA ................................................................................................................ 78 
EXCLUSION CRITERIA ............................................................................................................... 80 
USE OF PROHIBITED CONCOMITANT MEDICATIONS OR PROCEDURES ................................................ 82 
 
 
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Abbreviation 
Definition 
GLUC 
Glucose 
FL 
Follicular lymphoma 
 
 
HBsAg 
Hepatitis B surface antigen 
HCT 
Hematocrit 
HGB 
Hemoglobin 
ICH 
International Conference on Harmonization 
IDMC 
Independent data monitoring committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
 
 
INR 
International normalized ratio 
ITT 
Intent-to-treat 
IV 
Intravenous 
K 
Potassium 
LDH 
Lactate dehydrogenase 
LYM 
Lymphocyte 
MALT 
Mucosa-associated lymphoid tissue 
MedDRA 
Medical dictionary for regulatory activities 
MCL 
Mantle cell lymphoma 
MG 
Magnesium 
MONO 
Monocyte 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MZL 
Marginal zone lymphoma 
NCI 
National cancer institute 
NA 
Not available 
NE 
Not evaluable 
NEUT 
Neutrophil 
NHL 
Non-Hodgkin’s lymphoma 
NMR 
No metabolic response 
ORR 
Objective response rate 
OS 
Overall survival 
PCST 
Prior Cancer Systemic Therapy 
PD 
Progressive disease 
PET 
Positron-emission tomography 
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Abbreviation 
Definition 
PFS 
Progression-free survival 
PHOS 
Phosphorous 
PK 
Pharmacokinetic 
PLAT 
Platelet count 
PMD 
Progressive metabolic disease 
PMR 
Partial metabolic response 
PP 
Per Potocol 
PPD 
Product of perpendicular diameters 
PROT 
Total protein 
PR 
Partial response 
PT 
Preferred term 
QT 
QT interval  
QTc 
Corrected QT interval 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
QW 
Once every week 
Q3W 
Once every three weeks 
RBC 
Red blood cells 
R-CHOP 
Rituximab - Cyclophosphamide Hydroxydaunomycin Oncovin 
Prednisone 
R/R 
Relapsed/refractory 
RR 
RR interval  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SMCC 
Succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate 
SOC 
System organ class 
SP 
Safety population 
SPD 
Sum of products of diameters 
SRC 
Safety review committee 
t1/2 
Terminal half-life 
TBL 
Total bilirubin 
TAb 
Total Antibody 
TEAE 
Treatment-emergent adverse event 
TLS 
Tumor lysis syndrome 
Tmax 
Time to reach maximum concentration 
TTR 
Time to response 
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Abbreviation 
Definition 
ULN 
Upper limit of normal 
URATE 
Uric acid 
UREAN 
Blood urea nitrogen 
Vss 
Volume of distribution at steady state 
WBC 
White blood cells 
WHO-DD 
World Health Organization – data dictionary 
 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analyses for the clinical trial Debio 
1562-201 entitled “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”. This SAP is compliant with 
protocol amendment 6, dated of 2020-04-24. It will be finalized prior to the database lock 
for the primary analysis. Production version of the eCRF dated from 2019-03-12 was used. 
In this Phase 2 study, the safety and anti-tumor activity of Debio 1562 in combination with 
rituximab will be investigated for the treatment of subjects with relapsed/refractory (R/R) 
diffuse large B-cell lymphoma (DLBCL) and other forms of non-Hodgkin’s lymphoma (NHL) 
in study part 1, and in relapsed DLBCL only in study parts 2 and 3. 
2 
STUDY OBJECTIVES 
2.1 Primary Objective(s) 
The primary objectives of this study are to: 
- 
Determine the safety and tolerability of the proposed Debio 1562 dose regimens in 
combination with rituximab; 
- 
Determine the anti-tumor activity of the proposed Debio 1562 dose regimens in 
combination with rituximab. 
2.2 Secondary Objectives 
The secondary objectives of this study are to: 
- 
Characterize the pharmacokinetics (PK) of Debio 1562 in combination with rituximab; 
- 
Determine time to event outcomes (progression-free survival [PFS], time to response 
[TTR], duration of response [DoR], and overall survival [OS]); 
- 
Assess the immunogenicity of Debio 1562 (anti-drug antibodies [ADA]) when 
administered in combination with rituximab. 
2.3 Exploratory Objectives 
The exploratory objectives of this study are to: 
- 
Correlate the extent of CD37 and CD20 antigen expression in tumor samples with 
anti-tumor activity of Debio 1562 and rituximab combination; 
 
 
 
 
 
 
 
 
 
 
- 
Assess health-related quality of life (HRQoL). 
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3 
STUDY ENDPOINTS 
3.1 Primary Endpoint(s) 
The primary endpoints of this study are: 
- 
Incidence of treatment-emergent adverse events (TEAEs), clinically significant 
changes in clinical laboratory test results, electrocardiogram (ECG), and vital sign 
measurements; 
- 
Objective response rate (ORR) defined as the proportion of subjects with a best 
overall response of partial response (PR) or complete response (CR) as assessed by 
the 2014 Lugano classification of response assessments of NHL (Cheson, 2014). 
3.2 Secondary Endpoints 
The secondary endpoints of this study are: 
- 
PK parameters for both Debio 1562 and rituximab (evaluated but not limited to): 
maximum concentration (Cmax), area under the curve (AUC0 t, AUCinf), terminal half-
life (t1/2), clearance, volume of distribution at steady state (Vss), and time to reach 
maximum concentration (Tmax); 
- 
Efficacy time-to-event endpoints: 
o 
Progression-free survival (PFS) defined as the duration between the first dose 
date of Debio 1562 and the date of progressive disease (PD) or death due to any 
cause, whichever occurs first. As this study has randomized and non-randomized 
parts, starting date for the calculation of PFS is set to the first dose date of Debio 
1562; 
o 
Time to response defined as the duration between the first dose date of Debio 
1562 and the date of first objective response (PR or CR). This will be computed 
for responders only. As this study has randomized and non-randomized parts, 
starting date for the calculation of TTR is set to the first dose date of Debio 
1562; 
o 
Duration of response (DoR) defined as the duration between the date of first 
objective response (PR or CR) and the date of PD or death due to any cause, 
whichever occurs first. This will be computed for responders only; 
o 
Overall survival (OS) defined as the duration between the first dose date of Debio 
1562 and the date of death due to any cause. As this study has randomized and 
non-randomized parts, starting date for the calculation of OS is set to the first 
dose date of Debio 1562; 
- 
Immunogenicity of Debio 1562: Presence of human anti-drug antibody. 
Unless otherwise specified in subsequent sections, pharmacokinetics, 
 
and immunogenicity analyses are beyond the scope of this document. They will be covered 
by dedicated analysis plans. 
3.3 Exploratory Endpoints 
The exploratory endpoints of this study are: 
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- 
Expression levels of CD37, CD20 by immunohistochemistry (IHC, protein) and/or 
mRNA detection and correlation of these measures to clinical response criteria; 
 
 
  
 
 
 
 
 
 
 
 
 
- 
Health-related quality of life (HRQoL) will be evaluated based on the functional 
assessment of cancer therapy-lymphoma (FACT-Lym). It is comprised of: 
o 
The functional assessment of cancer therapy-general (FACT-G) version 4 (27 
items), scored in four domains: 
• 
Physical well-being (7 items); 
• 
Social/Family well-being (7 items); 
• 
Emotional well-being (6 items); 
• 
Functional well-being (7 items); 
o 
The FACT-Lymphoma Subscale, LymS, reflecting Lymphoma specific concerns (15 
items). 
The exploratory analyses including HRQoL analyses are beyond the scope of this document. 
They will be covered by dedicated analysis plans. 
 
 
 
 
4 
STUDY DESIGN AND TREATMENT 
4.1 Study Design 
This is an open label, multicenter, adaptive phase 2 clinical trial of Debio 1562 in 
combination with rituximab in subjects with DLBCL and other subtypes of B-cell NHL. 
The clinical trial includes a screening period, a treatment period, an end of treatment visit, a 
30-day safety follow-up visit, a response follow-up period if relevant, and a survival follow-
up period if relevant. 
The clinical trial consists of three parts: a safety run-in with its expansion Phase 21 (part 1), 
initial assessment of safety and efficacy of Q3W and QW dosing regimens of Debio 1562 
(part 2) and an expansion (part 3). 
4.1.1 Part 1: Safety run-in and Phase 2  
                                           
1 Phase 2 is described in protocol versions 1, 2, and 3, and includes Cohort 1 (R/R DLBCL) and Cohort 
2 (other NHL) 
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Subjects with DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone 
lymphoma/mucosa associated lymphoid tissue (MZL/MALT) or other NHL subtypes (with 
Sponsor’s approval) are eligible for enrollment in the safety run-in part. 
During the safety run-in, subjects are given Debio 1562 and rituximab IV on day 1 of each 
21 days cycle. Debio 1562 is given at a dose of 0.7 mg/kg, followed by 375 mg/m2 of 
rituximab. 
Safety run-in continued with a Phase 2: Cohort 1 (R/R DLBCL) and Cohort 2 (other R/R NHL 
subtypes; see protocol versions 1, 2, and 3). 
The Safety Review Committee (SRC) is comprised of the Sponsor’s Medical Director and 
Investigators from participating sites, and is responsible for safety data review during the 
course of the trial. 
Treatment emergent adverse events (TEAEs) occurring in patients enrolled into the safety 
run-in phase will be reviewed by the SRC. Once the Phase 2 dose is determined by the SRC, 
Cohorts 1 and 2 will open and enroll simultaneously, with rituximab and Debio 1562 being 
administered at the same schedule used in the safety run-in phase. 
4.1.2 Part 2: Initial assessment of safety and efficacy of Q3W and QW dosing 
regimens of Debio 1562 
Subjects with pathologically and clinically confirmed diagnosis of relapsed DLBCL are eligible 
for enrollment into two parallel cohorts. 
In cohort A, subjects are given Debio 1562 IV and rituximab IV on day 1 of each 21 days 
cycle. Debio 1562 is given at a dose of 0.7 mg/kg, followed by 375 mg/m2 of rituximab 
(same dose and schedule as in part 1). 
In cohort B, subjects are given Debio 1562 IV once every week (QW) and rituximab IV 
Q3W. Debio 1562 is given at a dose of 0.4, 0.2 and 0.2 mg/kg on day 1, 8 and 15 of each 
21 days cycle. Rituximab is given at a dose of 375 mg/m2 on day 1 of each 21 days cycle. 
Subjects in both cohorts will be treated for a maximum of six 21-day cycles. Subjects may 
exceptionally be granted treatment extension. 
An independent data monitoring committee (IDMC), comprised of independent experts in 
the field of hematology, oncology, PK and biostatistics, will perform regular reviews of 
cumulative safety, efficacy, and PK data in both cohorts A and B. 
Assignment of subjects to cohort A and cohort B will be done through a central allocation 
system (IWRS). One-to-one randomization will be done when both cohorts are open for 
recruitment and automatic allocation of subjects to cohort A during IDMC review of cohort 
B. 
4.1.3 Part 3: Expansion 
Part 3 of the study will enroll additional subjects with pathologically and clinically confirmed 
diagnosis of relapsed DLBCL to further assess the safety, proof of activity and PK of the 
dosing schedule recommended following the evaluation of Part 2 by the IDMC. 
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IDMC will perform regular reviews of cumulative safety, proof of activity and PK data 
available. 
Patients of the planned Part 3 were recruited under Part 2/3, no specific distinction was 
made between cohort 2 and 3. 
4.2 Safety Review Committee and Independent Data Monitoring Committee 
4.2.1 Safety Review Committee 
The safety review committee (SRC), comprised of the Sponsor’s medical director and 
investigators from participating sites, is responsible for safety data review during the course 
of part 1 (safety run-in). Please refer to Section 4.1.3.1 of the protocol for additional 
information on the SRC. The SRC determines whether the Debio 1562 dose of 0.7 mg/kg 
should be evaluated in the next part of the study, or whether an alternative dose should be 
evaluated. 
4.2.2 Independent Data Monitoring Committee 
The IDMC, comprised of independent experts in the field of hematology, oncology PK and 
biostatistics, will be responsible for the review of safety, proof of activity and PK data during 
the course of part 2 and part 3 of the clinical trial. 
Available cumulative safety, PK and anti-tumor activity data will be provided for review by 
the IDMC: 
- 
For part 2, cohort A: 
1. Once the 10th subject is evaluable for efficacy (i.e., patients should have 
performed at least one post baseline objective response assessment - unless 
there is earlier clear evidence of PD). Enrollment in this cohort will continue 
during the IDMC review; 
2. Once the 15th subject is evaluable for efficacy (i.e., patients should have 
performed at least one post baseline objective response assessment - unless 
there is earlier clear evidence of PD). Enrollment in this cohort will continue 
during the IDMC review; 
- 
For part 2, cohort B: 
1. Once the 3rd subject has completed one cycle of treatment. Enrollment in this 
cohort will continue during the IDMC safety review; 
2. Once the 6th subject has completed two cycles of treatment. Enrollment in this 
cohort will be paused during the IDMC safety review; 
3. Once the 12th subject has completed two cycles of treatment. Enrollment in this 
cohort will be paused during the IDMC safety review; 
At IDMC review 2 or 3, PK evaluation might be available to support potential IDMC 
recommendation to explore new QW dosing schedule. At the maximum, only one 
potential new dosing will be explored. In such a case, the same IDMC reviews (1-3) 
as described above will be repeated for evaluation of this new schedule. 
- 
For part 3: 
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After every 10 subjects have completed two cycles of treatment and are evaluable 
for efficacy (i.e., patients should have performed at least one post baseline objective 
response assessment - unless there is earlier clear evidence of PD). 
Please refer to Section 4.1.3.2 of the protocol and to the IDMC charter for additional 
information on the IDMC. 
4.3 Study Treatments 
The investigational study drug, Debio 1562, will be provided by Debiopharm International 
S.A. in 20 mL glass vials each containing 5 mL of a protein concentration of 8.0 mg/mL 
Debio 1562 in aqueous buffered solution of pH 5.0 ± 0.3. 
Rituximab will be supplied as a commercially available formulation. 
4.4 Overall End-of-Study 
The Overall End-of-Study is defined as the latter of the completion of the safety follow-up 
visit for the last patient remaining on treatment or one year from the last accrued patient’s 
first visit. 
4.5 Study Procedures 
Please refer to Appendix A, Appendix B and Appendix C for the description of the schedule 
of events. Study procedures are listed in Section 8 of the protocol. 
5 
RANDOMIZATION AND BLINDING 
This is an open label clinical trial. Table 1 is providing a description of the randomization 
characteristics and constraints during each study part. 
Table 1 - Study Parts and Randomization 
Study Part Randomization Comments 
Part 1 
No 
Subjects are given Debio 1562 (0.7 mg/kg) and 
rituximab IV (375 mg/m2) on day 1 of each 21 days 
cycle. 
Part 2 
Yes 
One-to-one block randomization will be done when both 
cohort A and cohort B are open for recruitment. Please 
refer to Section 4.1 for the automatic allocation to the 
open cohort during IDMC review 
Part 3 
Yes 
Open for enrolment if and only if at least one cohort is 
eligible for part 3: 
- One-to-one block randomization if both cohort A and 
cohort B are eligible to part 3; 
- If cohort A (resp. cohort B) is not eligible for part 3, 
subjects will be assigned to cohort B (resp. cohort A). 
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7 
ANALYSIS POPULATIONS 
7.1 Screened Population 
All subjects screened will be part of the screened population. 
7.2 All treated / Safety Population 
The All treated/safety population will include all patients from the screened population who 
received at least one dose of Debio 1562. Reporting in the All treated population will be 
done per the actual cohort as defined in the protocol. 
7.3 Efficacy Evaluable Population 
All subjects who received at least one dose of Debio 1562 and rituximab, and had both 
baseline and post-baseline evaluable disease assessment (including clinical progressive 
disease) will be part of the efficacy evaluable population. Reporting in the efficacy evaluable 
population will be done per the assigned treatment and cohort as per protocol (version 7, 
Section 10.2). 
 
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7.4 Per protocol population 
The per-protocol (PP) population will include all patients from the Efficacy evaluable 
population who do not have any protocol deviation that could confound the interpretation of 
efficacy analyses. Patients who died from disease progression before end of first cycle will 
also be part of the per-protocol population. 
The protocol deviations that could confound the interpretation of efficacy analyses include 
violation of key eligibility criteria (inclusion and/or exclusion) designed to ensure a specific 
subject population. It also includes the failing to collect data necessary to interpret the 
primary efficacy endpoints.  
A detailed description of the protocol deviations which will exclude patients from the PP 
population is given in Appendix K. 
  
7.5 PK Population 
All subjects who receive one dose of study drug and have at least one PK concentration 
result available post first dose (Debio 1562 or rituximab concentration, including value below 
limit of quantification). Reporting in the PK population will be done against the actual 
treatment received. 
8 
DATA HANDLING 
8.1 Missing Data 
Imputation rules for missing or partial dates are specified in Appendix J. No other imputation 
of missing data will be implemented. 
8.2 Coding 
Adverse events, medical history, concomitant procedures, prior cancer related surgery and 
prior radiotherapy will be coded using the last available version of the medical dictionary for 
regulatory activities (MedDRA). Prior medications, prior cancer systemic therapy and 
concomitant medications will be coded using the last available world health organization 
drug dictionary (WHO-DD). 
8.3 Handling of Values Below (or Above) a Threshold 
For statistical and graphical summaries of the safety laboratory tests, values below or above 
the limit of detection (e.g. ‘< 3’ or ‘>500’) are substituted with the lower/upper limit of 
detection (e.g. ‘< 3’ is substituted by 3, ‘> 500’ is substituted by 500). In data listings, the 
values will be shown as collected, e.g. including the < or > sign. 
8.4 Handling of Unscheduled Assessments or Retests 
Unscheduled assessments will not be used in the summary statistics, but will be used in the 
derivation of endpoints that are not related to a specific timepoint. All values collected will 
be displayed in listings. 
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9 
GENERAL STATISTICAL CONSIDERATIONS 
9.1 General Conventions 
All output will be generated in Rich Text Format (RTF) from Microsoft Word and pdf file 
formats and labeled according to the International Conference on Harmonization (ICH) 
recommendations (ICH E3). 
Unless otherwise specified, subjects enrolled in this study will be classified into the following 
reporting cohorts: 
- 
Safety run-in  
- 
R/R DLBCL Q3W (Cohort 1 of the Part 1 run in expansion) 
- 
Other R/R NHL subtypes (Cohort 2 of the Part 1 run in expansion) 
- 
Relapsed DLBCL Q3W (Cohort A of the Part 2/3) 
- 
Relapsed DLBCL QW (Cohort B of the Part 2/3) 
Continuous data will be described using descriptive statistics, including but not limited to: 
number of non-missing values (n), mean, standard deviation (SDev), median, minimum 
(Min) and maximum (Max). Categorical data will be described using the subject count and 
percentage in each category with a category for missing data. 
For summary statistics of all continuous variables, unless otherwise specified, the minimum 
and maximum will be displayed to the same level of precision as the reported data. The 
mean and median will be displayed to one level of precision greater than the collected data. 
The standard deviation will be displayed to two levels of precision greater than the data 
collected. 
P-values will be rounded to three decimal places. If a p-value is less than 0.001 it will be 
reported as “<0.001”, if a p-value is greater than 0.999 it will be reported as “1.000”. 
Subjects will be identified in the listings by the investigator site number combined with the 
subject identification number. 
When a count of zero is presented, the percentage (0% per definition) will be shown in the 
table, to draw attention to the non-zero counts. A row denoted “Missing” will be included in 
tables where specified in the shells to account for dropouts and missing values. The 
denominator for all percentages will be the number of subjects in that treatment group 
within the analysis set of interest, unless otherwise specified. 
Unless otherwise specified, baseline will be defined as the last non-missing evaluation prior 
to the first infusion of Debio 1562, whether on the date of the infusion or prior to that date. 
Study day will be calculated as follows: 
- 
if date of measurement/observation is on or after the first dose date of Debio 1562: 
Date of measurement/observation – first dose date of Debio 1562 +1 
- 
if date of measurement/observation is prior to the first dose date of Debio 1562: 
Date of measurement/observation – first dose date of Debio 1562. 
As this clinical trial has randomized and non-randomized parts, study day 1 will be defined 
as the day of first dose of Debio 1562. 
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A month length is calculated as 30.4375 days (365.25 days / 12 months). 
Partial missing date will be imputed for (see Appendix J): 
-
Dates for disease progression and death 
-
Start and end dates of concomitant medication and/or procedure 
-
Start dates of adverse events. 
Expected duration of each cycle is 21 days. The first treatment cycle for each specific 
subject starts with its first dose of Debio 1562. The last treatment cycle is defined as the 
cycle for which the last dose of Debio 1562 is started. Unscheduled visits, if included for 
analysis, will be specified in footnote of tables and figures. 
All analyses will be conducted using SAS Version 9.3 or higher. 

 
   
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9.3 Multi-Centre Studies 
Given the limited number of subjects expected per center, all centers will be pooled for the 
statistical analysis. 
 
9.4 Timing of Analyses 
The following analyses are planned to be performed: 
- 
SRC/IDMC mandated analyses 
- 
The primary analysis will be conducted after all enrolled patients have reached their 
3rd on-treatment scheduled response assessment or have discontinued from 
treatment.  
- 
The final analysis will be triggered one year after the last accrued patient’s first dose 
date. In the exceptional case that after the final analysis any patients might continue 
to receive study treatment under the protocol. Any subsequent data generated from 
this patient(s) will be summarized in an addendum report to be issued after the last 
treatment and the safety follow up visit of the last patient. 
 
Due to the COVID-19 epidemy and subsequent delays in data entry and cleaning, the 
primary analysis will in fact coincide with the final analysis. 
 
10 STATISTICAL ANALYSIS METHODS 
10.1 Disposition of Patients, Demographic and Baseline Data 
10.1.1 Screen Failures and Eligibility Criteria 
A subject is considered enrolled when informed consent is signed, eligibility criteria are met, 
and eligibility for Debio 1562 administration is confirmed. 
Number and percentage of subjects screened, screened but not enrolled, and reasons for 
not being enrolled will be summarized. 
Supportive by-subject listing for all subjects screened, along with whether the subject was a 
screen failure (as of <28 days prior to first dose of Debio 1562) and if yes, the reason for 
the screen failure.  
Additionally, a second by-subject listing will be provided showing whether the subject 
continued to meet eligibility criteria on Cycle 1 Day 1 prior to dosing, and if not, which 
inclusion/exclusion criteria were violated. 
10.1.2 Subject Disposition 
Subject disposition will be displayed in a listing and summarized in a table by cohort and 
overall for the safety population. 
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The number and percentage of subjects completing treatment, treatment discontinuation 
from Debio 1562, treatment discontinuation from rituximab, study discontinuation, along 
with reasons for discontinuation, and treatment regimen switching from QW to Q3W due to 
the Covid-19 pandemic will be presented in a table and a listing by cohort and overall. 
The primary reasons for treatment discontinuation from Debio 1562 and/or rituximab may 
include any of the following: progressive disease, adverse event, subject withdrew consent 
to treatment, subject withdrew consent to treatment and follow up, death, investigator 
decision (not related to an AE), study terminated by sponsor, significant protocol deviation, 
and other (reason will be specified in data listings). 
The primary reason for study discontinuation may include any of the following: subject 
withdrew consent, lost to follow up, significant protocol deviation, sponsor decision, 
investigator decision, death, study completion, and other (reason will be specified in data 
listings). 
10.1.3 Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the Institutional Review Board / 
Independent Ethics Committee and agreed to by the investigator. A major deviation occurs 
when there is non-adherence to the protocol by the subject or investigator that results in a 
risk to the subject, and/or the completeness, accuracy and reliability of the study data. All 
other deviations are minor. Descriptions of protocol deviations are listed in the Deviation 
Management Plan. 
Protocol deviations will be summarized in a table by cohort and overall and displayed in a 
supporting listing. 
10.1.4 Demographic and Baseline Characteristics 
Baseline demographics will be summarized and listed by cohort and overall for all subjects in 
the safety population and will be repeated for all subjects in the efficacy evaluable 
population. Baseline demographic data to be evaluated will include age, sex, ethnicity, race, 
childbearing potential, height, weight, body mass index (body mass in kg divided by the 
square of the body height in meter) and body surface area. Age will be recorded on the 
electronic case report form (eCRF). Age will also be displayed in categories of 18-65 and 
> 65 years of age. No inferential statistics will be generated. Subject pregnancy test results 
will be included in a separate by-subject listing. 
Moreover, baseline demographics will be summarized and listed 
 
 
. 
10.1.5 Medical History 
Medical history events will be coded using the medical dictionary for regulatory activities 
(MedDRA) per preferred term (PT) and system organ class (SOC). Summary of medical 
history will include number and percentage of subjects with a medical history condition 
overall, per SOC and per PT within each SOC. Listing will include condition/procedure, start 
and end dates and grade. 
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10.1.6 Disease Characteristics and Prior Therapy 
10.1.6.1 
Current Cancer Diagnosis 
The current diagnosis will include the type of lymphoma, grade, 
 
 
and method of assessment for DLBCL, Ann Arbor staging system at initial diagnosis and 
current stage, longest diameter (LDi, for listing only), shorter diameter perpendicular to LDi 
(SDi, for listing only), product of perpendicular diameters (PPD, for listing only), sum of the 
products of perpendicular diameters (SPD), results from cytogenetics/FISH/Molecular 
studies, 
, relapsed/refractory status, type of transformation if 
appropriate, extranodal disease status, Eastern cooperative oncology group (ECOG) 
performance status (PS). In addition, the International Prognostic Index (IPI) will be 
provided. The IPI is calculated2 as the number of times the 5 following factors are met: 
- 
Age above 60 years 
- 
LDH above the upper limit of normal (ULN) 
- 
Ann Arbor Stage III or IV 
- 
ECOG PS ≥2 
- 
Number of extranodal sites3 >1. 
According to the revised IPI categorization (R-IPI), the prognosis is considered very good for 
IPI=0, good for IPI=1-2, and poor for IPI=3-5 (Sehn 2007). 
 
All the aforementioned data will be summarized and listed by cohort and overall. Moreover, 
these data will also be summarized and listed 
 among the safety 
population, this will be repeated 
 among the efficacy evaluable population 
and repeated again 
 among the Per Protocol evaluable population. 
 
10.1.6.2 
Prior Cancer Systemic Treatments 
Prior cancer systemic therapy (PCST), radiotherapy and cancer related surgeries will be 
presented in separate listings. Number and percentage of subjects per number of PCST line 
(reasons therapy was given, best response, reasons for discontinuing, number of cycles for 
first and last regimen, time from first dose to recurrence (relapse or progression), time from 
                                           
2 If one or more of the 5 factors are unknown, a range of possible IPI will be calculated for the 
subject. If the range is within one of the groups (IPI=1-2 or IPI=3-5), then the patient will be 
included in the grouped R-IPI analysis in Table 3.   
3 Number of extranodal sites is different from number of extranodal lesions if there are >1 extranodal 
lesions per disease site. For example, if there are 2 extranodal lesions but they are both in the liver, 
this will be considered as 1 extranodal site (The International Non-Hodgkin's Lymphoma Prognostic 
Factors Project, 1993). For the purpose of IPI calculation, the spleen is considered as an extranodal 
site (whereas it is considered nodal for the Ann Arbor classification). Bone marrow involvement 
should also be taken into account: if either the bone marrow biopsy or the bone marrow aspirate 
have lymphoma involvement, this should be considered as involvement in the organ “Bone”. If liver is 
noted as having “diffuse liver involvement” at screening, that should also count as an organ. 
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last dose to recurrence), prior radiation (site, best response), and prior surgical procedure 
(residual disease) will be summarized. If the start and/or end date of PCST or the 
recurrence date is missing, it will be imputed (see Section 8.1). Moreover, these 
aforementioned data will also be summarized and listed 
 among the safety 
population and this will be repeated 
 among the efficacy evaluable 
population. 
 
10.1.7 Prior and Concomitant Medications/Procedures 
Medications/Procedures will be classified into two categories: 
- 
Prior, defined as medications/procedures with start date before the first dose date; 
- 
Concomitant, defined as medications/procedures administered during treatment 
period (from first dose date to the end of the period of safety observation). 
All prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary (WHO-DD; version MAR2016 or higher). If the start and/or end date of 
concomitant medications is missing, it will be imputed (see Section 8.1). 
Summary of prior and concomitant medication will include number and percentage of 
subjects with a concomitant medication overall, per ATC level 2 and per ATC level 4 within 
each ATC level 2. Separate supporting by-subject listings will be provided. 
Additionally, the number and percentage who received a transplant will be tabulated under 
the prior medications summary table. 
By-subject listing for concomitant procedures will be provided. 
 
10.1.8 Eastern Cooperative Oncology Group Performance Status 
Eastern cooperative oncology group (ECOG) performance status (Appendix I) will be 
assessed during screening and at other times specified in the schedule of events (Appendix 
A, Appendix B and Appendix C). All measurements will be displayed in a data listing. 
 
10.1.9 Bone Marrow Assessment 
If applicable, a  bone marrow biopsy or aspirate assessment will be performed within three 
months prior to the first dose. A repeat bone marrow biopsy or aspirate  may be performed 
per investigator’s discretion for subjects with bone marrow infiltration at baseline who have 
a CR. In order to better understand the effect of Debio 1562 on white blood cells, bone 
marrow biopsies or aspirates may also be requested for those subjects who experience 
grade 4 cytopenias. All measurements will be displayed in a data listing.  
10.1.10 
Tumor Biopsy 
Subjects must provide a fresh or archived tumor biopsy sample at screening; archived tissue 
obtained within one year of the screening period is acceptable, provided that the subject’s 
tumor(s) had not transformed during that time. Starting from protocol version 5, samples 
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obtained within 18 months of the screening period are acceptable. If transformation 
occurred one year (18 months for patients recruited according to protocol version 5 or later) 
prior to study treatment, the most recent tumor biopsy must be from after the latest 
transformation; otherwise a fresh biopsy must be collected. Tumor biopsy results from 
central laboratory 
will be displayed in a 
data listing. 
10.1.11 
Transfusion Log 
Subjects who received a transfusion during treatment will be presented in a listing including 
the date, blood product received, and indication. 
 
 
10.2 Efficacy Analyses 
All summaries will present data by cohort and overall for the efficacy evaluable population. 
The data summaries of Responses, OS, PFS, and DoR will also be presented by Cohorts and 
overall for the Efficacy evaluable population . Data summaries for OS and PFS analyses will 
also be presented for the All treated population.  
Subject level data will be provided in listings. 
10.2.1 Multiple Comparisons/Multiplicity 
No formal comparison between cohorts will be performed. Therefore, adjustment for 
multiple comparisons will not be required. 
Hypothesis testing will be done only for the primary efficacy endpoint. Therefore, 
adjustment for multiplicity will not be required. 
10.2.2 Radiologic Tumor Assessment 
Tumor response assessment is based on the Lugano classification of response assessment 
of Hodgkin and non-Hodgkin Lymphoma (Cheson, 2014, see Appendix H). 
Radiographic tumor evaluation by computed tomography (CT) or positron-emission 
tomography (PET)-CT scan of chest, neck, abdomen, and pelvis will be performed within 28 
days prior to first dose of study treatment. The anatomical regions to be assessed 
radiographically post baseline will be determined by individual subject’s extent of disease. 
Repeat assessments will be performed every 6 weeks +/- 1 week, beginning at cycle 1, day 
1 and will not shift as a result of delays in study treatment. The same radiographic 
assessment method used at screening should preferably be used at all subsequent 
evaluations.  
The results from the tumor assessments will be listed for target, non-target, and new lesions 
including: lesion number, date, site, and method. For target lesions their measurements 
(LDi, SDi and PPD), sum of product of diameters (SPD), and FDG-PET Deauville score will be 
provided. Non-target lesions will be assessed and listed as present, not present, or unknown 
and whether worsened or not. An overall response will be determined by the investigators 
following the recommendations from the 2014 Lugano classification. If a new tumor is 
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identified, the date of biopsy, site, size, diagnosis of lymphoma per biopsy, grade, 
 
, and method of assessment (if appropriate) will be listed. As per the 2014 Lugano 
classification, spleen and liver assessments will also be listed as appropriate. 
Subject maximum percent change from baseline for the SPD (MCL, DLBCL, MZL, and FL) 
and the associated best overall response will be plotted (waterfall plot) for the efficacy 
evaluable population. 
Subjects who have discontinued study treatment for reasons other than PD will be followed 
by radiographic assessment every 12 weeks (+/- 4 weeks), beginning from the time of the 
subject’s last on-treatment tumor assessment, until documentation of PD, or beginning 
subsequent anti-cancer therapy. The date of attempted contact, PD status, new anti-cancer 
therapy status, regimen, and dates will be listed. 
10.2.3 Primary Efficacy Analysis 
The BOR is the best response recorded from the start of the treatment until disease 
progression or initiation of new anti-cancer therapy or end of the study period, whichever 
occurs first. Additionally, best response will be evaluated from first dose date up to first on-
treatment scheduled assessment, up to second on treatment scheduled assessment, up to 
third on-treatment scheduled assessment, and up to End of the treatment period, i.e. up to 
the date of last cycle day 1 + 21 days..   
Response assessment will be determined by the investigator for each subject as: 
- 
Complete (metabolic) response (CMR/CR) 
- 
Partial (metabolic) response (PMR/PR) 
- 
No metabolic response or stable disease (NMR/SD) 
- 
Progressive (metabolic) disease (PMD/PD) 
- 
Not evaluated (NE) 
- 
Not done. 
The following rules will be applied to define period: 
- 
From first dose date up to first on-treatment scheduled assessment: 
o 
From first dose date up to 6 weeks + 7 days from first dose date 
- 
From first dose date up to second on-treatment scheduled assessment: 
o 
From first dose date up to 6 weeks + 7 days from first on-treatment 
scheduled scan if first on-treatment scheduled scan is performed 
o 
From first dose date up to 12 weeks + 14 days from first dose date if first on-
treatment scheduled scan is not performed 
- 
From first dose date up to third on-treatment scheduled assessment: 
o 
From first dose date up to 6 weeks + 7 days from second on-treatment 
scheduled scan if second on-treatment scheduled scan is performed 
o 
From first dose date up to 12 weeks + 14 days from first on-treatment 
scheduled scan if second on-treatment scheduled scan is not performed but 
first on-treatment scheduled scan is performed 
o 
From first dose date up to 18 weeks + 21 days from first dose date if first 
and second on-treatment scheduled scan are not performed. 
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The ORR is defined as the proportion of subjects with a BOR of PR or CR. The BOR and ORR 
will be tabulated along with percentages. 
Ninety-five and eighty percent two-sided exact confidence intervals (CIs) will be constructed 
using the Clopper-Pearson method (Clopper, 1934). For the analyses carried out by cohort, 
the one-sided exact binomial distribution will also be used to test the hypotheses that the 
ORR is below or on 40% and above or on 60%, respectively. 
 
The following sensitivity analysis will be performed: 
- 
An additional analysis will be done by censoring the Cohort B subjects who have 
switched to Q3W regimen at their last assessment date while they were still in QW 
regimen  
 
 
10.2.4 Secondary Efficacy Analyses 
Progression free survival (PFS), OS, and DoR will be analyzed using the Kaplan-Meier 
method in both summary tables and figures. The number and percentage of subjects 
censored and those with events will be summarized. Additionally, the median, 25th and 75th 
percentile estimates and 95% CI (where calculable based on Brookmeyer and Crowley 
1982), and minimum and maximum in months will be presented. The PFS rate, DoR rate 
and OS rate, calculated at 3, 6, 9, 12, 15, 18, 21, 24, and last point of observation months 
will be presented along with 95% CI (using the log-log transformation) based on Kaplan-
Meier product limit estimates. The denominator for event/censored rates will be the number 
of subjects within each cohort and total. Time to response will be analyzed using descriptive 
statistics only. 
10.2.4.1 
Progression Free Survival 
PFS is defined as the time (in months) between the date of the first Debio 1562 dose until 
the earliest of either first occurrence of PD (radiologic or clinical) or death. It is calculated 
as: 
(date of first PD/death - date of first Debio 1562 dose + 1) / 30.4375. 
The following censoring rules will be applied: 
1. Subjects who do not experience death or PD, nor initiate a new systemic therapy will 
be right-censored at the date of their last adequate tumor assessment (i.e. a tumor 
assessment not showing NE); 
2. Subjects having initiated a new systemic therapy before experiencing death or PD 
will be right-censored at the date of their last adequate tumor assessment prior to 
initiation of a new systemic therapy; 
3. Subjects who experienced death or PD after two or more consecutive missing or 
inadequate tumor assessments (i.e. 2*6*7 + 2*7 = 98 days, based on assessments 
every 6 +/- 1 week) while assessments are done every 6 +/- 1 week will be right-
censored at their latest adequate assessment before death or PD; 
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4. Subjects who experienced death or PD after one or more consecutive missing or 
inadequate tumor assessments (i.e. 12*7 + 4*7 = 112 days, based on assessments 
every 12 +/- 4 week) while assessments are done every 12 +/- 4 week will be right-
censored at their latest adequate assessment before death or PD; 
5. Subjects without a baseline or post-baseline assessment will be right-censored at the 
date of first administration of the Debio 1562 unless the subject died within 190 days 
from the first dose date (5*(21+3)+21+7+42 = 190 days, considered as an event at 
the date of death). 
If multiple event and censoring conditions are met for the same subject, then the condition 
with the earliest date will be selected. 
When an analysis cutoff date is implemented, only data occurring on or prior to the cutoff 
date will be used for analysis and subjects will be censored at the latest adequate 
assessment prior to cutoff date. 
The following sensitivity analyses will be performed: 
1. An additional sensitivity analysis for progression-free survival consists of ignoring 
the 3rd and 4th censoring rules. 
2. For progression-free survival, subjects who do not experience disease 
progression or death or who initiate anti-cancer therapy other than for a 
transplant or CAR-T   will be right-censored at the date of their last adequate 
tumor assessment using the same rules as above. Hence, data collected after a 
transplant therapy or CAR-T until PD, death or last adequate tumor assessment - 
whichever occurs first will be included in the PFS derivation.  
3. An additional analysis will be done by censoring the Cohort B subjects who have 
switched to Q3W regimen at their last assessment date while they were still in 
QW regimen  
4. An additional analysis will be done by censoring the subjects who died due to 
Covid-19 at their death date, if they haven’t progressed yet. 
 
10.2.4.2 
Duration of Response 
Duration of Response is defined as the time between the earliest date of CR or PR response 
and the date of the first occurrence of PD or death and calculated as: 
(date of first PD/death - date of first CR/PR + 1) / 30.4375. 
Censoring rules for PFS will be applied to DoR. The DoR will be estimated for all evaluable 
subjects who achieve an objective response of PR or CR. 
The sensitivity analyses for PFS will also be reproduced for DoR. 
 
10.2.4.3 
Time to Response 
Time to response is defined as the time from the date of the first dose until the date of first 
CR or PR. It is calculated as: 
(date of first CR/PR - date of first Debio 1562 dose + 1) / 30.4375. 
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Time to response will be estimated for all evaluable subjects who achieve an objective 
response of PR or CR. No subject censoring is involved. 
 
Time to complete response is defined as the time from the date of the first dose until the 
date of first CR. It is calculated as: 
(date of first CR - date of first Debio 1562 dose + 1) / 30.4375. 
Time to complete response will be estimated for all evaluable subjects who achieve an 
objective response of CR. No subject censoring is involved. 
10.2.4.4 
Overall Survival 
Overall Survival is defined as the time between the date of the first dose and the date of 
death. It is calculated as: 
(date of death – date of first Debio 1562 dose + 1) / 30.4375. 
Subjects who do not experience the event of death will be right-censored at their last date 
known to be alive as ‘Ongoing’ or ‘Lost to follow-up’. 
The date of attempted contact, survival status and - if new anti-cancer therapy was started - 
along with the respective regimen will be listed. 
The following sensitivity analyses will be performed: 
1. An additional analysis will be done by censoring the Cohort B subjects who have 
switched to Q3W regimen at their last assessment date while they were still in QW 
regimen 
2. An additional analysis will be done by censoring the subjects who died due to Covid-
19 at their death date, instead of considering that they died 
 
 
 
 
 
  
 
 
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10.3 Safety Analyses 
All safety analyses will be conducted on the safety population. All summaries will present 
data by cohort, unless otherwise specified. Safety evaluations will be based on the incidence 
and severity of adverse events (AEs), clinically significant changes or abnormalities in the 
subject’s laboratory results, vital signs, physical examination, ECG, and Eastern Cooperative 
Oncology Group (ECOG) score.  
10.3.1 Adverse Events 
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes 
occurring in any phase of a clinical study, whether or not considered study drug-related. 
This includes an exacerbation of a pre-existing condition. 
An AE will be considered to be a treatment-emergent adverse event (TEAE) if it begins or 
worsens on or after the first dose date of either Debio 1562 or rituximab, whichever occurs 
first, and before the last dose date of either Debio 1562 or rituximab + 30 days, whichever 
occurs last. 
A serious adverse event (SAE) is defined as any event that results in death, is life 
threatening, requires inpatient hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions, results in a congenital anomaly/birth defect, or may 
jeopardize the patient and require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Adverse events will be coded with the Medical Dictionary for Regulatory Activities (MedDRA; 
version 19.0 or later) and summarized per system organ class (SOC) and preferred term 
(PT). Severity grade will be defined according to the National Cancer Institute (NCI) 
common terminology criteria for adverse events (CTCAE) v4.03. 
A study drug related AE is an event where the investigator determined that the relationship 
to study drug (evaluated separately for Debio 1562 and rituximab) was “possibly related”, 
“probably related”, or “definitely related”. 
Only missing AE onset dates will be imputed as shown in Appendix I. Adverse events for 
which onset date could not be determined after imputation of missing date are considered 
to be treatment emergent. 
Adverse events will be summarized per SOC, PT, and CTCAE grade. For summaries by 
relationship, adverse events with missing relationship are counted as “Possibly Related”. 
Adverse events with missing CTCAE grade will not have CTCAE grade imputed. In 
tabulations, however, if the subject has at least one PT with a non-missing CTCAE grade, 
the non-missing grade will be displayed. 
In addition, the following groups of terms will be analyzed in a grouped manner: 
- 
Neutrophil count decreased (PT Code 10029366) and Neutropenia (PT Code 
10029354) 
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- 
 
As a subgroup analysis, the overall summary of all TEAEs will be done for subjects with a 
treatment duration inferior or equal to 6 cycles versus for subjects with a treatment duration 
greater than 6 cycles. 
Data listings will be provided for all AEs, SAEs, study drug related AEs, AEs resulting in study 
drug discontinuation, AEs considered as being dose-modifying events and AEs leading to 
death. Relationship to Debio 1562 or rituximab, and action taken regarding Debio 1562 
and/or rituximab administration, respectively will be provided. Non-TEAEs will be flagged in 
the listings. 
10.3.2 Deaths and Other Significant Adverse Events 
The primary cause of death will be presented in a table with the following reasons: PD, AE, 
Other, or Unknown; also whether an autopsy was performed or not. Separate summaries of 
deaths occurring on-study or within 30 days of last dose of either Debio 1562 or rituximab, 
and deaths after 30 days of last dose of either Debio 1562 or rituximab will also be 
provided. All deaths occurring on-study and during follow-up will be presented in a listing; 
deaths occurring after 30 days of last dose of either Debio 1562 or rituximab will be flagged. 
10.3.3 Clinical Laboratory Evaluations 
Screening laboratory evaluations (hematology, clinical chemistry, urinalysis, and 
coagulation) may be performed within 28 days before the first dose. Repeat testing will be 
performed as outlined in schedule of events (Appendix A, Appendix B and Appendix C) and 
as clinically indicated. Clinical laboratory results will be classified as Low, Normal, and High, 
or Normal/Abnormal according to the lab normal ranges, and will be graded according to 
NCI CTCAE, Version 4.03. 
All hematology, serum chemistry, urinalysis, and coagulation will be listed per subject for 
each assessment and descriptive statistics will be tabulated for selected criteria detailed 
below by cohort and overall. SI units will be used for listing and reporting. Changes and 
percent changes from baseline in hematology and serum chemistry will be calculated for 
each subject and subsequently summarized by cohort and overall. Shifts from baseline in 
hematology and serum chemistry values will also be summarized by CTCAE grade within 
cohorts and overall. Only scheduled visits will be included in change from baseline summary 
tables; however, unscheduled visits will be included in worse post-baseline shift tables, liver 
function tests summaries, and listings. 
 
10.3.3.1 
Hematology 
Hematology will include: hematocrit (HCT), hemoglobin (HGB), platelet count (PLAT), red 
blood cell (RBC) count, white blood cell (WBC) count with differential [i.e. neutrophils count 
(NEUT), lymphocyte (LYM), monocytes (MONO), eosinophils, and basophils (BASO)]. 
Shift from baseline to worst post-baseline low and high CTCAE grade for hematology 
parameters will be presented in a table for: HGB, RBC, NEUT, PLAT, LYM and WBC. In the 
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shift table based on being lower than a lower normal limit (worst low), a value above the 
upper normal limit will be considered as grade 0. 
 
10.3.3.2 
Serum chemistry 
Serum chemistry will include: albumin (ALB), alkaline phosphatase (ALP), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (UREAN), 
calcium (CA), chloride (CL), creatinine (CREAT), glucose (GLUC), lactate dehydrogenase 
(LDH), magnesium (MG), phosphorus (PHOS), potassium (K), Sodium, total bilirubin (BILI), 
total protein (PROT), Uric acid (URATE), and Immunoglobulin levels (i.e., IgG, IgA, and 
IgM).  
Shift from baseline to worst post-baseline CTCAE grade for serum chemistry parameters (i.e. 
ALB [worst low only], ALP, ALT, AST, CREAT, BILI, and URATE [worst high only], and PHOS, 
CA, CL, GLUC, MG, K, and SODIUM [both worst low and worst high]) will be presented in 
separate tables for CTCAE based on being higher or lower than normal limits, where 
applicable. In the shift table based on being higher than an upper normal limit (worst high) 
a value below the lower normal limit will be considered as grade 0. Likewise, in the shift 
table based on being lower than a lower normal limit (worst low), a value above the upper 
normal limit will be considered as grade 0. 
 
10.3.3.3 
Urinalysis and Pregnancy Test 
Urinalysis includes: appearance, specific gravity, and pH. Microscopic examination of 
sediment is to be performed if the specimen is positive for WBCs, proteins, or blood. Semi 
quantitative evaluations include using dipsticks for glucose, protein, bilirubin, ketones, 
leukocytes and blood. Urinalysis and pregnancy test laboratory results will be presented in 
separate listings. 
Coagulation 
Coagulation tests include: prothrombin time, International Normalized Ratio (INR), and 
activated partial thromboplastin time (aPTT). Coagulation results will be presented in a data 
listing. 
 
10.3.3.4 
Liver Function Test 
Clinically significant values in liver function tests will be summarized by the following 
categories using the maximum value while on treatment. The denominator for the 
summaries will be the number of subjects who had at least one non-missing value during 
treatment. Please note that the categories for each test are not mutually exclusive: 
- 
AST: 
o 
> 1xULN & ≤ 3xULN; 
o 
> 3xULN & ≤ 5xULN; 
o 
> 5xULN & ≤ 10xULN; 
o 
> 10xULN & ≤ 20xULN; 
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o 
> 20xULN; 
- 
ALT: 
o 
> 1xULN & ≤ 3xULN; 
o 
> 3xULN & ≤ 5xULN; 
o 
> 5xULN & ≤ 10xULN; 
o 
> 10xULN & ≤ 20xULN; 
o 
> 20xULN; 
- 
AST or ALT: 
o 
> 1xULN & ≤ 3xULN; 
o 
> 3xULN & ≤ 5xULN; 
o 
> 5xULN & ≤ 10xULN; 
o 
> 10xULN & ≤ 20xULN; 
o 
> 20xULN; 
- 
Total bilirubin (TBL): 
o 
> 1xULN & ≤ 2xULN; 
o 
> 2xULN; 
- 
Alkaline Phosphatase: 
o 
> 1.5xULN; 
- 
(AST or ALT) and TBL (all tests must be conducted within 72 hours): 
o 
AST or ALT > 3xULN and TBL > 1.5xULN & ≤ 2xULN; 
o 
AST or ALT > 3xULN and TBL > 2xULN; 
- 
(AST or ALT) and ALP and TBL (all tests must be conducted within 72 hours): 
o 
AST or ALT > 3xULN and ALP < 2xULN and TBL > 2xULN. 
 
10.3.3.5 
Vital Signs 
Vital sign measurements will include blood pressure, heart rate, temperature, and 
respiratory rate. Height will only be measured at screening and weight will be measured as 
indicated in the schedule of events (Appendix A, Appendix B and Appendix C). A change and 
percent change from baseline summary table, and a listing of measurement values by visit, 
will be provided for vital signs. Only scheduled visits will be included in change from baseline 
summary tables. All visits will be included in listings. 
 
10.3.4 Other Safety Measures 
10.3.4.1 
Physical Examination 
A complete physical examination including assessments of general appearance, skin, head 
(eyes, ears, nose, and throat), lungs, heart, abdomen, back, lymph nodes, extremities, and 
neurological system will be completed at screening and at end of treatment. Directed 
physical examinations will be completed at additional time points as specified in the 
schedule of events. The results of all time points will be displayed in a listing. 
 
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10.3.4.2 
Electrocardiogram 
Please refer to Appendix A, Appendix B and Appendix C for the schedule of events. 
ECG results including: Heart Rate, QT Interval, QTc Interval and method, and classification 
of Within Normal Limits, Abnormal Not Clinically Significant, and Abnormal Clinically 
Significant with a description for abnormal findings will be presented in data listings. 
QTcB based on Bazetts’ formula or QTcF based on Fredericia’s formula will be listed for all 
subjects under the method used by the local laboratory. The denominator for the summaries 
will be the number of subjects who had non-missing values at each visit time point. Only 
scheduled visits will be included in summary tables. All visits will be included in listings. 
Number and percentage of subjects in the following categories will be tabulated by cohort 
and overall for QTcF and QTcB: 
- 
> 450 ms; 
- 
> 480 ms; 
- 
> 500 ms; 
- 
change from baseline > 30 ms; 
- 
change from baseline > 60 ms; 
- 
> 500 ms and/or change from baseline > 60 ms; 
where they can be calculated using the following: 
- 
Bazett’s Formula: QTcB = QT / square-root (RR Interval); 
- 
Fredericia’s Formula: QTcF = QT / cube-root (RR Interval); 
- 
RR Interval = 60 / Heart Rate. 
The categories used in the tabulation are not mutually exclusive. Additionally, for the 
tabulations, where the local laboratory did not provide both a QTcB and a QTcF value, the 
values that were missing will be derived using the above formulas. 
Shift from baseline to worst post-baseline ECG results will be presented by cohort and 
overall. 
 
10.3.4.3 
B-Symptoms 
B-symptoms are defined as at least one of the following:  
- 
unexplained fevers greater than 38°C 
- 
drenching night sweats  
- 
weight loss greater than 10% of normal body weight over a period of 6 months or 
less.  
B-symptoms will be documented at screening, prior to every cycle and at end of treatment. 
All results will be displayed in a data listing. 
 
 
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10.4 Extent of Exposure 
Debio 1562 will be given intravenously: 
- 
On day 1 of each 21-day cycle for subjects assigned to a Debio 1562 Q3W dosing 
schedule cohort. Planned Debio 1562 dose for the Q3W dosing schedule is 0.7 
mg/kg; 
- 
On day 1, day 8 and day 15 of each 21-day cycle for subjects assigned to the Debio 
1562 QW dosing schedule cohort. Planned Debio 1562 dose for the QW dosing 
schedule is 0.4 mg/kg, 0.2 mg/kg and 0.2 mg/kg at day 1, day 8 and day 15 of each 
cycle. 
Rituximab will be given intravenously on day 1 of each 21-day cycle after the infusion of 
Debio 1562. Planned dose for rituximab is 375 mg/m2. 
For Debio 1562, the total dose of drug will be calculated based on each subject’s body 
weight. The weight used for calculation should be obtained prior to first treatment and 
thereafter should only be modified for relevant (≥10%) changes in baseline body weight 
(not influenced by weight gain or loss attributed to fluid retention). 
The exposure to Debio 1562 and rituximab will be summarized by cohort and overall, with 
summary statistics including mean, standard deviation, median, minimum, and maximum 
on: 
- 
Number of treatment cycles, defined as the number of cycles in the eCRF where 
non-zero dose of Debio 1562 was infused; 
- 
Treatment duration, expressed in weeks. It is calculated as: 
Ceiling ((date of last cycle day 1 – date of first dose + 21) / 7); 
- 
Total cumulative dose, expressed in mg. It is calculated as the sum of the actual 
dose administered in all cycles while the subject is on study drug; 
- 
Actual dose level: 
o 
Debio 1562 actual dose level, expressed in mg/(kg*cycle). It is calculated as:  
Total cumulative dose of Debio 1562 (mg) / (average pre-dose weight (kg) * 
number of cycles) 
o 
Rituximab actual dose level, expressed in mg/(m2*cycle). It is calculated as: 
Total cumulative dose of rituximab (mg) / (average pre-dose Body Surface Area 
(BSA) (m2) * number of cycles) 
Relative dose intensity per week (over the treatment duration) 
- 
Relative dose intensity per week, expressed in %. It is calculated as: Actual 
dose intensity / planned dose intensity * 100 
- 
Actual dose intensity, expressed in mg/week. It is calculated as: 
Total cumulative dose (mg) / duration of dosing (weeks).  
- 
Planned dose intensity, expressed in mg/week. It is calculated as 
Total planned cumulative dose in a cycle (mg/kg or mg/m2) * pre-dose weight (kg) 
or BSA (m2) / 3 (weeks) 
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The pre-dose weight used for this calculation should be obtained prior to first 
treatment, i.e. at Cycle 1 Day 1, and thereafter should only be modified for 
significant (≥ 10%) changes in body weight. 
Relative dose intensity (Listing)  
- 
Relative dose intensity, expressed in %. It is calculated as: actual cumulative 
dose received / planned cumulative dose during the same number of cycles * 100, 
where:  
- 
The number of cycles for this calculation will be taken as the number of initiated 
cycles up  
- 
to Cycle 6 included, or until PD, or until decision to end the treatment, whichever 
comes first. 
- 
The actual cumulative dose received will be calculated as the sum of doses that 
have been administered during the above-defined number of cycles. 
- 
The planned cumulative dose will be calculated as the planned per protocol dose 
(for Debio 1562: 0.8 mg/kg for Cohort B, 0.7 mg/kg for all other cohorts; for 
rituximab: 375 mg/m2) multiplied by the number of cycles initiated (up to Cycle 6 or 
until PD, or until decision to end the treatment, whichever comes first).  
 
The number and percentage of subjects who had interrupted, missed, delayed, or decreased 
dosing, and the reason(s) will be summarized for Debio 1562 and rituximab. For each 
modification action, each distinct reason will be reported in each specific category. 
Supportive by-subject listings of Debio 1562 and rituximab infusions will be presented. 
Infusion rate will be obtained from the relevant data in the EDC but also calculated as (mg 
in infusion)/(time of treatment end – time of treatment start). Both will be presented in 
listings.  
 
10.5 Pharmacokinetics 
Blood samples for pharmacokinetics will be collected as outlined in Appendix D(Safety run-In 
and Phase II), Appendix E (Cohort A, Part 2 and 3) and Appendix F (Cohort B, Part 2 and 3).  
Concentration of Debio 1562, anti-drug antibody (ADA) Debio 1562, Debio 1562 total 
antibody (TAb), DM1 Free, DM1-SMCC-lysine, DM1-SMCC, Rituximab, and ADA Rituximab 
will be summarized by cohort and per visit and also by regimen. The following summary 
statistics will be produced: the number of non-missing values, the arithmetic mean, the 
standard deviation, the coefficient of variation, the median, the first and third quartiles, the 
minimum, the maximum, the geometric mean, the geometric standard deviation and the 
geometric coefficient of variation. 
Concentrations that are below the limit of quantification will be handled as follows: 
- 
All pre-dose concentrations observed before cycle 1 day 1 that are below the limit of 
quantification will be imputed by: 
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o 
Zero for the computation of the mean, the standard deviation, and the 
coefficient of variation 
o 
Half the limit of quantification for the computation of the geometric mean, 
the geometric standard deviation, and the geometric coefficient of variation 
- 
All concentrations observed after the first dose date that are below the limit of 
quantification will be imputed by half the limit of quantification. 
PK parameters, including but not limited to Cmax, Tmax, t1/2 and AUC, will be summarized 
similarly as above for Debio 1562, Debio 1562 TAb, DM1 Free, DM1-SMCC-lysine, DM1-
SMCC and rituximab. 
The overall PK and PK/PD analyses will be described in a separate analysis plan. 
                                           
 
 
 
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10.7 Other Analyses 
 
10.7.1.1 
Health-Related Quality of Life 
Health-related quality of life will be evaluated based on the functional assessment of cancer 
therapy-lymphoma (FACT-Lym). Please refer to scoring manual (www.facit.org) for 
instruction for computing overall score and subscale scores. Full analysis of the health-
related quality of life questionnaire is beyond the scope of this document. It will be 
described in a separate analysis plan. 
 
10.8 Interim Analyses 
No formal interim analysis is planned for this study. However, available safety and PK data 
will be reviewed by the SRC during the course of study part 1 and by the IDMC during the 
course of part 2 and part 3 of the study (see Section 4.2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.8.1.2 
Stopping Rules for Safety 
The IDMC will review the safety data regularly and can recommend terminating or modifying 
any dosing regimen or the study to guard subjects’ safety. The IDMC will monitor all safety 
aspects with special focus on neutropenia, febrile neutropenia, hepatic damage, pneumonitis 
and neuropathy. 
11 SUMMARY OF CHANGES TO THE PROTOCOL 
Amendment history to the protocol can be found in Section 1.10 of the protocol. 
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13 APPENDICES 
Appendix A. 
SCHEDULE OF EVENTS OF SAFETY RUN-IN FOR Q3W DOSING (PART 1) 
Activity 
Screening 
Cycles 1 and 3 
Cycle 2 
Cycles 
≥ 4 
EOTj 
30-day 
Follow-upf, n 
 
≤28 days 
prior to  
1st dose 
Day 1k 
Day 2 
Day 3 
Day 8 
±1 
day 
Day15 
±1 day 
Day 1k 
Day 8 
±1 day 
Day 15 
±1 day 
Day 1k 
 
(30-42 
Days) 
Informed Consent 
● 
 
 
 
 
 
 
 
 
 
 
 
Demography 
● 
 
 
 
 
 
 
 
 
 
 
 
Confirm disease diagnosis, stage 
at diagnosis and current stage 
● 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
● 
 
 
 
 
 
 
 
 
 
 
 
Review and Document 
Inclusion/Exclusion Criteria 
● 
 
 
 
 
 
 
 
 
 
 
 
Confirm patient continues to 
satisfy I/E Criteria 
 
C1 only 
 
 
 
 
 
 
 
 
 
 
Physical examinationa 
● 
● 
 
 
 
 
● 
 
 
● 
● 
● 
Vital Signsb 
● 
● 
 
 
● 
●  
● 
●  
● 
● 
● 
● 
Weight 
● 
● 
 
 
 
 
● 
 
 
● 
● 
● 
Height 
● 
 
 
 
 
 
 
 
 
 
 
 
B-symptoms 
● 
● 
 
 
 
 
● 
 
 
● 
● 
● 
ECOG performance status 
● 
● 
 
 
 
 
● 
 
 
● 
● 
● 
Pregnancy test (urine or serum) 
● 
● 
 
 
 
 
● 
 
 
● 
● 
● 
Hematology and Chemistryc 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
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Activity 
Screening 
Cycles 1 and 3 
Cycle 2 
Cycles 
≥ 4 
EOTj 
30-day 
Follow-upf, n 
 
≤28 days 
prior to 1st 
dose 
Day 
1k 
Day 2 
Day 3 
Day 8 
±1 day 
Day 15 
±1 day 
Day 
1k 
Day 8 
±1 day 
Day 15 
±1 day 
Day 1k 
 
(30-42 
Days) 
Coagulationc 
● 
● 
 
 
 
 
● 
 
 
● 
● 
● 
Urinalysisc 
● 
● 
 
 
 
 
● 
 
 
● 
● 
● 
Viral Serology (HBsAg) 
● 
 
 
 
 
 
 
 
 
 
 
 
Radiologic tumor  
assessmentsd 
● 
 
Every 6 weeks (±1 week) from Cycle 1 Day 1 (no schedule shift due to dose 
delays)e 
●f 
 ●f 
Biopsy tumor tissueg 
● 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Assessmenth 
● 
 
Every 6 weeks (±1 week) from Cycle 1, Day 1 as Clinically Indicated 
 
 
ECG (12-lead)i 
● 
● 
● 
 
 
 
On Day 1 of Cycles 2 and 4 to coincide 
with PK draws (± 1 hour) 
● 
● 
Pharmacokinetic and 
Immunogenicity Assessments 
See Appendix D 
AE and SAE evaluation l 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Concomitant Medicationm 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Debio 1562 Infusion 
 
● 
 
 
 
 
● 
 
 
● 
 
 
Rituximab Infusion 
 
● 
 
 
 
 
● 
 
 
● 
 
 
a) 
Directed physical examination is acceptable while on study treatment and at the 30-day safety Follow-up Visit. Complete examination is required at screening and EOT. 
Physical examinations may be performed up to 3 days prior to study drug administration on Day 1 of all Cycles. 
b) Debio 1562 - vital signs (blood pressure, heart rate, temperature, and respiratory rate) will be measured immediately before each administration, every 30 min  5 min 
during the infusion (if applicable), and immediately after infusion. Rituximab - vital signs will be measured immediately before each administration, every 60 min  5 min 
during the infusion and immediately after infusion. For all cycles, patients must remain in the clinic for safety observation for one hour following completion of their rituximab 
infusion. 
c) 
Laboratory assessments may be performed up to 3 days prior to study drug administration in all cycles. All draws on Day 1 of treatment should be pre-dose. In the event 
of severe toxicity, repeat laboratory tests should be performed within 48 hours, and then followed at least twice weekly until re-treatment criteria are met.  
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Version 3.1 dated 2021-05-07 
 
Debiopharm International S.A. 
Serum Chemistry- ALB, ALK-P, ALT, AST, BUN, Ca, Cl, Creatinine, Glucose, LDH, Magnesium, Phosphorus, K, Na, Total bilirubin, Total protein, Uric acid, Immunoglobulin 
levels (IgG, IgA, IgM ).  
Hematology- Hct, Hgb, Platelet count, RBC count, WBC count with differential. 
Urinalysis - Appearance, specific gravity and pH, Semi-quantitative dipstick evaluation of glucose, protein, bilirubin, ketones, leukocytes and blood, Microscopic examination 
of sediment to be performed if urinalysis is positive for WBC, proteins or blood.  
Coagulation tests: T/INR and aPTT  
d) Radiographic tumor evaluation by CT or PET-CT scan of chest, neck, abdomen and pelvis will be performed within 28 days prior to first dose of study treatment. The 
anatomical regions to be assessed radiographically post baseline will be determined by individual patients’ extent of disease. Whenever possible, the same radiographic scan 
assessment used at screening (e.g., PET-CT) should be used at all subsequent radiographic evaluations. 
e) 
Post-baseline disease assessments will be performed every 6 weeks from Cycle 1, Day 1 and will not shift due to dose delays.  
f) 
Patients discontinuing Debio 1562 for reasons other than PD will have subsequent clinic visits for radiographic assessment every 12 weeks (± 4 weeks) from the time of 
their last on-study tumor assessment until PD, or starting a subsequent anti-cancer therapy. For patients who discontinue for PD, no radiographic scans will be required at 
the EOT visit or the follow-up visits. All patients will be followed for survival every 12 weeks (± 4 weeks) from the time of the 30-day safety Follow-up visit, for up to one 
year from the last patient’s first dose (Cycle 1 Day 1). Patients will not be required to visit the clinic for survival follow-up. 
g) Patients must have available pathology-informed tumor biopsy sample representative of the current disease, 
. 
h) If applicable, a bone marrow biopsy or aspirate will be performed within 3 months prior to first dose. A repeat bone marrow biopsy or aspirate will be required for patients 
with bone marrow infiltration at baseline who have a CR by imaging and physical examination, and will, in case possible and deemed acceptable by the Investigator, be 
performed every 6 weeks as clinically indicated. In order to better understand the effect of Debio 1562 on WBCs, bone marrow biopsies/aspirates may also be requested 
for those patients who experience grade 4 cytopenias. 
i) 
The screening ECG will be performed within 14 days prior to first treatment. In Cycles 1 and 3, ECGs will be performed within three hours prior to dose, at the end of the 
Debio 1562 infusion (to coincide with Cmax and PK blood draw) and 24  4 hours after infusion. An ECG will be performed on Day 1 of Cycles 2 and 4 (inclusive) to coincide 
with the pre-dose PK blood draw. An ECG at the 30-day Follow-up visit is not required unless clinically indicated or if the EOT assessment was missed. 
j) 
EOT visit should occur within 7 days of the decision to discontinue study treatment.  
k) 
Cycle 1 Day 1 assessments (ECOG, weight, B Symptoms and pregnancy test) do not need to be repeated if they are collected within 3 days of study drug administration. 
For all other cycles, the Day 1 window is ±3 days.  
l) 
The period of safety observation extends from the time of consent until 30 days after the patient’s last study treatment or until the AEs has resolved or stabilized or an 
outcome has been reached, whichever comes first. 
m) Concomitant medications should be collected beginning from within 4 weeks of Cycle 1, Day 1 until the end of the period of safety observation. 
n) In the event that a patient is unable to return to the clinic for a follow-up visit, telephone contact with the patient to assess AEs, concomitant medications, anti-cancer 
treatments will be conducted. 
 
 
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Debiopharm International S.A. 
Appendix B. 
SCHEDULE OF EVENTS OF COHORT A FOR Q3W DOSING (PART 2 AND 3) 
Activity 
Screening 
Cycles 1 and 2 
Cycles 3-6 q 
EOTl 
30-day 
Follow-upg, 
p 
 
≤28 days 
prior to  
1st dose 
Day 1m 
Day 2 
Day 3 
Day8 
±1 day 
Day15 
±1 day 
Day 1m 
 
(30-42 
Days) 
Informed Consent 
● 
 
 
 
 
 
 
 
 
Demography 
● 
 
 
 
 
 
 
 
 
Confirm disease diagnosis, 
stage at diagnosis and 
current stage 
● 
 
 
 
 
 
 
 
 
Medical History  
● 
 
 
 
 
 
 
 
 
Review and Document 
Inclusion/Exclusion Criteria 
● 
 
 
 
 
 
 
 
 
Confirm patient continues to 
satisfy I/E Criteria 
 
C1 only 
 
 
 
 
 
 
 
Physical examinationa 
● 
● 
 
 
 
 
● 
● 
● 
Vital Signsb 
● 
● 
 
 
● 
●  
● 
● 
● 
Health-related Quality of Lifec 
 
● 
 
 
 
 
● 
● 
● 
Weight 
● 
● 
 
 
 
 
● 
● 
● 
Height 
● 
 
 
 
 
 
 
 
 
B-symptoms 
● 
● 
 
 
 
 
● 
● 
● 
ECOG performance status 
● 
● 
 
 
 
 
● 
● 
● 
Pregnancy test (urine or 
serum) 
● 
● 
 
 
 
 
● 
● 
● 
Hematology and Chemistryd 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
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Version 3.1 dated 2021-05-07 
 
Debiopharm International S.A. 
Activity 
Screening 
Cycles 1 and 2 
Cycles 3-6 q 
EOTl 
30-day 
Follow-upg, p 
 
≤28 days 
prior to 1st 
dose 
Day 1m 
Day 2 
Day 3 
Day 8 
±1 day 
Day 15 
±1 day 
Day 1m 
 
(30-42 
Days) 
Coagulationd 
● 
● 
 
 
 
 
● 
● 
● 
Urinalysisd 
● 
● 
 
 
 
 
● 
● 
● 
Viral Serology (HBsAg) 
● 
 
 
 
 
 
 
 
 
Radiologic tumor  
Assessmentse 
● 
 
Every 6 weeks (± 1 week) from Cycle 1, Day 1 (no schedule shift due to 
dose delays)f 
●g 
●g 
Biopsy tumor tissueh 
● 
 
 
 
 
 
 
 
 
Bone Marrow Assessmenti 
● 
 
Every 6 weeks (± 1 week) from Cycle 1, Day 1 as Clinically Indicated 
 
 
ECG (12-lead)k 
● 
● 
● 
 
 
 
● 
● 
● 
Pharmacokinetic and 
Immunogenicity Assessments 
See Appendix E 
AE and SAE evaluation n 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Concomitant Medicationo 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Debio 1562 Infusion 
 
● 
 
 
 
 
● 
 
 
Rituximab Infusion 
 
● 
 
 
 
 
● 
 
 
a) 
Directed physical examination is acceptable while on study treatment and at the 30-day safety Follow-up Visit. Complete examination is required at screening and EOT. 
Physical examinations may be performed up to 3 days prior to study drug administration on Day 1 of all Cycles. 
b) Debio 1562 - vital signs (blood pressure, heart rate, temperature, and respiratory rate) will be measured immediately before each administration, every 30 min  5 min 
during the infusion (if applicable), and immediately after infusion. Rituximab - vital signs will be measured immediately before each administration, every 60 min  5 min 
during the infusion and immediately after infusion. Patients will remain in the clinic under monitoring for four hours after completion of the rituximab infusion for the first 
cycle. Post-administration safety monitoring could potentially be shortened (i.e. < 4 hours but at least 1 hour) following subsequent administration of rituximab, based on 
the judgement of the investigator. Patients receiving Debio 1562 only will also remain in the clinic under monitoring for one hour. 
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Debiopharm International S.A. 
c) 
HRQoL assessment at Day 1 of each cycle will be performed prior to Debio 1562 infusion. 
d) Laboratory assessments may be performed up to 3 days prior to study drug administration in all cycles. If the screening laboratory assessments are performed within 3 
days prior drug administration on Day 1 of Cycle 1, no assessments need to be repeated on Day 1 of Cycle 1. All draws on Day 1 of treatment should be pre-dose. In the 
event of severe toxicity, repeat laboratory tests should be performed within 48 hours, and then followed at least twice weekly until retreatment criteria are met.  
Serum Chemistry- ALB, ALK-P, ALT, AST, BUN, Ca, Cl, Creatinine, Glucose, LDH, Magnesium, Phosphorus, K, Na, Total bilirubin, Total protein, Uric acid, Immunoglobulin 
levels (IgG, IgA, IgM ).  
Hematology- Hct, Hgb, Platelet count, RBC count, WBC count with differential. 
Urinalysis - Appearance, specific gravity and pH, Semi-quantitative dipstick evaluation of glucose, protein, bilirubin, ketones, leukocytes and blood, Microscopic examination 
of sediment to be performed if urinalysis is positive for WBC, proteins or blood.  
Coagulation tests: T/INR and aPTT.  
If deemed necessary by the Investigator an additional hematological assessment can be performed on Day 15 of Cycles 3-6. 
e) 
Radiographic tumor evaluation by CT or PET-CT scan of chest, neck, abdomen and pelvis will be performed within 28 days prior to first dose of study treatment. The 
anatomical regions to be assessed radiographically post baseline will be determined by individual patients’ extent of disease. Whenever possible, the same radiographic scan 
assessment used at screening (e.g., PET-CT) should be used at all subsequent radiographic evaluations. 
f) 
Post-baseline disease assessments will be performed every 6 weeks from Cycle 1, Day 1 and will not shift due to dose delays.  
g) Patients discontinuing Debio 1562 for reasons other than PD will have subsequent clinic visits for radiographic assessment every 12 weeks (± 4 weeks) from the time of 
their last on-study tumor assessment until PD, or starting a subsequent anti-cancer therapy. For patients who discontinue for PD, no radiographic scans will be required at 
the EOT visit or the follow-up visits. All patients will be followed for survival every 12 weeks (± 4 weeks) from the time of the 30-day safety Follow-up visit, for up to one 
year from the last patient’s first dose (Cycle 1 Day 1). Patients will not be required to visit the clinic for survival follow-up. 
h) Patients must have available a pathology-informed tumor biopsy sample representative of the current disease, 
. 
i) 
If applicable, a bone marrow biopsy or aspirate will be performed within 3 months prior to first dose. A repeat bone marrow biopsy or aspirate will be required for patients 
with bone marrow infiltration at baseline who have a CR by imaging and physical examination, and will, in case possible and deemed acceptable by the Investigator, be 
performed every 6 weeks as clinically indicated. In order to better understand the effect of Debio 1562 on WBCs, bone marrow biopsies/aspirates may also be requested 
for those patients who experience grade 4 cytopenias. 
 
  
k) 
The screening ECG will be performed within 14 days prior to first treatment. In Cycles 1 and 2, ECGs will be performed within three hours prior to dose, at the end of the 
Debio 1562 infusion (to coincide with Cmax and PK blood draw) and 24  4 hours after infusion. An ECG will be performed on Day 1 of Cycles 3-6 to coincide with the pre-
dose PK blood draw. An ECG at the 30-day Follow-up visit is not required unless clinically indicated or if the EOT assessment was missed. 
l) 
EOT visit should occur within 7 days of the decision to discontinue study treatment.  
m) Cycle 1 Day 1 assessments (ECOG, weight, B Symptoms and pregnancy test) do not need to be repeated if they are collected within 3 days of study drug administration. 
For all other cycles, the Day 1 window is ±3 days.  
n) The period of safety observation extends from the time of consent until the 30 days after the patient’s last study treatment or until the AEs has resolved or stabilized or an 
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Version 3.1 dated 2021-05-07 
 
Debiopharm International S.A. 
outcome has been reached, whichever comes first. 
o) 
Concomitant medications should be collected beginning from 4 weeks prior to Cycle 1, Day until end of the period of safety observation. 
p) In the event that a patient is unable to return to the clinic for a follow-up visit, telephone contact with the patient to assess AEs, concomitant medications, and anti-cancer 
treatments will be conducted 
q) Permission to prolong the study treatment could be exceptionally granted by Study Sponsor if patients are deriving benefit from the study treatment and after complete 
presentation of the individual case by the Study Investigator, particularly the medical justification for extending the treatment and the re-assessment of the risk/benefit 
balance. The Sponsor’s decision will consider the availability of IMP at the time of request. A report of the discussions with the Sponsor must be filed in the source 
documentation. 
  
 
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Page 61 of 82 
Statistical Analysis Plan 
Version 3.1 dated 2021-05-07 
 
Debiopharm International S.A. 
Appendix C. 
SCHEDULE OF EVENTS OF COHORT B FOR QW DOSING (PART 2) 
Activity 
Screening 
Cycles 1 and 2 
Cycles 3-6 q 
EOTl 
30-day 
Follow-upg, 
p 
 
≤28 days 
prior to  
1st dose 
Day 1m 
Day 2 
Day 3 
Day8 
-1 to +3 
days 
Day15 
-1 to 
+3 
days 
Day 1m 
Day 8 
-1 to 
+3 
days 
Day 15 
-1 to 3 
days 
 
(30-42 
Days) 
Informed Consent 
● 
 
 
 
 
 
 
 
 
 
 
Demography 
● 
 
 
 
 
 
 
 
 
 
 
Confirm disease diagnosis, 
stage at diagnosis and 
current stage 
● 
 
 
 
 
 
 
 
 
 
 
Medical History  
● 
 
 
 
 
 
 
 
 
 
 
Review and Document 
Inclusion/Exclusion Criteria 
● 
 
 
 
 
 
 
 
 
 
 
Confirm patient continues to 
satisfy I/E Criteria 
 
C1 only 
 
 
 
 
 
 
 
 
 
Physical examinationa 
● 
● 
 
 
● 
● 
● 
● 
● 
● 
● 
Vital Signsb 
● 
● 
 
 
● 
● 
● 
● 
● 
● 
● 
Health-related Quality of Lifec 
 
● 
 
 
 
 
● 
 
 
● 
● 
Weight 
● 
● 
 
 
● 
● 
● 
● 
● 
● 
● 
Height 
● 
 
 
 
 
 
 
 
 
 
 
B-symptoms 
● 
● 
 
 
● 
● 
● 
● 
● 
● 
● 
ECOG performance status 
● 
● 
 
 
● 
● 
● 
● 
● 
● 
● 
Pregnancy test (urine or 
serum) 
● 
● 
 
 
● 
● 
● 
● 
● 
● 
● 
Hematology and Chemistryd 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
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Statistical Analysis Plan 
Version 3.1 dated 2021-05-07 
 
Debiopharm International S.A. 
Activity 
Screening 
Cycles 1 and 2 
Cycles 3-6 q 
EOTl 
30-day 
Follow-upg, 
p 
 
≤28 days 
prior to  
1st dose 
Day 1m 
Day 2 
Day 3 
Day8 
-1 to +3 
days 
Day15 
-1 to 
+3 
days 
Day 1m 
Day 8 
-1 to 
+3 
days 
Day 15 
-1 to 
+3 
days 
(30-42 
Days) 
 
Coagulationd 
● 
● 
 
 
● 
● 
● 
● 
● 
● 
● 
Urinalysisd 
● 
● 
 
 
● 
● 
● 
● 
● 
● 
● 
Viral Serology (HBsAg) 
● 
 
 
 
 
 
 
 
 
 
 
Radiologic tumor 
assessmentse 
● 
 
Every 6 weeks (± 1 week) from Cycle 1, Day 1 (no schedule shift due to dose 
delays)f 
●g 
●g 
Biopsy tumor tissueh 
● 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Assessmenti 
● 
 
Every 6 weeks (± 1 week) from Cycle 1, Day 1 as Clinically Indicated 
 
 
ECG (12-lead)k 
● 
● 
● 
 
● 
●  
● 
● 
● 
● 
● 
Pharmacokinetic and 
Immunogenicity Assessments 
See Appendix F 
AE and SAE evaluation n 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Concomitant Medicationo 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Debio 1562 Infusion 
 
● 
 
 
● 
● 
● 
● 
● 
 
 
Rituximab Infusion 
 
● 
 
 
 
 
● 
 
 
 
 
a) 
Directed physical examination is acceptable while on study treatment and at the 30-day safety Follow-up Visit. Complete examination is required at screening and EOT. 
Physical examinations may be performed up to 3 days prior to study drug administration on Day 1 of all Cycles. 
b) Debio 1562 - vital signs (blood pressure, heart rate, temperature, and respiratory rate) will be measured immediately before each administration, every 30 min  5 min 
during the infusion (if applicable), and immediately after infusion. Rituximab - vital signs will be measured immediately before each administration, every 60 min  5 min 
during the infusion and immediately after infusion. Patients will remain in the clinic under monitoring for four hours after completion of the rituximab infusion for the first 
cycle. Post-administration safety monitoring could potentially be shortened (i.e. < 4 hours but at least 1 hour) following subsequent administration of rituximab, based on 
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Statistical Analysis Plan 
Version 3.1 dated 2021-05-07 
 
Debiopharm International S.A. 
the judgement of the investigator. Patients receiving Debio 1562 only, i.e., on Day 8 and Day 15 of each cycle or due to rituximab intolerability, will also remain in the clinic 
under monitoring for one hour. 
c) 
HRQoL assessment at Day 1 of each cycle will be performed prior to Debio 1562 infusion. 
d) Laboratory assessments may be performed up to 3 days prior to study drug administration in all cycles. If the screening laboratory assessments are performed within 3 
days prior drug administration on Day 1 of Cycle 1, no assessments need to be repeated on Day 1 of Cycle 1. All draws on Day 1 of treatment should be pre-dose. In the 
event of severe toxicity, repeat laboratory tests should be performed within 48 hours, and then followed at least twice weekly until retreatment criteria are met.  
Serum Chemistry- ALB, ALK-P, ALT, AST, BUN, Ca, Cl, Creatinine, Glucose, LDH, Magnesium, Phosphorus, K, Na, Total bilirubin, Total protein, Uric acid, Immunoglobulin 
levels (IgG, IgA, IgM ).  
Hematology- Hct, Hgb, Platelet count, RBC count, WBC count with differential. 
Urinalysis - Appearance, specific gravity and pH, Semi-quantitative dipstick evaluation of glucose, protein, bilirubin, ketones, leukocytes and blood, Microscopic examination 
of sediment to be performed if urinalysis is positive for WBC, proteins or blood.  
Coagulation tests: T/INR and aPTT  
e) 
Radiographic tumor evaluation by CT or PET-CT scan of chest, neck, abdomen and pelvis will be performed within 28 days prior to first dose of study treatment. The 
anatomical regions to be assessed radiographically post baseline will be determined by individual patients’ extent of disease. Whenever possible, the same radiographic scan 
assessment used at screening (e.g., PET-CT) should be used at all subsequent radiographic evaluations. 
f) 
Post-baseline disease assessments will be performed every 6 weeks from Cycle 1, Day 1 and will not shift due to dose delays.  
g) Patients discontinuing Debio 1562 for reasons other than PD will have subsequent clinic visits for radiographic assessment every 12 weeks (± 4 weeks) from the time of 
their last on-study tumor assessment until PD, or starting a subsequent anti-cancer therapy. For patients who discontinue for PD, no radiographic scans will be required at 
the EOT visit or the follow-up visits. All patients will be followed for survival every 12 weeks (± 4 weeks) from the time of the 30-day safety Follow-up visit, for up to one 
year from the last patient’s first dose (Cycle 1 Day 1). Patients will not be required to visit the clinic for survival follow-up. 
h) Patients must have available a pathology-informed tumor biopsy sample representative of the current disease, 
. 
i) 
If applicable a bone marrow biopsy or aspirate will be performed within 3 months prior to first dose. A repeat bone marrow biopsy or aspirate will be required for patients 
with bone marrow infiltration at baseline who have a CR by imaging and physical examination, and will, in case possible and deemed acceptable by the Investigator, be 
performed every 6 weeks as clinically indicated. In order to better understand the effect of Debio 1562 on WBCs, bone marrow biopsies/aspirates may also be requested 
for those patients who experience grade 4 cytopenias. 
 
  
k) 
The screening ECG will be performed within 14 days prior to first treatment. On Day 1 of Cycles 1 and 2, ECGs will be performed within three hours prior to dose, at the 
end of the Debio 1562 infusion (to coincide with Cmax and PK blood draw) and 24  4 hours after infusion. On Day 8 and 15 of Cycles 1 and 2, ECGs will be performed within 
three hours prior to dose and at the end of the Debio 1562 infusion (to coincide with Cmax and PK blood draw) An ECG will be performed on Day 1 of Cycles 3-6 to coincide 
with the pre-dose PK blood draw. An ECG at the 30-day Follow-up visit is not required unless clinically indicated or if the EOT assessment was missed. 
l) 
EOT visit should occur within 7 days of the decision to discontinue study treatment.  
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Statistical Analysis Plan 
Version 3.1 dated 2021-05-07 
 
Debiopharm International S.A. 
m) Cycle 1 Day 1 assessments (ECOG, weight, B Symptoms and pregnancy test) do not need to be repeated if they are collected within 3 days of study drug administration. 
For all other cycles, the Day 1 window is ±3 days.  
n) The period of safety observation extends from the time of consent until 30 days after the patient’s last study treatment or until the AEs has resolved or stabilized or an 
outcome has been reached, whichever comes first. 
o) 
Concomitant medications should be collected beginning from 4 weeks prior to Cycle 1, Day 1 until the end of the period of safety observation. 
p) In the event that a patient is unable to return to the clinic for a follow-up visit, telephone contact with the patient to assess AEs, concomitant medications, and anti-cancer 
treatments will be conducted.  
q) Permission to prolong the study treatment could be exceptionally granted by Study Sponsor if patients are deriving benefit from the study treatment and after complete 
presentation of the individual case by the Study Investigator, particularly the medical justification for extending the treatment and the re-assessment of the risk/benefit 
balance. The Sponsor’s decision will consider the availability of IMP at the time of request. A report of the discussions with the Sponsor must be filed in the source 
documentation. 
 
 
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Page 65 of 82 
Statistical Analysis Plan 
Version 3.1 dated 2021-05-07 
 
Debiopharm International S.A. 
Appendix D. 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENT OF SAFETY RUN-IN FOR Q3W DOSING (PART 1) 
Activity 
Cycles 1 and 3 
Cycles  
2 and 4-8 
EOT 
30-Day 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 8 
Day 15 
Day1 
 
 
Blood samples for PK 
• Pre-dose 
• 5’ after 
EOI D1562 
• 5’ after 
EOI RTX 
• 244h 
after EOI 
D1562 
• 484h 
after EOI 
D1562 
● 
● 
• Pre-dose 
• 5’ after EOI 
RTX* 
● 
● 
Blood samples for immunogenicity (ADA) 
assessment 
• Pre-dose 
 
 
 
 
• Pre-dose 
● 
● 
Unscheduled PK and immunogenicity (ADA) 
samples 
As clinically indicated during active study treatmenta 
 
 
D1562: Debio 1562; EOI: End Of Infusion; EOOP: End Of Observational Period; RTX: Rituximab. 
* In the event that rituximab is discontinued, a post-dose blood draw will be taken following completion of the Debio 1562 infusion.  
a) Patients who experience a ≥ Grade 2 infusion reaction during or immediately following administration of Debio 1562 will have blood drawn for determination of drug 
concentration and antibodies to Debio 1562 (ADA). Two samples should be obtained: (1) within three hours of the onset of the reaction; and (2) one week later. 
 
 
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Statistical Analysis Plan 
Version 3.1 dated 2021-05-07 
 
Debiopharm International S.A. 
Appendix E. 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENT OF COHORT A FOR Q3W DOSING (PART 2) 
Activity 
Cycles 1 and 2 
Cycles 3-6 b 
EOT b 
30-Day 
Follow-up 
Day 1 
Day 2 
Day 3 
Day 8 
Day 15 
Day 1 
 
 
Blood samples for Debio 1562 
• Pre-dose 
• 5’ after 
EOI 
D1562 
• 2h after 
SOI RTX 
• 5’ after 
EOI RTX 
• EOOP 
• 244h 
after EOI 
D1562 
• 484h 
after EOI 
D1562 
● 
● 
• Pre-dose 
• 5’ after EOI 
D1562 
• 5’ after EOI RTX 
 
 
Blood samples for rituximab 
• Pre-dose 
• EOI RTX 
• 244h 
after EOI 
D1562 
• 484h 
after EOI 
D1562 
● 
● 
• Pre-dose 
• 5’ after EOI RTX 
● 
● 
Blood samples for immunogenicity (ADA) 
assessment 
• Pre-dose 
 
 
 
 
• Pre-dose 
● 
● 
Unscheduled PK and immunogenicity 
(ADA) samples 
As clinically indicated during active study treatmenta 
 
 
D1562: Debio 1562; EOI: End Of Infusion; EOOP: End Of Observational Period; RTX: Rituximab; SOI: Start Of Infusion, ●: Any time during the visit 
a) 
Patients who experience a ≥ Grade 2 infusion reaction during or immediately following administration of Debio 1562 will have blood drawn for determination of drug 
concentration and antibodies to Debio 1562 (ADA). Two samples should be obtained: (1) within three hours of the onset of the reaction; and (2) one week later. 
b) In patients who exceptionally continue the study treatment beyond C6, the last PK sample and the sample for immunogenicity (ADA) assessment will be taken at 
C7D1 at pre-dose blood draw instead of at the EOT visit. For patients already beyond C7D1 after Amendment 5, the last PK sample will be taken at D1 of the next 
possible subsequent cycle at pre-dose blood draw instead of at the EOT visit. No additional samples will be taken at the 30-day follow-up visit. 
 
 
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Page 67 of 82 
Statistical Analysis Plan 
Version 3.1 dated 2021-05-07 
 
Debiopharm International S.A. 
Appendix F. 
PHARMACOKINETIC AND IMMUNOGENICITY ASSESSMENT OF COHORT B FOR QW DOSING (PART 2) 
Activity 
Cycles 1 and 2 
Cycle 3 
Cycles 4-6 b 
EOT b 
30-Day 
Follow 
-up b 
Day 1 
Day 2 
Day 3 
Day 8 
Day 15 
Day1 
Day 8 
Day 15 
Day1 
Day 8 
Day 15 
 
 
Blood samples for Debio 1562 
• Pre-
dose 
• 5’ 
after 
EOI 
D1562 
• 2h 
after 
SOI RTX 
• 5’ 
after 
EOI RTX 
• EOOP 
• 
244h 
after 
EOI 
D1562 
• 484h 
after 
EOI 
D1562 
• Pre-
dose 
• 5’ 
after 
EOI 
D1562 
• 
EOOP 
• Pre-
dose 
• 5’ 
after 
EOI 
D1562 
• EOOP 
• Pre-
dose 
• 5’ 
after 
EOI 
D1562 
• 5’ 
after 
EOI 
RTX 
 
• Pre-
dose 
• 5’ 
after 
EOI 
D1562 
 
• Pre-
dose 
• 5’ 
after 
EOI 
D1562 
 
• Pre-
dose 
• 5’ 
after 
EOI 
D1562 
 
• Pre-
dose 
• 5’ 
after 
EOI 
D1562 
 
• Pre-
dose 
• 5’ 
after 
EOI 
D1562 
 
 
 
Blood samples for rituximab 
• Pre-
dose 
• EOI 
RTX 
• 
244h 
after 
EOI 
D1562 
• 484h 
after 
EOI 
D1562 
● 
● 
• Pre-
dose 
• EOI 
RTX 
● 
● 
• Pre-
dose 
• EOI 
RTX 
● 
● 
● 
● 
Blood samples for 
immunogenicity (ADA) 
assessment 
● 
 
 
 
 
● 
 
 
● 
 
 
● 
● 
Unscheduled PK and 
immunogenicity (ADA) 
samples 
As clinically indicated during active study treatmenta 
 
 
D1562: Debio 1562; EOI: End Of Infusion; EOOP: End Of Observational Period; RTX: Rituximab; SOI: Start Of Infusion 
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a) Patients who experience a ≥ Grade 2 infusion reaction during or immediately following administration of Debio 1562 will have blood drawn for determination of drug 
concentration and antibodies to Debio 1562 (ADA). Two samples should be obtained: (1) within three hours of the onset of the reaction; and (2) one week later. 
b) In patients who exceptionally continue the study treatment beyond C6, the last PK sample and the sample for immunogenicity (ADA) assessment will be taken at C7D1 at 
pre-dose blood draw instead of at the EOT visit. For patients already beyond C7D1 after Amendment 5, the last PK sample will be taken at D1 of the subsequent cycle at pre-
dose blood draw instead of at the EOT visit. N o additional sample will be taken at the 30-day follow-up. 
 
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Appendix H. 
RESPONSE ASSESSMENT OF HODGKIN AND NON-HODGKIN LYMPHOMA: THE LUGANO CLASSIFICATION (CHESON, 2014) 
Response and Site 
PET-CT Scan 
CT-based Response 
Complete Response 
Complete metabolic response 
Complete radiologic response (all of the 
following) 
Lymph nodes and extralymphatic sites 
Score 1, 2, or 3 with or without a residual mass on 5PS† 
In Waldeyer’s ring or extranodal sites with high physiologic 
uptake or with activation within spleen or marrow (e.g., 
with chemotherapy or myeloid colony-stimulating factors), 
uptake may be greater than normal mediastinum and/or 
iver. Complete metabolic response may be inferred if 
uptake at sites of initial involvement is no great than 
surrounding normal tissue even if the tissue has high 
physiologic uptake. 
Target nodes/nodal masses must regress to ≤ 1.5 
cm in LDi 
No extralymphatic sites of disease 
Non-measured lesions 
N/A 
Absent 
Organ enlargement 
N/A 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate
 
 
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Partial Response 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and extralymphatic sites 
Score 4 or 5† with reduced uptake compared with baseline 
and residual mass(es) of any size. 
At interim, these findings suggest responding disease. 
At end of treatment, these findings indicate residual 
disease. 
 ≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites 
 When a lesion is too small to measure on CT, 
assign 5 mm X 5 mm as the default value 
 When no longer visible, assign 0 X 0 mm 
Non-measured lesions 
N/A 
Absent/normal, regressed, but no increase 
Organ enlargement 
N/A 
Spleen must have regressed by ≥ 50% in length 
beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy or 
an interval scan. 
N/A 
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No response or stable disease 
No metabolic response 
Stable disease 
Target nodes/nodal masses, extranodal 
esions 
Score 4 or 5 with no significant change in FDG uptake from 
baseline at interim or end of treatment 
< 50% decrease from baseline in SPD of up to 6 
dominant, measurable nodes and extranodal sites; 
no criteria for progressive disease are met 
Non-measured lesions 
N/A 
No increase consistent with progression 
Organ enlargement 
N/A 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
N/A 
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Progressive disease 
Progressive metabolic disease 
Progressive disease requires at least 1 of the 
following 
Individual target nodes/nodal masses 
Score 4 or 5 with an increase in intensity of uptake from 
baseline and/or 
PPD progression 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at interim or 
end-of-treatment assessment 
An individual node/lesion must be abnormal with: 
LDi > 1.5 cm and 
Increase by > 50% from PPD nadir and 
An increase in LDi or SDi from nadir  
0.5 cm for lesions ≤ 2 cm 
cm for lesions > 2 cm 
In the setting of splenomegaly, the splenic length 
must increase by > 50% of the extent of its prior 
ncrease beyond baseline (e.g., a 15-cm spleen 
must increase to > 16 cm). If no prior 
splenomegaly, must increase by at least 2 cm from 
baseline 
New or recurrent splenomegaly 
Non-measured lesions 
None 
New or clear progression of preexisting non-
measured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather than 
another etiology (e.g., infection, inflammation). If 
uncertain regarding etiology of new lesions, biopsy or 
nterval scan may be considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any axis; if < 1.0 
cm in any axis, its presence must be unequivocal 
and must be attributable to lymphoma 
Assessable disease of any size unequivocally 
attributable to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
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Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; 
 LDi, longest transverse diameter of a 
lesion; MRI, magnetic resonance imaging; N/A: not applicable; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular 
diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant 
lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes should 
preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those 
in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Non-measured lesions: Any disease not 
selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as 
truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, 
ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or 
in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be 
no higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid growth factors). 
†PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake 
markedly higher than liver and/or new lesions; X new areas of uptake unlikely to be related to lymphoma. 
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Appendix I. 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
STATUS SCALE (OKEN, 1982) 
Grade 
Scale 
0 
Fully active, able to carry out all pre-disease performance without 
restriction. (Karnofsky 90-100) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework, office work. 
(Karnofsky 70-80) 
2 
Ambulatory and capable of all self-care but unable to carry out work 
activities. Up and about more than 50% of waking hours. (Karnofsky 50-
60) 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. (Karnofsky 30-40) 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair. (Karnofsky 10-20) 
 
 
 
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Appendix J. 
IMPUTATION ALGORITHM FOR PARTIAL AND MISSING DATES 
Adverse Event  
- 
If onset date is completely missing: 
o 
If AE end date is missing or on/after the date of first dose, then onset date is set 
to date of first dose 
o 
If AE end day is missing, but the month and year of the AE end date is larger 
than the month and year of the first dose date, then the onset date is set to the 
date of first dose 
o 
If AE end month is missing, but the year of the AE end date is larger than the 
year of the first dose date, then the onset date is set to the date of first dose  
o 
If AE end date is prior to the date of the first dose, then onset date is not 
imputed 
- 
If (onset year is present and month and day are missing) or (onset year and day are 
present and month is missing): 
o 
If year = year of first dose, then set onset month and day to month and day of 
first dose 
o 
If year < year of first dose, then set onset month and day to December 31st. 
o 
If year > year of first dose, then set onset month and day to January 1st. 
- 
If onset month and year are present and day is missing: 
o 
If year=year of first dose and 
 
If month = month of first dose then set day to day of first dose date 
 
If month < month of first dose then set day to last day of month 
 
If month > month of first dose then set day to 1st day of month 
o 
If year < year of first dose then set day to last day of month 
o 
If year > year of first dose then set day to 1st day of month 
- 
For all other cases, set onset date to date of first dose 
 
Concomitant Medications 
- 
If start date is completely missing or year is missing then start date will not be 
imputed. 
- 
If start year is present and month and day are missing then set start month and start 
day to January 1. 
- 
If start year and day are present and month is missing then set start month to 
January. 
- 
If start year and start month are present and start day is missing then set start day 
to 1st day of month. 
- 
If end date is completely missing or year is missing then end date will not be 
imputed. 
- 
If end year is present and month and day are missing then set end month and day 
to December 31. 
- 
If end year and day are present and month is missing then set end month to 
December. 
- 
If end year and end month are present and end day is missing then set end day to 
last day of the month. 
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Death and Disease Progression: 
In case of partial missing date the below imputation rules will be used for death date and 
disease progression date, provided that the imputed dates don’t contradict with other 
information in the database: 
- 
Missing day: 1st day of the month and year of death or progression; 
- 
Missing month: January of the year of death or progression; 
- 
Missing year or missing entire date will not be imputed. 
 
Prior Cancer Systemic Therapy (PCST) 
Missing dates will be reviewed during the Data Review meeting to assess the refractoriness 
status to first or last PCST. 
 
 
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Appendix K. 
CRITERIA OF PROTOCOL DEVIATIONS THAT CAN LEAD TO EXCLUSION 
FROM THE PER-PROTOCOL POPULATION 
 
 
Affecting efficacy – 
entails removal from 
Per Protocol 
population 
Inclusion criteria5 
 
1) For Part 1 of the study, patients must have histopathologically 
confirmed diagnosis of R/R DLBCL, FL, MZL/MALT, MCL, or other 
Sponsor approved NHL subtypes according to the WHO classification 
2008 for which standard measures do not exist or are no longer 
effective.  
Yes 
(no need for the 
diagnosis to be 
histopathologically 
confirmed) 
2) For Part 2 and Part 3 of the study, patients must have 
histopathologically and clinically confirmed diagnosis of relapsed 
DLBCL. Patients will be considered to have a relapsed disease if they 
showed a duration of response of at least 24 weeks after their first 
line of therapy. The following patients with relapsed DLBCL will be 
enrolled: 
i. Patients who received only one line of previous therapy and 
achieved either complete response (CR) or partial response (PR) 
for at least 24 weeks (from the last day of the last cycle) after their 
first line of therapy, but are not eligible for high dose 
chemotherapy with autologous stem cell transplantation (HD-
ASCT) 
ii. Patients who received more than one line of previous therapy 
(including HD-ASCT), and have achieved a duration of response 
(CR or PR) of at least 8 weeks (from the last day of the last cycle) 
after their last line of therapy.  
PotentiallyPotentially 
3) Patients must have received no more than six prior treatment 
regimens. Prior treatment with an anti-CD20 agent, either alone or 
in combination, is allowed.  
Yes 
4) Patients must be ≥ 18 years. 
Potentially 
5) Patients must have ECOG Performance Status 0 - 2. 
Yes 
                                           
5 Inclusion and exclusion criteria were taken from Protocol Version 7. Criteria in previous versions 
may be slightly different or have different numbering. 
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Affecting efficacy – 
entails removal from 
Per Protocol 
population 
6) Patients must meet the following laboratory criteria: 
• 
Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (1000/mm3) 
• 
Platelet count ≥ 50 x 109/L (50,000/mm3; patients must not have 
been transfused within 10 days previous of blood drawn for 
laboratory assessment) 
• 
Patients receiving therapeutic anticoagulation are eligible provided 
their 
anticoagulation 
parameters 
are 
within 
range 
(e.g. 
International Normalized Ratio [INR] 2-3 on Coumadin if 
applicable) and they have no history of ≥ Grade 2 bleeding while 
on anticoagulation therapy 
• 
For patients receiving therapeutic doses of anticoagulation: Platelet 
count ≥ 100 x 109/L (100,000/mm3; must not have been transfused 
within previous 10 days) 
• 
Hemoglobin ≥ 8.0 g/dL (may have been transfused) 
• 
Serum creatinine ≤ 2.0 x upper limit of normal (ULN) or 24-hour 
creatinine clearance of ≥ 60 mL/minute 
• 
AST ≤ 2.5 x ULN; ALT ≤ 2.5 x ULN and  
• 
Total bilirubin ≤ 1.5 x ULN; patients with documented diagnosis of 
Gilbert syndrome are eligible if total bilirubin ≤ 3.0 x ULN. 
Potentially 
7) Patients must have evaluable or measurable disease in accordance 
with the International Working Group Guidelines for Lymphoma 
(Cheson 2014).a 
Yes 
8) Patients who are Hepatitis B surface antigen (HBsAg) + (must be 
polymerase chain reaction [PCR] negative) who are taking antivirals 
are allowed to enroll.  
Potentially 
9) Male patients and female patients of child bearing potential 
participating in this study must agree to use two highly effective 
methods of contraception throughout the study and for at least 12 
weeks after the last dose of Debio 1562 and 12 months after the last 
dose of rituximab. Examples of acceptable birth control methods 
include but are not limited to the following methods: (e.g., oral, 
parenteral, or implantable hormonal contraceptive; tubal ligation; 
intra-uterine device; barrier contraceptive with spermicide; partner’s 
latex condom or vasectomy).  
No 
10) Patients must be willing to provide informed consent and be willing 
to comply with the study protocol. 
Not affecting, however 
if no ICF was signed 
patients will be 
excluded 
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Affecting efficacy – 
entails removal from 
Per Protocol 
population 
11) Patients must have available a pathology-informed fresh or archived 
tumor tissue biopsy reflecting the current DLBCL disease. If the tissue 
biopsy is older than 18 months from the screening visit and a fresh 
one cannot be available, patients should provide fine needle 
aspiration (FNA) samples. 
No 
Exclusion Criteria 
 
1) Patients with a diagnosis of CLL or Small Lymphocytic Lymphoma. 
Yes 
2) For Part 2 and Part 3 of the study, patients with primary refractory 
DLBCL (defined as progression of disease within 24 weeks after first 
line of treatment). 
Potentially 
3) For Part 2 and Part 3 of the study, patients that are eligible to 
undergo first time HD-ASCT. 
No 
4) For Part 2 and Part 3 of the study, patients with R/R FL, MZL/MALT, 
MCL, or any other NHL subtypes according to the WHO classification 
Potentially 
5) The following exclusions, with regard to prior therapy apply: 
• 
Not recovered from prior chemotherapy or radiation as per 
Investigator’s judgment.  
• 
Anti-CD20 monoclonal antibody therapy within 14 days of starting 
study treatment. 
• 
Prior therapy with other anti-CD37-targeting therapy. 
• 
Radioimmunotherapy within two months prior to starting study 
treatment. 
• 
Small 
molecule 
anti-cancer 
therapeutic 
agent, 
and 
all 
investigational agents within 5 x t1/2 or 14 days whichever is 
shorter. 
• 
Allogeneic stem cell transplantation in the safety run-in period. In 
Part 2 and Part 3 of the study, patients who have had an allogeneic 
stem cell transplant may be eligible if their GVHD is controlled, after 
investigator/Sponsor discussion.  
• 
Chronic, systemic treatment with corticosteroids unless the dose 
has been stable for >7 days and is equivalent to ≤ 10 mg of 
prednisone per day.   
• 
Patients who have not recovered from prior surgery.  Patients must 
have recovered or stabilized from the side effects of any major or 
minor surgical procedures prior to study treatment. 
Yes 
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Affecting efficacy – 
entails removal from 
Per Protocol 
population 
6) Patients who have had a prior anaphylactic or other severe infusion 
reaction such that the patient is unable to tolerate antibody 
administration. 
No 
7) Patients who have known central nervous system, meningeal, or 
epidural disease including brain metastases. 
Yes 
8) Patients who have received or are to receive vaccination with live 
viruses within 30 days of Cycle 1 Day1. 
No 
9) Impaired cardiac function or clinically significant cardiac disease such 
as: 
• 
New York Heart Association Class III or IV cardiac disease, 
including pre-existing clinically significant ventricular arrhythmia, 
congestive heart failure, or cardiomyopathy;  
• 
Unstable angina pectoris ≤ 6 months prior to starting study 
treatment; 
• 
Acute myocardial infraction ≤ 6 months prior to starting study 
treatment; or  
• 
Other clinically significant heart disease e.g., ≥ grade 3 
hypertension, history of labile hypertension, or history of poor 
compliance with an antihypertensive regimen. 
Yes 
10) Patients with ≥ Grade 2 peripheral neuropathy. 
No 
11) Patients with active hepatitis A, B or C infection. 
Yes 
12) Uncontrolled intercurrent illness, including but not limited to, ongoing 
or active infection, psychiatric illness that would limit compliance with 
study 
requirements, 
active 
autoimmune 
disease 
requiring 
immunosuppressive therapy, severe immune deficiency. 
Yes 
13) Known diagnosis of HIV infection. 
Yes 
14) Patients with a concurrent primary malignancy that requires 
treatment or that would confound the disease response 
interpretation for the disease under study. 
Potentially 
15) Women of child bearing potential who are pregnant or breast 
feeding. 
No 
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Affecting efficacy – 
entails removal from 
Per Protocol 
population 
16) Patients currently presenting interstitial lung disease, diffuse 
parenchymal lung disease, or with a past history of severe/Grade 3 
parenchymal lung disorders. 
Yes 
Use of prohibited concomitant medications or procedures 
 
Concurrent other anti-cancer therapy, or investigational therapy while 
on study treatment. 
Potentially 
Tumor assessment not performed per protocol 
 
Baseline tumor assessment >28 daysb before Cycle 1 Day 1 
Yes 
a Measurable is defined as: if screening is by CT: measurable in both diameters (i.e. both diameters 
are >1.0 cm), with LDi>1.5 cm for a lymph node lesion or LDi>1 cm for an extranodal lesion; if 
screening is by PET-CT: focal uptake in nodal and/or extranodal sites that is in keeping with 
lymphoma (Deauville score of 4 or 5). If screening by PET-CT but Deauville score <4, the CT criteria 
apply. 
b A 7-days windows was considered for baseline tumor assessment leading. A baseline tumor 
assessment performed less than 35 days prior Cycle 1 day 1 is considered compliant with protocol. 
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