An Open-Label, Phase I/II Study of ME-401 and R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma
Phase: PHASE1
Conditions: Diffuse Large B-Cell Lymphoma
Sponsor: Deepa Jagadeesh

C A S E 1 4 2 0 
Pa ge 1 
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S T U D Y  N U M B E R:  C A S E 1 4 2 0  
C li nical Trials. g o v: N C T 0 4 5 1 7 4 3 5 
Pr ot oc ol Date: 0 4/ 2 2/ 2 0 2 2 
S T U D Y TI T L E:  A n O p e n- La b el, P hase I/II st u d y of M E- 4 0 1 a n d R- C H O P i n Ne wl y 
Dia g n ose d Diff us e Lar g e B- Cell L y m p h o ma  
S P O N S O R I N V E S TI G A T O R:  
Dee pa J a ga dees h M D, M P H 
Cle vela n d Cli nic 
Ta ussi g Ca ncer Ce nt er 
9 5 0 0 E ucli d A ve n ue 
Cle vela n d, O H  4 4 1 9 5 
Cle ve la n d Cli nic S u b-I n v esti gat ors: 
R o bert Dea n, M D 
Bria n Hill, M D, P h D 
Bra d P o hl ma n, M D 
Allis o n Wi nter, M D 
O mer K oc, M D 
Pa ol o Cai mi, M D 
C hrist o p her D’ A n dr ea, P A- C  
Stac y Mat he ws, A P P 
Ge ne vie v e Cra ne, M D, P h D 
S T A TI S TI CI A N: 

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S T U D Y C O O R DI N A T O R: 
 
  
  
  
 
 
 
  
  
  
  
  
 
   
 
  
 
   
  
 
 
S P O N S O R:   
  
  
Case C o m pre he nsi ve Ca ncer Ce nter   
  
  
 
  
  
 
S P O N S O R I N V E S TI G A T O R: 
Dee pa J a ga dees h M D, M P H 
 
S U P P O R T/ F U N DI N G:   
M EI P har ma  
  
  
  
  
 
S U P P LI E D A G E N T : 
 
M E- 4 0 1, s u p plie d b y M EI P har ma  
 
I N D #:  
  
  
 
 
 
 
 
O T H E R A G E N T ( S):   
      R- C H O P:  Rit u xi ma b, D o x or u bici n, Vi ncristi ne,   
  
  
  
  
      C ycl o p h os p ha mi de, Pre d nis o ne  
 
 
 
 
 
 
 
 
 
 
 

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S U M M A R Y O F C H A N G E S 
 
 
Pr ot oc ol 
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Secti o n  
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6. 0, 
6. 1. 2, 
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treati n g i n vesti gat or discr eti o n 
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1 1. 1. 2 , 1 1. 2 
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start ne w treat me nt i n f ollo w u p e nter s ur vi val f oll o w u p.  
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Cra ne, M D  
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c ha n ge.  
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c m 
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8. 4  
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1 0. 1. 4  
A d diti o nal c orrelati ve bl o o d sa m ples 
 

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S T U D Y S C H E M A 
 
 
 

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P R O T O C O L S U M M A R Y 
 
Pr o t oc ol N u m ber/ Title  
A n O pe n- L a bel, P hase I/II st u d y of M E- 4 0 1 a n d R- C H O P 
i n Ne wl y Dia g n ose d Diff use Lar ge B -C ell L y m p h o ma  
St u d y P hase  
P hase I/II   
Brief Bac k gr o u n d/ Rati o n ale  
 
 
 
Rit u xi ma b- C H O P c ures a hi g h perce nta ge of pati e nts wit h 
diff use lar g e B-cell l y m p h o ma ( D L B C L) 1- 3, h o we ver u p t o 
4 0 % of patie nts will rela pse.  After rela pse treat m e nt 
o pti o ns are li mite d t o i nte nsi ve c he m ot hera p y, tra ns pla nt, or 
c hi meric a nti ge n r ece pt or T t hera p y, all of w hi c h are 
p ote ntiall y t o xic a n d s o me patie nts ar e n ot eli gi ble f or s uc h 
t hera pies4- 9.  I m pr o vi n g t he c ure rate i n t he u pfr o nt setti n g 
i n or der t o li mit t he nee d f or s uc h t her a pies is a desira ble 
g oal.   
 
T he acti vati o n of p h os p hati d yli n osit ol 3- ki nase i n hi bi t ors 
( PI 3 Kis) ulti matel y lea ds t o cell s ur vi val, pr oliferati o n, a n d 
i m m u ne re g ulati o n.  M E- 4 0 1 is a hi g hl y selecti ve i n hi bit or 
of t he δ  is of or m of PI 3 K, a n d s h o ws pr o misi n g cli nical 
acti vit y al o ne a n d i n c o m bi nati o n wit h rit u xi ma b i n t he 
treat me nt of i n d ole nt l y m p h o mas.  T he m ost c o m m o n gra de 
3 or hi g her a d verse e v e nts ( A Es) see n i n p hase I trials are 
ras h, diarr hea, ne utr o p e nia, tra ns a mi nitis, c olitis, a n d 
st o matitis 1 0- 1 2.  T he i nci de nce a n d se v erit y of t h ese A Es is 
sig nifica ntl y l o wer t ha n t hat see n wit h ot her PI 3 Kis. 
 
Base d o n pr ecli nical rati o nale a n d cli nical d ata of M E- 4 0 1 i n 
l y m p h oi d mali g na ncies, t he rela ps e rate wit h R- C H O P, a n d 
s h ortc o mi n gs of s ec o n d li ne t hera pies w e pr o p os e a p has e 
I/II st u d y t o e val uate 
M E- 4 0 1 pl us R- C H O P i n ne wl y 
dia g n ose d D L B C L.   
Pri mar y O bjecti ves 
P h ase I 
Pri mar y O bjecti ve 
T o deter mi ne t he r ec o m me n d p hase 2 d ose ( R P 2 D) of M E-
4 0 1 i n c o m bi nati o n wit h R- C H O P f or patie nts wit h ne wl y 
dia g n ose d D L B C L.   
 
Pri mar y E n d p oi nt 
D ose li miti n g t o xicit y ( D L T) as defi n e d b y n o n-
he mat ol o gic cli nicall y si g nifica nt gra d e 3 or 4 treat me nt-
relate d A Es or he mat ol o gic gra de 3 or 4 treat me nt relate d 
A Es t hat are cli nicall y si g nifica nt (as defi ne d i n s ecti o n 6. 3) 
d uri n g t he first c ycle, gra de d acc or di n g t o t he Nati o nal 
Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts ( C T C A E), Ver si o n 5.0.    

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P h a se II  
Pri mar y O bjecti ve 
T o esti mate t he cli nical acti vit y of M E- 4 0 1 i n c o m bi nati o n 
wit h R- C H O P i n patie nts wit h ne wl y dia g n ose d D L B C L, as 
meas ure d b y 1 y ear P F S rate.    
 
Pri mar y E n d p oi nt  
Ti me fr o m st u d y treat me nt i nitiati o n t o pr o gressi o n free 
s ur vi val, as defi ne d as t he ti me fr o m first d ose t o 
d oc u me nte d diseas e pr o gressi o n, or deat h fr o m a n y ca use, 
w hic he ver o cc urs first .   
Sec o n dar y O bj ecti ves 
P h ase I 
Sec o n dar y O bj ecti ve 
T o descri be t olera bilit y of M E- 4 0 1 i n c o m bi nati o n wit h R-
C H O P f or patie nts wit h ne wl y dia g n ose d D L B C L.   
 
Sec o n dar y E n d p oi nt 
Treat me nt r elate d A Es, Treat me nt dela ys ( # da ys treat me nt 
is dela ye d) 
 
P h ase II  
Sec o n dar y O bj ecti ves 
•  T o esti mate t he o ver all res p o nse rates ( c o m plete a n d 
partial re missi o n), d urati o n of res p o nse ( D O R), ti me t o 
pr o gressi o n ( T T P), a n d o verall s ur vi val ( O S) wit h 
M E- 4 0 1 pl us R- C H O P.  
•  T o c har acteri ze treat me nt-relate d A Es i n patie nts 
treate d wit h M E- 4 0 1 pl us R- C H O P. 
Sec o n dar y E n d p oi nts 
•  Res p o nse ( o ver all, c o m plete, a n d partial) as defi ne d b y 
L u ga n o criteri a 
•  D urati o n of Res p o nse d efi ne d as t he ti me fr o m 
d oc u me nte d res p o ns e ( C R or P R) t o t he ti me of 
c o nfir me d diseas e pr o gr essi o n or deat h d ue t o a n y 
ca use, w hic h e ver occ urs first 
•  O verall S ur vi val defi n e d as t he ti me fr o m first d os e of 
st u d y treat me nt t o deat h fr o m a n y ca us e 
•  Ti me t o Treat me nt Fail ur e defi ne d as t he ti me fr o m 
st u d y e ntr y t o a n y treat m e nt fail ure.  
•  Treat me nt r elate d A Es 
Please s ee secti o n 1 2. 1  f or f ull defi niti o ns  
C orrelati ve O bjecti ve(s) 
 
P h ase II  
C orrelati ve O bjecti ves  

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T o e x pl ore t he ass ociati o n bet wee n m olec ular s u bt y pi n g 
( via ne xt ge nerati o n se q u e nci n g a n d R N A se q u e nci n g) a n d 
res p o nse t o t her a p y (c o m plete res p o nse or partial r es p o nse).  
 
C orrelati ve E n d p oi nts 
M olec ular s u bt y pe as d efi ne d b y Sc h mitz et al. a n d C ha p u y 
et al. 1 3, 1 4 
Sa m ple Size 
P hase 1 
N = 6- 1 2 patie nts 
P hase 2 
N = 5 4  t otal ( 6 fr o m p has e I) 
Disease C o n diti o ns  
Diff use Lar ge B -Cell L y m p h o ma  
I nter ve nti o ns 
P hase I 
•  Sta n dar d d ose R- C H O P P L U S M E- 4 0 1 o n da ys 
da ys 1- 4 ( d ose le v el 1) a n d da ys 1- 7 ( d ose le v el 2) 
of a 2 1 da y c y cle x 6 c y cles 
•  M E- 4 0 1 will be d ose escalate d i n 3 + 3 sta n dar d 
desi g n wit h 2 d ose le vels  
•  Pretreat me nt P E T/ C T, I nteri m C T sca ns after 3 
c ycles, P ost treat me nt P E T/ C T 8 wee ks after 
treat me nt c o m pleti o n.  
P hase 2 
•  Sta n dar d d ose R- C H O P P L U S M E- 4 0 1 at R P 2 D o n 
a 2 1 da y c y cle x 6 c y cles  
•  Pretreat me nt P E T/ C T, I nteri m C T sca ns after 3 
c ycles, P ost treat me nt P E T/ C T 8 wee ks after 
treat me nt c o m pleti o n.  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

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T A B L E O F C O N T E N T S 
 
1. 0   
I N T R O D U C TI O N   
 
1. 1  Diff use Lar ge B- Cell L y m p h o ma   
1. 1. 1  PI 3 K p at h wa y a n d i m p orta nce i n l y m p h oi d mali g n anc y 
1. 1. 2  St u dies t o s u p p ort t he use of PI 3 K i n hi bit ors 
1. 1. 3  Use of PI 3 K i n D L B C L 
1. 2  M E- 4 0 1  
1. 3  R- C H O P 
  
1. 4  Rati o nale  
 
 
1. 5  Bac k gr o u n d a n d rati o nale of c orrelati ve st u di es  
 
2. 0 
O B J E C TI V E S A N D E N D P OI N T S 
2. 1 P hase I  
2. 1. 1  Pri mar y O bjecti ve 
2. 1. 2  Pri mar y E n d p oi nt 
2. 1. 3  Sec o n dar y O bj ecti ve 
2. 1. 4  Sec o n dar y E n d p oi nts  
 
2. 2 P hase II 
2. 2. 1  Pri mar y O bjecti ve 
2. 2. 2  Pri mar y E n d p oi nt 
2. 2. 3  Sec o n dar y O bj ecti ve 
2. 2. 4  Sec o n dar y E n d p oi nts 
2. 3 C orrelati ves 
2. 3. 1 C orrelati ve O bjecti ve 
2. 3. 2 C orrelati ve E n d p oi nt 
 
3. 0  
S T U D Y D E SI G N 
3. 1 St u d y Desi g n I ncl u di n g D ose Escalati o n/ C o h orts 
3. 2 
N u m ber of Partici pa nts 
3. 3 Re place me nt of Partici pa nts 
3. 4 E x pecte d D urati o n of Tr eat me nt a n d Partici pati o n   
 
 
3. 4. 1 D urati o n of Tr eat m e nt 
  
3. 4. 2 D urati o n of F oll o w U p 
 
4. 0   
P A R TI CI P A N T S E L E C TI O N 
4. 1 I n cl usi o n Criteria 
4. 2  E xcl usi o n Criteria 
4. 3 I n cl usi o n of W o me n a n d Mi n orities 
 
5. 0  
R E GI S T R A TI O N  
  
 
6. 0   
T R E A T M E N T P L A N 
6. 1 Treat me nt A d mi nistrati o n  
6. 2 P hase I D ose Es calati o n  
6. 3  Defi niti o n of D ose Li miti n g T o xicit y 

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6. 4  
Ge ner al C o nc o mita nt Me dicati o ns a n d S u p p orti ve Care G ui deli nes 
6. 5 Criteria f or Re m o val fr o m St u d y 
6. 6 
D urati o n of F oll o w- U p 
 
7. 0  
D O S E D E L A Y S / D O S E M O DI FI C A TI O N S 
 
8. 0  
A D V E R S E E V E N T S A N D P O T E N TI A L RI S K S 
8. 1   
A d verse E v e nts a n d P ote ntial Ris ks 
8. 2  
Defi niti o ns 
8. 3  
Seri o us A d verse E v e nt Re p ort F or m 
8. 4  
Re p orti n g Pr oce d ures f or Seri o us A d verse E v e nt  
8. 5  
Seri o us A d verse E v e nts a n d O n C ore T M     
8 . 6  
Data Safet y T o xi cit y C o m mittee 
8. 7  
Data a n d Saf et y M o nit ori n g Pla n 
 
9. 0  
P H A R M A C E U TI C A L I N F O R M A TI O N  
9. 1  
M E- 4 0 1 
 
9. 2  
C ycl o p h os p ha mi de 
9. 3  
D o x or u bici n 
9. 4  
Pe gfil grasti m 
9. 6  
Pre d nis o ne 
9. 7  
Rit u xi ma b 
9. 8  
Vi ncristi ne 
9. 9  
Tri met h o pri m/s ulfa met h o xaz ole ( T M P- S M X) 
9. 1 0 
Pe nta mi di ne (aer os olize d) 
9. 1 1 
Ac ycl o vir 
 
1 0. 0 
C O R R E L A TI V E  
1 0. 1  
M olec ular S u bt y pi n g  
 
1 1 . 0 
S T U D Y P A R A M E T E R S A N D C A L E N D A R 
1 1. 1 
St u d y Para meters 
1 1. 2 
Cale n dar 
 
1 2. 0 
R E S P O N S E A S S E S S M E N T 
1 2. 1 
Defi niti o ns 
  
1 2. 1. 1     Pr o gressi o n Fr ee S ur vi val 
 
1 2. 1. 2     O verall Res p o nse Rate 
 
1 2. 1. 3     C o m plete Res p o nse Rate 
 
1 2. 1. 4     Partial Res p o nse Rate 
 
1 2. 1. 5     D urati o n of Res p o nse 
 
1 2. 1. 6     O verall S ur vi val 
 
1 2. 1. 7     Ti me t o Treat m e nt Fail ure  
  
1 2. 2   Res p o nse Re vie w 
 
 

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1 3 . 0 
R E C O R D S T O B E K E P T/ R E G U L A T O R Y C O N SI D E R A TI O N S 
1 3. 1 
Data Re p orti n g 
1 3. 2 
Re g ulat or y C o nsi derati o ns  
  
 
1 4. 0 
S T A TI S TI C A L C O N SI D E R A TI O N S 
 
1 5. 0 R E F E R E N C E S 
 
  
A P P E N DI C E S  
  
 
A P P E N DI X A 
E C O G  
 
A P P E N DI X B 
Partici pa nt Pill Diar y 
 
A P P E N DI X C 
L u ga n o Classificati o n 
 
A P P E N DI X D 
List of C Y P 2 C 8 I n hi bit ors a n d I n d ucers 
 
A P P E N DI X E 
List of Dr u gs K n o w n t o Pr ol o n g Q T/ Q Tc I nter v al  
 
 
  
 
 

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1. 0   
I N T R O D U C TI O N 
 
1. 1  
B ac k gr o u n d  
Diff use lar g e B-cell l y m p h o ma ( D L B C L) is t he m ost c o m m o n t y pe of l y m p h o ma.  
Rit u xi ma b- C H O P c ures a hi g h perce nta ge of D L B C L, 1- 3 b ut u p t o 4 0 % rela pse.  T he 1 
ye ar pr o gressi o n fr ee s ur vi val ( P F S) ca n ra n ge 5 5- 8 5 % de pe n di n g o n t he p atie nt 
p o p ulati o n 1, 2, 6, 1 5. T he sta n dar d of care f or r ela pse d/refract or y (r/r) D L B C L is sec o n d li ne 
c he m ot hera p y f oll o we d b y a ut ol o g o us ste m cell tra ns pla ntati o n ( A S C T) 8. H o we ver, a 
su bset of tra ns pla nt eli gi ble patie nts d oes n ot q ualif y f or t he pr o ce d ur e d ue t o lac k of 
res p o nse t o or disease pr o gressi o n d uri n g sec o n d li ne t hera p y.  I n s o me st u dies, o nl y 5 0 % 
of patie nts c o ul d pr ocee d t o tra ns pla nt 5.  A d diti o nall y, t he rela pse rate after tra ns pla nt is 
ne arl y 4 0- 5 0 % as see n i n t he l o n g ter m a nal ysis of t he P RI M A trial 9.  C hi meric a nti ge n 
rece pt or ( C A R) T t her a p y was rece ntl y a p pr o v e d f or r/r D L B C L after t w o or m ore li nes 
of s yste mic t hera p y.  O bj ecti ve res p o ns e rat e ar e hi g h at 7 2 % a n d C R of 5 1 % 4.   
H o we ver, n ot all patie nts are eli gi ble f or C A R T t hera p y a n d we are a waiti n g l o n g-ter m 
data.  Patie nts w h o ar e i neli gi ble f or or r ela pse aft er A S C T or C A R T t hera p y ha ve n o 
l o n g-ter m eff ecti ve tr eat me nt o pti o ns a n d t his re mai ns a n u n met me dical nee d wit h n o 
a p pr o ve d or st a n dar d t hera p y.   Ma na g e me nt of p atie nts wit h pri mar y refract or y disease 
is a n ot her c halle n g e as t h e res p o nse rate t o sal va g e c he m ot hera p y i n t his p o p ulati o n is 
l o w at < 3 0 % 8, 1 6.  I m pr o vi n g t he res p o nse a n d rela pse rate t o u pfr o nt treat m e nt is m uc h 
ne e de d.   
 
I n hi bit ors of p h os p h ati d yli n osit ol 3 ki nases ( PI 3 K) ha ve si g nifica nt acti vit y i n 
l y m p h o ma. Fe w trials ha ve e x pl ore d t heir use i n a g gressi ve l y m p h o mas.  We pr o p ose a 
p hase I st u d y of M E- 4 0 1 a n d R C H O P  t o treat ne wl y dia g n ose d D L B C L.  Cli nical data 
s h ow t he effici e nc y of PI 3 K i n hi bit ors i n rela pse d/refr act or y (r/r) C L L a n d f ollic ular 
l y m p h o ma 1 7- 1 9.  Precli nical data s u g gest PI 3 K i n hi bit ors are effecti ve at pr o d uci n g cell 
d eat h i n D L B C L 2 0, 2 1.  Si n gle a ge nt PI 3 K i n hi bit ors ha ve bee n st u die d i n r/r D L B C L wit h 
va ria ble r es ults 2 2- 2 4. 
 
1. 1 . 1  PI 3 K p at h wa y a n d i m p orta nce i n l y m p h oi d mali g na nc y 
 
P h os p hati d yli n osit ol 3 ki nases ( PI 3 K) are h eter o di meric ez y m es t hat me diate 
si g nals fr o m cell s urface rece pt ors t o re g ulate t h e pr otei n s y nt hesis, ge ne tr a nscri pti o n, 
cell gr o wt h a n d m otilit y 2 5, 2 6.  T here are 4 cl asses of PI 3 K e nz y mes wit h class I is of or ms 
α , -β , -γ a n d -δ  bei n g t he m ost wi del y i m plicate d i n ne o plasia 2 5, 2 7.  PI 3 Ks are acti vat e d 
b y  t yr osi ne ki nases or g pr otei n c o u ple d r ece pt ors.  T he pat h wa y res ults i n 
p h os p h or ylati o n of p h os p hati d yli n osit ol 4, 5- bis p h os p hate ( PI P 2) t o p h os p hati d yli n osit ol 
( 3, 4, 5) – tri p h os p hate ( PI P 3) t hat lea ds t o acti vati o n of A K T, m T O R, a n d n uclear fact or 
ka p pa B ( N F- k B) pat h w a ys.   T his i n t ur n lea ds t o cell s ur vi val, pr olifer ati o n, a n d 
i m m u ne re g ulati o n 2 5, 2 8.  T he PI 3 K pat h wa y is d er e g ulate d i n ma n y mali g na ncies a n d ca n 
res ult i n o nc o ge nic tra nsf or mati o n 2 5, 2 7.   I n partic ular, t he PI 3 Kδ  is of or m is i m p orta nt i n 
he m at ol o gic mali g na ncies as it is hi g hl y e x presse d i n l y m p h oc ytes a n d l y m p h oi d tiss ue 
2 7.    
A n ot her tri g ger f or PI 3 K/ A K T pat h wa y acti vati o n is t he l oss of t u m or 
s u p pressi o n pr otei n P T E N, w hic h s u p presses t his pat h wa y a n d its d o w nstrea m tar gets 1 5.  

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I n c o ntrast t o PI 3 K, P T E N hel ps t o ge ner ate PI P 2 b y h y dr ol yzes of 3- p h os p hate a n d its 
a bse nce l ea ds t o i ncr ease d le vels of PI P 3 1 1.  P T E N is ofte n m utate d or sile nce d i n 
m ali g na nc y 2 8, 2 9.  I n D B L C L, a berr a nt PI 3 K si g nali n g a n d P T E N deleti o ns or m utati o ns 
are oft e n o bser v e d 2 1, 2 5, 3 0.   
 
  
Rece ntl y, Sc h mi dz et al. a n d C ha p u y et al. use d a d va nce d m olec ular testi n g ( via 
ne xt ge nerati o n se q ue n ci n g a n d R N A se q ue nci n g) t o s u b classif y D L B C L 1 3, 1 4.  C ha p u y et 
al. f o u n d fi ve r o b ust D L B C L s u bsets t hat pre dicte d o utc o me i n de pe n de nt of t he cli nical 
I nter nati o nal Pr o g n ostic I n de x 1 3.  T he s u bsets als o s u g geste d p ossi ble treat me nt strate gies.  
F o r e xa m ple, t h ose wit h cl uster 4 s u bt y pe ofte n ha ve alter n ati o ns i n PI 3 K a n d/ or P T E N 
pat h wa ys.  T h us, we h y p ot hesize t hat t hese patie nts ma y ha ve a better res p o nse t o M E- 4 0 1.   
 
 
1. 1. 2  St u dies t o s u p p ort t he use of PI 3 K i n hi bit ors 
  
 
  
T here are t hr ee F D A a p pr o ve d PI 3 K i n hi bit ors (i delalisi b, d u velisi b, a n d 
c o pa nlisi b) t o treat l y m p h oi d mali g na ncies i ncl u di n g rela pse d/refract or y f ollic ular B-cell 
n o n- H o d g ki ns l y m p h o ma, S L L, a n d C L L.  PI 3 K i n hi bit ors ha ve n ot bee n a p pr o ve d i n 
t he fr o nt li ne setti n g or f or D L B C L.  
 
I d elalisi b is a p ote nt, oral, selecti ve s mall m olec ul e i n hi bit or of PI 3 Kδ  a n d is 
a p pr o ve d f or i n d ole nt n o n- H o d g ki n’s l y m p h o ma (i N H L) a n d C L L treat me nt 1 9, 3 1. I n a 
p h ase II st u d y of 1 2 5 p atie nts wit h i N H L refract or y t o Rit u xi ma b or a n al k ylati n g a ge nt, 
i delalisi b 1 5 0 m g t wice dail y s h o we d a n o verall res p o nse rate of 5 7 %.  T he safet y pr ofile 
was acce pta ble wit h t he m ost c o m m o n gra de 3 or hi g her a d verse e v e nts bei n g 
ne utr o pe nia ( 2 7 % of pati e nts), ele vat e d a mi n otra nsferas e le vels ( 1 3 %), diarr hea ( 1 3 %), 
a n d p ne u m o nia ( 7 %) 1 9.  I delalsi b was st u die d i n c o m bi nati o n wit h Rit u xi ma b, 
b en da m usti ne, or b ot h i n a p hase I st u d y if 7 9 p atie nts wit h r/r i N H L.  O ver all res p o nse 
rates were 7 5 %, 8 8 %, a n d 7 9 % res pecti vel y.  T he m ost c o m m o n gra de 3 or hi g her 
a d verse e ve nts were n e utr o pe nia ( 4 1 %), p ne u m o nia ( 1 9 %), tr a nsa mi nase ele vati o n 
( 1 6 %), diarr hea/ c olitis ( 1 5 %) a n d r as h ( 9 %) 3 2.  P hase III st u dies wer e p urs ue d t o 
i nvesti gate t hese c o m bi n ati o ns h o we ver ter mi nate d d ue t o i ncreas e d deat h rates a n d 
a d verse e ve nts i n t he treat me nt ar ms.    
 
D u velisi b (I PI- 1 4 5), a hi g hl y selecti ve a n d p ote nt oral i n hi bit or of δ  a n d γ PI 3 K 
is of or ms, has acti vit y i n b ot h B a n d T cell l y m p h o ma.  I n a p has e I st u d y of d u velisi b i n 
a d va nce d he mat ol o gic m ali g na ncies, 3 1 patie nts u n der we nt t he d os e escalati o n p hase 
recei vi n g 8- 1 0 0 m g t wice dail y wit h a ma xi m u m t olerate d d ose ( M T D) of 7 5 m g BI D.  I n 
t he e x pa nsi o n p hase, 3 1 patie nts wit h rela pse d or refr act or y i N H L recei ve d d u velisi b 
2 5 m g or 7 5 m g wit h a n O R R of 5 8 % a n d 6 C Rs 1 8.  Gra de 3 or hi g her a d verse e ve nts 
oc c urr e d i n 8 4 % of p atie nts a n d i ncl u de d ne utr o p e nia ( 3 2 %), ala ni ne tr a ns a mi nase 
i ncreas e ( 2 0 %), as part ate tra nsa mi nase i ncreas e ( 1 5 %), a ne mia a n d t hr o m b oc yt o pe nia 
(eac h 1 4 %), diarr hea ( 1 1 %), a n d p ne u m o nia ( 1 0 %).  Ulti matel y, d u velisi b 2 5 m g BI D w as 
selecte d f or f urt her cli nical de vel o p me nt 3 3, 3 4.  A p hase II st u d y e v al uati n g d u velisi b as 
m o n ot hera p y f or i N H L h as cl ose d a n d res ults ha v e bee n s u b mitte d b ut n ot yet re p orte d 
( N C T 0 1 8 8 2 8 0 3).  A p has e I b st u d y of d u velisi b i n c o m bi nati o n wit h rit u xi ma b or 

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rit u xi ma b pl us be n da m usti ne f or r/r he m at ol o gic mali g na ncies was c o m plete d b ut res ults 
ha ve n ot bee n re p ort ( N C T 0 1 8 7 1 6 7 5). Precli nical m o dels ha ve bee n us e d t o st u d y 
d u velisi b i n c o m bi nati o n wit h ot her a ge nts a n d h a ve s h o w n d u velisi b wit h ster oi ds is 
m ore eff ecti ve t ha n si n gl e a ge nt treat me nt 3 5.   
C o pa nlisi b is a pa n-class I PI 3 K i n hi bit or wit h greatest affi nit y f or t he α  a n d δ  
is of or ms.  I n a p hase II st u d y, 1 4 2 patie nts wit h rela pse d or r efr act or y i N H L recei v e d 
i ntra ve n o us c o pa nlisi b.  T he O R R was 5 9 % a n d 1 2 % of patie nts ac hi e ve d a C R.  Gra de 3 
or hi g her t o xicities i ncl u de d tra nsie nt h y per gl y ce mia ( 4 1 %), tra nsie nt h y p erte nsi o n 
( 2 4 %), ne utr o p e nia ( 2 4 %), a n d l u n g i nfecti o n ( 1 5 %) 3 6.   
 
M E - 4 0 1 ( Z a n delisi b), a hi g hl y selecti ve i n hi bit or or PI 3 Kδ  t hat has n ot yet bee n 
F D A a p pr o ve d b ut s h o ws pr o misi n g cli nical acti vit y a n d a p hase II st u d y is o n g oi n g t o 
s u p p ort accelerat e d a p pr o val ( N C T 0 3 7 6 8 5 0 5).   It has bee n st u die d i n a p h ase 1 b d ose 
escalati o n trial f or patie nts wit h r/r f ollic ular l y m p h o ma or C L L/ S L L.   M E- 4 0 1 was 
gi ve n dail y o n da ys 1- 2 8 of a 2 8- da y c ycle.  Of t he 3 1 patie nts e nr olle d, 2 1 ha d f ollic ular 
l y m p h o ma wit h a n O R R of 7 5 % a n d 9 patie nts ha d C L L/ S L L wit h a n O R R of 1 0 0 %.  
Fi ve patie nts disc o nti n ue d M E- 4 0 1 d ue t o a d verse e ve nts.  T he m ost c o m m o n gra de 3 or 
hi g her a d verse e v e nts were ras h ( 2 6 %), diarr hea ( 1 6 %), ne utr o p e nia ( 1 0 %), ele vate d 
tra nsa mi nases ( 6 %), c olitis ( 6 %), a n d st o matitis ( 3 %) 1 0.  N o D L Ts were r e p orte d a n d 
ba se d o n P K data, t he l o west d ose, 6 0 m g, was c h ose n as t he rec o m me n d d ose m o vi n g 
f or war d 1 0.   
 
  
T he p hase 1 b e x pa n de d t o i ncl u de t w o a d diti o nal gr o u ps of patie nts w h o r ecei ve d 
c o m bi nati o n Rit u xi ma b a n d M E- 4 0 1 o n eit her a c o nti n u o us ( C S) or i nter mitte nt (I S) 
d osi n g sc he d ule.   T he i nter mitte nt d osi n g sc he d ule of M E- 4 0 1 ( d ail y f or 2 8 da ys f or 2 
c ycles t he n c h a n ge d t o d a ys 1- 7 e ver y 2 8 da ys wit h s u bse q ue nt c ycles) was ass ociate d 
wit h a l o wer r ate of gr a d e 3 A Es a n d w hile mai nt ai ni n g a si milar res p o nse rate.  All 
dela ye d gr a de 3 A Es of i nterest o n I S occ urre d wit hi n 1- 2 c ycles of s witc hi n g fr o m C S t o 
I S, s u g gesti n g t hat t hese mi g ht ha ve re pr ese nte d a dela ye d effect of dail y d osi n g 1 2.  A n 
u p date of t he f ollic ular l y m p h o ma c o h ort i n t he p hase I b trial w as pres e nte d at A S C O 
2 0 1 9 a n d t he I nter n al C o nfere n ce o n Mali g na nt L y m p h o ma 2 0 1 9.  A t otal of 4 8 patie nts 
wit h F L wer e treate d.  T we nt y disc o nti n ue d t hera p y: 9 f or pr o gressi o n of disease, 4 f or 
A Es, 4 wit h dre w c o ns e nt, a n d 3 f or A S C T.  Dela y e d (aft er c y cle 2) gr a de 3 i m m u ne 
relate d A Es (ir A Es) w er e see n i n 9/ 3 0 ( 3 0 %) p atie nts o n C S wit h t he m ost c o m m o n 
ir A Es bei n g diarr h ea/c olitis a n d ras h.  Si x patie nts wit h A Es were a ble t o res u me M E- 4 0 1 
o n I S wit h o ut rec urr e nce of A Es after a dr u g h oli d a y a n d ster oi ds.  Res p o ns e rates 
re mai ne d hi g h wit h o bjecti ve res p o nses see n i n 3 4/ 4 3 ( 7 9 %) patie nts.  T he st u d y als o 
s h o we d t hat pr o gr essi o n of disease o n I S c o ul d b e sal va ge d b y r e verti n g t o C S.  Of 3 8 
patie nts s witc he d t o I S, 3 3 ( 8 7 %) r e mai n o n t hera p y ( me dia n: 1 4. 5 m o nt hs), 2 6 o n I S a n d 
w h o s witc he d bac k t o C S d ue t o P O D 3 7- 3 9.  
 
 
1. 1. 3   Use of PI 3 K i n D L B C L 
 
W hile PI 3 K i n hi bit ors ha ve n ot be a p pr o v e d f or us e i n patie nts wit h D L B C L, 
se veral st u dies ha v e/ar e e val uati n g t heir r ole i n t he treat me nt of D L B C L.  I n a p hase I 

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stu d y e val uati n g t he use of i delasi b i n r/r he mat ol o gic mali g na ncies, 9 pati e nts wit h 
D L B C L were e nr olle d a n d n o res p o nse t o si n gle a ge nt treat me nt was o bs er ve d 2 2.  A 
p h ase II st u d y e v al uati n g c o pa nlisi b f or treat me nt of r/r D L B C L has bee n c o m plete d b ut 
f ull res ults ha ve n ot bee n p u blis he d.  Preli mi nar y data s h o ws O R R of 2 5 % ( 1 0 of 4 0) a n d 
C R, P R, a n d sta ble disease i n 5, 5, a n d 1 2 patie nts res pecti vel y.  T his st u d y s h o we d t hat 
res p o nse r ates were hi g h er i n A B C s u bt y pe vers us G C B s u bt y pe ( O R R 3 7. 5 % vers us 
1 3. 6 %) 2 3.  B u parlisi b is a pa n-class I PI 3 K i n hi bit or t hat was e v al uate d i n a p hase II st u d y 
f or t he treat me nt of r/r n o n- H o d g ki n l y m p h o ma.  Of t he 7 2 patie nts e nr olle d, 2 6 patie nts 
ha d D L B C L.  T he o ver all res p o nse rat e f or t h ose wit h D L B C L was 1 1. 5 % 2 4.   
 
1. 2   
M E- 4 0 1 
 
1. 2. 1  Precli nical Data  
M E- 4 0 1 (f or merl y referr e d t o as P W T- 1 4 3) is a n o vel, selecti ve PI 3 K δ  i n hi bit or wit h a n 
I C 50 of 0. 6 n M i n cell ular assa ys, a n d a m olec ular wei g ht of 5 7 6. 6 8.  M E- 4 0 1 has 
e x hi bite d si g nifica nt acti vit y a gai nst se veral h u ma n cell li nes a n d pri mar y p atie nt deri ve d 
t u m or cell sa m ples of vari o us he mat ol o gical mali g na ncies i n precli nical st u dies. T he 
acti vit y was si milar t o or i n ma n y cases gr eater t ha n t he res ults o btai ne d wit h eit her 
i delalisi b or i br uti ni b 4 0.    
 
Pr ecli nical saf et y st u dies de m o nstrate d t hat t he d o g was t he m ore s e nsiti ve s pecies wit h a 
n o o bser ve d a d v erse eff ect le vel ( N O A E L) of 3 m g/ k g/ da y i n 2 8- da y re p eat d ose st u dies. 
T he c o m bi ne d-se x m ea n C ma x a n d A U C 0- 2 4 hr v al ues f or M E- 4 0 1 o n Da y 2 8 at t his 
N O A E L were 1 7 5 n g/ m L a n d 1 7 4 0 hr * n g/ m L, res pecti vel y. T he t o xicit y o bser ve d at t he 
hi g hest d ose ( 1 0 m g/ k g/ da y) i n t he d o g saf et y st u dies i ncl u de d i ncreases i n 
tra nsa mi nases, Q T c pr ol o n gati o n, a n d de pleti o n of l y m p h oc ytes. Q Tc pr ol o n gati o n 
occ urr e d o n Da y 2 8, b ut n ot at t he Da y 1 p ost- d os e i nter val, w hic h m ost li kel y reflects 
dr u g acc u m ulati o n a n d hi g her plas ma M E- 4 0 1 c o n ce ntrati o ns. T he c o m bi ne d-se x mea n 
C ma x a n d A U C 0- 2 4 hr v al ues f or M E- 4 0 1 o n Da y 1 at 1 0 m g/ k g were 4 9 8 n g/ ml a n d 
6, 3 7 0 hr * n g/ ml, res pecti vel y, w hile o n Da y 2 8 t h e y wer e 1, 8 3 0 n g/ ml a n d 3 5, 4 0 0 
hr * n g/ ml, res pecti vel y 4 0, 4 1. 
 
 
1 . 2. 2 
Cli nical Data 
Refer t o secti o n 1. 1. 3 
 
1. 2. 3 
Cli nical P har mac o ki netics  
A si n gle d ose st u d y of M E- 4 0 1 acr oss a ra n g e of d ose le vels fr o m 1 0 m g t o 1 5 0 m g was 
c o n d ucte d i n t he U nite d Ki n g d o m i n n or mal healt h y v ol u nteers. T he pri mar y g oals wer e 
t o: 1) esta blis h bi oa vaila bilit y a n d preli mi nar y p har mac o ki netics ( P K); 2) assess t he 
i m pact of M E- 4 0 1 o n t he sta n dar d bi o mar ker assa y f or PI 3 Kδ  i n hi biti o n, s pecificall y 
i n hi biti o n of bas o p hil acti vati o n ( B A T) assesse d b y fl o w-c yt o metr y f or C D 6 3 e x pressi o n; 
a n d 3) assess cli nical saf et y. N o S A Es, se ver e A Es, A Es lea di n g t o deat h, or A Es lea di n g 
t o M E- 4 0 1 wit h dra wal w ere n ote d i n t he st u d y 4 1, 4 2.  
 
T h e P K res ults ca n b e s u m marize d as f oll o ws: b ot h C ma x a n d A U C ( 0 –last) 

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de m o nstrate d li near i n creases o ver t he d ose r a n ge of 1 0 m g t o 1 5 0 m g. T he mea n T 1/ 2 
f or M E- 4 0 1 w as 2 8- 2 9 h o urs fr o m 3 0- 1 5 0 m g, a n d a p pear e d d ose-i n d e pe n de nt. Plas ma 
le vels at later ti me p oi nts after t he 1 0 m g d ose wer e bel o w t he li mit of q ua ntitati o n, 
w hic h ma y be r es p o nsi ble f or t he see mi n gl y l o wer half-life at t hat d os e le vel 4 1, 4 2.  
T o  assess t he o n-tar get p har mac o d y n a mic effect of M E- 4 0 1, i n hi biti o n of PI 3 K si g nali n g 
i n peri p heral bl o o d bas o p hils was meas ure d via a p har mac o d y n a mic assa y ( bas o p hil 
acti vati o n test M EI P har ma I n c. Pr ot oc ol: M E- 4 0 1- 0 0 2 A me n d me nt 8 [ B A T]), w hic h 
meas ure d b as o p hil acti vati o n via C D 6 3 u pre g ulati o n f oll o wi n g e x- vi v o sti m ulati o n wit h 
a n a nti- F C εR 1 m o n ocl o n al a nti b o d y 4 1, 4 2.  
 
T h e B A T res ults f or M E- 4 0 1 clearl y de m o nstr ate t he bi ol o gic p ote nc y of M E- 4 0 1. Fr o m 
t he fitte d E ma x m o del, t he c o nce ntrati o ns of M E- 4 0 1 esti mate d t o gi ve 5 0 % a n d 9 0 % 
B A T i n hi biti o n (i.e., E C 5 0 a n d E C 9 0) of t he ma xi m u m effect ( E ma x 9 1. 6 %) were 0. 6 
n g/ ml a n d 5. 2 n g/ m L, res pecti vel y 4 1, 4 2.  
 
Ba se d o n t he B A T i n hi biti o n res ults, t he starti n g d ose le vel ( 6 0 m g) s h o ul d de m o nstrate 
cli nical acti vit y.   T he 6 0 m g d ose has bee n i de ntifie d as t he Rec o m me n d e d P hase 2 D ose 
( R P 2 D) o n t he basis of a hi g h res p o nse rat e, acce pta ble t o xicit y, a n d plas ma 
c o nce ntr ati o ns well a b o v e t he E C 9 0 of t he B A T i n healt h y v ol u nteers.   After c o m plet e 
e val uati o n of t he P K of t he 6 0, 1 2 0, a n d 1 8 0 m g d oses, a n d esti mati o n of t he P K 
para meters e x pecte d fr o m a 4 5 m g d ose, s u g gest s u b- o pti mal plas ma c o nce ntrati o ns (i.e., 
C mi n  c o nce ntrati o n of < 5 n g/ ml).   Gi ve n t his a n d t he a d diti o n of c he m ot her a p y i n t his 
stu d y, t he starti n g d ose will be 6 0 m g b ut a s h orte n ti me c o urse ( da ys 1- 4) wit h g oal d ose 
of 6 0 m g o n da ys 1- 7 of a 2 1 da y c y cle 4 1, 4 2.   
 
1. 3    
R- C H O P C he m ot her a p y 
C y cl o p h os p ha mi de, d o x or u bici n, vi ncristi ne a n d pre d nis o ne ( C H O P) h a ve bee n t he 
mai nsta y of treat me nt f or patie nts wit h a d va nce d sta ge D L B C L si nce its de vel o p me nt i n 
1 9 7 0s. A milest o ne p hase III tri al f o u n d t hat c o m ple x re gi me ns a d di n g ot h er 
c he m ot hera p y a ge nts t o C H O P, (i.e. m- B A C O D; Pr o M A C E- C yta B O M, a n d M A C O P- B) 
di d n ot de m o nstrate a n y si g nifica nt be nefit i n o verall s ur vi val ( O S), diseas e-fr ee s ur vi val 
( D F S), or re missi o n rate o ver C H O P 4 3. T he de vel o p me nt of rit u xi ma b – a m o n ocl o nal 
a nti b o d y tar geti n g t o C D 2 0 le d t o c o m bi ni n g t his a ge nt wit h c he m ot her a p y ( R- C H O P) 1, 2.  
 
1. 3 . 1 
Precli nical Data 
Rit u xi ma b is a ge neticall y e n gi neer e d, c hi meric m uri ne/ h u ma n m o n ocl o nal  
a nti b o d y directe d a g ai nst t he C D 2 0 a nti ge n f o u n d o n t he s urface of n or mal a n d mali g na nt 
pre- B a n d mat ur e B cells. T he a nti b o d y is a n I g G 1 κ  i m m u n o gl o b uli n c o ntai ni n g m uri ne 
li ght-a n d hea v y- c hai n varia ble re gi o n se q u e nces a n d h u ma n c o nsta nt re gi o n se q ue nces. 
Rit u xi ma b is c o m p ose d of t w o hea v y c hai ns of 4 5 1 a mi n o aci ds a n d t w o li g ht c hai ns of 
2 1 3 a mi n o aci ds ( base d o n c D N A a n al ysis) a n d has a n a p pr o xi mate m olec ular mass of 
1 4 5 k D. Rit u xi ma b has a bi n di n g affi nit y f or t he C D 2 0 a nti ge n of ~ 8. 0 n M. T here are a 
n u m ber of precli nical st u dies w hic h s u g gest t hat rit u xi ma b e xerts its t hera p e utic eff ect b y 
s o me c o m bi nati o n of a nti b o d y- de pe n de nt cell- me diate d c yt ot o xicit y ( A D C C), 
c o m ple me nt a n d/ or direct cell l ysis 4 4. Deter mi ni n g t he e xact mec ha nis m of rit u xi ma b is 
an  acti ve area of r esearc h.  

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1. 3 . 2 
Cli nical Data 
Se veral se mi nal st u dies d e m o nstrate d t hat t he o ver all s ur vi val of patie nts wit h D L B C L is 
i m pr o ve d w he n rit u xi ma b is a d de d t o C H O P 1, 2, 4 5. Sta n dar d d osi n g or R- C H O P is 3 7 5 
m g / m2 rit u xi ma b, 7 5 0 m g/ m2 c ycl o p h os p ha mi de, 5 0 m g/ m 2 d o x or u bici n, a n d 1. 4 m g/ m 2 
(ca p pe d at 2 m g) vi ncristi ne all gi ve n i ntra ve n o usl y o n da ys 1 a n d 1 0 0 m g pre d nis o ne 
gi ve n orall y o n da ys 1 – 5 e ver y 2 1 da ys f or 6 c y cles.  
 
1. 3. 3  
Cli nical P har mac o ki netics 
Rit u xi ma b li kel y acts s y ner gisticall y wit h c he m ot hera p y, i n w hic h case h a vi n g 
t hera pe utic le v els of rit u xi ma b t hr o u g h o ut all c ycles of t hera p y s h o ul d be be neficial. 
P har mac o ki netic st u dies of rit u xi ma b use d i n R- C H O P- 1 4 sc he d ule s h o w e d t hat 
rit u xi ma b le vels rise sl o wl y a n d a platea u is attai ne d o nl y after 5 c ycles 4 6. Base d o n t his 
o b ser vati o n, t he Ger ma n Hi g h Gra de N H L St u d y Gr o u p ( D S H N H L) e v al uate d t he 
be nefit of i nte nsif yi n g t h e rit u xi ma b d osi n g. T his c o nce pt w as c o m bi ne d wit h d ose 
i nte nsificati o n of c he m ot hera p y ( R- C H O P- 1 4). I n t he earl y p has e of t his D E N S E R-
C H O P trial, i ncrease d i nf ecti o us e ve nts occ urr e d, b ut wit h i ncrease d s u p p orti ve car e i n 
ter ms of pr o p h ylactic a nti micr o bials a n d P E G- fil grasti m t he re gi me n was felt t o be safe 
a n d eff ecti ve 4 7. N o net heless, t his a p pr oac h has n ot bee n ge nerall y a d o pte d. T his li kel y 
reflects t he a bse n ce of d ata o n its be nefit, as well as t he nee d f or e xte nsi ve a nti micr o bial 
pr o p h yla xis a n d gr o wt h f act or s u p p ort, as w ell as o bser ve d a n d p ot e ntial e xcess t o xicit y 
of t he 1 4 da y sc h e d ule.  
 
 
1. 5  
R ati o n ale  
As disc usse d a b o ve, ne wl y dia g n ose d D L B C L is treate d wit h R- C H O P b ut u p t o 4 0 % 
rela pse 1- 3.  After rela pse treat me nt o pti o ns are li mite d t o i nte nsi ve c he m ot hera p y, 
tra ns pla nt, or c hi meric a nti ge n rece pt or T t hera p y, all of w hic h are p ote ntiall y t o xic a n d 
s o me patie nts ar e n ot eli gi ble f or s uc h t h era pi es 4- 9.  I m pr o vi n g t he c ur e rat e i n t he u pfr o nt 
setti n g i n or der t o li mit t he nee d f or s uc h t hera pies is a desira ble g oal.   
 
T he acti vati o n of p h os p h ati d yli n osit ol 3- ki nase i n hi bit ors ( PI 3 Kis) ulti mat el y lea ds t o cell 
s ur vi val, pr oliferati o n, a n d i m m u ne re g ulati o n.  M E- 4 0 1 is a hi g hl y selecti ve i n hi bit or of 
t he δ  is of or m of PI 3 K, a n d s h o ws pr o misi n g cli nical acti vity al o ne a n d i n c o m bi nati o n wit h 
rit u xi ma b i n t he treat me nt of i n d ole nt l y m p h o mas.  T he m ost c o m m o n gra de 3 or hi g her 
a d verse e v e nts ( A Es) see n i n p hase I trials are ras h, diarr hea, ne utr o p e nia, tra nsa mi nitis, 
c olitis, a n d st o matitis 1 0- 1 2.  T he i nci de nce a n d se v erit y of t hese A Es is si g nifica ntl y l o wer 
t ha n t hat see n wit h ot her PI 3 Kis.  As disc usse d a b o ve, t his is partic ularl y tr ue wit h 
i nter mitte nt d osi n g 3 7- 3 9. 
 
Ba se d o n precli nical r ati o nale a n d cli nical data of M E- 4 0 1 i n l y m p h oi d mali g na ncies, t he 
rela pse r ate wit h R- C H O P, a n d s h ortc o mi n gs of sec o n d li ne t hera pi es we pr o p ose a p has e 
I/II st u d y t o e val uate M E- 4 0 1 pl us R- C H O P i n ne wl y dia g n ose d D L B C L.  D osi n g a n d 
sc he d ule ar e deri ve d fr o m p hase I a n d P K st u dies.  T he R P 2 D f or si n gle a ge nt is 6 0 m g 1 0-
1 2 , 4 0 a n d P K data s u g gest s u b- o pti mal d osi n g e ve n at t he 4 5 m g d ose 4 0.  T heref or e we will 
start wit h 6 0 m g d ose b ut gi ve n f or a s h orter d urati o n ( da ys 1- 4 of 2 1 da y c ycle) wit h t he 
g oal of reac hi n g f ull i nter mitte nt d osi n g of da ys 1- 7 of 2 1 da y c ycle.  M E- 4 0 1 o n da ys 1- 7 

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as i nter mitte nt d osi n g ( da ys 1- 7 of 2 8 da y c ycl es) h as s h o w n t o decrease t o xi cit y a n d retai n 
efficac y c o m p are d t o c o nti n u o us d osi n g 1 1, 1 2, 4 0. 
 
1 . 6  
B ac k gr o u n d a n d r ati o n ale of c orrel ati ve st u dies 
 
C urre ntl y, D L B C L is gr o u pe d i nt o t w o gr o u ps b y cell o f ori gi n – acti vate d B cell ( A B C) 
a n d ger mi nal ce nter B cell 4 8.  It has bee n s h o w n t hat t h ose wit h A B C s u bt y pe ha ve w orse 
o u tc o mes. Rece ntl y, Sc h mi dz et al. a n d C ha p u y et al. use d a d va nce d m olec ular testi n g ( via 
ne xt ge ner ati o n se q ue n ci n g a n d R N A se q u e nci n g) t o f urt her s u b cl assif y D L B C L 1 3, 1 4.  
C h a p u y et al. f o u n d fi ve r o b ust D L B C L s u bsets t hat pre dict e d o utc o me i n de pe n de nt of t h e 
cli nical I nter n ati o nal Pr o g n ostic I n d e x 1 3.  T he s u bsets als o s u g geste d p ossi ble treat me nt 
strate gies.  F or e xa m ple, t h ose wit h cl uster 4 s u bt y pe ofte n ha ve alter nati o ns i n PI 3 K a n d/ or 
P T E N pat h wa ys.  T h us, we h y p ot hesize t hat t hese patie nts ma y ha ve a better res p o nse t o 
M E- 4 0 1.   
 
 
2. 0   
O B J E C TI V E S A N D E N D P OI N T S  
 
2. 1 P h ase I  
2. 1. 1  Pri mar y O bjecti ve 
•  T o deter mi ne t he r ec o m me n de d p hase 2 d os e ( R P 2 D) of M E- 4 0 1 i n 
c o m bi nati o n wit h R- C H O P f or partici pa nts wit h ne wl y dia g n ose d D L B C L.   
2. 1. 2  Pri mar y E n d p oi nt 
•  D ose li miti n g t o xicit y ( D L T) as defi n e d b y si g nifica nt gra d e 3 or 4 
treat me nt-r elate d A Es t h at are n ot a m e n da ble t o o pti mal s u p p orti ve care or 
he mat ol o gic gra de 3 or 4 treat me nt relat e d A Es t h at are cli nicall y si g nifica nt 
(as defi ne d i n s ecti o n 6. 3) d uri n g t he first c ycl e, gr a de d acc or di n g t o t he 
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d v erse 
E ve nts ( C T C A E), Versi o n 5. 0.     
2. 1. 3  Sec o n dar y O bj ecti ve 
•  T o descri be t oler a bilit y of M E- 4 0 1 i n c o m bi nati o n wit h R- C H O P f or 
partici pa nts wit h ne wl y dia g n ose d D L B C L.   
2. 1. 4  Sec o n dar y E n d p oi nts 
•  Treat me nt r elate d A Es, Treat me nt dela ys ( # da ys tr eat me nt is dela ye d)  
  
2. 2 P h ase II 
2. 2. 1  Pri mar y O bjecti ve 
•  T o esti mate t he cli nical acti vit y of M E- 4 0 1 i n c o m bi nati o n wit h R- C H O P 
i n partici pa nts wit h ne wl y dia g n ose d D L B C L, as meas ure d b y 1 year P F S 
rate 
2. 2. 2  Pri mar y E n d p oi nt 
•  Ti me fr o m st u d y treat me nt i nitiati o n t o pr o gressi o n free s ur vi val, as 
defi ne d as t he ti me fr o m first d ose t o d oc u me nte d disease pr o gr essi o n, 
or deat h fr o m a n y ca us e, w hic he ver o cc urs first 
 
 

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2. 2 . 3  Sec o n dar y O bj ecti ve 
•  T o esti mate t he res p o nse rates (c o m plete a n d partial re missi o n), d urati o n 
of res p o nse ( D O R), ti me t o pr o gressi o n ( T T P), a n d o verall s ur vi val ( O S) 
wit h M E- 4 0 1 pl us R- C H O P. 
•  T o c har acterize treat me nt-relate d A Es i n p artici p a nts treate d wit h M E-
4 0 1 pl us R- C H O P. 
2. 2. 4  Sec o n dar y E n d p oi nts 
•  Res p o nse ( o ver all, c o m plete, a n d partial) as defi ne d b y L u ga n o criteri a.   
•  D urati o n of Res p o nse d efi ne d as t he ti me fr o m d o c u me nte d res p o ns e ( C R or 
  
P R) t o t he ti me of c o nfir me d disease pr o gressi o n or deat h d ue t o a n y ca us e, 
  
w hic he ver o cc urs first 
•  O verall S ur vi val defi n e d as t he ti me fr o m first d os e of st u d y treat me nt t o 
     deat h fr o m a n y ca use 
•  Ti me t o Treat me nt Fail ur e defi ne d as t he ti me fr o m st u d y e ntr y t o a n y 
  
treat me nt fail ur e.  
•  Treat me nt r elate d A Es 
Please see secti o n 1 2. 1 f or f ull defi niti o ns 
 
2. 3 C orrel ati v es 
2. 3. 1 C orrelati ve O bjecti ve 
•  T o e x pl ore if t here is a n ass ociati o n bet wee n m olec ular s u bt y pi n g ( via n e xt 
ge nerati o n se q u e nci n g a n d R N A se q ue nci n g) of t u m or tiss ue a n d treat me nt 
res p o nse.  
2. 3. 2 C orrelati ve E n d p oi nt 
•  M olec ular s u bt y pe as defi ne d b y Sc h mitz et al. a n d C ha p u y et al. 
1 3, 1 4.  See 
secti o n 1 0. 0.  
 
 
3. 0  
St u d y Desi g n 
T he pr o p ose d st u d y is a m ulti-i nstit uti o n, o pe n-la bel, p hase I/II st u d y desi g ne d t o e val uat e 
t he safet y a n d effi cac y of R- C H O P  + M E- 4 0 1 f or partici pa nts ne wl y dia g n ose d D L B C L.  
 
3. 1   
St u d y desi g n i ncl u di n g d ose esc al ati o n  
P hase I 
•  M E- 4 0 1 6 0 m g will be gi ve n o n da ys 1- 4 ( d os e le vel 1) O R da ys 1- 7 ( d os e 
le vel 2) of a 2 1 d a y c y cle wit h sta n dar d d ose R- C H O P x 6 c ycles.   
•  D ose escalati o n will be perf or me d i n a sta n dar d 3 + 3 desi g n.  See st u d y 
sc he ma o n pa g e 7 a n d secti o n 6. 0 f or treat me nt pl a n, i ncl u di n g d ose 
escalati o n.  
 
P hase II  
•  M E- 4 0 1 at R P 2 D will be gi ve n wit h sta n d ar d d os e R- C H O P e v er y 2 1 da ys x 6 
c ycles.   
 
 
 

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3. 2   
N u m ber of P artici p a nts 
P hase I 
•  T he p hase 1 p orti o n will e nr oll 6- 1 2 partici pa nts 
P hase II 
•  T he p hase II p orti o n will e nr oll a n a d diti o nal 4 7 partici pa nts, f or a t otal of 5 4 
partici pa nts i n t he p hase II p orti o n of t he st u d y ( 6 fr o m t he p hase I p orti o n).  
Ass u mi n g 4 9 of t he 5 4 ar e n ot l ost t o f oll o w u p b y 1 year, t he st u d y will ha ve 
8 0 % p o wer t o det ect a n i m pr o ve me nt i n 1- year P F S fr o m 6 5 % t o 8 0 % usi n g a 
o ne sa m ple l o g-ra n k t est usi n g a o ne-si de d t y pe 1 err or of 5 %.  
 
3. 3  
Re pl ace m e nt of P artici p a nts 
•  If a partici pa nt is wit h dra w n fr o m t he P hase I d os e escalati o n c o h ort f or a n y 
reas o n ot her t h a n t o xicit y pri or t o c o m pleti n g t he first 2 1 da ys of treat me nt, a 
re place me nt partici pa nt will be e nr olle d a n d will be assi g ne d t o t he sa me d ose 
le vel. N o s u bjects will be re place d aft er r ecei vi n g t he first 2 1 da ys of 
treat me nt. Partici pa nts re m o ve d fr o m st u d y d ue t o t o xicit y d uri n g p hase I 
c ycle 1 will be c o nsi dere d as a D L T r e gar dl ess of w het her t he t o xicit y f ulfills 
t he D L T criteria.  
 
•  F or t he p h ase II st u d y, a n y partici pa nt w h o r ecei v es a d ose of t he st u d y dr u g 
will be i ncl u de d i n t he pr o gressi o n-fr ee s ur vi val a nal ysis. N o s u bjects will be 
re place d aft er r ecei vi n g t he first d ose of st u d y treat me nt.  
 
3. 4   
E x pecte d D ur ati o n of Tre at m e nt a n d P artici p ati o n 
3. 4. 1  D urati o n of Tr eat me nt 
I n t he a bse n ce of tr eat me nt dela ys d ue t o a d verse e ve nts, treat me nt ma y c o nti n ue 
f or 6 c ycl es of 2 1 da ys i n le n gt h or u ntil o ne of t he f oll o wi n g criteria a p plies:  
•  Disease pr o gressi o n, 
•  Ill ness t hat pr e ve nts f urt h er a d mi nistrati o n of treat me nt,  
•  T he i n vesti gat or c o nsi ders it, f or safet y r eas o ns, t o be i n t he best i nterest of 
  
t he partici pa nts,  
•  A n y t o xicit y or ot her iss ue t hat ca uses d ela y of st u d y dr u g a d mi nistrati o n b y 
  
m ore t hat 4 wee ks,  
•  Ge ner al or s pecific c h a n ges i n t he partici pa nts’ c o n diti o n re n d t he patie nt 
  
u nacce pta ble f or f urt her treat me nt i n t he j u d g me nt of t he i n vesti gat or,  
•  Partici pa nt decisi o n t o wit h dra w fr o m t he tr eat me nt ( partial c o nse nt) or fr o m 
  
t he st u d y (f ull c o nse nt),  
•  Pre g na nc y d uri n g t he c o urse of t he st u d y f or a c hil d- beari n g partici pa nt,  
•  Deat h, or 
•  S p o ns or te m p oraril y s us pects or pre m at urel y disc o nti n ues t he st u d y 
 
 
T he d ate a n d re as o n f or disc o nti n u ati o n m ust be d oc u m e nte d.  E ver y eff ort 
s h o ul d be m a de t o c o m plete t he a p pr o pri ate assess m e nts. 
 
 
 

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3. 4 . 2  D urati o n of F oll o w U p 
•  Partici pa nts will be f oll o we d f or a t otal of 2 4 m o nt hs after c o m pleti o n of t h era p y 
or u ntil deat h, w hic he ver c o mes first. If t he p atie nt is u na ble t o f oll o w u p i n 
pers o n, virt ual visits ma y be use d t o ca pt ur e a p plica ble pr oce d ures d uri n g l o n g-
ter m f oll o w u p o nl y. If a virt ual visit is c o m plete d, e ver y atte m pt s h o ul d be ma de 
t o c o m plete t he re q uir e d assess me nts t h o u g h if t he y are n ot c o m plete d it will n ot 
be c o nsi der e d a pr ot oc ol de viati o n. F or patie nts t h at pr o gress or start a ne w 
treat me nt, t he y will be f oll o we d via p h o ne calls rat her t ha n cli nic visits if desire d. 
•  Partici pa nts will be f oll o we d f or t o xicit y f or 3 0 d a ys after t h e fi nal d ose of st u d y 
dr u g, a n d 9 0 da ys f or e val uati o n a n d ca pt ure of pr e-s pecifi e d A E SIs after t heir 
fi nal d ose of M EI- 4 0 1, or u ntil deat h, w hic he ver occ urs first.  T h e cli nical c o urse 
of eac h e ve nt will be f oll o we d u ntil res ol uti o n, sta bilizati o n, or u ntil it has bee n 
deter mi ne d t hat t he st u d y treat me nt or partici pati o n is n ot t he ca use wit h a c ut off 
of 2 4 m o nt hs after c o m pl eti o n of t hera p y. Seri o us a d verse e ve nts t hat are still 
o n g oi n g at t he e n d of t he st u d y peri o d will necessitate f oll o w- u p t o deter mi ne t he 
fi nal o utc o me. A n y seri o us a d verse e ve nt t hat occ urs after t h e st u d y peri o d a n d is 
c o nsi dere d t o be p ossi bl y relate d t o t he st u d y treat me nt or st u d y partici pati o n will 
be rec or de d a n d re p orte d i m me diatel y.  
 
 
4. 0  
P A R TI CI P A N T S E L E C TI O N 
Eac h of t he criteria i n t h e secti o ns t hat f oll o w m ust be met i n or der f or a p artici pa nt t o b e 
c o nsi dere d eli gi ble f or t his st u d y. Use t he eli gi bilit y criteria t o c o nfir m a partici pa nts’ 
eli gi bilit y.  
 
P artici p a nt’s N a m e  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Me dic al Rec o r d #  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Rese arc h N urse / St u d y C o or di n at or Si g n at ure:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
D ate _ _ _ _ _ _ _ _ _ _ 
 
Tre ati n g P h ysici a n [ Pri nt]  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Tre ati n g P h ysici a n Si g n at ure:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
D ate  _ _ _ _ _ _ _ _ _ _ 
 
 
 

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4. 1   
I ncl usi o n Criteri a 
 
 
Partici pa nts m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt:  
 
 
 
4. 1. 1 Partici pa nts 
m ust ha ve hist ol o gicall y c o nfir me d diff use lar ge 
B-cell 
l y m p h o ma ( D L B C L) a n d hi g h gra de B cell l y m p h o ma N O S ( n ot ot her wise 
s pecifie d).  Partici pa nts wit h pre vi o usl y dia g n ose d i n d ole nt l y m p h o ma (f ollic ular 
a n d mar gi nal z o n e l y m p h o ma b ut n ot s mall l y m p h oc ytic l y m p h o ma) w h o ha ve 
tra nsf or me d t o D L B C L are eli gi ble o nl y if t he y ha ve n ot pre vi o usl y bee n treate d 
f or i n d ole nt l y m p h o ma.  
o  If patie nts recei ve d si n gle rit u xi ma b ( ma xi m u m 4- 8 d oses 
wit h n o 
m ai nte na nce) f or t heir l o w gra de l y m p h o ma ≥1 2 m o nt hs pri or t o starti n g 
st ud y dr u g are eli gi ble t o partici pate  
 
 
 
4. 1 . 2 Partici pa nts m ust ha ve ra di o gra p hicall y meas ura ble diseas e. At least o ne bi-
di me nsi o nall y meas ura bl e lesi o n ≥ 1. 5 c m i n its l o n gest dia meter m ust be 
i dentifie d. 
a. Pre vi o usl y irra diate d lesi o ns s h o ul d n ot be c o u nte d as tar get lesi o n. 
b.  Lesi o ns t hat are i nte n d e d t o be use d t o c ollect tiss ue sa m ples f or 
bi o ps y s h o ul d n ot be c o u nte d as tar get lesi o ns.   
c. B o ne lesi o ns s h o ul d n ot be c o u nte d as tar get lesi o ns   
 
 
 
4. 1 . 3 Patie nts partici pati n g i n t he p hase II p art are all o we d t o recei ve bri ef ( < 1 5 
da ys) tr eat me nt wit h gl u c oc ortic oi ds ( ma x d ose of pre d nis o n e 4 0 m g) a n d/ or 1 
c ycle of c he m ot her a p y s uc h as R- C H O P [ or s o m e c o m p o ne nt(s) t here of] f or t he 
dia g n osis of B-cell l y m p h o ma pr o vi de d t he y h a d all necess ar y sta gi n g tests 
perf or me d pri or t o R- C H O P or ster oi ds i ncl u di n g C T a n d/ or P E T/ C T sca ns, a n d 
b o ne marr o w bi o ps y. Treat me nt m ust occ ur wit hi n 3 0 da ys pri or t o e nr oll m e nt.  
 
  
  
Pre vi o us treat me nt _ _ _ Y E S _ _ _ _ _ N o 
  
  
If Yes, Pleas e List Treat me nt  a ge nts a n d dates: 
  
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
 
4. 1. 4  N o pri or t her a p y wit h PI 3 K i n hi bit ors or Br ut o n t yr osi ne ki nase ( B T K) 
i n hi bit ors  
 
 
 
4. 1. 5 A ge ≥1 8 y ears. D osi n g or a d verse e ve nt d ata ar e li mite d o n t he us e of M E-
4 0 1 i n patie nts < 1 8 years of a ge, t heref ore c hil dr e n are e x cl u de d fr o m t his st u d y.   
 
 
 
4. 1 . 6 E C O G Perf or ma nce stat us ≤ 2. Perf or ma nce Stat us of 3 will be acce pte d if 
i m pair me nt is ca use d b y D L B C L c o m plicati o ns a n d i m pr o ve me nt is e x p ecte d o nce 
t hera p y is i nitiate d. [ See A p pe n di x A] 
 
 
 
4 . 1. 7 Partici pa nts m ust ha ve a d e q uate h e mat ol o gic, he patic, a n d re n al f u ncti o n as 
defi ne d bel o w:   
  
_ _ _ _ _ 4. 1. 7. 1  He m o gl o bi n > 9. 0 g/ dl u nless t he a ne mia is clearl y d u e t o D L B C L. 

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If t here is B M i n v ol ve me nt, t his criteria ca n b e wai ve d after disc ussi o n wit h t he S p o ns or 
I n v esti gat or  ( per i n vesti gat ors discreti o n).  
  
  
  
He m o gl o bi n: _ _ _ _ _ _ _ _ 
  
  
  
Date of T est: _ _ _ _ _ _ _ _ 
  
_ _ _ _ _ 4. 1. 7. 2  A bs ol ute ne utr o p hil c o u nt > 1, 0 0 0/ mc L, u nless t he ne utr o pe nia is  
  
  
  
clearl y d ue t o D L B C L. If t here is B M i n v ol ve me nt, t his criteria 
ca n be w ai ve d after disc ussi o n wit h t he S p o ns or I n vesti gat or ( per i n v esti gat or discreti o n) 
  
  
  
A bs ol ute ne utr o p hil c o u nt: _ _ _ _ _ _ _ _ 
  
  
  
Date of T est: _ _ _ _ _ _ _ _ 
  
_ _ _ _ _ 4. 1. 7. 3  Platelet c o u nt > 7 5, 0 0 0/ mcl u nless t hr o m b oc yt o pe nia is clearl y d ue 
  
  
  
t o D L B C L. If t here is B M i n v ol ve me nt, t his criteria ca n b e wai ve d 
after disc ussi o n wit h t he S p o ns or I n v esti gat or ( per i n vesti gat or discreti o n) 
  
  
  
Platelet c o u nt: _ _ _ _ _ _ _ _ 
  
  
  
Date of T est: _ _ _ _ _ _ _ _ 
.   
_ _ _ _ _ 4. 1. 7. 4  Bilir u bi n ≤ 2. 0 x U L N u nless c o nsi dere d sec o n dar y t o Gil bert’s  
  
 
s y n dr o me, i n w hic h cas e ≤ 3 x U L N  
  
  
  
T otal bilir u bi n: _ _ _ _ _ _ _ _ 
  
  
 
Date of T est: _ _ _ _ _ _ _ _ 
 
  
_ _ _ _ _ 4. 1. 7. 5  A S T ( S G O T) < 2. 0 x i nstit uti o nal u p per li mit of n or mal 
  
  
  
A S T ( S G O T): _ _ _ _ _ _ _ _ 
  
  
  
Date of T est: _ _ _ _ _ _ _ _ 
 
  
_ _ _ _ _ 4. 1. 7. 6  A L T ( S G P T) < 2. 0 x i nstit uti o nal u p per li mit of n or mal 
  
  
  
A L T ( S G P T): _ _ _ _ _ _ _ _ 
  
  
  
Date of T est: _ _ _ _ _ _ _ _ 
 
  
_ _ _ _ _ 4. 1. 7. 7  Creati ni ne clear a nce ≥4 5 m L/ mi n calc ulate d b y C oc kcr oft- G a ult or 
  
  
 
2 4 h o ur c ollecti o n   
  
  
  
Creati ni ne Cleara nce: _ _ _ _ _ _ _ _ 
  
  
 
Date of T est: _ _ _ _ _ _ _ _ 
 
 
 
4. 1. 8   A de q uate car diac f u ncti o n left ve ntric ular ejecti o n fracti o n ( L V E F) ≥ 
5 0 % as assesse d b y ec h o car di o gr a m or M U G A ( M ulti Gate d Ac q uisiti o n 
Sca n).   
 
 
 
4. 1 . 9   Q T-i nter val c orrecte d acc or di n g t o Fri derici a’s f or m ula ( Q Tc F) ≤ 4 5 0 
millisec o n ds ( ms); partici pa nts wit h Q Tc < 4 8 0 ms ec ma y be e nr olle d 
pr o vi de d t he Q Tc pr ol o n gati o n is d ue t o a ri g ht b u n dle bra nc h bl oc k a n d 
sta ble . 
 
 
 
4. 1. 1 0   Ne gati ve pre g na nc y test i n w o me n of c hil d- beari n g a ge. T h e effects of 
M E- 4 0 1 o n t he d e vel o pi n g h u ma n fet us are u n k n o w n. F or t his reas o n a n d 
beca use c he m ot hera pe uti c a ge nts use d i n t his st u d y are k n o w n t o b e ter at o ge nic, 
w o me n of c hil d- beari n g p ote ntial a n d 
me n 
m ust a gree t o use a de q uate 
c o ntrace pti o n ( d o u ble barrier met h o d of birt h c o ntr ol or a bsti ne nce) 2 w ee ks 

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pr i or t o i nitiati o n of treat me nt, f or t he d urati o n of st u d y partici pati o n a n d f or 3 
m o nt hs after c o m pleti n g treat me nt. S h o ul d a w o ma n bec o me pr e g na nt or 
s us pect t hat s he is pre g n a nt w hile s he or her part n er is partici pati n g i n t his st u d y, 
s he s h o ul d i nf or m t he treati n g p h ysicia n i m me diatel y. 
Me n m ust a gree t o 
refr ai n fr o m s per m d o n ati o n f or at least 9 0 da ys after t he last d ose of M E- 4 0 1. 
 
 
 
4. 1. 1 1  Partici pa nts m ust ha ve t he a bilit y t o u n dersta n d a n d t he willi n g ness t o si g n 
a writte n i nf or me d c o nse nt d oc u me nt. 
 
 
 
4. 1. 1 2   I nt er nati o nal Pr o g n ostic I n d e x m ust be d oc u me nte d:  
  
  
  
E C O G perf or ma nce stat us ≥2 _ _ _ _ _ ( 1 p oi nt)  
  
  
 
A ge ≥6 0 years _ _ _ _ _ ( 1 p oi nt)  
  
  
 
≥2  e xtra n o dal sites _ _ _ _ _ ( 1 p oi nt)  
  
  
 
L D H > u p per li mit of n or mal _ _ _ _ _ ( 1 p oi nt)  
  
  
  
A n n Ar b or Sta ge III or I V _ _ _ _ _ ( 1 p oi nt)  
  
  
Is t here e vi d e nce of tra nsf or mati o n fr o m i n d ole nt l y m p h o ma? _ _ yes _ n o  
 
4. 2  
E xcl usi o n Criteri a 
 
T he prese n ce of a n y of t h e f oll o wi n g will e xcl u de a partici pa nt fr o m st u d y e nr oll me nt. 
 
 
 
4. 2. 1 Partici pa nts recei vi n g a n y ot her i n vesti gati o nal a ge nts.  
 
 
 
4. 2. 2  K n o w n C N S i n v ol ve me nt b y l y m p h o ma. Partici pa nts at hi g h ris k f or 
sec o n dar y C N S i n v ol ve me nt b ut wit h o ut ne ur ol o gi c s y m pt o ms s us pecte d t o be d ue 
t o l y m p h o ma are all o w e d t o be e nr olle d a n d r ecei ve pr o p h ylactic i ntr at hecal 
c he m ot hera p y i n cl u di n g b ut n ot li mite d t o 
met h otre xate, c yt ara bi n e a n d 
gl uc oc ortic oi ds. Partici pa nts w h o are e nr olle d a n d s u bse q ue ntl y i de ntifie d t o ha ve 
pat h ol o gic c o nfir mati o n of C N S i n v ol ve me nt b y l y m p h o ma ma y be c o nti n ue d o n 
st u d y at t he discreti o n of t he pri nci pal i n vesti gat or.  
 
 
 
4. 2. 3  Hist or y of aller gic reacti o ns attri b ute d t o c o m p o u n ds of si milar c he mical or 
bi ol o gic c o m p ositi o n t o R- C H O P. 
 
 
 
4. 2. 4 Partici pa nts wit h o n g oi n g u nc o ntr olle d ill ness i ncl u di n g, b ut n ot li mite d t o 
o n g oi n g si g nifica ntl y acti ve i nfecti o ns re q uiri n g i ntra ve n o us a nti bi otics, 
h y perte nsi o n, a n gi na, arr h yt h mias, p ul m o nar y disease, or a ut oi m m u ne 
d ysf u ncti o n.  
 
 
 
4. 2. 6 U nc o ntr olle d a ut oi m m u ne he m ol ytic a ne mia or i m m u ne t hr o m b oc yt o pe nia. 
 
 
4. 2. 7  O n g oi n g dr u g-i n d uce d p ne u m o nitis.  

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4 . 2. 8  Hist or y of cli nicall y si g nifica nt gastr oi ntesti nal ( GI) c o n diti o ns, 
partic ularl y:  
o  K n o w n GI c o n diti o n t hat w o ul d i nterfer e wit h s wall o wi n g or t he oral 
a bs or pti o n or t olera n ce of st u d y dr u g  
o  Pre-e xisti n g mala bs or pti o n s y n dr o me or ot her cli nical sit uati o n t hat w o ul d 
affect oral a bs or pti o n  
 
 
 
4. 2. 9 Acti ve c o n gesti ve heart fail ure ( Ne w Y or k H eart Ass ociati o n [ N Y H A] Class 
> 2), s y m pt o matic isc he mia, or c o n d ucti o n a b n or malities u nc o ntr olle d b y 
c o n ve nti o nal i nter ve nti o n or m y ocar dial i nf ar cti o n wit hi n si x m o nt hs pri or t o 
e nr oll me nt.  
 
 
 
4. 2. 1 0   Partici pa nts w h o ha ve teste d p ositi ve f or h e patitis B s urface a nti ge n 
a n d/ or he patitis B c ore a nti b o d y P L U S ha ve detecta ble viral l oa d o n h e patitis B 
p ol y merase c h ai n reacti o n ( P C R) assa y ( partici pa nts wit h a ne gati ve P C R assa y 
are per mitte d wit h a p pr o priate a nti- viral pr o p h yla xis)  
 
 
 
4. 2. 1 1   P ositi ve he patitis C vir us a nti b o d y ( H C V A b) partici pa nts wit h p ositi ve 
he patitis C a nti b o d y are eli gi ble if t he y are ne g ati ve f or he p atitis C vir us b y P C R  
 
 
 
4. 2. 1 2   HI V- p ositi ve partici pa nts o n c o m bi nati o n a ntiretr o viral t her a p y are 
i neli gi ble beca use of t he p ote ntial f or p har mac o ki netic i nteracti o ns wit h M E- 4 0 1.  
 
 
 
4. 2. 1 3   Pre g na nt or br eastfee di n g w o me n are e x cl u de d fr o m t his st u d y beca use 
t here are n o st u dies assessi n g t he re pr o d ucti ve a n d de vel o p me ntal t o xicit y or 
e xcreti o n i nt o breast mil k of M E- 4 0 1. Beca use t h ere is a n u n k n o w n, b ut p ote ntial 
ris k f or a d verse e v e nts i n n ursi n g i nfa nts sec o n dar y t o treat me nt of t he m ot her 
wit h M E- 4 0 1, breastf ee di n g s h o ul d be disc o nti n ue d if t he m ot her is treate d wit h 
M E- 4 0 1.  T hese p ote ntial ris ks ma y als o a p pl y t o ot her dr u gs use d i n t his st u d y.  
 
 
 
4. 2. 1 4   Ot her mali g na nci es wit hi n t he past 3 years e xce pt f or a de q u atel y 
treate d car ci n o ma of t he cer vi x or b asal or s q ua m o us cell car ci n o mas of t h e 
s ki n, or l o w-ris k pr ostate ca ncer after c urati ve t her a p y.  
 
 
 
4. 2. 1 5   Partici pa nts w h o ha ve ha d maj or s ur gical pr oce d ur es or si g nifica nt 
tra u matic i nj ur y wit hi n 2 8 da ys pri or t o st u d y treat me nt.  
  
  
Date of L ast Maj or S ur ger y: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
  
  
Sc he d ule d Da y 1 of Pr ot oc ol Treat me nt: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
4. 2. 1 6  Ps yc hiatric ill ness/s ocial sit uati o ns t hat 
w o ul d i nter fer e 
wit h st u d y 
c o m plia nce  
 
4. 3  
I ncl usi o n of W o m e n a n d Mi n orities  
Me n, w o me n  a n d me m bers of all races a n d et h nic gr o u ps are eli gi ble f or t his trial. 
 
 

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5. 0   
R E GI S T R A TI O N  
All partici pa nts w h o ha ve bee n c o ns e nte d ar e t o be re gistere d i n t he O n C or e ™ Data bas e. 
F or t h ose p artici pa nts w h o are c o nse nte d, b ut n ot e nr olle d, t he reas o n f or e xcl usi o n m ust 
be rec or de d. 
 
All partici pa nts will be r e gistere d t hr o u g h Cle vel a n d Cli nic a n d will be pr o vi de d a st u d y 
n u m ber b y c o ntacti n g t he st u d y c o or di nat or (c o nt act i nf or mati o n o n pa ge 2).   
 
6. 0   
T R E A T M E N T P L A N 
Tre at me nt Re gi me n 
A ge nt 
Pre me dic ati o n  
D ose  
R o ute  
Sc he d ule  
C ycle 
Le n gt h 
Rit u xi ma b ( gi ve first)  
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 
( 5 0 m g) P O or I V, 
3 0 - 6 0 mi n utes 
pri or t o eac h 
i nf usi o n1.  
 
3 7 5 m g/ m 2  
I V/ S Q2  
Da y 1 
2 1 da ys 
C ycl o p h os p ha mi de  
N A  
7 5 0  m g/ m 2 
I V 
Da y 1  
D o x or u bici n  
N A  
5 0 m g/ m 2 
I V 
Da y 1  
Vi ncristi ne 
- N A-  
1. 4 m g/ m2 
( ma x 2 m g)  
I V 
Da y 1 
Pre d nis o ne  
-N A - 
1 0 0 m g  
P O  
Da ys 1 -5  
Pe gfil gasti m 4 , 5 
-N A - 
6 m g  
S C  
Da y 2  
M E- 4 0 1 
- N A-  
6 0 m g   
P O  
Da ys 1- 7 ( or 
1- 4 f or d ose 
le vel 1) 
P J P pr o p h yl a xis ( pic k O N E) 6 
T M P- S M X 
- N A-  
1 6 0 m g/ 8 0 0 
m g 
( d o u ble 
stre n gt h) 
P O  
T hree da ys 
wee kl y 
( M, W, F) 
Pe nta mi di ne  
- N A-  
3 0 0 m g  
aer os olize d  
E ver y 4 
wee ks  
V Z V pr o p h yl a xis 
 
Ac ycl o vir 7 
- NA-  
4 0 0 m g  
P O  
T wice dail y  
 
1.  H y dr o x yzi ne ma y be s u bstit ute d i n partici pa nts i nt olera nt of di p he n h y dra mi ne  
2.  First d ose of rit u xi ma b will be gi ve n I V a n d s u bse q ue nt d oses ca n be eit her I V or S Q base d o n 
i nstit uti o nal g ui deli nes. Rit u xi ma b i nf usi o n as per i nstit uti o nal sta n dar d. Rit u xi ma b bi osi milars are 
all o we d per i nstit uti o nal pr ot oc ol.   
3.  See M E- 4 0 1 d osi n g St u d y Sc he ma a n d Secti o n 6. 1. 1.   
4.  A d mi nistrati o n of gr o wt h fact ors as per i nstit uti o nal sta n dar ds. Fil grasti m 3 0 0 or 4 8 0 mc g I V/ S C 
dail y x 5- 1 0 da ys ( be gi n ni n g o n da y 2) per i nstit uti o nal sta n dar d ma y be s u bstit ute d if 
pe gfil grasti m is u na vaila ble.  Bi osi milars are all o we d per i nstit uti o nal pr ot oc ol.  
5.  O N P R O T M ( O n B o d y I njecti o n) is acce pta ble m o de of a d mi nistrati o n of pe gfil grasti m o n da y 1.  
Bi osi milars are all o we d per i nstit uti o nal pr ot oc ol.  

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6.  P J P pr o p h yla xis will c o nti n ue f or 2- 6 m o nt hs after disc o nti n uati o n of M E- 4 0 1 
7 . Ac ycl o vir will be gi ve n fr o m 6 m o nt hs after c o m pleti o n of c ycle 6  
 
6. 1   
Tre at m e nt A d mi nistr ati o n 
 
•  Treat me nt Re gi me n is n ote d a b o ve. 
•  Treat me nt ma y be a d mi nistere d eit her i n patie nt or o ut patie nt at t he discreti o n 
of treati n g p h ysicia n or i nstit uti o nal sta n dar d.  
•  A p pr o priate d os e m o difi cati o ns f or M E- 4 0 1 a n d R- C H O P are descri be d i n 
Secti o n 7. 0.  
•  I ntr a- partici pa nt d ose es calati o n is all o we d f or p artici pa nts treate d wit h M E-
4 0 1 at 6 0 m g da ys 1- 4 O N L Y after M E- 4 0 1 6 0 m g da ys 1- 7 has bee n gi ve n t o 
6 partici pa nts a n d is deter mi ne d t o be t he R P 2 D.  T his will nee d disc ussi o n wit h 
a n d a p pr o val b y st u d y PI.  
•  A ntie metic pre me dicati o n as per i nstit uti o nal sta n dar d 
•  Re p orte d a d verse e v e nts a n d p ote ntial ris ks of 
M E- 4 0 1 a n d R- C H O P ar e 
descri be d i n Secti o n 8. 0.  
•  N o i n vesti gati o nal or c o m mercial a g e nts or t hera pies ot her t ha n t h os e descri be d 
a b o ve ma y be a d mi nister e d wit h t he i nte nt t o treat t he partici pa nt's D L B C L. 
•  I n t h e case of patie nts w h o recei ve d 1 treat me nt of R- C H O P [ or s o me 
c o m p o ne nt(s) t her e of] pri or t o st u d y e nr oll me nt, will be gi n t he st u d y wit h C ycle 
2 st u d y treat me nt ( R- C H O P r o u n d 2). Patie nts s h o ul d recei ve at l east 6 f ull 
r o u n ds of R- C H O P ( bet wee n S O C a n d st u d y treat me nt c o m bi ne d) u nless 
ot her wise s pecifie d. 
o   I n t he cas e of patie nts w h o recei ve d 1 c y cle of R- C H O P [ or s o me 
c o m p o ne nt(s) t here of] pri or t o st u d y e nr oll me nt, t he scr ee ni n g wi n d o w 
e xte n ds t o < 6 0 da ys. 
 
6. 1. 1 
M E- 4 0 1 
 
•  Partici pa nts will recei ve M E- 4 0 1 6 0 m g b y m o ut h o n da ys 1- 4 or da ys 1- 7 of 
eac h 2 1 d a y c y cle.  O n da y 1 M EI will be a d mi nistere d 3 0 mi n utes – 9 0 mi n utes 
pri or t o R- C H O P c he m o 
•  M E- 4 0 1 is t o be ta ke n or all y o nce a d a y wit h a glass of water o n a n e m pt y 
st o mac h at least 1 h o ur pri or t o f o o d or 2 h o urs aft er f o o d at t he s a me ti me 
eac h d a y.  Partici pa nts u na ble t o ta ke M E- 4 0 1 o n a n e m pt y st o mac h ar e 
all o we d t o ta ke M E- 4 0 1 wit h a li g ht, n o n-fatt y s nac k.  If p ossi ble, s e par ate 
ta ki n g M E- 4 0 1 ca ps ules fr o m t hat of c o nc o mita nt me dicati o ns t hat ha ve a 
k n o w n eff ect o n p- gl yc o pr otei n, Breast Ca ncer R esista nce Pr otei n ( B C R P) 
tra ns p orter, a n d C Y P 2 C 8 s u bstrates, as well as c o nc o mita nt oral me dicati o ns 
t hat ha ve k n o w n i nter acti o ns wit h dr u gs t hat i n hi bit P- g p, B C R P, a n d 
C Y P 3 A 4. 
•  D ose escalati o n wit h 2 d oses o nl y.  D ose le vel 1 is 6 0 m g dail y o n da ys 1- 4 of 
eac h 2 1- da y c ycle.  D os e le vel 2 is 6 0 m g dail y o n da ys 1- 7 of eac h 2 1 da y 
c ycle.  See Secti o n 6. 2 f or d ose escalati o n.  
 

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6. 1 . 2 
R- C H O P 
•  Use act ual w ei g ht w he n calc ulati n g s urf ace area. T he start of treat me nt d oses 
f or all dr u gs ca n be use d f or all c ycl es u nless t he B S A c ha n ges b y > 5 % i n 
w hic h case d os es m ust be re- calc ul ate d. Aceta mi n o p he n ( 6 5 0 t o 1 0 0 0 m g) 
P O a n d di p he n h y dra mi ne ( 2 5 t o 5 0 m g) P O or I V are t o be a d mi nistere d 3 0 
t o 6 0 mi n utes pri or t o starti n g eac h i nf usi o n of rit u xi ma b. H y dr o x yzi ne ma y 
be s u bstit ute d i n partici pa nts i nt olera nt of di p he n h y dra mi ne..  
 
a. Pre d nis o ne 1 0 0 m g orall y da y 1 t hr o u g h 5 of s u bs e q ue nt c ycl es.  
b.  Rit u xi ma b 3 7 5 m g/ m 2 I V/ S Q o n da y 1 of eac h c ycle (e v er y 2 1 da ys). 
Rit u xi ma b bi osi milars are all o we d as p er i nstit uti o nal pr ot oc ol.   
c. C ycl o p h os p ha mi de 7 5 0 m g/ m 2 I V D a y 1 of eac h c ycle ( e ver y 2 1 d a ys)  
d.  D o x or u bici n 5 0 m g/ m 2 I V Da y 1 of eac h c ycle (e ver y 2 1 da ys)  
e. Vi ncristi ne 1. 4 m g/ m 2 I V ( Ma xi m u m d ose = 2. 0 m g) Da y 1 of eac h c ycle 
(e ver y 2 1 d a ys)  
f. A d mi nistrati o n of gr o wt h fact ors as p er i nstit uti o nal sta n dar ds. 
Pe gfil grasti m 6 m g S C da y 2 (e ver y 2 1 da ys) as p er i nstit uti o nal sta n dar ds. 
Fil grasti m 3 0 0 or 4 8 0 mc g I V/ S C dail y da ys x 5- 1 0 starti n g da y 2 ma y be 
s u bstit ute d if pe gfil grasti m is n ot a vaila ble.  O N P R O T M  is als o a n acce pta ble 
met h o d of a d mi nistrati o n o n da y 1.  Bi osi milars ma y be use d per 
i nstit uti o nal pr ot oc ols.  
 
6. 1. 3 
T u m or L ysis S y n dr o me 
T u m or l ysis s y n dr o me ( T L S) la bs i ncl u di n g basic c he mistr y pa nel ( B M P), L D H, 
uric aci d, calci u m a n d p h os p h or o us will be c hec k e d o n c ycle 1 da y 1 pri or t o 
starti n g treat me nt. Patie nts at ris k f or T L S will be ma na ge d as p er i nstit uti o nal 
g ui deli nes. All o p uri n ol 3 0 0 m g P O dail y f or 5- 7 d a ys ca n be us e d f or T L S 
treat me nt a n d/ or pr o p h yl a xis as per tr eati n g i n vesti gat or’s discreti o n. Ot her 
i nter ve nti o ns li ke i ntra ve n o us fl ui ds ca n be use d at per i nstit uti o nal g ui deli nes. 
T L S la bs s h o ul d be re peate d as per i nstit uti o nal g ui deli nes i n hi g h ris k patie nts.  
 
6. 1. 4  PJ P Pr o p h yla xis 
Partici pa nts s h o ul d recei ve eit her T M P- S M X or P e nta mi di ne f or PJ P pr o p h yla xis 
starti n g fr o m i nitiati o n of c he m ot hera p y t o 2- 6 m o nt hs after last d ose of M E- 4 0 1. 
Da ps o ne is a pr o hi bite d dr u g t o use f or pr o p h yl a xis.  
  
6. 1. 3. 1 Tri met h o pri m/s ulfa met h o xaz ol e ( T M P- S M X)  
Gi ve n as 1 6 0 m g/ 8 0 0 m g ( d o u ble stre n gt h) or all y o nce dail y t hree da ys 
per wee k.  
  
6. 1. 3. 1  Pe nta mi di ne 
  
  
Gi ve n as 3 0 0 m g aer os olize d o nce e ver y 4 wee ks. 
6. 1. 5 
V Z V Pr o p h yla xis 
Partici pa nts s h o ul d recei ve ac y cl o vir 4 0 0 m g BI D f or V Z V pr o p h yla xis fr o m 
i nitiati o n of c he m ot hera p y (c ycle 1, d a y 1) t o 6 m o nt hs after last d ose of M E- 4 0 1. 
6. 1. 4. 1 Ac ycl o vir 
  
Gi ve n as 4 0 0 m g orall y t wice dail y. 

C A S E 1 4 2 0  
  
  
  
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6. 2   
P h ase I D ose Esc al ati o n  
D ose escalati o n will pr ocee d wit hi n eac h c o h ort acc or d i n g t o t he f oll o wi n g sc he me. 
D ose-li miti n g t o xicit y ( D L T) is defi ne d i n secti o n 6. 3. 
 
N u m ber of P artici p a nts wit h 
D L T at a Gi ve n D ose Le vel 
Esc al ati o n Decisi o n R ule 
0 o ut of 3  
E nter 3 partici pa nts  at t he ne xt d ose le vel.  
1 o ut of 3 
E nter 3 m ore partici pa nts at t his d ose le vel. 
•  If 0 of t hese 3 p artici pa nts e x perie n ce D L T, 
pr ocee d t o t he n e xt d ose le vel. 
•  If 1 or m ore of t his gr o u p s uffer D L T, t he n 
d ose escal ati o n is st o p pe d, a n d t his d ose is 
declar e d t he ma xi mall y a d mi nistere d d ose. 
T hree ( 3) a d diti o nal parti ci pa nts will be 
e ntere d at t he ne xt l o west d ose le vel if o nl y 
3 partici pa nts wer e treate d pre vi o usl y at t hat 
d ose.  
> 2 
D ose escalati o n will be st o p pe d. T his d ose le vel 
will be declar e d t he ma xi mall y a d mi nistere d 
d ose ( hi g hest d ose a d mi nistere d). If 2 or m ore 
D L T o bser ve d i n 3 or 6 p artici pa nts at d ose le v el 
1, M T D is e xcee de d, a n d t he st u d y will be 
disc o nti n ue d (see secti o n 1 4. 0).   If t his occ urs i n 
d ose le vel 2, t hree ( 3) a d diti o nal partici pa nts will 
be e nter e d at t he ne xt l o west d ose le vel if o nl y 3 
s u bjects were treat e d pre vi o usl y at t hat d ose. 
< 1 o ut of 6 at hi g hest d os e le vel 
bel o w t he ma xi mall y 
a d mi nistere d d ose or at hi g hest 
d ose le vel if  a ble t o escalate d t o 
d ose le vel 2  
T his is ge nerall y t he rec o m me n de d ma xi mall y 
t olerate d d ose. At least 6 partici pa nts s h o ul d be 
e ntere d at t he rec o m me n de d p hase 2 d ose. 
 
6. 3  
Defi niti o n of D ose- Li miti n g T o xicit y  
 
Ma na ge me nt a n d d os e m o dificati o ns are o utli ne d i n Secti o n 7.    
 
D os e li miti n g t o xicit y will be defi ne d as a n y of t h e f oll o wi n g A Es t hat occ ur d uri n g c ycle 
1 (first 2 1 da ys) f or all d ose le vels wit h se verit y gra de d acc or di n g t o t he N CI C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E v e nts ( C T C A E), Versi o n 5. 0:  
 
N o n- he mat ol o gic D L Ts 
•  Gra de ≥3, n o n- he mat ol o gic t o xicit y.  T his e xcl u des fati g ue or  a n ore xi a lasti n g 
< 7 da ys.  

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He mat ol o gic D L Ts 
•  Gra de 4 n e utr o pe nia l asti n g ≥ 7 da ys des pite G- C S F 
•  Gra de 4 t hr o m b o c yt o pe nia 
•  Gra de ≥3 t hr o m b oc yt o p e nia wit h ≥ Gra de 2 blee di n g 
 
I n a d diti o n, t he f oll o wi n g will be c o nsi dere d D L Ts: 
•  A n y t o xicit y t hat re q uires a partici pa nt t o c o me off st u d y will be c o nsi dere d a 
D L T 
•  * F or patie nts wit h a n y t o xicit y t hat re q uires M E- 4 0 1 t o be hel d f or t he 2 n d 
c onsec uti ve c y cle, t he D L T wi n d o w will e xte n d t o 4 2 da ys. If M E- 4 0 1 ca n n ot 
be restart e d b y t he 3 r d c o nsec uti ve c ycl e, t hat will be c o nsi der e d a D L T.  
 
6. 4   
Ge ner al C o nc o mit a nt Me dic ati o ns a n d S u p p orti ve C are G ui deli nes 
T he f oll o wi n g me dicati o ns/t hera pies ar e pr o hi bite d d uri n g t he st u d y:  
•  Ot her i n vesti gati o n a ge nts; a n d 
•  Ca ncer t hera pies n ot me nti o ne d i n t his pr ot oc ol.   
T he f oll o wi n g me dicati o ns/t hera pies s h o ul d be us e d wit h ca uti o n: 
•  Dr u gs t hat aff ect t he C Y P 2 C 8 ( See A p pe n di x D) 
•  Dr u gs t hat aff ect t he Q T/ Q Tc i nter val ( See A p pe n di x E) 
•  Orall y a d mi nistere d dr u gs k n o w n t o i nteract wit h dr u gs t hat i n hi bit C Y P 3 A 4 
( htt ps:// dr u g-i nteracti o ns. me dici ne.i u.e d u/ Mai n- Ta ble.as p x) 
•  Orall y a d mi nistere d dr u gs k n o w n t o i nteract wit h dr u gs t hat i n hi bit t he 
i ntesti nal tra ns p orters B C R P a n d P- g p  
 
6. 5  
Criteri a f or R e m o v al fr o m St u d y ( See Secti o n 3. 4. 1 ) 
 
6. 6  
D ur ati o n of F oll o w U p (see Secti o n 3. 4. 2) 
 
7. 0   
D O S E D E L A Y S/ D O S E M O DI FI C A TI O N S 
All sc he d ule d visits will ha ve a ± 3- d a y wi n d o w d ue t o u na ntici pate d or u n a v oi da ble 
sc he d uli n g c o nflicts. F or he mat ol o gic or ot her t o xi cit y i n t he o pi ni o n of t he treati n g 
p h ysicia n attri b uta ble t o M E- 4 0 1 b ut n ot descri be d else w her e i n t he pr ot oc ol, treat me nt 
wit h M E- 4 0 1 ma y be hel d, after disc ussi o n wit h t he st u d y PI.  
 
7. 1 M E- 4 0 1 
        
T here will be n o d ose re d ucti o n base d o n t o xicit y, o nl y d ose dela ys or 
  
disc o nti n uati o n as nee de d bel o w.  
  
7. 1. 1 He mat ol o gic T o xicit y 
•  A N C > 1 0 0 0, a n d platelets > 7 5, 0 0 0 o n da y 1 of n e w c ycl e: N o 
c ha n ge i n d ose 
•  A N C < 1 0 0 0, a n d platelets < 7 5, 0 0 0 o n da y 1 of ne w c ycle: H ol d 
u ntil res ol ves.  Res u me at sa me d ose le vel.   
•  Gra de 4 t hr o m b o c yt o pe nia or Gra d e 4 ne utr o p e nia wit h ass ociate d 
s y m pt o ms (e. g. fe ver) a n yti me d uri n g a c ycle.  If n ote d o n da ys 1- 7 
t he n h ol d M E- 4 0 1 f or t he c o m pleti o n of c urr e nt c y cle.  If t o xicit y 

C A S E 1 4 2 0  
  
  
  
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res ol ves t o gra d e < 1, M E- 4 0 1 ca n be res u me d wit h t he s u bse q ue nt 
c ycle.  If t o xicit y d oes n ot res ol ve t he n c o nti n ue t o h ol d M E- 4 0 1 
u ntil t o xicit y is gra de < 1 or less.  
•  If t here is a persiste nt or rec urre nt he mat ol o gic t o xicit y a n d as per 
t he I n v esti gat or’s ass ess me nt t his is dee me d i nt olera ble a n d n ot 
relate d t o t he disease, dis c o nti n ue M E- 4 0 1.  
 
  
7. 1. 2 N o n- He mat ol o gic T o xicit y  
 
* N ote, f o r P h ase I, gr a d e 3 a n d 4 e ve nts are c o nsi dere d a D L T.   
 
M E- 4 0 1 D o s e M o difi c ati o n s a n d T o xi cit y M a n a g e m e nt 
T o xicit y  
Gr a d e   
M a n a g e m e nt of M E- 4 0 1 
M a n a g e m e nt of T o xicit y  
Di arr h e a / C olitis  
2 
H ol d M E- 4 0 1 u nless diarr hea 
c o nfir me d t o be d u e t o a n i nfecti o us 
a ge nt. 
If M E- 4 0 1 is hel d, o nce diarr hea 
res ol ves t o Gra d e ≤ 1, res u me M E-
4 0 1  at start of ne xt c y cle.   
 
T he ca us e of diarr hea s h o ul d be 
i n vesti gate d t o r ule o ut a n i nfecti o us 
ca use, i ncl u di n g cl ostri di u m difficile. 
H ol d M E- 4 0 1 a n d start l o pera mi de or 
si milar a nti- diarr heal a ge nt.  
If n o i m pr o ve me nt occ urs wit hi n 4 8 
h o urs, start pre d nis ol o ne 0. 5- 1 m g/ k g I V 
or oral b u des o ni de 9 m g dail y. Base d o n 
data fr o m t he P hase 1 b st u d y, 
partici pa nts wit h diarr h ea t hat was 
prece d e d b y r as h i n t he pri or 1- 2 wee ks 
ofte n e x perie nce d m ore pr ol o n ge d a n d 
se vere di arr h ea. T h us, if diarr hea is 
prece d e d b y r as h i n t he pri or wee ks, 
start pre d nis ol o ne 0. 5- 1 m g/ k g I V or 
oral b u des o ni de 9 m g dail y.  
Di arr h e a / C olitis  
3 
H ol d M E- 4 0 1 u ntil A E res ol ves t o 
Gra de ≤ 1, t he n, if cli nicall y 
i n dicate d, res u me M E- 4 0 1 at start of 
ne xt c ycle.  
F or r ec urre nce of Gra de 3 
diarr hea/c olitis, disc o nti n ue st u d y 
dr u g per ma n e ntl y.  
 
T he ca us e of diarr hea s h o ul d be 
i n vesti gate d t o r ule o ut a n i nfecti o us 
ca use, i ncl u di n g cl ostri di u m difficile. A 
c ol o n osc o p y is a p pr o priate t o d oc u me nt 
e vi de nce of c olitis  
Partici pa nts s h o ul d be h y drate d as 
cli nicall y i n dicate d a n d a d mi nistere d 
( met h yl) pre d nis ol o ne 1- 2 m g/ k g/ da y I V 
or e q ui vale nt or al s yste mic ster oi ds.  
•  If n o i m pr o ve me nt occ urs wit hi n 

C A S E 1 4 2 0  
  
  
  
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2 – 3 da ys, t he c ortic oster oi d d ose 
s h o ul d be i ncreas e d t o 2 
m g/ k g/ da y I V or e q ui val e nt oral 
s yste mic ster oi ds.  
O nce i m pr o ve d t o Gra de ≤ 1, start 
tap eri n g t he c ortic oster oi d as cli nicall y 
i n dicate d.  
Di arr h e a / C olitis  
4 
Per ma ne ntl y disc o nti n ue M E- 4 0 1.  
S a m e  as gr a d e 3 m a n a g e m e nt.  
C uta ne o us 
Reacti o ns a n d 
M uc ositis  
 
2 
H o l d M E- 4 0 1 u nless ras h ascert ai ne d 
t o be u nrelate d t o st u d y dr u g. If M E-
4 0 1 is hel d, o nce A E r es ol ves t o 
Gra de ≤ 1, res u me M E- 4 0 1 at start of 
ne x t c ycle.  
M o nit or partici pa nts wit h i ncreas e d 
fre q ue n c y. Per I n v esti gat or’s discreti o n, 
a nti- hista mi nes, t o pical ster oi ds, a n d 
s yste mic ster oi ds ma y be gi ve n.  
C uta ne o us 
Reacti o ns a n d 
M uc ositis  
 
> 3 
H ol d M E- 4 0 1 u ntil A E res ol ves t o 
Gra de ≤ 1, t he n, if cli nicall y 
i n dicate d, res u me M E- 4 0 1 at start of 
ne xt c ycle.  
F or r ec urre nce of Gra de 3, 
per ma ne ntl y disc o nti n ue M E- 4 0 1.  
M o nit or partici pa nts s as cli nicall y 
i n dicate d u ntil res ol uti o n. Oral 
a nti hista mi nes a n d s yste mic 
c ortic oster oi ds s uc h as pr e d nis o ne  
0. 5 – 1 m g/ k g/ da y ( or e q ui vale nt d ose of 
met h yl pre d nis ol o ne) s h o ul d be gi ve n 
u ntil ras h res ol ves t o Gra de ≤ 1. 
C uta ne o us 
Reacti o ns a n d 
M uc ositis  
 
A n y   
Per ma ne ntl y disc o nti n ue M E- 4 0 1 f or 
life-t hreat e ni n g t o xicit y, Ste ve ns- 
J o h ns o n s y n dr o me of a n y gra de, a n d 
t o xic e pi der mal necr ol ysis s y n dr o me 
( T E N S) of a n y gra de.  
Treat per i nstit uti o nal sta n dar d of care.  
 
H e p at ot o xicit y  
2 
F or A L T/ A S T > 3- 5 x U L N b ut < 5 
x U L N , mai ntai n M E- 4 0 1 d ose. 
M o nit or wee kl y wit h u ntil res ol ve d t o 
Gra de ≤ 1 x U L N.  
H e p at ot o xicit y  
3 
F or A L T/ A S T > 5- 2 0 x U L N, h ol d 
M E- 4 0 1 a n d m o nit or t wice least 
wee kl y u ntil res ol ve d t o Gra de ≤ 1 x 
U L N. T h e n, r es u me M E- 4 0 1 at start 
of ne xt c ycle 
 
F or r ec urre nce of Gra de 3, 
Treat per i nstit uti o nal sta n dar d of care, 
w hic h ma y i ncl u de a c o urse of 
c ortic oster oi ds i n cli nicall y i n dicate d.  
 
 
 

C A S E 1 4 2 0  
  
  
  
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pe r ma ne ntl y disc o nti n ue M E- 4 0 1.  
H e p at ot o xicit y  
4 
F or A L T/ A S T > 2 0 x U L N, 
per ma ne ntl y disc o nti n ue M E- 4 0 1.  
Treat per i nstit uti o nal sta n dar d of care, 
w hic h ma y i ncl u de a c o urse of 
c ortic oster oi ds i n cli nicall y i n dicate d.  
N o n-i nfecti o us 
p ne u m o nitis ( NI P)  
 
2 
H ol d M E- 4 0 1 u ntil A E res ol ves t o 
Gra de ≤ 1.  
Res u me M E- 4 0 1 at start of ne xt 
c ycle.  
Treat per i nstit uti o nal sta n dar d of care.  
 
N o n-i nfecti o us 
p ne u m o nitis ( NI P)  
> 3 
Per ma ne ntl y disc o nti n ue M E- 4 0 1.  
Treat per i nstit uti o nal sta n dar d of care, 
i ncl u di n g s yste mic c ortic oster oi ds. 
Ot her, n ot liste d 
a b o ve  
 
2 
H o l di n g M E- 4 0 1 is n ot re q uire d.   
Treat per i nstit uti o nal sta n dar d of care.  
3 
F or a n A E rel ate d t o M E- 4 0 1, h ol d 
M E- 4 0 1 u ntil A E res ol ves t o Gra de 
≤ 1. H o we ver, f or a n A E n ot relate d 
t o ME- 4 0 1, t his will be u p o n t he 
discreti o n of t he treati n g p h ysicia n. 
Res u me M E- 4 0 1 at start of ne xt 
c ycle. 
F or r ec urre nce of Gra de 3, 
disc o nti n ue per ma ne ntl y M E- 4 0 1.  
 
Treat per i nstit uti o nal sta n dar d of care.  
 
4 
Per ma ne ntl y disc o nti n ue M E- 4 0 1.  
 
Treat per i nstit uti o nal sta n dar d of care.  
 
Partici pa nts w h o i nterr u pt d osi n g f or ≥ 8 wee ks will ha ve M E- 4 0 1 per m a ne ntl y 
dis c o nti n ue d.  
 
 
7. 2 R- C H O P 
  
7. 2. 1 He mat ol o gic T o xicit y 
  
O n t he da y of starti n g eac h c ycle, h e mat ol o gic (a bs ol ute ne utr o p hil c o u nt, 
  
he m o gl o bi n a n d platelet) para meters m ust ha ve r es ol ve d t o baseli ne or gr a de 1. If 
  
t hese criteri a ar e n ot met, t hera p y will be hel d b y 1 wee k i ncr e me nts f or a 
  
ma xi m u m of 4 wee ks. If treat me nt ca n n ot b e gi ve n d uri n g t hat ti me fra me t he 

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partici pa nt will be re m o v e d fr o m st u d y.  
•  A N C > 1 0 0 0, a n d platelets > 7 5, 0 0 0 o n da y 1 of n e w c ycl e: N o 
c ha n ge i n d ose 
•  A N C < 1 0 0 0, a n d platelets < 7 5, 0 0 0 o n da y 1 of ne w c ycle: H ol d 
u ntil res ol ves.  Res u me at sa me d ose le vel.   
 
  
7. 2. 2 N o n- He mat ol o gic T o xicit y  
Gra de 2- 4 n o n- he m at ol o gic t o xicit y (e xce pt f ati g ue or a n or e xia lasti n g < 7 da ys or 
Gra de 3 n a usea a n d/ or v o miti n g t hat persists f or < 2 da ys f oll o wi n g a p pr o priate 
s u p p orti ve car e or n o n- cli nicall y si g nifica nt gra de 3 electr ol yte a b n or malities t hat 
ha ve bee n c orrect e d) t hat is treat me nt-relat e d m ust ret ur n t o a gr a de 1 or b etter 
pri or t o c o nti n ui n g treat me nt. If t hese criteria are n ot met, t hera p y will be hel d f or 
a ma xi m u m of 4 wee ks. If treat me nt ca n n ot be gi v e n d uri n g t hat ti me fra me t he 
partici pa nts will be re m o ve d fr o m st u d y.  
 
F or t o xicities dee m e d t o be relate d t o R- C H O P, d ose re d ucti o ns will be gi ve n as 
i n dicate d bel o w. I n t he case of r ec urre nce of t he s pecific gr a de 3- 4 n o n-
he mat ol o gic t o xicit y, t he partici pa nt will be re m o v e d fr o m st u d y. I n t he cas e of 
rec urre nce of gr a de 2 n o n- he mat ol o gic t o xicit y, c o nti n uati o n o n t he st u d y will be 
at t he discreti o n of t he pri nci pal i n vesti gat or.  
  
7. 2. 2. 1  Ne ur o pat h y 
. 
Gi ve n t he well- d oc u m e nte d a n d rel ati vel y hi g h i nci de nce of vi ncristi ne-
i n d uce d peri p heral ne ur o pat h y, d ose m o dificati o n of vi ncristi ne ca n b e 
perf or me d a n y ti me d uri n g treat me nt at t he discr eti o n of t he i n vesti gat or i n 
acc or d a nce wit h i nstit uti o nal practices.  
 
  
7. 2. 2. 2 He m orr ha gi c C ystitis  
I ntr a ve n o us h y dr ati o n f or c ycl o p h os p ha mi de as p er i nstit uti o nal sta n dar d.  
S h o ul d gr oss he mat uria de vel o p, c ycl o p h os p ha mi d e will be wit h hel d u ntil 
res ol uti o n of c ystitis. S u bse q ue nt c ycles will be gi ve n at 5 0 % of t he i nitial 
d ose of c ycl o p h os p h a mi de f or o ne c ycle a n d, if t olerate d, i ncrease d t o 
7 5 % of t he f ull d ose f or r e mai ni n g c ycles.  
 
  
7. 2. 2. 3  Car diac M o nit ori n g 
. 
Partici pa nts will be m o nit ore d cl osel y f or cli nical si g ns a n d s y m pt o ms of 
h y per v ole mia, p ul m o nar y e de ma or i n dicati o ns of c o n gesti ve heart fail ur e 
or s us pecte d car diac e v e nt. If cli nical s us pici o n arises, f urt her e val uati o n is 
at t he discreti o n of t he i n vesti gat or b ut ma y i ncl u de E K G, N-t er mi nal pr o-
brai n natri uretic p e pti de ( N T p- B N P) meas ur e me nt a n d p ossi bl y 
ec h ocar di o gra m. If car di ac assess me nt re veals si g nifica nt c ha n g es fr o m 
baseli ne i n car diac f u n cti o n or si g nifica nt ele vati o ns i n N T p- B N P, f urt her 
d osi n g wit h d o x or u bici n ca n o nl y pr ocee d after wit h a p pr o val fr o m t he 
pri nci pal i n vesti gat or a n d t he s p o ns or.  
 
  
7. 2. 2. 4  He patic T o xicit y 
. 
If t he bilir u bi n is bet wee n 1. 5 a n d 3. 0 m g/ dl o n da y 1 of a n y c ycl e 2- 6, 

C A S E 1 4 2 0  
  
  
  
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d o x or u bici n d ose will be re d uce d b y 2 5 % a n d vi ncristi ne d ose m ust be 
re d uce d b y 5 0 %. If t h e h e patic f u ncti o n has ret ur n e d t o n or mal b y da y 1 of 
t he s u bse q ue nt c ycl e, f ull d oses will be gi ve n. If bilir u bi n is > 3. 0 m g/ dl, 
d o x or u bici n a n d vi ncristi ne s h o ul d dela ye d i n 1 w ee k i ncr e me nts f or u p t o 
2 wee ks u ntil < 3. 0 m g/ dl a n d t he n gi ve n wit h t he a b o ve d ose r e d ucti o ns. 
If bilir u bi n re mai ns > 3. 0 m g/ dl, t he St u d y M o nit or m ust be c o ntacte d a n d 
t he St u d y PI ( or d esi g nee) will be n otifie d a n d t he partici pa nt will be 
disc o nti n ue d fr o m t hera p y.   
 
  
7. 2. 2. 5  Rit u xi ma b H y perse nsiti vit y/I nf usi o n Reacti o ns 
. 
Beca use rit u xi ma b is k n o w n t o ca use h y p erse nsiti vit y a n d i nf usi o n 
reacti o ns, it will be i nf us e d wit h gra d uate d i n cre m e ntal rates d e pe n di n g o n 
w het her it is bei n g gi ve n as a n i nitial d ose (c ycl e 1) or s u bse q ue nt d ose ( 2-
6), per i nstit uti o nal g ui deli nes. As t he se verit y of i nf usi o n reacti o ns 
i ncreas e, t he i nf usi o n of rit u xi ma b will be eit her sl o we d or hel d, as 
i n dicate d per i nstit uti o nal sta n dar ds.  
 
  
  
7. 2. 2. 6 N o n- He mat ol o gic T o xicit y attri b uta ble t o d o x or u bici n a n d/ or  
  
  
c ycl o p h os p ha mi de, e x cl u di n g ne ur o pat h y, s us pect e d rit u xi ma b reacti o ns  
  
  
a n d he m orr h a gic c ystitis. 
If n o n- he mat ol o gic t o xicit y is dee me d t o be d ue t o t he c o m p o ne nts of R-
C H O P rat her t ha n M E- 4 0 1 a n d is n ot ne ur o pat h y, a rit u xi ma b reacti o n or 
he m orr ha gic c ystitis, t he d oses of d o x or u bici n a n d c ycl o p h os p ha mi de will 
be m o difie d as i n dicate d bel o w.  
 
If t he i n vesti gat or ca n n ot deter mi ne w het h er n o n- he mat ol o gic t o xicities 
are d ue t o M E- 4 0 1 or R- C H O P, it will be ass u me d t hat t he y are d u e t o 
M E- 4 0 1 a n d ma na g e d as disc usse d a b o ve. As a b o ve, R- C H O P s h o ul d be 
hel d u ntil t o xicit y ret ur ns t o gra de 1 or b etter.  
 
N o n- H e m at ol o gi c T o xi cit y att ri b ut a bl e t o R- C H O P , e x cl u di n g n e u r o p at h y, 
s u s p e ct e d rit u xi m a b r e a cti o n s a n d h e m o r r h a gi c c y stiti s 
E v e nt 
G r a d e 
M a n a g e m e nt / N e xt 
D o s e f o r D o x o r u bi ci n 
M a n a g e m e nt / N e xt D os e 
f o r C y cl o p h o s p h a mi d e 
M a n a g e m e nt / N e xt 
D o s e f o r Vi n c ri sti n e 
< Gr a d e 1 
N o c h a n g e i n d os e.   
N o c h a n g e i n d os e.  
N o c h a n g e i n d os e. 
Gr a d e 2  
H ol d u ntil ≤ Gr a d e 1 
u nl ess s y m pt o ms w er e 
n ot o pti m all y 
m e dic all y m a n a g e d. 
R es u m e at s a m e d os e 
l e v el.  
 
H ol d u ntil ≤ Gr a d e 1. 
R es u m e at s a m e d os e 
l e v el.  
 
N o c h a n g e i n d os e. 
Gr a d e 3  
H ol d D o x or u bici n u ntil 
< Gr a d e 2.*  
R es u m e at 7 5 % of 
pr e vi o us d os e.**  
H ol d C ycl o p h os p h a mi d e 
u ntil < Gr a d e 2.* R es u m e 
at 7 5 % pr e vi o us d os e.**  
 
N o c h a n g e i n d os e. 

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Gr a d e 4  
Disc o nti n u e 
D o x or u bici n a n d tr e at 
p ati e nt wit h off 
pr ot oc ol t h er a p y.  
 
Disc o nti n u e 
C ycl o p h os p h a mi d e a n d 
tr e at p ati e nt wit h off 
pr ot oc ol t h er a p y.  
 
Disc o nti n u e vi ncristi n e 
a n d tr e at p ati e nt wit h 
off pr ot oc ol t h er a p y.  
 
*P ati e nts r e q uiri n g a d el a y of > 2 w e e ks s h o ul d g o off pr ot oc ol t h er a p y.  
**P ati e nts r e q uiri n g t w o d os e r e d ucti o ns s h o ul d g o off pr ot oc ol t h er a p y.  
 
8. 0  
A D V E R S E E V E N T S A N D P O T E N TI A L RI S K S  
 
8. 1  
A d verse E v e nts a n d P ote ntial Ris k  
 
8. 1. 1   M E- 4 0 1 
T o xicities i ncl u de d ne utr o pe nia, t hr o m b oc yt o pe ni a, a n d i m m u ne relat e d a d verse e v e nts 
(s ki n ras h, diarr h ea/c olitis, he pat ot o xicit y, p ne u m o nitis).  Disc ussi o n re gar di n g 
ma na ge me nt of t hes e t o xicities ca n be f o u n d i n Secti o n 7. 1.   
 
8. 1. 2   C ycl o p h os p ha mi de  
T o xicities i ncl u de m yel os u p pressi o n, na usea a n d v o miti n g, he m orr ha gic c ystitis, a n d 
al o pecia. C ystitis ca n be lar gel y pre v e nte d b y mai ntai ni n g a g o o d state of h y drati o n a n d 
g o o d uri ne fl o w d uri n g a n d after dr u g a d mi nistrati o n usi n g t he f oll o wi n g. Please r efer t o 
t he pac ka g e i nsert f or a c o m plete listi n g of all t o xicities.  
 
8. 1. 3  D o x or u bici n 
T o xicities i ncl u de m yel os u p pressi o n, st o matitis, al o pecia, na usea a n d v o miti n g, a n d ac ute 
a n d c hr o nic car di ac t o xicit y, ma nifeste d as arr h yt h mias or a c o n gesti ve car di o m y o pat h y, 
t he latter u nc o m m o n at t otal c u m ulati ve d oses less t ha n 5 0 0 m g/ m 2. T he dr u g ca uses 
l ocal necr osis if i nfiltrate d i nt o s u bc uta ne o us tiss ue. Please r efer t o t he pac ka ge i nsert f or 
a c o m plete listi n g of all t o xicities.  
 
8. 1. 4  Pe gfil grasti m 
T o xicities i ncl u de rar e a n a p h ylactic r eacti o ns wit h t he first d ose; b o ne pai n at sites of 
acti ve marr o w wit h c o nti n ue d a d mi nistrati o n. L ocal reacti o ns at i njecti o n sites. 
C o nstit uti o nal s y m pt o ms, i ncreas e d al kali ne p h os p hatase, L D H, uric aci d; w orse ni n g of 
pre-e xisti n g i nfla m mat or y c o n diti o ns. Please ref er t o t he pac ka g e i nsert f or a c o m plete 
listi n g of all t o xicities.  
 
8. 1. 5  Pre d nis o ne 
T o xicities i ncl u de i ns o m nia, a gitati o n, pr o xi mal m uscle wea k n ess, gl uc os e i nt olera nce, 
t hi n ni n g of s ki n, re distri b uti o n of b o d y fat, C us hi n g oi d facies, i m m u n os u p pressi o n, a n d 
pr o pe nsit y t o gastr oi ntesti nal ulcerati o n. Please ref er t o t he pac k a ge i nsert f or a c o m plete 
listi n g of all t o xicities.  
 

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8. 1 . 6  Rit u xi ma b  
Re p orte d a d verse e v e nts i ncl u di n g fe ver, c hills, hea dac h e, na usea, v o miti n g, r hi nitis, 
ast he nia, a n d h y p ote nsi o n, occ urr e d pri maril y d uri n g rit u xi ma b i nf usi o ns a n d t y picall y 
res p o n de d t o a n i nterr u pti o n of t he i nf usi o n a n d res u m pti o n at a sl o wer rate. Fatal 
I nf usi o n Reacti o ns: Se vere a n d f atal car di o p ul m o nar y e ve nts, i ncl u di n g a n gi oe de ma, 
h y p o xia, p ul m o nar y i nfiltrates, ac ut e res pir at or y distress s y n dr o me, m y ocar dial 
i nfarcti o n, a n d car di o ge nic s h oc k, ha ve b ee n r e p orte d. Ot her r eacti o ns i ncl u de t u m or l ysis 
s y n dr o me, c yt o pe nias i ncl u di n g pr ol o n ge d pa nc yt o pe nia, marr o w h y p o plasia, a n d late 
o nset ne utr o pe nia. T h ere is a n i ncreas e d rat e of i nf ecti o us e ve nts, he p atitis B reacti vati o n. 
Please ref er t o t he p ac ka ge i nsert f or a c o m plete listi n g of all t o xicities.  
 
8. 1. 7  Vi ncristi ne 
T o xicities i ncl u de peri p h eral ne ur o pat h y, c o nsti pati o n, a ut o n o mic ne ur o pat h y, a n d 
al o pecia. L o cal necr osis if i njecte d s u bc uta n e o usl y. Please ref er t o t he p ac k a ge i nsert f or 
a c o m plete listi n g of all t o xicities.  
 
8. 1. 8  Tri met h o pri m/s ulfa met h o xaz ole ( T M P- S M X) 
T o xicities f or tri met h o pri m/s ulfa met h o xaz ole ca n i ncl u de bl o o d d yscrasias, der mat ol o gic 
reacti o ns, he p atic necr osis, h y per kale mia a n d t hr o m b oc yt o pe nia.  H o we v er, at t he 
pr o p h ylactic d osi n g it is us uall y well t olerate d wit h rare t o xicities. Pleas e r efer t o t he 
pac ka g e i nsert f or a c o m plete listi n g of all t o xicities.  
 
8. 1. 9 Pe nta mi di ne (aer os olize d) 
T o xicities i ncl u de fati g ue, dizzi ness, decreas e d a p petite, res pirat or y s y m pt o ms (s uc h as 
c o u g h a n d S O B) b ut it is ge nerall y w ell t olerate d. Please ref er t o t he p ac ka ge i nsert f or a 
c o m plete listi n g of all t o xicities.  
 
8. 1. 1 0 Ac ycl o vir  
T o xicities i ncl u de ne ur ol o gic t o xicit y i ncl u di n g a gitati o n, tre m ors, deliri u m, hall uci nati o ns, 
an d m y ocl o n us, wit h hi g her ris k i n patie nt wit h re nal i ns ufficie nc y. Please refer t o pac ka ge 
i nsert f or a c o m plete listi n g of all t o xicities. 
 
8. 2   
Defi niti o ns  
 
8. 2. 1  
A d verse E ve nt   
A n  a d verse e ve nt ( A E) is a n y u nf a v ora bl e or u ni nte n de d e v e nt, p h ysical or ps yc h ol o gical, 
ass ociate d wit h a researc h st u d y, w hic h ca uses h ar m or i nj ur y t o a r esearc h partici pa nt as 
a res ult of t h e partici p a nt’s i n v ol ve me nt i n a r esear c h st u d y. T he e ve nt ca n i ncl u de 
a b n or mal la b orat or y fi n di n gs, s y m pt o ms, or disease ass ociate d wit h t he r esear c h st u d y. 
T he e ve nt d o es n ot necessaril y ha ve t o ha v e a ca usal relati o ns hi p wit h t he resear c h, a n y 
ris k ass ociate d wit h t he r esear c h, t he r esearc h i nter ve nti o n, or t he res ear c h assess me nts.  
 
A d verse e v e nts ma y be t he res ult of t he i nter ve nti o ns a n d i nteracti o ns use d i n t he researc h; 
t he c ollecti o n of i de ntifia ble pri vate i nf or mati o n i n t he researc h; a n u n d erl yi n g disease, 
dis or der, or c o n diti o n of t he partici pa nt; a n d/ or ot her circ u msta nces u nrelate d t o t he 
researc h or a n y u n derl yi n g disease, dis or der, or c o n diti o n of t he partici pa nt.  
 

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8. 2 . 2   Seri o us A d verse E ve nts  
A seri o us a d verse e ve nt ( S A E) is a n y a d verse e x p erie nce occ 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:  
•  Res ults i n de at h.   
•  Is a lif e-t hre ate ni n g a d verse e x perie nce.  T h e ter m life-t hr eate ni n g i n t he 
defi niti o n of seri o us refers t o a n a d verse e ve nt i n w hic h t he partici pa nt was at 
ris k of deat h at t he ti me of t he e v e nt.  It d o es n ot refer t o a n a d v erse e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h if it were m ore se ver e.  
•  Re q uires 
i n p atie nt 
h os pit aliz ati o n 
or 
pr ol o n g ati o n 
of 
e xisti n g 
h os pit aliz ati o n .  A n y a d verse e ve nt lea di n g t o h os pitalizati o n or pr ol o n gati o n 
of h os pitalizati o n will be c o nsi dere d as Seri o us, U N L E S S at least o ne of t he 
f oll o wi n g e x pectati o ns is met: 
o  T he a d missi o n res ults i n a h os pital sta y of less t ha n 2 4 h o urs O R  
o  T he a d missi o n is pre- pla n ne d (e. g., electi ve or s c he d ule d s ur g er y 
arra n g e d pri or t o t he start of t he st u d y) O R  
o  T he a d missi o n is n ot ass ociate d wit h a n a d v erse e ve nt ( e. g., s ocial 
h os pitalizati o n f or p ur p oses of res pite car e.  
H o we ver it s h o ul d be n ot e d t hat i n vasi ve treat me nt d uri n g a n y h os pitalizati o n ma y 
f ulfill t he criteria of “ me dicall y i m p orta nt” a n d as s uc h ma y be re p orta ble as a 
seri o us a d verse e ve nt de pe n de nt o n cli nical j u d g me nt.  I n a d diti o n w her e l ocal 
re g ulat or y a ut h orities s pecificall y re q uir e a m or e stri n ge nt defi niti o n, t he l ocal 
re g ulati o n ta kes pr ece d e nt.  
•  Res ults i n persiste nt or si g nific a nt dis a bilit y/i nc a p acit y .  T h e defi niti o n of 
disa bilit y is a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life’s 
f u ncti o ns. 
•  Is a c o n ge nit al a n o m al y/ birt h defect .  
•  Is a n i m p ort a nt m e dic al e ve nt.  I m p orta nt me dical e ve nts t hat ma y n ot res ult 
deat h, be life-t hreat e ni n g, or re q uir e h os pitalizati o n ma y be c o nsi der e d a s eri o us 
a d verse e x perie n ce w h e n, base d u p o n a p pr o priat e me dical j u d g me nt, t he y ma y 
je o par dize t he partici pa 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 mes liste d i n t his defi niti o n.  E xa m ples of s uc h m e dical 
e ve nts i ncl u de aller gic br o nc h os pas 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 disease or dis or ders, 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, or t he de v el o p me nt of dr u g d e pe n de nc y 
or dr u g a b use. T h e de v el o p me nt of a ne w ca n cer is al wa ys c o nsi der e d a n 
i m p orta nt me dical e ve nt. 
 
F or t he p ur p os e of t his st u d y t he f oll o wi n g e ve nts w o ul d n ot be c o nsi dere d a d verse 
e ve nts a n d w o ul d n ot be rec or d e d i n t he data b ase: 
•  A b n or mal la b orat or y fi n di n gs c o nsi dere d ass o ciate d t o t he ori gi nal disease 
 
8. 2. 3 
A d verse E ve nt E v al u ati o n  
T h e i n vesti gat or or desi g nee is r es p o nsi ble f or e ns uri n g t hat all a d v erse e ve nts ( b ot h seri o us 
a n d n o n-seri o us) o bs er ve d b y t he cli nical tea m or re p orte d b y t he p artici pa nt w hic h occ ur 
after t he p artici pa nt h as si g ne d t he i nf or me d c o nse nt are f ull y r ec or de d i n t he partici pa nt’s 
me dical rec or ds. S o urce d oc u me ntati o n m ust be a vaila ble t o s u p p ort all a d verse e v e nts.  

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A la b orat or y test a b n or malit y c o nsi dere d cli nicall y rele va nt ( e. g., ca usi n g t he partici pa nt 
t o wit h dra w fr o m t he st u d y, re q uiri n g treat me nt or ca usi n g a p pare nt cli nical ma nifestati o ns, 
res ult i n a dela y or d os e m o dificati o n of st u d y treat me nt, or j u d ge d r ele va nt b y t he 
i n vesti gat or), s h o ul d be r e p orte d as a n a d verse e v e nt.   
 
T he i n vesti gat or or s u b-i n vesti gat or (treati n g p h ysicia n if a p plica ble) will pr o vi de t he 
f oll o wi n g f or all a d verse e ve nts ( b ot h seri o us a n d n o n-seri o us): 
•  E ve nt ter m (as p er C T C A E) 
•  Descri pti o n of t he e v e nt 
•  Date of o nset a n d res ol uti o n 
•  E x pecte d ness of t he t o xicit y 
•  Gr a de of t o xicit y  
•  Attri b uti o n of rel ate d ness t o t he i n vesti g ati o n al a ge nt- (t his m ust be assi g ne d 
b y a n i n vesti g at or, s u b-i n vesti g at or, or t re ati n g p h ysici a n) 
•  Acti o n ta ke n as a r es ult of t he e v e nt, i ncl u di n g b ut n ot li mite d t o; n o c ha n ges, d ose 
i nterr u pte d, re d u ce d, disc o nti n ue d, etc. or acti o n ta ke n wit h re gar d t o t he e v e nt, i.e. 
n o acti o n, recei ve d c o n m e d or ot her i nter v e nti o n, etc. 
•  O utc o me of e v e nt 
 
Descri pti o ns a n d gr a di n g sc ales  f o u n d i n t he N CI C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts ( C T C A E) versi o n 5. 0  will be utilize d f or A E re p orti n g.  
 
A n  e x pecte d a d verse e ve nt  is a n e v e nt pre vi o usl y k n o w n or a ntici pate d t o res ult fr o m 
partici pati o n i n t he researc h st u d y or a n y u n d erl yi n g disease, dis or der, or c o n diti o n of t he 
partici pa nt. T h e e v e nt is us uall y liste d i n t he I n vesti gat or Br oc h ure, c o nse nt f or m or 
researc h pr ot o c ol.  
 
A n u ne x pecte d a d verse e ve nt is a n a d verse e ve nt n ot pre vi o usl y k n o w n or a ntici pate d t o 
res ult fr o m t he researc h st u d y or a n y u n derl yi n g disease, dis or der, or c o n diti o n of t he 
partici pa nt.  
 
Attri b uti o n  is t he relati o ns hi p bet wee n a n a d vers e e ve nt or seri o us a d vers e e ve nt a n d t he 
st u d y dr u g.  Attri b uti o n will be assi g ne d as f oll o ws: 
 
•  Defi nite – T he A E is clearl y relate d t o t he st u d y dr u g. 
•  Pr o ba ble – T he A E is li k el y relate d t o t he st u d y dr u g. 
•  P ossi ble – T he A E ma y be relate d t o t he st u d y dr u g. 
•  U nli kel y – T he A E is d o u btf ull y relate d t o t he st u d y dr u g. 
•  U nrelate d – T h e A E is cl earl y N O T relate d t o t he st u d y dr u g. 
 
Pr ot oc ol m ust s pecif y if attri b uti o n is re q uire d f or i n di vi d ual c o m p o ne nts of t he treat me nt 
re gi me n or t he tr eat me nt re gi me n as a w h ole. 
 
 
 

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8. 3  
S A E Re p ort F or m 
S A Es will be rec or d e d o n t he F D A F or m 3 5 0 0 A ( Me d Watc h) b ut s h o ul d o nl y be re p orte d 
as i nstr ucte d bel o w.  T h e electr o nic F D A S A E re p orti n g f or ms s h o ul d n ot be use d.   
 
8. 4   
Re p orti n g Pr oce d ures f or Seri o us A d verse E ve nts  
F or t he p ur p oses of s afet y re p orti n g, all a d verse e ve nts will be r e p orte d t h at occ ur o n or 
after C y cle 1 Da y 1 t hr o u g h 3 0 da ys after t he fi n al d ose of st u d y dr u g, a n d  9 0 da ys f or 
e val uati o n a n d ca pt ure of pre-s pecifie d A E SIs after t heir fi nal d os e of M EI- 4 0 1. A d vers e 
e ve nts, b ot h seri o us a n d n o n-seri o us, a n d deat hs t hat occ ur d uri n g t his peri o d will be 
rec or d e d i n t he s o urce d oc u me nts. All S A Es s h o ul d be m o nit ore d u ntil t he y are r es ol ve d 
or are clearl y d eter mi ne d t o be d ue t o a partici pa nt’s sta ble or c hr o ni c c o n diti o n or 
i nterc urr e nt ill ness(es). Relate d A Es a n d all A E SIs will be f oll o we d u ntil res ol uti o n t o 
baseli ne or gr a de 1 or sta bilizati o n.  
 
All A E SIs are liste d i n t he m ost rece nt versi o n of t he I n vesti g at or Br o c h ure. 
 
 
8. 4. 1 
S A E Re p orti n g Re q uire m e nts 
•  Partici pati n g i n vesti gat ors (all sites) m ust r e p ort all seri o us a d v erse e ve nts a n d 
a d verse e ve nts of s pecial i nterest ( A E SIs) t o t he Lea d Site Pri nci pal I n vesti gat or 
(e. g. S p o ns or-I n vesti gat or) wit hi n 2 4 h o urs  of disc o ver y or n otificati o n of t he 
e ve nt. T he p artici pati n g i n vesti gat or m ust als o pr o vi de f oll o w- u p i nf or mati o n o n 
t he S A E u ntil fi nal res ol uti o n.  
o  PI: Dee pa Ja g a dees h, M D (see fr o nt pa ge f or c o ntact i nf or mati o n) 
o  
 a n d t he lea d st u d y c o or di nat or (see fr o nt pa g e f or 
c o ntact i nf or mati o n) 
•  T he  Lea d Site  Pri nci pal I n vesti gat or will re vie w t he S A E a n d/ or A E SI a n d re p ort 
t he e ve nt t o t he F D A, M EI P har ma, e xter n al c olla b orat or(s), a n d I R B as a p plica ble. 
O nl y A Es a n d A E SIs meeti n g t he re g ulat or y defi niti o n of a seri o us a d vers e e ve nt 
s h o ul d be re p orte d t o 
M EI P har ma as disc usse d bel o w u n der 
M EI P har ma 
Re p orti n g Re q uire me nts. 
•  It is t he S p o ns or-I n vesti g at or’s res p o nsi bilit y (e. g. lea d site PI) t o e ns ure t hat A L L 
seri o us a d vers e e ve nts t h at occ ur o n t he st u d y (e. g. A L L S A Es t hat occ ur at eac h 
e nr olli n g i nstit uti o n) are re p orte d t o all partici pati n g sites. 
 
M EI P h ar m a Re p orti n g Re q uire m e nts:  
•  All S A Es, re gar dless of r elati o ns hi p t o st u d y dr u g, m ust be re p orte d t o M EI 
P har ma at 
 wit hi n 1 b usi ness da y of st u d y 
I n v esti gat or’s k n o wle d g e of t he e ve nt, d uri n g t he st u d y a n d t hr o u g h 3 0 da ys after 
recei vi n g t he last d ose of st u d y treat me nt. S A Es m ust be re p orte d i n a gree me nt 
wit h ter ms set f ort h i n t he st u d y c o ntract. 
•  Re p orts will be s u b mitte d usi n g F or m F D A 3 5 0 0 A ( Me d W atc h) a n d i ncl u de a 
narrati ve d escri pti o n of t he S A E(s), se v erit y gra d e, a p plica ble s eri o us ness criteria, 
start a n d st o p dates of t he e ve nt, o utc o me of t he e v e nt, a n d t he I n vesti gat or’s 
assess me nt of t he ca usal relati o ns hi p bet wee n t h e S A E(s) a n d M E- 4 0 1. 

C A S E 1 4 2 0  
  
  
  
Pa ge 4 0   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
•  T he  i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all A Es a n d S A Es t hat are 
o bser ve d or re p ort e d d uri n g t he st u d y, as o utli ne d i n t he pri or secti o ns, ar e 
rec or d e d o n t he C R F. 
•  It is t he r es p o nsi bilit y of t he S p o ns or-I n vesti gat or ( Cle vela n d Cli nic Pri nci pal 
I n v esti gat or) t o re p ort seri o us a d verse e ve nts t o t he dr u g s u p plier ( M EI P har ma) 
a n d t o t he U S F D A, as re q uire d. 
 
 
I nstit uti o n al Re vie w B o ar d Re p orti n g Re q uire m e nts: 
•  I n v esti gati ve sites will r e p ort a d verse e ve nts t o t h eir r es pecti ve I R B acc or di n g t o 
t he l ocal I R B’s p olicies a n d pr oce d ur es i n re p orti n g a d verse e ve nts.  
 
8. 5  
S A Es a n d O n C ore 
•  Al l S A Es will be e ntere d i nt o O n C ore.   
•  A c o p y of t he S A E f or m(s) s u b mitte d t o t he s p o ns or-i n vesti gat or is als o u pl oa de d 
i nt o O nc ore. 
  
 
 
8. 6   
D at a S afet y a n d T o xicit y C o m mittee  
It is t he res p o nsi bilit y of eac h site PI t o e ns ure t hat A L L S A Es occ urri n g o n t his trial 
(i nter nal or e xter nal) are re p orte d t o t he Case C o m pre he nsi ve Ca ncer Ce nter’s Data a n d 
Safet y T o xicit y C o m mittee. T his s u b missi o n is si m ulta ne o us wit h t heir s u b missi o n t o t he 
s p o ns or a n d/ or ot her r e g ulat or y b o dies.  
 
T he s p o ns or-i n vesti gat or is res p o nsi ble f or s u b mitti n g a n a n n ual re p ort t o t he D S T C as per 
C C C C Data a n d Safet y M o nit ori n g Pla n. 
  
8. 7  
D at a a n d S afet y M o nit o ri n g Pl a n ( D S M P) 
T his pr ot oc ol will a d here t o t he p olicies of t he Cas e C o m pre he nsi ve Ca n cer Ce nter Data 
a n d Safet y M o nit ori n g Pla n i n acc or da nce wit h N CI g ui deli nes.  
 
9. 0  
P H A R M A C E U TI C A L I N F O R M A TI O N  
A list of t he a d vers e e v e nts a n d p ote ntial ris ks ass ociate d wit h t he i n vesti gati o nal or 
c o m mercial a g e nts a d mi nistere d i n t his st u d y ca n be f o u n d i n Secti o n 8. 0 .    
 
 
9. 1 M E- 4 0 1 ( Z a n delisi b) 
 
 
Ot her Na mes:    
P W T- 1 4 3 
 
Classificati o n:   
PI 3 K d elta i n hi bit or 
 
 
Pr o d uct descri pti o n: Ca ps ules of 4 5 m g a n d 6 0 m g.  
 
S ol uti o n pre parati o n: N o pre par ati o n re q uir e d.  
 

C A S E 1 4 2 0  
  
  
  
Pa ge 4 1   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
St ora ge re q uir e me nts: M E- 4 0 1 s h o ul d be st ore d i n a c o ol place or at c o ntr olle d r o o m 
te m perat ur e, 1 5- 2 5° C ( 5 9- 7 7° F). S o me U S sites will st ore bet wee n 2 0- 2 5° C ( 6 8 - 7 7° F) 
per M E- 4 0 1 pr o d u ct la bel.   
 
R o u te of a d mi nistrati o n:  M E- 4 0 1 is t o be ta ke n or all y o nce a d a y wit h a glass of water 
o n a n e m pt y st o mac h at l east 1 h o ur pri or t o f o o d or 2 h o urs after f o o d at t h e sa me ti me 
eac h d a y.  Partici pa nts u na ble t o ta ke M E- 4 0 1 o n a n e m pt y st o mac h ar e all o we d t o ta ke 
M E- 4 0 1 wit h a li g ht, n o n-fatt y s nac k.  If p ossi ble, se parat e ta ki n g M E- 4 0 1 ca ps ules fr o m 
t hat of c o nc o mita nt me di cati o ns t hat ha ve a k n o w n effect o n p- gl yc o pr ot ei n, Breast 
Ca ncer Resista nce Pr otei n ( B C R P) tra ns p orter, a n d C Y P 2 C 8 s u bstrates, as well as 
c o nc o mita nt oral me dicati o ns t hat ha ve k n o w n i nteracti o ns wit h dr u gs t hat i n hi bit P- g p, 
B C R P, a n d C Y P 3 A 4.  
 
Dr u g Pr oc ur e me nt: M E- 4 0 1 will be s u p plie d b y M EI P har ma I n c.   
 
Dr u g A cc o u nta bilit y: T h e i n vesti gat or or d esi g nate d st u d y pers o n n el are r es p o nsi ble f or 
mai ntai ni n g acc urate dis pe nsi n g rec or ds of t he st u d y dr u g. All st u d y dr u gs m ust be 
acc o u nte d f or, i ncl u di n g st u d y dr u g acci de nt all y or deli beratel y d estr o ye d. U n der n o 
circ u msta nces will t he i n vesti gat or all o w t he i n vesti gati o nal dr u g t o be use d ot her t ha n as 
directe d b y t he pr ot oc ol. If a p pr o priate, dr u g st ora ge, dr u g dis pe nsi n g, a n d dr u g 
acc o u nta bilit y ma y be dele gate d t o t he p har m ac y s ecti o n of t he i n vesti gati ve site.  
 
Dr u g Destr ucti o n: At t he c o m pleti o n of t he st u d y, t her e will be a fi nal rec o nciliati o n of 
dr u g s hi p pe d, dr u g c o ns u me d, a n d dr u g re m ai ni n g. T his rec o nciliati o n will be l o g ge d o n 
t he dr u g r ec o nciliati o n f or m, si g ne d a n d dat e d. 
A n y discr e pa n cies n ote d 
will be 
i n vesti gate d, res ol ve d, a n d d oc u me nte d pri or t o ret ur n or destr u cti o n of u n use d st u d y dr u g. 
Dr u g destr o ye d o n site will be d oc u me nte d i n t he st u d y files.  
 
 
9. 2   
C ycl o p h os p h a mi de 
 
C he mical Na me:   
2-[ bis( 2-c hl or o et h yl)a mi n o]tetra h y dr o- 2 H- 1, 3, 2-  
  
 
  
  
  
o xaza p h os p h ori n e 2- o xi d e m o n o h y drate.  
Ot her Na mes:    
C yt o xa n T M 
Classificati o n:   
Nitr o ge n M ustar d, A nti n e o plastic A ge nt 
M o lec ular F or m ula: 
C7 H 1 5 Cl 7 N 2 O 2 P• H 2 O   
M o de of Acti o n:  
A n acti vate d f or m of c y cl o p h os p ha mi de, p h os p h ora mi de m ustar d,  
  
  
  
al k ylates or bi n ds wit h ma n y i ntracell ular m olec ul ar str uct ur es,  
  
  
  
i ncl u di n g n ucleic aci ds.  Its c yt ot o xic acti o n is pri maril y d ue t o  
  
  
  
cr oss-li n ki n g of stra n ds of D N A a n d R N A, as well as i n hi biti o n of  
  
  
  
pr otei n s y nt hesis.  
 

C A S E 1 4 2 0  
  
  
  
Pa ge 4 2   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
Me ta b olis m: 
  
  
  
A bs or pti o n:  
S yste mic: Bi oa vaila bilit y: > 7 5 % 
  
  
  
Meta b olis m:  S yste mic: He patic 
  
  
  
E xcreti o n:  
 S yste mic Re nal, 5 t o 2 5 % u nc ha n ge d. I n dial ysis:  
  
  
  
  
  
c ycl o p h os p ha mi de is dial yza ble.  
  
  
  
Eli mi nati o n Half Life:   
3 t o 1 2 h o urs.  
 
Pr o d uct descri pti o n: w hite cr ystalli ne p o w d er  
 
S ol uti o n pre parati o n: rec o nstit ute wit h N S t o i nject directl y, (i nf usi o n) diss ol ve i n Sterile 
Water f or I njecti o n, U S P ( 2 5 m L f or 5 0 0 m g, 5 0 m L f or 1 g, 1 0 0 m L f or 2 g); t he n dil ute 
i n D 5 W, 5 % de xtr os e i n 0. 9 % n or mal sali ne ( D 5 N S) or lactate d ri n gers ( D 5 L R or L R).  
 
St ora ge re q uir e me nts: St ora ge at or bel o w 7 7° F ( 2 5° C) is rec o m me n de d; t his pr o d uct will 
wit hsta n d brief e x p os ur e t o te m perat ures u p t o 8 6° F ( 3 0° C) b ut s h o ul d be pr otecte d fr o m 
te m perat ur es a b o ve 8 6° F ( 3 0° C).  
 
Sta bilit y: Rec o nstit ute d l y o p hilize d c ycl o p h os p ha mi de is c he micall y a n d p h ysicall y 
sta ble f or 2 4 h o urs at r o o m te m perat ure or f or si x da ys w he n r efri gerate d.  
 
R o ute of a d mi nistrati o n: S h ort i ntra ve n o us i nf usi o n o ver 3 0- 6 0 mi n utes. 
 
Dr u g Pr oc ur e me nt: C ycl o p h os p ha mi de will be o btai ne d fr o m c o m mer cial s o urces.  
 
9. 3  
D o x or u bici n 
C he mical Na me:   
1 4- H y dr o x y da u n o m yci n 
  
Ot her Na mes:    
D o x or u bici n H y dr oc hl ori de 
 
Classificati o n:   
A nt hrac ycli ne, A nti ne o plastic A ge nt 
 
M o lec ular F or m ula: 
C 2 7 H 2 9 N O 1 1 
 
M o de of Acti o n:  
D N A I nter calati o n   
 
Meta b olis m: 
  
  
A) Distri b uti o n Sites 
  
  
  
1) Pr otei n Bi n di n g: 7 4 % t o 7 6 % 
  
  
  
2) Ot her Distri b uti o n Sites Place nta: Place nt a c o n ce ntrati o ns of  
  
  
  
d o x or u bici n wer e 1. 2 n m ol/ g of tiss ue w he n a si n gle patie nt  
  
  
  
recei v e d d o x or u bici n a b o ut 4 8 h o urs bef ore d eli ver y. U m bilical  
  
  
  
c or d c o nce ntrati o ns were 0. 0 8 n m ol/ g i n t he sa me patie nt.  
  
  
B) Distri b uti o n Ki netics 
  
  
  
1) Distri b uti o n Half- Life: 5 mi n utes 
  
  
  
2) V ol u me of Distri b uti o n: 2 0 t o 3 0 liters/ kil o gra m  
  
  
C) Meta b olis m Sites a n d Ki netics Li ver, e xte nsi v e C ha n ges i n li ver  

C A S E 1 4 2 0  
  
  
  
Pa ge 4 3   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
  
 
    f u ncti o n ca use d b y h e pat ocell ular carci n o ma res ult i n ele vate d plas ma  
  
  
   c o nce ntr ati o ns of d o x or u bici n ol rat her t ha n d o x or u bici n 
  
  
D) Meta b olites  
  
  
  
1) D o x or u bici n ol, acti ve.  
  
  
  
2) A dria m yci n a gl y c o nes.  
  
  
E) Ki d ne y  
  
  
  
1) Re nal E xcr eti o n: 5 % t o 1 2 % 
  
  
  
2) O nl y 1 % a p pears i n t h e uri ne o ver 5 da ys; less t ha n 1 % a p pears  
  
  
  
    i n t he uri ne as a gl yc o n es.  
  
  
F) Ot her 
  
  
  
( 1) Bile, 4 0 % a n d ( 2) Feces, 5 0 % 
  
  
G) Pare nt C o m p o u n d  
  
  
  
1) Eli mi nati o n Half-life: 2 0 t o 4 8 h o urs.  
  
  
H) Meta b olites: D o x or u bici n ol, 2 0 t o 4 8 h o urs.  
 
Pr o d uct descri pti o n: D o x or u bici n H y dr oc hl ori de I njecti o n is a sterile par e nteral, is ot o nic 
s ol uti o n i n eit her si n gle d ose of m ulti- d ose vials.  
 
S ol uti o n pre parati o n: After rec o nstit uti o n, s ol uti o n is sta ble at r o o m te m perat ure f or 7 
da ys a n d i n t he refri ger at or bet wee n 2 a n d 8 de grees C f or 1 5 da ys. Pr otect fr o m s u nli g ht.  
 
St ora ge re q uir e me nts: St ore p o w der at c o ntr olle d r o o m te m perat ur e bet wee n 1 5 a n d 3 0 
de grees C ( 5 9 a n d 8 6 de grees F). St ore i n ori gi nal cart o n t o pr otect fr o m li g ht. Discar d 
a n y u n use d p orti o n  
 
Sta bilit y: D o x or u bici n 8 m g/ 5 0 0 m L i n gl uc ose 5 % was sta ble f or 7 da ys w he n st ore d i n 
P V C ( p ol y vi n yl c hl ori de) ba gs at 4 de gr ees C wit h li g ht pr otecti o n. T here w as als o n o 
l oss of d o x or u bici n w he n i nf use d via P V C i nf usi o n ba gs wit h P V C a d mi nistrati o n.  
D o x or u bici n 2 m g/ m L was sta ble f or u p t o 1 4 da ys at 3 or 2 3 de gr ees C a n d f or a n 
a d diti o nal 2 8 da ys at 3 0 de grees C i n p orta bl e p u m p reser v oirs.  
D o x or u bici n was sta ble (less t ha n 1 0 % l oss of p ote nc y) f or 2 4 da ys i n 0. 9 % s o di u m 
c hl ori de st ore d at 2 5 d e gr ees C i n P V C ( p ol y vi n yl c hl ori de) mi ni ba gs a n d s yri n ges at a 
p H of 6. 4 7. Als o, d o x or u bici n was sta ble f or at least 4 3 da ys i n 0. 9 % s o di u m c hl ori de 
( p H, 6. 4 7) a n d 5 % de xtr ose ( p H, 4. 3 6) at 4 a n d - 2 0 de grees C.  
Alt h o u g h d o x or u bici n d oes react wit h al u mi n u m, t he reacti o n is sl o w a n d d oes n ot res ult 
i n a s u bsta ntial l oss of p ote nc y. D o x or u bici n r ec o nstit ute d wit h 0. 9 % s o di u m c hl ori de 
i njecti o n or sterile water f or i njecti o n t o a c o n ce ntrati o n of 2 m g/ m L a n d c o m bi ne d wit h 
steel, plastic, or al u mi n u m was e xa mi ne d f or c ol or, p H, a n d p ote n c y. I n t he first 2 4 h o urs, 
p H c ha n ge d fr o m 4. 8 t o 4. 9 i n s ol uti o ns c o ntai ni n g plastic or steel. I n t he al u mi n u m-
c o ntai ni n g s ol uti o n, t he p H c ha n ge d fr o m 4. 8 t o 5. 2 a n d t he s ol uti o n c ha n ge d t o a dar ker 
r u b y re d. T here w as n o c ha n ge i n p ote nc y i n a n y of t he s ol uti o ns c o ntai ni n g steel a n d 
al u mi n u m, res pecti vel y. N o preci pitati o n was n ot e d; t heref ore, d o x or u bi ci n ma y be saf el y 
i njecte d t hr o u g h a n al u mi n u m- h u b be d nee dle. H o we ver, rec o nstit ute d d o x or u bici n s h o ul d 
n ot be st ore d i n s yri n ges ca p pe d wit h al u mi n u m- h u b be d nee dles.  
 
 

C A S E 1 4 2 0  
  
  
  
Pa ge 4 4   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
R o ute of a d mi nistrati o n:  
( 1). F or I V use o nl y; d o n ot a d mi nister I M or s u b c uta ne o usl y ( S C) 
( 2). A d mi nister sl o wl y i nt o freel y r u n ni n g I V of S o di u m C hl ori de I njecti o n, U S P or  
D 5 W o ver n ot less t ha n 3 t o 5 mi n utes, de pe n di n g o n t he size of t he v ei n a n d t he d osa ge; 
a v oi d vei ns o ver j oi nts or t h ose wit h p o or drai na ge; B utterfl y( R) nee dle i nserte d i nt o a 
lar ge vei n is prefer a ble.  
( 3). Care s h o ul d b e ta ke n t o a v oi d e xtra vas ati o n as se vere l o cal tiss ue necr osis will occ ur; 
e xtra vas ati o n ma y occ ur wit h or wit h o ut b ur ni n g or sti n gi n g, a n d e ve n if t here is bl o o d 
ret ur n o n as pir ati o n of t he nee dle 
( 4). If e xtra vas ati o n is s us pecte d, i m me diatel y st o p a d mi nistrati o n a n d rest art i n a n ot her 
vei n; i nter mitte ntl y a p pl y ice t o t he site f or 1 5 mi n utes, 4 ti mes dail y f or 3 da ys.  
 
Dr u g Pr oc ur e me nt: D o x or u bici n t o be o btai ne d fr o m c o m mercial s o urces.  
 
9. 4  
Pe gfil gr asti m 
C he mical Na me:   
N-( 3- h y dr o x y pr o p yl) met hi o n ylc ol o n y-sti m ulati n g fact or ( h u m a n),  
  
  
  
1-et her wit h α - met h yl-ω - h y dr o x y p ol y( o x yet h yle n e)  
  
O ther Na mes:    
Ne ulasta T M , rec o m bi na nt met hi o n yl h u ma n gra n ul oc yte c ol o n y- 
  
 
  
sti m ulati n g fact or ( G- C S F)  
 
Classificati o n:   
He mat o p oietic Gr o wt h Fact or  
 
M o lec ular F or m ula: C 8 4 9 H 1 3 4 8 N 2 2 3 O 2 4 4 S 9 •( C2 H 4 O) 
 
M o de of Acti o n:  
Bi os y nt hetic he mat o p oietic a ge nt t hat aff ects t he pr oliferati o n a n d  
  
  
  
differe ntiati o n of n e utr o p hils wit hi n b o ne marr o w.  
 
 
Meta b olis m:   
Re nal. Ne utr o p hil rece pt or bi n di n g is a n i m p orta nt fact or i n  
  
  
  
pe gfil grasti m cleara nce. Ser u m clear a nce is relate d t o t he n u m ber  
  
  
  
of circ ulati n g ne utr o p hils; ser u m c o nce ntr ati o ns of t he dr u g decli ne 
  
  
  
ra pi dl y wit h res ol uti o n of ne utr o pe nia.  
 
Pr o d uct descri pti o n: Pe gfil grasti m is pr o vi de d i n a dis pe nsi n g pac k c o ntai ni n g o ne 
s yri n ge.  
 
S ol uti o n pre parati o n: Pe gfil grasti m is s u p plie d as a preser v ati ve- free s ol uti o n c o ntai ni n g 
6 m g ( 0. 6 m L) at a c o n ce ntrati o n of 1 0 m g/ m L i n a si n gle- d ose s yri n ge wit h a 2 7 ga u ge, 
1/ 2 i nc h nee dle wit h a n Ultra Safe Ò Nee dl e G uar d.  
 
St ora ge re q uir e me nts: Pe gfil grasti m s h o ul d be st ore d refri ger ate d at 2° t o 8° C ( 3 6° t o 
4 6° F); s yri n ges s h o ul d b e ke pt i n t heir cart o n t o pr otect fr o m li g ht u ntil ti me of use. 
S ha ki n g s h o ul d be a v oi de d. Bef ore i njecti o n‚ pe gfil grasti m ma y be all o we d t o reac h 
r o o m te m perat ur e f or a ma xi m u m of 4 8 h o urs b ut s h o ul d be pr otecte d fr o m li g ht.  
 

C A S E 1 4 2 0  
  
  
  
Pa ge 4 5   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
St a bilit y: Pe gfil grasti m left at r o o m te m per at ure f or m ore t ha n 4 8 h o urs s h o ul d be 
discar de d. Freezi n g s h o ul d be a v oi de d; h o we v er, if acci d e ntall y fr oze n, pe gfil grasti m 
s h o ul d be all o we d t o t ha w i n t he refri g erat or b ef ore a d mi nistrati o n. If fr oze n a sec o n d 
ti me, pe gfil grasti m s h o ul d be discar d e d.  
 
R o u te of a d mi nistrati o n: S u bc uta ne o us i njecti o n  
 
Dr u g Pr oc ur e me nt: Pe gfil grasti m will be fr o m c o m mercial s o urces.  
 
9. 6  
Pre d nis o ne 
C h emical Na me:   
1 7, 2 1- di h y dr o x y pre g n a- 1, 4- die ne- 3, 1 1, 2 0-tri o ne  
Ot her Na mes:    
N o ne  
Classificati o n:   
A dre nal Gl uc oc ortic oi d, I m m u ne S u p pr essa nt  
M olec ular F or m ula: 
C 2 1 H 2 6 O 5  
 
M o de of Acti o n:  
Pre d nis o ne is a n a dr e n oc ortical ster oi d wit h salt-r etai ni n g   
  
  
  
pr o perties. It is a s y nt heti c gl uc oc ortic oi d a n al o g, w hic h is mai nl y  
  
  
  
use d f or a nti-i nfla m mat or y eff ects i n differe nt dis or ders of ma n y  
  
  
  
or ga n s yste ms. It ca us es pr of o u n d a n d varie d met a b olic eff ects,  
  
  
  
m o difies t he i m m u ne res p o nse of t he b o d y t o di verse sti m uli a n d is 
  
  
  
als o use d as re pl ace m e nt t hera p y f or a dr e n oc ortical deficie nt  
  
  
  
patie nts .  
 
 
Meta b olis m:   
A) Bi oa vaila bilit y  
  
  
  
  
1) Oral, r e g ular r eleas e: 9 2 %  
  
  
  
B) Distri b uti o n Sites  
  
  
  
  
1) Pr otei n Bi n di n g 7 0 %, T he acti ve met a b olite,   
 
  
  
  
  
pre d nis ol o ne, is n o nli nearl y b o u n d t o tra nsc orti n a n d  
  
  
  
  
al b u mi n .  
  
  
  
C) Distri b uti o n Ki netics  
  
  
  
  
1) V ol u me of Distri b uti o n 0. 4 t o 1 L/ k g  
  
  
  
D) Meta b olis m Sites 
  
  
  
  
1) Li ver, e xte nsi v e.  
  
  
  
  
  
a) T he li ver re d u ces t he 1 1- o x o gr o u p of pr e d nis o ne 
  
  
  
  
  
t o f or m t he bi ol o gicall y acti ve ster oi d, pre d nis ol o n e.  
 
  
  
  
  
  
b) Hist oricall y, pre d nis ol o ne has bee n rec o g nize d   
  
  
  
  
  
as t he pri mar y meta b olite of pre d nis o ne; h o w e ver,  
  
  
  
  
  
s o me w or k has esta blis he d t hat pre d nis o ne a n d  
  
  
  
  
  
pre d nis ol o ne u n der g o c o m ple x re versi ble  
 
  
  
  
  
  
meta b olis m. After oral d oses of pre d nis o ne or  
  
  
  
  
  
pre d nis ol o ne, t he plas ma c o nce ntr ati o n- ti me  
  
  
  
  
  
pr ofiles f or b ot h a g e nts are s u peri m p osa ble.  
 
 

C A S E 1 4 2 0  
  
  
  
Pa ge 4 6   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
Pr o d uct descri pti o n: A vaila ble as 1 m g, 2. 5 m g, 5 m g, 1 0 m g, 2 0 m g, a n d 5 0 m g ta blets 
a n d as oral s ol uti o n ( 5 m g/ 5 ml)  
 
S ol uti o n pre parati o n: A vaila ble as c o m mer ciall y- a vaila ble or al ta blets or pre- pr e par e d 
oral s ol uti o n.  
 
St ora ge re q uir e me nts: St ore at c o ntr olle d r o o m te m perat ure at 2 5 de gr ees C ( 7 7 de grees 
F), wit h e x c ursi o n per mitte d bet wee n 1 5 a n d 3 0 de grees C ( 5 9 a n d 8 6 d e gr ees F). Pr otect 
ta blets fr o m m oist ure.  
 
Sta bilit y: Ta blets are sta ble at r o o m te m per at ure u ntil t he date n ote d o n t he pac ka gi n g.  
 
R o ute of a d mi nistrati o n: Oral  
 
Dr u g Pr oc ur e me nt: Pre d nis o ne will be fr o m c o m mercial s o urces.  
 
 
9. 7  
Rit u xi m a b 
C h emical Na me:   
I D E C- C 2 B 8, C hi meric a nti- C D 2 0 m o n ocl o nal a nti b o d y,  
 
Ot her Na mes:    
Rit u xa n T M , Ma bt heraT M  
 
Classificati o n:   
M o n ocl o nal a nti b o d y, a nti ne o plastic a ge nt  
 
M o lec ular F or m ula: C 6 4 1 6 H 9 8 7 4 N 1 6 8 8 O 1 9 8 7 S 4 4  
 
 
M o de of Acti o n:  
Rit u xi ma b bi n ds wit h hi g h affi nit y t o C D 2 0- p ositi ve cells,   
  
  
  
perf or ms h u ma n eff ect or f u ncti o ns i n vitr o, a n d de pletes B cells i n  
  
  
  
vi v o. T he F A b d o mai n of rit u xi ma b bi n ds t o t he C D 2 0 a nti ge n o n  
  
  
  
B-l y m p h oc ytes a n d t he Fc d o mai n recr uits i m m u ne eff ect or  
  
  
  
f u ncti o ns t o me diate B cell l ysis i n vitr o. T he bi ol o gical eff ect is  
  
  
  
ma nifeste d b y B-cell de pleti o n i n peri p heral bl o o d, l y m p h n o des,  
  
  
  
a n d b o ne marr o w.  
 
 
Meta b olis m:   
N ot f ull y u n derst o o d. Ge nerall y belie ve d t o b e de gra de d  
 
  
  
  
n o ns pecificall y i n t he li ver.  
 
 
Pr o d uct descri pti o n: Rit u xi ma b is a sterile, clear, c ol orless, preser v ati ve-free li q ui d 
c o nce ntr ate f or i ntr a ve n o us (I V) a d mi nistrati o n.  
 
Rit u xi ma b bi osi milar use is per mitte d f or t his st u d y per i nstit uti o nal sta n dar ds. 
 
S ol uti o n pre parati o n: Usi n g a p pr o priate ase ptic tec h ni q ue, wit h dra w t he n ecessar y 

C A S E 1 4 2 0  
  
  
  
Pa ge 4 7   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
a mo u nt of rit u xi ma b a n d dil ute t o a fi nal c o nce ntr ati o n of 1 t o 4 m g/ m L i nt o a n i nf usi o n 
ba g c o ntai ni n g eit her 0. 9 % S o di u m C hl ori de or 5 % De xtr ose i n Water. Ge ntl y i n vert t he 
ba g t o mi x t he s ol uti o n. Discar d a n y u n us e d p orti o n left i n t he vial. Ca uti o n s h o ul d be 
ta ke n d uri n g t he pr e par ati o n of t he dr u g, as s ha ki n g ca n ca use a g gre gati o n a n d 
preci pitati o n of t he a nti b o d y.  
 
St ora ge re q uir e me nts: Rit u xi ma b is a sterile, clear, c ol orless, pres er vati ve-free li q ui d 
c o nce ntr ate f or i ntr a ve n o us (I V) a d mi nistrati o n. T he pr o d uct is f or m ulate d f or 
i ntra ve n o us a d mi nistrati o n i n 9. 0 m g/ m L s o di u m c hl ori de, 7. 3 5 m g/ m L s o di u m citrate 
di h y drate, 0. 7 m g/ m L p ol ys or bate 8 0, a n d Sterile Water f or I njecti o n. T he p H is a dj uste d 
t o 6. 5.  
 
Sta bilit y: Rit u xi ma b is bi ol o gicall y a n d c he micall y sta ble at 2° C t o 8° C ( 3 6° F t o 4 6° F) 
a n d has a pr o p os e d s helf life sta bilit y of 3 0 m o nt hs. O nce r ec o nstit ute d i nt o I V ba gs, 
rit u xi ma b is c he micall y sta ble f or u p t o 2 4 h o urs at 2° C t o 8° C ( 3 6° F t o 4 6° F), f oll o we d 
b y u p t o 2 4 h o urs at r o o m te m perat ure ( 2 3° C). H o we ver, si nce rit u xi ma b s ol uti o ns d o n ot 
c o ntai n preser vati ve, dil ute d s ol uti o ns s h o ul d be st ore d refri ger ate d ( 2° C t o 8° C). N o 
i nc o m pati bilities bet wee n rit u xi ma b a n d p ol y vi n ylc hl ori de or p ol yet h yle ne ba gs ha ve 
bee n o bser v e d. Rit u xi ma b vials s h o ul d be pr otecte d fr o m direct s u nli g ht. Rit u xi ma b vials 
are i nte n de d f or si n gle us e o nl y. D o n ot use be y o n d t he e x pirati o n date sta m pe d o n t he 
cart o n.  
 
R o ute of a d mi nistrati o n: D O N O T A D MI NI S T E R A S A N I N T R A V E N O U S P U S H O R 
B O L U S. D o n ot i nf use rit u xi ma b C o nc urre ntl y wit h a n ot her I V s ol uti o n or ot her I V 
me dicati o ns. Pre me dicati o n, c o nsisti n g of aceta mi n o p he n 6 5 0 m g t o 1 0 0 0 m g P O a n d 
di p he n h y dra mi ne 2 5 t o 5 0 m g I V or P O, will be a d mi nistere d bef or e eac h i nf usi o n of 
rit u xi ma b. Pre me dicati o n ma y atte n uate i nf usi o n-r elate d e v e nts. Si nce tra nsie nt 
h y p ote nsi o n ma y occ ur d uri n g rit u xi ma b i nf usi o n, a nti- h y perte nsi ve me di cati o ns will be 
wit h hel d 1 2 h o urs pri or t o rit u xi ma b i nf usi o n.  
 
Rit u xi ma b is a d mi nistere d i ntra ve n o usl y. A n i n-li ne filter is n ot re q uire d. T he i nitial rate 
is 5 0 m g/ hr f or t he first h o ur. If n o t o xicit y is see n, t he rate ma y b e escalate d gra d uall y i n 
5 0 m g/ h o ur i ncre me nts at 3 0- mi n ute i nter vals t o a ma xi m u m of 4 0 0 m g/ hr. If t he first 
d ose is well t olerate d, t he i nitial rate f or s u bse q ue nt d ose is 1 0 0 m g/ hr, i ncrease d 
gra d uall y i n 5 0 m g/ hr i ncre me nts at 3 0- mi n ute i nter vals, n ot t o e xcee d 4 0 0 m g/ hr.  
Rit u xi ma b i nf usi o n m ust be i nterr u pte d f or se vere reacti o ns. If t he patie nt e x perie nces 
fe ver a n d ri g ors, t he a nti b o d y i nf usi o n is disc o nti n ue d. T he se v erit y of t he si de effects 
will be e val uate d. I n m ost cases, t he i nf usi o n ca n be res u me d at a 5 0 % r e d ucti o n i n rate 
(e. g., fr o m 1 0 0 m g/ hr t o 5 0 m g/ hr) w he n s y m pt o ms ha ve c o m pletel y r es ol ve d. M ost 
patie nts w h o ha ve e x p eri e nce d n o n-lif e-t hr eate ni n g i nf usi o n-relate d r eacti o ns ha ve bee n 
a ble t o c o m plete t he f ull c o urse of rit u xi ma b t hera p y.  
 
F oll o wi n g t he a nti b o d y i nf usi o n, t he i ntra ve n o us li ne s h o ul d be mai ntai ne d f or 
me dicati o ns as nee d e d. If t here are n o c o m plicati o ns after o ne h o ur of o bser vati o n, t he 
i ntra ve n o us li ne ma y be disc o nti n ue d. T he patie nt s h o ul d be treate d acc or di n g t o t he best 
a vaila ble l ocal practices a n d pr oce d ures. I n p atie nts wit h detecta ble cir c ulati n g 

C A S E 1 4 2 0  
  
  
  
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Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
l ym p h o ma cells, t he i nitial i nf usi o n rate m ust be r e d uce d t o 2 5 m g/ hr; t hes e patie nts ma y 
e x perie n ce m or e fr e q ue nt a n d se ver e tra nsie nt f e ver a n d ri g ors, s h ort ness of breat h, a n d 
h y p ote nsi o n.  
 
N O T E: I n a d diti o n, alter nati ve rit u xi ma b i nf usi o n rates (i.e., “ra pi d rit u xi m a b i nf usi o n”) 
ca n be use d p er i nstit uti o nal g ui deli nes as l o n g as t he t otal n u m ber of milli gra ms of 
rit u xi ma b is t he sa me a n d t hat “ra pi d i nf usi o n” is n ot a d mi nistere d wit h t he patie nt’s first 
rit u xi ma b c ycle. F urt her, a rit u xi ma b i nf usi o n ti me s h o ul d n ot be less t ha n 9 0 mi n utes i n 
d urati o n.  
 
H ycel a ( S Q rit u xi m a b/ h y al ur o ni d ase h u m a n) 
 
Pr o d uct descri pti o n:  RI T U X A N H Y C E L A is a c o m bi nati o n of rit u xi ma b a n d 
h yal ur o ni dase h u ma n. Rit u xi ma b is a ge neticall y e n gi neere d c hi meric m uri ne/ h u ma n 
m o n ocl o nal I g G 1 ka p pa a nti b o d y directe d a g ai nst t he C D 2 0 a nti ge n. Rit u xi ma b has a n 
a p pr o xi mate m olec ular w ei g ht of 1 4 5 k D. Rit u xi ma b has a bi n di n g affi nit y f or t he C D 2 0 
a nti ge n of a p pr o xi mat el y 8. 0 n M. Rit u xi ma b is pr o d uce d b y ma m malia n cell ( C hi nese 
Ha mster O var y) s us pe nsi o n c ult ure i n a n utrie nt m e di u m t hat ma y c o ntai n t he a nti bi otic 
ge nta mici n. Ge nta mici n is n ot detecta ble i n t he fi n al pr o d uct. Rec o m bi na nt h u ma n 
h yal ur o ni dase is a n e n d o gl yc osi dase use d t o i ncr ease t he dis persi o n a n d a bs or pti o n of 
c oa d mi nistere d dr u gs w h e n a d mi nistere d s u bc uta n e o usl y. It is pr o d u ce d b y ma m malia n 
( C hi nese Ha mster O var y) cells c o ntai ni n g a D N A plas mi d e nc o di n g f or a s ol u ble 
fra g me nt of h u ma n h y al ur o ni dase ( P H 2 0). It is a gl yc os ylate d si n gle-c hai n pr otei n wit h 
a n a p pr o xi mate m olec ular wei g ht of 6 1 k D.  
 
RI T U X A N H Y C E L A (rit u xi ma b a n d h yal ur o ni dase h u ma n) I njecti o n is a c ol orless t o 
yell o wis h, clear t o o pal esce nt s ol uti o n s u p plie d i n sterile, preser vati ve-free, si n gle- d ose 
vials f or s u bc uta ne o us a d mi nistrati o n. Eac h m L of s ol uti o n c o ntai ns rit u xi ma b ( 1 2 0 m g), 
h yal ur o ni dase h u ma n ( 2, 0 0 0 U nits), L- histi di ne ( 0. 5 3 m g), L- histi di ne h y dr oc hl ori de 
m o n o h y drate ( 3. 4 7 m g), L- met hi o ni ne ( 1. 4 9 m g), p ol ys or bate 8 0 ( 0. 6 m g), α ,α -tr e hal ose 
di h y drate ( 7 9. 4 5 m g), a n d Water f or I njecti o n. 
 
Pr o d uct I nstr u cti o ns/ Details: 
•  Rit u xi ma b- h yal ur o ni dase ( Rit u xa n H ycela) 1 4 0 0 m g- 2 3, 4 0 0 u nits/ 1 1. 7 m L  
•  Patie nt’s m ust ha ve t oler ate d at least 1 f ull d ose of I V rit u xi ma b wit h o ut a seri o us 
reacti o n 
•  Pri or t o eac h d ose pre me dicate patie nts wit h aceta mi n o p he n 6 5 0 m g a n d 
di p he n h y dra mi ne 5 0 m g 
•  1 1. 7 m L is gi ve n s u bc uta ne o usl y o ver a p pr o xi matel y 5 mi n utes o n Da y 1 of a 2 8 
da y c ycle, b e gi n ni n g i n C ycle 2. 
•  I njecti o n s h o ul d be gi ve n i nt o t he s u bc uta ne o us tiss ue of t he a b d o me n. Ne v er 
i nject i nt o areas w h ere t h e s ki n is re d, br uise d, te n der or har d, or areas w here t her e 
are m oles or s cars. 
•  If a d mi nistrati o n is i nterr u pte d, c o nti n ue a d mi nisteri n g at t he sa me site, or at a 
differe nt site, b ut r estrict e d t o t he a b d o me n. 

C A S E 1 4 2 0  
  
  
  
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Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
•  T o a v oi d cl o g gi n g, attac h a d mi nistrati o n nee dle, or cat heter, o nl y w h e n t he patie nt 
is rea d y f or i njecti o n. 
•  If n ot use d i m me diatel y, pre par e d s yri n ge ma y b e st ore d i n t he refri ger at or at 2- 8 
◦C f or u p t o 4 8 h o urs a n d s u bse q ue ntl y f or 8 h o urs at r o o m te m p u p t o 3 0 ◦C 
•  Pat ie nts m ust be o bser ve d f or at least 1 5 mi n utes f oll o wi n g a d mi nistrati o n 
 
Dr u g Pr oc ur e me nt: Rit u xi ma b m ust be o btai ne d fr o m c o m mercial s o urces.  
 
9. 8  
Vi ncristi ne 
 
C he mical Na me:   
( 3a R, 3a 1 R, 4 R, 5 S, 5a R, 1 0 b R)- met h yl 4-acet o x y- 3a-et h yl- 9-
(( 5 S, 7 S, 9 S)- 5-et h yl- 5- h y dr o x y- 9-( met h o x y car b o n yl)- 
2, 4, 5, 6, 7, 8, 9, 1 0- octa h y dr o- 1 H- 3, 7- met h a n o[ 1] 
azac ycl o u n deci n o[ 5, 4- b]i n d ol- 9- yl)- 6-f or m yl- 5- h y dr o x y- 8-
met h o x y- 3a, 3a 1, 4, 5, 5a, 6, 1 1, 1 2- octa h y dr o- 1 H- i n d olizi n o[ 8, 1-
c d]car baz ole- 5- car b o x yl ate  
 
  
Ot her Na mes:    
O nc o vi n T M    
 
 
Classificati o n:   
Vi nca al kal oi d, mit otic i n hi bit or, a nti ne o plastic a ge nt  
 
 
M o lec ular F or m ula: C 4 6 H 5 6 N 4 O 1 0  
 
 
M o de of Acti o n:  
Vi ncristi ne s ulfate, a n o n c ol ytic vi nca al kal oi d, has a n u n k n o w n  
  
  
  
mec ha nis m of acti o n, alt h o u g h it is t h o u g ht t o be relate d t o t he  
  
  
  
arrest of re plicati n g cells at t he meta p hase st a ge t hr o u g h  
 
  
  
  
pre ve nti o n of micr ot u b ul e f or mati o n i n t he mit otic s pi n dle.  
 
Meta b olis m:   
A bs or pti o n: Pr otei n bi n di n g – yes 
  
  
  
Meta b olis m: He patic: C Y P 3 A 4 P 4 5 0 s u bfa mil y 
  
  
  
E xcreti o n: Fecal: a b o ut 8 0 %    Re nal: 1 0 % t o 2 0 % 
  
  
  
Dial yza ble: n o 
  
  
  
Eli mi nati o n Half Life 8 5 h ( 1 9 t o 1 5 5 h) 
 
Pr o d uct descri pti o n: Vi ncristi ne s ulfate is a w hite t o off- w hite p o w d er. Eac h m L c o ntai ns 
vi ncristi ne s ulfate, 1 m g ( 1. 0 8 μ m ol); ma n nit ol, 1 0 0 m g; a n d water f or i njecti o n, qs. 
A cetic aci d a n d s o di u m acetate h a ve bee n a d de d f or p H c o ntr ol. T he p H of Vi ncristi ne 
S ulfate I njecti o n, U S P ra n ges fr o m 3. 5 t o 5. 5.  
 
S ol uti o n pre parati o n: Dil ute o nl y i n N S or D 5 W; d o n ot dil ute i n s ol uti o ns t hat raise or 
l o wer t he p H o utsi de t he ra n ge of 3. 5- 5. 5. Dis pe ns e wit h pr o vi de d stic ker or o ver wra p 
t hat states " F A T A L I F GI V E N I N T R A T H E C A L L Y. F O R I N T R A V E N O U S U S E 

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O N L Y".  
 
St ora ge re q uir e me nts: T he rea d y-t o- use s ol uti o n s h o ul d be refri g erat e d d uri n g st ora ge, 
h o we ver, n o s p ecific te m perat ur e rec o m me n dati o ns are pr o vi de d b y t he ma n ufact urer. 
Pr otecti o n fr o m li g ht has bee n rec o m me n de d. If st ore d at r o o m te m perat ur e ( 1 5 t o 3 0 
de grees C) or i n a c o ol pl ace ( 8 t o 1 5 d e grees C), vi ncristi ne s ulfate is sta ble f or 1 m o nt h. 
If t he n refri gerate d, t he st a bilit y of vi ncristi ne s ulfate is as ori gi nall y la bele d b y t he 
ma n ufact ur er ( Lill y).  
 
Sta bilit y: Vi ncristi ne s ulfate i n 5 % de xtr ose i njecti o n is sta ble f or 2 4 h o urs i n b ot h glass 
a n d P V C c o ntai ners  
 
R o ute of a d mi nistrati o n: S yri n ges s h o ul d n ot be use d f or vi ncristi ne a d mi nistrati o n. 
A d mi nisteri n g via a mi ni ba g i nf usi o n is rec o m me n de d t o pr otect a g ai nst acci de ntal 
i ntrat hecal a d mi nistrati o n. A d mi nister via free-fl o wi n g i ntra ve n o us (I V) nee dle or 
cat heter; i nject directl y i nt o vei n or i nt o t u bi n g of a r u n ni n g I V i nf usi o n wit hi n 1 mi n ute. 
Vi ncristi ne is c o nsi dere d a vesica nt. Car e s h o ul d b e ta ke n t o a v oi d e xtr a vas ati o n.  
 
Dr u g Pr oc ur e me nt: Vi ncristi ne will be o btai ne d fr o m c o m mercial s o urces.  
 
1 0. 0 
C O R R E L A TI V E S T U DI E S 
 
1 0. 1  M olec ul ar S u bt y pi n g 
See Secti o n 2. 3 
 
1 0. 1. 1 Bac k gr o u n d  
See Secti o n 1. 5. 
 
1 0. 1. 2   Rati o nale f or A n al ysis 
See Secti o n 1. 5.   
 
1 0. 1. 3 Tiss ue Pr oc ure me nt 
 
T he f oll o wi n g materials s h o ul d be c ollecte d wit hi n 9 0 da ys of re gistr ati o n a n d se nt f or 
eac h p atie nt t hat si g ns c o nse nt. T he sli des a n d/ or tiss ue scr olls s h o ul d be pr e pare d after 
t he patie nt has si g ne d t he c o nse nt f or m t o partici p ate i n t he st u d y a n d wit hi n 4 wee ks of 
starti n g st u d y treat me nt. We prefer tiss ue s cr olls, b ut u nstai ne d sli des are acce pta bl e if 
scr olls are n ot a v aila ble.  
 
1.  Fiftee n 4 micr o n u nstai ne d secti o ns o n c har ge d ( pl us) sli des 
2.  F o ur 1 0 micr o n s ecti o ns/tiss ue scr olls (if a n i ncisi o nal or e xcisi o nal bi o ps y) or 
ei g ht 1 0 micr o n secti o ns/tiss ue scr olls (if nee dle bi o ps y) pref era bl y i n a t u b e t o 
mi ni mize de gra dati o n. Ot her wise, o n sli des is acce pta ble.  
 
1 0. 1. 4 Bl o o d Sa m ple 
 

C A S E 1 4 2 0  
  
  
  
Pa ge 5 1   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
T w o  1 0 ml he pari nize d gr ee n t o p t u bes ( 2 0 ml t otal) of peri p heral bl o o d will be o btai ne d 
at t he ti me of sa m ple c oll ecti o n (scr ee ni n g/ pri or t o treat me nt, pri or t o treat me nt of c ycle 
4, a n d t he n e n d of tr eat m e nt). 
 
T he gree n t o p he pari n t u bes will be pr ocess e d i nt o ali q u ots of plas ma a n d via ble 
m o n o n uclear cells.  
 
2( or q ua ntit y nee d e d o btai n 5 ml t otal plas ma) la ve n der t o p E D T A or, Strec k (if 
a vaila ble), t u bes will als o be use d t o c ollect a w h ole bl o o d sa m ple at Scree ni n g/ Baseli ne, 
E O T, a n d 1 2- m o nt h f oll o w- u p visits. 
 
1 0. 1. 5 S hi p me nt 
 
Please s hi p t he sli des/t u be t o t he Cle vela n d Cli nic Bi ore p osit or y at t he a d dress pr o vi de d 
bel o w: 
 
R o bert J. T o msic h P at h ol o g y a n d L a b or at or y Me dici ne I nstit ute ( R T- P L MI) 
A T T N: Dr. G e ne vie v e Cra ne 
2 1 1 9 East 9 3 Street, L 2 5 
Cle vela n d, O hi o 4 4 1 0 6 
 
Please s hi p t he bl o o d sa m ples t o t he Cle vela n d Cli nic P har mac ol o g y La b. T he Ma n ual of 
O perati n g Pr oce d ures ( M O P) c o ntai ns m ore detaile d i nstr ucti o ns o n s hi p me nt of t he sli des 
a n d bl o o d sa m ples. 
 
 
1 0. 1. 6 A nal ytical La b or at or y 
 
T he s peci me n will be a n al yze d via ne xt ge n erati o n se q ue nci n g a n d R N A se q ue nci n g as 
descri be d b y C ha p u y et al. 1 3.  T he assa y is n ot c urre ntl y a v aila ble b ut w he n it is, we will 
p erf or m testi n g i n t he la b orat or y at Cle vel a n d Cli nic or t hr o u g h use of a t hir d part y 
la b orat or y.   
 
F urt her i nf or mati o n a b o ut t he pla n ne d a nal yses c o ncer ni n g t hese c orr elati ve st u dies will 
be a d de d i n a pr ot oc ol a me n d me nt. 
 
1 1. 0  
S T U D Y P A R A M E T E R S A N D C A L E N D A R  
 
1 1. 1 
St u d y P ar a m eters 
 
1 1. 1. 1 Scree ni n g E val u ati o n  
Scree ni n g st u dies a n d e v al uati o ns will be use d t o deter mi ne eli gi bilit y of eac h 
partici pa nt f or st u d y i ncl usi o n.  All e val uati o ns m ust be c o m plete d < 4 5 da ys 
pri or t o a d mi nistrati o n of pr ot oc ol t hera p y, e xce pt w here ot her wise i n dicat e d or - 
i n t he case of p atie nts w h o recei v e d 1 c ycl e of R- C H O P [ or s o me c o m p o n e nt(s) 
t here of] pri or t o st u d y e nr oll me nt (i n t his case, wi n d o w e xte n ds t o < 6 0 da ys), a 

C A S E 1 4 2 0  
  
  
  
Pa ge 5 2   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
C T a n d/ or P E T/ C T, ec h ocar di o gr a m a n d b o ne marr o w bi o ps y m ust ha ve b ee n 
o btai ne d pri or t o treat me nt. 
•  I nf or me d C o nse nt 
•  Me dical Hist or y 
•  C o m plete P h ysical E xa m 
•  Hei g ht 
•  Wei g ht 
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pir at or y rate a n d 
te m perat ur e. 
•  C o nc urre nt Me dicati o ns Assess me nt i ncl u di n g prescri pti o n 
me dicati o ns, o ver t he c o u nter ( O T C) me dicati o ns a n d nat ural/ her bal 
s u p ple me nts 
•  E C O G Perf or ma n ce Stat us 
•  Baseli ne S y m pt o ms Assess me nt 
•  I PI s c ore d o c u me nte d 
•  La b orat or y St u dies:  
  
  
  
- C o m plete bl o o d c o u nt ( C B C) wit h differe ntial a n d platelets 
  
  
  
- Ser u m c he mistries: al b u mi n, al kali ne p h os p hatas e, t otal bilir u bi n,  
  
  
  
bicar b o nate, B U N, cal ci u m, c hl ori de, cr eati ni ne, gl uc ose,   
  
  
  
p otassi u m, t otal pr otei n, A S T ( S G O T), A L T ( S G P T), s o di u m 
- Lactat e de h y dr o g e nase ( L D H), uri c aci d, p h os p h or us 
  
  
  
- Calc ulate d creati ni ne cleara n ce will be d eter mi n e d usi n g   
  
  
  
C oc kcr oft- G a ult f or m ula if creati ni ne a n d/ or B U N are a b n or mal 
  
  
  
- Ser u m B- H C T f or w o m e n of c hil d beari n g p ote ntial 
  
  
  
- Uri nal ysis 
  
  
  
- Re m ote He patitis pa nel ( He patitis B S urface A nti ge n, He patitis B  
  
  
  
S urface A nti b o d y, He patitis B C ore A nti b o d y, He patitis C  
  
  
  
A nti b o d y) 
  
  
  
  
*If he patitis B s urface a nti ge n a n d/ or B c ore a nti b o d y is  
  
  
  
  
p ositi ve t he n He p B P C R assa y is re q uir e d 
  
  
  
  
*If he patitis C vir us a nti b o d y.  If p ositi ve nee d he p atitis C  
  
  
  
  
P C R is nee de d 
  
  
  
- HI V testi n g 
  
  
  
- C M V P C R testi n g 
•  E K G 
•  M U G A or ec h ocar di o gra m ( m ust be c o m plete d < 6 m o nt hs pri or t o 
a d mi nistrati o n of pr ot oc ol t hera p y) u nless t her e is cli nical e vi de nce f or 
ne w car diac s y m pt o ms wit hi n peri o d of ti me si nce t he car diac assess me nt.  
•  C T sca n of nec k, c hest, a b d o me n a n d pel vis wit h oral a n d I V c o ntrast 
( nec k ma y b e o mitte d at discreti o n of treati n g p h ysicia n).  
•  P E T/ C T sca n as baseli ne t u m or i ma gi n g assess me nt  
•  B o ne Marr o w As pir ate a n d Bi o ps y ( wit hi n 9 0 da ys of re gistrati o n)  
•  Dia g n ostic bi o ps y material se nt t o Cle vela n d Cli nic f or s u b gr o u p a nal ysis.  
•  C orrelati ve bl o o d dra w  
 

C A S E 1 4 2 0  
  
  
  
Pa ge 5 3   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
1 1 . 1. 2 Treat me nt Peri o d 
•  Treat me nt c y cles ar e 2 1 da ys l o n g.  
•  A visit wi n d o w of + 3 da ys is all o we d f or la bs  
•  A visit wi n d o w of + 3 da y is all o we d f or treat me nt  
•  A visit wi n d o w of + 1 4 da ys is all o we d f or f oll o w u p visits  
 
C ycle 1, D a y 1 
•  P h ysical E xa mi nati o n  
•  Wei g ht  
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pir at or y rate a n d te m per at ur e.  
•  C o nc urre nt Me dicati o ns Assess me nt i ncl u di n g prescri pti o n me dicati o ns, o ver-t he-
c o u nter ( O T C) me dicati o ns a n d nat ural/ her b al s u p ple me nts.  
•  E C O G perf or ma nce stat us   
•  La b orat or y St u dies:  
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial a n d platelets.  
o  Ser u m C he mistries: Ser u m c he mistr y pa nel: s o di u m, p otassi u m, c hl ori de, 
bicar b o nate, B U N, cr eati ni ne, calci u m, gl uc ose, t otal pr otei n, al b u mi n, 
al kali ne p h os p hatase, t ot al bilir u bi n, S G O T [ A S T], S G P T [ A L T] 
o  L D H, uric aci d, p h os p h or o us 
o  Pre g na nc y test, ser u m B- H C T, f or fe m ales of c hil d beari n g p ote ntial ( o n 
da y 1) 
o  C M V P C R 
•  E K G 
•  R- C H O P a d mi nistrati o n  
•  M E- 4 0 1 starte d ( d a ys 1- 7; * n ote: da ys 1- 4 f or d ose le vel 1 of p has e 1) 
•  Start Tri met h o pri m/s ulfa met h o xaz ole t hree da ys a wee k or Pe nt a mi di ne 
(aer os olize d) m o nt hl y 
•  Start ac ycl o vir 4 0 0 m g BI D 
 
C ycle 1, D a y 2 
•  
Pe gfil grasti m a d mi nistrati o n or O N P R O T M  weara ble de vice as per i nstit uti o nal 
sta n dar d 
o  Pe gfil grasti m 6 m g S C da y 2 (e ver y 2 1 da ys). Fil grasti m 3 0 0 or 4 8 0 mc g 
I V/ S C dail y da ys x 5- 1 0 starti n g da y 2 ma y be s u bstit ute d if pe gfil grasti m 
is n ot a vaila ble.  O N P R OT M  is als o a n acce pta ble met h o d of a d mi nistrati o n 
o n da y 1.  Bi osi milars ma y be use d per i nstit uti o nal pr ot oc ols.  
 
C ycle 1, D a y 8 ( P h ase I O nl y) 
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pir at or y rate a n d te m per at ur e.  
•  La b orat or y St u dies:  
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial  
o  Ser u m C he mistries: Ser u m c he mistr y pa nel: s o di u m, p otassi u m, c hl ori de, 
bicar b o nate, B U N, cr eati ni ne, calci u m, gl uc ose, t otal pr otei n, al b u mi n, 
al kali ne p h os p hatase, t ot al bilir u bi n, S G O T [ A S T], S G P T [ A L T] 
o  L D H, uric aci d, p h os p h or o us 

C A S E 1 4 2 0  
  
  
  
Pa ge 5 4   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
•  A d verse e ve nt e v al uati o n a n d d oc u me ntati o n 
 
C ycle 1, D a y 1 5 ( P h ase I O nl y) 
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pir at or y rate a n d te m per at ur e.  
•  La b orat or y St u dies:  
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial  
o  Ser u m C he mistries: Ser u m c he mistr y pa nel: s o di u m, p otassi u m, c hl ori de, 
bicar b o nate, B U N, cr eati ni ne, calci u m, gl uc ose, t otal pr otei n, al b u mi n, 
al kali ne p h os p hatase, t ot al bilir u bi n, S G O T [ A S T], S G P T [ A L T] 
•  A d verse e ve nt e v al uati o n a n d d oc u me ntati o n 
C ycle 2- 6, D a y 1 
•  P h ysical E xa mi nati o n  
•  Wei g ht  
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pir at or y rate a n d te m per at ur e.  
•  C o nc urre nt Me dicati o ns Assess me nt i ncl u di n g prescri pti o n me dicati o ns, o ver-t he-
c o u nter ( O T C) me dicati o ns a n d nat ural/ her b al s u p ple me nts.  
•  E C O G perf or ma nce stat us   
•  La b orat or y St u dies:  
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial a n d platelets.  
o  Ser u m C he mistries: Ser u m c he mistr y pa nel: s o di u m, p otassi u m, c hl ori de, 
bicar b o nate, B U N, cr eati ni ne, calci u m, gl uc ose, t otal pr otei n, al b u mi n, 
al kali ne p h os p hatase, t ot al bilir u bi n, S G O T [ A S T], S G P T [ A L T] 
o  L D H 
o  C M V P C R 
o  * C ycle 2 Da y 1 o nl y: uri c aci d a n d p h os p h or o us 
o  * C ycle 3 Da y 1 a n d C ycl e 6 Da y 1 o nl y: E K G 
o  * C ycle 4 Da y 1 o nl y: c orrelati ve bl o o d dra w 
•  R- C H O P a d mi nistrati o n  
•  M E- 4 0 1 starte d ( d a ys 1- 7; * n ote: da ys 1- 4 f or d ose le vel 1 of p has e 1) 
 
C ycle 2- 6, D a y 2 
•  
Pe gfil grasti m a d mi nistrati o n as per i nstit uti o nal sta n dar d. O N P R O T M  weara ble 
de vice o n da y 2 
o  Pe gfil grasti m 6 m g S C da y 2 (e ver y 2 1 da ys). Fil grasti m 3 0 0 or 4 8 0 
  mc g I V/ S C dail y da ys x 5- 1 0 starti n g da y 2 ma y be s u bs tit ute d if 
pe gfil grasti m is n ot a v aila ble.  O N P R O T M  is als o a n acce pta bl e met h o d 
of a d mi nistrati o n o n da y 1.  Bi osi milars ma y be use d per i nstit uti o nal 
pr ot oc ols 
 
C ycle 3, D a y 1 5- 2 1 
•  C T of nec k, c hest, a b d o me n, a n d pel vis wit h I V a n d P O c o ntrast f or r es p o nse 
assess me nt. Nec k C T ca n be o mitte d if n o i n v ol ve me nt at baseli ne.  
 
 

C A S E 1 4 2 0  
  
  
  
Pa ge 5 5   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
E n d of Tre at m e nt Res p o nse Assess m e nt – 8 wee ks ( +/- 7 d a ys) after t he first d a y of 
l ast tre at m e nt c y cle 
•  P h ysical E xa mi nati o n  
•  Wei g ht  
•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pir at or y rate a n d te m per at ur e.  
•  C o nc urre nt Me dicati o ns Assess me nt i ncl u di n g prescri pti o n me dicati o ns, o ver-t he-
c o u nter ( O T C) me dicati o ns a n d nat ural/ her b al s u p ple me nts.  
•  E C O G Perf or ma n ce Stat us  
•  A d verse E v e nt e val uati o n a n d d oc u me ntati o n 
•  La b orat or y St u dies:  
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial a n d platelets.  
o  Ser u m C he mistries: s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, 
creati ni ne, calci u m, gl uc ose, t otal pr otei n, al b u mi n, al kali ne p h os p hatase, 
t otal bilir u bi n, S G O T [ A S T], S G P T [ A L T] 
o  L D H 
o  C M V P C R 
o  He patitis B P C R if partici pa nt teste d p ositi ve f or h e patitis B s urface 
a nti ge n a n d/ or he p atitis B c ore a nti b o d y d uri n g s cree ni n g 
o  He patitis C P C R if partici pa nt teste d p ositi ve f or h e patitis C a nti b o d y o n 
scree ni n g 
o  C orrelati ve bl o o d dra w 
•  E K G 
•  B o ne marr o w bi o ps y ( m a y be o mitte d if scree ni n g b o ne marr o w bi o ps y was 
ne gati ve f or i n v ol ve m e nt b y l y m p h o ma).  
•  P E T a n d dia g n ostic C T of nec k, c hest, a b d o m e n, a n d pel vis wit h I V a n d P O 
c o ntrast f or r es p o nse assess me nt. Nec k C T ca n be o mitte d if n o i n v ol ve me nt at 
baseli ne. P E T sca n al o n e is acce pta bl e if dia g n ostic C T sca ns ar e decli ne d b y 
i ns ura nce c o m pa n y.  
 
F oll o w U p  
After c o m pleti o n of t he st u d y treat me nt t he partici pa nts will be f oll o we d f or a t otal of 2 
years or u ntil disease pr o gressi o n w hic he v er c o mes first. T he f oll o w u p visits will be 
d o ne at 6, 1 2, 1 8, a n d 2 4 m o nt hs after t he first da y of t he last c ycle of t her a p y. If t he 
patie nt is u na ble t o f oll o w u p i n pers o n, virt ual visits ma y be use d t o ca pt ure a p plica bl e 
pr oce d ur es d uri n g l o n g-t er m f oll o w u p o nl y. E ver y atte m pt s h o ul d be ma de t o c o m plete 
t he re q uire d assess me nts liste d bel o w, alt h o u g h if t he y are n ot c o m plet e d it will n ot be 
c o nsi dere d a pr ot oc ol de viati o n. 
 
T he f oll o w u p visits s h o ul d i ncl u de t he f oll o wi n g: 
•  P h ysical E xa mi nati o n 
•  Vital si g ns 
•  E C O G perf or ma nce stat us  
•  A d verse e ve nt e v al uati o n 
•  La b orat or y St u dies:  
o  C o m plete Bl o o d C o u nt ( C B C) wit h differe ntial a n d platelets.  

C A S E 1 4 2 0  
  
  
  
Pa ge 5 6   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
o  Se r u m C he mistries: s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, 
creati ni ne, calci u m, gl uc ose, t otal pr otei n, al b u mi n, al kali ne p h os p hatase, 
t otal bilir u bi n, S G O T [ A S T], S G P T [ A L T] 
o  L D H  
o  C M V P C R 
•  Dia g n ostic C T nec k, c hest, a b d o me n a n d pel vis sca n wit h I V a n d P O c o ntrast 
will be d o ne at 6, 1 2, a n d 2 4 m o nt hs if n o disease pr o gressi o n. Nec k C T ca n be 
o mitte d if n o i n v ol ve me nt at baseli ne 
•  * Disc o nti n ue PJ P pr o p h yla xis b y 6 m o nt h visit (ca n be st o p pe d bet w ee n 2- 6 
m o nt hs) 
•  * Disc o nti n ue ac ycl o vir at 6 m o nt h visit 
 
Patie nts w h o ha ve pr o gr essi ve disease or start ne w treat me nt ar e n ot re q uire d t o c o me i n 
f or cli nical f oll o w u p. T hese patie nts ca n be c o ntacte d o ver t he p h o ne b y t he st u d y 
pers o n nel t o o btai n t he f oll o wi n g i nf or mati o n: 
 
•  Disease stat us 
•  A d verse e ve nt e v al uati o n o nl y if patie nts ha ve r esi d ual persiste nt s y m pt o ms 
relate d t o st u d y treat me nt 
•  C urre nt l y m p h o ma treat me nt 
 
Patie nts will be f oll o we d f or t o xicit y f or 3 0 da ys, a n d 9 0 da ys f or e val uati o n a n d ca pt ure 
of pre-s pecifie d A E SIs, after treat me nt wit h M E- 4 0 1 has bee n disc o nti n ue d or u ntil deat h, 
w hic he ver occ urs first.  T he cli nical c o urse of eac h e ve nt will be f oll o we d u ntil res ol uti o n, 
sta bilizati o n, or u ntil has bee n deter mi ne d t hat t he st u d y treat me nt or partici pati o n is n ot 
t he ca use.  
 
Seri o us a d verse e ve nts ( S A E) t hat are still o n g oi n g at t he e n d of t h e st u d y peri o d will 
necessitate f oll o w- u p t o d eter mi ne t he fi nal o utc o m e. A n y s eri o us a d v erse e v e nt t hat occ urs 
after t he st u d y peri o d a n d is c o nsi dere d t o be p ossi bl y relate d t o t he st u d y treat me nt or 
st u d y partici pati o n will be rec or de d a n d re p orte d i m me diatel y. 
 

C A S E 1 4 2 0  
  
  
  
Pa ge 5 7   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
1 1. 2  
C ale n d ar  
Pr o c e d ur e s 
S c r e e ni n g 
C y cl e 1 
 
C y cl e 2 
C y cl e 3 
C y cl e s 4- 6  
E n d of 
Tr e at m e nt  
F oll o w U p o  
D a y s - 4 5 - 0  
D a y 1  
D a y 2    
D a y 8a  
D a y 1 5a  
D a y 1  
D a y 2  
D a y 1  
D a y 2  
D a y s 1 5- 2 1  
D a y 1  
D a y 2  
8 w e e k s aft er 
l a st tr e at m e nt 
6, 1 2, 1 8, 2 4 m o nt h s 
aft er  l a st tr e at m e ntk 
I nf or m e d C o n s e nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
I n cl u si o n/ E x cl u si o n 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
M e di c al Hi st or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
P h y si c al E x a m  
X  
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
 
Vit al Si g n s  
X  
X  
 
X  
X  
X  
 
X  
 
 
X  
 
X  
X  
H ei g ht/ W ei g ht m 
X  
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
X  
C o n c urr e nt  M e d s 
A s s e s s m e nt  
X 
X  
  
  
  
X  
  
X  
  
 
X  
  
X 
 
B a s eli n e S y m pt o m 
A s s e s s m e nt  
X 
X  
  
  
  
  
  
  
  
 
  
  
 
 
A d v er s e E v e nt 
E v al u ati o n  
 
  
  
X  
X  
X  
  
X  
  
 
X  
  
X 
X 
E C O G P erf or m a n c e 
St at u s  
X 
X  
  
  
  
X  
  
X  
  
 
X  
  
X 
X 
C B C wit h diff er e nti al  
X  
X  
 
X  
X  
X  
 
X  
 
 
X  
 
X  
X  
S er u m C h e mi str y  
X b  
X b  
 
X b  
X b  
X b  
 
X b  
 
 
X b  
 
X b  
X b  
L D H  
X  
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
Uri c A ci d  
X  
X  
 
X  
 
X  
 
 
 
 
 
 
 
 
P h o s p h or o u s  
X  
X  
 
X  
 
X  
 
 
 
 
 
 
 
 
Pr e g n a n c y T e st 
(W O C B P ) 
X 
X  
  
  
  
  
  
  
  
 
  
  
 
 
Uri n al y si s  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
R e m ot e H e p atiti s 
P a n el  
X 
  
  
  
  
  
  
  
  
 
  
  
 
 
H e p atiti s B a n d C 
P C R  
X f 
  
 
  
  
  
  
  
  
 
  
  
 
 
HI V  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C M V  
X  
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
X  
E C G 
X 
X  
  
  
  
  
  
X  
  
 
X l 
  
X 
 
E c h o or M U G A  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C T N e c k/ C h e st/    
A b d o m e n/ P el vi s  
X d  
  
  
  
  
  
  
  
  
Xd  
  
  
Xd  
X j 
P E T S c a n  
X e  
 
 
 
 
 
 
 
 
 
 
 
 
 
B o n e m arr o w bi o p s y  
X  
 
 
 
 
 
 
 
 
 
 
 
X g  
 
R -C H O P  
 
X  
 
 
 
X  
 
X  
 
 
X  
 
 
 
M E -4 0 1  
 
X c 
 
 
 
X c 
 
X c 
 
 
X c 
 
 
 
P e gfil gr a sti m or 
O n P R O T M  
 
  
X  
  
  
  
X  
  
X  
 
  
X  
 
 
P J P or V Z V 
pr o p h yl a xi s  
 
X h   
Xh 
X h   
Xh   
Xh   
Xh   
Xh   
Xh   
Xh  
X h   
Xh   
Xh  
X i 
C orr el ati v e Bl o o d 
X 
  
  
  
  
  
  
  
  
 
X n 
  
X 
X p  
 

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•  
A vi sit wi n d o w of ± 3 d a y s i s all o w e d f or l a b s 
•  
A vi sit wi n d o w of ± 3 d a y i s all o w e d f or tr e at m e nt. 
•   
A vi sit wi n d o w of ± 1 4 d a y s i s all o w e d f or f oll o w- u p vi sit s. 
 
 
 
a.  
C y cl e 1, D a y 8 a n d 1 5 e v al u ati o n i s f or p h a s e I o nl y. I n- p er s o n vi sit m a y b e r e pl a c e d wit h a p h o n e c all t o a s s e s s f or A E s if i n v e sti g at or b eli e v e s t h er e w o ul d b e n o 
i n cr e a s e d ri s k t o t h e s u bj e ct’ s s af et y. L a b s s h o ul d still b e dr a w n i n a c c or d a n c e wit h S O C pr o c e d ur e s. 
b.  
S o di u m, p ot a s si u m, c hl ori d e, bi c ar b o n at e, B U N, cr e ati ni n e, c al ci u m, gl u c o s e, t ot al pr ot ei n, al b u mi n, al k ali n e p h o s p h at a s e, t ot al bilir u bi n, S G O T [ A S T], S G P T [ A L T] 
c.  
P h a s e 1: M E- 4 0 1 will b e gi v e n o n d a y s 1- 4 ( d o s e l e v el 1) O R d a y s 1- 7 ( d o s e l e v el 2) of a 2 1 d a y c y cl e. . P h a s e 2: M E- 4 0 1 will b e gi v e n o n d a y s 1- 4 or d a y s 1- 7 of a 2 1-
d a y c y cl e d e p e n di n g o n t h e R P 2 D. P arti ci p a nt s s h o ul d t a k e M E- 4 0 1 o n a n d e m pt y st o m a c h.  P arti ci p a nt s u n a bl e t o t a k e M E- 4 0 1 o n a n e m pt y st o m a c h ar e all o w e d t o 
t a k e M E- 4 0 1 wit h a li g ht, n o n-f att y s n a c k.   
d.  
N e c k C T c a n b e o mitt e d if t h er e i s n o i n v ol v e m e nt, or s u s pi ci o n f or i n v ol v e m e nt, at s cr e e ni n g p er t h e di s cr eti o n of t h e i n v e sti g at or 
e.  
P E T a n d di a g n o sti c C T s c a n pr ef err e d, b ut P E T al o n e i s a c c e pt a bl e if u n a bl e t o o bt ai n b ot h. Di a g n o sti c C T s c a n s ar e a c c e pt a bl e if u n a bl e t o g et P E T al o n e.  
f.  
H e p atiti s B P C R o nl y r e q uir e d if t e st e d p o siti v e h e p atiti s B s urf a c e a nti g e n a n d/ or h e p atiti s B c or e a nti b o d y d uri n g s cr e e ni n g O R H e p atiti s C P C R o nl y r e q uir e d if 
p arti ci p a nt t e st e d p o siti v e f or h e p atiti s C a nti b o d y o n s cr e e ni n g 
g.  
B o n e m arr o w a s pir ati o n a n d bi o p s y m a y b e o mitt e d if s cr e e ni n g b o n e m arr o w bi o p s y w a s n e g ati v e f or i n v ol v e m e nt of l y m p h o m a 
h.  
P J P pr o p h yl a xi s wit h T M P/ S M X t hr e e d a y s w e e kl y or p e nt a mi n di n e m o nt hl y. Or V Z V pr o p h yl a xi s wit h A c y cl o vir BI D 
i.  
P J P pr o p h yl a xi s st o p p e d 2- 6 m o nt h s aft er l a st d o s e of M E- 4 0 1 or V Z V pr o p h yl a xi s st o p p e d 6 m o nt h s aft er l a st d o s e of M E- 4 0 1 
j.  
Di a g n o sti c C T n e c k, c h e st, a b d o m e n a n d p el vi s s c a n wit h I V a n d P O c o ntr a st will b e d o n e at 6, 1 2, a n d 2 4 m o nt h s if n o di s e a s e pr o gr e s si o n. N e c k C T c a n b e o mitt e d if 
n o i n v ol v e m e nt at b a s eli n e 
k.  
P arti ci p a nt s w h o h a v e pr o gr e s si v e di s e a s e ar e n ot r e q uir e d t o c o m e i n f or cli ni c al f oll o w u p. P arti ci p a nt s will b e c o nt a ct e d o v er t h e p h o n e t o o bt ai n t h e f oll o wi n g 
i nf or m ati o n at t h e s e ti m e p oi nt s: di s e a s e st at u s, a d v er s e e v e nt e v al u ati o n (f or p er si st e nt s y m pt o m s), a n d c urr e nt tr e at m e nt. P ati e nt s ar e all o w e d d o virt u al vi sit s f or l o n g 
t er m f oll o w u p o nl y, if u n a bl e t o f oll o w u p i n p er s o n.  
l.  
E K G o nl y o n C y cl e 6 D a y 1 
m.  
H ei g ht c oll e ct e d o nl y at s cr e e ni n g 
n.  
C orr el ati v e bl o o d ( h e p ari n t u b e s) c oll e ct e d o nl y o n S cr e e ni n g, C y cl e 4 D a y 1, a n d E O T. 
o.  
L o n g t er m f oll o w- u p vi sit s m a y b e c o m pl et e d vi a virt u al vi sit if n e c e s s ar y. E v er y att e m pt s h o ul d b e m a d e t o c o m pl et e t h e a s s e s s m e nt s d u e t h o u g h if t h e y ar e n ot 
c o m pl et e d t hi s i s n ot c o n si d er e d a pr ot o c ol d e vi ati o n. 
p.  
W h ol e bl o o d c orr el ati v e s a m pl e t o b e c oll e ct e d at S cr e e ni n g, E O T, a n d 1 2- m o nt h f oll o w- u p. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 2 . 0  
R E S P O N S E A S S E S S M E N T  
Res p o nse assess me nts will be e val uate d base d o n L u ga n o Criteria (refer t o A p pe n di x C).   
Patie nts will ha ve a P E T/ C T 8 wee ks +/- 7 da ys after e n d of treat me nt.  Please see secti o n 
1 0 f or t he sc he d ul e of t he i ma gi n g st u dies. Patie nts will ha ve pre-treat me nt a n d e n d of 
treat me nt F D G- P E T a n d/ or C T t o m o nit or t heir r es p o nse t o treat me nt. I nt eri m res p o nse 
will be assesse d after c ycl e 3 usi n g C T sca ns. D uri n g f oll o w u p patie nts will ha ve C T sca ns 
d o ne at 6, 1 2, a n d 2 4 m o nt hs after c o m pleti o n of t hera p y. 
 
All patie nts will be e val ua ble f or t o xicit y fr o m t he ti me of t heir first treat me nt wit h M E-
4 0 1.    
 
T he f oll o wi n g g ui deli nes are t o be us e d f or esta blis hi n g t u m or meas ure me nts at baseli ne 
a n d f or s u bse q u e nt c o m p aris o n:  
•  T he si x lar gest d o mi na nt n o des or e xtra n o dal mass es m ust be i de ntifie d at 
baseli ne.  
•  If t here ar e 6 or f e wer n o des a n d e xtr a n o dal masses, all m ust be liste d as 
d o mi na nt.  
If t here ar e m ore t ha n 6 i n v ol ve d n o des or e xtr a n o dal masses, t he 6 lar g est 
d o mi na nt n o des or e xtra n o dal masses s h o ul d be selecte d acc or di n g t o t he 
f oll o wi n g feat ures: 
•  n o des s h o ul d be clearl y meas ura ble i n at least t w o per pe n dic ular 
meas ure me nts  
•  n o des s h o ul d be fr o m as dis parate r e gi o ns of t he b o d y as p ossi ble  
•  Meas ure me nts f or all d o mi na nt n o des a n d e xtra n o dal masses will be re p orte d at 
baseli ne. Meas ure me nts o n n o n- d o mi na nt n o des are n ot re q uir e d. T he l y m p h 
n o des or e xtra n o dal mass es selecte d f or meas ure m e nt s h o ul d be meas ure d i n t w o 
per pe n dic ular dia meters, o ne of w hic h is t he l o n gest per pe n dic ular di a meter. T he 
l y m p h n o des s h o ul d be meas ure d i n ce nti meters t o t he nearest o n e te nt h of a 
ce nti meter ( e. g. 2. 0 c m, 2. 1c m, 2. 2 c m, etc.)  
 
 
1 2. 1 
Defi niti o ns 
 
1 2. 1. 1 Pr o gressi o n Fr ee S ur vi val 
Pr o gressi o n free s ur vi val ( P F S) is defi ne d as t h e ti me fr o m first d ose of st u d y treat me nt 
t o d oc u me nte d disease pr o gressi o n, or deat h fr o m a n y ca use, w hic he v er occ urs first.  
Data f or p artici pa nts w h o are still ali ve a n d free fr o m pr o gressi o n at t he ti me of data 
c ut off date, l ost t o f oll o w- u p, ha ve disc o nti n ue d t h e st u d y, or ha ve i nitiate d N P T will be 
ce ns ore d o n l ast assess m e nt ( or, if n o p ost- bas eli ne t u m or assess me nt, at t h e ti me of first 
d ose pl us 1 da y).   
 
1 2. 1. 2 O verall Res p o nse Rate 
O verall r es p o nse rate ( O R R) is defi ne d as all p atie nts t hat ac hi e ve a C R or P R base d o n 
e n d of treat me nt sca ns, usi n g t he L u ga n o Criteria.   
  
 

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1 2 . 1. 3 C o m plete Re missi o n Rate 
C o m plete res p o nse ( C R) rate is defi ne d as all patie nts t hat ac hie ve a C R b ase d o n e n d of 
treat me nt sca ns, usi n g t h e L u ga n o Criteria.    
 
1 2. 1. 4 Partial Re missi o n Rate 
Partial res p o nse r ate ( P R R) is defi ne d as all patie nts t hat ac hie ve a P R base d o n e n d of 
treat me nt sca ns, usi n g t h e L u ga n o Criteria.    
 
1 2. 1. 5 D urati o n of Res p o nse 
D urati o n of res p o ns e ( D O R) is o nl y meas ure d i n res p o n ders. D O R is defi n e d as t he ti me 
fr o m d oc u me nte d r es p o nse ( C R or P R) t o t he ti me of c o nfir me d disease pr o gressi o n or 
deat h d ue t o a n y ca use, w hic he ver o cc urs first partici pa nts w h o are still ali ve a n d fr ee 
fr o m pr o gressi o n at t he ti me of data c ut off date, l ost t o f oll o w- u p, ha ve disc o nti n ue d 
st u d y, or ha ve i nitiate d ot her n o n- pr ot o c ol a nti-t u m or t hera p y ( N P T) will be ce ns or e d at 
t he last t u m or assess me nt w he n partici pa nts are pr o gressi o n-fr ee.   
 
1 2. 1. 6 O verall S ur vi val  
O verall s ur vi val ( O S) is defi ne d as t he ti me fr o m first d ose of st u d y treat m e nt t o deat h 
fr o m a n y ca use.  D ata f or partici pa nts w h o ar e still ali ve at t he ti me of data c ut off date, 
l ost t o f oll o w- u p, ha ve disc o nti n ue d t he st u d y ( or, if n o p ost- baseli ne assess me nt, at t he 
ti me of first d ose pl us 1 da y) will be ce ns ore d o n l ast assess me nt. 
 
1 2. 1. 7 Ti me t o Treat me nt Fail ur e 
Ti me t o treat me nt f ail ure (e v e nt-fr ee s ur vi val) is meas ure d fr o m t he ti me fr o m st u d y e ntr y 
t o a n y treat me nt fail ure i ncl u di n g disc o nti n uati o n of treat me nt f or a n y r eas o n, s uc h as 
disease pr o gr essi o n, t o xicit y, patie nt prefer e nce, i nitiati o n of ne w treat me nt wit h o ut 
d oc u me nte d pr o gr essi o n, or deat h.  
 
1 2. 2     Res p o nse Re vie w 
Res p o nses will be re vie w e d b y t he i n vesti gat or ( PI or c o-i n vesti gat or) w h o is treati n g t he 
patie nt at eac h p artici pati n g site. Patie nts w h o ha ve bee n tr eate d wit h 3 or m ore c ycles of 
R- C H O P i n c o m bi nati o n wit h M E- 4 0 1 will be a vaila ble f or res p o ns e assess me nt.  
 
 
1 3. 0 
D A T A R E P O R TI N G / R E G U L A T O R Y C O N SI D E R A TI O N S  
 
A d verse e ve nt lists, g ui deli nes, a n d i nstr u cti o ns f or A E re p orti n g ca n be f o u n d i n Secti o n 
8. 0 ( A d vers e E ve nts: List a n d Re p orti n g Re q uire m e nts). 
 
1 3. 1 
D at a Re p orti n g  
T he A d varr a ™ E D C a n d O n C ore ® data bases will be utilize d, as re q uire d b y t he Case 
C o m pre he nsi ve Ca ncer Ce nter a n d Cle v ela n d Cli nic, t o pr o vi de data c ollecti o n f or b ot h 
accr u al e ntr y a n d trial dat a ma na ge me nt. A d v arr a ™ E D C a n d O n C ore ® ar e Cli nical Trials 
Ma na ge me nt S yste ms h o use d o n sec ure ser v ers. Access t o data t hr o u g h A d varr a ™ E D C 
a n d O n C ore ® is r estrict e d b y us er acc o u nts a n d assi g ne d r oles. O n ce l o g ge d i nt o t he 
A d varr a ™ E D C or O n C ore ® s yste m wit h a user I D a n d p ass w or d, A d varra ™ E D C a n d 

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O n C ore ® defi ne r ol es f or eac h user w hic h li mits access t o a p pr o priate dat a. A p plicati o ns 
f or user acc o u nts ca n be o btai ne d b y c o ntacti n g t he O n C ore ® A d mi nistrat or at O n C ore-
re gistrati o n @cas e.e d u f or O n C ore ® access, a n d ta ussi g o nc ore @ccf. or g f or A d varr a ™ 
E D C access. 
 
A d varr a ™ E D C is desi g ne d wit h t he ca pa bilit y f or st u d y set u p, acti v ati o n, trac ki n g, 
re p orti n g, data m o nit ori n g a n d r e vie w, a n d eli gi bilit y verificati o n.  W he n pr o perl y utilize d, 
A d varr a ™ E D C is 2 1 C F R 1 1 c o m plia nt.  T his st u d y will utilize electr o nic Case Re p ort 
F or m c o m pleti o n i n t he A d varr a ™ E D C d ata bas e. A cale n dar of e v e nts a n d re q uir e d f or ms 
are a v aila ble i n A d varra ™ E D C. 
 
1 3. 2 
Re g ul at or y C o nsi der ati o ns 
T he st u d y will be c o n d u cte d i n c o m plia nce wit h I C H g ui deli nes a n d wit h all a p plica ble 
fe der al (i ncl u di n g 2 1 C F R parts 5 6 & 5 0), state or l ocal la ws. 
1 3. 2. 1 
Writte n I nf or m e d c o nse nt  
Pr o visi o n of writte n i nf or me d c o ns e nt m ust be o btai ne d pri or t o a n y st u d y-relate d 
pr oce d ur es. T he Pri nci p al I n v esti gat or will e ns ure t hat t he partici pa nt is gi ve n f ull a n d 
a de q uate oral a n d writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris ks a n d be nefits 
of t he st u d y as well as t he partici pa nt’s fi n a ncial r es p o nsi bilit y. Partici pa nts m ust als o be 
n otifie d t hat t he y are fr ee t o disc o nti n ue fr o m t he st u d y at a n y ti me. T he s u bject s h o ul d be 
gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d be all o we d ti me t o c o nsi der t he i nf or mati o n 
pr o vi de d.  
T he ori gi nal, si g ne d writte n I nf or me d C o nse nt F or m m ust be ke pt wit h t he Researc h C h art 
i n c o nf or ma nce wit h t he i nstit uti o n’s sta n dar d o perati n g pr oce d ur es. A c o p y of t he si g ne d 
writte n I nf or me d 
C o nse nt F or m 
m ust be gi ve n t o t he partici pa nt. 
A d diti o nall y, 
d oc u me ntati o n of t he c o nse nti n g pr ocess s h o ul d b e l ocate d i n t he r esearc h c hart. 
1 3. 2. 2 Partici pa nt Data Pr otecti o n 
I n acc or da n ce wit h t he H ealt h I nf or m ati o n P orta bilit y a n d Acc o u nta bilit y A ct ( HI P A A), a 
partici pa nt m ust si g n a n a ut h orizati o n t o release m e dical i nf or m ati o n t o t he s p o ns or a n d/ or 
all o w t he s p o ns or, a re g ulat or y a ut h orit y, or I nstit uti o nal Re vie w B oar d access t o s u bject’s 
me dical i nf or mati o n t hat i ncl u des all h os pital r ec or ds rele v a nt t o t he st u d y, i ncl u di n g 
partici pa nts’ me dical hist or y.  
 
1 3. 2. 3  Rete nti o n of rec or ds  
T he Pri nci pal I n v esti gat or of T he Case C o m pre he nsi ve Ca ncer Ce nter s u per vises t he 
rete nti o n of all d oc u me ntati o n of a d v erse e ve nts, rec or ds of st u d y dr u g recei pt a n d 
dis pe nsati o n, a n d all I R B c orres p o n de n ce f or as l o n g as nee de d t o c o m pl y wit h l ocal, 
nati o nal a n d i nter nati o nal re g ulati o ns. N o rec or ds will be destr o ye d u ntil t he Pri nci pal 
I n v esti gat or c o nfir ms d estr ucti o n is per mitte d.  
 
1 3. 2. 4  A u dits a n d i ns pecti o ns  
A ut h orize d re prese nt ati ves of t he s p o ns or, a re g ulat or y a ut h orit y, a n I n de pe n de nt Et hics 
C o m mittee (I E C) or a n I nstit uti o nal Re vie w B oar d (I R B) ma y visit t he site t o perf or m 

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a udits or i ns pecti o ns, i n cl u di n g s o urce d ata v erificati o n. T he p ur p os e of a n a u dit or 
i ns pecti o n is t o s yste maticall y a n d i n de pe n de ntl y e xa mi ne all st u d y-relate d acti vities a n d 
d oc u me nts t o deter mi ne w het her t h ese acti vities were c o n d u cte d, a n d data wer e r ec or de d, 
a nal yse d, a n d acc uratel y re p orte d acc or di n g t o t he pr ot oc ol, G o o d Cli nical Practice ( G C P), 
g ui deli nes of t he I nt er nati o nal C o nfere nce o n H ar m o nizati o n (I C H), a n d a n y a p plica ble 
re g ulat or y r e q uire me nts.  F or m ulti-ce nter st u dies, partici pati n g sites m ust i nf or m t he 
s p o ns or-i n vesti gat or of p e n di n g a u dits.  
 
 
1 4. 0  S T A TI S TI C A L C O N SI D E R A TI O N S  
 
P hase I 
•  T he pri mar y e n d p oi nt of p hase I is D L T d uri n g t h e first c ycle. T he tar g et 
t o xicit y rate is n o m ore t ha n 3 0 %. Sta n dar d “ 3 + 3 ” desi g n will be use d f or 
p hase I part wit h 2 pre-s p ecifie d d ose l e vels, starti n g fr o m le vel 1.  If 0/ 3 D L T 
o bser ve d, d ose l e vel will be escal ate d. If 1/ 3 D L T o bser ve d, a d diti o nal 3 
partici pa nts will be e nr olle d o n t he c urr e nt le vel. If 2 or m ore D L T o bser v e d 
i n 3 or 6 partici pa nts, M T D is e xcee de d, a n d d os e le vel will de-es calate. If t his 
ha p pe ns i n d ose le vel 1, t he st u d y will be disc o nti n ue d as t her e M EI is o nl y 
ma n ufact ur e d as 6 0 m g t a blets c urr e ntl y. Si nce t here is n o l o wer d ose t o 
deescal ate, we will disc o nti n ue t he st u d y.   If 1/ 6 D L T o bser ve d, d os e le vel 
will escalate.  R P 2 D is defi ne d as t he d os e le vel wit h 1 or less D L T o ut of 6 
patie nts. 
•  T he sec o n d ar y e n d p oi nts, T R A Es a n d treat me nt d ela ys, will be c haracterize d 
wit h descri pti ve statistics.   
 
P hase II 
•  T he pri mar y e n d p oi nt f or t he p hase II is 1 y ear P F S.  T he n ull rate was set as 
6 5 % a n d we e x pect M E 4 0 1 + C H O P will i ncrease 1- year P F S t o 8 0 %. A t otal 
of 5 4 partici pa nts treate d o n R P 2 D ( wit h t he a ntici pati o n of n o m ore t ha n 5 
patie nts l ost t o f oll o w u p b y 1 year) will e ns ure a p o wer of 8 0 % at o ne-si d e d 
t y pe I err or rat e of 5 % t o detect s uc h a differe nce usi n g a o ne sa m ple l o g-r a n k 
test4 6 a gai nst t he n ull 1- yr rate.   
•  Se c o n dar y e n d p oi nts are defi ne d i n Secti o n 1 2. 1.   
o  T o esti mate t he res p o nse rates (c o m plete a n d partial r e missi o n), 
d urati o n of res p o nse ( D O R), ti me t o pr o gressi o n ( T T P), a n d o verall 
s ur vi val ( O S) wit h 
M E- 4 0 1 pl us R- C H O P. Res p o nse rates will be 
re p orte d as pr o p orti o ns al o n g wit h e xact 9 5 % c o nfi de nce i nter v als. 
D O R, T T F, a n d O S will be esti mate d usi n g Ka pla n- Meier met h o ds.  
o  T o c har acteri ze treat me nt-relate d A Es i n partici pa nts treate d wit h M E-
4 0 1 pl us R- C H O P.  T R A Es will be s u m marize d b y c ycle a n d gra de 
usi n g descri pti ve statistics.  
 
Ba yesia n M o nit ori n g R ule f or Saf et y ( P hase II O nl y). 
T o e ns ure partici pa nts safet y, a Ba yesia n r ule 4 9 will be use d t o m o nit or D L T rate a n d st o p 
t he trial earl y if e xcessi v e t o xicit y rate is o bser v e d. We use a B eta ( 0. 3, 0. 7) pri or f or t he 

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true rate of D L T, w hic h c orres p o n ds t o t he tar g et t o xicit y rate of 3 0 %. We will st o p t he 
trial f or t o xicit y if Pr( D L T rate > 3 0 %| data) > 0. 9, i.e. st o p t he trial if p osteri or 
pr o ba bilit y of D L T rate hi g her t ha n 3 0 % gi ve n d ata is greater t ha n 0. 9. All 5 4 patie nts 
treate d o n R 2 P D will be m o nit ore d b y t his r ule i n c o h orts of 6. Ta ble 1 s u m marizes earl y 
st o p pi n g r ules a n d ta ble 2 s u m marizes o per ati n g c haracteristics. 
 
T a bl e 1. S af et y st o p pi n g b o u n d ari es f or t o xicit y m o ni tori n g i n p h as e II. P ati e nts 
will b e m o nit or e d i n c o h orts of 6. Tri al will b e st o p p e d e arl y d u e t o e xc essi v e 
t o xicit y if n u m b er of D L Ts o bs er v e d w as gr e at er or e q u al t o t h e b o u n d ari es. E. g. if 
6 o ut of t h e first 1 2 p ati e nts e x p eri e nc e d D L T, w e will st o p e arl y f or t o xicit y. 
Si mil arl y, if 9 / 1 8, 1 1 / 2 4, 1 3 / 3 0, 1 5 / 3 6, 1 7 / 4 2, or 1 9 / 4 8 D L Ts o bs er v e d, w e will 
st o p t h e tri al e arl y. 
T ot al N u m b er of 
P ati e nts Tr e at e d  
6  
1 2  
1 8  
2 4  
3 0  
3 6  
4 2  
4 8  
St o p if N u m b er of 
D L T o bs er v e d > =  
4  
6  
9  
1 1  
1 3  
1 5  
1 7  
1 9  
 
 
Ta ble 2. S u m mar y of o perati n g c har acteristics bas e d o n 1 0, 0 0 0 si m ulati o ns usi n g 
m o nit ori n g r ules s pecifie d i n ta ble 1. E. g. If t he tr ue D L T rat e is 5 0 %, t he earl y 
st o p pi n g pr o ba bilit y is 0.9 7 . 
Sce nari o 
Tr ue D L T Rate  
Pr( Earl y 
St o p p pi n g)  
A vera g e 
Sa m ple Size  
A vera g e N u m ber of 
D L T s O bser v e d  
1  
0. 2  
0. 0 3  
5 2. 5  
1 0. 5  
2  
0. 3  
0. 2 4  
4 5. 4  
1 3. 6  
3  
0. 4  
0. 7 1  
3 0. 1  
1 2. 0  
4  
0. 5  
0. 9 7  
1 6. 7  
8. 4  
 
 
 
 A nal ysis Pla n 
Descri pti ve statistics will be use d f or t o xicit y pr ofile a n d res p o ns e stat us. L o gistic 
re gressi o n m o del will be use d t o ass ociate patie nt c haracteristics wit h res p o nse stat us. 
P F S a n d O S will be esti mate d usi n g Ka pla n- Mei er met h o d. O ne-sa m ple l o g-ra n k test will 
be use d t o c o m par e o bser ve d 1- year P F S rat e a gai nst n ull rate. C o x pr o p orti o nal hazar d 
m o del will be use d t o ass ociate patie nt c h aracteristics wit h P F S a n d O S. Ot her statistical 
a nal yses will be carrie d o ut as a p pr o priate. 
 
 
C orrelati ves  
•  P F S base d o n m olec ular s u bt y pe will be e x pl ore d usi n g Ka pla n- Meier met h o d 
de pe n di n g o n t he n u m ber of partici pa nts i n eac h s u bt y pe.  
 
Accr u al Rate  
•  T he p hase I p orti o n of t he trial ai ms t o accr ue pati e nts at 2 lar ge aca d e mic 
ce nters i n O hi o wit h parti ci pati o n of b ot h t he Cle vela n d Cli nic a n d U ni versit y 

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H o s pitals t hr o u g h t he Case C o m pre he nsi ve Ca ncer Ce nter.  At t he Cle vel a n d 
Cli nic Ta ussi g Ca ncer Ce nter, we h a ve s ee n o ver 1 2 0 ne wl y dia g n ose d 
D L B C L patie nts per year f or t he last 3 years. A r ece ntl y c o m plete d p has e I 
st u d y i n ne wl y dia g n ose d D L B C L t hat re q uire d 2 4 partici pa nts c o m plete d 
e nr oll me nt i n 2 years. W e nee d f e wer patie nts a n d esti mate t hat we will accr ue 
1- 2 patie nts per m o nt h d uri n g t he p hase I p orti o n of t he st u d y a n d c o m plet e 
e nr oll me nt wit hi n 1 2- 1 8 m o nt hs.  
•  T he p hase II p orti o n of t he trial will a d d 1- 3 a d diti o nal sites.  D uri n g t he p hase 
II p orti o n of t he st u d y, w e esti mate we will accr u e 2- 4 partici pa nts per m o nt h 
a n d c o m plete e nr oll me nt i n less t ha n 2 4 m o nt hs. F or c o m pleti o n of t he p has e I 
a n d II p orti o n of t he st u d y wit h at least a year of f oll o w u p we esti mate it will 
ta ke 3- 4 years.  
 
 
 
 
 
 
 
 
 
 

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R E F E R E N C E S  
1.  
C oiffier B, Le pa g e E, Briere J, et al. C H O P c he m ot hera p y pl us rit u xi ma b 
c o m pare d wit h C H O P al o ne i n el derl y patie nts wit h diff use lar ge- B-cell l y m p h o ma. T he 
Ne w E n gla n d j o ur n al of me dici ne 2 0 0 2; 3 4 6: 2 3 5- 4 2. 
2.  
Pfre u n dsc h u h M, K u h nt E, Tr u m per L, et al. C H O P-li ke c he m ot her a p y wit h or 
wit h o ut rit u xi ma b i n y o u n g patie nts wit h g o o d- pr o g n osis diff use lar ge- B-cell l y m p h o ma: 
6- year res ults of a n o p e n-la bel ra n d o mise d st u d y of t he Ma b T hera I nter nati o nal Trial 
( MI n T) Gr o u p. T he La n cet O nc ol o g y 2 0 1 1; 1 2: 1 0 1 3- 2 2. 
3.  
Se h n L H, D o nal ds o n J, C h ha na b hai M, et al. I ntr o d ucti o n of c o m bi ne d C H O P 
pl us rit u xi ma b t hera p y dr a maticall y i m pr o ve d o utc o me of diff use lar ge B-cell l y m p h o ma 
i n Britis h C ol u m bia. J o ur nal of cli nical o nc ol o g y : official j o ur nal of t h e A merica n 
S ociet y of Cli nical O nc ol o g y 2 0 0 5; 2 3: 5 0 2 7- 3 3. 
4.  
B o uc h k o uj N, Kasa m o n Y L, de Clar o R A, et al. F D A A p pr o val S u m mar y: 
A xica bta ge n e Cil ole ucel f or Rela pse d or Refr act or y Lar ge B- Cell L y m p h o ma. Cli nical 
ca ncer r esearc h : a n official j o ur nal of t he A meri ca n Ass ociati o n f or Ca n cer Resear c h 
2 0 1 8. 
5.  
Gissel brec ht C, Va n D e n Neste E. H o w I ma na g e patie nts wit h rela pse d/r efract or y 
diff use lar g e B cell l y m p h o ma. Britis h j o ur nal of hae mat ol o g y 2 0 1 8; 1 8 2: 6 3 3- 4 3. 
6.  
Ba d ura S, Tesa n o vic T, Pfeifer H, et al. Differ e ntial effects of selecti ve i n hi bit ors 
tar geti n g t he PI 3 K/ A K T/ m T O R pat h wa y i n ac ute l y m p h o blastic le u ke mia. Pl o S o ne 
2 0 1 3; 8:e 8 0 0 7 0. 
7.  
Hitz F, C o n n ors J M, Gas c o y ne R D, et al. O utc o m e of patie nts wit h pri mar y 
refr act or y diff use lar g e B cell l y m p h o ma after R- C H O P treat me nt. A n nals of he mat ol o g y 
2 0 1 5; 9 4: 1 8 3 9- 4 3. 
8.  
P hili p T, G u gliel mi C, Ha ge n bee k A, et al. A ut ol o g o us b o ne marr o w 
tra ns pla ntati o n as c o m pare d wit h sal va ge c he m ot hera p y i n r ela pses of c he m ot hera p y-
se nsiti ve n o n- H o d g ki n's l y m p h o ma. T he Ne w E n gla n d j o ur nal of me dici ne 
1 9 9 5; 3 3 3: 1 5 4 0- 5. 
9.  
Salles G. U p date d 6 Y ear F oll o w- U p Of T he P RI M A St u d y C o nfir ms T he Be nefit 
Of 2- Year Rit u xi ma b Mai nte na nce I n F ollic ular L y m p h o ma Patie nts Res p o n di n g T o 
Fr o ntli ne I m m u n oc he m ot hera p y. Bl o o d 2 0 1 3; 1 2 2: 5 0 9. 
1 0.  
S o u merai J P, J M; Ja ga dees h, D; Sal ma n, H S; Ke n kre, V P; Asc h, A S; Stat his, A; 
Re d d y, N M; Ias o n os, A; G halie, R; Zele netz, A D. I nitial r es ults of a d ose escalati o n 
st u d y of a selecti ve a n d str uct urall y differe ntiate d PI 3 Kδ  i n hi bit or, M E- 4 0 1, i n 
rela pse d/r efr act or y ( R/ R) f ollic ular l y m p h o ma ( F L) a n d c hr o ni c l y m p h oc ytic le u ke mia 
( C L L)/s mall l y m p h oc ytic l y m p h o ma ( S L L). J Cli n O nc ol 3 6, n o 1 5 _s u p pl ( Ma y 2 0 2 0 1 8) 
7 5 1 9- 7 5 1 9. 
1 1.  
Pfeifer M, Le nz G. PI 3 K/ A K T a d dicti o n i n s u bsets of diff use lar ge B-cell 
l y m p h o ma. Cell c ycle 2 0 1 3; 1 2: 3 3 4 7- 8. 
1 2.  
Pfeifer M, Gra u M, Le n ze D, et al. P T E N l oss defi nes a PI 3 K/ A K T p at h wa y-
de pe n de nt ger mi nal ce nt er s u bt y pe of diff use lar g e B-cell l y m p h o ma. Pr ocee di n gs of t he 
Nati o nal Aca d e m y of Sci e nces of t h e U nite d States of A merica 2 0 1 3; 1 1 0: 1 2 4 2 0- 5. 
1 3.  
C ha p u y B, Ste wart C, D u nf or d AJ, et al. M olec ular s u bt y pes of diff use l ar g e B 
cell l y m p h o ma are ass oci ate d wit h disti nct pat h o ge nic mec h a nis ms a n d o utc o mes. Nat ur e 
me dici ne 2 0 1 8; 2 4: 6 7 9- 9 0. 

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1 4 .  
Sc h mitz R, Wri g ht G W, H ua n g D W, et al. Ge n etics a n d Pat h o ge nesis of Diff use 
Lar ge B- Cell L y m p h o ma. T he Ne w E n gl a n d j o ur n al of me dici ne 2 0 1 8; 3 7 8: 1 3 9 6- 4 0 7. 
1 5.  
S o n g M S, Sal me na L, Pa n d olfi P P. T he f u ncti o ns a n d re g ulati o n of t he P T E N 
t u m o ur s u p press or. Nat Re v M ol Cell Bi ol 2 0 1 2; 1 3: 2 8 3- 9 6. 
1 6.  
Hitz F, C o n n ors J M, Gas c o y ne R D, et al. O utc o m e of patie nts wit h pri mar y 
refr act or y diff use lar g e B cell l y m p h o ma after R- C H O P treat me nt. A n nals of He mat ol o g y 
2 0 1 5; 9 4: 1 8 3 9- 4 3. 
1 7.  
Fli n n I W, K a hl B S, Le o nar d J P, et al. I delalisi b, a selecti ve i n hi bit or of 
p h os p hati d yli n osit ol 3- ki nase- delta, as t her a p y f or pre vi o usl y treate d i n d ole nt n o n-
H o d g ki n l y m p h o ma. Bl o o d 2 0 1 4; 1 2 3: 3 4 0 6- 1 3. 
1 8.  
Fli n n I W, O' Brie n S, K a hl B, et al. D u velisi b, a n o vel oral d ual i n hi bit or of PI 3 K-
delta, ga m ma, is cli nicall y acti ve i n a d va n ce d h e mat ol o gic mali g na ncies. Bl o o d 
2 0 1 8; 1 3 1: 8 7 7- 8 7. 
1 9.  
G o pal A K, Ka hl B S, de V os S, et al. PI 3 K d elta i n hi biti o n b y i delalisi b i n patie nts 
wit h rela pse d i n d ole nt l y m p h o ma. T he Ne w E n gl a n d j o ur nal of me dici n e 2 0 1 4; 3 7 0: 1 0 0 8-
1 8. 
2 0.  
Kl o o B, Na gel D, Pfeif er M, et al. Critical r ole of PI 3 K si g nali n g f or N F- k a p pa B-
de pe n de nt s ur vi val i n a s u bset of acti vate d B- cell-li ke diff use lar g e B-cell l y m p h o ma 
cells. Pr ocee di n gs of t h e Nati o nal Aca d e m y of Sci e nces of t h e U nite d States of A merica 
2 0 1 1; 1 0 8: 2 7 2- 7. 
2 1.  
Za n g C, E uc ker J, Li u H, et al. I n hi biti o n of pa n-cl ass I p h os p hati d yl-i n osit ol- 3-
ki nase b y N V P- B K M 1 2 0 effecti vel y bl oc ks pr olif erati o n a n d i n d uces cell d eat h i n diff use 
lar ge B-cell l y m p h o ma. Le u ke mia & l y m p h o ma 2 0 1 4; 5 5: 4 2 5- 3 4. 
2 2.  
Ka hl B. Cli nical Safet y a n d Acti vit y I n a P has e 1 St u d y of C A L- 1 0 1, A n Is of or m-
Selecti ve I n hi bit or of P h os p hati d yli n osit ol 3- Ki nase P 1 1 0 δ , I n Patie nts wit h Rela pse d or 
Re fract or y N o n- H o d g ki n L y m p h o ma. Bl o o d 2 0 1 0; 1 1 6: 1 7 7 7. 
2 3.  
Le nz G. P hase II st u d y of si n gle-a ge nt c o p a nlisi b i n patie nts wit h rela pse d or 
refr act or y diff use lar g e B-cell l y m p h o ma ( D L B C L). . J o ur nal of Cli nical O nc ol o g y 
2 0 1 7; 3 5: 7 5 3 6-. 
2 4.  
Y o u nes A, Salles G, Marti nelli G, et al. Pa n- p h os p hati d yli n osit ol 3- ki nase 
i n hi biti o n wit h b u parlisi b i n patie nts wit h rela pse d or refract or y n o n- H o d g ki n l y m p h o ma. 
Hae mat ol o gica 2 0 1 7; 1 0 2: 2 1 0 4- 1 2. 
2 5.  
Ja b b o ur E, Ott ma n n O G, Dei ni n ger M, H oc h h a us A. Tar geti n g t he 
p h os p h oi n ositi de 3- ki nase pat h wa y i n he m at ol o gic mali g na ncies. H ae mat ol o gica 
2 0 1 4; 9 9: 7- 1 8. 
2 6.  
Mea d o ws S A, Ve g a F, K as his hia n A, et al. PI 3 K d elta i n hi bit or, G S- 1 1 0 1 ( C A L-
1 0 1), atte n uates p at h wa y si g nali n g, i n d uces a p o pt osis, a n d o verc o mes si g nals fr o m t he 
micr oe n vir o n me nt i n cell ular m o dels of H o d g ki n l y m p h o ma. Bl o o d 2 0 1 2; 1 1 9: 1 8 9 7- 9 0 0. 
2 7.  
C urra n E, S mit h S M. P h os p h oi n ositi de 3- ki nase i n hi bit ors i n l y m p h o ma. C urre nt 
o pi ni o n i n o nc ol o g y 2 0 1 4; 2 6: 4 6 9- 7 5. 
2 8.  
Fr u ma n D A, C hi u H, H o p ki ns B D, Ba gr o dia S, Ca ntle y L C, A bra ha m R T. T he 
PI 3 K Pat h w a y i n H u ma n Disease. Cell 2 0 1 7; 1 7 0: 6 0 5- 3 5. 
2 9.  
C ha n g F, Lee J T, Na v ola nic P M, et al. I n v ol v e me nt of PI 3 K/ A kt pat h w a y i n cell 
c ycle pr o gressi o n, a p o pt osis, a n d ne o plastic tra nsf or mati o n: a tar get f or ca ncer 
c he m ot hera p y. Le u ke mia 2 0 0 3; 1 7: 5 9 0- 6 0 3. 

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3 0 .  
Le nz G, Wri g ht G W, E mre N C, et al. M olec ul ar s u bt y pes of diff use lar ge B-cell 
l y m p h o ma arise b y disti nct ge netic pat h w a ys. Pr ocee di n gs of t he N ati o nal Aca de m y of 
Scie nces of t he U nite d States of A meri ca 2 0 0 8; 1 0 5: 1 3 5 2 0- 5. 
3 1.  
F ur ma n R R, S har ma n J P, C o utre S E, et al. I delalisi b a n d rit u xi ma b i n rela pse d 
c hr o nic l y m p h oc ytic le u k e mia. T he Ne w E n gla n d j o ur nal of me dici ne 2 0 1 4; 3 7 0: 9 9 7-
1 0 0 7. 
3 2.  
de V os S, Wa g ner-J o h nst o n N D, C o utre S E, et al. C o m bi nati o ns of i delalisi b wit h 
rit u xi ma b a n d/ or be n da m usti ne i n patie nts wit h rec urre nt i n d ole nt n o n- H o d g ki n 
l y m p h o ma. Bl o o d a d va nces 2 0 1 6; 1: 1 2 2- 3 1. 
3 3.  
Fli n n I W, Patel M, O ki Y, et al. D u velisi b, a n or al d ual PI 3 K- delta, g a m ma 
i n hi bit or, s h o ws cli nical acti vit y i n i n d ole nt n o n- H o d g ki n l y m p h o ma i n a p hase 1 st u d y. 
A merica n j o ur n al of he m at ol o g y 2 0 1 8; 9 3: 1 3 1 1- 7. 
3 4.  
O' Brie n S, Patel M, Ka hl B S, et al. D u velisi b, a n oral d ual PI 3 K- d elta, ga m ma 
i n hi bit or, s h o ws cli nical a n d p har mac o d y na mic acti vit y i n c hr o nic l y m p h oc ytic le u ke mia 
a n d s mall l y m p h oc ytic l y m p h o ma i n a p hase 1 st u d y. A merica n j o ur n al of he mat ol o g y 
2 0 1 8; 9 3: 1 3 1 8- 2 6. 
3 5.  
Faia K, W hite K, M ur p h y E, et al. T he p h os p h oi n ositi de- 3 ki nase ( PI 3 K)-
delta, ga m ma i n hi bit or, d u velisi b s h o ws precli nical s y ner g y wit h m ulti ple tar gete d 
t hera pies i n he mat ol o gic mali g na ncies. Pl o S o ne 2 0 1 8; 1 3:e 0 2 0 0 7 2 5. 
3 6.  
Dre yli n g M, Sa nt or o A, M ollica L, et al. P h os p hati d yli n osit ol 3- Ki nase I n hi biti o n 
b y C o pa nlisi b i n Rela pse d or Refract or y I n d ole nt L y m p h o ma. J o ur nal of cli nical 
o nc ol o g y : official j o ur nal of t he A merica n S ociet y of Cli nical O nc ol o g y 2 0 1 7; 3 5: 3 8 9 8-
9 0 5. 
3 7.  
Zele netz AJ, D; Re d d y, N M;  Stat his, A; Sal ma n, H S; Asc h, A S; Ke n kre, V P; 
J ha n gia ni, H S; Ias o nas, A; S o u merai, J D; Ll ori n, J; Pa gel, J M. Res ults of t he PI 3 Kδ  
i nh i bit or M E- 4 0 1 al o ne or wit h rit u xi ma b i n rela ps e d/refr act or y ( R/ R) f ollic ular 
l y m p h o ma ( F L). J Cli n O nc ol 3 7, 2 0 1 9 (s u p pl; a bstr 7 5 1 2). 
3 8.  
Zele netz A S, J D; Ja g a dees h, D; Re d d y, N; Stat his, A; Asc h, A S; Sal ma n, H S; 
Ke n kre, V P; J ha n gia ni, H; Ias o n os, A; Patel, K; G halie, R G; Pa gel, J M. Preli mi nar y 
Safet y a n d Efficac y Res ults wit h a n I nter mitte nt Sc he d ule of t he PI 3 k δ  I n hi bit or M E- 4 0 1 
Al o ne or i n C o m bi nati o n wit h Rit u xi ma b f or B- Cell Mali g na ncies. Bl o o d; 1 3 2: 2 8 9 3. 
3 9.  
Zele netz AJ, D; Re d d y, N M;  Stat his, A; Sal ma n, H S; Asc h, A S; Ke n kre, V P; 
J ha n gia ni, H S; Ias o nas, A; S o u merai, J D; Ll ori n, J; Pa gel, J M. T H E PI 3 Kδ  I N HI BI T O R 
M E ‐4 0 1 ± RI T U XI M A B I N R E L A P S E D/ R E F R A C T O R Y ( R/ R) F O L LI C U L A R  
L Y M P H O M A ( F L), C H R O NI C L Y M P H O C Y TI C L E U K E MI A ( C L L), A N D S M A L L 
L Y M P H O C Y TI C L Y M P H O M A ( S L L). He mat ol o gical o nc ol o g y 2 0 1 9; 3 7: 1 7 6- 7. 
4 0.  
W u J, Ya n g S. A si m ulati o n- base d sa m ple size cal c ulati o n met h o d f or pre-cli nical 
t u m or xe n o graft e x p eri m e nts. J o ur nal of bi o p har m ace utical statistics 2 0 1 8; 2 8: 4 3 7- 5 0. 
4 1.  
M EI P har ma. P W T- 1 4 3: A 2 8- Da y Oral T o xicit y St u d y i n Bea gle D o gs wit h a 
2 8- Da y Rec o v er y Peri o d. Re p ort N o 2 2 8 1- 0 0 3; 2 0 1 5. 
4 2.  
A T w o- Ar m, P hase 1 b, O pe n- La b el, D ose Es calati o n St u d y of M E- 4 0 1 i n 
S u bjects wit h Rela pse d/ Refract or y C hr o nic L y m p h oc ytic Le u ke mia/ S mall L y m p h oc ytic 
L y m p h o ma ( C L L/ S L L) or F ollic ular L y m p h o ma ( F L) a n d a n O pe n- La b el St u d y of M E-
4 0 1 i n C o m bi nati o n wit h Rit u xi ma b i n S u bjects wit h Rela pse d/ Refract or y C L L/ S L L or 
B-cell N o n- H o d g ki n’s L y m p h o ma. Pr ot oc ol N u m ber: M E- 4 0 1- 0 0 2 ( N C T 0 2 9 1 4 9 3 8). 

C A S E 1 4 2 0  
  
  
  
Pa ge 6 9   
  
  
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4 3 .  
W u J. Sa m ple size calc ul ati o n f or testi n g differ e nces bet wee n c ur e rates wit h t he 
o pti mal l o g-ra n k test. J o ur nal of bi o p har mace utical statistics 2 0 1 7; 2 7: 1 2 4- 3 4. 
4 4.  
Rit u xa n (rit u xi ma b) [ pac ka ge i nsert]. Bi o ge n a n d Ge netec h, Sa n Fa ncisc o, C A. 
2 0 1 8. 
4 5.  
Fe u gier P, V a n H o of A, Se b ba n C, et al. L o n g-ter m res ults of t he R- C H O P st u d y 
i n t he treat me nt of el derl y patie nts wit h diff use lar ge B-cell l y m p h o ma: a st u d y b y t he 
Gr o u pe d' Et u de d es L y m p h o mes de l' A d ulte. J o ur nal of cli nical o nc ol o g y : official 
j o ur nal of t he A meri ca n S ociet y of Cli nical O nc ol o g y 2 0 0 5; 2 3: 4 1 1 7- 2 6. 
4 6.  
W u J. Sa m ple size calc ul ati o n f or t he o ne-s a m ple l o g-ra n k test. P har mace utical 
statistics 2 0 1 5; 1 4: 2 6- 3 3. 
4 7.  
W u J. P o wer a n d s a m ple size f or r a n d o mize d p h ase III s ur vi val trials u n der t he 
Wei b ull m o del. J o ur nal of bi o p har mace utical statistics 2 0 1 5; 2 5: 1 6- 2 8. 
4 8.  
Wat he n J K, T h all P F. Ba yesia n a da pti ve m o del s electi o n f or o pti mizi n g gr o u p 
se q ue ntial cli nical trials. Statistics i n me dici ne 2 0 0 8; 2 7: 5 5 8 6- 6 0 4. 
4 9.  
T hall P F, Si m o n R M, Este y E H. Ba yesia n s e q ue ntial m o nit ori n g desi g ns f or 
si n gle-ar m cli nical trials wit h m ulti ple o utc o mes. Statistics i n me dici ne 1 9 9 5; 1 4: 3 5 7- 7 9. 
5 0.  
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 per ati ve O nc ol o g y Gr o u p. A merica n j o ur nal of cli nical o n c ol o g y 
1 9 8 2; 5: 6 4 9- 5 5. 
5 1.  
C hes o n B D, Fis her RI, B arri n gt o n S F, et al. Rec o m me n dati o ns f or i nitial 
e val uati o n, sta gi n g, a n d r es 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. J o ur nal of cli nical o nc ol o g y : official j o ur nal of t he A merica n 
S ociet y of Cli nical O nc ol o g y 2 0 1 4; 3 2: 3 0 5 9- 6 8. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A P P E N DI X A 
 
Perf o r m a nce St at us Criteri a 5 0 
 
E C O G Perf or m a nce St at us Sc ale 
Gra de  
Descri pti o n  
 
0 
 
N or mal acti vit y. F ull acti ve, a ble t o 
carr y o n all pre- disease p erf or ma n ce 
wit h o ut restricti o n.  
 
1 
S y m pt o ms, b ut a m b ulat or y. Restricte d 
i n p h ysicall y stre n u o us acti vit y, b ut 
a m b ulat or y a n d a ble t o carr y o ut w or k 
of a li g ht or se de ntar y nat ure (e. g., 
li g ht h o use w or k, office w or k). 
 
2 
I n b e d < 5 0 % of t he ti me.  A m b ulat or y 
a n d ca p a ble of all self-care, b ut u na ble 
t o carr y o ut a n y w or k acti vities. U p 
a n d a b o ut m ore t ha n 5 0 % if wa ki n g 
h o urs.  
 
3 
I n b e d > 5 0 % of t he ti me.  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 or e t ha n 5 0 % of wa ki n g 
h o urs.  
 
4 
1 0 0 % be dri d de n.  C o m pletel y 
disa ble d.  Ca n n ot carr y o n a n y self-
care. T otall y c o nfi ne d t o be d or c hair. 
5  
Dea d.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A P P E N DI X B 
 
P A R TI CI P A N T C A P S U L E DI A R Y 
P artici p a nt N a m e _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Pr ot oc ol # _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ P artici p a nts St u d y I D 
_ _ _ _ _ _ _ _ _ _   
C ycle #: _ _ _ _ _ _ _     
       M o nt h #: _ _ _ _ _ _ _                                   
D ate 
D a y 
# of _ _ _ _ _  m g M E- 4 0 1  c a ps ules a n d 
ti me t a ke n  
C o m me nts 
 
1  
 
 
 
2  
 
 
 
3  
 
 
 
4  
 
 
 
5  
 
 
 
6  
 
 
 
7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A P P E N DI X C 
 
Assess m e nt of Res p o nses b ase d o n L u g a n o Criteri a as defi ne d b y C hes o n et al  5 1 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A P P E N DI X D 
 
List of C Y P 2 C 8 I n hi bit ors a n d I n d ucers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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