Clinical trial NCT04517435
Conditions: Diffuse Large B-Cell Lymphoma
Sponsor: Deepa Jagadeesh
Start date: 2021-04-28; Completion date: 2023-05-17
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done to evaluate if ME-401 can improve the treatment of patients with diffuse large b-celllymphoma (DLBCL). Many patients with DLBCL that are treated with the standard of care (R-CHOP) are cured. However, a little less than half of patients will have their cancer come back despite being treated. Once DLBCL comes back, it is much harder to treat and treatment is much more aggressive. This study will combine ME-401 with R-CHOP. There are 2 parts to this study: part1 referred to as phase I and part 2 referred to as phase 2. The goal of the phase I study is to find the safest dose to give patients in combination with R-CHOP. The goal of the phase 2 study is to use the safest dose (found in phase 1) in combination with R-CHOP to see if it decreases the rate of cancer coming back after it is treated.

Detailed description:
This study is a multi-institution, open-label, phase I/II study designed to evaluate the safety and efficacy of R-CHOP + ME-401 for participants with newly diagnosed DLBCL.

Objectives for the phase I portion of this study are as follows:

Primary objectives:

* To determine the recommended phase 2 dose (RP2D) of ME-401in combination with R-CHOP for participants with newly diagnosed DLBCL.
* To describe tolerability of ME-401 in combination with R-CHOP for participants with newly diagnosed DLBCL.

Objectives for the phase II portion of this study are as follows:

* To estimate the clinical activity of ME-401 in combination with R-CHOP in participants with newly diagnosed DLBCL, as measured by 1 year PFS rate
* To estimate the response rates (complete and partial remission),duration of response (DOR), time to progression (TTP), and overall survival (OS) with ME-401 plus R-CHOP.
* To characterize treatment-related AEs in participants treated with ME-401 plus R-CHOP.

Arms: arm 1: Participants will receive ME-401 dose dependent on dose-escalation schedule at time of enrollment - all will receive standard dose R-CHOP. ME-401 (60 mg) will be given on days 1-4 (dose level 1) OR days 1-7 (dose level 2) of a 21 day cycle with standard dose R-CHOP x 6 cycles.
Interventions: intervention 1: ME-401 intervention 2: Rituximab intervention 3: Cyclophosphamide intervention 4: Doxorubicin intervention 5: Vincristine intervention 6: Prednisone
Intervention descriptions: intervention 1: ME-401 (60 mg) will be given by mouth every 21 days for 6 cycles on days 1-4 (dose level 1) OR days 1-7 (dose level 2) of a 21 day cycle. Dose escalation will be performed in a standard 3+3 design intervention 2: 375 mg/m2 IV/subcutaneous rituximab day 1 of 21-day cycle.

First dose of rituximab will be given IV and subsequent doses can be either IV or SQ based on institutional guidelines. intervention 3: 750 mg/m2 IV Cyclophosphamide day 1 of 21-day cycle intervention 4: 50 mg/m2 IV Doxorubicin day 1 of 21-day cycle intervention 5: 1.4 mg/m2 (max 2 mg) IV Vincristine intervention 6: 100mg PO Prednisone Days 1-5 of 21-day cycle

Protocol documents:
Prot_SAP_000.pdf: 
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S T U D Y  N U M B E R:  C A S E 1 4 2 0  
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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 
D a te 
Secti o n  
C h a n ge 
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C o ver Pa ge 
Cle vela n d Cli nic S u b-I, St u d y C o or di nat or secti o n u p date d, re m o ve d 
PI si g nat ur e li ne as t his is c o ntai ne d i n a se p arate d oc u me nt  
0 8/ 2 0/ 2 0 2 1 
6. 0, 
6. 1. 2, 
9. 7  
A d di n g bi osi milar use of Rit u xi ma b is per mitte d f or t his st u d y per 
treati n g i n vesti gat or discr eti o n 
0 8/ 2 0/ 2 0 2 1 
3. 4. 2; 
1 1. 1. 2 , 1 1. 2 
All o wi n g virt ual visits f or l o n g-ter m f oll o w u p visits. Patie nts t hat 
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.  
0 8/ 2 0/ 2 0 2 1 
1 0. 1. 5 
C ha n ge Cle vela n d Cli nic Bi ore p osit or y s hi p pi n g A T T N t o Ge ne vi e ve 
Cra ne, M D  
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3. 2 
C ha n ge d t o “ T h e p has e 1 p orti o n will e nr oll 6- 1 2 partici pa nts” fr o m 
4 -1 2  
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1 0. 1. 3   
U p date d tiss ue re q uir e me nts per t he la b’s pr efere n ces. 
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1 3. 1 
C ha n ge d F orte t o A d varra t o be c o nsiste nt wit h c o m pa n y na me 
c ha n ge.  
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4. 1. 2 
C ha n ge d st u d y I ncl usi o n Criteria t o a n y t u m or meas uri n g at least 1. 5 
c m 
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8. 4  
Re m o ve d defi niti o n of A E SI; refer e nce I B f or lat est defi niti o ns 
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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. 


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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 


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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 


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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.  
 
 
 


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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, 


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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. 
 
 
 


C A S E 1 4 2 0  
  
  
  
Pa ge 3 9   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
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.  
 


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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.  
 
 


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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 


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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 


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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. 


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•  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  
  
  
  
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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  
  
  
  
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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  
  
  
  
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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  
  
  
  
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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  
  
  
  
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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  
 


C A S E 1 4 2 0  
  
  
  
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Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
•  
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C A S E 1 4 2 0  
  
  
  
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C A S E 1 4 2 0  
  
  
  
Pa ge 6 0   
  
  
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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.   
  
 


C A S E 1 4 2 0  
  
  
  
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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 


C A S E 1 4 2 0  
  
  
  
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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 


C A S E 1 4 2 0  
  
  
  
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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   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C A S E 1 4 2 0  
  
  
  
Pa ge 7 0   
  
  
Versi o n date: 0 4/ 2 2/ 2 0 2 2   
 
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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ICF_001.pdf: 
C O N S E N T F O R C A N C E R R E S E A R C H  
Pr oject  Title:  A n  O pe n -La 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-Cell  L y m p h o ma ( C A S E 1 4 2 0) 
Cli nic al Tri als Re gistr ati o n N u m ber: N C T 0 4 5 1 7 4 3 5  
S p o ns or: Cle vela n d Cli nic/ Case C o m pre he nsi ve Ca ncer Ce nter  
Pri nci p al I n vesti g at or:     Dee p a J a g a dees h, M D , M P H 
        Cle vela n d Cli nic F o u n dati o n 
C A S E 1 4 2 0 
C o nse nt Versi o n Date: 0 8/ 0 4/ 2 0 2 2 
1 of 2 3 
Ca ncer r esearc h st u dies are c o or di n ate d b y p h ysici a ns a n d scie ntists fr o m Cle vela n d Cli nic a n d 
Case Wester n Reser v e U ni versit y ( C W R U) t hr o u g h t he NI H N ati o nal Ca ncer I nstit ute ( N CI) 
desi g nate d Case C o m pre he nsi ve Ca ncer Ce nter ( Case C C C).  T he g oal of t his c olla b orati o n is t o 
e n ha nce ca n cer treat me nt a n d researc h i n N ort heast O hi o. T his st u d y is c urre ntl y bei n g offere d at 
Cle vela n d Cli nic ( C C).  
O ne or m ore of t he I n v esti gat ors c o n d ucti n g t his st u d y ser ve as c o ns ulta nts f or t he c o m pa n y t h at 
ma kes pr o d ucts use d i n t his st u d y.  T hese fi na ncial i nterests are wit hi n per missi ble li mits 
esta blis he d b y t he l ocal i nstit uti o nal C o nflict of I nterest P olic y.   If y o u ha v e a n y q uesti o ns 
re gar di n g c o nflicts of i nterest, pleas e as k y o u st u d y d oct or or call t he Cle vela n d Cli nic 
I nstit uti o nal Re vie w B oar d at 
Ke y I nf or m ati o n: T he f oll o wi n g is a s h ort s u m mar y of t his st u d y t o hel p y o u deci de w h et her or 
n ot t o be a part of t his st u d y.  M ore detaile d i nf or mati o n is liste d later o n i n t his f or m. 
W h y a m I bei n g i n vite d t o t a ke p art i n a rese a rc h st u d y ?  
We i n vite y o u t o ta ke part i n a researc h st u d y beca use y o u ha ve a t y pe of ca ncer k n o w n as 
Diff use Lar ge B -Cell L y m p h o ma ( D L B C L) .  
W h at s h o ul d I k n o w a b o ut a rese arc h st u d y ?  
• 
S o me o ne will e x plai n t his researc h st u d y t o y o u.
•  
W het her or n ot y o u ta ke part is u p t o y o u.
•  
Y o u ca n c h o os e n ot t o ta ke part.
•  
Y o u ca n a gree t o ta k e part a n d later c ha n ge y o ur mi n d.
•  
Y o ur decisi o n will n ot be hel d a gai nst y o u.
•  
Y o u ca n as k all t he q uesti o ns y o u wa nt bef ore y o u deci de.
W h y is t his rese arc h bei n g d o ne ?  
We ar e st u d yi n g a dr u g calle d M E- 4 0 1, als o k n o w n as za n delisi b, w hic h is a n i n vesti gati o nal 
(e x peri me nt al) dr u g bei n g de vel o pe d t o treat certai n t y pes of l y m p h o ma a n d le u ke mia. M E- 4 0 1 
i n hi bits, or bl oc ks, a m olec ule calle d PI 3 K delta, w hic h is t y picall y prese nt i n n or mal 
l y m p h oc ytes a n d l y m p h o ma cells. B y bl oc ki n g PI 3K delta, M E - 4 0 1 w as s h o w n t o s u p press 
ca ncer gr o wt h i n se v eral la b orat or y st u dies. M E- 4 0 1 is e x peri me ntal beca use it is n ot a p pr o ve d 
b y t he F o o d a n d Dr u g A d mi nistrati o n ( F D A). 


 
C A S E 1 4 2 0 C o nse nt  
Versi o n Date: 0 8/ 0 4/ 2 0 2 2 
 
  2 of 2 4 
      
 
 
 
•  T he p ur p ose of t his st u d y is t o e val uate if M E - 4 0 1 ca n i m pr o ve t he treat me nt of patie nts 
wit h diff use lar ge b-cell l y m p h o ma ( D L B C L). Ma n y patie nts wit h D L B C L are treate d 
wit h t he sta n dar d of car e treat me nt k n o w n as R- C H O P. R -C H O P sta n ds f or a series of 
dr u gs calle d  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 a n d Pre d nis o ne. 
After r ecei vi n g R - C H O P ma n y patie nts g o i nt o l o n g-ter m re missi o n, ho we ver, a little less 
t ha n half of patie nts will ha ve t heir ca ncer c o me b ac k des pite bei n g treate d.  O nce 
D L B C L c o mes bac k, it is m uc h har der t o treat a n d treat me nt is m uc h m ore a g gressi ve. 
T his st u d y will c o m bi ne treat me nt of M E - 4 0 1 wit h R-C H O P.  
 
•  T here are 2 p arts t o t his st u d y: part 1 is referre d t o as p hase I a n d part 2 is referre d t o as 
p hase II .   
o  T he g oal of t he p h ase I st u d y is t o fi n d t he safest d osi n g sc he d ule t o gi ve patie nts 
M E - 4 0 1 i n c o m bi nati o n wit h R-C H O P  
o  T he g oal of p has e II is t o use t he safest d osi n g sc h e d ule (f o u n d i n p has e I ) i n 
c o m bi nati o n wit h R- C H O P t o see if it decreases t he rate of ca n cer c o mi n g bac k 
after it is treate d.   
 
H o w l o n g will t he rese arc h l ast a n d w h at will I nee d t o d o ? 
Y o u will recei ve t h e  dr u gs R-C H O P pl us M E - 4 0 1 f or 6 c ycl es. Eac h c ycle l asts 2 1 da ys. After 
y o u fi nis h t he st u d y treat me nt y o ur d oct or will c o nti n ue t o watc h y o u f or si de effects a n d f oll o w 
y o ur c o n diti o n f or u p t o 2 4 m o nt hs.  
 
Y o u will be as ke d t o ta ke a c o m bi nati o n of M E- 4 0 1 a n d R- C H O P a n d ret ur n t o t he cli nic 
peri o dicall y f or r o uti ne tests a n d pr oce d ures t hr o u g h o ut y o ur ti me o n st u d y. 
 
As me nti o ne d a b o ve t her e are t w o p h ases t o t his st u d y.  I n eac h p hase p atie nts will be gi ve n R-
C H O P pl us M E - 4 0 1 f or 6 c ycles ( 2 1 d a ys per c ycle) u nless t here are si d e effects.  R -C H O P is 
gi ve n o n da y 1.  T his i ncl u des 4 me dicati o ns t hat are gi ve n i nt o y o ur vei ns (i ntra ve n o us).  
Pre d nis o ne is a pill y o u ta ke b y m o ut h t hat is gi ve n o n da ys 4- 5. M E- 4 0 1 is a ca ps ule ta k e n b y 
m o ut h gi ve n o n da ys 1- 4 or da ys 1- 7 of eac h c ycle , de pe n di n g o n w hic h p h ase of t he st u d y y o u 
ta ke part i n.   
 
M ore detaile d i nf or mati o n a b o ut t he st u d y pr oce d ures ca n b e f o u n d u n d er “ W hat e xtra tests a n d 
pr oce d ur es will I ha ve if I ta k e part i n t his st u d y?” 
 
Is t here a n y w a y bei n g i n t his st u d y c o ul d be b a d f or me ? 
T he si de effects of st u d y treat me nt ma y be a mi n or i nc o n ve nie nce or c o ul d be se vere e n o u g h t o 
be life -t hreate ni n g or ca use deat h. Y o u will be w atc he d cl osel y f or si de effects, a n d t he dr u g will 
be st o p pe d if u n wa nte d or seri o us si de effects de v el o p.  
 
M ore detaile d i nf or mati o n a b o ut t he ris ks of t his st u d y ca n be f o u n d u n d er “ W hat p ossi ble ris ks 
ca n I e x p ect fr o m ta ki n g part i n t his st u d y?” 
 
 


 
C A S E 1 4 2 0 C o nse nt  
Versi o n Date: 0 8/ 0 4/ 2 0 2 2 
 
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W h at p ossi ble be nefits c a n I e x pect f r o m t a ki n g p art i n t his st u d y ?  
We ca n n ot k n o w if y o u will ha ve a n y be n efit as a res ult of y o ur partici pati o n i n t he st u d y; it is 
p ossi ble t he st u d y treat me nt ma y i m pr o ve y o ur ca ncer, w hic h m a y gi ve y o u relief fr o m s o me 
s y m pt o ms, i m pr o ve y o ur q ualit y of life or pr ol o n g y o ur s ur vi val. H o we v er, it is p ossi ble t hat 
y o ur c o n diti o n c o ul d w orse n. T here is n o pr o of t hat c o m bi ni n g M E- 4 0 1 wit h R- C H O P will be 
m ore usef ul t ha n t he us u al treat me nt ( R - C H O P) f or t he t y pe of ca ncer t hat y o u ha ve. Y o ur 
partici pati o n i n t his st u d y will hel p t o o btai n i nf or mati o n a b o ut treati n g s u bjects wit h  diff use 
lar ge b-cell l y m p h o ma ( D L B C L) . 
 
W h at is t he us u al a p pr o ac h t o m y  diff use l ar ge b -cell l y m p h o m a ( D L B C L) ?  
Ma n y patie nts wit h D L B C L are treate d wit h t he st a n dar d of care  treat me nt k n o w n as R-C H O P. 
R- C H O P sta n ds f or a seri es of dr u gs i nserte d i nt o y o ur vei n (i ntra ve n o us) calle d Rit u xi ma b, 
D o x or u bici n, Vi ncristi ne, a n d C ycl o p h os p ha mi de, al o n g wit h Pre d nis o ne t hat is ta ke n orall y. 
 
W h at are m y ot her c h oi ces if I d o n o t t a ke p art i n t his st u d y ? 
If y o u deci d e n ot t o ta ke part i n t his st u d y, y o u ha ve ot her c h oices. F or e xa m ple: 
 y o u ma y c h o ose t o ha ve t he us ual a p pr o ac h des cri be d a b o ve 
 y o u ma y c h o ose t o ta ke p art i n a differe nt st u d y, if o ne is a vaila ble 
 or y o u ma y c h o ose n ot t o be treate d  f or ca ncer. F or e xa m ple: c o mf ort/ palliati ve care  
 
Det aile d I nf or m ati o n:  T he f oll o wi n g is m ore detaile d i nf or m ati o n a b o ut t his st u d y i n 
a d diti o n t o t he i nf or mati o n liste d a b o ve.  
 
W h at are t he st u d y gr o u ps ?   
As me nti o ne d a b o ve t her e are t w o p arts  t o t his st u d y. T hese parts will be referre d t o as p hase I 
a n d p hase II. I n eac h p h ase, patie nts will be gi ve n R -C H O P pl us M E - 4 0 1 f or 6 c ycles u nless 
t here are si de effects.   
•  Eac h c y cle is 2 1 da ys  
•  R- C H O P is gi ve n o n da y 1.  T his i ncl u des 4 me dicati o ns t hat are gi v e n i nt o y o ur vei ns 
(i ntra ve n o us).  Pr e d nis o ne is a pill y o u ta ke b y m o ut h t hat is gi ve n o n da ys 1- 5.  
•  M E - 4 0 1 is a ca ps ule ta k e n b y m o ut h gi ve n o n t he f oll o wi n g da ys: 
o  P hase I: da ys 1 -4 of eac h c ycle  or d a ys 1-7 of eac h c ycle.  
o  P hase II: rec o m me n de d d urati o n esta blis he d fr o m p hase I 
T he g oal of t he p h ase I st u d y is t o fi n d t he safest d osi n g sc he d ule t o gi ve patie nts M E- 4 0 1 i n 
c o m bi nati o n wit h R- C H O P. Differ e nt d urati o ns of t he st u d y dr u g M E- 4 0 1 will be gi ve n t o 
se veral st u d y partici pa nts. T he first se veral st u d y partici pa nts will recei ve a s h orter d urati o n of 
M E - 4 0 1, o n da ys 1- 4 of eac h c ycle . If t he dr u g d o es n ot ca use s eri o us si de effects, it will be 
gi ve n t o ot her st u d y partici pa nts f or a l o n ger d urati o n of ti me, da ys 1- 7 of eac h c y cle . 
 
T he g oal of t he p h ase 2 st u d y is t o use t he safest d osi n g sc he d ule of M E - 4 0 1 (f o u n d i n p hase I) 
i n c o m bi nati o n wit h R-C H O P t o see if it decreases t he rate of ca ncer c o mi n g bac k aft er it is 
treate d.   


 
C A S E 1 4 2 0 C o nse nt  
Versi o n Date: 0 8/ 0 4/ 2 0 2 2 
 
  4 of 2 4 
      
 
 
Please s pea k wit h y o ur d oct or a b o ut w hic h st u d y p hase y o u will be e nteri n g i nt o. 
H o w m a n y pe o ple will t a ke p art i n t his st u d y ?  
 
•  P has e I:  T his will i ncl u de 6- 1 2 patie nts. T his will occ ur at Cle v ela n d Cli nic ( C C).  
•  P hase II: T his will i ncl u de a p pr o xi matel y 5 0 patie nts. T his will occ ur at Cle vela n d Cli nic 
( C C), U ni versit y H os pitals ( U H), a n d a fe w a d diti o nal ce nters t h at are n ot c o nfir me d  at 
t his ti me.  
 
W h at e xtr a t ests a n d pr oce d ures will I h a ve if I t a ke p art i n t his st u d y ?  
 
As a partici pa nt  i n t his st u d y y o u will be as ke d t o c o m plete t he visits bel o w i n v ol vi n g t he 
f oll o wi n g tests a n d pr oce d ures: 
 
Scree ni n g   
T his will re q uire a visit t o t he cli nic.  At t his visit, t he f oll o wi n g scree ni n g pr oce d ures will be 
perf or me d t o d eter mi ne if y o u ca n ta k e part i n t his st u d y.  All of t he e val uati o ns liste d bel o w 
m ust be c o m plete d < 4 5 da ys pri or t o starti n g t he trial.  If y o u ha ve alrea d y recie v ed a d ose of R-
C H O P a n d are  eli gi ble f or t he st u d y scree ni n g, y o ur scree ni n g wi n d o w will be e xte n de d t o < 6 0 
da ys.  
•  I nf or me d C o nse nt 
•  De m o gra p hics c ollecte d, s uc h as y o ur a g e, race, g e n der, et c.  
•  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 pirat or y rate a n d te m perat ure. 
•  We will as k y o u if y o u ta ki n g a n y 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 or nat ural/ her b al s u p ple me nts 
•  E C O G Perf or ma n ce Stat us (t his descri bes h o w w ell y o u are f u n cti o ni n g i n y o ur 
dail y acti vities).  
•  Baseli ne S y m pt o ms Assess me nt ( A n assess me nt t o see w hat s y m pt o ms y o u are 
ha vi n g) 
•  Bl o o d a n d uri ne sa m ples will be c ollecte d f or safet y a n d dia g n ostic tests t o ma ke 
s ure yo ur or g a ns ar e f u ncti o ni n g well  
- T his i ncl u des tests f or h e patitis, c yt o me gal o vir us ( viral i nfecti o n), a n d HI V (see 
ris k secti o n bel o w f or e x pla nati o n) 
•  C orrelati ve Bl o o d Dra w ( T his is a n a d diti o nal bl o o d dra w ta ke n f or st u d y 
p ur p oses o nl y a n d is descri be d i n m ore detail bel o w. A p pr o xi matel y 6 teas p o o ns 
of e xtra bl o o d will be ta k e n f or a d diti o nal st u d y p ur p oses )  
•  If y o u ar e a f e male w h o c o ul d bec o me pre g n a nt w e will ha ve y o u ta ke a 
pre g na nc y t est.  Y o u will nee d t o pr o vi de a uri ne s a m ple  
•  E K G ( Electr ocar di o gra m – stic k pa ds will be place d o n y o ur c h est a n d c o n necte d 
t o a mac hi ne s o we ca n c hec k t he r h yt h m of y o ur heart) 


 
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•  M U G A or ec h ocar di o gra m (see ris k secti o n bel o w f or e x pla n ati o ns)  
•  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 ( n ec k ma y 
be o mitte d at disc reti o n of treati n g p h ysicia n) (see risk secti o n bel o w f or 
e x pla nati o n) 
•  P E T/ C T (see ris k secti o n bel o w f or e x pl a nati o n) 
•  B o ne Marr o w As pir ate a n d Bi o ps y ( T his is sta n dar d of care f or m ost patie nts, 
e ven if y o u are n ot o n t his st u d y) (s ee risk secti o n bel o w f or e x pl a nati o n) 
 
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 pirat or y rate a n d te m perat ure.  
•  We will as k y o u if y o u ta ki n g a n y 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 or n at ural/ her bal s u p ple me nts 
•  E C O G perf or ma nce stat us   
•  We will as k a b o ut a n y s y m pt o ms y o u are ha vi n g 
•  Bl o o d sa m ples will be c ollecte d t o see h o w w ell y o ur or ga ns are f u n cti o ni n g 
•  If y o u ar e a f e male w h o c o ul d bec o me pre g n a nt w e will ha ve y o u ta ke a pre g na nc y test.  
Y o u will nee d t o pr o vi de a uri ne sa m ple.  
•  E K G  
•  R- C H O P a d mi nistrati o n (f or t he first treat me nt t his will ta ke a p pr o xi matel y 6 h o urs) .  
•  M E - 4 0 1 starte d ( gi ve n d a ys 1- 4 or da ys 1- 7) 
o  Y o u will nee d t o kee p a dr u g diar y f or e ver y d ose of M E- 4 0 1 t hat is ta ke n. T his 
will i ncl u de t he date, n u m ber of M E- 4 0 1 ca ps ules ta ke n, a n d t he ti me of t he d ose. 
•  Start ta ki n g a me dicati o n calle d Tri met h o pri m/s ulfa met h o xaz ol e or Pe nta mi di ne t o hel p 
pre ve nt a l u n g i nf ecti o n calle d p ne u m oc ystis jir o vecii.  M E- 4 0 1 ma y i ncrease y o ur ris k of 
t his i nfecti o n w hic h is w h y y o u will ta ke o ne of t hese me dicati o ns.     
1.  Tri met h o pri m/s ulfa met h o xaz ole is gi ve n b y m o ut h, t hree da ys a wee k.    
 
2.  Pe nta mi di ne is i n hale d a n d gi ve n o nce m o nt hl y.    
Y o u will ta ke t his u ntil 2 -6 m o nt hs after fi nis hi n g treat me nt  
•  Start a me dicati o n calle d Ac ycl o vir t hat will be ta k e n t wice a d a y.  
 
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.  T his is a me di cati o n gi ve n 
t o patie nts w h o get R- C H O P.  It hel ps i ncreas e i nfecti o n fi g hti n g cells ( ne utr o p hils) 
w hic h hel ps y o ur b o d y’s a bilit y t o fi g ht i nfecti o ns. It ca n be gi ve n as a s u bc uta ne o us 
i njecti o n (j ust u n der t he s ki n) i n t he cli nic or y o u ca n wear a de vi ce o n y o ur ar m t hat 
i njects it at h o me.  
 
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 pirat or y rate a n d te m perat ure.  
•  Bl o o d sa m ples will be c ollecte d t o see h o w w ell y o ur or ga ns are f u n cti o ni n g 
•  We will as k y o u if y o u ar e ha vi n g a n y c o n cer ns or ne w s y m pt o ms.  
C ycle 1, D a y 1 5 ( P h ase I O nl y)  


 
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•  Vital si g ns i ncl u di n g: bl o o d press ure, p ulse, res pirat or y rate a n d te m perat ure.  
•  Bl o o d sa m ples will be c ollecte d t o see h o w w ell y o ur or ga ns are f u n cti o ni n g 
•  We will as k y o u if y o u ar e ha vi n g a n y c o n cer ns or ne w s y m pt o ms.  
 
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 pirat or y rate a n d te m perat ure.  
•  We will as k y o u if y o u ta ki n g a n y 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 or n at ural/ her bal s u p ple me nts 
•  E C O G perf or ma nce stat us   
•  We will as k a b o ut a n y s y m pt o ms y o u are ha vi n g 
•  Bl o o d sa m ples will be c ollecte d t o see h o w w ell y o ur or ga ns are f u n cti o ni n g  
o  * C ycle 2 Da y 1 o nl y: A d diti o nal bl o o d sa m ples t o c hec k y o ur uric aci d a n d 
p h os p h or o us le vels (a p pr o xi matel y 1- 2 teas p o o ns of bl o o d) will be dra w n t o 
e xa mi ne y o ur or g a n f u ncti o n  
o  * C ycle 4 Da y 1 o nl y: C orrelati ve Bl o o d Dra w f or st u d y p ur p oses (a p pr o xi matel y 
6 teas p o o ns of bl o o d) 
•  E K G   * C ycle 3 Da y 1 a n d C ycle 6 Da y 1 o nl y 
•  R- C H O P a d mi nistrati o n ( T his will ta ke a p pr o xi m atel y 4 h o urs) 
•  M E - 4 0 1 starte d ( gi ve n d a ys 1- 7 or da ys 1- 4) 
o  Y o u will nee d t o kee p a dr u g diar y f or e ver y d ose of M E- 4 0 1 t hat is ta ke n. T his 
will i ncl u de t he date, n u m ber of M E- 4 0 1 ca ps ules ta ke n, a n d t he ti me of t he d ose. 
 
C ycle 2 - 6, 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  
 
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 c o ntrast f or res p o nse ass ess me nt gi ve n 
i ntra ve n o usl y (t hr o u g h a vei n) a n d orall y  ( b y m o ut h). Nec k C T ca n be o mitte d if t here is 
n o i n v ol ve me nt at baseli ne.  
 
E n d of Tre at m e nt ( E O T) Res p o nse Assess me nt – 8 wee ks ( + /- 7 d a ys) after l ast tre at me nt   
•  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 pirat or y rate a n d te m perat ure.  
•  We will as k y o u if y o u ta ki n g a n y 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 or n at ural/ her bal s u p ple me nts 
•  A d verse E v e nt E val uati o n  
•  We will as k a b o ut a n y s y m pt o ms y o u are ha vi n g 
•  Bl o o d sa m ples will be c ollecte d t o see h o w w ell y o ur or ga ns are f u n cti o ni n g  
•  C orrelati ve Bl o o d Dra w f or st u d y p ur p oses  
•  E K G  


 
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•  B o ne marr o w bi o ps y ( ma y be o mitte d if scree ni n g b o ne marr o w bi o ps y di d n ot s h o w 
l y m p h o ma).  
•  P E T a n d dia g n ostic C T of nec k, c h est, a b d o me n, a n d pel vis wit h c o ntrast i nserte d i nt o 
y o ur vei n a n d b y m o ut h (see bel o w f or m ore d etails).  T his test will hel p us assess if t he 
treat me nt w or k e d f or y o ur l y m p h o ma.  
 
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. 
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 last c ycle of t hera p y. If 
y o u are u na bl e 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 ble 
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. Please disc uss t his o pti o n wit h y o ur st u d y d oct or if 
y o u t hi n k it will be necessar y. 
 
•  P h ysical E xa mi nati o n  
•  Vital si g ns  
•  E C O G perf or ma nce stat us  
•  We will as k a b o ut a n y s y m pt o ms y o u are ha vi n g 
•  Bl o o d sa m ples will be c ollecte d t o see h o w w ell y o ur or ga ns are f u n cti o ni n g  
•  C T nec k, c hest, a b d o m e n a n d pel vis sca n will be d o ne at 6, 1 2 a n d 2 4 m o nt hs t o e val uate 
if t he D L B C L is bac k or still g o ne 
•  * Disc o nti n ue Tri met h o pri m/s ulfa met h o xaz ole or Pe nta mi di ne b y 6 m o nt h visit (ca n be 
st o p pe d bet wee 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 ose l y m p h o ma c o mes bac k aft er treat me nt are n ot re q uire d t o c o me i nt o cli nic f or 
f oll o w u p. T he y ca n b e calle d o n t he p h o ne t o disc uss t he f oll o wi n g:  
•  Disease stat us  
•  We will as k y o u a b o ut a n y s y m pt o ms y o u are ha vi n g 
•  C urre nt l y m p h o ma treat me nt 
 
 
D uri n g t he st u d y t he f oll o wi n g will be a d diti o n al rese arc h pr oce d ures:  
 
M ost of t he e xa ms, tests, a n d pr oce d ures y o u will ha ve are part of t he us ual a p pr oac h f or y o ur 
ca ncer. H o w e ver, t h ere ma y be s o me e xtra tests t hat y o u will nee d t o ha ve if y o u ta ke part i n t his 
st u d y. Y o u will n ot be c har ge d f or a n y e xtra tests. Tests a n d fre q ue nc y of tests t hat are s olel y 
ass ociate d wit h t his st u d y a n d are n ot p art of r o uti ne me dical care are liste d as f oll o ws:  
 
 Uri ne test - At scree ni n g visit 
 Test t o c hec k f or c yt o me gal o vir us i nfecti o n (a ki n d of her pes vir us t h at ca n ca use da m a ge 
t o pe o ple wit h wea k e ne d i m m u ne s yste ms) - At scree ni n g  visit, C ycle 1 Da y 1 visit of 
e ver y c y cle, E O T visit , a n d all f oll o w u p visits 
 Pre g na nc y test ( H C G bl o o d dra w) f or w o me n of c hil d beari n g p ote ntial- At C ycle 1 Da y 1 
visit, if a p plica ble  
 C orrelati ve Bl o o d Dra w- At scree ni n g visit, C ycle 4 Da y 1, E O T visit , at 1- year f oll o w- u p 


 
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visit  
 Ec h ocar di o gra m ( E K G)- At C ycle 1 Da y 1, C ycle 3 Da y 1, C ycle 6 D a y 1, a n d E O T visit 
 
C orrel ati v e Tests ( E xt r a Tests)  
T he tiss ue c ollecti o n/a nal ysis a n d a d diti o nal bl o o d sa m ples are re q uire d i n or der f or y o u t o ta ke 
part i n t his st u d y beca use t he researc h o n t he s a m ple is a n i m p orta nt part of t he st u d y.   
 
E xtra Tiss ue C ollecti o n/ A nal ysis:  
•  Tests will be d o ne o n t he l y m p h o ma bi o ps y sa m ple t hat was o btai ne d at dia g n osis a n d at 
t he e n d of treat me nt visit. T hese bi o psies are part of y o ur t y pical care a n d y o u will n ot 
ha ve ne w or e xtr a bi o psies c o m plete d s olel y f or t his st u d y.   
C orrelati ve Bl o o d Dra w: 
•  F o ur e xtr a t u bes of bl o o d, eac h c o ntai ni n g 1 0 ml (t he e q ui vale nt of a b o ut 8 teas p o o ns of 
bl o o d) will be c ollecte d at t he scree ni n g visit,  at t he e n d of treat me nt  ( E O T) visit , a n d at 
t he 1- year f oll o w- u p visit.  O nl y 2 e xtra t u bes (a b o ut 4 teas p o o ns) of bl o o d will be 
c ollecte d pri or t o tr eat me nt of C ycle 4.  
 
T he f oll o wi n g a p plies t o all c orrel ati ve tests c o m plete d f or t his researc h st u d y . C orrelati ve tests 
are a d diti o nal sa m ples of bl o o d a n d tiss ue c ollecte d o nl y f or researc h p ur p oses: 
•  All sa m ples c ollecte d as part of t his researc h st u d y will be la bele d wit h a st u d y i de ntifier 
or c o de t hat is u ni q ue t o y o u a n d will n ot be la bel e d or st ore d wit h na mes or ot her direct 
li n ks t o y o ur i de ntit y. T his u ni q ue i de ntifier will all o w us t o li n k i nf or mati o n o btai ne d 
fr o m y o ur sa m ples a n d y o ur me dical i nf or mati o n, b ut will n ot all o w st u d y pers o n nel, t o 
i de ntif y y o u.  
•  Res ults fr o m a n y testi n g/a nal ysis o n y o ur sa m ples will als o be la bele d wit h y o ur u ni q ue 
i de ntifier c o de a n d will n ot i ncl u de y o ur na me or ot her i nf or mati o n t hat c o ul d i de ntif y 
y o u. T he c o nfi de ntialit y of a n y ce ntral c o m p uter rec or d will be caref ull y g uar de d, a n d n o 
i nf or mati o n b y w hic h y o u ma y be i de ntifie d will be release d or p u blis he d.  
•  Y o ur na me will n ot be us e d i n a n y re p orts or p u blicati o ns a b o ut t he res earc h st u d y. N o 
i nf or mati o n t hat ma y i de ntif y y o u will be release d or p u blis he d.  
•  T he res ults fr o m t hese e x pl orat or y tests will be use d f or researc h p ur p os es o nl y, a n d will 
n ot be s hare d wit h y o u or use d i n y o ur care. T his researc h will n ot c ha n ge t he care y o u 
recei v e fr o m y o ur st u d y d oct or, b ut ma y be usef ul t o g ui de t he treat me nt of f ut ure 
patie nts wit h t he st u d y dr u gs.  
•  Neit her y o u n or y o ur healt h care pla n/i ns ura n ce carrier will be bille d f or t h e c ollecti o n or 
a nal ysis of t he tiss ue or bl o o d t hat will be use d f or t his st u d y. 
 
T he tiss ue a n d bl o o d sa m ples c ollecte d i n t he c orrelati ve secti o n ma y c o nt ai n ge netic testi n g. 
T he pri vac y of t he r esear c h i nf or mati o n ge nerate d fr o m y o ur D N A ( ge ne) s a m ple will be 
pr otecte d as m u c h as p ossi ble.  If t his i nf or m ati o n were release d t o y o u, y o ur fa mil y, or t hir d 
parties, t here c o ul d be a d verse ps yc h ol o gical effects f or y o u or y o ur fa mi l y me m bers.  T her e 
c o ul d als o be u n desira bl e effects o n y o u or y o ur fa mil y me m bers’ a bilit y t o o btai n a j o b or 
i ns ura nce.  I n or der t o mi ni mize t hese ris ks, e very eff ort will be ma d e t o kee p all ge netic 
researc h i nf or m ati o n o btai ne d fr o m y o ur bl o o d sa m ple c o nfi de ntial. B ut a bs ol ute c o nfi de ntialit y 
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T he res ults of t he a n al ysis of y o ur D N A d o n e as p art of t his st u d y will n ot be gi ve n t o y o u. Y o ur 
D N A ( ge n es), or y o ur cells t hat ca n be use d t o ma ke y o ur D N A, will be st ore d f or researc h 
p ur p oses.   
 
Y o ur D N A s a m ples ma y be use d f or a n y scie ntific p ur p ose i n v ol vi n g t his pr oject a n d/ or a n y 
ot her pr oject.  
 
At a n y ti me, y o u ma y as k t o ha ve y o ur sa m ples t hat were c ollecte d f or res earc h t esti n g be 
destr o ye d b y c o ntacti n g t he st u d y d oct or. If y o u d o t his, all of t he re mai ni n g sa m ples will be 
destr o ye d s o t hat n o m or e researc h ca n b e d o ne. H o we ver, a n y i nf or m ati o n c ollecte d fr o m y o ur 
sa m ples bef or e y o ur r e q u est t o destr o y t he m will be ke pt b y t he Cle vela n d Cli nic. If y o u deci de 
t o st o p partici pati n g i n t he st u d y, b ut d o n ot re q uest destr ucti o n of y o ur sa m ples, Cle vela n d 
Cli nic ma y c o nti n ue t o use y o ur sa m ples f or t his pr oject as w ell as a n y ot h er pr ojects.  
 
Ge netic I nf or m ati o n N o n discri mi n ati o n Act ( GI N A)  
 
A Fe d eral la w, calle d t he Ge netic I nf or mati o n N o n discri mi nati o n Act ( GI N A), effecti ve Ma y 2 1, 
2 0 1 0, ge nerall y ma k es it ille gal f or healt h i ns ura n ce c o m pa ni es, gr o u p healt h pla ns, a n d m ost 
e m pl o yers t o discri mi nate a gai nst y o u base d o n y o ur ge netic i nf or m at i o n. T his la w ge nerall y will 
pr otect y o u i n t he f oll o wi n g wa ys:  
 
•  Healt h i ns ura nce c o m pa nies a n d gr o u p healt h pla ns ma y n ot re q uest y o ur g e netic 
i nf or mati o n t hat we get fr o m t his researc h. 
•  Healt h i ns ura nce c o m pa nies a n d gr o u p healt h pla ns ma y n ot use y o ur ge netic i nf or mati o n 
w he n ma ki n g decisi o ns r e gar di n g y o ur eli gi bilit y or pre mi u ms.  
•  E m pl o yers wit h 1 5 or m ore e m pl o yees m a y n ot use y o ur ge netic i nf or mati o n t hat we get 
fr o m t his researc h w h e n ma ki n g a decisi o n t o hire, pr o m ote, or fire y o u or w he n setti n g 
t he ter ms of y o ur e m pl o y me nt.  
 
Be a war e t hat t his Fe d eral la w d oes n ot pr otect y o u a gai nst ge netic discri mi nati o n b y c o m pa nies 
t hat sell life i ns ura nce, disa bilit y i ns ura nce, or l o n g-ter m care i ns ura n ce. 
 
 
W h at p ossi ble  ris ks c a n I e x pect f r o m t a ki n g p art i n t his st u d y ?  
 
Y o u ma y ha ve all, s o me, or n o ne of t he k n o w n si d e effects des cri be d i n t he f oll o wi n g secti o ns. 
T here is als o a ris k t hat ot her rar e or u n k n o w n si d e effects ma y occ ur. Y o ur d oct ors a n d n urs es 
will c hec k y o u cl osel y f or si de eff ects, a n d ma y gi ve y o u me dici nes or ot her treat me nts t o st o p or 
re d uce s o m e of t hese eff ects. S o me si de effects ma y g o a wa y s o o n after t he st u d y me dicati o n is 
st o p pe d, b ut i n s o me cases, si de eff ects ma y be s eri o us, l o n g lasti n g, a n d/ or per ma n e nt. T here is 
e ve n a c ha nce t hat a si de effect ma y ca use deat h.  
 
Here are i m p orta nt p oi nts a b o ut h o w y o u a n d t he st u d y d oct or ca n ma k e si de effects less of a 
pr o ble m: 


 
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 Tell t he st u d y d oct or if y o u n otice or feel a n yt hi n g differe nt s o t he y ca n see if y o u are 
ha vi n g a si de effect.  
 T he st u d y d oct or ma y be a ble t o treat s o me si de effects.  
 T he st u d y d oct or ma y a dj ust t he st u d y dr u gs t o tr y t o re d uce si de effects. 
 
T he ta bles bel o w s h o w t h e m ost c o m m o n a n d t he m ost seri o us si de effects t hat researc hers k n o w 
a b o ut. T here mi g ht be ot her si de effects t hat researc hers d o n ot y et k n o w a b o ut. If i m p orta nt n e w 
si de effects ar e f o u n d, t h e st u d y d oct or will disc uss t hese wit h y o u. 
 
 
M E -4 0 1 Ris ks a n d Si de Effects : 
•  M E - 4 0 1 is a n i n vesti gati o nal dr u g a n d it has n ot b ee n c o m bi ne d wit h c h e m ot hera p y. It is 
n ot p ossi ble t o pre dict all of t he ris ks a n d u n wa nt e d effects t hat mi g ht ha p pe n if y o u ta ke 
M E - 4 0 1. T he f oll o wi n g ta bles descri b e t he si de effects t hat ha v e bee n s ee n i n pre vi o us 
patie nts ta ki n g M E- 4 0 1 a n d si de effects t hat c o ul d be of c o ncer n.  
•   
 
C O M M O N,  S O M E  M A Y  B E  S E RI O U S  
I n 1 0 0 p e o ple recei vi n g M E - 4 0 1, 
m ore  t ha n 1 0 a n d u p t o 1 0 0 ma y  ha ve:  
•  Diarr hea  
•  Na usea  ( u neas e a n d disc o mf ort i n t he st o mac h, ofte n wit h t he ur ge t o v o mit) 
•  Fati g ue (feeli n g tire d) 
•  Ne utr o p hil c o u nt decreas e d  ( decrease i n certai n w hite bl o o d cells t hat hel p fi g ht i nfecti o ns) 
•  A S T  i ncrease d 
•  Platelet  c o u nt decr ease d  ( bl o o d cells t hat c o ntr ol blee di n g) 
•  Ras h  mac ul o pa p ular (ras h wit h  b u m ps) 
 
 
 
O C C A SI O N A L, S O M E M A Y B E  S E RI O U S  
I n 1 0 0 p e o ple recei vi n g M E - 4 0 1, 
1 a n d u p t o 1 0 ma y  ha ve: 
•  Ne utr o pe nia ( decreas e i n certai n w hite bl o o d cells t hat hel p fi g ht i nfecti o ns)  
•  A ne mia (l o w n u m ber of r e d bl o o d cells or he m o gl o bi n i n t he bl o o d) 
•  A b d o mi nal (st o mac h) pai n 
•  C o nsti pati o n 
•  St o matitis  ( m o ut h s ores) 


 
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O C C A SI O N A L, S O M E M A Y B E  S E RI O U S  
I n 1 0 0 p e o ple recei vi n g M E - 4 0 1, 
1 a n d u p t o 1 0 ma y  ha ve: 
•  C olitis  (i nfla m mati o n of  t he c ol o n)  
•  Gastr oes o p ha g eal r efl u x disease  ( G E R D, or heart b ur n) 
•  A b d o mi nal diste nsi o n (s w olle n a b d o me n) 
•  D ys pe psia (i n di gesti o n) 
•  Dr y m o ut h 
•  V o miti n g  
•  Flat ule nce  ( gas) 
•  Oral pai n  
•  Fe ver  
•  E de ma peri p h eral (s w elli n g of ha n ds a n d l o wer le gs) 
•  Ast he nia (feeli n g tire d, w ea k) 
•  P ne u m o nia 
•  U p per r es pirat or y tr act i nfecti o n  
•  Si n usitis  (si n us i nfecti o n) 
•  Her pes z oster (s hi n gles)  
•  C o nj u ncti vitis (e ye i nfecti o n) 
•  C yt o me gal o vir us i nfecti o n ( C M V) 
•  A L T i ncrease d (li ver e nz y mes) 
•  Le u k o pe nia (l o w w hite bl o o d cell c o u nt) 
•  Bl o o d creati ni ne i ncr ease d  (a waste pr o d uct fr o m ki d ne ys, ma y i n dicate decreas e d 
ki d ne y f u ncti o n) 
•  Wei g ht decr eas e d  
•  Bl o o d al kali ne p h os p ha tase i ncrease d (li ver e nz y m e) 
•  L y m p h oc yte c o u nt decrease d or i ncreas e d (a t y pe of w hite bl o o d cell) 
•  Electr ocar di o gra m qt pr ol o n ge d (irre g ular fast h eart beat)  
•  Bl o o d bilir u bi n i ncrease d 
•  Decr ease d a p petite  
•  H y per kale mia ( hi g h le vels of p otassi u m i n t he bl o o d) 
•  De h y drati o n 
•  T u m or l ysis s y n dr o me (r a pi d deat h of ca ncer cells) wit hi n 1 t o 2 da ys after starti n g 
treat me nt, w hic h if n ot pr o perl y treat e d ca n ca use se vere m e dical c o m plicati o ns, 
i ncl u di n g deat h. Y o u ma y nee d t o be a d mitte d t o t he h os pital f or t he pre ve nti o n or 
treat me nt of t u m or l ysis s y ndr o me 
•  Art hral gia  (j oi nt pai n) 
•  M yal gia ( m uscle pai n) 
•  M uscle s pas ms  
•  M usc ular wea k ness  


 
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O C C A SI O N A L, S O M E M A Y B E  S E RI O U S  
I n 1 0 0 p e o ple recei vi n g M E - 4 0 1, 
1 a n d u p t o 1 0 ma y  ha ve: 
•  Hea dac he  
•  Dizzi ness  
•  D ys ge usia (a b n or mal taste) 
•  I ns o m nia 
•  Ac ute ki d ne y i nj ur y 
•  C o u g h a n d/ or pr o d ucti ve c o u g h 
•  D ys p nea 
•  Nasal c o n gesti o n (st uff y n ose) 
•  Or o p har y n g eal (t hr o at) p ai n  
•  P ne u m o nitis ( y o u will be prescri be d a me dicati o n t o hel p pre ve nt a p ossi ble l u n g 
i nfecti o n) 
•  U p per- air wa y c o u g h s y n dr o me 
•  Ras h  
•  Pr uritis  
•  Der matitis ac neif or m  (s ki n i nfla m mati o n) 
•  Dr y s ki n 
•  Dr u g er u pti o n (s ki n r eacti o n) 
•  Er yt he ma (r e d ness) 
•  H y perte nsi o n ( hi g h bl o o d press ure)  
 
 
A p ote ntiall y R A R E A N D S E RI O U S  c o n diti o n, car di o m y o pat h y (a c o n diti o n w here t he h eart 
m uscle ca n bec o me e nlar ge d a n d wea k a n d is l ess a ble t o p u m p bl o o d t hr o u g h t he b o d y. T his c o ul d 
p ote ntiall y lea d t o heart val ve pr o bl e ms, irre g ular heart beats, a n d h eart fail ure) was re p orte d i n 1 
st ud y partici pa nt i n a diff ere nt st u d y.  
 
 
Rit u xi m a b, C ycl o p h os p h a mi de, D o x or u bici n, Vi ncristi ne, a n d Pre d nis o ne ( R -C H O P)  
•  R- C H O P is sta n dar d of care f or patie nts wit h ne wl y dia g n ose d D L B C L.   
 
 
C ycl 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) Ris ks a n d Si de Effects : 
C O M M O N,  S O M E  M A Y  B E  S E RI O U S  
I n 1 0 0 p e o ple r ecei vi n g C ycl 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), 
m ore  t ha n 2 0 a n d u p t o 1 0 0 ma y  ha ve:  


 
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•  Hair  l oss 
•  C o nsti pati o n, na usea,  v o miti n g, l oss of a p petite 
•  S ores  i n m o ut h 
•  I nfecti o n, es p eciall y  w he n  w hite  bl o o d cell c o u nt is l o w 
•  A bse nce  of  me nstr ual  peri o d w hic h  ma y  decrease  t he a bilit y t o ha ve c hil dre n 
•  Bl o o d i n uri ne 
•  Re d  c ol ore d uri ne, s ali va, or s weat 
•  Pai n  or re d ness at t he site of i njecti o n or area of pre vi o us ra diati o n 
•  N u m b ness a n d ti n gli n g of fi n gers or t o es 
•  Hea dac he,  ja w pai n  a n d/ or m uscle  pai n  
•  Wea k n ess  a n d diffic ult y  wal ki n g 
•  I n c hil dre n a n d a d olesce nts: decreas e d  hei g ht 
•  L oss  of b o ne tiss ue 
•  M o o d s wi n gs 
•  S ki n c ha n ges,  ac n e  
•  S welli n g  of t he b o d y, tire d ness, br uisi n g 
•  S welli n g  of l o wer le gs 
•  Hi g h  bl o o d press ure  w hi c h  ma y  ca us e hea d ac h es,  dizzi ness,  bl urre d  visi o n 
•  Pai n  i n bell y  
•  I n crease d a p p etite a n d w ei g ht gai n  
•  Wei g ht  gai n  i n t he bell y, face, b ac k  a n d s h o ul ders 
 
 


 
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O C C A SI O N A L,  S O M E  M A Y  B E  S E RI O U S  
I n 1 0 0 p e o ple r ecei vi n g C ycl 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), 
fr o m 4 t o 2 0 ma y  ha ve:  
•  Da ma ge  t o t he b o n e  marr o w  (irre v ersi ble) w hi c h  ma y  ca use i nfecti o n, blee di n g,  ma y  re q uire 
tra nsf usi o ns 
•  Da ma ge  t o t he b o n e w hic h  ma y  ca use j oi nt pai n  a n d l oss of m oti o n  
•  L oss  or a bse nce of s per m w hic h  ma y  lea d t o a n i n a bilit y t o fat her c hil dre n  
•  St uff y  n ose 
•  Fl ui d  ar o u n d t he heart  
•  Heart  f ail ure or h eart  attac k w hic h  ma y  ca use s h ort ness of breat h,  s w elli n g of a n kles, c o u g h 
or tire d ness w hic h  ma y  o cc ur  years  after t he d os e 
•  S welli n g  of t he b o d y w hic h  ma y  ca us e s h ort ness of  breat h  
•  S welli n g  a n d re d ness at t he site of t he me dicati o n  i njecti o n or area of pre vi o us ra diati o n 
•  S ores  i n t he t hr oat or st o mac h 
•  Diarr hea  
•  He patitis  (i nfla m mati o n of li ver) w hic h  ma y  ca us e yell o w e yes a n d s ki n 
•  Aller gic  reacti o n w hic h  ma y  ca use ras h, l o w bl o o d press ure,  w h eezi n g,  s h ort ness of breat h, 
s welli n g of t he face or t hr oat 
•  Ca ncer  of t h e b o ne marr o w  (le u ke mia) ca use d b y c he m ot hera p y 
•  Da ma ge  t o or g a ns w hic h  ma y  ca use i nfecti o n, blee di n g, ma y  re q uire tra nsf usi o ns 
•  Dar ke ni n g of t h e nail  be ds  or s ki n or ha n ds a n d feet 
•  L oss  of nails  
•  A ne mia  w hic h  ma y  ca us e tire d ness, or ma y  re q uire tra nsf usi o n 
•  Dr o o pi n g e yeli ds  
•  H oarse n ess  
•  Cl o u di ness of t he e ye, vis ual dist ur ba nces 
•  Gla uc o ma  ( c o n diti o n da ma gi n g t he ner ves  i n t he e ye)  
•  N o n -heali n g  w o u n d 
•  Dia betes  
•  Ki d ne y st o nes 
•  Heart b ur n  
 


 
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R A R E,  A N D  S E RI O U S  
I n 1 0 0 p e o ple r ecei vi n g C ycl 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), 
3 or fe w er ma y  ha ve: 
•  Se vere  s ki n ras h wit h  blisters  a n d peeli n g  w hic h  ca n i n v ol ve m o ut h  a n d ot her  parts  of  t h e 
b o d y 
•  A ne w  ca ncer i ncl u di n g ca ncer of  b o ne marr o w  (le u ke mia) ca us e d b y c h e m ot hera p y  
•  S welli n g  of t he brai n  w hi c h  ma y  ca us e dizzi ness  a n d c o nf usi o n 
•  Scarri n g  of t he l u n gs 
•  I nfecti o n, es p eciall y  w he n  w hite  bl o o d cell c o u nt is l o w 
•  Br uisi n g, blee di n g 
•  Se vere  bl o o d i nfecti o n 
•  Seiz ure  
•  Blee di n g  fr o m s ores i n t h e st o mac h 
•  Br o ke n b o nes 
 
Rit u xi ma b  Ris ks a n d Si de  Effects  
C O M M O N, S O M E M A Y B E S E RI O U S  
Si de effects t hat ha ve bee n see n i n patie nts w h o ha ve recei ve d Rit u xi ma b i ncl u de:  
•  Fe ver  
•  Hea dac he  
•  V o miti n g  
•  Ast he nia (feeli n g wea k a n d ha vi n g n o e ner g y) 
•  A n gi oe de ma (s w elli n g t hat aff ects dee p er la y ers i n y o ur s ki n) 
•  P ul m o nar y i nfiltrates (s u bsta nces t hat li n ger i n t he l u n gs) 
•  M y ocar dial i nfarcti o n ( h eart attac k)  
•  Ne utr o pe nia  (c o n diti o n  i n  w hic h  t he  n u m ber  of  w hite  bl o o d  cells,  calle d  ne utr o p hils,  is  
a b n or mall y l o w) 
•  C hills  
•  Na usea  
•  R hi nitis ( nasal i nfla m mati o n)  
•  H y p ote nsi o n (l o w bl o o d press ure) 
•  H y p o xia (a decr ease of o x y ge n reac hi n g b o d y tiss ues) 
•  Ac ute res pir at or y distress s y n dr o me (a se v ere, life -t hreate ni n g me dical c o n diti o n c haracterize d 
b y wi des prea d i nfla m mati o n i n t he l u n gs) 
•  T u m or l ysis s y n dr o me ( T u m or l ysis s y n dr o me is ca use d b y ra pi d killi n g of t u m or cells d uri n g 
treat me nt. W h e n t he t u m or cells die, t he y rel ease t heir c o nte nts i nt o t h e bl o o dstrea m. If cell 
killi n g is ver y ra pi d, t his ca n affect bl o o d c h e mistries a n d t he ki d n e ys. I n se vere cases, t his ca n 
lea d t o s h ut d o w n of ki d ne y f u ncti o n re q uiri n g dial ysis) 
•  Marr o w h y p o plasia (a c o n diti o n w here y o u b o ne marr o w c o nt ai ns ver y fe w bl o o d cells) 
•  I n crease d ris k of i nfecti o n 


 
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P ote nti al Ris k or Disc o mf ort fr o m  Rese a rc h  P r oce d ures   
 
Bl o o d S a m ples  
Bl o o d dra ws ma y ca us e pai n, blee di n g, a n d/ or br uisi n g. Y o u ma y fai nt a n d/ or get a n i nfecti o n 
wit h re d ness a n d irritati o n at t he place w here t he n ee dle e nt ers y o ur vei n.  
 
HI V testi n g  
As part of t his pr ot oc ol, y o u will be teste d f or HI V ( h u ma n i m m u n o defici e nc y vir us), w hi c h is 
t he vir us t hat ca uses t he ac q uire d i m m u n o defi cie nc y s y n dr o me ( AI D S). Y o u will be n otifie d of 
t he res ults of t he testi n g, a n d c o u nsele d as t o t he mea ni n g of t he res ults, w het her t he y are 
p ositi ve or ne gati ve. If t h e test i n dicates t hat y o u are i nfecte d wit h HI V, y o u will recei ve 
a d diti o nal c o u nseli n g a b o ut t he si g nifica nce f or y o ur me dical care a n d p ossi ble ris ks t o ot her 
pe o ple. We are re q uir e d t o re p ort all p ositi ve res ults t o t he O hi o State B oar d of Healt h. T he t est 
res ults will be ke pt c o nfi de ntial t o t he e xte nt per missi ble u n der t he la w. If y o u d o n ot wa nt t o be 
teste d f or HI V, t he n y o u s h o ul d n ot a gree t o partici pate i n t his st u d y.  
 
He p atitis Testi n g  
T he state of O hi o a n d a p plica ble re g ulati o ns re q uire la b orat ories t o re p ort ne w cas es of H e patitis 
B, a n d He patitis C i nfecti o n t o g o ver n me ntal a ge n cies. T he re p orts ma y i ncl u de t he patie nt ’s 
na me, s ocial sec urit y n u m ber, a n d ot her i d e ntif yi n g i nf or mati o n. I nf or mati o n a b o ut t hese ne w 
i nfecti o ns is use d t o trac k t hese diseases state wi de a n d nati o n wi de. Ot her t h a n t his re q uire d 
re p orti n g, y o ur r es ults will be treate d c o nfi de ntiall y b y t he researc h st u d y st aff.  
 
Electr oc a r di o gr a m ( E C G)  
S o me pe o ple's s ki n reacts t o t he stic k y patc hes t hat attac h t he el ectr o d es t o t he c hest f or t he 
E C G.  T his s ki n irritati o n us uall y disa p pears w h e n t he patc hes are re m o ve d. S o me me n ma y 
ha ve s o me c h est hair s ha ve d.  
 
E C H O or M U G A Sc a n  
Ec h ocar di o gra ms ( E C H Os) a n d M U G A ( m ulti gate d ac q uisiti o n) sca ns are t w o tests t hat e val uate 
heart f u n cti o n. Y o u a n d y o ur d oct or ma y c h o os e eit her o ne of t h ese t o be d o ne d uri n g t his st u d y. 
Y o u d o n ot nee d t o ha ve b ot h.  
 
•  T here are n o k n o w n ris ks fr o m a n ec h ocar di o gra m beca use t h e test uses o nl y s o u n d 
wa ves t o e val u ate y o ur h eart. T hes e hi g h -fre q ue n c y s o u n d wa ves h a ve n ot bee n s h o w n t o 
ha ve a n y h ar mf ul effects. A micr o p h o ne is r u b be d acr oss t he c h est o n t o p of a l u bricati n g 
gel t o pr o d uce t he pict ures. S o me c ol d ness of t he g el a n d press ure fr o m t he micr o p h o ne 
mi g ht be felt.  
•  I n a M U G A s ca n a n i njecti o n of a s mall a m o u nt of a ra di o acti ve material is ma de i nt o a 
vei n a n d t he n pict ures ar e ma de of t he h eart’s p u m pi n g acti o n. Y o u ma y feel s o me 
disc o mf ort fr o m t he nee dle i nserte d i nt o y o ur vei n d uri n g t he M U G A sca n. T his test 
i n v ol ves e x p os ure t o ra di ati o n. T he t otal a m o u nt of ra diati o n t hat y o u will recei ve fr o m 
o ne M U G A sca n is a b o ut 5. 1 8 m S v ( millisie vert) or 5 1 8 mre m ( millire m). T his is 
a p pr o xi matel y e q ui vale nt t o a w h ole b o d y e x p os ure of 6 3 0 da ys ( 1. 7 2 6 y ears) of 
e x p os ure t o nat ur al bac k gr o u n d ra diati o n. T his use i n v ol ves mi ni mal ris k. Pers o ns 


 
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partici pati n g i n t his researc h will ha ve 2 M U G A s ca ns, alt h o u g h s o me c o ul d ha ve 3. Y o u 
are all o w e d t o c h o ose t o ha ve a n ec h ocar di o gra m i nstea d of a M U G A sca n if y o u prefer 
a n d y o u ma y disc uss t his wit h y o ur d oct or.  
 
Ris ks of C T a n d P E T/ C T sc a ns  
If y o u ta ke p art i n t his researc h, y o u will ha ve o ne or m ore me dical i ma gi n g st u dies w hic h use 
ra diati o n. T he i ma gi n g st u dies will i ncl u de a C T sca n a n d P E T/ C T sca ns. T o gi ve y o u a n i dea 
a b o ut h o w m uc h ra diati o n y o u will get, we will ma ke a c o m paris o n wit h a n e ver y- d a y sit uati o n. 
E ver y o ne r ecei ves a s mall a m o u nt of u na v oi da ble ra diati o n eac h year. S o me of t his ra diati o n 
c o mes fr o m s pace a n d s o me fr o m nat urall y - o cc urri n g ra di oacti ve f or ms of water a n d mi nerals. 
T his resear c h gi ves y o ur b o d y t he e q ui vale nt of a b o ut 2 e xtra years' w ort h of t his nat ural 
ra diati o n. T he r a diati o n d ose we ha v e disc usse d is w hat y o u will recei v e fr o m t his st u d y o nl y, 
a n d d oes n ot i ncl u de a n y e x p os ure y o u ma y h a ve recei ve d or will recei ve fr o m ot her tests. 
•  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: T his is a n i ma gi n g 
test t hat ta kes se ver al x-r a ys of y o ur b o d y a n d t h e n all o ws us t o l o o k f or areas of ca ncer.  
Y o u will get c o ntrast (a s pecial d ye t o ma k e t he i ma ges easier t o rea d) i njecte d i n y o ur 
vei n a n d y o u will dri n k c o ntrast.  S o me pe o ple ha ve aller gic reacti o ns t o t he d ye b ut t his 
is rare.  
•  P E T/ C T:   This is a n i ma gi n g test li ke t he C T disc usse d a b o ve h o w e ver i nstea d of 
c o ntrast, y o u get a r a di oacti ve s u bsta nce i njecte d i nt o y o ur vei n.  T his is basicall y s u gar 
t hat is t he n ta ke n u p b y y o ur b o d y.  Areas of ca ncer ta ke u p m ore of t his s u gar s o we ca n 
see w here t he ca ncer is i n y o ur b o d y.  
 
B o ne M arr o w As pir at e a n d Bi o ps y  
 
A b o ne marr o w as pirat e is t he re m o val of a s m all a m o u nt of li q ui d fr o m t he s oft tiss ue i nsi de 
y o ur b o ne, calle d t h e b o n e marr o w. A b o ne marr o w bi o ps y is w he n  a s mall a m o u nt of t he s oli d 
b o ne marr o w tiss ue is c ollecte d.  
 
T here are als o ris ks ass ociate d wit h ta ki n g sa m ples of y o ur b o ne marr o w. Y o ur st u d y d oct or will 
i nsert a nee dl e i nt o y o ur hi p or breast b o ne t o wit h dra w a s a m ple of fl ui d c o ntai ni n g b o ne 
marr o w cells. T he ris ks of b o ne marr o w sa m pli n g c o m m o nl y i ncl u de disc o mf ort, pai n, re d ness, 
s welli n g, a n d/ or br uisi n g w here t he s a m ple is ta ke n fr o m y o ur hi p or c h est. S o meti mes blee di n g 
ca n occ ur at t he place w h ere t he s a m ple is dra w n. Fai nti n g a n d i nfecti o n ca n ha p pe n, b ut rarel y. 
Ma n y patie nts als o e x perie nce s or e ness or stiff n ess i n t he hi ps f or se veral da ys after t h e 
pr oce d ur e.  
T h o u g h n ot c o m m o n, t here ma y be si de effects of ha vi n g a b o ne marr o w as pirati o n a n d bi o ps y 
s uc h as t he f oll o wi n g:  
•  Press ure a n d/ or p ai n w he n t he nee dle is i nserte d, as well as w he n t he b o n e marr o w is 
re m o ve d wit h a s yri n ge ( as pirati o n)  
•  Blee di n g w here t h e nee dl e is i nserte d i nt o t he s ki n a n d tiss ue o ver t he b o ne  
•  Br uisi n g w here t he nee dl e is i nserte d i nt o t he s ki n a n d tiss ue o ver t he b o ne  
•  Pai n w here t he n ee dle is i nserte d i nt o t he s ki n a n d tiss ue o ver t he b o ne  
•  I nfecti o n w h ere t he n ee dl e is i nserte d i nt o t he s ki n a n d tiss ue o ver t he b o ne  
 


 
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Rare si de effects ma y i ncl u de t he f oll o wi n g:  
•  I nfecti o n of t he b o n e  
•  E xte nsi ve blee di n g at t he bi o ps y site  
 
 
Re pr o d ucti ve Ris ks   
 
•  Y o u s h o ul d n ot get pre g n a nt, breastfee d, or fat her a ba b y w hile i n t his st u d y. T he M E- 
4 0 1 use d i n t his st u d y c o ul d be ver y da ma gi n g t o a n u n b or n ba b y. W o me n m ust n ot 
d o nate e g gs d uri n g t he st u d y. If y o u are a w o m a n w h o ca n ha v e c hil dre n ( n ot s ur gicall y 
sterile or p ost- me n o pa us al), y o u will ha ve a pre g n a nc y test bef ore y o u ca n be i n t his 
st u d y. If y o u are pre g n a nt, y o u ca n n ot be i n t his st u d y. Tell y o ur st u d y d oct or ri g ht a wa y 
if y o u s us pect t hat y o u ha ve bec o me pre g n a nt w hile i n t he st u d y. If y o u b ec o me pre g n a nt 
d uri n g t his ti me, y o u ma y be as ke d t o wit h dra w fr o m t he st u d y a n d t he st u d y d oct or will 
as k t o c ollect i nf or mati o n a b o ut t he pre g na n c y a n d its o utc o me.  
 
•  W o me n of c hil d- b eari n g p ote ntial a n d me n m ust a gree t o use a de q uat e c o ntrace pti o n 
( d o u ble barri er met h o d of birt h c o ntr ol or a bsti ne n ce) 2 w ee ks pri 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. Met h o ds of birt h c o ntr ol y o u ca n use i n cl u de i ntra uteri ne de vice (I U D), 
h or m o nal ( birt h c o ntr ol pills, i njecti o ns, i m pla nts), c o n d o ms, dia p hra g m, t u bal li gati o n 
(“t u bes ties”), v asect o m y (f or males), or c o m plete a bsti ne nce. C hec k wit h t he st u d y 
d oct or a b o ut w hat t y pes of birt h c o ntr ol, or pre g n a nc y pre v e nti o n, t o use w hile i n t his 
st u d y. Y o ur d oct or ca n tal k t o y o u a b o ut t hese a n d ot her birt h c o ntr ol o pti o ns.  
 
•  S h o ul d a w o ma n bec o me pre g na nt or s us pect t hat s he is pre g na nt w hile s he or her part ner 
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.  
 
•  If y o u ar e a ma n, y o u m ust a gree t o refrai n fr o m s per m d o nati o n f or at least 9 0 da ys after 
t he last d ose of M E- 4 0 1. If y o ur part ner bec o mes pre g na nt d uri n g t his ti me, t he st u d y 
d oct or will as k t o c ollect i nf or mati o n a b o ut t he pre g na nc y a n d its o utc o me. Y o ur part ner 
will be as ke d t o si g n a c o nse nt f or m if t his occ urs.  
 
U n k n o w n Ris ks  
 
Si de effects t hat are n ot y et k n o w n ma y als o occ ur. T he si de effects of st u d y treat me nt ma y be a 
mi n or i nc o n ve nie nce or c o ul d be se ver e e n o u g h t o be life-t hreate ni n g or ca use deat h. Y o u will be 
watc he d cl osel y f or si de effects, a n d t he dr u g will be st o p pe d if u n wa nte d or seri o us si de effects 
de vel o p.  
 
T here ma y als o be ot her u n k n o w n eff ects t hat c o ul d har m y o u ( or y o ur e m br y o or fet us, if y o u 
bec o me pr e g na nt or f at her a c hil d) d uri n g t he ti me y o u ta ke part i n t he st u d y or after t h e st u d y 
has bee n c o m plet e d.  
Ps yc h ol o gic al or S oci al Ris ks Ass oci ate d Wit h L oss of Pri v ac y 
 


 
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•  Y o ur pri vac y is v er y i m p orta nt t o us a n d we will use ma n y safet y meas ures t o pr otect 
y o ur pri vac y.  H o we ver, i n s pite of all t he safet y meas ures t hat w e will use, we ca n n ot 
g uara ntee t hat y o ur i de ntit y will ne ver bec o me k n o w n.  
•  W hile neit her t he p u blic n or t he c o ntr olle d- access data bases d e vel o pe d f or t his pr oject 
will c o ntai n i nf or mati o n t hat is tra diti o nall y use d t o i de ntif y y o u, s uc h as y o ur na me, 
a d dress, tele p h o n e n u m ber, or S ocial Sec urit y n u m ber, pe o ple ma y d e vel o p wa ys i n t he 
f ut ure t hat w o ul d all o w s o me o ne t o li n k y o ur me dical i nf or mati o n i n o ur data bases bac k 
t o y o u. It als o is p ossi ble t hat t here c o ul d be vi olati o ns t o t he sec urit y of t he c o m p uter 
s yste ms use d t o st ore t he c o des li n ki n g y o ur ge neti c a n d me dical i nf or mati o n t o y o u. 
•  T here als o ma y be ot her pri vac y ris ks t hat we h a v e n ot f oresee n.  
 
 
W h at p ossi ble be nefits  c a n I e x pect fr o m t a ki n g p art i n t his st u d y ?  
 
Ta ki n g part i n t his st u d y ma y or ma y n ot ma ke y o ur healt h better. T h ere is n o pr o of t hat 
c o m bi ni n g M E- 4 0 1 wit h R- C H O P will be m ore usef ul t ha n t he us ual treat me nt ( R - C H O P) f or 
t he t y pe of ca n cer t hat y o u ha ve. I nf or mati o n fr o m t his st u d y will hel p d oct ors lear n m ore a b o ut 
M E -4 0 1 as a tr eat me nt f or patie nts wit h Diff use L ar ge B - Cell L y m p h o ma. T his i nf or mati o n 
c o ul d hel p f ut ure ca ncer patie nts.  
 
W h at h a p pe ns t o t he i nf or m ati o n c ollecte d f or t he rese a rc h ?  
 
Y o ur i nf or mati o n will be ke pt i n a c o de d f or m a n d n ot attac he d t o y o ur na m e. We will st ore t he 
c o de i n a sec ure area a n d all o w o nl y t he st u d y tea m (t he researc h ers, researc h n urse a n d ot h er 
st u d y staff) t o ha ve access t o t his c o de. We will kee p t his c o de i n or der t o m ai ntai n a li n k 
bet wee n y o ur na me a n d t he i nf or mati o n a b o ut y o u creat e d a n d c ollecte d d uri n g t his st u d y. T he 
c o de d i nf or mati o n, wit h o ut y o ur na me attac h e d, m a y be s hare d wit h ot hers o utsi de t he researc h. 
 
If i de ntifiers are r e m o ve d fr o m y o ur i de ntifia ble pri vate i nf or mati o n or i de ntifia ble sa m ples t hat 
are c ollecte d d uri n g t his r esear c h, t hat i nf or mati o n or t h ose sa m ples c o ul d b e use d f or f ut ure 
researc h st u dies or distri b ute d t o a n ot her i n vesti g at or f or f ut ure researc h st u dies wit h o ut y o ur 
a d diti o nal i nf or me d c o ns e nt. 
 
C a n I st o p t a ki n g p art i n t his st u d y ? 
 
Yes. Y o u ca n deci d e t o st o p at a n y ti me a n d y o u m a y still be treate d at y o ur h os pital or cli nic. 
Tell y o ur st u d y d oct or if y o u are t hi n ki n g a b o ut st o p pi n g or deci de t o st o p. Y o u s h o ul d tal k t o 
t he d oct or a b o ut lea vi n g t he st u d y bef ore y o u deci de s o t hat he/s he ca n fi n d o ut if y o u are ha vi n g 
a n y si de eff ects fr o m st u d y treat me nt. A n ot her reas o n t o tell y o ur d oct or t hat y o u are t hi n ki n g 
a b o ut st o p pi n g is s o t hat he/s he ca n tal k t o y o u a b o ut a n y ot her treat me nts t hat c o ul d be hel pf ul 
t o y o u. If y o u st o p, y o u ca n deci de w het her or n ot t o let t he st u d y d oct or c o nti n ue t o pr o vi de 
y o ur me dical i nf or mati o n t o t he or ga nizati o n r u n ni n g t he st u d y. 
 
If y o u deci d e t o st o p bei n g i n t his st u d y, y o u will still be as ke d t o c o me bac k t o t he h os pital or 
cli nic f or t he e n d of treat me nt tests as descri be d. Y o u ma y als o be as k e d t o ta ke part i n f oll o w- u p 


 
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p h o ne calls a n d/ or visits. T his i nf or mati o n is i m p orta nt t o ma ke s ure t hat t h ere are n o lasti n g si de 
effects fr o m t he st u d y treat me nt a n d t o see if y o ur ca ncer g ot better, sta y e d t he sa me, or g ot 
w orse after treat me nt.  
 
T he st u d y d oct or will tell y o u a b o ut ne w i nf or mati o n or c ha n ges i n t he st u d y t hat ma y affect 
y o ur healt h or y o ur willi n g ness t o c o nti n ue i n t he st u d y. 
 
T he st u d y d oct or ma y ta k e y o u o ut of t he st u d y: 
 If y o ur healt h c ha n ges a n d t he st u d y is n o l o n ger i n y o ur best i nterest 
 If ne w i nf or mati o n bec o mes a vaila ble 
 If y o u d o n ot f oll o w t he st u d y re q uire me nts  
 If t he st u d y is st o p pe d b y t he s p o ns or, I nstit uti o nal Re vie w B oar d (I R B) or F D A.  
 
T he st u d y d oct or ma y st o p y o u fr o m ta ki n g part i n t his st u d y at a n y ti me if he/s he t hi n ks it is i n 
y o ur best i nterest, or if y o u d o n ot f oll o w t he st u d y r ules. Y o ur st u d y d oct or ma y deci de t o st o p 
t his st u d y f or eit her me dical or ot her reas o ns at a n y ti me wit h o ut y o ur c o nse nt. Y o ur st u d y 
d oct or will tell y o u if t his ha p pe ns a n d will tal k t o y o u a b o ut ot her treat me nt o pti o ns.  
 
 
W h at are m y ri g hts i n t his st u d y ? 
 
Y o ur partici pati o n i n t his researc h st u d y is v ol u ntar y.  C h o osi n g n ot t o partici pate will n ot alter 
y o ur us ual healt h care or i n v ol ve a n y pe nalt y or l oss of be nefits t o w hic h y o u are ot her wise 
e ntitle d.  If y o u deci d e t o j oi n t he st u d y, y o u ma y wit h dra w at a n y ti me a n d f or a n y reas o n 
wit h o ut pe nalt y or l oss of be nefits.  If i nf or mati o n ge nerat e d fr o m t his st u d y is p u blis he d or 
prese nte d, y o ur i de ntit y will n ot be re veale d.   
 
I n t he e ve nt ne w i nf or mati o n bec o mes a vaila ble t h at ma y affect t he ris ks or be nefits ass ociat e d 
wit h t his st u d y or y o ur willi n g ness t o partici pate i n it, y o u will be n otifie d s o t hat y o u ca n deci d e 
w het her or n ot t o c o nti n u e partici pati n g.   
 
W h at are t he c osts of t a ki n g p art i n t his st u d y ?  
 
Y o ur i n v ol ve me nt i n t his researc h st u d y is v ol u ntar y a n d y o u will n ot be pai d f or y o ur 
partici pati o n.  
 
T he st u d y a ge nt, M E - 4 0 1 will be pr o vi de d free of c har ge b y t h e dr u g s u p plier M EI P har m a, 
w hile  y o u are p artici pati n g i n t his st u d y.  Neit her y o u n or y o ur i ns ura nce pr o vi der will be 
res p o nsi ble f or t he c osts of a n y res ear c h- o nl y tests or pr oce d ures.  T he bl o o d w or k f or researc h 
p ur p oses will n ot be c har ge d t o y o u. T he secti o n calle d “ d uri n g t he st u d y t h e f oll o wi n g will be 
a d diti o nal researc h pr o ce d ures ” als o r efers t o st u d y pr oce d ures o utsi de of y o ur t y pical sta n dar d 
of car e.  
 
T he f oll o wi n g tests are o utsi de of y o ur sta n dar d treat me nt a n d will be pai d f or b y t he res earc h 
st u d y: 


 
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 St u d y dr u g M E- 4 0 1 
 Uri ne test - At scree ni n g visit 
 Test t o c hec k f or c yt o me gal o vir us i nfecti o n (a ki n d of her pes vir us t h at ca n ca use da m a ge 
t o pe o ple wit h wea k e ne d i m m u ne s yste ms)- At scree ni n g visit, C ycle 1 Da y 1 visit of 
e ver y c y cle, E O T visit, a n d all f oll o w u p visits 
 Pre g na nc y test ( H C G Q u a ntitati ve bl o o d dra w) f or w o me n of c hil d beari n g p ote ntial- At 
C ycle 1 Da y 1 visit, if a p plica ble 
 C orrelati ve Bl o o d Dra w- At scree ni n g visit, C ycle 4 Da y 1, a n d E O T visit 
 Ec h ocar di o gra m ( E K G)- At C ycle 1 Da y 1, C ycle 3 Da y 1, C ycle 6 D a y 1, a n d E O T visit 
 Patie nt Par ki n g f or eac h visit 
 
Y o u a n d/ or y o ur healt h pla n/i ns ura nce c o m pa n y will nee d t o pa y f or s o me or all of t he c osts of 
treati n g y o ur ca ncer i n t his st u d y (i.e., me dical hist or y, re vie w of me dicati o ns, p h ysical e xa ms, 
perf or ma n ce stat us, r o uti ne bl o o d tests, pre g na nc y test, x-ra ys a n d/ or s ca ns f or t u m or 
meas ure me nt).  Y o u or y o ur healt h i ns ura nce c o m p a n y will be bille d f or parts of t he st u d y t hat 
are sta n d ar d care f or y o ur disease. Y o ur healt h i ns ura nce c o m pa n y ma y or ma y n ot pa y f or t hese 
c har ges. S o me h ealt h pla ns will n ot pa y t hese c osts f or pe o ple ta ki n g part i n st u dies. C hec k wit h 
y o ur healt h pla n or i ns ur a nce c o m pa n y t o fi n d o ut w hat t he y will pa y f or. T a ki n g part i n t his 
st u d y ma y or ma y n ot c ost y o ur i ns ura nce c o m pa n y m ore t ha n t he c ost of getti n g re g ular ca ncer 
treat me nt. 
 
F or m ore i nf or mati o n o n cli nical trials a n d i ns ura n ce c o v era g e, y o u ca n visit t he Nati o nal Ca ncer 
I nstit ute’s We b site at htt p:// w w w.ca ncer. g o v/cli nicaltrials/lear ni n ga b o ut. 
 
W h at h a p pe ns if I a m i nj ure d  or h urt  bec a use I t o o k p art i n t his st u d y ? 
 
If y o u belie ve t h at y o u ar e i nj ure d as a res ult of t h e researc h pr oce d ures b ei n g perf or me d, please 
i m me diatel y c o ntact t he st u d y d oct or. 
 
Cle vela n d Cli nic has n ot set asi de a n y m o ne y t o p a y y o u or t o pa y f or y o ur treat me nt if y o u 
s uffer a res ear c h rel ate d i nj ur y as a res ult of b ei n g i n t he st u d y. If i nj ur y o cc urs as a res ult of 
y o ur i n v ol ve me nt i n t his researc h, me dical treat m e nt is a vaila ble fr o m Cle vela n d Cli nic  or 
a n ot her me dical facilit y b ut y o u/ y o ur me dical i ns ura nce will be res p o nsi bl e f or t he c ost of t his 
treat me nt.  A r esearc h i nj ur y is a n i nj ur y t hat ha p p e ns as a res ult of ta ki n g part i n t his researc h 
st u d y.  If y o u are i nj ur e d b y a me dical treat me nt or pr oce d ure t hat y o u w o ul d ha ve recei ve d e ve n 
if y o u were n’t i n t he st u d y, t hat is n ot c o nsi dere d a “researc h i nj ur y ”. T here are n o pla ns f or 
pa y me nt of me dical e x pe nses or ot her pa y m e nts, i ncl u di n g l ost wa ges, f or a n y researc h relat e d 
i nj ur y.  T o hel p a v oi d i nj ur y, it is ver y i m p orta nt t o f oll o w all st u d y directi o ns. 
 
F urt her i nf or mati o n a b o ut resear c h -r elate d i nj uries is a vaila ble b y c o ntacti n g t he Cle vela n d 
Cli nic I nstit uti o nal Re vie w B oar d at 
. 
 


 
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W h at else d o I nee d t o k n o w ?  
Y o ur i nf or mati o n a n d sa m ples ma y be use d t o create pr o d ucts or t o deli ver ser vices, i ncl u di n g 
s o me t hat ma y be s ol d a n d/ or ma ke m o ne y f or ot h ers. If t his ha p p e ns, t here are n o pla ns t o tell 
y o u, or t o pa y y o u, or t o gi ve a n y c o m pe nsati o n t o y o u or y o ur fa mil y.   
 
 
HI P A A A U T H O RI Z A TI O N  
A ut h oriz ati o n t o Use or Discl ose ( Rel e ase) He alt h I nf or m ati o n t h at I de ntifies Y o u f or a 
Rese arc h St u d y   
 
If y o u v ol u nteer t o partici pate i n t his researc h, y o ur pr otecte d h ealt h i nf or mati o n ( P HI) t hat 
i de ntifies y o u will be use d or discl ose d t o Dee p a J a ga dees h , M D, M P H  a n d t he researc h st u d y 
staff at Cle vela n d Cli nic f or t he p ur p oses of t his researc h a n d t o Case West er n Reser v e 
U ni versit y f or a d mi nistrati o n.  
 
T he P HI t hat we ma y us e or discl ose (r elease) f or t his researc h ma y i ncl u de y o ur na me, a d dress, 
p h o ne n u m ber, date of birt h, S ocial Sec urit y n u m ber, i nf or mati o n fr o m y o ur me dical rec or d, la b 
tests, or certai n i nf or mati o n relati n g t o y o ur healt h or c o n diti o n.. 
 
S o me of t he tests a n d pr o ce d ures d o n e s olel y f or t his researc h st u d y ma y als o be place d i n y o ur 
me dical rec or d s o ot her d oct ors k n o w y o u are i n t his st u d y.  U p o n c o m pleti o n of t he st u d y, y o u 
ma y ha ve access t o t he researc h i nf or mati o n t hat is c o ntai ne d i n y o ur me dical rec or d.   
 
I n a d diti o n t o t he i n vesti gat ors a n d res earc h staff liste d a b o ve, y o ur P HI m a y be l o o ke d at b y 
ot her gr o u ps i n v ol ve d wit h t he st u d y s uc h as t he Cle vela n d Cli nic I nstit uti o nal Re vie w B oar d 
a n d t he Case C o m pre h e nsi ve Ca ncer Ce nt er Pr ot o c ol Re vie w a n d M o nit ori n g C o m mittee.  Y o ur 
P HI ma y als o be use d b y a n d/ or discl ose d (releas e d) t o: 
 
 Case C o m pre he nsi ve Ca ncer Ce nter , its st u d y m o nit ors a n d re prese ntati ves 
 Case C o m pre he nsi ve Ca ncer Ce nter me m bers, c olla b orat ors, a n d lice ns ees  
 M EI P har ma, its lice nsees a n d c olla b orat ors 
 T he F o o d a n d Dr u g A d mi nistrati o n; 
 T he De part me nt of Healt h a n d H u ma n Ser vices; 
 T he Nati o nal Ca ncer I nstit ute ( N CI);  
 Ot her I nstit uti o nal Re vie w B oar ds;  
 Data Safet y a n d M o nit ori n g B oar ds;  
 
O nce y o ur p ers o nal h ealt h i nf or mati o n is release d it ma y be re- discl ose d a n d n o l o n ger pr otect e d 
b y pri vac y la ws. 
 
Y o ur res ear c h i nf or mati o n ma y be use d a n d discl ose d i n defi nitel y, b ut y o u ma y st o p t hese uses 
a n d discl os ures at a n y ti me b y writi n g t o:  
 
 
 




 
C A S E 1 4 2 0 C o nse nt  
Versi o n Date: 0 8/ 0 4/ 2 0 2 2 
 
  2 4 of 2 4 
      
 
 
 
Y o u ma y call t he N ati o nal Ca ncer I nstit ute's Ca ncer I nf or mati o n Ser vice at:  
1- 8 0 0- 4- C A N C E R ( 1 - 8 0 0- 4 2 2- 6 2 3 7)  
 
Y o u ma y als o visit t he N CI We b site at htt p://ca ncer. g o v/ 
 
F or N CI’s cli nical trials i nf or mati o n, g o t o: htt p://ca ncer. g o v/cli nicaltrials/  
 
F or N CI’s g e ner al i nf or mati o n a b o ut ca ncer, g o t o htt p://ca ncer. g o v/ca n ceri nf o/  
 
Y o u will get a c o p y of t his f or m.  If y o u wa nt m ore i nf or mati o n a b o ut t his st u d y, as k y o ur st u d y 
d oct or.   
 
 
U S N ati o n al I nstit utes of He alt h ( NI H) Cli nic al Tri al D at a b ase:     
A descri pti o n of t his cli nical trial will be a vaila bl e o n htt p:// w w w. Cli nical Trials. g o v , if 
a p plica ble,  as re q uire d b y U. S. La w. T his We b sit e will n ot i ncl u de i nf or mati o n t hat ca n i de ntif y 
y o u. At m ost, t he We b site will i ncl u de a s u m mar y of t he res ults. Y o u ca n searc h t his We b site at 
a n y ti me. 
 
 
 
Si g n at ur e 
Si g ni n g bel o w i n dicates t hat y o u ha ve bee n i nf or m e d a b o ut t he res earc h st u d y i n w hic h y o u 
v ol u ntaril y a gree t o p artici pate; t hat y o u ha ve as k e d a n y q uesti o ns a b o ut t h e st u d y t hat y o u ma y 
ha ve; a n d t hat t he i nf or mati o n gi ve n t o y o u has per mitte d y o u t o ma ke a f ull y i nf or me d a n d free 
decisi o n a b o ut y o ur parti ci pati o n i n t he st u d y.  B y si g ni n g t his c o nse nt f or m, y o u d o n ot wai ve 
a n y le gal ri g hts, a n d t he i n vesti gat or(s) or s p o ns or(s) are n ot relie ve d of a n y lia bilit y t he y ma y 
ha ve.  A c o p y of t his c o nse nt f or m will be pr o vi de d t o y o u. 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Si g nat ure of Partici pa nt  
  
 
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Pri nte d Na me of Partici p a nt  
  
 
I h a ve disc usse d t h e i nf or mati o n c o ntai ne d i n t his d oc u me nt wit h t he partici pa nt a n d it is m y 
o pi ni o n t hat t he partici pa nt u n dersta n ds t he ris ks, be nefits, alter n ati ves a n d pr oce d ures i n v ol ve d 
wit h t his researc h st u d y. 
 
  
  
  
  
  
  
  
  
  
 
Si g nat ure of Pers o n O btai ni n g C o nse nt  
 
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Pri nte d Na me of Pers o n O btai ni n g C o nse nt