Clinical trial NCT01420679
Conditions: Peripheral T-cell Lymphoma
Keywords: Lymphoproliferative Disorders Lymphoma Non-Hodgkin's Lymphoma T-cell Lymphoma
Sponsor: Spectrum Pharmaceuticals, Inc
Start date: 2011-08-01; Completion date: 2017-12-01
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to see if pralatrexate extends response and survival following CHOP-based chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone) and if pralatrexate improves response in patients with partial response following CHOP-based chemotherapy. Patients will either receive pralatrexate or be under observation. All patients will receive vitamins B12 and folic acid and attend regular clinic visits to evaluate their disease and health.

Detailed description:
This was an international, multi-center, randomized, Phase 3, open-label study of sequential pralatrexate versus observation in patients with previously undiagnosed PTCL who have achieved an objective response following initial treatment with CHOP-based chemotherapy.

Upon documentation of completion of an objective response following at least 6 cycles of a designated CHOP-based chemotherapy confirmation of histopathology by independent review, and confirmation that all eligibility criteria were met, patients were randomized in a 2:1 ratio to either pralatrexate or observation, according to a permuted block design with stratification factor of Tumor Response per Investigator at completion of CHOP-based therapy (Complete Response \[CR\] vs Partial Response \[PR\]).

All patients who receive at least 1 dose of pralatrexate were followed for safety through 35 (± 5) days after their last dose of pralatrexate or until all treatment-related AEs have resolved or returned to baseline/Grade 1, whichever is longer, or until it was determined that the outcome does not change with further follow-up.

Arms: arm 1: Patients randomized to the Pralatrexate Arm will receive pralatrexate injection and Vitamins B12 and Folic Acid until a criterion for pralatrexate injection treatment discontinuation is met. arm 2: Patients randomized to the Observation Arm will receive Vitamins B12 and Folic Acid and remain under observation until a criterion for observation discontinuation is met.
Interventions: intervention 1: Pralatrexate Injection
Intervention descriptions: intervention 1: Intravenous (IV) push administration over 30 seconds to 5 minutes via a patent IV line containing normal saline (0.9% sodium chloride).

Initial dose: 30 mg/m2

Administered weekly for 3 weeks of a 4-week cycle until criteria for discontinuation per the protocol are met.

Protocol documents:
Prot_000.pdf: 
Offici al Titl e:  
A  M ulti -c e nt er, R a n d o miz e d, P h as e 3 St u d y of S e q u e nti al 
Pr al atr e x at e V ers us O bs er v ati o n i n P ati e nts wit h Pr e vi o usl y  
U n di a g n os e d P eri p h er al T -c ell L y m p h o m a W h o H a v e Ac hi e v e d a n 
O bj ecti v e R es p o ns e F oll o wi n g I niti al Tr e at m e nt wit h C H O P -b as e d  
C h e m ot h er a p y  
N C T 0 1 4 2 0 6 7 9  
N C T  Nu m b er: 
D oc u m e nt  D at e : 
Pr ot oc ol V ersi o n 2 . 1: 3 1 Oct o b er 2 0 1 1  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 of 9 5 
Cli ni c al St u d y Pr ot o c ol 
St u d y Title: 
A M ulti-ce nter, Ra n d o mize d, P hase 3 St u d y of Se q ue ntial 
Pralatre xate Vers us O bser vati o n i n Patie nts wit h Pre vi o usl y 
U n dia g n ose d Peri p heral T-cell L y m p h o ma W h o Ha ve Ac hie ve d a n 
O bjecti ve Res p o nse F oll o wi n g I nitial Treat me nt wit h C H O P- base d 
C he m ot hera p y 
St u d y N u m ber: 
P D X- 0 1 7 
St u d y P h ase: 
3 
St u d y Dr u g: 
Pralatre xate I njecti o n 
I N D N u m ber: 
5 2, 6 0 4 
E u dr a C T N u m ber: 
2 0 1 0- 0 2 2 2 3 0- 8 1 
S p o ns or: 
All os T hera pe utics, I nc. 
S p o ns or C o nt act: 
, M D 
 
 U S A 
P h o ne: 
 
Fa x: 
 
 
Pr ot oc ol Versi o n/ D ate: 
2. 1/ 3 1 Oct 2 0 1 1 
 
T his st u d y will be c o n d ucte d acc or di n g t o G o o d Cli nical Practice ( G C P) as descri be d b y t he 
G C P Directi ve a n d E ur o pea n U ni o n ( E U) Dire cti ve ( 2 0 0 1/ 2 0/ E C) a n d ot her a p plica ble G C P 
re q uire me nts of t he re gi o ns w here t he st u d y is c o n d ucte d.  All esse ntial d oc u me nts will be 
arc hi ve d. 
C o nfi de nti alit y St ate me nt 
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt, par tic ularl y u n p u blis he d data, is t he pr o pert y or 
u n der c o ntr ol of All os T hera pe u tics, I nc., a n d is pr o vi de d t o y o u i n c o nfi de nce as a n 
i n vesti gat or, p ote ntial i n vesti gat or, or c o ns ulta nt, f or revie w b y y o u, y o ur staff, a n d a n 
a p plica ble I nstit uti o nal Re vie w B oar d, Et hics C o m mittee, or Researc h Et hics B oar d.  T he 
i nf or mati o n is o nl y t o be use d b y y o u i n c o n necti o n wit h a ut h orize d cli nical st u dies of t he 
i n vesti gati o nal dr u g descri be d i n t he pr ot oc ol.  Y o u will n ot discl ose a n y of t he i nf or mati o n 
t o ot hers wit h o ut writte n a uth orizati o n fr o m All os T hera pe uti cs, I nc., e xce pt t o t he e xte nt 
necessar y t o o btai n i nf or me d c o nse nt fr o m t h ose pers o ns t o w h o m t he dr u g ma y be 
a d mi nistere d.  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
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S Y N O P SI S 
St u d y Title: 
A M ulti-ce nter, Ra n d o mize d, P hase 3 St u d y of Se q ue ntial Pralatre xate Vers us O bser vati o n i n 
Patie nts wit h Pre vi o usl y U n dia g n ose d Peri p he ral T-cell L y m p h o ma W h o Ha ve Ac hie ve d a n 
O bjecti ve Res p o nse F oll o wi n g I nitial Trea t me nt wit h C H O P- base d C he m ot hera p y  
St u d y N u m ber: 
P D X- 0 1 7 
St u d y P h ase: 3 
St u d y Ce nters Pl a n ne d: T his will be a n i nter nati o nal, m ulti-ce nter st u d y.  
O bjecti ves: 
Pri mar y  
• 
Deter mi ne t he efficac y of pralatre xate c o m p are d t o o bser vati o n w he n a d mi nistere d t o 
patie nts wit h pre vi o usl y u n dia g n ose d peri p heral T-cell l y m p h o ma ( P T C L) w h o ha ve 
ac hie ve d a n o bjecti ve res p o nse after c o m pleti n g at least 6 c ycles of 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)- base d treat me nt. 
Sec o n dar y  
• 
Deter mi ne t he safet y of pralatre xate w h e n a d mi nistere d f oll o wi n g a c o urse of 
C H O P- base d treat me nt t o patie nts wit h pre vi o usl y u n dia g n ose d P T C L. 
Effic ac y E n d p oi nts: 
Pri mar y  
• 
Pr o gressi o n-free s ur vi val ( P F S) a n d o verall s ur vi val ( O S) 
Sec o n dar y  
• 
O bjecti ve res p o nse (c o m plete re s p o nse [ C R] or partial resp o nse [ P R]) t o pralatre xate 
vers us o bser vati o n 
Tre at me nt Pl a n: 
T his is a n i nter nati o nal, m ulti-ce nter, ra n d o mize d, P hase 3, o pe n-la bel st u d y of se q ue ntial 
pralatre xate vers us o bser vati o n i n patie nts wit h pre vi o usl y u n dia g n ose d P T C L w h o ha ve 
ac hie ve d a n o bjecti ve res p o nse f o ll o wi n g i nitial treat me nt wit h C H O P- base d c he m ot hera p y.  
U p o n d oc u me ntati o n of c o m pleti o n of a n o bjecti v e res p o nse f oll o wi n g at least 6 c ycles of a 
desi g nate d C H O P- base d c he m ot hera p y c o nf ir mati o n of hist o pat h ol o g y b y i n de pe n de nt 
re vie w, a n d c o nfir mati o n t hat all eli gi bilit y criteria are met, patie nts will be ra n d o mize d i n a 
2: 1 rati o t o eit her pralatre xate or o bser va ti o n, acc or di n g t o a per m ute d bl oc k desi g n wit h 
stratificati o n fact or of: 
• 
Res p o nse per i n vesti gat or at c o m pleti o n of  C H O P- base d t hera p y (c o m plete res p o nse 
[ C R] vs partial res p o nse [ P R]) 
Patie nts ra n d o mize d t o t he Pralatre xate Ar m will recei ve pralatre xate as a n i ntra ve n o us (I V) 
p us h a d mi nistere d o ver a mi ni m u m of 3 0 sec o n ds  u p t o a ma xi m u m of 5 mi n utes via a pate nt 
free-fl o wi n g I V li ne c o ntai ni n g n or mal sali ne ( 0. 9 % s o di u m c hl ori de [ Na Cl]) wee kl y f or 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
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3 wee ks ( ± 1 da y at eac h ti me p oi nt) of a 4- wee k c ycle.  T he i nitial d ose of pralatre xate will 
be 3 0 m g/ m 2, w hic h base d o n pr ot oc ol- defi ne d criteria, ma y be re d uce d t o 2 0 m g/ m2 wit h 
p ote ntial f urt her re d ucti o ns t o 1 5 a n d 1 0 m g/ m 2.  Pralatre xate will c o nti n ue t o be 
a d mi nistere d u ntil a criteri o n f or st u d y treat me nt disc o nti n uati o n is met or u p t o a ma xi m u m 
of 2 years. 
Patie nts ra n d o mize d t o t he O bser vati o n Ar m will re mai n u n der o bser vati o n, atte n d cli nic 
visits e ver y 4 wee ks, a n d be c o ntacte d b y a h ealt hcare pr ofessi o nal d uri n g wee k 2 of e ver y 
4- wee k peri o d u ntil a criteri o n f or st u d y treat me nt disc o nti n uati o n is met.   
All patie nts will recei ve vita mi n s u p pl e me ntati o n, c o nsisti n g of vita mi n B 1 2 1 m g 
i ntra m usc ular (I M) e ver y 8- 1 0 wee ks a n d f olic aci d 1- 1. 2 5 m g b y m o ut h ( p o) o nce a da y 
( q d).  Vita mi n s u p ple me ntati o n will be gi n at least 7 da ys pri or t o t he pr ojecte d i nitiati o n of 
pralatre xate/ o bser vati o n a n d c o nti n ue t hr o u g h o u t t he st u d y u ntil t he I nitial F oll o w- u p Visit. 
N u m ber of P atie nts Pl a n ne d:  
 A t otal of 5 4 9 patie nts will be ra n d o mize d 2: 1 t o pralatre xate or o bser vati o n.   
T ar get P o p ul ati o n:  
A d ult patie nts wit h pre vi o us l y u n dia g n ose d P T C L w h o ha ve ac hie ve d a n o bjecti ve res p o nse 
after c o m pleti o n of i nitial treat me nt of at leas t 6 c ycles of o ne of t he f oll o wi n g C H O P- base d 
t hera p y re gi me ns: 
a. C H O P 2 1 
b.  C H O P 1 4 
c. C H O E P 
d.  Ot her C H O P varia nts 
D ur ati o n of Tre at me nt:  
Patie nts will recei ve st u d y treat me nt ( pralatre x ate or o bser vati o n) u ntil o ne of t he f oll o wi n g 
criteria f or st u d y treat me nt  disc o nti n uati o n a p plies: 
• 
De vel o p me nt of pr o gres si ve disease ( P D) 
• 
I nitiati o n of ra diati o n t hera p y ( R T) or s yste mic c he m o/ bi ol o gical t hera p y f or treat me nt of 
P T C L 
• 
Recei pt of s yste mic ster oi ds > 1 0 da ys, wit h t he e xce pti o n of t h ose as state d i n e xcl usi o n 
criteri o n # 5 
• 
De vel o p me nt of a n a d verse e ve nt ( A E) t hat i nterferes wit h t he patie nt’s partici pati o n 
• 
L ost t o f oll o w- u p 
• 
Patie nt decisi o n 
• 
I n vesti gat or decisi o n 
• 
S p o ns or decisi o n 
I n a d diti o n, f or patie nts ra n d o mize d t o t he Pralatre xate Ar m, t he f oll o wi n g treat me nt 
disc o nti n uati o n criteria a p pl y: 
• 
3 or m ore c o nsec uti ve d oses of pralatre xate o mitte d or m ore t ha n 2 8 da ys bet wee n d oses 
of pralatre xate 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
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• 
Treat me nt wit h pralatre xate f or 2 years 
St u d y D ur ati o n: 
All patie nts w h o recei ve at le ast 1 d ose of pralatre xate will be f oll o we d f or safet y t hr o u g h 
3 5 ( ± 5) da ys after t heir last d ose of pralatre xate or u ntil all treat me nt-relate d A Es ha ve 
res ol ve d or ret ur ne d t o baseli ne/ Gra de 1, w hic hever is l o n ger, or u ntil it is deter mi ne d t hat 
t he o utc o me will n ot c ha n ge wit h f urt her f oll o w- u p. 
Patie nts w h o are ra n d o mize d t o t he O bser v ati o n Ar m w h o d o n ot disc o nti n ue t he st u d y 
wit hi n 3 da ys of ra n d o mi zati o n will be f oll o we d f or safet y u ntil 3 5 ( ± 5) da ys after t he st u d y 
treat me nt disc o nti n uati o n criteria are met.  
All patie nts w h o are ra n d o mize d will ha ve  f oll o w- u p u ntil o bjecti vel y d oc u me nte d P D; 
t hereafter, patie nts are f oll o we d f or s ur vi val.  T he ti mi n g of f oll o w- u p will be at 8 wee ks 
( ± 1 wee k) t he n e ver y 1 2 wee ks ( ± 1 wee k) t hr o u g h 3 years p ost-ran d o mizati o n, a n d t he n 
e ver y 2 4 wee ks ( ± 4 wee ks) t hereafter t hr o u g h 7 years p ost-ra n d o mizati o n.  P D will be 
c o nfir me d b y ce ntral re vie w u ntil t he firs t P F S a nal ysis ( descri be d bel o w), a n d per 
i n vesti gat or assess me nt t hereafter. 
All s u bse q ue nt t hera pies f or P T C L will be c o llecte d f or u p t o 7 years fr o m ra n d o mizati o n; 
t he best res p o nse t o t he first s u bse q ue nt t hera p y will be c ollecte d.  S ur vi val f oll o w- u p will 
c o nti n ue f or u p t o 7 years fr o m ra n d o mizati o n. 
As disc usse d i n t he statistical met h o ds secti o n, a n a nal ysis will be perf or me d w he n b ot h 
2 8 0 P F S e ve nts a n d 1 2 8 O S e ve nts ha ve occ urre d.  If t he P F S a nal ysis is n ot si g nifica nt at 
t he 0. 0 5 le vel, t he st u d y will be st o p pe d. 
Eli gi bilit y Criteri a 
I ncl usi o n Criteria 
1.  Patie nt’s P T C L hist ol o g y has bee n c o nfir me d as o ne of t he f oll o wi n g b y a n i n de pe n de nt 
pat h ol o g y re vie wer, usi n g t he Re vise d E ur o pea n A merica n  L y m p h o ma ( R E A L) W orl d 
Healt h Or ga nizati o n ( W H O) disease classificati o n: 
a. T/ nat ural killer ( N K)- cell le u ke mia/l y m p h o ma 
b.  A d ult T-cell l y m p h o ma/l e u ke mia ( h u m a n T-cell le u ke mia vir us [ H T L V] 1 +) 
c. A n gi oi m m u n o blastic T-cell l y m p h o ma  
d.  A na plastic lar ge cell l y m p h o ma ( A L C L), pri m ar y s yste mic t y pe, e xcl u di n g a na plastic 
l y m p h o ma ki nase p ositi ve ( AL K +) wit h I nter nati o nal Pr o g n ostic I n de x (I PI) sc ore 
< 2 at i nitial dia g n osis a n d C R afte r c o m pleti o n of C H O P- base d t hera p y 
e. P T C L- u ns pecifie d 
f. E nter o pat h y-t y pe i ntesti nal l y m p h o ma 
g.  He pat os ple nic T-cell l y m p h o ma 
h.  S u bc uta ne o us pa n nic uli tis T-cell l y m p h o ma 
i. Tra nsf or me d m yc osis f u n g oi des 
j. E xtra n o dal T/ N K-cell l y m p h o ma  nasal or nasal t y pe 
k.  Pri mar y c uta ne o us ga m ma- delta T-cell l y m p h o ma 
l. Pri mar y c uta ne o us C D 8 + a g gressi ve e pi der mic c yt ot o xic T-cell l y m p h o ma 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
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2.  D oc u me ntati o n t hat t he patie nt has c o m plete d  at least 6 c y cles of C H O P- base d t hera p y, 
i ncl u di n g: 
a. C H O P 2 1  
b.  C H O P 1 4 
c. C H O E P 
d.  Ot her C H O P varia nts: i ncl u des all 4 c o m p o ne nts of C H O P re prese nte d, wit h 
s u bstit uti o n all o we d f or a n y 1 c o m p o ne nt wit h a dr u g of t he sa me mec ha nis m of 
acti o n (e g, varia nt a nt hrac ycli nes).  A d diti o nal c o m p o ne nts t o C H O P are all o we d, 
wit h t he e xce pti o n of ale mt uz u ma b; r it u xi ma b ma y be c o m bi ne d wit h C H O P 
pr o vi de d t hat it is n ot gi ve n wit h i n 3 c ycles of ra n d o mizati o n. 
3.  Patie nt has ac hie ve d a C R or P R per i n ve sti gat or’s assess me nt f oll o wi n g c o m pleti o n of 
C H O P- base d t hera p y a n d has ha d a ra di ol o g ical assess me nt wit hi n 2 1 da ys pri or t o 
ra n d o mizati o n. 
4.  ≥ 1 8 years of a ge. 
5.  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us ≤ 2. 
6.  A de q uate he mat ol o gical, he patic, a n d re nal f u ncti o n as defi ne d b y: 
a. A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1 0 0 0/ µ L 
b.  Platelet c o u nt ≥ 1 0 0, 0 0 0/ µ L 
c. T otal bilir u bi n ≤ 1. 5 m g/ d L 
d.  As partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T) ≤ 2. 5 ×  u p per 
li mit of n or mal ( U L N), ( A S T/ A L T < 5 ×  U L N if d oc u me nte d he patic i n v ol ve me nt 
wit h l y m p h o ma).  All patie nts wit h he pa titis B vir us ( H B V)-p ositi ve ser ol o g y m ust 
ha ve li ver f u ncti o n tests w it hi n t he a b o ve para meters. 
e. Creati ni ne ≤ 1. 5 m g/ d L (if t he patie nt’s creati ni ne is > 1. 5 m g/ d L, t he n t he calc ulate d 
creati ni ne cleara nce m ust be ≥ 5 0 m L/ mi n). 
7.  Fe males of c hil d beari n g p ote nti al (ie, e xcl u di n g patie nts w h o are p ost me n o pa usal f or at 
least 1 year [ > 1 2 m o nt hs since last me nses] or are s ur gicall y sterilize d) m ust: 
a. Ha ve a ne gati ve ser u m pre g na nc y test w it hi n 1 4 da ys pri or t o ra n d o mizati o n a n d 
b.  A gree t o practice a me dicall y acce pta ble c o ntrace pti ve re gi me n fr o m st u d y treat me nt 
i nitiati o n u ntil at least 3 0 da ys after t he last a d mi nistrati o n of pralatre xate. 
8.  Males w h o are se x uall y acti ve, i ncl u di n g t h ose wit h a pre g na nt part ner, m ust a gree t o 
practice a me dicall y acce pta ble barrier met h o d c o ntrace pti ve re gi me n (e g, c o n d o ms) 
w hile recei vi n g pralatre xate a n d f or 9 0 da ys af ter t he last a d mi nistrati o n of pralatre xate. 
9.  Patie nt has gi ve n writte n i nf or me d c o nse nt (I C). 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
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E xcl usi o n Criteria  
1.  Patie nt has:  
a. Prec urs or T/ N K ne o plas ms  
b.  A L C L ( A L K +)  wit h I PI sc ore < 2 at i ni tial dia g n osis a n d C R after c o m pleti o n of 
C H O P- base d t hera p y 
c. T-cell pr ol y m p h oc ytic le u ke mia ( T- P L L) 
d.  T-cell lar ge gra n ular l y m p h oc ytic le u ke mia 
e. M yc osis f u n g oi des, ot her t ha n tra nsf or me d m yc osis f u n g oi des  
f. Sézar y s y n dr o me 
g.  Pri mar y c uta ne o us C D 3 0 + dis or ders:  A L C L a n d l y m p h o mat oi d pa p ul osis 
2.  If t here is a hist or y of pri or mali g na ncies other t ha n t h ose e xce pti o ns liste d bel o w, t he 
patie nt m ust be disease-free f or ≥ 5 years.  Patie nts wit h t he f oll o wi n g pri or mali g na ncies 
less t ha n 5 years bef ore st u d y e ntr y ma y still be e nr olle d if t he y ha ve recei ve d treat me nt 
res ulti n g i n c o m plete res ol uti o n of t he ca ncer a n d c urre ntl y ha ve n o cli nical, ra di ol o gic, 
or la b orat or y e vi de nce of acti ve or rec urre nt disease. 
a. N o n- mela n o ma s ki n ca ncer  
b.  Carci n o ma i n sit u of t he cer vi x 
c. L ocalize d pr ostate ca ncer 
d.  L ocalize d t h yr oi d ca ncer 
3.  Patie nt has recei ve d pri or treat me nt (c he m ot hera p y or ra diati o n) f or P T C L, ot her t ha n a 
si n gle all o we d C H O P re gi men, wit h t he e xce pti o n of: 
a. Patie nts wit h nasal N K l y m p h o ma are per mitte d t o ha ve recei ve d l ocal ra diati o n 
t hera p y n o less t ha n 4 wee ks pri or t o ra n d o mizati o n. 
b.  Patie nts wit h tra nsf or me d m yc osis f u n g oi des are per mitte d t o ha ve recei ve d 1 
s yste mic si n gle-a ge nt c he m ot hera p y ( ot her t ha n met h otre xate) pri or t o tra nsf or mati o n 
of t heir disease. 
4.  Pri or e x p os ure t o pralatre xate. 
5.  Recei pt of s yste mic c ortic oster oi ds wit hi n 3 wee ks of st u d y treat me nt, u nless patie nt has 
bee n ta ki n g a c o nti n u o us d ose of ≤ 1 0 m g/ da y of oral pre d nis o ne or e q ui vale nt f or at least 
4 wee ks or as part of a C H O P pre d nis o ne ta per.   
6.  Pla n ne d use of a n y treat me nt f or P T C L d uri n g t he c o urse of t he st u d y. 
7.  Patie nt has: 
a. H u ma n i m m u n o deficie nc y vir us ( HI V)- p osit i ve dia g n osis wit h a C D 4 c o u nt of 
< 1 0 0 m m 3 or detecta ble viral l oa d wit hi n past 3 m o nt hs a n d is recei vi n g 
a nti-retr o viral t hera p y. 
b.  H B V- p ositi ve ser ol o g y a n d is recei vi n g i nterf er o n t hera p y or has li ver f u ncti o n test 
res ults o utsi de t he para meters of st u d y i ncl usi o n criteria.  Patie nts are per mitte d t o 
recei ve ot her a nti viral t hera pies if t he t hera p y has bee n a d mi nistere d at a sta ble d ose 
f or ≥ 4 wee ks.  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 of 9 5 
c. He patitis C vir us ( H C V) wit h detecta ble viral l oa d or i m m u n o l o gical e vi de nce of 
c hr o nic acti ve disease or recei v i n g/re q uiri n g a nti viral t hera p y. 
d.  S y m pt o matic ce ntral ner v o us s yste m ( C N S) me tastases or lesi o ns f or w hic h treat me nt 
is re q uire d. 
e. U nc o ntr olle d h y perte nsi o n or c o n gesti ve hear t fail ure Class III/I V acc or di n g t o t he 
Ne w Y or k Heart Ass ociati o n’s He art Fail ure G ui deli nes (see 
htt p:// w w w.a merica n heart. or g/ pr ese nter.j ht ml?i de ntifier = 3 0 6 5 0 8 0). 
f. Acti ve u nc o ntr olle d i nfecti o n, u n derl yi n g me dical c o n diti o n i ncl u di n g u nsta ble 
car diac disease, or ot her seri o us ill ness t hat w o ul d i m pair t he a bilit y of t he patie nt t o 
recei ve pr ot oc ol treat me nt.   
8.  Patie nt has ha d maj or s ur ger y wit hi n 2 wee k s pri or t o st u d y e ntr y; ot her t ha n f or li ne 
place me nt or bi o ps y pr oce d ure.  
Test Pr o d uct, D ose, a n d M o de of A d mi nistr ati o n:  
Pralatre xate will be a d mi nistere d via I V  p us h o ver a mi ni m u m of 3 0 sec o n ds u p t o a 
ma xi m u m of 5 mi n utes.  O ne c ycle is 4 wee ks i n d urati o n c o nsisti n g of wee kl y d osi n g at a 
starti n g d ose of pralatre xate 3 0 m g/ m 2 f or 3 wee ks, f oll o we d b y 1 wee k of rest.  D ose 
re d ucti o n t o 2 0 m g/ m2 wit h f urt her re d ucti o ns t o 1 5 a n d 1 0 m g/ m2 will be all o we d f or 
defi ne d t o xicit y.   
Pralatre xate will be a d mi nistere d i nt o a pate nt free-fl o wi n g I V li ne c o ntai ni n g n or mal sali ne 
( 0. 9 % s o di u m c hl ori de [ Na Cl]). 
Effic ac y Assess me nts: 
T he pri mar y efficac y set, als o referre d t o as t he i nte nt-t o-treat p o p ulati o n, i ncl u des all 
ra n d o mize d patie nts.  Eac h patie nt will be i ncl u de d i n t he treat me nt gr o u p assi g ne d at 
ra n d o mizati o n, re gar dless of t he treat me nt recei ve d.  T his a nal ysis set will be use d f or t he 
pri mar y a nal yses of all efficac y e n d p oi nts. 
T u m or Res p o nse Assess me nts  
Meas ure d fr o m ra n d o mi zati o n, res p o nse e val uati o ns  are t o occ ur at 8 wee ks ( ± 1 wee k) t he n 
e ver y 1 2 wee ks ( ± 1 wee k) t hr o u g h 3 years p ost-ra n d o mizati o n, t he n e ver y 2 4 wee ks 
( ± 4 wee ks) t hr o u g h 7 years p ost-ra n d o mizati o n.  T u m or res p o nse will be deter mi ne d b y 
ce ntral re vie w at least u ntil t he a nal ysis of P F S.  If P F S a nal ys is is n ot si g nifica nt at t he 0. 0 5 
le vel at t hat a nal ysis, t he st u d y will be st o p pe d.   
Pr o gressi o n-free S ur vi val  
P F S ti me is calc ulate d as t he n u m ber of da ys fr o m ra n d o mizati o n t o t he date of o bjecti ve 
d oc u me ntati o n of P D or deat h, re gar dless of ca use ( date of P D or deat h - date of 
ra n d o mizati o n + 1).  Patie nts w h o are ali ve wit h o ut a disease res p o nse assess me nt of P D will 
be ce ns ore d at t heir last disease assess me nt da te or t he date of ra n d o mizati o n, w hic he ver is 
later.  Date of pr o gressi o n will n ot be i m p ute d f or patie nts wit h missi n g t u m or assess me nt(s) 
bef ore  a n assess me nt of P D.  Patie nts w h o wit h dr a w fr o m treat me nt pri or t o P D will be 
f oll o we d f or disease stat us w he ne ver p ossi ble, e ve n if s u bse q ue nt t hera p y, i ncl u di n g 
tra ns pla nt, has bee n i nitiate d pri or t o d oc u me nte d P D per ce ntral re vie w at least u ntil t he P F S 
a nal ysis.  Patie nts w h o ha ve n o res p o nse assess me nts after baseli ne will be ce ns ore d at 
ra n d o mizati o n.   


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 8 of 9 5 
O verall S ur vi val  
O verall s ur vi val ti me is  calc ulate d as t he n u m ber of da ys fr o m ra n d o mizati o n t o t he date of 
deat h, re gar dless of ca use ( date of deat h - date of ra n d o mizati o n + 1).  S ur vi val f oll o w- u p 
will c o nti n ue f or u p t o 7 years fr o m ra n d o mizati o n. 
S afet y Assess me nts:  
All patie nts w h o are ra n d o mize d t o t he Pral atre xate Ar m w h o recei ve at least 1 d ose of 
pralatre xate pl us all patie nts ra n d o mize d t o t he O bser vati o n Ar m w h o d o n ot disc o nti n ue t he 
st u d y wit hi n 3 da ys of ra n d o mizati o n will be e valua ble f or safet y.  Safet y will be e val uate d 
b y assess me nt of p h ysical e xa mi nati o ns, cli nical  la b orat or y val ues, treat me nt-e mer ge nt A Es 
(all gra des), S A Es, a n d disc o nti n uati o ns d ue t o treat me nt-relate d A Es.  Safet y will be 
assesse d acc or di n g t o t he Nati o nal Ca ncer I n stit ute ( N CI) C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( C T C A E) scale, Versi o n 4. 0.  
P h ar m ac o ki netic Assess me nts: 
T here will be s parse sa m pli n g f or p o p ulati o n p har mac o ki netics ( P O P P K).  A p pr o xi matel y 
t w o-t hir ds of t he patie nts ra n d o mize d t o t he Pralatre xate Ar m ( n ≈ 2 4 5) w h o c o nse nt t o 
plas ma sa m pli n g will ha ve sa m pli n g perf or me d at c ycle 1, d ose 1 ( pre-i njecti o n, e n d of 
i njecti o n, a n d 8 a n d 2 4 h o urs p ost-i njecti o n).  Of t hese 2 4 5 patie nts, 2 0 patie nts at select sites 
will als o ha ve plas ma sa m pli n g perf or me d at c ycle 2, d ose 3 ( pre-i njecti o n, e n d of i njecti o n, 
a n d 8 a n d 2 4 h o urs p ost-i njecti o n). 
St atistic al Met h o ds: 
T he sa m ple size is base d o n c o m pari n g t he tr eat me nt gr o u ps wit h res pect t o t he pri mar y 
efficac y e n d p oi nts of P F S a n d O S.  T here will be 1 fi nal a nal ysis of P F S, a n d 2 i nteri m a n d 
1 fi nal a nal ysis of O S.  T he first i nteri m a nal ys is of O S will be perf or me d at t he sa me ti me as 
t he P F S a nal ysis.  T he first a nal ysis will be perf or me d w he n b ot h 2 8 0 P F S e ve nts a n d 
1 2 8 O S e ve nts ha ve occ urre d.  T he o nl y a nal ys is f or P F S will be perf or me d at t his first 
a nal ysis p oi nt, a n d will be asse sse d at t he 0. 0 5 le vel of si g nifica nce.  If P F S is si g nifica nt at 
t he 0. 0 5 le vel, t he first i nteri m a nal ysis will be c o n d ucte d o n s ur vi val at t his ti me.  If t he P F S 
a nal ysis is n ot si g nifica nt at t he 0. 0 5 le vel, t h e st u d y will be st o p pe d.  T he sec o n d i nteri m a n d 
fi nal a nal yses f or O S will be perf or me d w he n t w o-t hir ds ( 2 5 6) a n d all 3 8 5 O S e ve nts ha ve 
occ urre d, res pecti vel y.  
T he stratifie d l o g-ra n k test w ill be t he pri mar y met h o d use d t o test t he h y p ot hesis t hat 
pralatre xate e xte n ds P F S a n d O S relati ve t o o bser vati o n.  I n a d diti o n, t he stratifie d C o x 
re gressi o n m o del will be use d t o calc ulate t he P F S a n d s ur vi val hazar d rati o ( H R), al o n g wit h 
t heir 9 5 % c o nfi de nce i nter val ( CIs).  Res ults of t he u nstratifie d C o x re gressi o n m o del (a n d 
l o g-ra n k test) will als o be prese nte d.  T he pro p orti o nal hazar ds ass u m pti o n of t he C o x m o del 
will be assesse d.   
A D M C will peri o dicall y re vie w safet y data at re g ularl y sc he d ule d meeti n gs a n d at t he sa me 
ti me as eac h a nal ysis of efficac y.  T he first f or mal safet y re vie w will occ ur w he n 
a p pr o xi matel y 1 0 0 patie nts ha ve bee n ra n d o m ize d a n d c o m pl ete d at least 8 wee ks p ost-
ra n d o mizati o n pralatre xate/ o bservati o n or ha ve disc o nti n ue d. 
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 9 of 9 5 
At eac h i nteri m a nal ysis f or s ur vi val, t he st u d y ma y be st o p pe d f or o ver w hel mi n g e vi de nce 
of f utilit y or s u peri orit y acc or di n g t o s pecifie d b o u n daries.  T he D M C ma y als o ma ke 
rec o m me n dati o ns re gar di n g a dj ust me nts t o t he sa m ple size, if t he y are warra nte d. 
D ate of Pr ot oc ol:  3 1 Oct 2 0 1 1 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 0 of 9 5 
T A B L E O F C O N T E N T S 
S Y N O P SI S ...................................................................................................................... ........... 2 
T A B L E O F C O N T E N T S ......................................................................................................... 1 0  
LI S T O F I N- T E X T T A B L E S .................................................................................................. 1 4  
LI S T O F I N- T E X T FI G U R E S................................................................................................. 1 4  
LI S T O F A P P E N DI C E S .......................................................................................................... 1 4  
LI S T O F A B B R E VI A TI O N S .................................................................................................. 1 6  
1  
I N V E S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E S T R U C T U R E ...................... 2 2  
2  
I N T R O D U C TI O N ...........................................................................................................2 3  
2. 1  
Bac k gr o u n d I nf or mati o n o n N o n- H o d g ki n’s L y m p h o mas .................................... 2 3  
2. 2  
Classificati o n of T-cell L y m p h o mas ...................................................................... 2 3  
2. 3  
Pr o g n osis of T-cell L y m p h o mas ............................................................................ 2 4  
2. 3. 1  
C urre nt First-li ne T hera p y f or Peri p heral T-ce ll L y m p h o ma ......................2 7  
3  
P R A L A T R E X A T E .......................................................................................................... 3 0  
3. 1  
P h ysical, C he mical, P har mace utical Pr o perties ..................................................... 3 0  
3. 2  
N o ncli nical St u dies wi t h Pralatre xate .................................................................... 3 1 
3. 2. 1  
N o ncli nical P har mac ol o g y ........................................................................... 3 1  
3. 2. 1. 1  
Xe n o graft St u dies i n L y m p h o ma M o dels............................................ 3 2  
3. 2. 2  
N o ncli nical T o xic ol o g y ............................................................................... 3 5  
4  
O N C O L O G Y S T U DI E S WI T H P R A L A T R E X A T E ...................................................... 3 6  
4. 1  
St u dies i n Patie nts wit h L y m p h o pr oliferati ve Mali g na ncies ................................. 3 6  
4. 1. 1  
Si n gle- A ge nt St u dies ................................................................................... 3 6  
4. 1. 2  
C o m bi nati o n St u dies .................................................................................... 3 7  
4. 2  
St u dies i n Patie nts wit h S oli d T u m ors ................................................................... 3 8  
4. 2. 1  
All os Si n gle-a ge nt St u dies ........................................................................... 3 8  
4. 2. 2  
M S K C C St u dies i n Patie nts wit h S oli d T u m ors .......................................... 3 9  
4. 3  
Safet y O ver vie w of O nc ol o g y Patie nts Recei vi n g Pralatre xate ............................ 4 0  
4. 3. 1  
Preca uti o ns ................................................................................................... 4 0  
4. 4  
Cli nical P har mac ol o g y ........................................................................................... 4 1  
4. 4. 1  
P har mac o ki netics ......................................................................................... 4 1  
5  
R A TI O N A L E F O R T H E C U R R E N T S T U D Y ............................................................... 4 2  
6  
S T U D Y O BJ E C TI V E S .................................................................................................... 4 3  
7  
I N V E S TI G A TI O N A L P L A N ..........................................................................................4 4  
7. 1  
Vita mi n A d mi nistrati o n ......................................................................................... 4 4  
7. 2  
Pralatre xate A d mi nistrati o n ................................................................................... 4 4  
7. 3  
St u d y D urati o n ....................................................................................................... 4 4  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 1 of 9 5 
7. 4  
Treat me nt M o dificati o ns of Pralatre xate ............................................................... 4 5  
7. 4. 1  
He mat ol o gical A d verse E ve nts .................................................................... 4 6  
7. 4. 2  
N o n- he mat ol o gical A d verse E ve nts ............................................................ 4 6  
8  
P A TI E N T P O P U L A TI O N ............................................................................................... 4 8  
8. 1  
N u m ber of Patie nts a n d Patie nt Selecti o n .............................................................. 4 8  
8. 2  
I ncl usi o n of Fe males a n d Mi n orities ......................................................................4 8  
8. 3  
I ncl usi o n Criteria ................................................................................................... 4 8 
8. 4  
E xcl usi o n Criteria .................................................................................................. 4 9  
9  
S T U D Y D R U G A N D P H A R M A C E U TI C A L I N F O R M A TI O N ................................... 5 2  
9. 1  
Pralatre xate I njecti o n ............................................................................................. 5 2  
9. 1. 1  
Pralatre xate I njecti o n F or m ulati o n .............................................................. 5 2  
9. 1. 2  
Pralatre xate I njecti o n St ora ge a n d Ha n dli n g ............................................... 5 2  
9. 1. 3  
Pac ka gi n g/ La beli n g...................................................................................... 5 2  
9. 1. 4  
Pralatre xate I njecti o n D o sa ge a n d A d mi nistrati o n ......................................5 2  
9. 1. 4. 1  
Pre parati o n a n d Pralatre xate I njecti o n D ose Calc ulati o n..................... 52  
9. 1. 5  
A d mi nistrati o n of Pral atre xate I njecti o n ...................................................... 5 3  
9. 2  
Dr u g Acc o u nta bilit y............................................................................................... 5 3  
1 0  S T U D Y P R O C E D U R E S ................................................................................................. 5 4  
1 0. 1  
Scree ni n g................................................................................................................ 5 4  
1 0. 2  
Patie nt Ra n d o mizati o n ........................................................................................... 5 5  
1 0. 3  
Pralatre xate Treat me nt/ O bser vati o n I nitiati o n ....................................................... 5 5  
1 0. 3. 1  
Pralatre xate A d mi nistrati o n ......................................................................... 5 5  
1 0. 4  
Pralatre xate Ar m Pr oce d ures ................................................................................. 5 6  
1 0. 4. 1  
Pralatre xate C ycle 1, D ose 1 ........................................................................ 5 6  
1 0. 4. 2  
Pralatre xate Ar m: C ycle 1, D oses 2- 3 .......................................................... 5 6  
1 0. 4. 3  
Pr oce d ures f or S u bse q ue nt C ycles, D oses 1- 3 f or a Ma xi m u m of 2 
Years ............................................................................................................ 5 7  
1 0. 5  
O bser vati o n Ar m Pr oce d ures ................................................................................. 5 7  
1 0. 5. 1  
O bser vati o n Ar m: Baseli ne Visit ................................................................. 5 7  
1 0. 5. 2  
O bser vati o n Ar m: Wee k 2 of E ver y 4- wee k Peri o d f or a Ma xi m u m of 2 
Years ............................................................................................................ 5 7  
1 0. 5. 3  
O bser vati o n Ar m:  E ver y 2 8 da ys ( ± 3 da ys) f or a Ma xi m u m of 2 Years ... 5 8  
1 0. 6  
Res p o nse E val uati o n .............................................................................................. 5 8  
1 0. 7  
I nitial F oll o w- u p Visit............................................................................................5 9  
1 0. 7. 1  
Pralatre xate Ar m .......................................................................................... 5 9  
1 0. 7. 2  
O bser vati o n Ar m .......................................................................................... 5 9  
1 0. 8  
F oll o w- u p Visits..................................................................................................... 6 0  
1 0. 9  
L o n g-ter m F oll o w- u p ............................................................................................. 6 0  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 2 of 9 5 
1 1  D U R A TI O N O F T R E A T M E N T ..................................................................................... 6 0  
1 1. 1  
Criteria f or St u d y Treat me nt Disc o nti n uati o n ....................................................... 6 0  
1 2  L A B O R A T O R Y T E S T S ................................................................................................. 6 1  
1 2. 1  
L ocal La b orat or y Tests .......................................................................................... 6 1  
1 2. 1. 1  
He mat ol o g y .................................................................................................. 6 1  
1 2. 1. 2  
C he mistr y ..................................................................................................... 6 1  
1 2. 2  
Ce ntral La b orat or y ................................................................................................. 6 2  
1 2. 2. 1  
Plas ma P har mac o ki netics ............................................................................. 6 2  
1 2. 2. 2  
I n de pe n de nt Pat h ol o g y Re vie w ...................................................................6 2  
1 2. 2. 3  
Me dical P h ot o gra p h y ................................................................................... 6 2  
1 2. 2. 4  
Ce ntral Ra di ol o g y I ma gi n g .......................................................................... 6 2  
1 3  C O N C O MI T A N T M E DI C A TI O N S ............................................................................... 6 3  
1 3. 1  
A ntie metic T hera p y ............................................................................................... 6 3  
1 3. 2  
He mat o p oietic Gr o wt h Fact ors .............................................................................. 6 3  
1 3. 3  
M uc ositis Ma na ge me nt .......................................................................................... 6 3  
1 3. 4  
C ortic oster oi d Use ................................................................................................. 6 3  
1 3. 5  
Pr o p h ylactic A nti-i nfecti ve A ge nts ........................................................................ 6 4  
1 3. 6  
Pai n Ma na ge me nt................................................................................................... 6 4  
1 3. 7  
Bl o o d Pr o d ucts ....................................................................................................... 6 4  
1 3. 8  
Ot her S u p p orti ve Care Me dicati o ns....................................................................... 6 4  
1 3. 9  
Ra di ot hera p y, C yt ot o xic T hera p y, Bi ol o gic T hera p y, or I m m u ne Res p o nse 
M o difiers ................................................................................................................ 6 4  
1 4  A D V E R S E E V E N T S ....................................................................................................... 6 5  
1 4. 1  
Defi niti o n ............................................................................................................... 6 5  
1 4. 2  
G ui deli nes f or Rec or di n g a n d Attri b uti o n Sc ori n g of A d verse E ve nts ................. 6 6  
1 4. 3  
Rec or di n g of A d verse E ve nts ................................................................................ 6 6  
1 4. 3. 1  
Rec or di n g of A d verse E ve nts ...................................................................... 6 6  
1 4. 3. 2  
Gra di n g of A d verse E ve nts .......................................................................... 6 6  
1 4. 4  
F oll o w- u p of A d verse E ve nts ................................................................................ 6 6  
1 4. 5  
Relati o ns hi p ........................................................................................................... 6 6  
1 4. 6  
Seri o us A d verse E ve nts ......................................................................................... 6 7  
1 4. 6. 1  
Defi niti o n ..................................................................................................... 6 7  
1 4. 6. 2  
Seri o us A d verse E ve nt Re p orti n g ................................................................ 6 7  
1 4. 6. 3  
E xcl usi o ns t o Seri o us A d vers e E ve nt Re p orti n g Re q uire me nts .................. 6 8  
1 4. 7  
Re pr o d ucti ve Ris ks ................................................................................................ 6 9  
1 4. 7. 1  
Pre g na nc y N otificati o n ................................................................................ 6 9  
1 5  S T A TI S TI C A L P L A N ..................................................................................................... 7 0  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 3 of 9 5 
1 5. 1  
O bjecti ves .............................................................................................................. 7 0  
1 5. 2  
E n d p oi nts ............................................................................................................... 7 0  
1 5. 2. 1  
Efficac y E n d p oi nts ....................................................................................... 7 0  
1 5. 2. 2  
Safet y E n d p oi nts .......................................................................................... 7 0  
1 5. 3  
A nal ysis P o p ulati o n ............................................................................................... 7 0  
1 5. 3. 1  
Pri mar y A nal ysis Set/I nte nt -t o-treat A nal ysis Set .......................................7 0  
1 5. 3. 2  
Safet y A nal ysis Set ...................................................................................... 7 1  
1 5. 3. 3  
I nteri m A nal yses Sets .................................................................................. 7 1 
1 5. 4  
Sa m ple Size ............................................................................................................ 7 1  
1 5. 5  
Stratificati o n ........................................................................................................... 7 2  
1 5. 6  
A nal ysis Pla ns ........................................................................................................ 7 2  
1 5. 6. 1  
I nteri m A nal yses of O S ................................................................................ 7 2 
1 5. 6. 2  
Fi nal A nal yses of Efficac y E n d p oi nts .......................................................... 7 3  
1 5. 7  
Efficac y E n d p oi nts ................................................................................................. 7 4  
1 5. 7. 1  
Pr o gressi o n-free S ur vi val............................................................................. 7 4  
1 5. 7. 2  
O verall S ur vi val ........................................................................................... 7 4  
1 5. 7. 3  
O bjecti ve Res p o nse Rate ............................................................................. 7 5  
1 5. 8  
Safet y A nal ysis ...................................................................................................... 7 5  
1 5. 8. 1  
A d verse E ve nts ............................................................................................ 7 5  
1 5. 8. 2  
A d verse E ve nts Gr o u pe d b y Si milar Preferre d Ter m .................................. 7 6  
1 5. 8. 3  
La b orat or y Para meters ................................................................................. 7 6  
1 6  S T U D Y M A N A G E M E N T .............................................................................................. 7 7  
1 6. 1  
I n vesti gat or Res p o nsi bilities ..................................................................................7 7  
1 6. 1. 1  
G o o d Cli nical Practice ................................................................................. 7 7  
1 6. 1. 2  
I R B/ E C/ R E B A p pr o val ................................................................................7 7  
1 6. 1. 3  
I nf or me d C o nse nt.........................................................................................7 7  
1 6. 1. 4  
St u d y Files a n d Rete nti o n of Rec or ds .......................................................... 7 7  
1 6. 2  
Rec or di n g a n d C ollecti n g of Data .......................................................................... 7 8  
1 6. 2. 1  
Case Re p ort F or ms ....................................................................................... 7 8  
1 6. 2. 2  
Data Clarificati o n F or ms.............................................................................. 7 8  
1 6. 2. 3  
Self-e vi de nt C orrecti o ns .............................................................................. 7 9  
1 6. 2. 4  
Dr u g Acc o u nta bilit y..................................................................................... 7 9  
1 6. 3  
Pr ot oc ol C o m plia nce .............................................................................................. 8 0  
1 6. 4  
S p o ns or Res p o nsi bilities ........................................................................................ 8 0  
1 6. 4. 1  
A me n d me nts t o t he Pr ot oc ol ........................................................................ 8 0  
1 6. 4. 2  
Safet y M o nit ori n g ........................................................................................ 8 0  
1 6. 5  
J oi nt I n vesti gat or/ S p o ns or Res p o nsi bilities ........................................................... 8 1 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 4 of 9 5 
1 6. 5. 1  
Access t o I nf or mati o n f or M o nit ori n g a n d A u diti n g ................................... 8 1  
1 6. 5. 2  
Ter mi nati o n of t he St u d y ............................................................................. 8 1  
1 6. 5. 3  
P u blicati o n P olic y ........................................................................................ 8 1  
1 6. 6  
C o nfi de ntialit y ....................................................................................................... 8 1  
1 7  R E F E R E N C E S ................................................................................................................ 8 2  
 
LI S T O F I N- T E X T T A B L E S 
Ta ble 2. 1  
W H O T-cell L y m p h o ma  Classificati o n8 ......................................................2 4  
Ta ble 2. 2  
L y m p h o ma-i n de pe n de nt Pr o g n ostic Ris k  Fact ors per t he I nter nati o nal 
Pr o g n ostic I n de x .......................................................................................................... 2 5  
Ta ble 2. 3  
C o m paris o n of C o m plete Res p o nse Rate  a n d 5- Year O verall S ur vi val i n 
B- a n d T-cell Ne o plas ms 1 0 ...........................................................................................2 7  
Ta ble 3. 1.  
I n Vitr o C o m paris o n of Met h otre xate A nal o gs ........................................... 3 2  
Ta ble 3. 2.  
C o m paris o n of Gr o wt h I n hi biti o n b y Pralatre xate a n d Met h otre xate 
A gai nst H u ma n L y m p h o ma Cell Li nes ....................................................................... 3 3  
Ta ble 3. 3.  
Treat me nt of H u ma n H T ( Diff use Lar ge B Cell) N o n- H o d g ki n's 
L y m p h o ma Xe n o grafts i n N O D/ S CI D Mice ............................................................... 3 3  
Ta ble 3. 4.  
Treat me nt of H u ma n R L ( Tra nsf o r me d F ollic ular) N o n- H o d g ki n's 
L y m p h o ma Xe n o grafts i n N O D/ S CI D Mice ............................................................... 3 4  
Ta ble 3. 5.  
Treat me nt of H u ma n S KI- D L B C L- 1 ( De N o v o Diff use Lar ge B- Cell) 
N o n- H o d g ki n's L y m p h o ma Xe n o gr afts i n N O D/ S CI D Mice ...................................... 3 4  
Ta ble 7. 1.  
Pralatre xate Treat me nt M o dificat i o ns f or He mat ol o gical A Es ................... 4 6 
Ta ble 7. 2.  
Pralatre xate Treat me nt M o di ficati o ns f or M uc ositis ...................................4 7  
Ta ble 7. 3.  
Pralatre xate Treat me nt M o difi cati o ns f or Treat me nt-relate d 
Car di o vasc ular, Der mat ol o gical, He patic, Ne ur ol o gic, Re nal, or  Res pirat or y A Es ....4 7  
 
LI S T O F I N- T E X T FI G U R E S 
Fi g ure 2. 1.  
5- year O verall S ur vi val b y Hist ol o gic T y pe 1 ...............................................2 6  
Fi g ure 2. 2.  
O verall S ur vi val b y Hist ol o gic T y pe 1 ..........................................................2 8  
Fi g ure 3. 1.  
I n Vi v o S CI D Bei ge Xe n o graft M o del of S KI- D L B C L- 1 ...........................3 5  
 
LI S T O F A P P E N DI C E S 
A p pe n di x 1  
Sc he d ule of St u d y Pr oce d ures / E val uati o ns Ta ble f or 
Pralatre xate Treat me nt ................................................................................................. 8 6  
A p pe n di x 2  
Sc he d ule of St u d y Pr oce d ures/ E val u ati o ns Ta ble f or O bser vati o n ..... 8 7  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 5 of 9 5 
A p pe n di x 3  
E C O G Perf or ma nce Scale .................................................................... 8 8  
A p pe n di x 4  
T he I nter nati o nal W or ks h o p Criteria 4 3 ................................................8 9  
A p pe n di x 5  
S p o ns or Si g nat ure ................................................................................ 9 4  
A p pe n di x 6  
I n vesti gat or Si g nat ure ..........................................................................9 5  
 
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 6 of 9 5 
LI S T O F A B B R E VI A TI O N S 
A E 
a d verse e ve nt 
AI D S 
ac q uire d i m m u n o de ficie nc y s y n dr o me 
A L C L 
a na plastic lar ge cell l y m p h o ma 
A L K 
a na plastic l y m p h o ma ki nase 
A L T 
ala ni ne a mi n otra nsferase 
A N C 
a bs ol ute ne utr o p hil c o u nt 
Ara- C 
c ytara bi ne or c yt osi ne ara bi n osi de 
A S T 
as partate a mi n otra nsferase 
A T C 
A nat o mical T hera pe utic C he mical 
A U C 
area u n der t he c ur ve 
A U C ∞ 
area u n der t he c ur ve t o i nfi nit y 
β - h C G 
β - h u ma n c h ori o nic g o na d otr o pi n 
B S A 
b o d y s urface area 
° C 
de grees Celsi us 
C A S 
C he mical A bstracts Ser vice 
C F R 
C o de of Fe deral Re g ulati o ns 
C H O P 
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 1 4  
C H O P gi ve n e ver y 2 wee ks or 1 4 da ys 
C H O P 2 1  
C H O P gi ve n e ver y 3 wee ks or 2 1 da ys 
CI 
c o nfi de nce i nter val 
c m 
ce nti meter 
C ma x  
ma xi m u m c o nce ntrati o n 
C N S 
ce ntral ner v o us s yste m 
C R 
c o m plete res p o nse 
C R A 
cli nical researc h ass ociate 
C R F 
case re p ort f or m 
C R O 
cli nical researc h or ga nizati o n  
C R u 
u nc o nfir me d C R 
C T 
c o m p ute d t o m o gra p h y 
C T A 
cli nical trial a gree me nt 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 7 of 9 5 
C T C A E 
C o m m o n Ter mi n ol o g y Crit eria f or A d verse E ve nts 
C T C L 
c uta ne o us T-cell l y m p h o ma 
C T E P 
Ca ncer T hera p y E val uati o n Pr o gra m 
D C F 
Data Clarificati o n F or ms 
D H F R 
di h y dr of olate re d uctase 
d L 
deciliter 
D L B C L 
diff use lar ge B-cell 
D L T 
d ose-li miti n g t o xicit y 
D M C 
Data M o nit ori n g C o m mittee 
E B V 
E pstei n Barr vir us 
E C 
Et hics C o m mittee 
E C G 
electr ocar di o gra m 
E C O G 
Easter n C o o perati ve O nc ol o g y Gr o u p 
E D C 
electr o nic data ca pt ure 
E S H A P 
et o p osi de, met h yl pre d nis ol o ne, c ytara bi ne, a n d cis plati n 
E U 
E ur o pea n U ni o n 
° F 
de grees Fa hre n heit 
F D A 
F o o d a n d Dr u g A d mi nistrati o n 
F D G 
fl u or o de o x y gl uc ose 
F F S 
fail ure-free s ur vi val 
F P G S 
f ol yl p ol y gl uta m yl s y nt hetase 
G C P 
g o o d cli nical practice 
G- C S F 
gra n ul oc yte c ol o n y-sti m ulati n g fact or 
Ge m 
ge mcita bi ne 
G F R 
gl o mer ular filtrati o n rate 
G L P 
g o o d la b orat or y practice 
G M- C S F  
gra n ul oc yte- macr o p ha ge  c ol o n y-sti m ulati n g fact or 
H B V 
he patitis B vir us 
Hct 
he mat ocrit 
H C V 
he patitis C vir us 
H g b 
he m o gl o bi n 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 8 of 9 5 
HI V 
h u ma n i m m u n o deficie nc y vir us 
H R 
hazar d rati o 
H T L V 
h u ma n T-cell le u ke mia vir us 
I B 
I n vesti gat or’s Br oc h ure 
I C 
i nf or me d c o nse nt 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I C5 0 
half ma xi m u m i n hi bit or y c o nce ntrati o n 
I L S G 
I nter nati o nal L y m p h o ma St u d y Gr o u p 
I M 
i ntra m usc ular 
I N D 
i n vesti gati o nal ne w dr u g 
I N N 
i nter nati o nal n o n pr o prietar y na me 
I P 
i ntra perit o neal 
I PI 
I nter nati o nal Pr o g n ostic I n de x 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
i nteracti ve res p o nse tec h n ol o g y 
I V 
i ntra ve n o us 
I V R S 
i nteracti ve v oice res p o nse s yste m 
I W C 
I nter nati o nal W or ks h o p Criteria 
k g 
kil o gra m 
K i 
i n hi biti o n c o nsta nt 
K m  
bi n di n g c o nsta nt 
L 
liter 
L D H 
lactic de h y dr o ge nase 
m 2 
s q uare meter 
M A L T 
m uc osa-ass ociate d l y m p hatic tiss ue l y m p h o mas 
M C 
ma ntle cell 
Me d D R A
®   
me dical dicti o nar y f or re g ulat or y acti vities 
m g 
milli gra m 
mi n 
mi n ute 
m L 
milliliter 
m m 
milli meter 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 1 9 of 9 5 
m Os m ol 
milli os m ole 
M RI 
ma g netic res o na nce i ma gi n g 
M S K C C  
Me m orial Sl oa n- Ke tteri n g Ca ncer Ce nter 
M T D 
ma xi m u m t olerate d d ose 
M T X 
met h otre xate 
Na Cl 
s o di u m c hl ori de 
N C C N 
Nati o nal C o m pre he nsi ve Ca ncer Net w or k 
N CI 
Nati o nal Ca ncer I nstit ute 
N D A 
Ne w Dr u g A p plicati o n 
N H L 
n o n- H o d g ki n’s l y m p h o ma 
N K 
nat ural killer  
N, n, or n o.  
n u m ber 
N O D/ S CI D  
n o n- o bese, dia betic/se vere c o m bi ne d i m m u n o deficie nt 
N O S 
n ot ot her wise s pecifie d 
N S AI D 
n o n-ster oi dal a nti-i nfla m mat or y dr u g 
N S C L C 
n o n-s mall cell l u n g ca ncer 
n M 
na n o m olar 
n m ol 
na n o m ole 
O R R 
o verall res p o nse rate 
O S 
o verall s ur vi val 
P B S C T 
peri p heral bl o o d ste m cell tra ns pla nt 
P D 
pr o gressi ve disease 
P D X 
pralatre xate, ( R S )- 1 0- pr o par g yl- 1 0- deazaa mi n o pteri n 
P E T 
p ositr o n e missi o n t o m o gra p h y 
P F S 
pr o gressi o n-free s ur vi val 
P K 
p har mac o ki netics 
p M 
pic o m olar 
p o 
oral 
P O P P K 
p o p ulati o n P K 
P R 
partial res p o nse 
P T C L 
peri p heral T-cell l y m p h o ma 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 2 0 of 9 5 
P T C L- U  
P T C L- u ns pecifie d 
q 
e ver y 
q d 
o nce a da y 
R E A L 
Re vise d E ur o pea n A merica n L y m p h o ma 
R E B 
Researc h Et hics B oar d 
R F C- 1 
re d uce d f olate carrier- 1 
R S 
rect us si nister; a race mic mi xt ure of a c hiral c o m p o u n d 
R T 
ra diati o n t hera p y 
S A E 
seri o us a d verse e ve nt 
S A E R 
seri o us a d verse e ve nt re p ort 
S D 
sta ble disease 
S E 
sta n dar d err or 
S N 
site n otificati o n 
S O C 
s yste m or ga n class 
S P D 
s u m of t he pr o d uct of t he dia meters 
S RI 
S o ut her n Researc h I nstit ute 
S RI I nter nati o nal  
Sta nf or d Researc h I nstit ute I nter nati o nal 
t1/ 2 
half-life 
T C C 
tra nsiti o nal cell carci n o ma 
T E N 
t o xic e pi der mal necr ol ysis 
T- L B 
prec urs or T-l y m p h o blastic l y m p h o ma 
T- P L L 
T-cell pr ol y m p h oc ytic le u ke mia 
U L N 
u p per li mit of n or mal 
U S 
U nite d States 
U S A N 
U nite d States A d o pte d Na me 
U S P 
U nite d States P har mac o peia 
µ g 
micr o gra m 
μ L 
micr oliter 
μ M 
micr o m olar 
µ m ol 
micr o m ole 
V ma x  
ma xi m u m rate c o nsta nt 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 2 1 of 9 5 
W B C 
w hite bl o o d cells 
W H O 
W orl d Healt h Or ga nizati o n 
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 2 2 of 9 5 
1 
I N V E S TI G A T O R S A N D S T U D Y A DMI NI S T R A TI V E S T R U C T U R E 
Pri or t o st u d y i nitiati o n, t he i n vesti gat or at eac h site m ust pr o vi de t o All os T hera pe utics, I nc. 
( All os) a si g ne d pr ot oc ol si g nat ure pa ge, a f ull y e xec ute d a n d si g ne d U nite d States ( U S) 
F or m F o o d a n d Dr u g A d mi nistrati o n ( F D A) 1 5 7 2, a n d a Fi na ncial Discl os ure F or m.  
Fi na ncial Discl os ure F or ms m ust als o be c o m p lete d f or all s u bi n vesti gat ors liste d o n t he U S 
F or m F D A 1 5 7 2 w h o will be directl y i n v ol ve d i n  t he treat me nt or e val uati o n of researc h 
patie nts i n t his st u d y. 
T he st u d y will be a d mi nistere d a n d m o nit ore d b y e m pl o yees or re prese ntati ves of All os.  
Cli nical researc h ass ociates ( C R As) will m o n it or eac h site o n a peri o dic basis a n d perf or m 
verificati o n of s o urce d oc u me ntati o n f or eac h patie nt.  T he Cli nical Dr u g Safet y a n d 
P har mac o vi gila nce De part me nt at All os will be  res p o nsi ble f or e ns uri n g ti mel y re p orti n g of 
e x pe dite d seri o us a d verse e ve nt re p orts ( S A E Rs) t o re g ulat or y a ge ncies a n d i n vesti gat ors. 
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 2 3 of 9 5 
2 
I N T R O D U C TI O N 
2. 1 
B a c k gr o u n d I nf or m ati o n o n N o n- H o d g ki n’ s L y m p h o m a s 
I ncl u de d u n der t he cate g or y of l y m p h o ma are s o me of t he fastest gr o wi n g a n d m ost 
a g gressi ve ca ncers ( B ur kitt’s l y m p h o ma, l y m p h o blastic l y m p h o ma/le u ke mia), as well as 
s o me of t he m ost i n d ole nt (s mall l y m p h oc ytic l y m p h o ma, f ollic ular l ym p h o ma, a n d mar gi nal 
z o ne l y m p h o ma), ma ki n g l y m p h o ma o ne of t he m o st heter o ge ne o us gr o u ps of mali g na ncies.  
It is t his c o nsi dera ble bi ol o gical di versit y t hat i m p oses si g nifica nt c halle n ges i n 
u n dersta n di n g t he cell of ori gi n a n d differe ntiati n g t he s o meti mes s u btle disti ncti o ns bet wee n 
t he relate d s u bt y pes of disease, as well as i n i de ntif yi n g t he best treat me nts f or eac h.  T-cell 
l y m p h o mas re prese nt a heter o ge ne o us arra y of a g gressi ve n o n- H o d g ki n’s l y m p h o ma ( N H Ls) 
a n d acc o u nt f or a p pr o xi matel y 1 0- 1 5 % of all ne wl y dia g n ose d cases of N H L i n t he U S. 1- 3 
W hile t he eti ol o g y of t he l y m p h o ma diseas es re mai ns lar gel y u n k n o w n, it is clear t hat 
be gi n ni n g pri or t o 1 9 5 0, a n e pi de mic of N H L, b ut n ot ot her he mat o p oietic ne o plas ms, was 
d oc u me nte d i n ma n y p o p ulati o ns, wit h a n es ti mate d 5 0 % i ncrease i n t he a ge-a dj uste d 
i nci de nce fr o m 1 9 7 0- 1 9 9 0 i n t he U S.4- 6  W hile re p orts s u g gest t hat t he stee p rise i n i nci de nce 
ma y ha ve sl o we d i n rece nt years, ca uti o n n ee ds t o be e xercise d i n i nter preti n g t hese 
i nci de nce rates gi ve n t he i n n u mera ble fact ors t hat ca n i nfl ue nce t hese statistics, li ke ac q uire d 
i m m u n o defi cie nc y s y n dr o me ( AI D S), ne w dia g n ostic tec h ni q ues, a n d ot her eti ol o gic fact ors, 
s uc h as i nfecti o ns.  I nteresti n gl y, i n d ustrialize d nati o ns e x perie nce a hi g her i nci de nce of 
N H L t ha n d o de vel o pi n g c o u ntries, wit h t he hi g h est i nci de nce rate i n t he w orl d occ urri n g i n 
t he U S a n d Ca na da.7  T hese statistics ra n k N H L as t he si xt h m ost c o m m o n ca ncer a n d t he 
si xt h m ost c o m m o n ca use of ca ncer deat h, acc o u ntin g f or 4 % of all ca ncers a n d 4 % of ca ncer 
deat hs.  W hile t he y are c o nsi dere d bi ol o gicall y di verse diseases wit h re s pect t o t heir cell of 
ori gi n, all are t h o u g ht t o be  deri ve d fr o m l y m p h oc ytes. 
2. 2 
Cl a s sifi c ati o n of T- c ell L y m p h o m a s 
As me nti o ne d, T-cell l y m p h o ma s acc o u nt f or a p pr o xi matel y 1 0-1 5 % of all ne wl y dia g n ose d 
cases of N H L i n t he U S.  Acc or di n g t o t he W orl d Healt h Or ga nizati o n ( W H O) classificati o n, 
T-cell l y m p h o mas are di vi de d i nt o a vari et y of s u bt y pes, as s h o w n bel o w i n Ta ble 2. 1 . 
Acc or di n g t o t his classificati o n, t here are c o nsi d ere d t o be at least 1 6 disti nct s u bt y pes of 
T-cell l y m p h o ma. 8 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 2 4 of 9 5 
T a bl e 2. 1  
W H O T- c ell L y m p h o m a Cl a s sifi c ati o n 8  
M at ure T- a n d N K-cell Ne o pl as ms 
 
T-cell pr ol y m p h oc ytic le u ke mia 
T-cell lar ge gra n ular l y m p h oc ytic le u ke mia 
C hr o nic l y m p h o pr oliferati ve dis or der of N K-cells 
A g gressi ve N K-cell le u ke mia 
E B V + T-cell l y m p h o pr oliferati ve dis or der of c hil d h o o d 
A d ult T-cell l y m p h o ma/le u ke mia 
E xtra n o dal T-cell/ N K-cell l y m p h o ma, nasal t y pe 
E nter o pat h y-ass ociate d T-cell l y m p h o ma 
He pat os ple nic T-cell l y m p h o ma 
S u bc uta ne o us pa n nic ulitis -li ke T-cell l y m p h o ma 
M yc osis f u n g oi des 
Sézar y s y n dr o me 
Pri mar y c uta ne o us C D 3 0 + T-cell l y m p h o pr oliferati ve dis or ders 
Pri mar y c uta ne o us ga m ma- delta T-cell l y m p h o mas 
Peri p heral T-cell l y m p h o ma, N O S 
A n gi oi m m u n o blastic T-cell l y m p h o ma 
A na plastic lar ge cell l y m p h o ma, A L K + t y pe 
A na plastic lar ge cell l y m p h o ma, A L K- t y pe 
 
N K = nat ural killer  
E B V = E pstei n Barr vir us 
N O S = n ot ot her wise s pecifie d 
A L K = a na plastic l y m p h o ma ki nase 
2. 3 
Pr o g n o si s of T- c ell L y m p h o m a s 
Al m ost all T/ nat ural killer ( N K)-cell l y m p h o ma s are a g gressi ve diseases re q uiri n g s yste mic 
c he m ot hera p y.  T here are select T-cell s u bsets of  disease t hat are c o nsi dere d m ore i n d ole nt, 
i ncl u di n g T-cell lar ge gra n ular l y m p h oc ytic le u ke mia, pr i mar y c uta ne o us C D 3 0 + dis or ders 
(i ncl u di n g a na plastic lar ge cell l y m p h o ma [ A L CL] a n d l y m p h o mat oi d pa p ul osis), or m yc osis 
f u n g oi des/ Sézar y s y n dr o me. 
I n ge neral, T/ N K-cell diseases are ass ociate d wit h a w orse pr o g n osis c o m pare d wit h t heir 
B-cell c o u nter parts.  It is n ot  e ntirel y clear w h y T-cell l y mp h o mas ha ve a w orse pr o g n osis; 
h o we ver, se veral t he ories ha ve bee n a d va nce d  ar o u n d t he f u n da me ntal bi ol o gical differe nces 
bet wee n B- a n d T-cell l y m p h o mas wit h re gar d  t o t heir i ntri nsic c he m ose nsiti vit y.  T he 
o bser vati o n has als o bee n ma de t hat patie nts wit h T-cell l y mp h o mas ge nerall y prese nt wit h 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 2 5 of 9 5 
m ore hi g h-ris k disease, at least base d o n t he I nter nati o nal Pr o g n ostic I n de x (I PI). 9  T he I PI 
all o ws f or t he ris k stratificati o n of patie nts wi t h all t y pes of l y m p h o ma, a n d has bee n a p plie d 
t o patie nts wit h b ot h i n d olent a n d a g gressi ve l y m p h o mas. 9  T his i n de x is base d u p o n 
5 i m p orta nt pr o g n ostic fact ors: a ge, East er n C o o perati ve O nc ol o g y Gr o u p ( E C O G) 
Perf or ma nce Stat us, a b n or mal le vels of l actic de h y dr o ge nase ( L D H), n u m ber of e xtra n o dal 
sites, a n d sta ge, wit h hi g her sc ores i n dicati n g w orse o utc o me. 9  Ta ble 2. 2 pr o vi des 
i nf or mati o n o n t he relati ve ris k of deat h ass ociate d wit h eac h of t hese pr o g n ostic fact ors. 
T a bl e 2. 2  
L y m p h o m a-i n d e p e n d e nt Pr o g n o sti c Ri s k F a ct or s p er t h e 
I nt er n ati o n al Pr o g n o sti c I n d e x 
F act or  
Rel ati ve Ris k 
of De at h 
A ge ( ≤ 6 0 vers us > 6 0) 
1. 9 6 
Ser u m L D H ( ≤ 1 x n or mal vers us > 1 x n or mal) 
1. 8 5 
E C O G Perf or ma nce Stat us ( 0 or 1 vers us 2- 4) 
1. 8 0 
Sta ge of Disease (I or II vers us III or I V) 
1. 4 7 
E xtra n o dal Site  I n v ol ve me nt (≤ 1 site vers us > 1 site) 
1. 4 8 
T he I PI is calc ulate d b y a d di n g t he n u m ber of ris k fact ors i de ntifie d a b o ve, res ulti n g i n t he classificati o n of 
patie nts wit h l o w (a n y 1 ris k fact or), l o w-i nter me diate  (a n y 2 ris k fact ors), hi g h-i nter me diate (a n y 3 ris k 
fact ors), a n d hi g h ( 4- 5 ris k fact ors) ris k disease. 
Assess me nt of t hese pr o g n ostic fact ors i n a lar ge c o h ort of B-cell a n d T-cell l y m p h o mas 
s u g geste d t hat T-cell p he n ot y pe ap pears t o be a n i n de pe n de nt a d verse pr o g n ostic fact or i n 
a d diti o n t o t he I PI sc ore. 1 0  Of n ote, a p pr o xi matel y 8 0 % of patie nts wit h peri p heral T-cell 
l y m p h o ma ( P T C L) ha ve a n I PI of 2 or hi g her at dia g n osis c o m pare d wit h 6 9 % of patie nts 
wit h diff use lar ge B-cell l y m p h o ma.
1  Fi g ure 2. 1  dis pla ys t he 5- year s ur vi val b y hist ol o gical 
s u bt y pe. 1 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 2 6 of 9 5 
Fi g ur e 2. 1.  5- y e ar O v er all S ur vi v al b y Hi st ol o gi c T y p e 1 
0
 
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
A n a pl a sti c l ar g e T/ n ull- c ell
M ar gi n al z o n e B- c ell, M A L T
F olli c ul ar, all gr a d e s
L y m p h o pl a s m a c yt oi d
M ar gi n al z o n e B- c ell, n o d al
S m all l y m p h o c yti c ( C L L)
Pri m ar y m e di a sti n al l ar g e B- c ell
Hi g h- gr a d e B- c ell, B ur kitt-li k e
D L B C L
B ur kitt' s
M a ntl e c ell
Pr e c ur s or T-l y m p h o bl a sti c
P T C L, all t y p e s
5- yr o v er all s ur vi v al, %
 
W hile ne ver f ull y esta blis he d i n a n y pr os pecti v e ra n d o mize d cli nical st u d y, it is reas o na bl y 
well acce pte d t hat T-cell l y m p h o mas are m ore c halle n gi n g t o effecti vel y treat t ha n B-cell 
l y m p h o mas.  Ta ble 2. 3  prese nts s o me of t hese data.1 0  F or e xa m ple, i n t he pre vi o usl y 
me nti o ne d st u d y, t he 5- year s ur vi val rate f or patie nts wit h 1, 2, or 3 ris k fact ors wit h 
B- vers us T-cell l y m p h o ma was 6 3 % vers us  6 0 %, 5 3 % vers us 3 6 %, a n d 3 5 % vers us 2 3 %, 
res pecti vel y.  Si milar tre n ds were als o o bser ve d f or t he rate of c o m plete res p o nses ( C R). 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 2 7 of 9 5 
T a bl e 2. 3  
C o m p ari s o n of C o m pl et e R e s p o n s e R at e a n d 5- Y e ar O v er all 
S ur vi v al i n B- a n d T- c ell N e o pl a s m s 1 0  
I PI F act ors  
Li ne a ge Assi g n me nt 
C o m plete Re missi o n 
R ate ( %) 
5- Ye ar O ver all 
S ur vi v al ( %) 
O verall 
B- 
T- 
6 3 % 
5 4 % 
5 3 % 
4 1 % 
0 
B- 
T- 
8 1 % 
8 2 % 
8 4 % 
7 7 % 
1 
B- 
T- 
7 1 % 
7 3 % 
6 3 % 
6 0 % 
2 
B- 
T- 
6 3 % 
5 8 % 
5 3 % 
3 6 % 
3 
B- 
T- 
5 2 % 
3 5 % 
3 5 % 
2 3 % 
T hese data are c orr o b orate d t o s o me e xte nt b y t he cate g orizati o n of differe nt o verall s ur vi val 
( O S) rates b y hist ol o gical s u bt y pe usi n g t he I nter nati o nal L y m p h o ma St u d y Gr o u p (I L S G) 
classificati o n, w hic h s u b- di vi de d t he l y m p h o mas i nt o 4 br oa d gr o u pi n gs, i ncl u di n g: ( 1) t h ose 
wit h 5- year o verall s ur vi val rate of great er t ha n 7 0 % i ncl u di n g f ollic ular l y m p h o ma, 
mar gi nal z o ne B-cell l y m p h o ma of m uc osa-ass ociate d l y m p hatic tiss ue l y m p h o mas 
( M A L T t y pe), a n d a na plastic l y m p h o ma ki nase ( A L K) p ositi ve a na plastic lar ge T-cell 
l y m p h o ma; ( 2) t h ose hist ol o gical s u bt y pes wit h 5- year s ur vi val rates of 5 0 %- 7 0 %, i ncl u di n g 
s mall l y m p h oc ytic, l y m p h o plas mac yt oi d, a n d n o dal mar gi nal z o ne B-cell l y m p h o mas; 
( 3) t h ose l y m p h o mas wit h 5- year o verall s ur vi val rates of 3 0 %- 4 9 %, i ncl u di n g diff use lar ge 
B-cell l y m p h o ma, pri mar y me diasti nal lar ge B- cell l y m p h o ma, a n d t he hi g h- gra de, B-cell, 
B ur kitt-li ke a n d B ur kitt l y m p h o mas; a n d fi na ll y, ( 4) t h ose hist ol o gical s u bt y pes wit h t he 
w orse o verall pr o g n osis a n d 5- year s ur vi val rate s less t ha n 3 0 %, i ncl u di n g P T C L, prec urs or 
T-l y m p h o blastic l y m p h o ma, a n d ma ntle cell l y m p h o ma. 1 1  T hese res ults ha ve bee n m ore 
rece ntl y c o nfir me d b y ot hers s h o wi n g t hat patie nts wit h P T C L ha ve a n es peciall y p o or 
o utc o me wit h a 5- year o verall s ur vi val rate of o nl y 2 6 % f oll owi n g treat me nt wit h sta n dar d 
d o x or u bici n-c o ntai ni n g re gi me ns. 1 2 
T hese o bser vati o ns str o n gl y s u g gest t hat patie nt s wit h T-cell l y m p h o ma are i n nee d of ne w 
treat me nt o pti o ns. 
2. 3. 1 
C urr e nt Fir st-li n e T h er a p y f or P eri p h er al T- c ell L y m p h o m a 
T here are c urre ntl y n o a p pr o ve d a ge nts f or firs t-li ne treat me nt of P T C L.  Patie nts wit h t he 
m ost a g gressi ve T-cell l y m p h o ma  s u bt y pes recei ve ver y little c li nical be nefit fr o m sta n dar d 
t hera pies1 3, 1 4 , 1 5, a n d ne w treat me nt c o m bi nati o ns are nee de d t o i m pr o ve b ot h pr o gressi o n-free 
s ur vi val ( P F S) a n d O S i n t he patie nt p o p ulati o n u n der st u d y i n t his pr ot oc ol. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 2 8 of 9 5 
T he di verse nat ure a n d rarit y of T-cell l y m p h o mas p ose a c hal le n ge t o t he s yste matic st u d y 
of t hese mali g na ncies a n d t he i d e ntificati o n of “sta n dar d” t her a pe utic strate gies.  Rece nt 
re vie ws ha ve atte m pte d t o c haracterize treat me nt a p pr oac hes t o P T C L, as well as t o descri be 
ne w a ge nts t hat ha ve p ote ntial acti vit y a gai nst a variet y of t hese diseases. 1 3, 1 4  First-li ne 
treat me nt of patie nts wit h P T C L ge nerall y co nsists of c o m bi nati o n c he m ot hera p y, pri maril y 
wit h 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), b ut res p o nse is 
ac hie ve d i n a p pr o xi matel y half t he patie nts a n d is ge nerall y of s h ort d urati o n. 1 2 , 1 6  T he 
me dia n s ur vi val f or P T C L, i ncl u di n g all s u bt y pes, is 1- 3 years.
1,  1 7 ,1 5  Fi g ure 2. 2 dis pla ys t he 
O S of P T C L, as well as t hat f or prec urs or  T-l y m p h o blastic l y m p h oma a n d t he B-cell N H L 
wit h t he l o west O S, ma ntle cell.  I n a st u d y e val uati n g 4 differe nt c he m ot hera p y re gi me ns i n 
2 8 8 patie nts wit h P T C L a n d 1 5 9 5 patie nts wit h B-cell l y m p h o ma, t he 5- year e ve nt-free 
s ur vi val rate was 3 2 % f or P T C L patie nts. 1 0  F or t he m ost c o m m o n hist ol o gic s u bt y pe of 
P T C L, P T C L- u ns pecifie d ( P T C L- U), w hic h c o m pri se a p pr o xi matel y 3 4 % of all cases see n i n 
N ort h A merica, t he 5- year fail u re-free s ur vi val ( F F S) is 2 0 %.1 8  
Fi g ur e 2. 2.  O v er all S ur v i v al b y Hi st ol o gi c T y p e1 
 
T- L B = prec urs or T-l y m p h o blastic l y m p h o ma 
P T C L = peri p heral T-cell l y m p h o ma 
M C = ma ntle cell 
O utc o me data f or patie nts wit h T-cell l y m p h o ma w h o recei ve first-li ne C H O P are li mite d.  
A retr os pecti ve st u d y of t he I nte r nati o nal T- Cell L ym p h o ma Pr oject de m o nstrate d a 5- year 
O S rate of 3 2 % a n d a 5- year F F S rate of 2 0 % f or patie nts wit h P T C L- U, wit h wi del y var yi n g 
res ults f or ot her s u bt y pes, m ost of w h o m recei ve d a n a nt hrac ycli ne-c o ntai ni n g re gi me n.1 8  I n 
a retr os pecti ve e val uati o n of 9 6 patie nts di a g n ose d wit hi n t he No n- H o d g ki n’s L y m p h o ma 
Classificati o n Pr oject, R u di ger et  al re p ort a si milar fi n di n g, wit h 5- year O S a n d F F S rates of 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 2 9 of 9 5 
2 6 % a n d 2 0 %, res pecti vel y, f or P T C L pa tie nts treate d wit h a d o x or u bici n-c o ntai ni n g 
re gi me n.1 2  T he esti mate d me dia n F F S i n t hese patie nts is a p pr o xi matel y 6 m o nt hs. 
T he first-li ne res p o nse rates t o a nt hrac ycli ne-c o ntai ni n g re gi me ns, i ncl u di n g C H O P 
c he m ot hera p y, f or patie nts wit h P T C L ha ve b ee n re p orte d t o ra n ge bet wee n 5 0 % a n d 7 0 %, 
yet t he l o n g-ter m s ur vi val of t hese patie nts re mai ns dis mal.1 8  A variet y of ot her 
a nt hrac ycli ne- base d c o m bi nati o n t hera pies ha ve als o s h o w n acti vit y, i ncl u di n g i nf usi o nal 
treat me nt pr o gra ms, s uc h as C H O P pl us et o p osi de.1 9  N o n-al k ylat or base d treat me nt 
pr o gra ms e x pl oiti n g n ucle osi de a nal o gs li ke de o x yc of or m yci n, fl u dara bi ne, ge mcita bi ne, a n d 
cla dri bi ne, as well as m o n ocl o nal a nti b o di es/i m m u n ot o xi ns, a n d hi g h- d ose c he m ot hera p y 
f oll o we d b y peri p heral bl o o d ste m cell tra ns pla nt ( P B S C T) ha ve als o bee n use d i n patie nts 
wit h T-cell l y m p h o mas wit h var yi n g de grees of s uccess. 2 0  W hile earl y data s u g gest t hat 
t hese strate gies ma y be m ore effecti ve at i n d uci n g mea ni n gf ul d ura ble C Rs, ma n y patie nts 
ne ver ac hie ve t he re missi o ns necessar y t o ma ke  P B S C T feasi ble a n d t here are n o ra n d o mize d 
data a vaila ble t hat all o w a deter mi nati o n t hat P B S C T is s u peri or t o ot her f or ms of u p-fr o nt 
c o n ve nti o nal c o m bi nati o n c he m ot hera p y pr o gra ms. 2 1 
T he esse ntial t hera pe utic g oal wit h t his P T C L patie nt p o p ulati o n is t o c o ntr ol disease 
pr o gressi o n i n or der t o pr ol o n g t he cli nical be nefit ac hie ve d fr o m i nte nsi ve c he m ot hera p y 
re gi me ns s uc h as C H O P a n d C H O P- base d t hera p y a n d s o e xte n d s ur vi val. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 3 0 of 9 5 
3 
P R A L A T R E X A T E 
3. 1 
P h y si c al, C h e mi c al, P h ar m a c e uti c al Pr o p erti e s 
Na me of Dr u g Pr o d uct 
Pralatre xate I njecti o n ( Pralatre xate S ol uti o n f or I nf usi o n 
i n t he E ur o pea n U ni o n [ E U]) 
Na me of Acti ve P har ma ce utical 
I n gre die nt 
Pralatre xate 
U nite d States A d o pte d Na me 
( U S A N) C o u ncil C he mical Na me
( 2S )- 2-[[ 4-[( 1R S )- 1-[( 2, 4- dia mi n o pteri di n- 6- yl) 
met h yl] b ut- 3- y n yl] be nz o yl ]a mi n o] pe nta ne di oic aci d 
Ot her C he mical Na mes 
(R S )- 1 0- pr o par g yl- 1 0- deazaa mi n o pteri n 
I nter nati o nal n o n pr o prietar y na me (I N N) C he mical 
Na me: N - { 4-[ 1-( 2, 4- dia mi n o pteri di n- 6- yl) pe nt- 4- y n- 2-
yl] be nz o yl }- L - gl uta mic aci d  
C he mical A bstracts Ser vi ce ( C A S) Na me: L- gl uta mic 
aci d, N-[ 4-[ 1-[( 2, 4- dia mi n o- 6- pteri di n yl) met h yl]- 3-
b ut y n- 1- yl] be nz o yl] 
U S A N a n d I N N N o n pr o prietar y 
Na me 
Pralatre xate 
Tra de Na me 
F O L O T Y N ®  
P har mac ol o gical Class 
A nti ne o plastic a ge nt/a nti meta b olite/f olic aci d a nal o g 
( A nat o mical T hera pe utic C he mical [ A T C] c o de L 0 1 
B A 0 5) 
E m pirical F or m ula 
C 2 3H 2 3N 7O 5 
M olec ular Wei g ht 
4 7 7. 5 
C he mistr y A bstract Re gistr y 
N u m ber 
1 4 6 4 6 4- 9 5- 1 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 3 1 of 9 5 
Str uct ural F or m ula 
N
N
N
N
N
H
C O 2 H
H
N H 2
H 2 N
O
H
*
a n d e pi m er at C *
C O 2 H
C H
 
F or detaile d i nf or mati o n a b o ut t he ge nera l p har mac ol o g y, p har mac o ki netics ( P K), a n d 
n o ncli nical t o xic ol o g y a n d efficac y st u dies of pralatre xate, refer t o t he c urre nt pralatre xate 
I n vesti gat or’s Br oc h ure (I B) su p plie d b y All os.  T his d oc u me nt m ust be re vie we d pri or t o 
i nitiati n g t he st u d y. 
3. 2 
N o n cli ni c al St u di e s wit h Pr al atr e x at e 
3. 2. 1 
N o n cli ni c al P h ar m a c ol o g y 
Pralatre xate, a met h otre xate a nal o g, was i nitia ll y de vel o pe d b y Me m orial Sl oa n- Ketteri n g 
Ca ncer Ce nter ( M S K C C) i n c olla b orati o n wit h  S o ut her n Researc h I nstit ute ( S RI) a n d 
Sta nf or d Researc h I nstit ute I nter nati o nal ( S RI I nter nati o nal).  Pralatre xate is a s y nt hetic 
1 0- deazaa mi n o pteri n a ntif olate.  T he 1 0- deazaa mi n o pteri ns are a class of rati o nall y desi g ne d 
a ntif olates de m o nstrati n g greater a ntit u m or e ffects t ha n met h otre xate i n i n vitr o t u m or 
m o dels a n d h u ma n t u m or xe n o grafts i n mice. 2 2- 2 4 
Pralatre xate is a f olate a nal o g meta b olic i n hi bit or t hat c o m petiti vel y i n hi bits t he e nz y me 
di h y dr of olate re d uctase ( D H F R).  I n i n vitr o st u dies, pralatre xate s h o we d i m pr o ve d c yt ot o xic 
acti vit y a gai nst a pa nel of ca ncer cell li nes c o m pare d wit h met h otre xate.  T he i m pr o ve d 
c yt ot o xic acti vit y is li kel y d ue t o pralatre xate  bei n g a m ore efficie nt per mea nt f or re d uce d 
f olate tra ns p ort a n d it bei n g m ore efficie ntl y p ol y gl uta m ylate d b y t he e nz y me 
f ol yl p ol y gl uta m yl sy nt hetase ( F P G S). 2 3,  2 5  Si milar t o w hat has bee n re p orte d f or 
met h otre xate, cell ular u pta ke of pralatre xate  is t h o u g ht t o occ ur via t he re d uce d f olate 
carrier- 1 ( R F C- 1) me m bra ne pr otei n.  T his pr otei n has e v ol ve d t o efficie ntl y tra ns p ort 
re d uce d nat ural f olates i nt o hi g hly pr oliferati ve cells, i n or der t o meet t he de ma n ds f or p uri ne 
a n d p yri mi di ne n ucle oti des d uri n g cell re plica ti o n.  I nsi de t he cell, pralatre xate is 
p ol y gl uta m ylate d b y F P G S, a n e nz y me i n v ol ve d i n p ol y gl uta m ylati o n of re d uce d nat ural 
f olates.  T heref ore, pralatre xate ma y act as a c o m petiti ve i n hi bit or f o r p ol y gl uta m ylati o n of 
nat ural f olates.  F urt her, it is belie ve d t hat t h e a d diti o n of gl uta mate resi d ues t o pralatre xate 
lea ds t o i ncrease d i ntracell ular half-life, t h us all o wi n g f or pr ol o n ge d dr u g acti o n i n mali g na nt 
cells.  T he relati ve i ncrease i n cell ular u pta ke a n d differe nces i n p ol y gl uta mate f or mati o n i n 
n or mal vers us mali g na nt cells ma y acc o u nt f or t h e e n ha nce d acti vit y of pralatre xate.     
Pralatre xate de m o nstrate d a 1 0-f ol d greater  rate of p ol y gl uta m ylati o n b y F P G S t ha n 
met h otre xate ( Ta ble 3. 1 ).  I n a c yt ot o xicit y assa y usi n g a n u m ber of h u ma n n o n-s mall cell 
l u n g ca ncer ( N S C L C) a n d breast ca ncer cell li nes, pralatre xate was f o u n d t o be s u peri or t o 
b ot h met h otre xate ( 1 3- t o 4 0-f ol d l o wer I C 5 0 [ half ma xi m u m i n hi bit or y c o nce ntrati o n]) a n d 
a n ot her met h otre xate a nal o g, e dat re xate ( 2- t o 4-f ol d l o wer I C5 0). 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 3 2 of 9 5 
T a bl e 3. 1.  
I n Vitr o C o m p ar i s o n of M et h otr e x at e A n al o g s 
 
Pr al atre x ate  
E d atre x ate  
Met h otre x ate  
D H F R I n hi biti o n, K i ( p M) 
1 3. 4 
5. 8 
4. 9 
F P G S Acti vit y, V ma x / Km  
2 3. 2 
1 0. 3 
2. 2 
I n vitr o Acti vit y 
I C5 0 C o nce ntrati o n (μ M): 
 
 
 
  M D A- 4 6 8 ( breast) 
0. 1 1 
0. 3 9 
4. 5 
  S K- B R III ( breast) 
0. 2 8 
0. 9 9 
4. 2 
  Z R- 7 5- 1 ( breast) 
0. 2 6 
0. 8 6 
3. 5 
  S K- L C 8 ( N S C L C) 
0. 4 2 
1. 2 4 
1 0. 3 
  S K- L C 1 6 ( N S C L C) 
0. 1 1 
0. 2 6 
2. 1 
D H F R = di h y dr of olate re d uctase; K i = i n hi biti o n c o nsta nt; p M = pic o m olar; F P G S = f ol yl p ol y gl uta m yl 
s y nt hetase; V ma x  = ma xi m u m rate c o nsta nt; Km  = bi n di n g c o nsta nt; I C5 0 = half ma xi m u m i n hi bit or y 
c o nce ntrati o n; μ M = micr o m olar; N S C L C = n o n-s mall cell l u n g ca ncer
 
Scree ni n g of pralatre xate i n t he Nati o nal Ca ncer I nstit ute ( N CI) 6 0- Cell Scree n s u g gest 
p ote nt c yt ot o xic acti vit y acr oss a br oa d s pect r u m of t u m or t y pes, i ncl u di n g le u ke mia, 
N S C L C, c ol o n ca ncer, ce ntral ner v o us s yste m  ca ncer, mela n o ma, o varia n ca ncer, re nal 
ca ncer, a n d breast ca ncer. 
Pralatre xate was e val uate d f o r gr o wt h i n hi bit or y acti vit y a gai nst h u ma n t u m or cell li nes 
re prese nti n g hea d a n d nec k ca ncer ( H LaC), breast ca ncer ( M D A- M B- 2 3 1, M D A- M B- 4 3 5), 
a n d N S C L C ( A 5 4 9, M V 5 2 2).  U n der t he e x peri me nt al c o n diti o ns, pralatre xate, teste d as a 
si n gle a ge nt, was m ost acti ve i n t he M V 5 2 2 l u n g a n d M D A- M B - 2 3 1 breast cell li nes wit h 
I C5 0 val ues of 1 2. 8 n M ( M V 5 2 2) a n d 1 8. 0 n M ( M D A-M B- 2 3 1).  C yt ot o xicit y of pralatre xate 
was c o m par a ble i n H La C a n d M D A- M B- 4 3 5 wit h I C 5 0 val ues of 2 5. 8 n M a n d 2 4. 1 n M.  T he 
A 5 4 9 l u n g a de n ocarci n o ma li ne was l east se nsiti ve t o pralatre xate (I C 5 0 = 6 5. 1 n M).  I n a 
hea d-t o- hea d c o m paris o n wit h c o n ve nti o nal t her a pe utics, pralatre xate was m ore c yt ot o xic 
t ha n cis plati n i n e ver y ca ncer cell li ne teste d a n d s u peri or t o  paclita xel i n t he M D A- M B- 2 3 1 
breast a n d b ot h l u n g li nes.  Pral atre xate als o de m o nstrate d s u pe ri or acti vit y vers us d oceta xel 
i n t he M V 5 2 2 l u n g li ne.   
O verall, t he N CI- 6 0 cell li ne res ults, as well as i n vitr o testi n g i n a d diti o nal h u ma n t u m or cell 
t y pes, i n dicates t hat pralatre xate e x hi bits si g nifica nt c yt ot o xic acti vit y acr oss a n u m ber of 
s oli d a n d l y m p h o pr oliferati ve t u m or t y pes. 
3. 2. 1. 1 
X e n o gr aft St u di e s i n L y m p h o m a M o d el s 
Beca use met h otre xate is acti ve i n t he trea t me nt of a g gressi ve N H L, t he efficac y of 
pralatre xate a n d met h otre xate were c o m parati vel y e val uate d a gai nst 5 l y m p h o ma cell li nes: 
R L (tra nsf or me d f ollic ular l y m p h o ma), H T, S K I- D L B C L- 1 ( diff use lar ge B-cell l y m p h o ma), 
Raji ( B ur kitt’s), a n d Hs 4 4 5 ( H o d g ki n’s disease).  After 5 da ys  of c o nti n u o us i n vitr o 
e x p os ure, pralatre xate de m o nstrat e d 8- t o 2 0-f ol d gr eater c yt ot o xicit y t h a n met h otre xate i n 
all cell li nes (Ta ble 3. 2 ). 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 3 3 of 9 5 
T a bl e 3. 2.  
C o m p ari s o n of Gr o wt h  I n hi biti o n b y Pr al atr e x at e a n d 
M et h otr e x at e A g ai n st H u m a n L y m p h o m a C ell Li n e s 
Cell li ne  
L y m p h o m a t y pe 
I C5 0 Pr al atre x ate 
( n M) 
I C5 0 Met h otre x ate 
( n M) 
P  v al ue 
Hs 4 4 5 
H o d g ki n’s disease  
1. 6 ± 0. 8 
3 2 ± 2. 2  
0. 0 4 5 5 
H T 
Diff use lar ge B-cell  
3. 0 ± 0. 4 
3 5 ± 5. 0  
0. 0 2 3 6 
Raji 
B ur kitt’s 
2. 0 ± 0. 3 
1 6 ± 0. 8  
0. 0 0 3 4 
R L 
Tra nsf or me d f ollic ular  
2 3 ± 2. 0 
2 1 0 ± 4 0  
0. 0 4 2 9 
S KI- D L B C L- 1  
Diff use lar ge B-cell  
5. 1 ± 0. 1 
4 8 ± 2. 5  
0. 0 0 3 5 
I C5 0 = half ma xi m u m i n hi bit or y c o nce ntrati o n, n M = na n o m olar 
Ne xt, pralatre xate a n d met h otre xate were e val uate d i n t u m or xe n o graft m o dels of 3 h u ma n 
N H L cell li nes.  T u m or- beari n g n o n- o bese, dia betic/se vere c o m bi ne d i m m u n o deficie nt 
( N O D/ S CI D) mice were treate d wit h sali ne (co ntr ol) or t he ma xi m u m t olerate d d oses 
( M T Ds) of met h otre xate ( 4 0 m g/ k g) or pralatre xate ( 6 0 m g/k g) via a n i ntra perit o neal (I P) 
r o ute t wice wee kl y f or 2 wee ks.  Al m ost 9 0 % of H T l y m p h o mas treate d  wit h pralatre xate 
c o m pletel y re gresse d, w hereas t h ose treate d w it h met h otre xate s h o we d o nl y m o dest gr o wt h 
dela ys ( Ta ble 3. 3). 
T a bl e 3. 3.  
Tr e at m e nt of H u m a n H T ( D iff u s e L ar g e B C ell) N o n- H o d g ki n' s 
L y m p h o m a X e n o gr aft s i n N O D/ S CI D Mi c e 
A ge nt 
D ose 
( m g/ k g) 
Wei g ht
c h a n ge
( %) 
T u m or 
di a meter 
( m m ± S E) 
T u m or 
v ol u me 
( m m3 ± S E) 
A ver a ge t u m or 
re gressi o n ( %) 
C o m plete 
re gressi o ns 
( n o./t ot al) 
C o ntr ol  
—  
+ 1 3. 3  
1 1. 2 ± 1. 3  
+ 6 4 1 ± 2 5 2  
— 
0/ 8 
Met h otre xate  
4 0  
- 9. 8  
8. 7 ± 2. 0  
+ 3 0 0 ± 2 2 5  
— 
0/ 7 
Pralatre xate  
6 0  
- 8. 9  
0. 5 ± 0. 3  
- 9 5 ± 0. 8  
9 9 
8/ 9 
N O D/ S CI D = n o n- o bese, dia betic/se vere c o m bi ne d i m m u n o deficie nt; m g = milli gra m; k g = kil o gra m; 
m m = milli meter; n o. = n u m ber; S E = sta n dar d err or  
I n 2 ot her m o dels, c o m plete t u m or re gressi o n rates of 5 6 % ( R L, Ta ble 3. 4 ) a n d 
3 0 % ( S KI- D L B C L- 1, Ta ble 3. 5 ) were o bser ve d after pralatre xate treat me nt.  N o t u m or 
re gressi o ns a n d o nl y mi n or gr o wt h i n hi biti o n was n ote d i n t he met h otre xate-treate d a ni mals. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 3 4 of 9 5 
T a bl e 3. 4.  
Tr e at m e nt of H u m a n R L ( T r a n sf or m e d F olli c ul ar) N o n- H o d g ki n' s 
L y m p h o m a X e n o gr aft s i n N O D/ S CI D Mi c e 
A ge nt 
D ose 
( m g/ k g) 
Wei g ht 
c h a n ge 
( %) 
T u m or di a meter
( m m ± S E) 
C h a n ge i n 
t u m or v ol u me
( m m3 ± S E) 
T u m or 
re gressi o n 
( %) 
C o m plete 
re gressi o ns 
( n o./t ot al) 
C o ntr ol  
—  
+ 1 5. 9  
1 2. 5 ± 1. 3  
+ 1 2 2 8 ± 2 3 8  
— 
0/ 7 
Met h otre xate  
4 0  
- 1 4. 8  
1 0. 9 ± 0. 5  
+ 6 1 8 ± 1 0 8  
— 
0/ 1 2 
Pralatre xate  
6 0  
- 1 1. 1  
2. 7 ± 1. 1  
- 4 6 ± 3 4  
5 7 
5/ 9 
N O D/ S CI D = n o n- o bese, dia betic/se vere c o m bi ne d i m m u n o deficie nt; m g = milli gra m; k g = kil o gra m; 
n o. = n u m ber; S E = sta n dar d err or  
T a bl e 3. 5.  
Tr e at m e nt of H u m a n S KI- D L B C L- 1 ( D e N o v o Diff u s e L ar g e B- C ell) 
N o n- H o d g ki n' s L y m p h o m a X e n o gr aft s i n N O D/ S CI D Mi c e 
A ge nt 
D ose 
( m g/ k g) 
Wei g ht 
c h a n ge 
( %) 
T u m or di a meter  
( m m ± S E) 
C h a n ge i n 
t u m or v ol u me
( m m3 ± S E) 
T u m or 
re gressi o n 
( %) 
C o m plete 
re gressi o ns 
( n o./t ot al) 
C o ntr ol  
—  
+ 4. 9  
1 2 ± 0. 3  
+ 7 8 6 ± 6 4 6  
—  
0/ 8 
Met h otre xate  
4 0  
+ 1. 9  
9. 5 ± 0. 4  
+ 2 9 9 ± 5 8  
—  
0/ 1 0 
Pralatre xate  
6 0  
- 1. 2  
3. 5 ± 0. 7  
- 8 1 ± 1 6 
5 4  
3/ 1 0 
N O D/ S CI D = n o n- o bese, dia betic/se vere c o m bi ne d i m m u n o deficie nt; m g = milli gra m; k g = kil o gra m; 
n o. = n u m ber; S E = sta n dar d err or  
T hese res ults de m o nstrate t hat pralatre xate has t he p ote ntial t o e x hi bit greater acti vit y a gai nst 
h u ma n N H L t ha n met h otre xate. 
A ntif olates a n d c yti di ne a nal o gs ha ve ha d a r ole i n t he treat me nt of ma n y ki n ds of 
l y m p h o pr oliferati ve mali g na ncies.  Met h otre xate is k n o w n t o s y ner gize wit h c ytara bi ne i n a 
sc he d ule- de pe n de nt ma n ner.  T he c o m bi nati o n of pralatre xate a n d t he c yti di ne a nal o g 
ge mcita bi ne ( 2’, 2’- difl u or o de oz yc yti di ne) wa s st u die d.  T he acti vit y of t he sta n dar d 
c o m bi nati o n of met h otre xate/c ytara bi ne was c o m p are d wit h t hat of pralatre xate/ ge mcita bi ne. 
A xe n o graft e x peri me nt i n t he S KI- D L B C L- 1 m o del was c o n d ucte d at o ne- q uarter of t he 
M T D of pralatre xate a n d ge mcita bi ne ( 1 5 m g/ k g eac h).  A si milar d ose re d ucti o n f or 
met h otre xate a n d c ytara bi ne was n ot perf or me d gi ve n t he lac k of acti vit y see n at t he M T D i n 
a n e x pl orat or y st u d y.  C o ntr ol gr o u ps ha d t o be  e ut ha nize d earl y d ue t o e xcessi ve t u m or 
gr o wt h, as di d a ni mals recei vi n g met h otre xate ( 6 0 m g/ k g) al o ne, c ytara bi ne ( 3 0 0 m g/ k g) 
al o ne, or b ot h dr u gs i n c o m bi na ti o n.  I n c o ntrast, treat me nt wit h pralatre xate, ge mcita bi ne, or 
c o m bi nati o ns of t hese 2 at 2 5 % of t he M T D was mar ke dl y m ore efficaci o us.  C o m plete 
t u m or re gressi o ns were o nl y o bser ve d i n t h ose a ni mals recei vi n g pralatre xate f oll o we d b y 
ge mcita bi ne ( Fi g ure 3. 1 ).  T hese i n vi v o e x peri me nts clearl y esta blis h a mar ke d s u peri orit y 
of pralatre xate a n d ge mcita bi ne w he n gi ve n i n  a se q ue ntial fas hi o n.  T hese res ults raise t he 
p ossi bilit y t hat pralatre xate, wit h or wit h o ut t he sc he d ule d a d mi nistrati o n of ge m cita bi ne, 
ma y pr o vi de a ne w treat me nt m o dalit y f or select l y m p h o pr oliferati ve mali g na ncies. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 3 5 of 9 5 
Fi g ur e 3. 1.  I n Vi v o S CI D B ei g e X e n o gr aft M o d el of S KI- D L B C L- 1 
 
 
S CI D = se vere c o m bi ne d i m m u n o deficie nt; M T X = met h otre xate; Ara- C = c ytara bi ne; P D X or P = pralatre xate; 
Ge m or G = ge mcita bi ne; C R = c o m plete re missi o n/res p o nse 
 
3. 2. 2 
N o n cli ni c al T o xi c ol o g y 
A c o m pre he nsi ve ac ute a n d s u bac ute t o xic ol o g y e val uati o n pr o gra m has bee n perf or me d t o 
g o o d la b orat or y practices ( G L P) c o m plia nce a n d per I nter nati o nal C o nfere nce o n 
Har m o nisati o n (I C H) g ui da nce t o e m ulate t he r o ute, d ose, a n d sc he d ul e of pralatre xate 
a d mi nistrati o n use d i n cli nical de vel o p me nt,  i ncl u di n g: car di o vasc ular a n d ne ur ol o gical 
safet y assess me nts; si n gle a n d re peat- d ose t o xic olo g y st u dies i n rats a n d d o gs; i n vitr o a n d i n 
vi v o ge n ot o xicit y st u dies t o deter mi ne m uta ge nic p ote ntial of pralatre xate; e m br y ofetal 
de vel o p me nt a n d mater nal t o xicit y st u dies i n rats; a n d l ocal t olera nce st u dies i n rats.  
Pralatre xate di d n ot s h o w e vi d e nce of car di o vasc ular or ne ur ol o gic t o xicit y.  T o xic ol o gical 
assess me nts i n rats a n d d o gs re veale d t he a ntici pate d d ose-li miti n g t o xicities ( D L Ts) of t he 
gastr oi ntesti nal a n d he mat ol o gical s yste ms.  Pralatre xate was f o u n d t o ha ve l o w m uta ge nic 
p ote ntial i n a pa nel of ge n ot o xi cit y assa ys.  Si milar t o ot he r a ntif olates, pralatre xate was 
f o u n d t o be t o xic t o de vel o pi n g e m br y os i n e mbr y ofetal de vel o p me nt st u dies i n rats a n d 
ra b bits.  Pralatre xate was n ot t o xic i n l ocal t olera nce st u dies i n rats.  Refer t o t he pralatre xate 
I B f or f urt her i nf or mati o n o n n o ncli nical t o xic ol o g y st u dies c o n d ucte d wit h pralatre xate. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 3 6 of 9 5 
4 
O N C O L O G Y S T U DI E S WI T H P R A L A T R E X A T E 
O ver 6 0 0 a d ult ca ncer patie nts ha ve recei ve d pralatre xate i n 1 5 o n g oi n g or c o m plete d 
P hase 1 or 2 cli nical o nc ol o g y st u dies.   
F or detaile d i nf or mati o n a b o ut t he o nc ol o g y st u d ies of pralatre xate, refer t o t he c urre nt 
pralatre xate I B. 
4. 1 
St u di e s i n P ati e nt s wit h L y m p h o pr olif er ati v e M ali g n a n ci e s  
4. 1. 1 
Si n gl e- A g e nt St u di e s 
St u d y P D X- 0 2- 0 7 8 is a P hase 1/ 2 st u d y i n patie nts wit h rela pse d or refract or y a g gressi ve 
N H L or H o d g ki n’s disease.  After i nitial assess me nt of a n e ver y ot her wee k sc he d ule, a 
wee kl y sc he d ule wit h vita mi n B 1 2 a n d f olic aci d s u p ple me ntati o n was i nitiate d.  I n t he i nitial 
versi o n of t he st u d y, t h e starti n g d ose of pral atre xate was 1 3 5 m g/ m 2 a d mi nistere d e ver y 
ot her wee k wit h i ntra patie nt d ose escalati o n.  W he n D L Ts occ urre d at t he d ose of 4 5 m g/ m2  
f or 6 wee ks of a 7- wee k c ycle, t he M T D was deter mi ne d t o be 3 0 m g/ m2/ wee k f or 6 wee ks 
o n a 7- wee k c ycle.   
Data fr o m P D X- 0 2- 0 7 8, were p u blis he d o n 4 8 pa tie nts e val ua ble f or res p o nse i n t he st u d y.2 6  
Res p o nses were o bser ve d i n 1 5 of 4 8 e val ua ble patie nts, f or a n o verall res p o nse rate ( O R R) 
of 3 1 %.  F o urtee n of 2 6 ( 5 4 %) e val ua ble patie nts wit h T-cell l y m p h o ma res p o n de d t o 
pralatre xate treat me nt ( 8 wit h C Rs a n d 6 wit h partial res p o nses [ P Rs]).  A m o n g t he 
2 0 e val ua ble patie nts wit h B-cell l y m p h o ma, 1 patie nt ac hie ve d a P R. 
D ue i n part t o t he res p o nses see n i n t he P D X 0 2- 0 7 8 st u d y, it was deci de d t o e x pl ore 
pralatre xate as a si n gle a ge n t i n rela pse d/refract or y P T C L i n st u d y P D X- 0 0 8.  P D X- 0 0 8 is a 
P hase 2, si n gle-ar m, n o n-ra n d o mize d, o pe n-la bel,  i nter nati o nal, m ulti-ce nter, re gistrati o n-
directe d st u d y desi g ne d t o e val uate t he safet y a n d efficac y of pralatre xate w he n a d mi nistere d 
c o nc urre ntl y wit h vita mi n B 1 2 a n d f olic aci d s u p ple me ntati o n t o patie nts wit h rela pse d or 
refract or y P T C L.  T he st u d y c o m plete d e nr oll ment of 1 1 5 patie nts i n A pr 2 0 0 8; 1 1 1 patie nts 
recei ve d at least 1 d ose of pralatre xate a n d were c o nsi d ere d e val ua ble f or safet y.  
T he o bjecti ves of t he st u d y were t o deter m i ne t he efficac y, safet y, a n d P K pr ofile of 
pralatre xate wit h c o nc urre nt vita mi n B 1 2 a n d f olic aci d s u p ple me ntati o n w he n a d mi nistere d 
t o patie nts wit h rela pse d or refract or y P T C L.  T he pri mar y efficac y e n d p oi nt of t he st u d y was 
res p o nse rate a n d sec o n dar y efficac y e n d p oi nts were d urati o n of res p o nse, P F S, a n d O S.  
Data fr o m P D X- 0 0 8 were prese nte d i n t he cli n ical st u d y re p ort, w hic h was s u b mitte d i n Ne w 
Dr u g A p plicati o n ( N D A) t o t he U S F D A.  I n Se p 2 0 0 9, t he F D A gra nte d accelerate d 
a p pr o val f or pralatre xate i n t he treat me nt of patie nts wit h rela pse d or refract or y P T C L.  
Pralatre xate is mar kete d  i n t he U S as F O L O T Y N®  ( Pralatre xate I njecti on) at a c o nce ntrati o n 
of 2 0 m g/ m L f or use i n t his patie nt p o p ulati o n. 
I n P D X- 0 0 8, pralatre xate was a d ministere d at a d ose of 3 0 m g/ m 2/ wee k f or 6 wee ks i n a 
7- wee k c ycle.  T he pr ot oc ol al l o we d f or d ose re d ucti o n t o 2 0 m g/ m2/ wee k if a patie nt 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 3 7 of 9 5 
e x perie nce d pr ot oc ol- defi ne d a d verse e ve nts ( A Es).  A patie nt was c o nsi dere d e val ua ble if 
he/s he recei ve d at least 1 d ose of pralatre xate a n d met t he maj or i ncl usi o n criteri o n 
# 1, ie, t he dia g n osis of eli gi ble P T C L hist o pat h ol o gical s u bt y pe c o nfir me d b y ce ntral 
pat h ol o g y re vie w.  I n t he P D X- 0 0 8 st u d y, 1 0 9 pa tie nts were c o nsi dere d e val ua ble f or 
efficac y.  T we nt y- ni ne perce nt ( n  = 3 2) of e val ua ble patie nts e x perie nce d eit her a C R, a n 
u nc o nfir me d C R ( C R u), or a P R, as assesse d b y ce ntral i n de pe n de nt o nc ol o g y re vie w.  
T hirt y- ni ne perce nt of patie nts ( n = 4 3) e x perie nce d eit her a C R/ C R u or P R, as assesse d b y 
t he st u d y i n vesti gat ors.2 7  T he res p o nses o bser ve d were d ura ble as assesse d b y i n de pe n de nt 
ce ntral re vie w, wit h a me dia n d urati o n of 1 0. 1 m o nt hs a n d a Ka pla n- Meier esti mate of 
6 0 % f or t he pr o ba bilit y of ac hie vi n g a d urati o n of res p o nse ≥ 6 m o nt hs.  T he me dia n P F S 
a n d O S f or t he 1 0 9 patie nts as esti mate d b y t he Ka pla n- Meier met h o d were 3. 5 m o nt hs 
(ra n ge 1 da y - 2 3. 9 m o nt hs) a n d 1 4. 5 m o nt hs (ra n ge 1. 0- 2 4. 1 m o nt hs), res pecti vel y. 
St u d y P D X- 0 1 0 is a P hase 1, o pe n-la bel, m ulti- ce nter st u d y desi g ne d t o deter mi ne a n 
effecti ve a n d well-t olerate d d ose a n d sc he d ule of pralatre xate as a si n gle a ge nt w he n 
a d mi nistere d c o nc urre ntl y wit h vita mi n B 1 2 a n d f olic aci d s u p ple me ntati o n t o patie nts wit h 
rela pse d or refract or y c uta ne o us T-cell l y m p h oma ( C T C L).  F oll o wi n g preli mi nar y re vie w of 
safet y a n d res p o nse data fr o m t he d osin g re gi me ns e x pl ore d t h us far, 1 5 m g/ m 2 f or 3/ 4 wee ks 
was deter mi ne d t o be t he d ose utilize d i n t he d ose e x pa nsi o n p hase of  t he st u d y, i n w hic h a n 
a d diti o nal 2 0 patie nts will be e val uate d.    
I nteri m efficac y data were prese nte d at t he 1 5t h C o n gress of t he E ur o pea n He mat ol o g y 
Ass ociati o n o n t he P D X- 0 1 0 st u d y i n patie nts wit h C T C L. 2 8  I n vesti gat or-assesse d res p o nses 
were o bser ve d i n 1 9 of 4 7 e val ua ble patie nts ( 4 0 %), i ncl u di n g 2 C Rs a n d 1 7 P Rs.  Fi nal 
efficac y data will be a nal yze d at t he c o m pleti o n of t he st u d y. 
St u d y P D X- 0 1 5 is a P hase 2, si n gle-ar m, n o n -ra n d o mize d, o pe n-la bel, m ulti-ce nter st u d y 
desi g ne d t o e val uate t he efficac y a n d safet y/t ole ra bilit y of pralatre xate w he n a d mi nistere d 
c o nc urre ntl y wit h vita mi n B 1 2 a n d f olic aci d s u p ple me ntati o n t o patie nts wit h rela pse d or 
refract or y B-cell N H L. T his st u d y is o n g oi n g a n d n o data are c urre ntl y a vaila ble. 
4. 1. 2 
C o m bi n ati o n St u di e s 
Pralatre xate is bei n g st u die d as c o m b i nati o n treat me nt wit h ge mcita bi ne i n 
rela pse d/refract or y l y m p h o pr oliferati ve mali g na ncies ( P D X- 0 0 9).  St u d y P D X- 0 0 9 is a 
P hase 1/ 2a, o pe n-la bel, m ulti-ce nter st u d y of pr alatre xate a n d ge mcita bi ne a d mi nistere d o n 
se q ue ntial da ys, or t he sa me da y de pe n di n g o n c o h ort, wit h vita mi n B 1 2 a n d f olic aci d 
s u p ple me ntati o n t o patie nts wit h rela pse d or refract or y l y m p h o pr oliferati ve mali g na ncies.  
T he P hase 1 p orti o n of t he st u d y was n o nra n d o mize d, w hile t he P hase 2 p orti o n is 
ra n d o mize d bet wee n sa me da y d osi n g or se q ue ntial da y d osi n g.  T he o bjecti ves of t he st u d y 
are: 1) t o deter mi ne t he M T D a n d rec o m me n de d P hase 2 d ose of t he c o m bi nati o n of 
pralatre xate a n d ge mcita bi ne ( P hase  1); 2) t o e val uate t he safet y a n d t olera bilit y of escalati n g 
d oses of pralatre xate a n d ge mcita bi ne ( P hase 1); 3) t o deter mi ne t h e P K pr ofile of t he 
c o m bi nati o n of pralatre xate a n d ge mcita bi ne ( P ha se 1 a n d 2a); a n d 4) t o c o nfir m t olera bilit y 
a n d assess preli mi nar y efficac y i n patie nts wit h  rela pse d or refract or y H o d g ki n’s l y m p h o ma, 
P T C L, a n d B-cell l y m p h o ma ( P hase 2a). 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 3 8 of 9 5 
I nteri m efficac y data were prese nte d i n a p oster prese ntati o n at t he 5 1st A n n ual A merica n 
S ociet y of He mat ol o g y Meeti n g o n t he 3 3 patie nts  e nr olle d i n t his st u d y w h o were e val ua ble 
f or res p o nse.2 9  F o ur of 7 patie nts wit h H o d g ki n’s l y m p h o ma, 2 of 1 1 patie nts wit h P T C L, 
a n d 2 of 1 5 patie nts wit h diff use lar ge B-cel l l y m p h o ma ( 1 of w h o m als o ha d P T C L) 
ac hie ve d a P R.  Fi nal efficac y data will be a nal yze d at t he c o m pleti o n of t he st u d y. 
4. 2 
St u di e s i n P ati e nt s wit h S oli d T u m or s  
4. 2. 1 
All o s Si n gl e- a g e nt St u di e s 
I n t he P hase 1 st u d y, P D X- 0 0 7, i n vesti gati n g pralatre xate as a si n gle a ge nt wit h vita mi n 
s u p ple me ntati o n i n patie nts wit h relapse d N S C L C, d osi n g starte d at 1 5 0 m g/ m 2 e ver y 
2 wee ks a n d i nitiall y escalate d i n 4 0 m g/ m 2 i ncre me nts t o 2 7 0 m g/ m2 e ver y ( q) 2 wee ks.  
Base d o n t he D L Ts e x perie nce d i n t he 3 2 5 m g/ m 2 c o h ort of Treat me nt Gr o u p A, t he M T D 
f or Treat me nt Gr o u p A was deter mi ne d t o be 2 7 0 m g/ m2.  C o h orts i n Treat me nt Gr o u p B 
were i nitiate d at d ose le vels  bel o w t he M T D deter mi ne d f or Treat me nt Gr o u p A t o f urt her 
assess t he safet y a n d t olera bi lit y of pralatre xate.  T he starti n g d ose f or Treat me nt Gr o u p B 
was 2 3 0 m g/ m 2.  Alt h o u g h D L Ts were o bser ve d at t he 1 9 0 m g/ m2 d ose gi ve n e ver y 2 of 
4 wee ks, t hese D L Ts were of l o wer gra de ( 2  patie nts b ot h wit h Gra de 2 m uc ositis) t ha n 
D L Ts o bser ve d i n a n y ot her c o h ort, a n d t h eref ore, t his d ose is t he rec o m me n de d 
P hase 2 d ose.  
St u d y P D X- 0 1 1 is a P hase 2, o pe n-la bel, m u lti-ce nter st u d y of pralatre xate w he n 
a d mi nistere d c o nc urre ntl y wit h vita mi n B 1 2 a n d f olic aci d s u p ple me ntati o n i n patie nts wit h 
a d va nce d or metastatic rela pse d tra nsiti o nal cell carci n o ma ( T C C) of t he uri nar y bla d der.  
T he o bjecti ves of t his st u d y ar e: 1) t o deter mi ne t he o bjec ti ve res p o nse rate ( C R + P R); 
2) t o deter mi ne t he d urati o n of res p o nse, cl i nical be nefit rate, P F S, a n d O S; a n d 3) t o 
e val uate t he safet y a n d t olera bilit y of pralatre xate wit h c o nc urre nt vita mi n B 1 2 a n d f olic aci d 
s u p ple me ntati o n i n patie nts wit h a d va nce d or metastatic rela pse d T C C of t he uri nar y bla d der.   
St u d y P D X- 0 1 2 is a ra n d o mize d, o pe n-la bel,  m ulti-ce nter P hase 2 b st u d y c o m pari n g 
pralatre xate a n d erl oti ni b i n patie nts wit h  Sta ge III B/I V N S C L C w h o are or ha ve bee n 
ci garette s m o kers.  T he o bjecti ves of t he st u d y are: 1) t o esti mate t he efficac y of pralatre xate 
as assesse d b y o verall s ur vi val c o m pare d t o t hat  of erl oti ni b; 2) t o esti mate t he efficac y of 
pralatre xate as assesse d b y res p o nse rate c o m pare d t o t hat of erl oti ni b; 3) t o esti mate t he 
efficac y of pralatre xate as asse sse d b y P F S c o m pare d t o t hat of erl oti ni b; a n d 4) t o e val uate 
t he safet y a n d t olera bilit y of q 2 wee ks a d mi nistrati o n of pralatre xate i n patie nts wit h Sta ge 
III B/I V N S C L C.   
St u d y P D X- 0 1 4 is a n o pe n la bel, m ulti-ce nter, P hase 2 st u d y of pralatre xate i n fe male 
patie nts wit h Pre vi o usl y-treate d a d va nce d or metastatic breast ca ncer w h o ha ve faile d pri or 
treat me nt(s).   
St u d y P D X- 0 1 6 is a P hase 1, n o nra n d o mize d, o pe n- la bel, si n gle-ar m, c o m bi ne d cli nical 
p har mac ol o g y a n d cli nical st u d y t o e val uate t he e xcreti o n a n d meta b olic pr ofile of 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 3 9 of 9 5 
pralatre xate a n d t o relate t hese fi n di n gs t o c o nc urre nt P K assess me nts i n patie nts wit h 
a d va nce d ca ncer.   
4. 2. 2 
M S K C C St u di e s i n P ati e nt s wit h S oli d T u m or s 
St u d y P D X- 9 7- 0 0 6 was a P hase 1, si n gle-ce nter , d ose-escalati o n st u d y t o deter mi ne t he 
M T D a n d sc he d ule ( wee kl y or bi wee kl y) of si n gle-a ge nt pralatre xate.  T he st u d y was 
c o n d ucte d e xcl usi vel y i n patie nts wit h N S C L C,  w h o ha d bee n pre vio usl y treate d wit h a 
me dia n of 2 pri or c he m ot hera p y re gi me ns. 3 0  T hirt y-fi ve patie nts were e nr olle d a n d 3 3 were 
treate d.  I nitiall y, pralatre xate was a d mi nistere d at a d ose of 3 0 m g/ m 2 wee kl y f or 3 of 4 
wee ks.  T he pr ot oc ol was a me n de d t o a q 2 wee ks treat me nt o n a 4- w ee k c ycle, wit h d ose 
escalati o n fr o m 1 5 - 1 7 0 m g/ m 2.  T he wee kl y treat me nt wit h pralatre xate f or 3 wee ks i n a 
4- wee k c ycle was d ose li miti n g at 3 0 m g/ m 2.  Alteri n g t he treat me nt sc he d ule, h o we ver, t o q 
2 wee ks (i n a 4- wee k c ycle) all o we d m uc h hi g her d oses t o be a d mi nistere d.  T he M T D a n d 
rec o m me n de d P hase 2 d ose was 1 5 0 m g/ m2.  O ne patie nt i n St u d y P D X- 9 7- 0 0 6, w h o 
recei ve d t he M T D of 1 5 0 m g/ m2, ac hie ve d a P R, a n d 6 patie nts ac hie ve d sta ble disease ( S D). 
St u d y P D X- 9 9- 0 5 3 was a P hase 2, o pe n-la bel, si n gl e-ce nter st u d y e val ua ti n g t he efficac y of 
si n gle-a ge nt pralatre xate i n patie nts wit h Sta ge III B or Sta ge I V N S C L C. 3 1  T hirt y- ni ne 
patie nts were e nr olle d a n d treate d.  Patie nts recei ve d pralatre xate q 2 wee ks o n a 4- wee k 
c ycle.  T we nt y- ni ne patie nts were treate d i n t he 1 5 0 m g/ m 2 d ose gr o u p.  T o decrease t he 
i nci de nce of st o matitis, t he last 1 0 patie nts e nr olle d were treate d wit h 1 3 5 m g/ m2 of 
pralatre xate.  I n st u d y P D X- 9 9- 0 5 3, t he me dia n d urati o n of s ur vi val f or all patie nts was 
1 3 m o nt hs ( mea n = 1 6 m o nt hs), wit h me dia n  d urati o ns of 1 6 m o nt hs f or t he 1 5 0 m g/ m2 
gr o u p a n d 7. 5 m o nt hs f or t he 1 3 5 m g/ m 2 gr o u p. 
St u d y P D X 9 9- 0 8 3 was a P hase 1, o pe n-la bel, si n gle-ce nter, d ose-esca lati o n st u d y e val uati n g 
t he c o m bi nati o n of pralatre xate wit h a ta xa ne ( paclita xel or d oceta xel) i n a d ult patie nts wit h 
a d va nce d s oli d t u m ors. 3 2  F ort y-ei g ht patie nts were e nr olle d a n d treate d.  F ort y-si x of t h ose 
patie nts ha d N S C L C.  T he i nitial star ti n g d ose of pralatre xate was 1 1 0 m g/ m2 c o m bi ne d wit h 
1 7 5 m g/ m 2 of paclita xel a d mi nistere d o n t he sa me da y q 2 wee ks i n a 4- wee k c ycle, h o we ver, 
D L Ts pre ve nte d deter mi nati o n of a t olera bl e d ose wit h t his c o m bi nati o n.  T he M T D a n d 
rec o m me n de d P hase 2 d ose of t he pralatre xate- d oceta xel c o m bi nati o n wit h vita mi ns was 
1 2 0 m g/ m 2 of pralatre xate wit h 3 5 m g/ m2 d oceta xel a d mi nistere d o n t he sa me da y o nce 
q 2 wee ks.  O ne patie nt i n P D X- 9 9- 0 8 3 treate d bel o w t he M T D (treate d wit h pralatre xate 
9 0 m g/ m 2 + paclita xel 1 7 5 m g/ m2, wit h o ut vita mi n s u p ple me ntati o n) ac hie ve d a P R a n d 
3 2 patie nts ha d S D, 1 0 of w h o m were treate d wit h o ut vita mi ns a n d 2 2 of w h o m recei ve d 
vita mi ns. 
St u d y P D X 0 1- 0 1 4 was a P hase 1, o pe n-la bel, si n gle-ce nter, d ose-escalati o n st u d y t o 
deter mi ne t he M T D f or pralatre xate a n d pr o be neci d gi ve n i n c o m bi nati o n q 2 wee ks i n 
patie nts wit h s oli d t u m ors. 1 3  Se ve ntee n patie nts were e nr olle d.  T he pralatre xate d ose was 
ke pt at 4 0 m g/ m 2; t he d ose escalati o n of pr o be neci d pr ocee de d fr o m 7 0 t o 2 3 3 m g/ m 2.  
Treat me nt wit h pralatre xate i n c o m bi nati o n wit h pr o be neci d q 2 wee ks o n a 4- wee k c ycle 
e xcee de d t he M T D at 4 0 m g/ m 2 pralatre xate a n d 2 3 3 m g/ m2 pr o be neci d d ue t o st o matitis.  
T he M T D a n d rec o m me n de d P hase 2 d ose of t h e pralatre xate a n d pr o be neci d c o m bi nati o n 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 4 0 of 9 5 
was 4 0 m g/ m 2 of pralatre xate a d mi nistere d wit h 1 4 0 m g/ m2 pr o be neci d q 2 wee ks.  N o 
patie nt ac hie ve d a C R or P R, b ut 5 patie nts e x peri e nce d S D.  T he c o m bi nati o n of pralatre xate 
wit h pr o be neci d di d n ot de m o nstrate e n ha nce d t h era pe utic acti vit y a n d t he d ose le vels t hat 
were t olerate d were li mite d.   
St u d y P D X 0 1- 0 7 6 was a P hase 2, o pe n-la bel, si n gle-ce nter st u d y i n patie nts wit h 
u nresecta ble mali g na nt ple ural mes ot heli o ma. 3 3  Se ve ntee n patie nts were e nr olle d a n d 
1 6 patie nts were treate d.  T he d os e of pralatre xate was 1 3 5 m g/ m 2 i ntra ve n o us (I V) 
q 2 wee ks o n a 4- wee k c ycle.  N o patie nt i n t he st u d y ac hie ve d a C R or a P R; h o we ver, 
1 0 patie nts ha d S D ( d urati o n ra n ge: 2 + t o 4 7 m o nt hs).  T he me dia n ti me t o pr o gressi ve 
disease ( P D) f or all 1 6 patie nts treate d i n t he st u d y was 3 m o nt hs.  T he me dia n d urati o n of 
s ur vi val f or all 1 6 patie nts was 5. 5 m o nt hs. 
4. 3 
S af et y O v er vi e w of O n c ol o g y P a ti e nt s R e c ei vi n g Pr al atr e x at e 
4. 3. 1  
Pr e c a uti o n s 
B o ne m arr o w s u p pressi o n : Pralatre xate ma y s u p press b o ne marr o w f u ncti o n, ma nifeste d b y 
ne utr o pe nia, t hr o m b oc yt o pe nia, a n d a ne mia .  D ose m o dificati o ns are descri be d i n 
Secti o n 7. 4 ( Ta ble 7. 1 ) base d o n a bs ol ute ne utr o p hil co u nt ( A N C) a n d platelet c o u nts pri or t o 
eac h d ose. 
M uc ositis : Treat me nt wit h pralatre xate ma y ca use m uc ositis.  If ≥ Gra de 2 m uc ositis is 
o bser ve d, t he d ose s h o ul d be m o difie d acc or di n g t o Secti o n 7. 4, Ta ble 7. 2 . 
Der m at ol o gic re acti o ns : Pralatre xate has bee n ass ociate d wit h se vere der mat ol o gic reacti o ns, 
w hic h ma y res ult i n deat h.  T hese der mat ol o gic reacti o ns ha ve bee n re p orte d i n cli nical 
st u dies ( 1 4/ 6 6 3 patie nts [ 2. 1 %]) a n d p ost mar keti n g e x perie nce, a n d ha ve i ncl u de d s ki n 
e xf oliati o n, ulcerati o n, a n d t o xic e pi der mal necr ol ysis ( T E N).  T hese reacti o ns ma y be 
pr o gressi ve a n d i ncrease i n se verit y wit h f urt her treat me n t, a n d ma y i n v ol ve s ki n a n d 
s u bc uta ne o us sites of k n o w n l y m p h o ma.  Patie nts wit h s ki n reacti o ns m ust  be m o nit ore d 
cl osel y, a n d if s ki n reacti o ns are se vere, st u d y treat me nt ma y be m o difie d or disc o nti n ue d 
(see Secti o n 7. 4, Ta ble 7. 3 ). 
T u m or lysis sy n dr o me :  T u m or l ysis s y n dr o me has bee n re p orte d i n patie nts wit h l y m p h o ma 
recei vi n g pralatre xate.  Patie nts recei vi n g pralatre xate s h o ul d be m o nit ore d cl osel y a n d 
treate d f or c o m plicati o ns. 
F olic aci d a n d vit a mi n B 1 2 s u p ple me nt ati o n:  Patie nts m ust be i nstr ucte d t o ta ke f olic aci d 
a n d vita mi n B 1 2 t o p ote ntiall y re d uce treat me nt-relate d he mat ol o gical t o xicit y a n d m uc ositis 
(see Secti o n 7. 1 ). 
Pre g n a ncy a n d bre astfee di n g :  Pralatre xate ma y ca use fetal har m w he n a d mi nistere d t o a 
pre g na nt w o ma n.  Pralatre xate was e m br y ot o xic a n d fet ot o xic i n rats a n d ra b bits.  It is n ot 
k n o w n w het her pralatre xate is e xcrete d i n h u ma n  mil k.  Ma n y dr u gs are e xcrete d i n h u ma n 
m il k a n d t here is t he p ote ntial f or seri o us a d verse reacti o ns i n n ursi n g i n fa nts fr o m t his dr u g.  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 4 1 of 9 5 
St u d y treat me nt m ust n ot be a d mi nistere d d uri n g pre g na nc y or w he n  breastfee di n g (see 
Secti o n 1 4. 7 ). 
Re n al i m p air me nt :  Pralatre xate has n ot bee n f or mall y teste d i n patie nts wit h m o derate a n d 
se vere re nal i m pair me nt.  Patie nts m ust ha ve a de q uate re nal f u ncti o n t o be eli gi ble f or 
i ncl usi o n i n t his st u d y, as defi ne d i n Secti o n 8. 3 . 
He p atic i m p air me nt :  Pralatre xate has n ot bee n f or mall y teste d i n patie nts wit h he patic 
i m pair me nt.  Patie nts m ust ha ve a de q uate he patic f u ncti o n t o be eli gi ble for i ncl usi o n i n t his 
st u d y, as defi ne d i n Secti o n 8. 3.  Li ver f u ncti o n test a b n or malities ha ve bee n o bser ve d after 
pralatre xate a d mi nistrati o n, b ut  are us uall y n ot ca use f or m o dificati o n of pralatre xate 
treat me nt.  H o we ver, persistent li ver f u ncti o n test a b n or malit ies ma y be i n dicat ors of li ver 
t o xicit y a n d ma y re q uire d ose m o difi cati o n (see Ta ble 7. 3 ). 
Patie nts recei vi n g pralatre xate s h o ul d be m o nit ore d cl osel y beca use A Es ma y occ ur at a n y 
ti me d uri n g t hera p y.  F or detaile d i nf or mati o n a b o ut t he safet y pr ofile of pralatre xate, refer t o 
t he c urre nt pralatre xate I B. 
4. 4 
Cli ni c al P h ar m a c ol o g y 
4. 4. 1 
P h ar m a c o ki n eti c s 
Pralatre xate R a n d S diastere o mers f oll o w a p pare nt firs t- or der P K wit h t he area u n der t he 
c ur ve t o i nfi nit y ( A U C ∞) i ncreasi n g i n a near li near ma n ner wit h d ose.  T otal, re nal, a n d n o n-
re nal cleara nces as well as v ol u me of distrib uti o n were c o nsta nt w it hi n ( n o mi nal) d oses 
ra n gi n g fr o m 3 0 m g/ m2 t o 3 2 5 m g/ m2.  C o m pari n g t he 2 diastere o mers, plas ma e x p os ures of 
t he R diastere o mer e xcee d t h ose of t he S diastere o mer b y a p pr o xi matel y 2-f ol d; t he reas o n 
f or t his is u nclear at t his p oi nt.  F or a m ore detaile d descri pti o n of pralatre xate P K a n d 
p o p ulati o n P K ( P O P P K), see t he pralatre xate I B. 
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 4 2 of 9 5 
5 
R A TI O N A L E F O R T H E C U R R E N T S T U D Y 
Patie nts wit h P T C L are i n nee d of a d diti o nal treat me nt o pti o ns.  Pralatre xate e x hi bite d 
e nc o ura gi n g acti vit y i n n o ncli nical i n vitr o a n d i n vi v o m o dels of l y m p h o ma.  T his acti vit y 
was e val uate d cli nicall y i n a P hase 1/ 2 st u d y ( P D X- 0 2- 0 7 8) i n patie nts wit h l y m p h o ma i n 
w hic h a res p o nse rate of 5 4 % was o bser ve d i n patie nts wit h T-cell l y m p h o ma. 2 6  Efficac y 
a nal yses fr o m t he P hase 2 st u d y P D X- 0 0 8, w hic h wa s c o n d ucte d i n patie nts wit h rela pse d or 
refract or y P T C L, i n dicates t hat pralatre xate ex hi bite d cli nicall y si g nifica nt acti vit y i n t he 
patie nts u n der st u d y, de m o nstrati n g a n o verall res p o nse rate of 2 9 % a n d me dia n d urati o n of 
res p o nse of 1 0. 1 m o nt hs. 
C H O P a n d C H O P- base d treat me nts are t he m o st c o m m o nl y use d t hera pe utic re gi me ns f or 
patie nts wit h ne wl y dia g n ose d P T C L.  H o we ver, as a maj orit y of t hese patie nts pr o gress or 
rela pse f oll o wi n g C H O P, t he P F S o utc o me f or patients res p o n di n g t o C H O P re mai ns dis mal.  
I n t he P D X- 0 0 8 st u d y, 1 5 e val ua ble patie nts recei ve d pralatre xate as t heir sec o n d-li ne 
treat me nt after C H O P, 7 of w h o m ( 4 7 %) res p o n de d t o pralat re xate b y ce ntral re vie w.  Base d 
o n t he res p o nses o bser ve d i n t he P D X- 0 0 8 st u d y, t he c urre nt pr ot oc ol will deter mi ne f or 
t h ose patie nts w h o res p o n d t o CH O P t hera p y w het her pralatre xate  a d mi nistere d directl y after 
c o m pleti o n of a C H O P re gi me n ca n i m pr o ve P F S  a n d O S relati ve t o o bser vati o n directl y 
after c o m pleti o n of a C H O P re gi me n.   
As descri be d i n Secti o n 4. 1. 1 , pralatre xate a d mi nistere d at 3 0 m g/ m2 has bee n t olerate d a n d 
de m o nstrate d t o ha ve a t hera pe utic effect  i n patie nts wit h l y m p h o ma i n st u dies 
P D X- 0 2- 0 7 8 a n d P D X- 0 0 8.  T he pr o p ose d d osi n g re gi me n f or t his st u d y i ncl u des wee kl y 
d osi n g f or 3 wee ks f oll o we d b y 1 wee k of rest.  T his differs sli g htl y fr o m P D X- 0 0 8, w hic h 
utilize d a d osi n g re gi me n of wee kl y a d mi nistra ti o n f or 6 wee ks f oll o we d b y 1 wee k of rest.  
A n a nal ysis of t he P D X- 0 0 8 res ults re veale d t h at of t he 5 7 treate d patie nts w h o recei ve d t he 
first 3 d oses wit h o ut a d ose m o dificati o n, 2 4 patie nts ( 4 2 %) re q uire d a d ose m o dificati o n, 
i ncl u di n g p ossi bl y treat me nt disc o nti n uati o n, pri or t o t he rest week, ie, at eit her d oses 4, 5, or 
6.  T h us, all o wi n g a brea k after 3 d oses ma y i ncr ease t he l o n g-ter m t olera bilit y t o f ull- d ose 
pralatre xate.  T heref ore, t he i nitial d ose a n d fre q ue nc y of pralatre xate i n P D X- 0 1 7 will be 
3 0 m g/ m 2 a d mi nistere d I V wee kl y f or 3 wee ks, wit h 1 wee k rest ( 4- wee k c ycle), wit h 
s u bse q ue nt d ose re d ucti o n(s) base d o n t o xicit y.  All patie nts will recei ve vita mi n 
s u p ple me ntati o n c o nsisti n g of vita mi n B 1 2 a n d f olic aci d. 
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 4 3 of 9 5 
6 
S T U D Y O B J E C TI V E S 
T he pri mar y o bjecti ve of t his st u d y is: 
• 
Deter mi ne t he efficac y of pralatre xate c o m p are d t o o bser vati o n w he n a d mi nistere d t o 
patie nts wit h pre vi o usl y u n dia g n ose d P T C L  w h o ha ve ac hie ve d a n o bjecti ve res p o nse 
after c o m pleti n g at least 6 c ycl es of C H O P- base d treat me nt. 
T he sec o n dar y o bjecti ve of t his st u d y is: 
• 
Deter mi ne t he safet y of pralatre xate w h e n a d mi nistere d f oll o wi n g a c o urse of 
C H O P- base d treat me nt t o patie nts wit h pre vi o usl y u n dia g n ose d P T C L. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 4 4 of 9 5 
7 
I N V E S TI G A TI O N A L P L A N 
T his is a n i nter nati o nal, m ulti-ce nter, ra n d o mize d, P hase 3, o pe n-la bel st u d y of se q ue ntial 
pralatre xate vers us o bser va ti o n i n patie nts w h o ha ve ac hie ve d a n o bjecti ve res p o nse 
f oll o wi n g i nitial treat me nt wit h C H O P- base d c he m ot hera p y i n patie nts wit h pre vi o usl y 
u n dia g n ose d P T C L.  Patie nts will be ra n d o mize d 2: 1 t o eit her pralatre xate or o bser vati o n.  
Patie nts will be stratifie d b y: 
• 
Res p o nse per i n vesti gat or at c o m pleti o n of C H O P- base d t hera p y ( C R vs P R) 
7. 1 
Vit a mi n A d mi ni str ati o n  
Vita mi n s u p ple me ntati o n f or patie nts i n b ot h ar ms of t he st u d y will c o nsist of vita mi n B 1 2 
1 m g i ntra m usc ular (I M) e ver y 8- 1 0 wee ks a n d f olic aci d 1- 1 . 2 5 m g orall y ( p o) o nce a da y 
( q d).  Vita mi n s u p ple me ntati o n will be gi n at least 7 da ys pri or t o t he pr ojecte d i nitiati o n of 
pralatre xate/ o bser vati o n a n d c o nti n ue t hr o u g h o u t t he st u d y u ntil t he I nitial F oll o w- u p Visit 
(Secti o n 1 0. 7 ). 
7. 2 
Pr al atr e x at e A d mi ni str ati o n 
O ne c ycle of pralatre xate t hera p y is 4 wee ks i n  d urati o n a n d c o nsists of 3 wee kl y d oses of 
pralatre xate I V p us h o ver 3 0 sec o n ds a n d u p t o 5 mi n utes, wit h 1 wee k of rest .  T he i nitial 
d ose of pralatre xate will be 3 0 m g/ m 2/ wee k.  F or patie nts wit h a b o d y s urface area ( B S A) 
> 2 m 2, t he a d mi nistere d d ose will be calc ulate d usi n g a ca p pe d B S A val ue of 2 m2.  
Pralatre xate d ose re d ucti o n t o 2 0 m g/ m 2 wit h f urt her re d ucti o n t o 1 5 a n d 1 0 m g/ m2 will be 
all o we d f or defi ne d t o xicities (see Secti o n 7. 4 ).  Pralatre xate will c o nti n ue t o be a d mi nistere d 
u ntil a criteri o n f or st u d y treat me nt disc o nti n uati o n is met ( Secti o n 7. 3 ) or u p t o a ma xi m u m 
of 2 years. 
7. 3 
St u d y D ur ati o n  
Patie nts will recei ve st u d y treat me nt ( pralatre xat e or o bser vati o n) u ntil o ne of t he criteria 
liste d bel o w f or st u d y treat me nt disc o nti n uati o n a p plies: 
• 
De vel o p me nt of P D 
• 
I nitiati o n of ra diati o n t hera p y ( R T) or s yste mic c he m o/ bi ol o gical t hera p y f or treat me nt of 
P T C L 
• 
Recei pt of s yste mic ster oi ds f or > 1 0 da ys , wit h t he e xce pti o n of t h ose as state d i n 
e xcl usi o n criteri o n # 5 (see Secti o n 8. 4 ) 
• 
De vel o p me nt of a n A E t hat i nterferes wit h t he patie nt’s partici pati o n 
• 
L ost t o f oll o w- u p 
• 
Patie nt decisi o n 
• 
I n vesti gat or decisi o n 
• 
S p o ns or decisi o n 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 4 5 of 9 5 
I n a d diti o n, f or t h ose patie nts ra n d o mize d t o t he Pralatre xate Ar m, a d diti o nal pralatre xate 
treat me nt disc o nti n uati o n criteria are: 
• 
3 or m ore c o nsec uti ve d oses of pralatre xate o mitte d or m ore t ha n 2 8 da ys bet wee n d oses 
of pralatre xate  
• 
Treat me nt wit h pralatre xate f or 2 years 
All patie nts w h o recei ve at le ast 1 d ose of pralatre xate will be f oll o we d f or safet y t hr o u g h 
3 5 ( ± 5) da ys after t heir last d ose of pralatre xate or u ntil all treat me nt-relate d A Es ha ve 
res ol ve d or ret ur ne d t o baseli ne/ Gra de 1, w hic hever is l o n ger, or u ntil it is deter mi ne d t hat 
t he o utc o me will n ot c ha n ge wit h f urt her f oll o w- u p. 
Patie nts w h o are ra n d o mize d t o t he O bser v ati o n Ar m w h o d o n ot disc o nti n ue t he st u d y 
wit hi n 3 da ys of ra n d o mi zati o n will be f oll o we d f or safet y u ntil 3 5 ( ± 5) da ys after st u d y 
treat me nt disc o nti n uati o n criteria are met. 
All patie nts w h o are ra n d o mize d will be f o ll o we d u ntil o bjecti vel y d oc u me nte d P D f or u p t o 
7 years fr o m ra n d o mizati o n.  T he details of re s p o nse f oll o w- u p are pr o vi de d i n Secti o n 1 0. 8 .  
P D will be c o nfir me d b y ce ntral re vie w  u ntil t he first P F S a nal ysis, see Secti o n 1 5. 6. 1 , a n d 
per i n vesti gat or assess me nt t hereafter.  S u bse q ue nt t hera pies f or P T C L will be c ollecte d f or 
u p t o 7 years fr o m ra n d o mizati o n; t he best res p o n se t o t he first s u bse q ue nt t hera p y will be 
c ollecte d.  S ur vi val f oll o w- u p will c o nti n ue f or u p t o 7 years fr o m ra n d o mizati o n. 
As disc usse d i n Secti o n 1 5. 6. 1, a n a nal ysis will be perf or me d w he n b ot h 2 8 0 P F S e ve nts a n d 
1 2 8 O S e ve nts ha ve occ urre d.  If t he P F S a nal ys is is n ot si g nifica nt at t he 0. 0 5 le vel, t he 
st u d y will be st o p pe d. 
7. 4 
Tr e at m e nt M o difi c ati o n s of Pr al atr e x at e 
Pralatre xate d ose m o difi cati o ns will be all o we d acc or di n g t o t he criteria o utli ne d bel o w i n 
Ta ble 7. 1 , Ta ble 7. 2 , a n d Ta ble 7. 3 .  D ose re d ucti o n t o 2 0 m g/ m2 wit h f urt her re d ucti o ns t o 
1 5 m g/ m 2 a n d 1 0 m g/ m2 will be all o we d f or t he t o xicities defi ne d i n t he ta bles bel o w.  If a n 
A E occ urs t hat pre ve nts t he a d mi nistrati o n of pralatre xate o n t he sc he d ule d d osi n g da y 
(±  1 da y), t he d ose will be o mitte d t hat wee k an d t he patie nt will be reassesse d t he f oll o wi n g 
wee k t o pr ocee d t o t he ne xt d ose of t he c ycle.   


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 4 6 of 9 5 
7. 4. 1 
H e m at ol o gi c al A d v er s e E v e nt s 
Treat me nt m o dificati o n f or he m at ol o gic al  A Es occ urri n g o n t he pla n ne d d osi n g da y will be 
ma de as o utli ne d i n Ta ble 7. 1. 
T a bl e 7. 1.  
Pr al atr e x at e Tr e at m e nt M o difi c ati o n s f or H e m at ol o gi c al A E s 
He m at ol o gic al P ar a meter o n Pl a n ne d 
D osi n g D a y 
Acti o n 
A N C ≥ 1 0 0 0/μ L ( ≤ Gra de 2)  
or  
platelets ≥ 5 0, 0 0 0/μ L ( ≤ Gra de 2)  
•  
N o c ha n ge i n pralatre xate d ose. 
A N C ≥ 5 0 0/μ L a n d < 1, 0 0 0/ μ L ( Gra de 3) 
wit h o ut fe ver 
•  
A d mi nister c yt o ki ne pr o p h yla xis a n d/ or treat me nt per 
A S C O g ui deli nes. 3 4 . 
•  
D o n ot a d mi nister pralatre xate u ntil rec o ver y t o 
≤ Gra de 2 (≥ 1 0 0 0/μ L).  U p o n rec o ver y t o ≤ Gra de 2, 
a d mi nister pralatre xate wit h o ut a c ha n ge i n d ose. 
A N C ≥ 5 0 0/μ L a n d < 1, 0 0 0/ μ L ( Gra de 3) 
ass ociate d wit h si n g le oral te m perat ure 
≥ 3 8. 1°C re q uiri n g pare nteral a nti bi otics  
or  
A N C < 5 0 0/ μ L ( Gra de 4)  
•  
A d mi nister c yt o ki ne pr o p h yla xis a n d/ or treat me nt per 
A S C O g ui deli nes. 3 4  
•  
D o n ot a d mi nister pralatre xate u ntil rec o ver y t o 
≤ Gra de 2 (≥ 1 0 0 0/μ L).  U p o n rec o ver y t o ≤ Gra de 2, 
a d mi nister pralatre xate wit h o ut a c ha n ge i n d ose.   
•  
If re occ urre nce wit hi n 2 8 da ys, re d uce t he pralatre xate 
d ose t o t he ne xt l o wer d ose le vel.   
•  
Disc o nti n ue pralatre xate if e ve nt re occ urs at 1 0 m g/ m 2 
des pite c yt o ki ne s u p p ort. 
Platelets < 5 0, 0 0 0/ μ L ( ≥ Gra de 3)  
•  
D o n ot a d mi nister pralatre xate u ntil rec o ver y t o 
≤ Gra de 2 (≥ 5 0, 0 0 0/μ L).  U p o n rec o ver y t o ≤ Gra de 2, 
a d mi nister pralatre xate wit h o ut a c ha n ge i n d ose.  
•  
If a platelet c o u nt of Gra de 4 ( < 2 5, 0 0 0/μ L) re occ urs 
wit hi n 2 8 da ys, re d uce t he pralatre xate d ose t o t he ne xt 
l o wer d ose le vel. 
•  
Disc o nti n ue pralatre xate if a platelet c o u nt of Gra de 4 
( < 2 5, 0 0 0/μ L) occ urs t wice wit hi n 2 8 da ys at 
1 0 m g/ m 2. 
A N C – a bs ol ute ne utr o p hil c o u nt 
°C – de grees Celsi us 
7. 4. 2 
N o n- h e m at ol o gi c al A d v er s e E v e nt s 
F or all i nsta nces of m uc ositis occ urri n g o n t he pla n ne d d osi n g da y, treat me nt m o dificati o ns 
will be ma de as o utli ne d i n Ta ble 7. 2 .  F or tre at me nt-rel ate d c ar di o v asc ul ar, 
der m at ol o gic al, he p atic, ne ur ol o gic,  re n al, or res pir at or y A Es, treat m e nt m o dificati o ns 
will be ma de as o utli ne d i n Ta ble 7. 3 .  F or all ot her n o n- hemat ol o gical treat me nt-relate d 
A Es, treat me nt m o dificati o ns s h o ul d be ma de at t he i n vesti gat or’s discreti o n. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 4 7 of 9 5 
T a bl e 7. 2.  
Pr al atr e x at e Tr e at m e nt  M o difi c ati o n s f or M u c o siti s 
M uc ositis Gr a de o n 
Pl a n ne d D osi n g 
D a y  
Acti o n 
0 or 1 
•  
N o c ha n ge i n pralatre xate d ose. 
2 
•  
O mit t his wee k’s d ose of pralatre xate. A d mi nister wit h n o c ha n ge i n 
pralatre xate d ose if res ol uti o n t o Gra de 0- 1. 
•  
If re occ urre nce, o mit t his wee k’s d ose, u p o n res ol uti o n t o Gra de 0- 1, 
re d uce t he d ose t o ne xt l o wer d ose le vel.. 
3  
D o n ot a d mi nister pralatre xate u ntil rec o ver y t o Gra de 0- 1.  
•  
U p o n rec o ver y t o Gra de 0- 1, re d uce t o ne xt l o wer d ose le vel  
•  
Disc o nti n ue pralatre xate if ≥ Gra de 3 m uc ositis persists f or 
≥ 2 c o nsec uti ve wee ks or re occ urs wit hi n 2 8 da ys if o n 1 0 m g/ m2 
4 
•  
Disc o nti n ue pralatre xate. 
 
T a bl e 7. 3.  
Pr al atr e x at e Tr e at m e nt M o difi c ati o n s f or Tr e at m e nt-r el at e d 
C ar di o v a s c ul ar, D er m at ol o gi c al, H e p ati c, N e ur ol o gi c, R e n al, or 
R e s pir at or y A E s 
E ve nt Gr a de  
Acti o n 
0- 2 
•  
N o c ha n ge i n pralatre xate d ose. 
3 
D o n ot a d mi nister pralatre xate u ntil rec o ver y t o ≤ Gra de 2. 
•  
U p o n rec o ver y t o ≤ Gra de 2 a d mi nister pralatre xate wit h o ut a c ha n ge 
i n d ose. 
•  
If t he patie nt e x perie nces t he sa me Gra de 3 treat me nt-relate d A E d o 
n ot a d mi nister u ntil rec o ver y t o ≤ Gra de 2 a n d a d mi nister wit h a 
re d ucti o n t o t he ne xt l o wer d ose le vel. 
•  
Disc o nti n ue pralatre xate if t he sa me Gra de 3 treat me nt-relate d A E 
rec urs wit hi n 2 8 da ys at 1 0 m g/ m2. 
4 
•  
Disc o nti n ue pralatre xate.  
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 4 8 of 9 5 
8 
P A TI E N T P O P U L A TI O N  
8. 1 
N u m b er of P ati e nt s a n d P ati e nt S el e cti o n 
T he tar get patie nt p o p ulati o n is a d ult patie nts  wit h pre vi o usl y u n dia g n ose d P T C L w h o ha ve 
ac hie ve d a n o bjecti ve res p o nse afte r pre-st u d y first-li ne treat me nt wit h at least 6 c ycles of 
o ne of t he f oll o wi n g C H O P- base d treat me nts: 
a. C H O P 2 1  
b.  C H O P 1 4 
c. C H O E P 
d.  Ot her C H O P varia nts 
A t otal of 5 4 9 patie nts will be ra n d o mize d  2: 1 t o pralatre xate or o bser vati o n. 
8. 2 
I n cl u si o n of F e m al e s a n d Mi n oriti e s 
E ntr y i nt o t his st u d y is o pe n t o males a n d fe ma les of a n y et h nic ori gi n.  Race a n d ge n der are 
n ot k n o w n t o affect s ur vi val o u tc o me i n t his disease, n or are t he y k n o w n t o be ass ociate d 
wit h differe ntial s ur vi val b y treat me nt.  Fe males a n d mi n orities will be acti vel y recr uite d f or 
t his pr ot oc ol.   
8. 3 
I n cl u si o n Crit eri a  
A patie nt will be eli gi ble f or i ncl usi o n o nl y if all of t he f oll o wi n g criteria a p pl y: 
1.  Patie nt’s P T C L hist ol o g y has bee n c o nfir me d as o ne of t he f oll o wi n g b y a n i n de pe n de nt 
pat h ol o g y re vie wer, usi n g t he Re vise d E ur o pea n A meri ca n L y m p h o ma ( R E A L) W H O 
disease classificati o n 
a. T/ N K-cell le u ke mia/l y m p h o ma 
b.  A d ult T-cell l y m p h o ma/l e u ke mia ( h u m a n T-cell le u ke mia vir us [ H T L V] 1 +) 
c. A n gi oi m m u n o blastic T-cell l y m p h o ma  
d.  A L C L, pri mar y s yste mic t y pe, e xcl u di n g A L K +  wit h I PI sc ore < 2 at i nitial dia g n osis 
a n d C R after c o m pleti o n of C H O P- base d t hera p y 
e. P T C L- u ns pecifie d 
f. E nter o pat h y-t y pe i ntesti nal l y m p h o ma 
g.  He pat os ple nic T-cell l y m p h o ma 
h.  S u bc uta ne o us pa n nic uli tis T-cell l y m p h o ma 
i. Tra nsf or me d m yc osis f u n g oi des 
j. E xtra n o dal T/ N K-cell l y m p h o ma  nasal or nasal t y pe 
k.  Pri mar y c uta ne o us ga m ma- delta T-cell l y m p h o ma 
l. Pri mar y c uta ne o us C D 8 + a g gressi ve e pi der mic c yt ot o xic T-cell l y m p h o ma 
2.  D oc u me ntati o n t hat t he patie nt  has c o m plete d at least 6 c ycles of C H O P- base d t hera p y, 
i ncl u di n g: 
• 
C H O P 2 1  


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Versi o n 2. 1  
 
 
 
 
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• 
C H O P 1 4 
• 
C H O E P 
• 
Ot her C H O P varia nts: i ncl u des all 4 c o m p o ne nts of C H O P re prese nte d, wit h 
s u bstit uti o n all o we d f or a n y 1 c o m p o ne nt wit h a dr u g of t he sa me mec ha nis m of 
acti o n (e g, varia nt a nt hrac ycli nes).  A d diti o nal c o m p o ne nts t o C H O P are all o we d, 
wit h t he e xce pti o n of ale mt uz u ma b; r it u xi ma b ma y be c o m bi ne d wit h C H O P 
pr o vi de d t hat it is n ot gi ve n wit h i n 3 c ycles of ra n d o mizati o n.  
3.  Patie nt has ac hie ve d a C R or P R per i n ve sti gat or’s assess me nt f oll o wi n g c o m pleti o n of 
C H O P- base d t hera p y a n d has ha d a ra di ol o g ical assess me nt wit hi n 2 1 da ys pri or t o 
ra n d o mizati o n. 
4.  ≥ 1 8 years of a ge. 
5.  E C O G perf or ma nce stat us ≤ 2. 
6.  A de q uate he mat ol o gical, he patic, a n d re nal f u ncti o n as defi ne d b y: 
a. A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1 0 0 0/ µ L 
b.  Platelet c o u nt ≥ 1 0 0, 0 0 0/ µ L 
c. T otal bilir u bi n ≤ 1. 5 m g/ d L 
d.  As partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T) ≤ 2. 5 ×  u p per 
li mit of n or mal ( U L N), ( A S T/ A L T < 5 ×  U L N if d oc u me nte d he patic i n v ol ve me nt 
wit h l y m p h o ma).  All patie nts wit h he pa titis B vir us ( H B V)-p ositi ve ser ol o g y m ust 
ha ve li ver f u ncti o n tests w it hi n t he a b o ve para meters. 
e. Creati ni ne ≤ 1. 5 m g/ d L (if t he patie nt’s creati ni ne is > 1. 5 m g/ d L, t he n t he calc ulate d 
creati ni ne cleara nce m ust be ≥ 5 0 m L/ mi n). 
7.  Fe males of c hil d beari n g p ote nti al (ie, e xcl u di n g patie nts w h o are p ost me n o pa usal f or at 
least 1 year [ > 1 2 m o nt hs since last me nses] or are s ur gicall y sterilize d) m ust: 
a. Ha ve a ne gati ve ser u m pre g na nc y test w it hi n 1 4 da ys pri or t o ra n d o mizati o n a n d 
b.  A gree t o practice a me dicall y acce pta ble c o ntrace pti ve re gi me n fr o m st u d y treat me nt 
i nitiati o n u ntil at least 3 0 da ys after t he last a d mi nistrati o n of pralatre xate. 
8.  Males w h o are se x uall y acti ve, i ncl u di n g t h ose wit h a pre g na nt part ner, m ust a gree t o 
practice a me dicall y acce pta ble barrier met h o d c o ntrace pti ve re gi me n (e g, c o n d o ms) 
w hile recei vi n g pralatre xate a n d f or 9 0 da ys af ter t he last a d mi nistrati o n of pralatre xate. 
9.  Patie nt has gi ve n writte n i nf or me d c o nse nt (I C). 
8. 4 
E x cl u si o n Crit eri a 
A patie nt will n ot be eli gi ble f or i ncl usi o n if a n y of t he f oll o wi n g criteria a p pl y: 
1.  Patie nt has:  
a. Prec urs or T/ N K ne o plas ms 
b.  A L C L ( A L K +) wit h I PI sc ore < 2 at i ni tial dia g n osis a n d C R after c o m pleti o n of 
C H O P- base d t hera p y 
c. T-cell pr ol y m p h oc ytic le u ke mia ( T- P L L) 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
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d.  T-cell lar ge gra n ular l y m p h oc ytic le u ke mia 
e. M yc osis f u n g oi des, ot her t ha n tra nsf or me d m yc osis f u n g oi des  
f. Sézar y s y n dr o me 
g.  Pri mar y c uta ne o us C D 3 0 + dis or ders:  A L C L a n d l y m p h o mat oi d pa p ul osis 
2.  If t here is a hist or y of pri or mali g na ncies other t ha n t h ose e xce pti o ns liste d bel o w, t he 
patie nt m ust be disease-free f or ≥ 5 years.  Patie nts wit h t he f oll o wi n g pri or mali g na ncies 
less t ha n 5 years bef ore st u d y e ntr y ma y still be e nr olle d if t he y ha ve recei ve d treat me nt 
res ulti n g i n c o m plete res ol uti o n of t he ca ncer a n d c urre ntl y ha ve n o cli nical, ra di ol o gic, 
or la b orat or y e vi de nce of acti ve or rec urre nt disease. 
a. N o n- mela n o ma s ki n ca ncer  
b.  Carci n o ma i n sit u of t he cer vi x 
c. L ocalize d pr ostate ca ncer 
d.  L ocalize d t h yr oi d ca ncer 
3.  Patie nt has recei ve d pri or treat me nt (c he m ot hera p y or ra diati o n) f or P T C L, ot her t ha n a 
si n gle all o we d C H O P re gi men, wit h t he e xce pti o n of: 
a. Patie nts wit h nasal N K l y m p h o ma are per mitte d t o ha ve recei ve d l ocal ra diati o n 
t hera p y n o less t ha n 4 wee ks pri or t o ra n d o mizati o n. 
b.  Patie nts wit h tra nsf or me d m yc osis f u n g oi des are per mitte d t o ha ve recei ve d 
1 s yste mic si n gle-a ge nt c he m ot hera p y ( o t her t ha n met h otre xate) pri or t o 
tra nsf or mati o n of t heir disease. 
4.  Pri or e x p os ure t o pralatre xate. 
5.  Recei pt of s yste mic c ortic oster oi ds wit hi n 3 wee ks of st u d y treat me nt, u nless patie nt has 
bee n ta ki n g a c o nti n u o us d ose of ≤ 1 0 m g/ da y of oral pre d nis o ne or e q ui vale nt f or at least 
4 wee ks or as part of a C H O P pre d nis o ne ta per. 
6.  Pla n ne d use of a n y treat me nt f or P T C L d uri n g t he c o urse of t he st u d y. 
7.  Patie nt has:  
a. H u ma n i m m u n o deficie nc y vir us ( HI V)- p osit i ve dia g n osis wit h a C D 4 c o u nt of 
< 1 0 0 m m 3 or detecta ble viral l oa d wit hi n past 3 m o nt hs a n d is recei vi n g 
a nti-retr o viral t hera p y. 
b.  H B V- p ositi ve ser ol o g y a n d is recei vi n g i nterf er o n t hera p y or has li ver f u ncti o n test 
res ults o utsi de t he para meters of st u d y i ncl usi o n criteria.  Patie nts are per mitte d t o 
recei ve ot her a nti viral t hera pies if t he t hera p y has bee n a d mi nistere d at a sta ble d ose 
f or ≥ 4 wee ks.  
c. He patitis C vir us ( H C V) wit h detecta ble viral l oa d or i m m u n o l o gical e vi de nce of 
c hr o nic acti ve disease or recei v i n g/re q uiri n g a nti viral t hera p y. 
d.  S y m pt o matic ce ntral ner v o us s yste m ( C N S) me tastases or lesi o ns f or w hic h treat me nt 
is re q uire d. 
e. U nc o ntr olle d h y perte nsi o n or c o n gesti ve hear t fail ure Class III/I V acc or di n g t o t he 
Ne w Y or k Heart Ass ociati o n’s He art Fail ure G ui deli nes (see 
htt p:// w w w.a merica n heart. or g/ pr ese nter.j ht ml?i de ntifier = 3 0 6 5 0 8 0). 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
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f. Acti ve u nc o ntr olle d i nfecti o n, u n derl yi n g me dical c o n diti o n i ncl u di n g u nsta ble 
car diac disease, or ot her seri o us ill ness t hat w o ul d i m pair t he a bilit y of t he patie nt t o 
recei ve pr ot oc ol treat me nt.   
8.  Patie nt has ha d maj or s ur ger y wit hi n 2 wee k s pri or t o st u d y e ntr y; ot her t ha n f or li ne 
place me nt or bi o ps y pr oce d ure.  
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 5 2 of 9 5 
9 
S T U D Y D R U G A N D 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 
Pr al atr e x at e I nj e cti o n 
9. 1. 1 
Pr al atr e x at e I nj e cti o n F or m ul ati o n 
Pralatre xate I njecti o n ( Pralatr e xate S ol uti o n f or I nf usi o n i n t he E U) will be s u p plie d b y All os 
a n d will ha ve bee n teste d a n d release d acc or di n g t o esta blis he d s pecificati o ns.  Pralatre xate 
I njecti o n is f or m ulate d as a sterile s ol uti o n f or i njecti o n a n d will be s u p plie d i n si n gle- use 
glass vials c o ntai ni n g a n is ot o nic pare nteral s ol uti o n at a c o nce ntrati o n of 2 0 m g/ m L of 
pralatre xate.  T he os m ol alit y of Pralatre xate I njecti o n is ~ 3 0 0 m Os m ol/ k g.  T he f or m ulati o n 
is a clear yell o w s ol uti o n. 
9. 1. 2 
Pr al atr e x at e I nj e cti o n St or a g e a n d H a n dli n g 
Pralatre xate I njecti o n is a c yt ot o xic a ntica n cer a ge nt.  Ca uti o n s h o ul d be e xercise d i n 
ha n dli n g, pre pari n g, a n d a d mi nisteri n g of t h e s ol uti o n.  T he use of gl o ves a n d ot her 
pr otecti ve cl ot hi n g is rec o m me n de d.  If Pralatre xate I njecti o n c o mes i n c o ntact wit h t he s ki n, 
i m me diatel y a n d t h or o u g hl y was h wit h s oa p a n d water.  If Pralatre xa te I njecti o n c o mes i n 
c o ntact wit h m uc o us me m bra nes, fl us h t h or o u g hl y wit h water.   
T he i nstit uti o nal, l ocal, a n d all a p plica ble p olicies a n d pr oce d ures m ust be f oll o we d f or 
pr o per ha n dli n g a n d dis p osal of c he m ot hera p y dr u gs. 
Pralatre xate I njecti o n m ust be  st ore d refri gerate d at 2- 8°C ( 3 6- 4 6° F) (see U nite d States 
P har mac o peia [ U S P] C o ntr olle d C ol d Te m perat ure) u ntil use.  Pralatre xate I njecti o n vials 
s h o ul d be st ore d i n ori gi nal cart o n t o pr otect fr o m li g ht u ntil use.  Pralatre xate I njecti o n vials 
c o ntai n n o preser vati ves a n d are i n te n de d f or si n gle use o nl y.  Vials of Pralatre xate I njecti o n 
m ust be st ore d u n der sec ure d c o n diti o ns wit h  access li mite d t o a ut h orize d st u d y pers o n nel 
o nl y.  After wit h dra wal of d ose, discar d vial i ncl u di n g a n y u n use d p orti o n.   
9. 1. 3 
P a c k a gi n g/ L a b eli n g 
T he c o nte nts of t he la bel will be i n acc or da nce wit h all a p plica ble re g ulat or y re q uire me nts. 
9. 1. 4 
Pr al atr e x at e I nj e cti o n D o s a g e a n d A d mi ni str ati o n 
9. 1. 4. 1 
Pr e p ar ati o n a n d Pr al atr e x at e I nj e cti o n D o s e C al c ul ati o n  
A p pr o priate mas k, pr otecti ve cl ot hi n g, e ye pr otecti o n, gl o ve s, a n d Class II vertical 
la mi nar-airfl o w safet y ca bi nets are re q uire d d uri n g pre parati o n a n d ha n dli n g.  Please refer t o 
t he St u d y I nstr ucti o ns pr o vi de d b y All os/ desi g nee f or detaile d g ui da nce re gar di n g 
dis pe nsi n g, dis p osal, a n d acc o u nta bi lit y of Pralatre xate I njecti o n. 
Pralatre xate I njecti o n m ust be i nf use d as t he v ol u me of a d mi nistrati o n base d o n t he ori gi nal 
c o nce ntrati o n of 2 0 m g/ m L.   


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 5 3 of 9 5 
T he B S A will be calc ulate d base d o n t he patie nt’ s act ual wei g ht o btai ne d wit hi n 2 da ys pri or 
t o t he first Pralatre xate I njecti o n d ose of eac h c ycle, u nless ot her wise n ote d i n  Secti o n 1 0. 4 .  
T he patie nt will recei ve t he sa me Pralatre xate I njecti o n d ose ( base d o n t he B S A calc ulate d at 
c ycle 1) t hr o u g h o ut treat me nt u nless t he patie nt’s act ual wei g ht c ha n ges b y ≥ 1 0 %.  T he 
v ol u m e t o be i nf use d will be base d o n t he f oll o wi n g calc ulati o n: 
V ol u me ( m L) = ( Patie nt B S A [ m 2]) x ( pralatre xate d ose [ m g/ m2]) 
2 0 m g/ m L ( pralatre xate c o nce ntrati o n) 
Patie nts wit h a B S A > 2 m 2 will be ca p pe d at 2 m2. 
9. 1. 5 
A d mi ni str ati o n of Pr al atr e x at e I nj e cti o n  
Pralatre xate I njecti o n is a clear, yell o w s ol uti o n.  Pare nteral dr u g pr o d ucts s h o ul d be 
i ns pecte d vis uall y f or partic ulate matter a n d disc ol orati o n pri or t o a d mi nistrati o n, w he ne ver 
s ol uti o n a n d c o ntai ner per mit.  D o n ot use a n y vials e x hi biti n g partic ulate matter or 
disc ol orati o n.   
T he calc ulate d d ose of Pralatre xate I njecti o n s h o ul d be ase pticall y wit h dra w n i nt o a s yri n ge 
f or i m me diate use.  D o n ot dil ute Pralatre xate I njecti o n. 
A p pr o priate pr oce d ures f or c yt ot o xic a ge nts  m ust be f oll o we d f or a d mi nistrati o n of 
Pralatre xate I njecti o n. 
Pralatre xate I njecti o n will be  a d mi nistere d as a n I V p us h o ver a mi ni m u m of 3 0 sec o n ds u p 
t o a ma xi m u m of 5 mi n utes i nt o a pate nt I V li ne c o ntai ni n g n or mal sali ne ( 0. 9 % s o di u m 
c hl ori de [ Na Cl] at a n i nitial d ose of 3 0 m g/ m 2.  If t he I V p us h of pralatre xate is i nterr u pte d or 
dela ye d, t he a d mi nistrati o n s h o ul d be  restarte d as s o o n as p ossi ble. 
T he p har macist/ desi g nee ma y dis pe nse Pralatre xate I njecti o n t o t he researc h tea m i n t he vial 
or i n a pre-fille d s yri n ge acc or di n g t o t he i nstit uti o nal practice.  Pralatre xate I njecti o n vials 
will be dis p ose d of i m me diatel y after use.  T he vial a n d re mai ni n g v ol u me of Pralatre xate 
I njecti o n s h o ul d be discar de d acc or di n g t o t he i nstit uti o n’s p olic y f or dis p osal of c yt ot o xic 
a ge nts. 
9. 2 
Dr u g A c c o u nt a bilit y 
All os re q uires t hat dr u g acc o u nta bilit y l o gs be mai ntai ne d.  T hese l o gs m ust rec or d q ua ntities 
of Pralatre xate I njecti o n recei ve d fr o m All o s a n d q ua ntities dis pe nsed t o patie nts, i ncl u di n g 
l ot/ batc h n u m ber, date dis pe nse d, patie nt i de ntifier n u m ber, patie nt i nitials, pr ot oc ol n u m ber, 
d ose, bala nce f or war d, a n d t he i nitials of  t he pers o n dis pe nsi n g t he me dicati o n. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
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1 0 S T U D Y P R O C E D U R E S 
St u d y pr oce d ures are s u m marize d i n A p pe n di x 1  a n d A p pe n di x 2 , Sc he d ule of St u d y 
Pr oce d ures/ E val uati o ns Ta bles. 
1 0. 1 
S cr e e ni n g  
T he pr oce d ures a n d e val uati o ns re q uire d f o r ra n d o mizati o n are s u m marize d bel o w.  
Ra n d o mizati o n of eli gi ble patie nts m ust occ ur wit hi n 6 wee ks of da y 1 of t he last pla n ne d 
c ycle of C H O P- base d c he m ot hera p y.     
1.  Re vie w eli gi bilit y criteria. 
2.  O btai n writte n I C f or pat h ol o g y re vie w pri or t o se n di n g pat h ol o g y s peci me n(s) t o 
i n de pe n de nt path ol o g y re vie wer. 
3.  Se n d t he pat h ol o g y s peci me n(s) t o i n de pe n de nt pat h ol o g y re vie wer (see Secti o n 1 2. 2. 2 ).  
I n de pe n de nt pat h ol o g y re vie w of t u m or tiss ue s peci me ns a n d c o nfir mati o n of dia g n osis 
m ust occ ur pri or t o ra n d o m izati o n a n d ca n occ ur a n y ti me after t he i nitial P T C L 
dia g n osis, pr o vi de d t hat t he patie nt has c o nse nte d t o t he pat h ol o g y re vie w.   
U nless ot her wise s pecifie d, t he f oll o wi n g pr o ce d ures a n d e val uati o ns will be perf or me d 
wit hi n 2 1 da ys pri or t o ra n d o mizati o n: 
1.  O btai n writte n I C f or partici pati o n i n t his  st u d y pri or t o i nitiatin g a n y st u d y pr oce d ure 
t hat is n ot c o nsi dere d sta n dar d of care. 
2.  Re vie w eli gi bilit y criteria. 
3.  Re vie w me dical c hart a n d rec o r d me dical/s ur gical hist or y. 
4.  D oc u me nt hist o pat h ol o g y fr o m l ocal pat h ol o g y re p ort. 
5.  D oc u me nt I PI sc ore at i nitial dia g n osis. 
6.  Rec or d baseli ne/c urre nt me dical stat us, i ncl u di n g B s y m pt o ms relate d t o P T C L. 
7.  D oc u me nt dates of C H O P- base d c he m ot hera p y.   
8.  D oc u me nt t he i n vesti gat or’s assess me nt of  res p o nse after recei pt of C H O P- base d 
c he m ot hera p y. 
9.  D oc u me nt k n o w n meas ura ble disease para mete rs b y o btai ni n g t he f oll o wi n g ra di o gra p hic 
i ma gi n g:    
•  
C o m p ute d t o m o gra p h y ( C T) of c hest, nec k, a b d o me n, a n d pel vis ( ma g netic res o na nce 
i ma gi n g [ M RI] all o we d if t he patie nt ca n n ot t olerate t he I V c o ntrast). 
•  
Ot her i ma gi n g tec h ni q ues d oc u me nti n g diseas e site ot her t ha n c hest, nec k, a b d o me n, 
a n d pel vis, if a p plica ble. 
1 0.  Perf or m w h ole b o d y p ositr o n e missi o n t o m o gra p h y ( P E T) ( base of s k ull t o mi d-t hi g h) if 
l ocal sta n dar d of care. 
1 1.  D oc u me nt c uta ne o us disease wit h me dical p h ot o gra p h y of u p t o 5 tar get lesi o ns, w hic h 
will be c h ose n b y t he i n vesti gat or (refer t o St u d y I nstr ucti o ns). 




Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
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1 0. 4 
Pr al atr e x at e Ar m Pr o c e d ur e s 
1 0. 4. 1 
Pr al atr e x at e C y cl e 1, D o s e 1 
T he f oll o wi n g e val uati o ns a n d pr oce d ures m u st ta ke place wit hi n 3 da ys f oll o wi n g 
ra n d o mizati o n a n d pri or t o treat me nt i nitiati o n ( pralatre xate c ycle 1, d ose 1), u nless 
ot her wise n ote d bel o w: 
1.  Rec or d c urre nt me dicati o ns i ncl u di n g c o m plia nce wit h vita mi n s u p ple me ntati o n 
a d mi nistere d fr o m 7 da ys pri or t o ra n d o mizati o n (see Secti o n 1 3 ). 
2.  Assess a n d rec or d B s y m pt o ms . 
3.  Rec or d st u d y- pr oce d ure-re late d A Es a n d attri b uti o n 
(see htt p://cte p.ca ncer. g ov/re p orti n g/ctc. ht ml). 
4.  Rec or d wei g ht i n kil o gra ms ( k g), hei g ht i n  ce nti meters (c m) a n d calc ulate B S A.  T he 
patie nt’s wei g ht a n d B S A, t o calc ulate t h e v ol u me of t he pralatre xate d ose ma y be 
assesse d u p t o 7 da ys pri or t o c ycle 1, d ose 1. 
5.  L ocal la b orat or y: C ollect pre-i njec ti o n bl o o d f or he mat ol o g y a n d c he mistr y 
(i ncl u di n g baseli ne L D H) (see Secti o n 1 2. 1 ).  If a n y of t he la b orat or y eli gi bilit y criteria 
are n o l o n ger met at t his ti me, dela y treat me nt f or u p t o 1 wee k u ntil t hese val ues ret ur n  
t o t he s pecifie d para meters, as f oll o ws: A N C ≥ 1 0 0 0/ µ L, platelet c o u nt ≥ 1 0 0, 0 0 0/ µ L, 
t otal bilir u bi n ≤ 1. 5 m g/ d L, A S T a n d A L T ≤ 2. 5 ×  U L N ( A S T/ A L T <  5 ×  U L N if 
d oc u me nte d he patic i n v ol ve me nt wit h l y m p h o ma), creati ni ne ≤ 1. 5 m g/ d L or calc ulate d 
creati ni ne cleara nce ≥ 5 0 m L/ mi n. 
6.  C ollect pre-i njecti o n bl o o d sa m ple f or P K (see Secti o n 1 2. 2. 1 ).  P K sa m pli n g will be 
perf or me d at c ycle 1, d ose 1 u ntil sa m ples ha ve bee n o btai ne d o n 2 4 5 patie nts.  O btai n 
sa m ples u ntil n otifie d b y All os or desi g nee.   
7.  A d mi nister pralatre xate I V  p us h o ver a mi ni m um of 3 0 sec o n ds u p t o a ma xi m u m of 
5 mi n utes. 
8.  C ollect bl o o d sa m ples f or P K at t he e n d of i njecti o n a n d at 8 an d 2 4 h o urs p ost-i njecti o n 
(see Secti o n 1 2. 2. 1).  P K sa m pli n g will be perf or me d at c ycle 1, d ose 1 u ntil sa m ples 
ha ve bee n o btai ne d o n 2 4 5 patie nts.  O btai n  sa m ples u ntil n otifie d b y All os or desi g nee. 
1 0. 4. 2 
Pr al atr e x at e Ar m: C y cl e 1, D o s e s 2- 3 
1.  Rec or d A Es a n d attri b uti o n (see htt p://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml).  Refer t o 
Secti o n 7. 4  f or t he pralatre xate d ose m o dificati o n criteria. 
2.  Rec or d c urre nt me dicati o ns i ncl u di n g c o m plia nce wit h vita mi n s u p ple me ntati o n. 
3.  Re vie w date of pre vi o us vita mi n B 1 2 i njecti o n.  A d mi nister vita mi n B1 2 1 m g I M 
q 8- 1 0 wee ks. 
4.  L ocal la b orat or y: C ollect bl o o d f or he mat ol o g y a n d c he mistries wit hi n 1 da y pri or t o 
eac h pralatre xate d ose.  
5.  If t he patie nt is n ot e x perie nci n g a n y A Es t hat warra nt treat me nt m o dificati o n or 
disc o nti n uati o n, a d mi nister pralatre xate I V  p us h o ver a mi ni m u m of 3 0 sec o n ds u p t o a 
ma xi m u m of 5 mi n utes.   


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 5 7 of 9 5 
1 0. 4. 3 
Pr o c e d ur e s f or S u b s e q u e nt C y cl e s, D o s e s 1- 3 f or a M a xi m u m of 2 Y e ar s 
Patie nts ma y c o nti n ue t o recei ve pralatre xate u n less t he patie nt e x perie nces a n y of t he criteria 
n ote d i n pr ot oc ol Secti o n 1 1. 1 . 
1.  Pri or t o eac h ne w c ycle: rec or d wei g ht i n k g a n d calc ulate B S A.  T he patie nt’s wei g ht 
a n d B S A ma y be assesse d u p t o 2 da ys pri or t o t he start of eac h c ycle. 
2.  Pri or t o eac h ne w c ycle: Assess a n d rec or d B s y m pt o ms u p t o 2 da ys pri or t o t he start of 
eac h c ycle. 
3.  Rec or d A Es a n d attri b uti o n (see htt p://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml).  Refer t o 
Secti o n 7. 4  f or t he pralatre xate d ose m o dificati o n criteria. 
4.  Rec or d c urre nt me dicati o ns i ncl u di n g c o m plia nce wit h vita mi n s u p ple me ntati o n. 
5.  Re vie w date of pre vi o us vita mi n B 1 2 i njecti o n.  A d mi nister vita mi n B1 2 1 m g I M 
q 8- 1 0 wee ks. 
6.  L ocal la b orat or y: C ollect bl o o d f or he mat ol o g y a n d c he mistries (i ncl u di n g L D H d uri n g 
wee k 1) wit hi n 1 da y pri or t o ea c h pralatre xate d ose (see Secti o n 1 2. 1 ).  
7.  At c ycle 2, d ose 3, c ollect pre-i njecti o n bl o o d sa m ple f or P K i n 2 0 patie nts at select sites 
(see Secti o n 1 2. 2. 1 ). 
8.  If t he patie nt is n ot e x perie nci n g a n y A Es t hat warra nt treat me nt m o dificati o n or 
disc o nti n uati o n, a d mi nister pralatre xate I V  p us h o ver a mi ni m u m of 3 0 sec o n ds u p t o a 
ma xi m u m of 5 mi n utes. 
9.  At c ycle 2, d ose 3, c ollect bl o o d sa m ples f or P K i n 2 0 patie nts at select sites 
pre-i njecti o n, e n d of i njecti o n, a n d 8 a n d 2 4 h o urs p ost-i nje cti o n (see Secti o n 1 2. 2. 1). 
1 0. 5 
O b s er v ati o n Ar m Pr o c e d ur e s 
1 0. 5. 1 
O b s er v ati o n Ar m: B a s eli n e Vi sit  
T he f oll o wi n g e val uati o ns a n d pr oce d ures m u st ta ke place wit hi n 3 da ys f oll o wi n g 
ra n d o mizati o n, u nless ot her wise n ote d bel o w: 
1.  Rec or d c urre nt me dicati o ns i ncl u di n g c o m plia nce wit h vita mi n s u p ple me ntati o n 
a d mi nistere d fr o m 7 da ys pri or t o ra n d o mizati o n (see Secti o n 1 3 ). 
2.  Assess a n d rec or d B s y m pt o ms. 
3.  Rec or d st u d y- pr oce d ure-relate d A Es a n d attri b uti o n (see 
htt p://cte p.ca ncer. g o v/r e p orti n g/ctc. ht ml). 
4.  Rec or d wei g ht i n k g a n d hei g ht i n c m u p t o 7 da ys pri or t o baseli ne visit. 
5.  L ocal la b orat or y: C ollect bl o o d f or he mat ol o g y a n d c he mistr y (i ncl u di n g baseli ne L D H) 
(see Secti o n 1 2. 1).  
1 0. 5. 2 
O b s er v ati o n Ar m: W e e k 2 of E v er y 4- w e e k P eri o d f or a M a xi m u m of 2 
Y e ar s 
T he patie nt will be c o ntacte d (e g, p h o ne call or c li nic visit) wee k 2 of e ver y 4- wee k peri o d.  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 5 8 of 9 5 
1.  Rec or d A Es a n d attri b uti o n (see htt p ://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml). 
1 0. 5. 3 
O b s er v ati o n Ar m:  E v er y 2 8 d a y s ( ± 3 d a y s) f or a M a xi m u m of 2 Y e ar s 
1.  Rec or d A Es a n d attri b uti o n (see htt p ://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml). 
2.  Assess a n d rec or d B s y m pt o ms. 
3.  Rec or d c urre nt me dicati o ns i ncl u di n g c o m plia nce wit h vita mi n s u p ple me ntati o n. 
4.  Re vie w date of pre vi o us vita mi n B 1 2 i njecti o n.  A d mi nister vita mi n B1 2 1 m g I M 
q 8- 1 0 wee ks. 
5.  L ocal la b orat or y: C ollect bl o o d f or he mat ol o g y a n d c he mistries (i ncl u di n g L D H) (see 
Secti o n 1 2. 1 ). 
1 0. 6 
R e s p o n s e E v al u ati o n  
Res p o nse a n d pr o gressi o n of disease will be e val uate d b y usi n g t he I nter nati o nal W or ks h o p 
Criteria (I W C, A p pe n di x 4 ).  All res p o nses will be e val uate d b y a desi g nate d, i n de pe n de nt 
ce ntral re vie w at least u ntil t he P F S a nal ysis (see Secti o n 1 5. 6. 1 ).  T he i n vesti gat or’s 
assess me nt of res p o nse will als o be c ollecte d.  All necessar y d oc u me ntati o n t o deter mi ne 
res p o nse will be c ollecte d at t he i n vesti gati o nal sites a n d se nt t o t he ce ntral re vie wer.  T he 
first res p o nse e val uati o n is t o occ ur 8 wee ks ( ± 1 wee k) after ra n d o mizati o n.  S u bse q ue nt 
res p o nse e val uati o ns are t o occ ur e ver y 1 2 wee ks ( ± 1 wee k) ti me d fr o m ra n d o mizati o n 
t hr o u g h 3 years p ost-ra n d o mizati o n, t he n e ver y 2 4 wee ks ( ± 4 wee ks) t hr o u g h 7 years p ost-
ra n d o mizati o n.  U nsc he d ule d res p o nse assess me nts will als o be se nt t o  t he ce ntral re vie wer 
f or e val uati o n.  Res p o nse assess me nts will occ ur u ntil P D per ce ntral re vie w, at least u ntil t he 
P F S a nal ysis.   
T he f oll o wi n g pr oce d ures/tests are t o be  perf or me d f or eac h res p o nse e val uati o n: 
1.  Ra di o gra p hic i ma gi n g ( use sa me i ma gi n g t ec h ni q ue as pre- pralatre xate/ o bser vati o n 
scree ni n g):  
•  
C T of c hest, nec k, a b d o me n, a n d pel vis ( M RI all o we d if t he patie nt ca n n ot t olerate 
t he I V c o ntrast) 
•  
W h ole b o d y P E T ( base of s k ull t o mi d-t hi g h) if perf or me d as per l ocal sta n dar d of 
care  
•  
Ot her i ma gi n g tec h ni q ues d oc u me nti n g dise ase site(s) ot her t ha n c hest, nec k, 
a b d o me n, a n d pel vis, if a p plica ble. 
2.  If a p plica ble, assess c uta ne o us disease usi n g me dical p h ot o gra p h y (refer t o St u d y 
I nstr ucti o ns).  
3.  D oc u me nt disease-relate d fi n di n gs per p h ysical e xa mi nati o n. 
4.  If t he patie nt has a C R b y i ma gi n g, a b o ne marr o w bi o ps y/as pirate assess me nt 
(i ncl u di n g i m m u n o hist oc he mistr y) m ust be perf or me d t o c o nfir m C R if b o ne marr o w 
bi o ps y/as pirate res ults were  p ositi ve or i n deter mi nate pri or t o ra n d o mizati o n t o 
pralatre xate/ o bser vati o n.  O nce a patie nt’ s b o ne marr o w is ne gati ve f or l y m p h o ma, t he 
b o ne marr o w bi o ps y/as pirate will be re peate d o nl y w he n cli nicall y i n dicate d u nless it is 
t he patie nt’s o nl y site of disease. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 5 9 of 9 5 
5.  A t u m or bi o ps y ma y be perf or me d if nee de d  t o c o nfir m a res p o nse e val uati o n as per 
i n vesti gat or discreti o n. 
6.  D oc u me nt i n vesti gat or’s assess me nt of res p o nse. 
1 0. 7 
I niti al F oll o w- u p Vi sit  
1 0. 7. 1 
Pr al atr e x at e Ar m 
All patie nts w h o recei ve at leas t 1 d ose of pralatre xate will atte n d t he I nitial F oll o w- u p Visit 
3 5 ( ±  5) da ys after t he last d ose of pralatre xate.   
I n t he e ve nt t he patie nt wit h dra ws c o nse nt t o a n y f urt her st u d y partici pati o n a n d ref uses t o 
atte n d t he I nitial F oll o w- u p Visit, t he f oll o wi n g pr oce d ures a n d e val uati o ns m ust be 
perf or me d a t t he ti me t he patie nt wit h dra ws c o nse nt. 
1.  Rec or d c o nc o mita nt me dicati o ns t hr o u g h 3 0 da ys after t he last pralatre xate d ose. 
2.  Rec or d all A Es a n d attri b uti o n t hr o u g h 3 0 da ys after t he last pralatre xate d ose.  Fr o m 
3 1 da ys after t he last pralatre xate d ose,  o nl y rec or d pralatre xate-relate d A Es a n d 
attri b uti o n (see htt p://cte p.ca n cer. g o v/re p orti n g/ctc. ht ml).  
3.  Assess a n d rec or d B s y m pt o ms. 
4.  Perf or m p h ysical e xa mi nati o n.  D oc u me nt a n y ne w or w orse ne d fi n di n gs as A Es. 
5.  Assess a n d rec or d E C O G perf or ma nce stat us (see A p pe n di x 3 ). 
6.  L ocal la b orat or y: c ollect bl o o d f or he mat ol o g y a n d ser u m c he mistr y (i ncl u di n g L D H, 
see Secti o n 1 2. 1 ).  
7.  Re vie w d osi n g of f olic aci d a n d d oc u me nt c o m plia nce.  
8.  I nstr uct patie nt t o disc o ntin ue f olic aci d a n d vita mi n B 1 2. 
9.  Rec or d reas o n f or disc o nti n uati o n of pralatre xate ( Secti o n 1 1. 1 ). 
1 0.  Rec or d first s u bse q ue nt t hera p y f or P T C L, if a p plica ble.   
 
1 0. 7. 2 
O b s er v ati o n Ar m 
Patie nts w h o are ra n d o mize d t o t he O bser vati o n Ar m will atte n d t he I nitial F oll o w- u p Visit 
3 5 da ys ( ± 5 da ys) after st u d y treat me nt disc o nti n uati o n criteria are m et.   
I n t he e ve nt t he patie nt wit h dra ws c o nse nt t o a n y f urt her st u d y partici pati o n a n d ref uses t o 
atte n d t he I nitial F oll o w- u p Visit, t he f oll owi n g pr oce d ures a n d e val uati o ns m ust be 
perf or me d at t he ti me t he pa tie nt wit h dra ws c o nse nt. 
1.  Rec or d c o nc o mita nt me dicati o ns t hr o u g h 3 0 da ys after st u d y treat me nt disc o nti n uati o n 
criteria ( Secti o n 1 1. 1) are met.  
2.  Rec or d all A Es a n d attri b uti o n (see htt p://cte p.ca ncer. g o v/ re p orti n g/ctc. ht ml) t hr o u g h 
3 0 da ys after st u d y treat me nt disc o nti n uati o n criteria ( Secti o n 1 1. 1) are met.  
3.  Assess a n d rec or d B s y m pt o ms. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 6 0 of 9 5 
4.  Perf or m p h ysical e xa mi nati o n.  D oc u me nt a n y ne w or w orse ne d fi n di n gs as A Es.  
5.  Assess a n d rec or d E C O G perf or ma nce stat us (see A p pe n di x 3 ). 
6.  L ocal la b orat or y: c ollect bl o o d f or he mat ol o g y a n d ser u m c he mistr y (i ncl u di n g L D H, 
see Secti o n 1 2. 1 )  
7.  Re vie w d osi n g of f olic aci d a n d d oc u me nt c o m plia nce. 
8.  I nstr uct patie nt t o disc o nti n ue f olic aci d a n d vita mi n B 1 2. 
9.  Rec or d reas o n f or disc o nti n uati o n of o bser vati o n ( Secti o n 1 1. 1 ). 
1 0.  Rec or d first s u bse q ue nt t hera p y f or P T C L, if  a p plica ble.  First s u bse q ue nt t hera p y f or 
P T C L is at t he i n vesti gat or’s disc reti o n a n d ca n i ncl u de pralatre xate. 
1 0. 8 
F oll o w- u p Vi sit s 
All patie nts w h o are ra n d o mize d are t o ha ve  f oll o w- u p as o utli ne d bel o w u ntil o bjecti vel y 
d oc u me nte d P D; t hereafter, patie nts are f oll o we d f or s ur vi val.  T he ti mi n g of f oll o w- u p will 
be at 8 wee ks ( ± 1 wee k), t he n e ver y 1 2 wee ks ( ± 1 wee k) t hr o u g h 3 years p ost-
ra n d o mizati o n, a n d t he n e ver y 2 4 wee ks (± 4 wee ks) t hereafter t hr o u g h 7 years p ost-
ra n d o mizati o n.  P D will be c o nfir me d b y ce ntral re vie w u ntil t he fi rst P F S a nal ysis, see 
Secti o n 1 5. 6. 1 , a n d per i n vesti gat or assess me nt t hereafter. 
T he f oll o wi n g pr oce d ures/e val uati o ns m ust be perf or me d at eac h f oll o w- u p ti me p oi nt. 
1.  Rec or d st u d y-treat me nt-relate d A Es (see htt p://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml). 
2.  E val uati o n of res p o nse (see Secti o n 1 0. 6  f or tests a n d pr oce d ures). 
3.  Rec or d s u bse q ue nt t hera pies f or P T C L a n d d oc u me nt t he best res p o nse t o t he first 
s u bse q ue nt t hera p y.  
1 0. 9 
L o n g-t er m F oll o w- u p  
All s u bse q ue nt t hera pies f or P T C L will be c o llecte d f or u p t o 7 years fr o m ra n d o mizati o n 
a n d t he best res p o nse t o t he first s u bse q ue nt t hera p y will be d oc u me nte d.  O nce patie nts ha ve 
d oc u me nte d P D, s ur vi val stat us a n d s u bse q ue nt t hera pies will be c ollecte d o n all patie nts 
a p pr o xi matel y e ver y 6 m o nt hs t hr o u g h 7 years fr o m ra n d o mizati o n.   
1 1 D U R A TI O N O F T R E A T M E N T 
All patie nts are free t o wit h dra w  fr o m partici pati o n i n t his st u d y at a n y ti me, f or a n y reas o ns, 
s pecifie d or u ns pecifie d, a n d wit h o ut prej u dice.  T he reas o n f or t he patie nt disc o nti n ui n g 
pralatre xate/ o bser vati o n or ter mi nati n g fr o m t he st u d y m ust be rec or de d o n t he case re p ort 
f or m ( C R F).  Pralatre xate will c o nti n ue t o be a d mi nistere d u ntil a criteri o n f or st u d y 
treat me nt disc o nti n uati o n is met (Secti o n 7. 3 ) or u p t o a ma xi m u m of 2 years. 
1 1. 1 
Crit eri a f or St u d y Tr e a t m e nt Di s c o nti n u ati o n  
Patie nts will recei ve st u d y treat me nt ( pralatre x ate or o bser vati o n) u ntil o ne of t he f oll o wi n g 
criteria f or st u d y treat me nt  disc o nti n uati o n a p plies: 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 6 1 of 9 5 
• 
De vel o p me nt of P D  
• 
I nitiati o n of R T or s yste mic c he m o/ biol o gical t hera p y f or treat me nt of P T C L 
• 
Recei pt of s yste mic ster oi ds > 1 0 da ys, wit h t he e xce pti o n of t h ose as state d i n e xcl usi o n 
criteri o n # 5 (see Secti o n 8. 4 ) 
• 
De vel o p me nt of a n A E t hat i nterferes wit h t he patie nt’s partici pati o n 
• 
L ost t o f oll o w- u p 
• 
Patie nt decisi o n 
• 
I n vesti gat or decisi o n 
• 
S p o ns or decisi o n 
I n a d diti o n, f or t h ose patie nts ra n d o mize d t o t he Pralatre xate Ar m, a d diti o nal pralatre xate 
treat me nt disc o nti n uati o n criteria are: 
• 
3 or m ore c o nsec uti ve d oses of pralatre xate o mitte d or m ore t ha n 2 8 da ys bet wee n d oses 
of pralatre xate  
• 
Treat me nt wit h pralatre xate f or 2 years 
Patie nts will be see n f or t he I nitial F o ll o w- u p Visits as o utli ne d i n Secti o n 1 0. 7 . 
If a n i n vesti gat or feels t hat a patie nt w o ul d c o nti n ue t o be nefit fr o m pralatre xate t hera p y after 
c o m pleti o n of 2 years’ t hera p y, t he y s h o ul d di sc uss wit h t he s p o ns or’s me dical c o ntact a n d 
a gree w het her or n ot it is a p pr o priate t o c o nti n ue treat me nt. 
1 2 L A B O R A T O R Y T E S T S 
1 2. 1 
L o c al L a b or at or y T e st s 
T he f oll o wi n g pa nels will be d o ne l ocall y wit h t he desi g nate d tests.  C o pies of c urre nt 
la b orat or y certificati o ns a n d n or mal ra n ges will be pr o vi de d t o All os at st u d y start a n d u p o n 
e ver y re ne wal t hr o u g h o ut t he d urati o n of pr alatre xate or o bser vati o n f or t he l o n gest 
partici pati n g patie nt at t he site. 
1 2. 1. 1 
H e m at ol o g y 
Tests t o be c o n d ucte d are w hite bl o o d cell ( W B C) c o u nt, he m o gl o bi n ( H g b) c o nce ntrati o n, 
he mat ocrit ( Hct), platelet c o u nt, a n d A N C. 
1 2. 1. 2 
C h e mi str y 
Tests t o be c o n d ucte d are creati n i ne, t otal bilir u bi n, A S T, A L T, L D H, t otal pr otei n, al b u mi n, 
a n d β - h C G pre g na nc y test at scree ni n g (if a p plica ble). 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 6 2 of 9 5 
1 2. 2 
C e ntr al L a b or at or y 
1 2. 2. 1 
Pl a s m a P h ar m a c o ki n eti c s 
At sites partici pati n g i n plas ma sa m pli n g f or P K a nal ysis, a p pr o xi matel y 2 4 5 patie nts 
ra n d o mize d t o t he Pralatre xate Ar m (t w o-t hir ds of t he pla n ne d t otal) w h o c o nse nt t o plas ma 
sa mpli n g will ha ve sa m pli n g perf or me d at c ycl e 1, d ose 1 ( pre-i njecti o n, e n d of i njecti o n, 
a n d 8 a n d 2 4 h o urs p ost-i njecti o n).  Of t hese 2 4 5 pa tie nts, 2 0 patie nts at select sites will als o 
ha ve plas ma sa m pli n g perf or me d at c ycle 2, d os e 3 ( pre-i njecti o n, e n d of  i njecti o n, a n d 8 a n d 
2 4 h o urs p ost- i njecti o n). 
Plas ma sa m ples will be s plit i n 2 e q ual ali q u ots a n d fr oze n i n se parate t u bes f or a nal ysis of 
pralatre xate c o nce ntrati o n.  T he c o nce ntrati o ns  of pralatre xate at eac h ti me- p oi nt will be 
deter mi ne d usi n g vali date d bi oa nal ytical met h o ds at M PI Researc h.  See St u d y I nstr ucti o ns 
pr o vi de d b y All os/ desi g nee f or detaile d g ui da n ce re gar di n g t he c ollect i o n, pr ocessi n g, a n d 
s hi p me nt of sa m ples. 
Sta n dar d P K para meters will be esti mate d fr o m t he li mite d plas ma sa m pli n g (e g, area u n der 
t he c ur ve [ A U C], ma xi m u m c o nce ntrati o n [ Cma x ], a n d half-life [t1/ 2]), a n d P O P P K a nal yses 
will be c o n d ucte d via n o nli near mi xe d-effects m o deli n g t o esti mate P O P P K para meters f or 
pralatre xate. 
1 2. 2. 2 
I n d e p e n d e nt P at h ol o g y R e vi e w 
C o nfir mati o n of P T C L hist o pat h ol o g y s u bt y pe will be perf or me d b y a n i n de pe n de nt 
pat h ol o g y re vie wer.  Pat h ol o g y s peci me ns fr o m t he patie nt’s i nitial dia g n osis will be se nt t o 
i n de pe n de nt pat h ol o g y re vie w.  C o nfir mati o n of a n eli gi ble  P T C L hist o pat h ol o g y s u bt y pe 
m ust be d oc u m e nte d b y t he i n de pe n de nt pat h ol o g y re vie wer pri or t o  ra n d o mizati o n.  See 
St u d y I nstr ucti o ns pr o vi de d b y All os/ desi g n ee f or detaile d g ui da nce re gar di n g sa m ple 
re q uire me nts a n d t he pre parati o n a n d s hi p me nt of sli des.  
1 2. 2. 3 
M e di c al P h ot o gr a p h y 
D oc u me ntati o n of c uta ne o us disease wit h me di cal p h ot o gra p h y will be perf or me d b y t he site 
at scree ni n g a n d at eac h res p o nse assess me nt, if a p plica ble.   Up t o 5 tar get lesi o ns will be 
c h ose n b y t he i n vesti gat or a n d p h ot o gra p he d.   See St u d y I nstr ucti o ns pr o vi de d b y t he ce ntral 
me dical p h ot o gra p h y la b orat or y ( C a nfiel d Scie ntific, I nc.) f or detaile d g ui da nce re gar di n g 
p h ot o gra p h re q uire me nts a n d tra nsfer. 
1 2. 2. 4 
C e ntr al R a di ol o g y I m a gi n g 
Ra di ol o gic i ma gi n g of eac h pati e nt will be c o m plete d at scree ni n g a n d at eac h res p o nse 
assess me nt as descri be d i n Secti o ns 1 0. 1  a n d 1 0. 6 .  All sca ns will be se nt t o a desi g nate d, 
i n de pe n de nt ce ntral re vie wer u ntil at least t he first i nteri m a nal ysis.   See St u d y I nstr ucti o ns 
pr o vi de d b y t he ce ntral re vie wer ( C ore La b Part ners) f or detaile d g ui da nce re gar di n g i ma gi n g 
re q uire me nts a n d tra nsfer. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 6 3 of 9 5 
1 3 C O N C O MI T A N T M E DI C A TI O N S 
All me dicati o ns a d mi nistere d fr o m 7 da ys pr i or t o ra n d o mizati o n t hro u g h 3 0 da ys after t he 
last pralatre xate a d mi nistratio n, or t hr o u g h 3 0 da ys after treat m e nt disc o nti n uati o n criteria are 
met f or patie nts i n t he O bser vati o n Ar m, will be  rec or de d o n t he C R F.  A d diti o ns, deleti o ns, 
or c ha n ges of d osa ge of me dicati o ns will als o be n ote d. 
1 3. 1 
A nti e m eti c T h er a p y 
T here is n o e vi de nce t o e x pect dr u g- dr u g i ntera cti o ns bet wee n pralatre xate a n d sta n dar d 
a ntie metic t hera p y a n d n o s pecific a ntie metic t hera p y has yet bee n pr o ve n t o be s u peri or o ver 
ot hers i n t he setti n g of pralat re xate a d mi nistrati o n.  T heref ore, pr o p h yla xis a n d treat me nt of 
na usea a n d v o miti n g ca n be a d mi nistere d acc or d i n g t o t he sta n dar d of care wit hi n t he 
i nstit uti o n; h o we ver, a d mi nistrati o n is n ot rec o m me n de d pri or t o t he first d ose beca use of t he 
l o w e met o ge nicit y of pralatre xate.   
Ster oi ds are n ot all o we d f or pr o p h yla xis or treat me nt of na usea/ v o miti n g. 
1 3. 2 
H e m at o p oi eti c Gr o wt h F a ct or s 
He mat o p oietic gr o wt h fact ors ma y be a d mi nistere d i n acc or da nce wit h t he i nstr ucti o ns f or 
treat me nt m o dificati o n f or he mat ol o gical e ve nts i n Ta ble 7. 1 .  Er yt hr o p oieti n will be all o we d 
if it is j u d ge d b y t he i n vesti gat or t o be i n t he best i nterest of t he patie nt (e g, f or patie nts wit h 
u n derl yi n g a ne mia or u nacce pta ble he mat ol o gic t o xicit y).  Ot her he mat o p oietic gr o wt h 
fact ors (e g, gra n ul oc yte c ol o n y-sti m ulati n g fact or [ G- C S F], gra n ul oc yte- macr o p ha ge c ol o n y-
sti m ulati n g fact or [ GM- C S F]), wit h t he e xce pti o n of pe gfil grasti m ( Ne ulasta
® , A m ge n), are 
t o be a d mi nistere d per pac ka ge i nsert.   
1 3. 3 
M u c o siti s M a n a g e m e nt 
Patie nts recei vi n g pralatre xate s h o ul d be assesse d f or ris k of  m uc ositis pri or t o start of 
treat me nt wit h c o nti n ue d assess me nt f or s y m pt oms pri or t o eac h d ose.  Me dicati o ns a n d 
m o ut h was hes, i ncl u di n g salt a n d s o da m o ut h was hes, use d f or pro p h yla xis a n d/ or treat me nt of 
m uc ositis m ust be rec or de d as c o nc o mita nt me dicati o ns.  D ose m o dificati o ns f or m uc ositis 
are f o u n d i n Ta ble 7. 2 ; h o we ver, i n vesti gat ors s h o uld refer t o t he Nati o nal C o m pre he nsi ve 
Ca ncer Net w or k ( N C C N) Tas k F orce Re p ort f or t he Pre ve nti o n a n d Ma na ge me nt of 
M uc ositis i n Ca ncer Care f or assista n ce wit h ris k assess me nt a n d gra di n g of m uc ositis, 
g ui da nce o n s y m pt o m ma na ge me nt, a n d patie n t e d ucati o n t o ols o n effecti ve oral care 
re gi me ns a n d re p orti n g of m uc ositis s y m pt o ms.3 5 
1 3. 4 
C orti c o st er oi d U s e 
Patie nts are all o we d t o be gi n st u d y treat me nt w hile recei vi n g s yste m ic c ortic oster oi ds 
pr o vi de d t he patie nt has bee n  ta ki n g a c o nti n u o us d ose of ≤ 1 0 m g/ da y of oral pre d nis o ne or 
e q ui vale nt f or at least 4 wee ks or as part of a C H O P pre d nis o ne ta per.  Ot her c o nc o mita nt 
s yste mic c ortic oster oi d t herap y d uri n g t he pralatre xate treat m e nt/ o bser vati o n p hase of t his 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 6 4 of 9 5 
st u d y is pr o hi bite d ( wit h e xce pti o n of c orticoster oi ds a d mi nistere d  f or a n o n-l y m p h o ma 
c o n diti o n, e g, br o nc hitis, f or ≤ 1 0 da ys).  I n hale d or t o pical ster oi ds (a d mi nistere d f or reas o ns 
ot her t ha n t o treat c uta ne o us disease) are all o we d. 
1 3. 5 
Pr o p h yl a cti c A nti-i nf e cti v e A g e nt s 
Use of pr o p h ylactic a nti bi otics/a nti virals/a ntif u n gals is  all o we d a n d ma y be a d mi nistere d at 
t he discreti o n of t he i n vesti gator.  If a nti bi otic pr o p h yla xis is i n dicate d, alter nati ves t o 
s ulfa met h o xaz ole/tri met h o pri m m ust be c o nsi dere d as it has a ntif olate acti vit y.  D ue t o t he 
p ossi bilit y of a d diti ve t o xicit y (i ncl u di n g m yel os u p pressi o n) w he n use d i n c o m bi nati o n wit h 
pralatre xate, c o nc urre nt use of t he 2 dr u gs s h o ul d be a v oi de d. 
1 3. 6 
P ai n M a n a g e m e nt 
Pai n ma na ge me nt s h o ul d be a d dresse d pr o m ptl y b y t he atte n di n g p h ysicia n ma na gi n g t he 
patie nt.  D ue t o t he c o ntri b uti o n of re nal e xcreti o n (a p pr o xi matel y 3 4 %) t o t he o verall 
cleara nce of pralatre xate, c o nc o mita nt a d mi nistrati o n of n o n- ster oi dal a nti-i nfla m mat or y 
dr u gs ( N S AI Ds) a n d pr o be neci d ma y res ult i n de la ye d cleara nce of pralatre xate.  T hese dr u gs 
s h o ul d be use d wit h ca uti o n w hile patie nts are e nr olle d i n t his st u d y; alter nati ves t o N S AI Ds 
a n d pr o be neci d s h o ul d be c o nsi dere d w he n p ossi ble. 
1 3. 7 
Bl o o d Pr o d u ct s 
Bl o o d pr o d uct tra nsf usi o ns are all o we d pe r t he discreti o n of t he i n vesti gat or. 
1 3. 8 
Ot h er S u p p orti v e C ar e M e di c ati o n s 
T he a d mi nistrati o n of a p petite -sti m ulati n g h or m o nes (e g, me gestr ol acetate) is all o we d t o 
c o ntr ol a n ore xia a n d cac he xia. 
1 3. 9 
R a di ot h er a p y, C yt ot o xi c T h er a p y,  Bi ol o gi c T h er a p y, or I m m u n e 
R e s p o n s e M o difi er s 
N o R T, ot her c yt ot o xic a ge nts, bi ol o gic t her a p y, i m m u ne res p o nse m o difiers, or ste m cell 
tra ns pla nt are t o be a d mi nistere d t o patie nts u ntil pralatre xate/ o bser vati o n has bee n 
disc o nti n ue d.   


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 6 5 of 9 5 
1 4 A D V E R S E E V E N T S 
1 4. 1 
D efi niti o n 
A n A E is defi ne d as a n y u nt o war d me dical occ u rre nce i n a patie nt or cli nical i n vesti gati o n 
patie nt, te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d 
relate d t o t he me dici nal pr o d uct.  T heref ore, a n A E ca n be a n y u nfa v ora ble a n d u ni nte n de d 
si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease ( ne w or e xacer bate d) 
te m p orall y ass ociate d wit h t he use of a me dicinal pr o d uct.  T his defi niti o n of a n A E will be 
e xte n de d i n t his st u d y t o i ncl u de  a n y u nt o war d me dical occ urre nce i n patie nts partici pati n g i n 
t he O bser vati o n Ar m of t he st u d y, as well. 
T he ter m “t o xicit y” is n ot clearl y defi ne d b y re g ulat or y or ga nizati o ns a n d is c urre ntl y use d 
o nl y f or hist orical reas o ns b y t he N CI.  T her ef ore, t he ter m “a d verse e ve nt” is use d 
t hr o u g h o ut t his d oc u me nt t o refer t o a n y u nfav ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), s y m pt o m, or diseas e te m p orall y ass ociate d wit h t he st u d y dr u g, 
as well as a n y ot her st u d y-treat me nt-relate d t o xicities.  H o we ver, si nce t his is a n 
i n vesti gati o nal st u d y, all t o xicities are c o nsi dere d A Es a n d m ust be re p orte d. 
E xa m ples of a n A E i ncl u de: 
• 
E xacer bati o n of a c hr o nic or i nter mitte nt pre-e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncrease i n fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n. 
• 
Ne w c o n diti o ns detecte d or dia g n ose d after i n vesti gati o nal pr o d uct a d mi nistrati o n, e ve n 
t h o u g h it ma y ha ve bee n prese nt pri or t o t he start of t he st u d y. 
• 
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g i nteracti o n. 
• 
Si g ns, s y m pt o ms, or t he cli nical se q uel ae of a s us pecte d o ver d ose of eit her 
i n vesti gati o nal pr o d uct or a c o nc urre nt me dicati o n. 
• 
A Es ma y i ncl u de pre-treat me nt or p ost-treat me nt e ve nts t hat occ ur as a res ult of pr ot oc ol-
ma n date d pr oce d ures (ie, i n vasi ve pr oce d ures, m o dificati o n of patie nt’s pre vi o us 
t hera pe utic re gi me n). 
E xa m ples of a n A E d o n ot i ncl u de  a/a n: 
• 
Me dical or s ur gical pr oce d ures (e g, e n d os c o p y, a p pe n dect o m y); t he c o n diti o n t hat lea ds 
t o t he pr oce d ure is a n A E. 
• 
Sit uati o ns w here a n u nt o war d me dical o cc urre nce d oes n ot occ ur (e g, s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital). 
• 
A ntici pate d da y-t o- da y fl uct uati o ns of pre-e x isti n g disease(s) or co n diti o n(s) prese nt or 
detecte d at t he start of t he st u d y t hat d o n ot w orse n. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 6 6 of 9 5 
1 4. 2 
G ui d eli n e s f or R e c or di n g a n d A ttri b uti o n S c ori n g of A d v er s e 
E v e nt s 
Ti mel y a n d c o m plete re p orti n g of A Es is esse ntial.  M o nit ori n g a n d d oc u me ntati o n of all 
A Es all o ws f or i de ntificati o n of p ote ntial st u d y - dr u g or d ose-relate d A Es, a n d f or a d here nce 
t o re g ulat or y re q uire me nts.  Please refer t o t he C R F C o m pleti o n G ui deli nes l ocate d i n t he 
st u d y bi n der f or detaile d i nstr ucti o ns. 
1 4. 3 
R e c or di n g of A d v er s e E v e nt s 
1 4. 3. 1 
R e c or di n g of A d v er s e E v e nt s  
A n y A E t hat occ urs fr o m t he ti me t he st u d y I C  is o btai ne d u ntil ra n d o mizati o n nee ds t o be 
rec or de d o n t he A E C R F pa ge(s), o nl y  if t he e ve nt was relate d t o a st u d y pr oce d ure.  All 
ot her A Es/fi n di n gs pri or t o ra n d o mizati o n m ust  be rec or de d as baseli ne fi n di n gs o n t he 
a p plica ble C R F pa ge(s). 
A n y A E t hat occ urs fr o m ra n d o mizati o n t hr o u g h 3 0 da ys after t he last d ose of pralatre xate or 
t hr o u g h 3 0 da ys after treat me nt disc o nti n uatio n criteria are met f or t he O bser vati o n Ar m 
m ust be rec or de d o n t he A E C R F.  Fr o m 3 1 da ys  after t he last d ose of pralatre xate, o nl y A Es 
t hat are relate d t o pralatre xate nee d t o be ca pt ure d o n t he A E C R F.  
1 4. 3. 2 
Gr a di n g of A d v er s e E v e nt s 
T his st u d y will utilize t he N C I C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) 
Scale, Versi o n 4. 0 f or A E gra di n g ( htt p ://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml). 
1 4. 4 
F oll o w- u p of A d v er s e E v e nt s 
All A Es a n d si g nifica nt a b n or mal la b orat or y val ues m ust be f oll o we d u p i n acc or da nce wit h 
t he I C H G o o d Cli nical Practice ( G C P) g ui deli nes, a n d ot her a p plica ble re g ulat or y 
re q uire me nts (e g, U S C o de of Fe deral Re g ulati o ns [ C F R]). 
1 4. 5 
R el ati o n s hi p 
T he relati o ns hi p of t he e ve nt t o pralatre xate wi ll be assesse d usi n g t he f oll o wi n g defi niti o ns: 
N ot Rel ate d : 
E vi de nce e xists t hat t he A E ha s a n eti ol o g y ot her t ha n pralatre xate (s uc h as, pre-e xisti n g 
c o n diti o n, u n derl yi n g disease, i nterc urre nt ill ness, or c o nc o mita nt me dicati o ns). 
Rel ate d : 
A te m p oral relati o ns hi p e xists bet wee n t he e ve n t o nset ( or w orse ni n g) a n d t he a d mi nistrati o n 
of pralatre xate.  It ca n n ot be rea dil y e x plai ne d b y t he patie nt’s cli nical state,  i nterc urre nt 
ill ness, or c o nc o mita nt me dicati o ns.  I n case of cessati o n or re d ucti o n of t he d ose, t he e ve nt 
a bates or res ol ves, a n d it rea p pears u p o n c halle n ge. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 6 7 of 9 5 
It s h o ul d be e m p hasize d t hat i neffecti ve treat me nt s h o ul d n ot be c o nsi dere d as ca usall y 
relate d i n t he c o nte xt of A E re p orti n g. 
T hese criteria, i n a d diti o n t o g o o d cli nical j u d g me nt, s h o ul d be use d as a g ui de f or 
deter mi ni n g t he ca usal assess me nt. 
1 4. 6 
S eri o u s A d v er s e E v e nt s 
I n t he i nterest of patie nt care a n d t o all o w All os t o f ulfill all re g ulat or y re q uire me nts, a n y 
seri o us a d verse e ve nt ( S A E), re gar dless of ca usal relati o ns hi p t o pralatre xate, m ust be 
re p orte d t o All os wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt. 
1 4. 6. 1 
D efi niti o n 
S A Es are defi ne d ( C F R 3 1 2. 3 2, I C H of Tec h nical Re q uire me nts f or Re gistrati o n of 
P har mace uticals f or H u ma n Use E 2 A G ui deli ne) as  t h ose A Es t hat meet a n y of t he f oll o wi n g 
criteria: 
• 
Res ults i n deat h. 
• 
Is life-t hreate ni n g: ie, a n y e ve nt t hat, i n t he o pi ni o n of t he i n vesti gat or, p oses a n 
i m me diate ris k of deat h fr o m t hat e ve nt. 
• 
Re q uires i n patie nt h os pitaliza ti o n or pr ol o n gati o n of e xistin g h os pitalizati o n (e xcl u di n g 
h os pitalizati o ns f or st u d y t hera p y, disease- relate d pr oce d ures, or place me nt of a n 
i n d welli n g cat heter, u nless ass ociate d wit h ot her S A Es). 
• 
Res ults i n a persiste nt or si g nifica nt disa bilit y/i nca pacit y. 
• 
Res ults i n a c o n ge nital a n o mal y/ birt h defect. 
• 
I ncl u des i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life-t hreate ni n g or res ult 
i n deat h or h os pitalizati o n b ut ma y je o par dize t he patie nt or ma y req uire i nter ve nti o n t o 
pre ve nt 1 of t he o utc o mes lis te d i n t his defi niti o n. 
1 4. 6. 2 
S eri o u s A d v er s e E v e nt R e p orti n g 
• 
A n y S A E t hat occ urs fr o m t he ti me t he st u d y I C is o btai ne d u ntil ra n d o mizati o n nee ds t o 
be re p orte d o nl y if t he e ve nt was relate d t o a st u d y pr oce d ure. 
• 
A n y S A E t hat occ urs fr o m ra n d o mizati o n t h r o u g h 3 0 da ys after t he last d ose of 
pralatre xate or t hr o u g h 3 0 da ys after treat me nt disc o nti n ua ti o n criteria are met f or t he 
O bser vati o n Ar m m ust be re p orte d t o All os wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt.  
Fr o m 3 1 da ys after t he last d ose of pralatre xate, patie nts will c o nti n ue t o be assesse d f or 
S A Es t hat are relate d t o pralatre xate. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 6 8 of 9 5 
• 
S A Es (re gar dless of ca usalit y) m ust  be re p orte d a n d t he S A E R fa xe d wit hi n 2 4 h o urs of 
k n o wle d ge of t he e ve nt t o : 
All os T hera pe utics, I nc. 
Pri mar y C o ntact: Cli nical Dr u g Safet y a n d 
P har mac o vi gila nce De part me nt 
P h o ne: 
 
Fa x: 
 or 
 
E mail: all os dr u gsafet y @all os.c o m 
All os ma y re q uest a d diti o nal i nf or mati o n fr o m  t he i n vesti gat or t o e ns ure t he ti mel y 
c o m pleti o n of acc urate safet y re p orts.  Safet y data  t hat are critical t o t he re p orta bilit y of a n 
S A E, s uc h as ca usalit y assess me n t a n d seri o us criteria, s h o ul d be i ncl u de d i n t he i nitial fa x 
f or S A E R.  If o mitte d, a ti mel y res p o nse t o dr u g safet y data q ueries recei ve d fr o m All os or 
a n All os desi g nee is e x pecte d. 
T he i n vesti gat or m ust ta ke all t hera pe utic m eas ures necessar y f or res ol uti o n of t he S A E.  
A n y me dicati o ns necessar y f or tr eat me nt of t he S A E m ust be r ec or de d o nt o t he c o nc o mita nt 
me dicati o n secti o n of t he patie nt’s C R F. 
S A Es t hat are pralatre xate-relate d will be  f oll o we d u ntil res ol uti o n or ret ur ne d t o 
baseli ne/ Gra de 1, w hic he ver is l o n ger, or u ntil  it is deter mi ne d t hat t he o utc o me will n ot 
c ha n ge wit h f urt her f oll o w- u p. 
A d diti o nall y, t he S A E m ust be  e ntere d o n t he A E pa ge(s) of t he C R F.  F oll o w- u p S A E Rs 
nee d t o be s u b mitte d t o All os as s o o n as a d diti o nal i nf or mati o n re gar di n g t he e ve nt bec o mes 
a vaila ble (e g, dia g n osis is ma de, la b orat or y or test res ults, e ve nt c o urse, o utc o me, etc).  T he 
All os C R A or desi g nee will c ollect t h e ori gi nal S A E R fr o m t he site. 
All os/ desi g nee will be res p o nsi ble f or re p orti n g S A Es t o t he re g ulat or y a ut h orities i n 
acc or da nce wit h a p plica ble e x pe dite d re p orti n g re g ulat or y g ui deli nes.  T he i n vesti gat or is 
res p o nsi ble f or s u b mitti n g S A Es t o his/ her I nstit uti o nal Re vie w B oar d (I R B)/ Et hics 
C o m mittee ( E C)/ Researc h Et hics B oar d ( R E B). 
1 4. 6. 3 
E x cl u si o n s t o S eri o u s A d v er s e E v e nt R e p orti n g R e q uir e m e nt s 
T he f oll o wi n g are n ot c o nsi dere d S A Es: 
• 
Sit uati o ns w here a n u nt o war d me dical occ urre nce di d n ot occ ur (e g, s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital). 
• 
A ntici pate d da y-t o- da y fl uct uati o ns of pre-e x isti n g disease(s) or co n diti o n(s) prese nt or 
detecte d pri or t o ra n d o mizati o n t hat d o n ot w orse n. 
• 
Electi ve h os pitalizati o ns s olel y f or t he i nitia ti o n of s u bse q ue nt t hera p y f or t he disease 
bei n g st u die d. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 6 9 of 9 5 
1 4. 7 
R e pr o d u cti v e Ri s k s 
Pralatre xate m ust n ot be use d  d uri n g pre g na nc y or breastfee din g.  Pre- me n o pa usal fe males of 
c hil d beari n g p ote ntial will f oll o w a n a p pr o ve d, me dicall y acce pte d birt h c o ntr ol re gi me n 
(e g, birt h c o ntr ol pills, i ntra uteri ne de vice, c o n d o ms, i m pla nts) or a gree t o a bstai n fr o m 
heter ose x ual i nterc o urse w hile partici pati n g i n  t he st u d y a n d f or 3 0 da ys f oll o wi n g t he last 
d ose of pralatre xate.   
Males w h o are se x uall y acti ve m ust a gree t o practice a me dicall y acce pta ble barrier met h o d 
c o ntrace pti ve re gi me n (e g, c o n d o ms) or a gree t o  a bstai n fr o m heter ose x ual i nterc o urse w hile 
recei vi n g pralatre xate a n d f or 9 0 da ys after t he last a d mi nistrati o n of pralatre xate. 
1 4. 7. 1 
Pr e g n a n c y N otifi c ati o n 
Pre g na ncies i n v ol vi n g a st u d y patie n t or a patie nt’s part ner t hat occ ur fr o m t he first d ose of 
pralatre xate t hr o u g h 3 0 da ys afte r t he last d ose of pralatre xate m ust be br o u g ht t o t he 
atte nti o n of t he treati n g p h ysicia n i m me diatel y a n d re p orte d t o All os w it hi n 2 4 h o urs after t he 
i n vesti gat or has gai ne d k n o wle d ge of t he e ve nt, usi n g t he Pre g na nc y N otificati o n F or m.  T he 
i n vesti gat or m ust re p ort a n y s uc h e ve nt t o All os wit hi n 2 4 h o urs via tele p h o ne a n d via fa x 
(see c o ntact i nf or mati o n i n Secti o n 1 4. 6. 2 ).  F oll o w- u p i nf or mati o n re gar di n g t he o utc o me of 
t he pre g na nc y will be re q ueste d b y t he All os Cli nical Dr u g Safet y a n d P har mac o vi gila nce 
De part me nt.  
Treat me nt will be disc o n ti n ue d f or all patie nts w h o bec o me pre g na nt d uri n g partici pati o n i n 
t his st u d y. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 0 of 9 5 
1 5 S T A TI S TI C A L P L A N  
1 5. 1 
O bj e cti v e s 
Pri mar y  
• 
Deter mi ne t he efficac y of pralatre xate c o m p are d t o o bser vati o n w he n a d mi nistere d t o 
patie nts wit h pre vi o usl y u n dia g n ose d P T C L  w h o ha ve ac hie ve d a n o bjecti ve res p o nse 
after c o m pleti n g at least 6 c ycl es of C H O P- base d treat me nt. 
Sec o n dar y  
• 
Deter mi ne t he safet y of pralatre xate w h e n a d mi nistere d f oll o wi n g a c o urse of 
C H O P- base d treat me nt t o patie nts wit h pre vi o usl y u n dia g n ose d P T C L. 
1 5. 2 
E n d p oi nt s 
1 5. 2. 1 
Effi c a c y E n d p oi nt s 
Pri mar y  
• 
P F S a n d O S. 
Sec o n dar y  
• 
O bjecti ve res p o nse ( C R or P R) t o pralatre xate vers us o bser vati o n. 
T he pri mar y a nal yses of P F S a n d res p o nse will us e t he ce ntral re vie w t u m or assess me nts per 
I W C wit h o ut usi n g P E T.  A d diti o nal a nal yses of P F S a n d res p o nse will use I W C, i ncl u di n g 
P E T, a n d i n vesti gat ors’ assess me nt of res p o nse. 
1 5. 2. 2 
S af et y E n d p oi nt s 
T he safet y e n d p oi nts i ncl u de: 
• 
I nci de nce a n d se verit y of treat me nt-e mer ge nt A Es. 
• 
C ha n ges i n la b orat or y val ues. 
1 5. 3 
A n al y si s P o p ul ati o n 
1 5. 3. 1 
Pri m ar y A n al y si s S et/I nt e nt-t o-tr e at A n al y si s S et 
T he pri mar y efficac y set, als o referre d t o as t he i nte nt-t o-treat p o p ulati o n, i ncl u des all 
ra n d o mize d patie nts.  Eac h patie nt will be i ncl u de d i n t he treat me nt gr o u p assi g ne d at 
ra n d o mizati o n, re gar dless of t he treat me nt recei ve d.  T his a nal ysis set will be use d f or t he 
pri mar y a nal yses of all efficac y e n d p oi nts. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 1 of 9 5 
1 5. 3. 2 
S af et y A n al y si s S et 
T he safet y a nal ysis set c o nsists of all patie nts ra n d o mize d t o t he Pralatre xate Ar m w h o 
recei ve at least 1 d ose of pralatre xate pl us all patie nts ra n d o mize d t o t he O bser vati o n Ar m 
w h o d o n ot disc o nti n ue t he st u d y wit hi n 3 da ys of ra n d o mizati o n.  T his a nal ysis set will be 
use d f or t he pri mar y a nal yses  of all safet y e n d p oi nts. 
1 5. 3. 3 
I nt eri m A n al y s e s S et s 
O ne a nal ysis of P F S, a n d 2 f or mal i nteri m a n al yses a n d a fi nal a nal ysis of O S will be 
perf or me d.  T he first a nal ysis will be pe rf or me d w he n b ot h 2 8 0 P F S e ve nts a n d 1 2 8 O S 
e ve nts ha ve occ urre d.  T he o nl y a nal ysis f or P F S will be perf or me d at t his first a nal ysis, a n d 
will be assesse d at t he 0. 0 5 le vel of si g nifica n ce.  If P F S is si g nifica nt at t he 0. 0 5 le vel, a n 
a nal ysis will be c o n d ucte d o n O S at t his ti me.  If P F S is n ot si g nifica nt at t he 0. 0 5 le vel, t he 
st u d y will be st o p pe d.  T w o a d diti o nal a nal yses of s ur vi val will be perf or me d w he n 
a p pr o xi matel y t w o-t hir ds of 3 8 5 deat hs, a n d a ll 3 8 5 deat hs ha ve occ urre d, res pecti vel y. 
1 5. 4 
S a m pl e Si z e 
A t otal of 5 4 9 ra n d o mize d patie nt s are pla n ne d f or t his st u d y.   
O utc o me data f or patie nts wit h T-cell l y m p h o ma w h o recei ve first-li ne C H O P is li mite d.  A 
retr os pecti ve st u d y of t he I nter nati o nal T- Cell L y m p h o ma Pr oject de m o nstrate d a 5- year O S 
rate of 3 2 % a n d a 5- year F F S rate of 2 0 % f or patie nts wit h P T C L- N O S , wit h wi del y var yi n g 
res ults f or ot her s u bt y pes.1 8  Me dia n O S f or t hese patie nts di d n ot see m t o be a f u ncti o n of 
w het her t he patie nt recei ve d a n a nt hrac ycli ne- base d i n d ucti o n t hera p y.  I n a retr os pecti ve 
e val uati o n of 9 6 patie nts dia g n ose d wit hi n t he N o n- H o d g ki n’s L y mp h o ma Classificati o n 
Pr oject, R u di ger et al re p ort  a si milar fi n di n g, wit h 5- year O S a n d F F S rates of 2 6 % a n d 
2 0 %, res pecti vel y, f or P T C L patie nts trea te d wit h a d o x or u bici n-c o ntai ni n g re gi me n.1 2  
Per Fi g ure 1 of t he R u di ger p u blicati o n, t he esti mate d me dia n F F S i n t hese patie nts is 
a p pr o xi matel y 6 m o nt hs.   
Re p orts of res p o nse rate t o firs t-li ne C H O P- base d re gi me ns i n patie nts wit h P T C L are als o 
a vaila ble.  Galla mi ni, et al  ( 2 0 0 7) c o n d ucte d a s mall st u d y ( n = 2 4 e val ua ble) e val uati n g 
C H O P pl us ale mt uz u ma b a d mi nistere d e ver y 4 wee ks f or a t otal of 2 8 wee ks. 1 6  T he y 
o bser ve d a n o verall res p o nse rate of 7 5 % ( 7 1 % C R, 4 % P R).  I n  a se parate re p ort, Galla mi ni, 
et al perf or me d a retr os pecti v e a nal ysis of 3 8 5 patie nts wit h P T C L- U, wit h t he maj orit y 
( 7 8 %) recei vi n g c he m ot hera p y c o ntai ni n g a nt hrac ycli ne.3 6  T he y re p orte d a n o verall 
res p o nse rate of 7 4 % ( 5 3 % C R, 2 1 % P R) i n t he 3 7 2 e val ua ble patie nts.  Merca dal a n d 
c ollea g ues re p orte d o n a series of 4 1 patie nts ≤ 6 5 years ol d w h o were pla n ne d t o recei ve 
6 c ycles of i nte nsi ve c he m ot hera p y ( hi g h- d ose C H O P alter nati n g wit h et o p osi de, 
met h yl pre d nis ol o ne, c ytara bi ne, a n d cis plati n  [ E S H A P]) f oll o we d b y a ut ol o g o us ste m cell 
tra ns pla ntati o n, if i n res p o nse.3 7  T we nt y-ei g ht patie nts ( 6 8 %) recei ve d t he pla n ne d 6 c o urses 
of t hera p y, 6 ( 1 5 %) patie nts recei ve d 5 c o urse s of t hera p y, a n d 7 ( 1 7 %) recei ve d less t ha n 
5 c o urses.  F oll o wi n g t he c he m ot hera p y p hase, t he C R rate was 4 9 % a n d t he P R rate was 
1 0 %.  Ki m a n d c olla b orat ors a d mi nistere d C H O P  pl us et o p osi de a n d ge mcita bi ne t o a c o h ort 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 2 of 9 5 
of 2 6 first-li ne P T C L patie nts. 3 8  T he me dia n n u m ber of c ycles a d mi nistere d was 4, a n d t he 
o verall res p o nse rate was 7 7 % ( 6 2 % C R, 1 5 % P R).  A b o u ya bis a n d c o llea g ues perf or me d a 
meta-a nal ysis of n o n- A L C L P T C L patie nts r ecei vi n g a nt hrac ycli ne- base d c he m ot hera p y i n 
t he first-li ne setti n g.3 9  A t otal of 3 1 st u dies were i de ntified i n v ol vi n g a t otal of 1 9 9 6 patie nts.  
T he o verall C R rate was 5 5 % a n d t he 5- year O S rate was 3 7 %. 
Acr oss all of t hese re p orte d st u dies, a p pr o xi matel y  5 0 % of patie nts ac hie ve a C R t o first-li ne 
C H O P, wit h a n a d diti o nal 1 0- 2 0 % ac hie vi n g a P R.  F urt her m ore, t he 5- year P F S is 
a p pr o xi matel y 2 0 %, wit h a me dia n P F S of a p pr o xi matel y 9 m o nt hs i n all patie nts.  F or t he 
P D X- 0 1 7 st u d y, we ass u me o ne-t hir d of patie nts will ha ve disease refract or y t o C H O P, a n d 
t hat t he me dia n P F S i n t hese patie nts will be 3 m o nt hs.  C o u ple d wit h a n o verall me dia n P F S 
of 9 m o nt hs, a n d ass u mi n g e x p o ne ntiall y distri b ute d P F S, t his i m plies t he me dia n P F S i n 
patie nts w h o res p o n d t o C H O P is a p pr o xi matel y  1 6 m o nt hs.  S u btracti n g o ut 6 m o nt hs f or 
C H O P a d mi nistrati o n a n d was h o ut  pri or t o ra n d o mizati o n res ults i n a n esti mate d 1 0 m o nt h 
me dia n P F S f or t he O bser vati o n Ar m patie nts i n t his st u d y. 
T he sa m ple size is base d o n c o m pari n g t he tr eat me nt gr o u ps wit h res pect t o t he pri mar y 
efficac y e n d p oi nts of P F S a n d O S.  Ass u mi n g pr o p orti o nal hazar ds, a tr ue  hazar d rati o ( H R) 
o n O S of 0. 7 3, a n d a 2: 1 ra n d o mizati o n (treat me nt: o bser vati o n) wit h a t otal of 5 4 9 patie nts 
( 3 6 6 i n t he treat me nt gr o u p vs 1 8 3 i n t he o bser vati o n gr o u p), a t otal of 3 8 5 O S e ve nts 
( deat hs) will pr o vi de at least 8 0 % p o wer t o s h o w H R < 1. 0 0 usi n g a 2-si de d stratifie d 
l o g-ra n k test at a 0. 0 5 si g nifica nce le vel (al p ha = 0. 0 5), ass u mi n g a n accr ual peri o d of 
5 4 m o nt hs a n d a f oll o w u p peri o d of 3 0 m o nt hs.  F or a H R o n P F S of 0. 6 7, a n d a 
2: 1 ra n d o mizati o n (treat me nt: o bser vati o n), a t otal of 2 8 0 P F S e ve nts ( P D + deat hs) will 
pr o vi de at least 8 0 % p o wer t o s h o w H R < 1. 0 0 usi n g a 2-si de d stratifie d l o g-ra n k test at a 
0. 0 5 si g nifica nce le vel (al p ha = 0. 0 5).   
1 5. 5 
Str atifi c ati o n  
Patie nts meeti n g ra n d o mizati o n eli g i bilit y criteria will be ra n d o mize d 2: 1 t o t he Pralatre xate 
Ar m or t he O bser vati o n Ar m acc or di n g t o a pe r m ute d bl oc k desi g n, bala nci n g wit hi n t he 
f oll o wi n g strat u m. 
• 
Res p o nse per i n vesti gat or at c o m pleti o n of C H O P- base d t hera p y ( C R vs P R) 
1 5. 6 
A n al y si s Pl a n s 
1 5. 6. 1 
I nt eri m A n al y s e s of O S 
T w o f or mal i nteri m a nal yses a n d a fi nal a nal ysis  of O S will be perfor me d.  T he first i nteri m 
a nal ysis will be perf or me d w he n b ot h 2 8 0 P F S e ve nts a n d 1 2 8 O S e ve nts ha ve occ urre d.  
T he o nl y a nal ysis f or P F S will be perf or me d at t his ti me, a n d will be assesse d at t he 
0. 0 5 le vel of si g nifica nce.  If P F S is si g nifica nt at  t he 0. 0 5 le vel, a n i nteri m a nal ysis will be 
c o n d ucte d o n s ur vi val at t his ti me.  If t here ar e 1 2 8 O S e ve nts, or 1/ 3 of t he i nf or mati o n of 
3 8 5 deat hs, i ncl u de d i n t he first i nteri m a nal ys is of O S, t he le vel of si g nifica nce (al p ha) 
w o ul d be 0. 0 0 0 2, acc or di n g t o O’ Brie n a n d Fle mi n g. 4 0  If P F S is si g nifica nt, a test f or f utilit y 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 3 of 9 5 
of O S will n ot be c o n d ucte d at t he first i nteri m a n al ysis si nce s uc h a res ult c o ul d n ot occ ur.  
T he sec o n d i nteri m a nal ysis f or O S will be perf or me d w he n t w o-t hir ds ( 2 5 6) of t he s ur vi val 
e ve nts ha ve occ urre d, at t he 0. 0 1 3 le vel of si g nifica nce.  T he H R st o p pi n g b o u n d f or f utilit y 
at t his i nteri m a nal ysis will be 1. 0 5 ( 9 5 % c o nf i de nce i nter val [ CI]: 0. 8 0, 1. 2 9).  If t he H R f or 
O S is greater t ha n 1. 0 5, t he st u d y will be st o p pe d .  T he fi nal a nal ysis f or s ur vi val will be 
perf or me d w he n 3 8 5 O S e ve nts ha ve occ urr e d, at t he 0. 0 4 6 le vel of si g nifica nce.   
A D M C will peri o dicall y re vie w safet y data at re g ularl y sc he d ule d meeti n gs a n d at t he sa me 
ti me as eac h i nteri m a nal ysis of efficac y.  T he first f or mal safet y re vie w will occ ur w he n 
a p pr o xi matel y 1 0 0 patie nts ha ve bee n ra n d o m ize d a n d c o m pl ete d at least 8 wee ks p ost-
ra n d o mizati o n pralatre xate/ o bservati o n or ha ve disc o nti n ue d. 
 
At eac h i nteri m a nal ysis f or s ur vi val, t he st u d y ma y be st o p pe d f or o ver w hel mi n g e vi de nce 
of f utilit y or s u peri orit y acc or di n g t o s pecifie d b o u n daries.  T he D M C ma y als o ma ke 
rec o m me n dati o ns re gar di n g a dj ust me nts t o t he sa m ple size, if t he y are warra nte d. 
1 5. 6. 2 
Fi n al A n al y s e s of Effi c a c y E n d p oi nt s 
T he pri mar y efficac y a nal ysis o n P F S will be perf or me d w he n a p pr o xi matel y 2 8 0 P F S e ve nts 
a n d 1 2 8 O S e ve nts ha ve occ urre d.  T his is es ti mate d t o occ ur a p pr o xi matel y 4 8 m o nt hs after 
t he first patie nt is ra n d o mize d.  All os will set a data c ut- off date f or t he pri mar y efficac y 
a nal yses i n a ntici pati o n of 2 8 0 t h P F S e ve nt a n d 1 2 8t h O S e ve nt.  T he pri mar y efficac y 
a nal ysis o n O S will be perf or me d w he n a p pr o xi matel y 3 8 5 O S e ve nts ha ve occ urre d. 
A ste p- d o w n pr oce d ure will be use d f or a nal yzi n g t he c o- pri mar y e n d p oi nts of P F S a n d O S.  
If t he P F S e n d p oi nt is si g nifica nt at t he 0. 0 5 le vel t he O S e n d p oi nt will be teste d at a n o verall 
si g nifica nce le vel of 0. 0 5.  H o we ver, if t he P F S e n d p oi nt fails t o s h o w si g nifica nce, t he st u d y 
will be st o p pe d a n d O S will n ot be teste d.  T he st u d y will meet its pri mar y o bjecti ve if b ot h 
t he P F S a n d O S e n d p oi nts are si g nifica nt.  T he i nteri m a nal ysis f or O S will be i m ple me nte d 
usi n g t he err or-s pe n di n g a p pr oac h of La n a n d De Mets acc or di n g t o t he u nifie d fa mil y 
a p pr oac h wit h b o u n dar y relati o ns hi ps of O’ Brie n a n d Fle mi n g f or earl y st o p pi n g t o reject t he 
n ull h y p ot hesis (s u peri orit y). 4 1  T he b o u n daries f or earl y st o p pin g d ue t o fail ure t o reject t he 
n ull h y p ot hesis (f utilit y) will be deter mi ne d acc o r di n g t o t he u nifie d fa mil y a p pr oac h wit h 
b o u n dar y s ha pe para meters o n t he sa m ple mea n scale t hat res ult fr o m c h o osi n g 
P  = 2. 0 (all R a n d A para meters i n t he u nifie d fa mil y a p pr oac h set e q ual t o zer o) 4 2. 
T he pri mar y a nal yses of P F S a n d o bjecti ve res p o nse will use t he ce ntral re vie w t u m or 
assess me nts per I W C wit h o ut usi n g P E T.  A d diti o nal a nal yses of P F S a n d res p o nse will use 
I W C, i ncl u di n g P E T, a n d i n vesti gat ors’ assess me nt of res p o nse.  A d ditio nal details re gar di n g 
ce ntral re vie w will be pr o vi de d i n t he re vie wer’s c harter.  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 4 of 9 5 
1 5. 7 
Effi c a c y E n d p oi nt s  
1 5. 7. 1 
Pr o gr e s si o n-fr e e S ur vi v al 
P F S ti me is calc ulate d as t he n u m ber of da ys fr o m ra n d o mizati o n t o t he date of o bjecti ve 
d oc u me ntati o n of P D or deat h, re gar dless of ca use ( date of P D or deat h - date of 
ra n d o mizati o n + 1).  Patie nts w h o are ali ve wit h o ut a disease res p o nse assess me nt of P D will 
be ce ns ore d at t heir last disease assess me nt da te or t he date of ra n d o mizati o n w hic he ver is 
later.  Date of pr o gressi o n will n ot be i m p ute d f or patie nts wit h missi n g t u m or assess me nt(s) 
bef ore  a n assess me nt of P D.  Patie nts w h o wit h dra w fr o m treat me nt pri or t o P D wit h o ut 
wit h dra wi n g c o nse nt will be f oll o we d f or di sease stat us w he ne ver p ossi ble, e ve n if 
s u bse q ue nt t hera p y, i ncl u di n g tra ns pla nt, has bee n i nitiate d pri or t o d oc u me nte d P D per 
ce ntral re vie w at least u ntil t he P F S a nal ysis.  Patie nts w h o ha ve n o res p o nse assess me nts 
after baseli ne will be ce ns o re d at ra n d o mizati o n.   
Strata use d i n t he a nal yses will be t h ose use d f or st u d y ra n d o mizati o n (as rec or de d o n t he 
I R T).  Wit h t his tec h ni q ue, t he H R ca n be c o nsiste ntl y esti mate d (ass u mi n g t he pr o p orti o nal 
hazar ds m o del is c orrect), as t he p ote ntial bias d ue t o t he as y m metric visits is re m o ve d.  It 
als o c orrects f or t he T y pe I err or i nflati o n a n d retai ns t he n o mi nal st u d y p o wer.   
T he pri mar y a nal ysis of P F S will be base d o n P D as deter mi ne d b y i n de pe n de nt ce ntral 
re vie w bli n de d t o treat me nt gr o u p assi g n me nt.  A se parate c harter will detail s pecifics a b o ut 
ce ntral re vie w o perati o n a n d res p o nse/ P D defi ni ti o n details.  A d diti o nal a nal yses will use t he 
i n vesti gat ors’ assess me nt of res p o nse. 
T he stratifie d l o g-ra n k test w ill be t he pri mar y met h o d use d t o test t he h y p ot hesis t hat 
pralatre xate e xte n ds P F S relati ve t o o bser vati o n.  I n a d diti o n, t he stra tifie d C o x re gressi o n 
m o del will be use d t o calc ulate t he P F S ( H R), al o n g wit h t he 9 5 % c o nfi de nce i nter val ( CI).  
Res ults of t he u nstratifie d C o x re gressi o n m o del (a n d l o g-ra n k test) will als o be prese nte d.  
T he pr o p orti o nal hazar ds ass u m pti o n of  t he C o x m o del will be assesse d. 
1 5. 7. 2 
O v er all S ur vi v al 
O S ti me is calc ulate d as t he n u m ber of da ys  fr o m ra n d o mizati o n t o t he date of deat h, 
re gar dless of ca use ( date of deat h - date of ra n d o mizati o n + 1).  S ur vi val f oll o w- u p will 
c o nti n ue f or u p t o 7 years fr o m ra n d o mizati o n. 
T he stratifie d l o g-ra n k test w ill be t he pri mar y met h o d use d t o test t he h y p ot hesis t hat 
pralatre xate e xte n ds O S relati ve t o o bser vati o n.  I n a d diti o n, t he O S H R, al o n g wit h 9 5 % CIs, 
will be esti mate d via t he stratifie d C o x m o del.  Strata use d i n t hese a nal yses will be t h ose 
use d f or st u d y ra n d o mizati o n (as rec or de d usi n g t he I R T).  Res ults of  t he u nstratifie d C o x 
re gressi o n m o del (a n d l o g-ra n k test) will als o be prese nte d.  T he pr o p orti o nal hazar ds 
ass u m pti o n of t he C o x m o del will be assesse d.   


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 5 of 9 5 
1 5. 7. 3 
O bj e cti v e R e s p o n s e R at e 
T he n u m ber a n d perce nta ge of patie nts wit h a n  o bjecti ve res p o nse of C R or P R will be 
s u m marize d.  T he perce nta ge will be calc ulate d b y di vi di n g t he n u m ber of patie nts wit hi n 
eac h cate g or y of res p o nse b y t he n u m ber of patie n ts wit h meas ura ble disease at baseli ne.  
Eac h patie nt will be c o u nte d wit hi n o nl y 1 re s p o nse gr o u p, wit h t he o verall best res p o nse 
d uri n g t he st u d y as t he classificati o n gr o u p.  T h e treat me nt gr o u ps will be c o m pare d wit h 
res pect t o o bjecti ve res p o nse rate ( C R + P R) usi n g t he stratifie d C oc hra n- Ma ntel- Hae nszel 
test.  A 2-si de d 9 5 % e xact CI will be calc ulate d f or t he differe nce i n o bjecti ve res p o nse rates 
bet wee n t he 2 treat me nt gr o u ps.  Descri pti ve statistics will be pr o vi de d f or best t u m or 
res p o nse f or eac h treat me nt gr o u p.   
1 5. 8 
S af et y A n al y si s 
A nal ysis of safet y will be perf or me d o n t he safe t y a nal ysis set.  St u d y data will be m o nit ore d 
o n a n o n g oi n g basis b y t he cli nical st u d y tea m t o e ns ure patie nts’ safet y. 
1 5. 8. 1 
A d v er s e E v e nt s 
T he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) will be use d t o c o de all A Es t o 
a s yste m or ga n class ( S O C) a n d a preferre d ter m .  Patie nt i nci de nce of A Es will be ta b ulate d 
b y S O C, preferre d ter m, a n d se verit y gra de f o r all A Es, S A Es, treat me nt-relate d A Es, a n d 
treat me nt-relate d S A Es.  Eac h of t hese o ut p uts will i ncl u de ta b ulati o n b y ma xi m u m se verit y 
f or eac h S O C a n d preferre d ter m as re p orte d b y t he i n vesti gat or base d o n C T C A E, 
Versi o n 4. 0.  If a n A E ca n n ot be gra de d ba se d o n C T C A E, t he i n vesti gat or will assi g n a 
se verit y base d o n 1 = mil d, 2 = m o derate, 3 = se vere, 4 = life t hreate ni n g, a n d 5 = deat h 
relate d t o A E.  S u m maries of A Es, S A Es, treatme nt-relate d A Es, a n d treat me nt-relate d S A Es 
occ urri n g i n at least 5 % of t he patie nts will be pr o vi de d i n desce n di n g or der of fre q ue nc y b y 
S O C a n d preferre d ter m. 
A d diti o nal ta bles s u m marizi n g patie nt i nci de nce ( b y preferre d ter m) of t he f oll o wi n g will be 
ge nerate d: 
• 
All A Es 
• 
S A Es 
• 
Treat me nt-relate d A Es 
• 
Treat me nt-relate d S A Es 
• 
Gra de 3 or hi g her A Es 
• 
A Es lea di n g t o t he disc o nti n uati o n of pralat re xate or o bser vati o n or re m o val fr o m st u d y 
• 
A Es lea di n g t o d ose re d ucti o ns of t he st u d y dr u g 
• 
A Es wit h i nci de nce ≥ 5 % 
• 
Deat hs 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 6 of 9 5 
1 5. 8. 2 
A d v er s e E v e nt s Gr o u p e d b y Si mil ar Pr ef err e d T er m 
S u m mar y ta bles of treat me nt e mer ge nt, treat me nt-relate d, seri o us, a n d seri o us treat me nt-
relate d A Es gr o u pe d b y si milar preferre d ter m will be prese nte d.  F or t his prese ntati o n, 
certai n si milar preferre d ter ms ha ve bee n i de ntifie d a n d will be c o de d t o t he sa me preferre d 
ter m i n or der t o prese nt t he e ve nt i n a u nif or m ma n ner.  T hese ter ms are prese nte d i n t he 
statistical a nal ysis pla n (a d diti o nal preferre d ter ms ma y be i de ntifie d wit hi n eac h cate g or y 
d uri n g data re vie w a n d a d de d t o t his list).  
Se parate o ut p uts will be pr o vi de d f or s u b gr o u ps defi ne d b y a ge gr o u p ( < 6 5, ≥ 6 5), ge n der, 
a n d race (if feasi ble).   
Detaile d listi n gs f or all A Es a n d listi n gs a n d/ or narrati ves will be pr o vi de d f or seri o us a n d 
si g nifica nt A Es, a n d deat hs ( wit h ‘ o n st u d y’ deat hs [ deat hs t hat occ ur bef ore t he e n d of safet y 
f oll o w u p peri o d] i de ntifie d). 
1 5. 8. 3 
L a b or at or y P ar a m et er s 
La b orat or y para meters f or he mat ol o g y a n d bl o o d c he mistr y will be s u m marize d at baseli ne 
a n d last o bser ve d val ue.  A d diti o nall y, t he ma xi m u m a n d mi ni m u m o bser ve d p ost baseli ne 
val ues will be s u m marize d al o n g wit h t he c h a n ge fr o m baseli ne t o t he ma xi m u m o bser ve d 
val ue, mi ni m u m o bser ve d val ue, a n d last o bser ve d val ue.  Ta bles of s hifts i n se verit y 
( C T C A E Versi o n 4. 0) fr o m baseli ne f or selecte d la b orat or y para meters a n d selecte d 
ti me- p oi nts ma y als o be pr o vi de d.  A listi n g of all la b orat or y assess me nts ma y be pr o vi de d. 
I nci de nce of la b orat or y a b n or malities a n d s u bject i nci de nce of Gra de 3 or 4 la b orat or y 
t o xicities will be prese nte d.  S u m maries of he mat ol o g y a n d ser u m c he mistr y para meters 
al o n g wit h gra de s hifts fr o m baseli ne will be prese nte d. 
Sta n dar d P K para meters will be esti mate d fr o m t he li mite d plas ma sa m pli n g (e g, A U C, C ma x , 
a n d t 1/ 2). 
P O P P K a nal yses will be c o n d ucte d via n o nli near  mi xe d-effects m o deli n g t o esti mate P O P P K 
para meters f or pralatre xate, i n cl u di n g t y pical val ues, i nter-i n di vi d ual variati o n, a n d resi d ual 
varia bilit y after a d mi nistrati o n of  pralatre xate i n t he patie nt p o p ulati o n, a n d t o esti mate t he 
effects of i n di vi d ual-s pecific c o variate fact ors (e g, de m o gra p hics, disease state, etc) t hat ma y 
be pre dicti ve of t he u ne x plai ne d ra n d o m varia b ilit y i n pralatre xate P K.  I n a d diti o n, t he 
relati o ns hi p bet wee n t he P K of pralatre xate a n d res p o nse (safet y a n d efficac y) will be 
e x pl ore d. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 7 of 9 5 
1 6 S T U D Y M A N A G E M E N T 
1 6. 1 
I n v e sti g at or R e s p o n si biliti e s  
1 6. 1. 1 
G o o d Cli ni c al Pr a cti c e  
T he i n vesti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n f ull c o m plia nce wit h t he 
pri nci ples of t he “ Declarati o n of Helsi n ki ” (as a me n de d i n T o k y o, Ve nice, H o n g K o n g, a n d 
S o ut h Africa), I C H g ui deli nes, or wit h t he la ws a n d re g ulati o ns of t he c o u ntr y i n w hic h t he 
researc h is c o n d ucte d.  B y si g ni n g t he U S F or m F D A 1 5 7 2, “ State me nt of I n vesti gat or”, t he 
i n vesti gat or c o m mits t o a d here t o a p plica ble secti o ns of t he U S C F R parts 5 0 “ Pr otecti o n of 
H u ma n S u bj ects”, 5 4 “ Fi na ncial Discl os ure b y Cli nical I n vesti gat or s”, 5 6 "I nstit uti o nal 
Re vie w B oar ds”, a n d 3 1 2 s u b part D “ Res p o nsi bi lities of S p o ns ors a n d I n vesti gat ors”.  All 
i n vesti gat ors will e ns ure a d here nce t o I C H g uideli nes f or G C P a n d Cli nical Safet y Data 
Ma na ge me nt. 
1 6. 1. 2 
I R B/ E C/ R E B A p pr o v al 
T he i nstit uti o n’s I R B/ E C/ R E B, or ot her c o m m ittee f u ncti o ni n g i n a si milar ca pacit y, will 
re vie w a n d a p pr o ve t he pr ot oc ol, i nitial a n d re vise d I C d oc u me nts, pr ot oc ol a me n d me nts, 
a n d safet y ite ms.  After a p pr o val b y t he IR B/ E C/ R E B, d oc u me ntati o n of a p pr o val a n d t he 
a p pr o ve d I C d oc u me nt will be se nt t o All os/ desi g n ee bef ore a n y patie nt is e nr olle d i nt o t his 
st u d y. 
1 6. 1. 3 
I nf or m e d C o n s e nt  
T he i n vesti gat or is res p o nsi ble f or pre pari n g t he writte n I C d oc ume nt f or t his st u d y.  All os or 
its desi g nee will pr o vi de t he i n vesti gat or wit h te m plates f or a n I C d oc u me nt.  T he 
i n vesti gat or ma y rearra n ge or re w or d t he c o nte nts of t hese te m plates, or ma y a d d ot her 
ele me nts or la n g ua ge, pr o vi de d t he mea ni n g a n d c o nte nt are n ot c ha n ge d or  delete d.  All os or 
desi g nee m ust re vie w a n d a p pr o ve t he I C d oc u me n t t hat is use d b y t he i n vesti gat or f or t his 
st u d y pri or t o I R B/ E C/ R E B s u b missi o n. 
Writte n I C will be o btai ne d fr o m all patie nts pa rtici pati n g i n t his st u d y, i n acc or da nce wit h 
I C H G C P a n d c urre nt re g ulat or y re q uire me nts.  T he case hist or y f or eac h patie nt m ust 
d oc u me nt t hat t he I C pr ocess wa s o btai ne d pri or t o partici patio n i n t he st u d y.  T he ori gi nal 
I C d oc u me nt will be ke pt i n t he patie nt’s rec or d, a n d a c o p y will be pr o vi de d t o t he patie nt. 
1 6. 1. 4 
St u d y Fil e s a n d R et e nti o n of R e c or d s 
T he i n vesti gat or m ust retai n all st u d y rec or ds u ntil at least 2 years after t he last a p pr o val of a 
mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d 
mar keti n g a p plicati o ns i n a n I C H re gi o n or at  least 2 years ha ve ela pse d si nce t he f or mal 
disc o nti n uati o n of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct as per 2 1 C F R 3 1 2. 6 2 
a n d I C H G C P E 6 4. 9. 5 a n d 5. 5. 1 2.  T hese d oc u me nts m ust be retai ne d f or a l o n ger peri o d, 
h o we ver, if re q uire d b y t he a p plica ble re g ulat or y re q uire me nts or b y a n a gree me nt wit h 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 8 of 9 5 
All os.  It is t he res p o nsi bilit y of t he s p o ns or t o i nf or m t he i n vesti gat or as t o w he n t hese 
d oc u me nts n o l o n ger nee d t o be retai ne d.  If t he i n vesti gat or rel ocates, or f or a n y reas o n 
desires t o dis p ose of t he rec or d s, t he st u d y rec or ds ma y be tra nsferre d t o a n ot her i nstit uti o n, 
a n ot her i n vesti gat or, or t o t h e s p o ns or u p o n writte n a gree me nt bet wee n t he i n vesti gat or a n d 
t he s p o ns or. 
1 6. 2 
R e c or di n g a n d C oll e cti n g of D at a 
I n acc or da nce wit h I C H a n d G C P g ui deli nes, t he i n vesti gat or will mai ntai n c o m plete, 
acc urate, le gi ble, a n d easil y retrie va ble data , a n d will all o w pers o n nel a ut h orize d b y All os 
access t o all st u d y data at a n y ti me.  S uc h data s hall als o be sec ure d i n or der t o pre ve nt l oss 
of data. 
1 6. 2. 1 
C a s e R e p ort F or m s 
All os ma y ma ke use of electr o nic da ta ca pt ure ( E D C) or pa per C R Fs. 
W he n usi n g pa per, All os’ C R Fs are pri nte d o n n o car b o n-re q uire d pa pe r t o per mit m ulti ple 
c o pies.  T he i n vesti gat or will retai n t he b ott o m c o p y f or his/ her st u d y files.  Data c ollecte d 
f or eac h patie nt will be rec or de d o n t he C R Fs.  T he i n vesti gat or is res p o nsi ble f or e ns uri n g 
t hat all data s u b mitte d are tr ue, acc urate, a n d ulti matel y c o m plete. 
C o m plete d C R Fs will be re vie we d a n d si g ne d b y a n i n vesti gat or liste d o n t he U S F or m F D A 
1 5 7 2 or e q ui vale nt.  T he C R A will verif y t he C R F data wit h t he patie nt’s s o urce data, 
e val uate t he data f or acc urac y, c o nsiste nc y, a n d c o m plete ness, a n d will e ns ure t hat all f or ms 
wit h missi n g data a n d/ or err ors are ulti matel y a d dresse d. 
W he n usi n g E D C, data c ollecte d f or eac h patie n t will be e ntere d b y site staff i nt o a n E D C 
data base.  T he i n vesti gat or is res p o nsi ble f o r e ns uri n g t hat all data s u b mitte d are tr ue, 
acc urate, a n d ulti matel y c o m plete. 
C o m plete d, E D C data will be re vie we d b y a n i n vesti gat or liste d o n t he U S F or m F D A 1 5 7 2 
or e q ui vale nt.  T his re vie w will be d oc u me nte d  b y t he i n vesti gat or or e q ui vale nt l o g gi n g i nt o 
t he E D C data base a n d pr o vi di n g si g n off usin g his/ her 2 1 C F R Part 1 1c o m plia nt electr o nic 
si g nat ure.  T he C R A will verif y t he C R F data wit h t he patie nt’s s o urce data, e val uate t he data 
f or acc urac y, c o nsiste nc y, a n d c o m plete ness, a n d will e ns ure t hat all scree ns wit h missi n g 
data a n d/ or err ors are ulti matel y a d dresse d. 
Acc urate a n d c o m plete C R Fs f or a patie nt, eit her  via pa per or E D C, m ust be s u b mitte d t o 
All os i n a ti mel y ma n ner. 
1 6. 2. 2 
D at a Cl arifi c ati o n F or m s 
Data Clarificati o n F or ms ( D C Fs), s uc h as Q u eries, Site N otificati o ns, a n d C R A A d de n da, 
will be use d b y All os staff or desi g nee t o atte m p t t o c orrect or clarif y missi n g, i nc o m plete, or 
ill o gical data.  Q ueries a n d Site N otificati o n ma y be c o m plete d i n di vi d uall y b y a n 
a p pr o priate pers o n o n t he Dele gati o n of A ut h orit y f or m, b ut m ust be re vie we d, a n d t he 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 7 9 of 9 5 
trac ki n g c o vers heet si g ne d b y, a n i n vesti gat or liste d o n t he U S F or m F D A 1 5 7 2 or 
e q ui vale nt.  C R A A d de n da ma y be c o m plete d b y  t he C R A b ut m ust be re vie we d a n d si g ne d 
b y a n i n vesti gat or liste d o n t he U S  F or m F D A 1 5 7 2 or e q ui vale nt. 
F or E D C st u dies, t his pr ocess is perf or me d electr o nicall y. 
1 6. 2. 3 
S elf- e vi d e nt C orr e cti o n s 
C R F data are e x pecte d t o be acc urate, c o nsis te nt, a n d c o m plete.  All os Cli nical Data 
Ma na ge me nt de part me nt or desi g nee (e g, a cli n ical researc h orga niza ti o n [ C R O]) ma y a p pl y 
t he f oll o wi n g c o n ve nti o ns t o c orrect t he All os data base wit h o ut iss ui n g a D C F t o site staff.  
H o we ver, a D C F ma y still be ge nerate d as nee de d f or clarificati o n/c o nfir mati o n. 
 
• 
Hea der data will be c orrecte d if t he err or is  o b vi o us a n d a c orrecti o n is s u p p orte d b y t he 
re mai n der of t he C R Fs. 
• 
D u plicate data will be delete d u nless t he C R F s pecificall y all o ws f or re peat val ues.  F or 
e xa m ple, if i de ntical la b val ues (i ncl u di n g date a n d ti me, if a p plica ble) are rec or de d f or a 
pr ot oc ol-s pecifie d visit a n d f or a miscella ne o us/ u nsc he d ule d visit,  o nl y t he pr ot oc ol 
s pecifie d visit data will be e ntere d i n t he data base. 
• 
Data rec or de d wit hi n t he case b o o k ca n be m o ve d t o t he a p pr o priate C R F fiel d if n o data 
are c ha n ge d.  
• 
Rele va nt c o m me nts or mar gi nalia will be a d de d t o t he C o m me nts secti o n. 
• 
Miss pelli n gs ma y be c orrecte d o nl y if t he c orrecti o n clarif ies (e g, e na bles c o di n g), b ut 
d oes n ot c ha n ge, t he mea ni n g or c o nte xt ual use of t he w or d.  
• 
L o n g te xt fiel ds will be s h or te ne d, if nee de d, usi n g ge nerall y acce pte d a b bre viati o ns t hat 
d o n ot c ha n ge t he cli nical mea ni n g of t he te xt. 
• 
Dates (e g, year b o u n dar y, da y/ m o nt h i n versi o n)  will be c orrecte d if t he c ha n ge is 
s u p p orte d b y t he re mai n der of t he C R Fs. 
• 
O nl y t he St o p Date will be rec or de d if a St o p Date a n d “ C o nti n ui n g" ( or si milar) are 
pr o vi de d. 
• 
A n i n dicat or fiel d left bla n k or mar ke d “ n o”  (e g, A Es prese nt?) will be u p date d t o “ yes” 
if data are prese nt. 
• 
If a fiel d w here “If Ot her, s pecif y” ( or si milar sit uati o n) i ncl u des data b ut t he b o x is bla n k 
( or si milar), t he b o x will be c hec ke d f or t he data base.  
• 
If t he res ol uti o n area of a Site N otificatio n ( S N) is bla n k b ut t h e S N is si g ne d, t he 
res p o nse fr o m t he site will be i nter prete d as “ A gree”. 
1 6. 2. 4 
Dr u g A c c o u nt a bilit y 
I n acc or da nce wit h all a p plica ble re g ulat or y re q uire me nts, t he i n vesti gat or or desi g nate d site 
staff m ust mai ntai n pralatre xate acc o u nta bilit y rec or ds t hr o u gh o ut t he c o urse of t he st u d y.  
T his pers o n(s) will d oc u me nt t he a m o u nt of pralatre xate a d mi nistere d t o patie nts.  T he C R A 
will re vie w i n ve nt or y a n d acc o u nta bilit y d oc u me ntati o n d uri n g m o nit ori n g visits. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 8 0 of 9 5 
T he i n vesti gat or will n ot s u p pl y i n vesti gati o nal st u d y dr u g t o other i n vesti gat ors n ot liste d o n 
t he U S F or m F D A 1 5 7 2 or e q ui valent.  I n vesti gati o nal st u d y dr u g use, ot her t ha n as directe d 
b y t his pr ot oc ol, is n ot all o we d wit h o ut pri or a ut h orizati o n fr o m All os. 
All u n use d vials of pralatre xate m ust be acc o u nte d  f or at t he site a n d mai ntai ne d i n a sec ure d, 
l oc ke d st ora ge area wit h access li mite d t o a ut h orize d st u d y pers o n nel o nl y.  Si nce 
pralatre xate is c yt ot o xic, use d vials will be de str o ye d per i nstit uti o n, l ocal, a n d all a p plica ble 
p olicies a n d pr oce d ures.  After st u d y c o ncl usi o n, all u n use d vials of pralatre xate ma y be 
destr o ye d at t he site, f oll o wi n g verificati o n of acc o u nta bilit y b y a n All os re prese ntati ve. 
1 6. 3 
Pr ot o c ol C o m pli a n c e 
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he st u d y is c o n d ucte d i n acc or da nce wit h t he 
pr oce d ures a n d e val uati o ns de scri be d i n t his pr ot oc ol. 
1 6. 4 
S p o n s or R e s p o n si biliti e s 
1 6. 4. 1 
A m e n d m e nt s t o t h e Pr ot o c ol 
A n y a me n d me nt t o t he pr ot oc ol, as dee me d a p pr o priate b y All os, will be i m ple me nte d as t he 
st u d y pr o gresses.  All os ma y als o ma ke s uc h c h a n ges t o t he pr ot oc ol, as it dee ms necessar y 
f or safet y reas o ns, or as ma y be re q uire d b y t he re g ulat or y a ut h orities.  A me n d me nts will be 
s u b mitte d t o t he I R B/ E C/ R E B f or writte n a p pr o val, bef ore i m ple me ntati o n.  T he e x pe dite d 
re vie w pr oce d ure f or a n a me n d me nt is a p pr o priate o nl y if mi n or c ha n ges are ma de i n t he 
pr ot oc ol. 
1 6. 4. 2 
S af et y M o nit ori n g 
T he cli nical dr u g safet y of pr alatre xate will be c o nti n u o usl y  e val uate d b y t he St u d y Me dical 
M o nit or o n a n o n g oi n g basis d uri n g t he c o urse of t his cli nical st u d y.  All S A Es f or 
pralatre xate i n t his st u d y a n d all ot her o n g oi n g cli nical st u dies  wit h pralatre xate will be 
pr ocesse d i n c o m plia nce wit h c u rre nt re g ulat or y g ui deli nes b y t he All os Cli nical Dr u g Safet y 
a n d P har ma c o vi gila nce gr o u p.  T his pr ocessi n g will i ncl u de a f or mal assess me nt of eac h 
S A E b y t he p h ysicia n me dical m o nit or f or cli nical dr u g safet y.  I n a d diti o n, a c u m ulati ve 
re vie w of all S A Es fr o m all s o urces will be assesse d o n a bi m o nt hl y basis f or c ha n ge i n 
fre q ue nc y a n d se verit y of t he S A Es b y t he p h ysicia n me dical m o nit or f or cli nical dr u g safet y 
as a si g nal detecti o n/tre n d e val uati o n. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 8 1 of 9 5 
1 6. 5 
J oi nt I n v e sti g at or/ S p o n s or R e s p o n si biliti e s 
1 6. 5. 1 
A c c e s s t o I nf or m ati o n f or M o nit ori n g a n d A u diti n g 
I n acc or da nce wit h I C H G C P g ui deli nes a n d 2 1 C F R 3 1 2, t he C R A/a u dit or m ust ha ve direct 
access t o t he patie nt’s s o urce d oc u me ntati o n i n or der t o verif y t he data rec or de d i n t he C R Fs.  
T he C R A is res p o nsi ble f or r o uti ne re vie w of t he C R Fs at re g ular i nter vals t hr o u g h o ut t he 
st u d y a n d t o verif y a d here nce t o t he pr ot oc ol, as well as t he c o m plete ness, c o nsiste nc y, a n d 
acc urac y of t he data bei n g rec or de d.  T he C R A/a u dit or m ust ha ve access t o a n y patie nt 
rec or ds nee de d t o verif y t he e ntries o n t he C R Fs.  T he i n vesti gat or a grees t o c o o perate wit h 
t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d i n t he c o urse of t hese m o nit ori n g/a u diti n g 
visits are res ol ve d. 
1 6. 5. 2 
T er mi n ati o n of t h e St u d y 
F or reas o na ble ca use, eit her t he i n vesti gat or  or t he s p o ns or, All os, ma y ter mi nate t he 
i n vesti gat or’s partici pati o n i n t his st u d y, pro vi de d a writte n n otice is s u b mitte d wit hi n t he 
ti me peri o d pr o vi de d f or i n t he Cli nical Trial A gree me nt ( C T A).  I n a d diti o n, All os ma y 
ter mi nate t he st u d y at a n y ti me u p o n i m me diate n otice f or a n y reas o n, i ncl u di n g b ut n ot 
li mite d t o, All os’ belief t hat ter mi nati o n is necessar y f or t he safet y of patie nts. 
1 6. 5. 3 
P u bli c ati o n P oli c y 
All os rec o g nizes t he i m p orta nce of c o m m u nicati o n of me dical st u d y data, a n d e nc o ura ges t he 
p u blicati o n of s uc h data i n re p uta ble scie ntific j o ur nals a n d t he prese ntati o n of s uc h data at 
scie ntific se mi nars a n d c o nfere nces.  A n y pr o p ose d p u blicati o n or prese ntati o n of t he data 
ge nerate d fr o m t he st u d y m ust be  pr o vi de d t o All os f or ti mel y revie w i n acc or da nce wit h t he 
ter ms of t he C T A bet wee n t he i n vesti gat or, t he i nstit uti o n, a n d All os.  All os s hall n ot, i n its 
scie ntific p u blicati o ns or pr o m oti o nal material, q u ote fr o m p u blica ti o ns b y i n vesti gat ors 
wit h o ut f ull ac k n o wle d g me nt of t he s o urce.  Cr iteria f or i ncl usi o n i n a ut h ors hi p i n a n y 
p u blicati o ns res ulti n g fr o m t he st u d y will be deter mi ne d a n d c o m m u nicate d i n writi n g t o all 
partici pati n g pri nci pal i n vesti gat ors. 
1 6. 6 
C o nfi d e nti alit y 
All i nf or mati o n pr o vi de d t o t he i n vesti gat or b y All os, i ncl u di n g n o ncli nical data, pr ot oc ols, 
C R Fs, a n d ver bal a n d writte n i nf or mati o n, will be ke pt strictl y c o nfi de ntial a n d c o nfi ne d t o 
t he cli nical pers o n nel i n v ol ve d i n c o n d ucti n g t his st u d y, a n d n o discl os ure s hall be ma de 
e xce pt i n acc or da nce wit h a n y ri g ht of p u blicati o n gra nte d t o t h e i n vesti gat or.  All pers o n nel 
will ha n dle patie nt data i n a c o nfi de ntial ma n ner i n acc or da nce wit h a p plica ble re g ulati o ns 
g o ver ni n g cli nical researc h.  U p o n re q uest b y a re g ulat or y a ut h orit y s uc h as t he U S F D A a n d 
ot her re g ulat or y a ut h orities w orl d wi de, t he i n vesti gat or/i nstit uti o n m ust ma ke a vaila ble f or 
direct access all re q ueste d st u d y-re late d rec or ds or re p orts ge nerate d as a res ult of a patie nt’s 
partici pati o n i n t his st u d y.  T his i nf or ma ti o n ma y be relate d i n c o nfi de nce t o t he 
I R B/ E C/ R E B or ot her c o m mittee f u ncti o ni n g i n a si milar ca pacity.  I n a d diti o n, n o re p orts or 
i nf or mati o n a b o ut t he st u d y or its pr o gress will be pr o vi de d t o a n y o ne n ot i n v ol ve d i n t he 
st u d y ot her t ha n t o All os, or i n c o nfi de nce t o t he I R B/ E C/ R E B or si milar c o m mittee, e xce pt 
if re q uire d b y la w. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 8 2 of 9 5 
1 7 R E F E R E N C E S 
1 . 
T he N o n- H o d g ki n's L y m p h o ma Classificati o n Pr oject. A c li nical e val uati o n of t he 
I nter nati o nal L y m p h o ma St u d y Gr o u p classificati o n of  n o n- H o d g ki n's l y m p h o ma. . 
Bl o o d 1 9 9 7; 8 9( 1 1): 3 9 0 9- 1 8.  
 
2 . 
He n ness y B T, Ha nra ha n E O, Dal y P A. N o n- H o d g ki n l y m p h o ma: a n u p date. La ncet 
O nc ol 2 0 0 4; 5( 6): 3 4 1- 5 3.  
 
3 . 
Dear de n C E, F oss F M. Peri p heral T-cell l y m p h o mas: dia g n osis a n d ma na ge me nt. 
He mat ol O nc ol Cli n N ort h A m 2 0 0 3; 1 7( 6): 1 3 5 1- 6 6.  
 
4 . 
Z he n g T, Ma y ne S T, B o yle P, et al. E pi de mi ol o g y of n o n- H o d g ki n l y m p h o ma i n 
C o n nectic ut. 1 9 3 5- 1 9 8 8. Ca ncer 1 9 9 2; 7 0( 4): 8 4 0- 9.  
 
5 . 
Cart wri g ht R A, Gil ma n E A, G ur ne y K A. Ti me  tre n ds i n i nci de nce of hae mat ol o gical 
mali g na ncies a n d relate d c o n diti o ns . Br J Hae mat ol 1 9 9 9; 1 0 6( 2): 2 8 1- 9 5. 
 
6 . 
S ur veilla nce, e pi de mil o g y, a n d e n d res ults ( S E E R) Pr o gra m 
( w w w.seer.ca ncer. g o v/ p u blic data) S E E R Stat Data base:  I nci de nce- S E E R 9 Re gs 
P u blic Use. N o v. 2 0 0 3 S u b ( 1 9 7 3- 2 0 0 1), Nati o nal Ca ncer I nstit ute, D C C P S, 
S ur veilla nce Researc h Pr o gra m, Ca ncer St atistics Bra nc h, releas e d A pril 2 0 0 4, base d 
o n t he N o ve m ber 2 0 0 3 s u b missi o n.  
 
7 . 
De vesa S S, Fears T. N o n- H o d g ki n's l y m p h o ma ti me tre n ds: U nite d States a n d 
i nter nati o nal data. Ca ncer Res 1 9 9 2; 5 2( 1 9 S u p pl): 5 4 3 2s- 5 4 4 0s.  
 
8 . 
S wer dl o w S H, I nter nati o nal A ge nc y f o r Researc h o n Ca ncer., W orl d Healt h 
Or ga nizati o n. W H O classificati o n of t u m o urs of hae mat o p oietic a n d l y m p h oi d 
tiss ues. 4t h e d. L y o n, Fra nce: I nter natio nal A ge nc y f or Researc h o n Ca ncer; 2 0 0 8.  
 
9 . 
S hi p p M A. Pr o g n ostic fact ors i n a g gre ssi ve n o n- H o d g ki n's l y m p h o ma: w h o has 
" hi g h-ris k" disease? Bl o o d 1 9 9 4; 8 3( 5): 1 1 6 5- 7 3. 
 
1 0 . 
Gissel brec ht C, Ga ular d P, Le pa ge E, et al. Pr o g n ostic si g nifica nce of T-cell 
p he n ot y pe i n a g gressi ve n o n- H o d g ki n' s l y m p h o mas. Gr o u pe d' Et u des des 
L y m p h o mes de l' A d ulte ( G E L A). Bl o o d 1 9 9 8; 9 2( 1): 7 6- 8 2.  
 
1 1 . 
Harris N L, Jaffe E S, Stei n H, et al. A re vise d E ur o pea n- A merica n classificati o n of 
l y m p h oi d ne o plas ms: a pr o p osal fr o m t he I nter nati o nal L y m p h o ma St u d y Gr o u p. 
Bl o o d 1 9 9 4; 8 4( 5): 1 3 6 1- 1 3 9 2.  
 
1 2 . 
R u di ger T, Weise n b ur ger D D, A n ders o n J R , et al. Peri p heral T-cell l y m p h o ma 
(e xcl u di n g a na plastic lar ge-cell l y m p h oma): res ults fr o m t he N o n- H o d g ki n's 
L y m p h o ma Classificati o n Pr ojec t. A n n O nc ol 2 0 0 2; 1 3( 1): 1 4 0- 9. 
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 8 3 of 9 5 
1 3 . 
F ur y M G, Kr u g L M, Azz oli C G, et al. A p ha se I cli nical p harmac ol o gic st u d y of 
pralatre xate i n c o m bi nati o n wit h pr o be neci d i n a d ults wit h a d va nce d s oli d t u m ors. 
Ca ncer C he m ot her P har mac ol 2 0 0 5: 1- 7.  
 
1 4 . 
O' C o n n or O A. De vel o pi n g ne w dr u gs f or t he treat me nt of l y m p h o ma. E ur J Hae mat ol 
S u p pl 2 0 0 5( 6 6): 1 5 0- 8.  
 
1 5 . 
Sa va ge KJ. Peri p heral T-cell l y m p h o mas. Bl o o d Re v 2 0 0 7; 2 1( 4): 2 0 1- 1 6.  
 
1 6 . 
Galla mi ni A, Zaja F, Patti C, et al. Ale mt uz u ma b ( Ca m pat h- 1 H) a n d C H O P 
c he m ot hera p y as first-li ne treat me nt of peri p heral T-cell l y m p h o ma: res ults of a 
GI TI L ( Gr u p p o Italia n o Tera pie I n n o vati ve nei Li nf o mi) pr os pecti ve m ultice nter trial. 
Bl o o d 2 0 0 7; 1 1 0( 7): 2 3 1 6- 2 3 2 3.  
 
1 7 . 
Ar mita ge J O, V ose J M, Weise n b ur ger D D. T o war ds u n dersta n di n g t he peri p heral T-
cell l y m p h o mas. A n n O nc ol 2 0 0 4; 1 5( 1 0): 1 4 4 7- 9.  
 
1 8 . 
V ose J, Ar mita ge J, Weise n b ur ger D. I n ter nati o nal peri p heral T-cell a n d nat ural 
killer/ T-cell l y m p h o ma st u d y: pat h ol o g y fi n di n gs a n d cli nical o utc o mes. J Cli n O nc ol 
2 0 0 8; 2 6( 2 5): 4 1 2 4- 3 0.  
 
1 9 . 
Wils o n W H, Gr oss bar d M L, Pittal u ga S, et al. D ose-a dj uste d E P O C H c he m ot hera p y 
f or u ntreate d lar ge B-cell l y m p h o mas: a p har mac o d y na mic a p pr oac h wit h hi g h 
efficac y. Bl o o d 2 0 0 2; 9 9( 8): 2 6 8 5- 9 3.  
 
2 0 . 
Riz vi M A, E ve ns A M, Tall ma n M S, et al. T-cell n o n- H o d g ki n l y m p h o ma. Bl o o d 
2 0 0 6; 1 0 7( 4): 1 2 5 5- 6 4.  
 
2 1 . 
M o u nier N, Gissel brec ht C, Briere J, et  al. Pr o g n ostic fact ors i n patie nts wit h 
a g gressi ve n o n- H o d g ki n's l y m p h o ma treate d b y fr o nt-li ne a ut otr a ns pla ntati o n after 
c o m plete re missi o n: a c o h ort st u d y b y t h e Gr o u pe d' Et u de des L y m p h o mes de 
l' A d ulte. J Cli n O nc ol 2 0 0 4; 2 2( 1 4): 2 8 2 6- 3 4. 
 
2 2 . 
Sc h mi d F A, Sir ot na k F M, Otter G M, et al. Ne w f olate a nal o gs of t he 1 0- deaza-
a mi n o pteri n series: mar ke dl y i ncrease d a ntit u m or acti vit y of t he 1 0-et h yl a nal o g 
c o m pare d t o t he pare nt c o m p o u n d a n d me t h otre xate a gai nst s o me h u ma n t u m or 
xe n o grafts i n n u de mice. Ca ncer Treat Re p 1 9 8 5; 6 9( 5): 5 5 1- 3.  
 
2 3 . 
Sir ot na k F M, De Gra w JI, M occi o D M, et al. Ne w f olate a nal o gs of t he 1 0- deaza-
a mi n o pteri n series. Basis f or str uct ural  desi g n a n d bi oc he mical a n d p har mac ol o gic 
pr o perties. Ca ncer C he m ot her P har mac ol 1 9 8 4; 1 2( 1): 1 8- 2 5.  
 
2 4 . 
Sir ot na k F M, De Gra w JI, Sc h mi d F A, et al. Ne w f olate a nal o gs of t he 1 0- deaza-
a mi n o pteri n series. F urt her e vi de nce f or mar ke dl y i ncrease d a ntit u m or efficac y 
c o m pare d wit h met h otre xate i n ascitic a n d s oli d m uri ne t u m or m o dels. Ca ncer 
C he m ot her P har mac ol 1 9 8 4; 1 2( 1): 2 6- 3 0.  
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 8 4 of 9 5 
2 5 . 
Sir ot na k F M, Sc h mi d F A, Sa m uels L L, et al. 1 0- Et h yl- 1 0- deaza-a mi n o pteri n: 
str uct ural desi g n a n d bi oc he mical, p har mac ol o gic, a n d a ntit u m or pr o perties. N CI 
M o n o gr 1 9 8 7; 5: 1 2 7- 3 1.  
 
2 6 . 
O' C o n n or O A, H or witz S, Ha mli n P, et al . P hase II-I-II st u d y of t w o differe nt d oses 
a n d sc he d ules of pralatre xate, a hi g h-affi nit y  s u bstrate f or t he re d uce d f olate carrier, 
i n patie nts wit h rela pse d or refract or y l y m p h o ma re veals mar ke d acti vit y i n T-cell 
mali g na ncies. J Cli n O nc ol 2 0 0 9; 2 7( 2 6): 4 3 5 7- 6 4.  
 
2 7 . 
S h ust o v A R, Pr o B, H or witz S M, et al . Pralatre xate i n patie nts wit h 
rela pse d/refract or y peri p heral T-cell l y m p h o ma ( P T C L): Relati o ns hi p bet wee n 
res p o nse a n d s ur vi val (a bstract 8 0 5 4). . A mer S oc of Cli nical O nc ol; 2 0 1 0. Accesse d: 
( 2 8J u n 2 0 1 0). 
htt p:// w w w.asc o. or g/ A S C O v 2/ Meeti n gs/ A bs tracts? & v m vie w =a bst _ detail _ vie w &c o n
fI D = 7 4 &a bstractI D = 5 4 2 1 8.  
 
2 8 . 
H or witz M, D u vic M, Ki m Y, et al. Pralatre xate efficac y a n d t olera bilit y i n patie nts 
wit h rela pse d or refract or y c uta ne o us  T-cell l y m p h o ma ( C T C L) (a bstract 0 3 0 0). 
Hae mat ol o gica 2 0 1 0; 9 5( S u p pl 2): 1 2 0.  
 
2 9 . 
H or witz S M, V ose J M, A d va ni R, et al. Pral atre xate a n d ge mcita bi ne i n patie nts wit h 
rela pse d or refract or y l y mp h o pr oliferati ve mali g na ncies:  p hase 1 res ults. ( p oster 
prese ntati o n). Prese nte d at A merica n S ociet y of He mat ol o g y ( A S H) 5 1st A n n ual 
Meeti n g, Dec 5- 8; Ne w Orlea ns, L A. 2 0 0 9.  
 
3 0 . 
Kr u g L M, N g K K, Kris M G, et al. P h ase I a n d p har mac o ki netic st u d y of 1 0-
pr o par g yl- 1 0- deazaa mi n o pteri n, a ne w a ntif olate. Cli n Ca ncer Res 2 0 0 0; 6( 9): 3 4 9 3- 8.  
 
3 1 . 
Kr u g L M, Azz oli C G, Kris M G, et al. 1 0- pr o par g yl- 1 0- deazaa mi n o pteri n: a n 
a ntif olate wit h acti vit y i n patie nts wit h pr e vi o usl y treate d n o n-s mall cell l u n g ca ncer. 
Cli n Ca ncer Res 2 0 0 3; 9( 6): 2 0 7 2- 8.  
 
3 2 . 
Azz oli C G, Kr u g L M, G o mez J, et al. A p hase  1 st u d y of pralatre xate i n c o m bi nati o n 
wit h paclita xel or d oceta xel i n patie nts w it h a d va nce d s oli d t u m ors. Cli n Ca ncer Res 
2 0 0 7; 1 3( 9): 2 6 9 2- 8.  
 
3 3 . 
Kr u g L M, Heela n R T, Kris M G, et al. P has e II Trial of Pralatre xate ( 1 0- Pr o par g yl-
1 0- deazaa mi n o pteri n, P D X) i n Patie nts wit h U nresecta ble Mali g na nt Ple ural 
Mes ot heli o ma. J T h orac O nc ol 2 0 0 7; 2( 4): 3 1 7- 3 2 0.  
 
3 4 . 
S mit h TJ, K hatc heressia n J, L y ma n G H, et al. 2 0 0 6 u p date of rec o m me n dati o ns f or 
t he use of w hite bl o o d cell gr o wt h fact ors: a n e vi de nce- base d cli nical practice 
g ui deli ne. J Cli n O nc ol 2 0 0 6; 2 4( 1 9): 3 1 8 7- 2 0 5.  
 
3 5 . 
Be nsi n ger W, Sc h u bert M, A n g K K, et al. N C C N Tas k F orce Re p ort. pre ve nti o n a n d 
ma na ge me nt of m uc ositis i n ca ncer care . J Natl C o m pr Ca nc Net w 2 0 0 8; 6 S u p pl 
1: S 1- 2 1; q uiz S 2 2- 4.  


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 8 5 of 9 5 
 
3 6 . 
Galla mi ni A, Stelita n o C, Cal vi R, et al. Peri p heral T-cell l y m p h o ma u ns pecifie d 
( P T C L- U): a ne w pr o g n ostic m o del fr o m a retr os pecti ve m ultice ntric cli nical st u d y. 
Bl o o d 2 0 0 4; 1 0 3( 7): 2 4 7 4- 9.  
 
3 7 . 
Merca dal S, Bri o nes J, Xic o y B, et  al. I nte nsi ve c he m ot hera p y ( hi g h- d ose 
C H O P/ E S H A P re gi me n) f oll o we d b y a ut o l o g o us ste m-cell tra ns pla ntati o n i n 
pre vi o usl y u ntreate d patie nts wit h peri p heral T-cell l y m p h o ma. A n n O nc ol 2 0 0 8.  
 
3 8 . 
Ki m J G, S o h n S K, C hae Y S, et al. C H O P  pl us et o p osi de a n d ge mcita bi ne ( C H O P-
E G) as fr o nt-li ne c he m ot hera p y f or patie nts wit h peri p heral T cell l y m p h o mas. 
Ca ncer C he m ot her P har mac ol 2 0 0 6; 5 8( 1): 3 5- 9.  
 
3 9 . 
A b o u ya bis A N, S he n o y PJ, Lec h o wicz MJ, et al. I nci de nce a n d o utc o mes of t he 
peri p heral T-cell l y m p h o ma s u bt y pes i n t he U nite d States. Le u k L y m p h o ma 
2 0 0 8; 4 9( 1 1): 2 0 9 9- 1 0 7.  
 
4 0 . 
O' Brie n P C, Fle mi n g T R. A m ulti ple testi n g pr oce d ure f or cli nical trials. Bi o metrics 
1 9 7 9; 3 5: 5 4 9- 5 6.  
 
4 1 . 
La n K K G, De Mets D L. Discrete se q ue ntial b o u n daries f or cli nical trials. Bi o metri ka 
1 9 8 3; 7 0( 3): 6 5 9- 6 3.  
 
4 2 . 
Kittels o n J M, E mers o n S S. A u nif yi n g fa m il y of gr o u p se q ue ntial test desi g ns. 
Bi o metrics 1 9 9 9; 5 5( 3): 8 7 4- 8 2.  
 
4 3 . 
C hes o n B D, Pfist ner B, J u wei d M E, et al . Re vise d res p o nse criteria f or mali g na nt 
l y m p h o ma. J Cli n O nc ol 2 0 0 7; 2 5( 5): 5 7 9- 8 6. 
 
 
 
 






Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1 
 
 
 
 
C o nfi de ntial 
Pa ge 8 8 of 9 5 
A p p e n di x 3  
E C O G P erf or m a n c e S c al e 
E C O G Gr a de  
Perf or m a nce  
0 
F ull y acti ve, a ble t o carr y o n a ll pre- disease perf or ma nce wit h o ut 
restricti o n. 
1 
Restricte d i n p h ysicall y stre n u o us acti vit y, b ut a m b ulat or y a n d a ble 
t o carr y o ut w or k of a li g ht or se de ntar y nat ure, e. g., li g ht h o use 
w or k, office w or k. 
2 
A m b ulat or y a n d ca pa ble of all self- care, b ut u na ble t o carr y o ut a n y 
w or k acti vities.  U p a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs. 
3 
Ca pa ble of o nl y li mite d self-care, c o nfi ne d t o be d or c hair m ore 
t ha n 5 0 % of wa ki n g h o urs 
4 
C o m pletel y disa ble d.  Ca n n ot ca rr 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 
 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
Re pri nte d wit h per missi o n.  © 2 0 0 8 A merica n S ociet y of Cli nical O nc ol o g y.  All ri g hts reser ve d. 
C hes o n, B D et al: J Cli n O nc ol 2 5( 5), 2 0 0 7: 5 7 9- 8 6. 
 
C o nfi de ntial 
Pa ge 8 9 of 9 5 
A p p e n di x 4  
T h e I nt er n ati o n al W or k s h o p Crit eri a 4 3      
T he desi g nati o n of c o m plete res p o nse ( C R) re q uires t he f oll o wi n g ( Ta ble 1 ): 
1.  
C o m plete disa p peara nce of all detect a ble cli nical e vi de nce of disease a n d 
disease-relate d s y m pt o ms if  prese nt bef ore t hera p y. 
2a.  T y picall y ( 1 8F)fl u or o de o x y gl uc ose ( F D G)-a vi d l y m p h o ma: i n patie nts wit h n o 
pretreat me nt p ositr o n e missi o n t o m o gra p h y ( P E T) sca n or w he n t he P E T sca n was 
p ositi ve bef ore t hera p y, a p ost-treat me nt resi d ual mass of a n y size is per mitte d as l o n g 
as it is P E T ne gati ve. 
2 b.  Varia bl y F D G-a vi d l y m p h o mas/ F D G a v i dit y u n k n o w n: i n patie nts wit h o ut a 
pretreat me nt P E T sca n, or if a pretreat me nt  P E T sca n was ne gati ve, all l y m p h n o des a n d 
n o dal masses m ust ha ve re gresse d o n c o m p ute d t o m o gra p h y ( C T) t o n or mal size 
( ≤ 1. 5 c m i n t heir greatest tra ns verse dia meter f or n o des > 1. 5 c m bef ore t hera p y).  
Pre vi o usl y i n v ol ve d n o des t hat  were 1. 1 t o 1. 5 c m i n t heir l o n g a xis a n d m ore t ha n 
1. 0 c m i n t heir s h ort a xis bef ore treat me nt m ust ha ve decrease d t o ≤ 1. 0 c m i n t heir s h ort 
a xis after treat me nt. 
3.  
T he s plee n a n d/ or li ver, if c o nsi dere d e nla r ge d bef ore t hera p y o n t he basis of a p h ysical 
e xa mi nati o n or C T sca n, s h o ul d n ot be pal p a ble o n p h ysical e xa mi nati o n a n d s h o ul d be 
c o nsi dere d n or mal size b y i ma gi n g st u dies , a n d n o d ules relate d t o l y m p h o ma s h o ul d 
disa p pear.  H o we ver, deter mi nati o n of s ple nic i n v ol ve me nt is n ot al wa ys relia ble 
beca use a s plee n c o nsi dere d n or mal i n si ze ma y still c o ntai n l y m p h o ma, w hereas a n 
e nlar ge d s plee n ma y reflect variati o ns  i n a nat o m y, bl o o d v ol u me, t he use of 
he mat o p oietic gr o wt h fact ors, or ca uses ot her t ha n l y m p h o ma. 
4.  If t he b o ne marr o w was i n v ol ve d b y l y m p h o ma  bef ore treat me nt, t he i nfiltrate m ust 
ha ve cleare d o n re peat b o ne marr o w bi o ps y.  T he bi o ps y sa m ple o n w hic h t his 
deter mi nati o n is ma de m ust be a de q uate ( wit h a g oal of > 2 0 m m u nilateral c ore).  If t he 
sa m ple is i n deter mi nate b y m or p h ol o g y, it s h o ul d be ne gati ve b y 
i m m u n o hist oc he mistr y.  A sa m ple t hat is negati ve b y i m m u n o hist oc he mistr y b ut t hat 
de m o nstrates a s mall p o p ulati o n of cl o nal l y m p h oc ytes b y fl o w c yt o metr y will be 
c o nsi dere d a C R u ntil data bec o me a vaila ble de m o nstrati n g a clear differe nce i n patie nt 
o utc o me. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
 Versi o n 2. 1 
 
 
 
 
Re pri nte d wit h per missi o n.  © 2 0 0 8 A merica n S ociet y of Cli nical O nc ol o g y.  All ri g hts reser ve d. 
C hes o n, B D et al: J Cli n O nc ol 2 5( 5), 2 0 0 7: 5 7 9- 8 6. 
 
C o nfi de ntial 
Pa ge 9 0 of 9 5 
T a bl e 1:  
R e s p o n s e D efi niti o n s f or Cli ni c al Tri al s 
Res p o nse 
Defi niti o n 
N o d al M asses 
S plee n, Li ver 
B o ne M arr o w 
C R 
Disa p peara nce of all 
e vi de nce of disease 
(a) F D G-a vi d or P E T p ositi ve pri or t o t hera p y; 
mass of a n y size per mitte d if P E T ne gati ve 
( b) Varia bl y F D G-a vi d or P E T ne gati ve; 
re gressi o n t o n or mal size o n C T 
N ot pal pa ble, n o d ules 
disa p peare d 
I nfiltrate cleare d o n re peat bi o ps y; 
if i n deter mi nate b y m or p h ol o g y, 
i m m u n o hist oc he mistr y s h o ul d be 
ne gati ve 
P R 
Re gressi o n of 
meas ura ble disease a n d 
n o ne w sites 
≥ 5 0 % decrease i n S P D of u p t o 6 lar gest 
d o mi na nt masses; n o i ncrease i n size of ot her 
n o des 
(a) F D G-a vi d or P E T p ositi ve pri or t o t hera p y; 
1 or m ore P E T p ositi ve at pre vi o usl y i n v ol ve d 
site 
( b) Varia bl y F D G-a vi d or P E T ne gati ve; 
re gressi o n o n C T 
≥ 5 0 % decrease i n S P D 
of n o d ules (f or si n gle 
n o d ule i n greatest 
tra ns verse dia meter); n o 
i ncrease i n size of li ver 
or s plee n 
Irrele va nt if p ositi ve pri or t o 
t hera p y; cell t y pe s h o ul d be 
s pecifie d 
S D 
Fail ure t o attai n C R/ P R 
or P D 
(a) F D G-a vi d or P E T p ositi ve pri or t o t hera p y; 
P E T p ositi ve at pri or sites of disease a n d n o 
ne w sites o n C T or P E T 
( b) Varia bl y F D G-a vi d or P E T ne gati ve; n o 
c ha n ge i n size of pre vi o us lesi o ns o n C T   
 
 
Rel a pse d dise ase 
or P D 
A n y ne w lesi o n or 
i ncrease b y ≥ 5 0 % of 
pre vi o usl y i n v ol ve d 
sites fr o m na dir 
A p peara nce of a ne w lesi o n(s) > 1. 5 c m i n a n y 
a xis, ≥ 5 0 % i ncrease i n S P D of m ore t ha n 
1 n o de, or ≥ 5 0 % i ncrease i n l o n gest dia meter 
of a pre vi o usl y i de ntifie d n o de > 1 c m i n s h ort 
a xis 
Lesi o ns P E T p ositi ve if F D G-a vi d l y m p h o ma 
or P E T p ositi ve pri or t o t hera p y 
> 5 0 % i ncrease fr o m 
na dir i n t he S P D of a n y 
pre vi o us lesi o ns 
Ne w or rec urre nt i n v ol ve me nt 
C R = c o m plete re missi o n 
P R = partial re missi o n 
F D G = ( 1 8F)fl u or o de o x y gl uc ose  
S P D = s u m of t he pr o d uct of t he dia meters 
P E T = p ositr o n e missi o n t o m o gra p h y  
S D = sta ble disease 
C T = c o m p ute d t o m o gra p h y   
P D = pr o gressi ve disease 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1 
 
 
 
 
Re pri nte d wit h per missi o n.  © 2 0 0 8 A merica n S ociet y of Cli nical O nc ol o g y.  All ri g hts reser ve d. 
C hes o n, B D et al: J Cli n O nc ol 2 5( 5), 2 0 0 7: 5 7 9- 8 6. 
 
C o nfi de ntial 
Pa ge 9 1 of 9 5 
T he use of t he a b o ve defi niti o n f or C R a n d t hat bel o w f or partial res p o nse ( P R) eli mi nates 
t he cate g or y of c o m plete res p o nse u nc o nfir me d ( C R u). 
T he desi g nati o n of P R re q uires al l of t he f oll o wi n g (Ta ble 1 ):  
1.  
At least a 5 0 % decrease i n t h e s u m of t he pr o d uct of t he di a meters ( S P D) of u p t o 6 of 
t he lar gest d o mi na nt n o des or n o dal masses. T hese n o des or masses s h o ul d be selecte d 
acc or di n g  t o all of t he f oll o wi n g: t he y s h o ul d be clearl y meas ura ble i n at least 
2 per pe n dic ular di me nsi o ns; if p ossi ble t he y s h o ul d be  fr o m dis parate re gi o ns of t he 
b o d y; a n d t he y  s h o ul d i ncl u de me diasti nal a n d retr o perit o neal areas of disease  w he ne ver 
t hese sites are i n v ol ve d. 
2.   N o i ncrease s h o ul d be o bser ve d i n t he size  of t he ot her n o des, li ver, or s plee n. 
3.   S ple nic a n d he patic  n o d ules m ust re gress b y ≥ 5 0 % i n t heir S P D or, f or si n gle n o d ules, 
i n t he greatest tra ns verse dia meter.  
4.   
Wit h t he  e xce pti o n of s ple nic a n d he patic n o d ules, i n v ol ve me nt  of ot her  or ga ns is 
us uall y assessa ble a n d n o meas ura ble  disease s h o ul d be prese nt.   
5.   B o ne marr o w assess me nt is irrele va nt f or deter mi nati o n  of  a P R if t he sa m ple was 
p ositi ve bef ore treat me nt.  H o we ver, if p ositi ve, t he cell t y pe s h o ul d be s pecifie d (e g, 
lar ge-cell l y m p h o ma or s mall ne o plastic B cells).  Patie nts w h o ac hie ve a C R b y t he 
a b o ve criteria, b ut w h o ha ve persiste nt m or p h ol o gic b o ne marr o w i n v ol ve me nt will be 
c o nsi dere d partial res p o n ders. 
W he n t he b o ne marr o w was i n v ol ve d bef ore t hera p y a n d a cli nical C R was ac hie ve d, 
b ut wit h n o b o ne marr o w assess me nt after tr eat me nt, patie nts s h o ul d be c o nsi dere d 
partial res p o n ders. 
6.   N o ne w sites of disease s h o ul d be o bser ve d.   
7.  
T y picall y F D G-a vi d l y m p h o ma: f or patie nts wit h n o pretreat me nt P E T sca n or if t he 
P E T sca n was p ositi ve bef ore t hera p y, t he p ost-treat me nt P E T s h o ul d be p ositi ve i n at 
least 1 pre vi o usl y i n v ol ve d site. 
8.  
Varia bl y F D G-a vi d l y m p h o mas/ F D G-a v i dit y u n k n o w n: f or patie nts wit h o ut a 
pretreat me nt P E T sca n, or if a pretreat me nt  P E T sca n was ne gati ve, C T criteria s h o ul d 
be use d. 
I n patie nts wit h f ollic ular l y m p h o ma or ma ntle-cell l y m p h o ma, a P E T sca n is o nl y 
i n dicate d wit h 1 or at m ost 2 resi d ual masses t hat ha ve re gresse d b y m ore t ha n 5 0 % o n 
C T; t h ose wit h m ore t ha n 2 resi d ual lesi o ns are u nli kel y t o be P E T ne gati ve a n d s h o ul d 
be c o nsi dere d partial res p o n ders. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1 
 
 
 
 
Re pri nte d wit h per missi o n.  © 2 0 0 8 A merica n S ociet y of Cli nical O nc ol o g y.  All ri g hts reser ve d. 
C hes o n, B D et al: J Cli n O nc ol 2 5( 5), 2 0 0 7: 5 7 9- 8 6. 
 
C o nfi de ntial 
Pa ge 9 2 of 9 5 
Sta ble disease ( S D) is defi ne d as t he f oll o wi n g ( Ta ble 1 ):  
1.   A patie nt is c o nsi dere d t o ha ve S D w he n he or s he fails t o attai n t he criteria nee de d f or a 
C R or P R, b ut d oes n ot f ulfill t h ose f or pr o gre ssi ve disease (see Rela pse d Disease [after 
C R]/ Pr o gressi ve Disease [after P R, S D]). 
2.  
T y picall y F D G-a vi d l y m p h o mas: t he P E T s h o ul d be p ositi ve at pri or sites of disease 
wit h n o ne w areas of i n v ol ve me nt o n t he p ost-treat me nt C T or P E T. 
3.  
Varia bl y F D G-a vi d l y m p h o mas/ F D G-a v i dit y u n k n o w n: f or patie nts wit h o ut a 
pretreat me nt P E T sca n or if t he pretreat me nt P E T was ne gati ve, t here m ust be n o 
c ha n ge i n t he size of t he pre vi o us le si o ns o n t he p ost-treat me nt C T sca n. 
Rela pse d Disease (after C R)/ Pr o gressi ve  Disease (after P R, S D) ( Ta ble 1) 
L y m p h n o des s h o ul d be c o nsi dere d a b n or mal if t h e l o n g a xis is m ore t ha n 1. 5 c m re gar dless 
of t he s h ort a xis.  If a l y m p h n o de has a l o n g a xis of 1. 1 t o 1. 5 c m, it s h o ul d o nl y be 
c o nsi dere d a b n or mal if its s h ort a xis is m ore t ha n 1. 0.  L y m p h n o des ≤ 1. 0 x ≤ 1. 0 c m will 
n ot be c o nsi dere d as a b n or mal f o r rela pse or pr o gressi ve disease. 
1.  
A p peara nce of a n y ne w lesi o n m ore t ha n 1. 5 c m i n a n y a xis d uri n g or at t he e n d of 
t hera p y, e ve n if ot her lesi o ns are decreasi n g i n size.  I ncrease d F D G u pta ke i n a 
pre vi o usl y u naffecte d site s h o ul d o nl y be c o nsi dere d rela pse d or pr o gressi ve disease 
after c o nfir mati o n wit h ot her mo dalities.  I n patie nts wit h n o  pri or hist or y of p ul m o nar y 
l y m p h o ma, ne w l u n g n o d ules i de ntifie d b y C T are m ostl y be ni g n.  T h us, a t hera pe utic 
decisi o n s h o ul d n ot be ma de s olel y o n t he basis of t he P E T wit h o ut hist ol o gic 
c o nfir mati o n. 
2.  
At least a 5 0 % i ncrease fr o m na dir i n t he S P D  of a n y pre vi o usl y i n v ol ve d n o des, or i n a 
si n gle i n v ol ve d n o de, or t he size of ot her lesi o ns (e g, s ple nic or he patic n o d ules).  T o be 
c o nsi dere d pr o gressi ve disease, a l y m p h n o de w it h a dia meter of t he s h ort a xis of less 
t ha n 1. 0 c m m ust i ncrease b y ≥ 5 0 % a n d t o a size of 1. 5 x 1. 5 c m or m ore t ha n 1. 5 c m i n 
t he l o n g a xis. 
3.  
At least a 5 0 % i ncrease i n t h e l o n gest dia meter of a n y si n gle pre vi o usl y i de ntifie d n o de 
m ore t ha n 1 c m i n its s h ort a xis. 
4.  
Lesi o ns s h o ul d be P E T p ositi ve if o bser ve d  i n a t y pical F D G-a vi d l y m p h o ma or t he 
lesi o n was P E T p ositi ve bef ore t hera p y u nless t he lesi o n is t o o s mall t o be detecte d wit h 
c urre nt P E T s yste ms ( < 1. 5 c m i n its l o n g a xis b y C T). 
Meas ura ble e xtra n o dal disease s h o ul d be asse sse d i n a ma n ner si milar t o t hat f or n o dal 
disease.  F or t hese rec o m me n dati o ns, t he s pl ee n is c o nsi dere d n o da l disease.  Disease 
t hat is o nl y assessa ble (e g, ple ural eff usi o ns, b o ne lesi o ns) will be rec or de d as prese nt or 
a bse nt o nl y, u nless, w hile a n a b n or malit y is  still n ote d b y i ma gin g st u dies or p h ysical 
e xa mi nati o n, it is f o u n d t o be hist ol o gicall y ne gati ve. 


Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1 
 
 
 
 
Re pri nte d wit h per missi o n.  © 2 0 0 8 A merica n S ociet y of Cli nical O nc ol o g y.  All ri g hts reser ve d. 
C hes o n, B D et al: J Cli n O nc ol 2 5( 5), 2 0 0 7: 5 7 9- 8 6. 
 
C o nfi de ntial 
Pa ge 9 3 of 9 5 
I n cli nical trials w here P E T is u na vaila ble t o t he vast maj orit y of partici pa nts, or w here 
P E T is n ot dee me d necessar y or a p pr o priate  f or use (e g, a trial i n patie nts wit h M A L T 
l y m p h o ma), res p o nse s h o ul d be assesse d as ab o ve, b ut o nl y usi n g C T sca ns. H o we ver, 
resi d ual masses s h o ul d n ot be assi g ne d C R u stat us, b ut s h o ul d be c o nsi dere d partial 
res p o nses. 




Pralatre xate I njecti o n 
 
All os T hera pe utics, I nc. 
Cli nical St u d y Pr ot oc ol: P D X- 0 1 7 
 
Versi o n 2. 1  
 
 
 
 
C o nfi de ntial 
Pa ge 9 5 of 9 5 
A p p e n di x 6  
I n v e st i g at or Si g n at ur e 
St u d y Title: 
A M ulti-ce nter, Ra n d o mize d, P hase 3 St u d y of Se q ue ntial 
Pralatre xate Vers us O bser vati o n i n Patie nts wit h Pre vi o usl y 
U n dia g n ose d Peri p heral T-cell L y m p h o ma W h o Ha ve Ac hie ve d a n 
O bjecti ve Res p o nse F oll o wi n g I nitial Treat me nt wit h C H O P- base d 
C he m ot hera p y 
St u d y N u m ber: 
P D X- 0 1 7 
Versi o n N u m ber/ 
Fi n al D ate: 
2. 1/ 3 1 Oct 2 0 1 1 
I ha ve rea d t he pr ot oc ol, i ncl u di n g all a p pe n dices, a n d I a gree t hat it c o ntai ns all necessar y 
details f or me a n d m y staff t o c o n d uct t his st u d y as descri be d.  I will c o n d uct t his st u d y i n 
c o m plia nce wit h all a p plica ble re g ulati o ns a n d g u i deli nes as state d i n t he pr ot oc ol a n d ot her 
i nf or mati o n s u p plie d t o me.  I will ma ke a reaso na ble eff ort t o c o m plete t he st u d y wit hi n t he 
ti me desi g nate d. 
I will pr o vi de all st u d y pers o n nel u n der m y s u per visi o n wit h c o pies of t he pr ot oc ol a n d 
access t o all i nf or mati o n pr o vi de d b y All os T hera p e utics, I nc. or desi g nees.  I will disc uss 
t his material wit h t he m t o e ns ure t hat t he y are f ull y i nf or me d a b o ut t he dr u g(s) a n d t he st u d y. 
 
 
 
 
 
 
Pri nci pal I n vesti gat or Na me ( Pri nte d)  
 
Si g nat ure 
 
 
 
Date 
 
Site N u m ber 
 

SAP_001.pdf: 
Official Title: 
A  Multi-center, Randomized, Phase 3 Study of Sequential 
Pralatrexate Versus Observation in Patients with Previously 
Undiagnosed Peripheral T-cell Lymphoma Who Have Achieved an 
Objective Response Following Initial Treatment with CHOP-based 
Chemotherapy 
NCT Number: 
NCT01420679 
Document Date: 
SAP Version 1.2: 18 April 2012 


Pralatrexate 
 
Allos Therapeutics, Inc. 
PDX-017 Statistical Analysis Plan 
 
Version 1.2 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL PDX-017 
A Multi-center, Randomized, Phase 3 Study of Sequential Pralatrexate 
Versus Observation in Patients with Previously Undiagnosed Peripheral T-
cell Lymphoma Who Have Achieved an Objective Response Following 
Initial Treatment with CHOP-based Chemotherapy 
 
 
18 APR 2012 
 
 
 
 
 
 
 
Author:
 
 
Biostatistician:
 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION .............................................................................................................4 
2 
OBJECTIVES ....................................................................................................................4 
2.1 
Primary Objective ....................................................................................................4 
2.2 
Secondary Objective ................................................................................................4 
3 
STUDY DESIGN...............................................................................................................4 
3.1 
Stratification Factors ................................................................................................5 
3.2 
Sample Size Considerations .....................................................................................5 
3.3 
Interim Analyses ......................................................................................................6 
4 
STUDY ENDPOINTS AND COVARIATES ...................................................................8 
4.1 
Primary Efficacy Endpoints .....................................................................................8 
4.2 
Secondary Efficacy Endpoint ..................................................................................8 
4.3 
Safety Endpoints ......................................................................................................8 
4.4 
Potential Covariates .................................................................................................8 
5 
ABBREVIATIONS AND DEFINITIONS ........................................................................9 
5.1 
Abbreviations ...........................................................................................................9 
5.2 
Definitions..............................................................................................................11 
6 
ANALYSIS SUBSETS ....................................................................................................12 
6.1 
Primary Analysis Set..............................................................................................12 
6.2 
Safety Analysis Set ................................................................................................12 
6.3 
Interim Analysis Set ...............................................................................................13 
6.4 
Subgroup Analyses ................................................................................................13 
7 
DATA SCREENING AND ACCEPTANCE ..................................................................13 
7.1 
General Principles ..................................................................................................13 
7.2 
Handling of Missing and Incomplete Data ............................................................13 
7.3 
Testing/Validation Plan .........................................................................................13 
8 
STATISTICAL METHODS OF ANALYSIS .................................................................14 
8.1 
General Principles ..................................................................................................14 
8.2 
Patient Accountability ............................................................................................14 
8.3 
Important Protocol Deviations ...............................................................................14 
8.4 
Demographic and Baseline Characteristics ...........................................................14 
8.5 
Efficacy Endpoints .................................................................................................14 
8.5.1 
Progression-free Survival.............................................................................14 
8.5.2 
Overall Survival ...........................................................................................14 
8.5.3 
Objective Response Rate .............................................................................15 
8.5.4 
Additional Analysis .....................................................................................15 
8.5.5 
Sensitivity Analyses .....................................................................................15 
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8.6 
Safety Analyses ......................................................................................................15 
9 
LIST OF PLANNED TABLES, FIGURES, LISTINGS, AND APPENDICES .............18 
10  REFERENCES ................................................................................................................22 
11  APPENDICES .................................................................................................................23 
11.1 
Table/Figure/Listing Shells ....................................................................................23 
11.2 
Reference Values/Severity Grades ........................................................................23 
11.3 
Handling of Dates, Incomplete Dates, and Missing Dates for Adverse Events 
and Concomitant Medications ...............................................................................23 
11.4 
Preferred Terms for Adverse Events Grouped by Similar Preferred Term ...........25 
LIST OF TABLES 
Table 9.1. 
Planned Tables .......................................................................................18 
Table 9.2. 
Planned Listings .....................................................................................20 
Table 9.3. 
Planned Figures ......................................................................................21 
Table 11.1. 
Adverse Events Grouped by Similar Preferred Term ............................25 
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Pralatrexate 
 
Allos Therapeutics, Inc. 
PDX-017 Statistical Analysis Plan 
 
Version 1.2 
1 
INTRODUCTION 
The purpose of this statistical analysis plan is to provide details of the statistical analyses that 
have been outlined within version 2.1 of the protocol for pralatrexate study PDX-017 dated 
31 Oct 2011.  The scope of this plan includes the interim and final analyses.  The analyses 
detailed within this plan will help to evaluate the efficacy and safety of pralatrexate as 
sequential therapy in patients with peripheral T-cell lymphoma (PTCL) who have achieved 
an objective response following initial treatment of first-line cyclophosphamide, doxorubicin, 
vincristine, and prednisone (CHOP)-based regimen. 
2 
OBJECTIVES 
2.1 
Primary Objective 
Determine the efficacy of pralatrexate compared to observation when administered to 
patients with previously undiagnosed PTCL who have achieved an objective response after 
completing at least 6 cycles of CHOP-based treatment. 
2.2 
Secondary Objective 
Determine the safety of pralatrexate when administered following a course of CHOP-based 
treatment to patients with previously undiagnosed PTCL. 
3 
STUDY DESIGN 
This is an international, multi-center, randomized, Phase 3, open-label study of sequential 
pralatrexate versus observation in patients with previously undiagnosed PTCL who have 
achieved an objective response following initial treatment with CHOP-based chemotherapy. 
Upon documentation of an objective response following at least 6 cycles of a designated 
CHOP-based chemotherapy, confirmation of histopathology by independent review, and 
confirmation that all eligibility criteria are met, patients will be randomized in a 2:1 ratio to 
either pralatrexate or observation, according to a permuted block design (block sizes of 3) 
stratified by response per investigator at completion of CHOP-based therapy (complete 
response [CR] vs partial response [PR]). 
Patients randomized to the Pralatrexate Arm will receive pralatrexate as an intravenous (IV) 
push administration over a minimum of 30 seconds up to a maximum of 5 minutes via a 
patent free-flowing IV line containing normal saline (0.9% sodium chloride [NaCl])   
weekly for 3 weeks (± 1 day at each time point) of a 4-week cycle.  The initial dose of 
pralatrexate will be 30 mg/m2 which, based on protocol-defined criteria, may be reduced to 
20 mg/m2 with potential further reduction to 15 mg/m2 and 10 mg/m2.  There will be sparse 
sampling for pharmacokinetics (PK).  Pralatrexate will continue to be administered until a 
criterion for study treatment discontinuation is met or up to a maximum of 2 years. 
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Version 1.2 
Patients randomized to the Observation Arm will remain under observation, attend clinic 
visits every 4 weeks, and receive a follow-up phone call from a healthcare professional 
during each week 2 of 4 until a criterion for study treatment discontinuation is met for a 
maximum of 2 years. 
All patients will receive vitamin supplementation, consisting of vitamin B12 1 mg 
intramuscularly (IM) every (q) 8-10 weeks and folic acid 1-1.25 mg by mouth (po) once a 
day (qd).  Vitamin supplementation will begin at least 7 days prior to the projected initiation 
of pralatrexate/observation and continue throughout the study until the Initial Follow-up 
Visit. 
Patients will be followed for safety until 35 (± 5) days after the study treatment 
discontinuation criteria are met.  Patients will be followed to determine time to progressive 
disease (PD) and survival for up to 7 years from randomization or until 35 (± 5) days after 
the last dose of pralatrexate, whichever is longer.  Patients who withdraw from treatment 
prior to PD without withdrawing consent will be followed for disease status whenever 
possible, even if subsequent therapy, including transplant, has been initiated prior to 
documented PD per central review, at least until the first interim analysis. 
3.1 
Stratification Factors 
The randomization will be stratified by response per investigator at completion of 
CHOP-based therapy (CR vs PR). 
3.2 
Sample Size Considerations 
A total of approximately 549 randomized patients are planned for this study. 
Outcome data for patients with T-cell lymphoma who receive first-line CHOP are limited.  
A retrospective study of the International T-Cell Lymphoma Project demonstrated a 5-year 
overall survival (OS) rate of 32% and a 5-year failure-free survival (FFS) rate of 20% for 
patients with peripheral T-cell lymphoma unspecified (PTCL-U), with widely varying results 
for other subtypes.1  Median OS for these patients did not seem to be a function of whether 
the patient received an anthracycline-based induction therapy.  In a retrospective evaluation 
of 96 patients diagnosed within the Non-Hodgkin’s Lymphoma Classification Project, 
Rudiger et al  report a similar finding, with 5-year OS and FFS rates of 26% and 20%, 
respectively, for PTCL patients treated with a doxorubicin-containing regimen.2  Per Figure 1 
of the Rudiger publication, the estimated median FFS in these patients is approximately 
6 months.   
Reports of response rate to first-line CHOP-based regimens in patients with PTCL are also 
available.  Gallamini et al, conducted a small study (n = 24 evaluable) evaluating CHOP plus 
alemtuzumab administered every 4 weeks for a total of 28 weeks.3  They observed an overall 
response rate of 75% (71% CR, 4% PR).  In a separate report, Gallamini et al, performed a 
retrospective analysis of 385 patients with PTCL-U, with the majority (78%) receiving 
chemotherapy containing anthracycline.4  They reported an overall response rate of 
74% (53% CR, 21% PR) in the 372 evaluable patients.  Mercadal and colleagues reported on 
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a series of 41 patients ≤ 65 years old who were planned to receive 6 cycles of intensive 
chemotherapy (high-dose CHOP alternating with etoposide, methylprednisolone, cytarabine, 
and cisplatin [ESHAP]) followed by autologous stem cell transplantation if in response.5  
Twenty-eight patients (68%) received the planned 6 courses of therapy, 6 patients (15%) 
received 5 courses of therapy, and 7 (17%) received less than 5 courses.  Following the 
chemotherapy phase, the CR rate was 49% and the PR rate was 10%.  Kim and collaborators 
administered CHOP plus etoposide and gemcitabine to a cohort of 26 first-line PTCL 
patients.6  The median number of cycles administered was 4, and the overall response rate 
was 77% (62% CR, 15% PR).  Abouyabis and colleagues performed a meta-analysis of 
non-anaplastic large cell lymphoma (ALCL) PTCL patients receiving anthracycline-based 
chemotherapy in the first-line setting.7  A total of 31 studies were identified involving a total 
of 1996 patients.  The overall CR rate was 55% and the 5-year OS rate was 37%. 
Across all of these reported studies, approximately 50% of patients achieve a CR to first-line 
CHOP, with an additional 10-20% achieving a PR.  Furthermore, the 5-year progression-free 
survival (PFS) is approximately 20%, with a median PFS of approximately 9 months in all 
patients.  For sample size calculations for the PDX-017 study, we assume that one-third of 
these patients will have disease refractory to CHOP and that the median PFS in these patients 
will be 3 months.  Coupled with an overall median PFS of 9 months, and assuming 
exponentially distributed PFS, this implies the median PFS in patients who respond to CHOP 
is approximately 16 months.  Subtracting out 6 months for CHOP administration and 
washout prior to randomization results in an estimated 10-month median PFS for 
Observation Arm patients in PDX-017. 
The sample size is based on comparing the treatment groups with respect to the primary 
efficacy endpoints of PFS and OS.  Assuming proportional hazards, a true hazard ratio (HR) 
on OS of 0.73, and a 2:1 randomization (treatment:observation) with a total of 549 patients 
(366 in the treatment group vs 183 in the observation group), a total of 385 OS events 
(deaths) will provide at least 80% power to show HR < 1.00 using a 2-sided stratified 
log-rank test at a 0.05 significance level (alpha = 0.05), assuming an accrual period of 
54 months and a follow-up period of 30 months.  For a HR on PFS of 0.67, a total of 
280 PFS events (PD + deaths) will provide at least 80% power to show HR < 1.00 using 
a 2-sided stratified log-rank test at a 0.05 significance level. 
Further assuming that PFS is exponentially distributed, that the median PFS in the control 
group is 10 months, and that uniform enrollment will occur over 54 months, under the 
alternative hypothesis that HR = 0.67, the 280th event will occur approximately 48 months 
after the first patient is randomized.  Allos will set a data cut-off date for the primary efficacy 
analysis in anticipation of the 280th PFS event and 128th OS event. 
3.3 
Interim Analyses 
A step down procedure will be used for analyzing the co-primary endpoints of PFS and OS.  
If the PFS endpoint is significant at the 0.05 level the OS endpoint will be tested at an overall 
significance level of 0.05.  However, if the PFS endpoint fails to show significance, the study 
will be stopped and OS will not be tested.  The study will meet its primary objective if both 
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Version 1.2 
the PFS and OS endpoints are significant.  The interim analyses for OS will be implemented 
using the error-spending approach of Lan and DeMets according to the unified family 
approach with boundary relationships of O’Brien and Fleming for early stopping to reject the 
null hypothesis (superiority).8, 9  The boundaries for early stopping due to failure to reject the 
null hypothesis (futility) will be determined according to the unified family approach with 
boundary shape parameters on the sample mean scale that result from choosing P = 2.0 
(all R and A parameters in the unified family approach set equal to zero).10 
There will be 1 final analysis of PFS, and 2 interim and 1 final analyses of OS. The first 
interim analysis of OS will be performed at the same time as the PFS analysis.  The first 
interim analysis will be performed when both 280 PFS events and 128 OS events have 
occurred.  The only analysis for PFS will be performed at this first analysis point, at the 
0.05 level of significance.  If PFS is significant at the 0.05 level, the first interim analysis will 
be conducted on survival at this time.  If the PFS analysis is not significant at the 0.05 level, 
the study will be stopped.  If there are 128 OS events, or one-third of the information of 
385 deaths, included in the first interim analysis of OS, the level of significance (alpha) 
would be 0.0002, according to O’Brien and Fleming.8, 9  If PFS is significant, a test for 
futility of OS will not be conducted at the first interim analysis since such a result could not 
occur.  The second interim analysis for OS will be performed when two-thirds (256) of the 
survival events have occurred, at the 0.013 level of significance.  The HR stopping bound for 
futility at this interim analysis will be 1.05 (95% confidence interval [CI]: 0.80, 1.29).  If the 
HR for OS is greater than 1.05, the study will be stopped.  The final analysis for survival will 
be performed when 385 OS events have occurred, at the 0.046 level of significance.  
The stratified log-rank test (stratified by response to prior CHOP-based therapy) will be the 
primary method used to test the hypothesis that pralatrexate extends PFS and OS relative to 
observation.  In addition, the stratified Cox regression model will be used to calculate the 
PFS and survival hazard ratio (HR), along with their 95% CIs.  Results of the unstratified 
Cox regression model (and log-rank test) will also be presented.  The proportional hazards 
assumption of the Cox model will be assessed. 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will evaluate safety after approximately 100 patients 
have been randomized and have completed at least 8 weeks post-randomization 
pralatrexate/observation or have discontinued.  Safety evaluations will also be performed at 
the same time of each interim analysis of efficacy. All interim analyses will be performed by 
the DMC. 
At each interim analysis for survival, the DMC will make a recommendation to Allos to 
either stop or continue the study.  The study could be stopped for overwhelming evidence of 
superiority or futility according to specified boundaries.  At the first interim analysis for 
survival, the DMC could also make the recommendation to Allos to submit a regulatory 
filing based on positive results of the PFS endpoint plus a trend of survival in favor of the 
pralatrexate treatment group.  Allos may discuss the DMC’s recommendations with 
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regulatory authorities before any such action is taken.  The DMC may also make 
recommendations regarding adjustments to the sample size, if they are warranted. 
4 
STUDY ENDPOINTS AND COVARIATES 
4.1 
Primary Efficacy Endpoints 
The co-primary efficacy endpoints are PFS and OS. 
4.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is objective response (CR or PR) to pralatrexate versus 
observation. 
The primary analyses of PFS and objective response at the first interim analysis will use the 
central review of tumor assessments per International Workshop Criteria (IWC) without 
positron emission tomography (PET).  Additional analyses of PFS and objective response 
will use IWC, including PET, and investigators’ assessment of response.  Additional details 
regarding central review will be provided in the reviewer’s charter. 
4.3 
Safety Endpoints 
Safety endpoints include: 
• Incidence and severity of treatment-emergent adverse events (AEs). 
• Changes in laboratory values. 
4.4 
Potential Covariates 
The following covariates will be considered in covariate-adjusted and other exploratory 
analyses: 
• Stratification factor (CR vs PR to prior CHOP-based therapy); 
• The International Prognostic Index (IPI) score at initial diagnosis (plus individual 
components as collected); 
• Histology (PTCL-U vs transformed mycosis fungoides vs ALCL vs other); and 
• Region. 
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5 
ABBREVIATIONS AND DEFINITIONS 
5.1 
Abbreviations 
AE 
adverse event 
ALCL 
anaplastic large cell lymphoma 
ATC 
Anatomical Therapeutic Chemical  
AUC 
area under the curve 
CHOP 
cyclophosphamide, doxorubicin, vincristine, and prednisone 
CI 
confidence interval 
CM 
concomitant medication 
Cmax 
maximum concentration 
CR 
complete response 
CRT 
case report tabulations 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ESHAP 
etoposide, methylprednisolone, cytarabine, and cisplatin 
FAS 
full analysis set 
FFS 
failure-free survival 
HR 
hazard ratio 
IM 
intramuscularly 
IPD 
important protocol deviation 
IPI 
International Prognostic Index 
IRT 
interactive response technology 
IV 
intravenous 
IWC 
International Workshop Criteria 
K-M 
Kaplan-Meier 
m2 
square meter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
NaCl 
sodium chloride 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
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PDX 
(RS)-10-propargyl-10-deazaaminopterin (pralatrexate) 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
po 
by mouth  
POPPK 
population PK 
PR 
partial response 
PTCL 
peripheral T-cell lymphoma 
PTCL-U 
peripheral T-cell lymphoma unspecified 
q 
every 
qd 
once a day 
SAE 
serious adverse event 
SD 
stable disease 
SOC 
system organ class 
t1/2 
half-life 
TLGs 
tables, listings, and graphs 
WHODRUG World Health Organization Drug 
 
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5.2 
Definitions 
Screening Phase 
The screening phase is the period between signing of informed consent and randomization. 
Baseline 
For efficacy assessments, baseline is defined as the last assessment prior to randomization.  
For safety assessments, baseline is defined as the last assessment prior to study day 1. 
Study Day 1 
Study day 1 is defined as the treatment start date.  By convention, when known, assessments 
that occur on the same date as the treatment start date but that occur before treatment will be 
assigned as study day 0; those occurring in the same day but after treatment start will be 
assigned as study day 1.  For patients randomized to the Observation Arm, study day 1 will 
be assigned to all patients who do not withdraw from the study prior to 3 days post-
randomization, and will be equal to the randomization date plus 3 days. 
Cycle 
For patients randomized to the Pralatrexate Arm, a cycle will be calculated as the time from 
the first administration of pralatrexate for the given cycle to the day before the first 
administration of the subsequent cycle.  The last cycle for a patient will be calculated as the 
time from the first administration of protocol-specified treatment for the given cycle plus 
4 weeks or to the last dose administered within the cycle, whichever is longer. 
Complete Response 
CR is defined based on the IWC.11  The same imaging method(s) used to document disease 
pre-randomization are to be used for post-randomization response assessments. 
Partial Response 
PR is defined based on the IWC.11  The same imaging method(s) used to document disease 
pre-randomization are to be used for post-randomization response assessments. 
Objective Response 
Objective response is defined as a tumor response assessment of either CR or PR based on 
IWC.11  The same imaging method(s) used to document disease during screening are to be 
used for subsequent response assessments. 
Stable Disease 
SD is defined using IWC.11 
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Progressive Disease 
PD is defined using IWC.11 
Progression-free Survival Time  
PFS time is calculated as the number of days from randomization to the date of objective 
documentation of PD or death, regardless of cause (PD date/death date - date of 
randomization + 1).  Patients who are alive without a disease response assessment of PD will 
be censored at their last disease assessment date or the date of randomization, whichever is 
later.  Date of progression will not be imputed for patients with missing tumor assessment(s) 
before an assessment of PD.  Patients who withdraw from treatment prior to PD without 
withdrawing consent will be followed for disease status whenever possible, even if 
subsequent therapy, including transplant, has been initiated prior to documented PD per 
central review at least until the first interim analysis.  Patients who have not died and who 
have no response assessments after baseline will be censored at randomization. 
Overall Survival Time 
OS time is calculated as the number of days from randomization to death (date of death - date 
of randomization + 1).  Patients who have not died (no record of death) or are lost to 
follow-up will be censored at the date of last contact.  Patients who withdraw from study visit 
participation will be followed for survival status.  OS will be reported in months. 
Treatment-emergent Adverse Event 
A treatment-emergent AE is defined as an AE that occurs on or after study day 1 and that is a 
higher grade than was present just prior to study day 1. 
6 
ANALYSIS SUBSETS  
6.1 
Primary Analysis Set 
The primary efficacy set, also referred to as the intent-to-treat population or full analysis set 
(FAS), will include all randomized patients.  Each patient will be included in the treatment 
group assigned at randomization, regardless of the treatment received.  This analysis set will 
be used for the primary analyses of all efficacy endpoints. 
6.2 
Safety Analysis Set 
The safety analysis set consists of all patients randomized to the Pralatrexate Arm who 
receive at least 1 dose of pralatrexate plus all patients randomized to the Observation Arm 
who do not discontinue study within 3 days of randomization.  This analysis set will be used 
for the primary analyses of all safety endpoints. 
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6.3 
Interim Analysis Set 
There are 2 formal interim analyses planned for this study: 1 after both 280 PFS events and 
128 OS events have occurred and 1 after 256 OS events have occurred.  The interim analysis 
set will include all randomized patients who have at least 8 weeks of follow-up (ie, those 
who have reached the first scheduled response assessment) or who have discontinued the 
study prior to the first scheduled response assessment.  This analysis set will only be used in 
the analysis of objective response rate (ORR). 
6.4 
Subgroup Analyses 
The summaries of the primary and secondary efficacy variables and the comparisons of the 
treatment groups will be performed for subgroups defined by the covariates identified in 
Section 4.4. 
Summaries of treatment-emergent AEs will be provided for subgroups defined by age 
(< 65 vs ≥ 65), gender, and race (if feasible). 
7 
DATA SCREENING AND ACCEPTANCE 
7.1 
General Principles 
The case report tabulations (CRTs) will be built for this study.  Data will be reviewed and 
cleaned prior to the creation of the final CRTs for this study. 
7.2 
Handling of Missing and Incomplete Data 
Missing and incomplete data will be identified through a review of tables and listings for this 
study.  Missing and incomplete data will be identified for investigation, and possible 
resolution, by Allos Data Management prior to the study database lock. 
In general, missing data will be treated as missing, unless otherwise specified.  Missing and 
incomplete dates for AEs, concomitant medications, and historical data will be imputed 
within this study based on the conventions described in Section 11.3.  Any AE with no stop 
date will be considered ongoing. 
7.3 
Testing/Validation Plan 
SAS® Version 8.2 or higher on the Windows system will be used for all CRT and tables, 
listings, and graphs (TLGs) creation.12  Departmental standard macros will be used whenever 
appropriate for the creation of these items.  These macros, as well as SAS®, have already 
passed a rigorous validation process and further validation will not take place, although 
outputs will be verified.  The verification of all outputs, as well as the review of all programs 
and macros created specifically for this study, will be conducted as outlined in Allos 
Standard Operating Procedures. 
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8 
STATISTICAL METHODS OF ANALYSIS 
8.1 
General Principles 
Unless otherwise indicated, analyses will be performed on the FAS. 
8.2 
Patient Accountability 
The number of patients randomized (FAS) and in the safety analysis set will be summarized 
by treatment group and stratum.  The reason for treatment discontinuation and study 
discontinuation will be summarized. 
The number of patients included in each analysis set will be presented. 
8.3 
Important Protocol Deviations  
The incidence of important protocol deviations (IPDs) will be summarized for each treatment 
group based on the IPDs identified within the database by the clinical study team.  These 
specific IPDs will be detailed in a separate document. 
8.4 
Demographic and Baseline Characteristics 
Demographics (age, gender, race, geriatric age group [< 65 years old vs ≥ 65 years old]) and 
other baseline disease characteristics including Eastern Cooperative Oncology Group 
(ECOG) performance status, IPI, and histopathology will be summarized using descriptive 
statistics for the FAS. 
8.5 
Efficacy Endpoints 
8.5.1 
Progression-free Survival 
The stratified log-rank test will be the primary method used to test the hypothesis that 
pralatrexate extends PFS relative to observation.  In addition, the stratified Cox regression 
model will be used to calculate the PFS HR, along with the 95% CI.  Strata used in these 
analyses will be those used for study randomization (as recorded using the interactive 
response technology [IRT]). Results of the unstratified Cox regression model (and log-rank 
test) will also be presented.  The proportional hazards assumption of the Cox model will be 
assessed.   
8.5.2 
Overall Survival 
The stratified log-rank test will be the primary method used to test the hypothesis that 
pralatrexate extends OS relative to observation.  In addition, the stratified Cox regression 
model will be used to calculate the OS HR, along with the 95% CI.  Strata used in these 
analyses will be those used for study randomization (as recorded using the IRT). Results of 
the unstratified Cox regression model (and log-rank test) will also be presented.  The 
proportional hazards assumption of the Cox model will be assessed. 
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It is recognized a priori that pralatrexate may be administered to Observation Arm patients 
subsequent to meeting treatment discontinuation criteria and thus, interpretability of the 
effect on OS may be confounded by crossover. 
8.5.3 
Objective Response Rate  
The number and percentage of patients with an objective response of CR or PR, relative to 
disease status at the time of study entry, will be summarized by treatment group.  The 
percentage will be calculated by dividing the number of patients within each category of 
response by the number of patients with measurable disease at baseline.  Each patient will be 
counted within only 1 response group, with the overall best response during the study as the 
classification group.  The treatment groups will be compared with respect to objective 
response rate (PR + CR) using the stratified Cochran-Mantel-Haenszel test.  A 2-sided 
95% exact CI will be calculated for the difference in objective response rates between the 
2 treatment groups.  Descriptive statistics will be provided for overall best tumor response for 
each treatment group. 
8.5.4 
Additional Analysis 
The relationship of the covariates listed in Section 4.4 to PFS time, OS time, and tumor 
response rate will be explored using a logistic regression model for tumor response rate and 
Cox proportional hazards regression models (univariate and multivariate) for the 
time-to-event endpoints. 
8.5.5 
Sensitivity Analyses 
A sensitivity analysis using the grouped survival methods of Prentice and Gloeckler may be 
performed on PFS time to assess the robustness of the results if there appears to be large 
differences in PD assessment patterns between the treatment groups.13 
If there is substantial crossover of observation patients to pralatrexate use, a sensitivity 
analysis for OS may be conducted censoring such patients at the date of first pralatrexate use. 
8.6 
Safety Analyses 
Analysis of safety will be performed on the safety analysis set.  Study data will be monitored 
on an ongoing basis by the clinical study team including the medical monitor and the clinical 
drug safety team’s routine activities to ensure patients’ safety. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all AEs to 
a system organ class (SOC) and a preferred term.  Patient incidence of AEs will be tabulated 
by SOC, preferred term, and severity grade for all treatment-emergent AEs, serious adverse 
events (SAEs), treatment-related AEs, and treatment-related SAEs.  Each of these outputs 
will include tabulation by maximum severity for each SOC and preferred term as reported by 
the investigator based on Common Terminology Criteria for Adverse Events (CTCAE), 
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Version 4.0.  If an AE cannot be graded based on CTCAE, the investigator will assign a 
severity based on 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, and 5 = Death 
related to AE.  Summaries of AEs that are treatment-emergent, SAEs, treatment-related AEs, 
and treatment-related SAEs occurring in at least 5% of the patients will be provided in 
descending order of frequency by SOC and preferred term. 
Additional tables summarizing patient incidence (by preferred term) of the following will be 
generated: 
• 
All AEs; 
• 
SAEs; 
• 
Treatment-related AEs; 
• 
Treatment-related SAEs; 
• 
Grade 3 or higher AEs; 
• 
AEs leading to the discontinuation of pralatrexate or removal from study; 
• 
AEs leading to dose reductions of the study drug; 
• 
AEs with incidence ≥ 5%; and 
• 
Deaths. 
Adverse Events Grouped by Similar Preferred Term 
Summary tables of treatment emergent, treatment-related, serious, and serious 
treatment-related AEs grouped by similar preferred term will be presented.  For this 
presentation, certain similar preferred terms were identified and coded to the same preferred 
term in order to present the event in a uniform manner.  Terms are presented in Table 11.1 of 
Appendix 11.4 (additional preferred terms may be identified within each category during 
data review and added to this list).  
Separate outputs will be provided for subgroups defined by age group (< 65 and ≥ 65), 
gender, and race (if feasible). 
Detailed listings for all AEs and listings and/or narratives will be provided for serious and 
significant AEs and deaths (with “on-study” deaths [deaths that occur before the end of 
safety follow-up period] identified). 
Laboratory Parameters 
Laboratory parameters for hematology and blood chemistry will be summarized at baseline 
and last observed value.  Additionally, the maximum and minimum observed post-baseline 
values will be summarized along with the change from baseline to the maximum observed 
value, minimum observed value, and last observed value.  A listing of all laboratory 
assessments may be provided. 
Incidence of laboratory abnormalities and subject incidence of Grade 3 or 4 laboratory 
toxicities will be presented.  Summaries of hematology and serum chemistry parameters 
along with shifts in severity (CTCAE Version 4.0) from baseline for selected laboratory 
parameters will be presented. 
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Plasma Pharmacokinetics 
Standard PK parameters will be estimated from the limited plasma sampling (eg, area under 
the curve [AUC], maximum concentration [Cmax], and half-life [t1/2]). 
Population PK (POPPK) analyses will be conducted via nonlinear mixed-effects modeling to 
estimate POPPK parameters for pralatrexate, including typical values, inter-individual 
variation, and residual variability after administration of pralatrexate in the patient 
population, and to estimate the effects of individual-specific covariate factors 
(eg, demographics, disease state, etc) that may be predictive of the unexplained random 
variability in pralatrexate PK.  In addition, the relationship between the PK of pralatrexate 
and response (safety and efficacy) will be explored. 
Eastern Cooperative Oncology Group Performance Status 
ECOG performance status scores will be summarized for each treatment group at each 
assessed time-point (ie, baseline and initial follow-up).  The change in scores from baseline 
to the initial follow-up visit will also be summarized.  A listing of ECOG scores will also be 
provided. 
Protocol-specified Treatment Administration 
For the Pralatrexate Arm, descriptive statistics will be calculated for total number of cycles 
started, the number of doses of each protocol-specified treatment, and the cumulative dose of 
each protocol-specified treatment.  A cycle will be considered “started” if a patient receives 
any protocol-specified treatment during that cycle.  The number and percentage of patients 
with modifications (including dose reductions, dose delays, or doses withheld) from the 
prescribed dosing of each of the protocol-specified treatments will be summarized by type of 
dose modification and reason for the dose modification.  The overall number of dose 
reductions/omissions/delays per patient will also be summarized. 
Electrocardiogram 
A listing of all observed electrocardiogram (ECG) results will be provided. 
Concomitant Medications 
The number and proportion of patients receiving each reported medication will be 
summarized by Anatomical Therapeutic Chemical (ATC) code and preferred term for each 
treatment group as coded by the World Health Organization Drug (WHODRUG) dictionary.  
A listing of all concomitant medications by patient will also be provided. 
B-symptoms and Pruritus 
Presence of B-symptoms (fever, night sweats, and weight loss), along with pruritus, will be 
captured at baseline and will also be collected post-randomization to determine if pralatrexate 
has an effect on these symptoms relative to observation.  Time to onset (worsening) of any, 
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along with time to onset of each, will be analyzed using the Cox model for the safety analysis 
set.  Similarly, improvement in these symptoms may also be analyzed. 
9 
LIST OF PLANNED TABLES, FIGURES, LISTINGS, AND 
APPENDICES 
Table, listing, and figure shells will be created prior to the final analysis and will include 
information regarding the structure of each output.  The following tables (Table 9.1), listings 
(Table 9.2), and figures (Table 9.3) could be provided.  
Table 9.1. 
Planned Tables 
Title 
Description 
Patient Disposition – FAS 
Tabulates the disposition of all patients, including the number of 
patients randomized, the number of patients who receive 
protocol-specified treatment, the number of patients who were 
randomized and never received protocol-specified treatment.  
The reason for protocol-specified treatment discontinuation and 
the reason for study discontinuation will also be summarized.  
Long-term follow-up will be summarized based on the most 
recent assessment (alive, dead, lost to follow-up, consent 
withdrawn). 
Baseline Demographics – FAS 
Tabulates summary statistics of the demographics (gender, race, 
age, geriatric age group < 65, ≥ 65). 
Baseline Characteristics – FAS 
 
Tabulates baseline disease characteristics. 
Patient Accountability – FAS 
Tabulates the number of patients within each analysis set and the 
reason for exclusion from each analysis set. 
Pralatrexate Administration – FAS 
(Pralatrexate Arm) 
Summarizes the total number of cycles started, the number of 
doses received, duration of treatment, the cumulative dose of 
treatment, the number and percentage of patients with 
modifications by type of dose modification and reason for the 
dose modification.  The number of dose reductions/ 
omissions/delays per patient will also be summarized. 
PFS – FAS 
Summary of PFS results including median (95% CI) PFS time by 
treatment arm, HR (95% CI), and log-rank P value. 
PFS estimates (95% CIs) from K-M curves at specific time 
points (eg, 6-month intervals). 
OS – FAS 
Summary of OS results including median (95% CI) survival time 
by treatment arm, HR (95% CI), and log-rank P value. 
Survival estimates (95% CIs) from K-M curves at specific time 
points (eg, 6-month intervals). 
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Title 
Description 
Objective Response Rate – FAS 
Summary of ORR results 
Subsequent Therapy – FAS 
Summary of number of patients receiving subsequent therapy, 
including stem-cell transplant, and timing of subsequent therapy.  
Also includes response status when subsequent therapy was 
received. 
Overall Summary of Treatment 
Emergent AEs – Safety Analysis Set 
High-level summary of treatment-emergent, serious, 
treatment-related, and serious treatment-related AEs.  Only 
include treatment-emergent AEs (this applies to all AE tables). 
Treatment-emergent AEs – Safety 
Analysis Set  
Summary by SOC and preferred term for each treatment group. 
Treatment-emergent AEs Grouped 
by Similar Preferred Term – Safety 
Analysis Set  
Summary by preferred term for each treatment group, where 
selected AEs are grouped by similar preferred term as indicated 
in the appendix. 
Treatment-emergent SAEs – Safety 
Analysis Set  
Summary by SOC and preferred term for each treatment group. 
Treatment-emergent SAEs Grouped 
by Similar Preferred Term – Safety 
Analysis Set  
Summary by preferred term for each treatment group, where 
selected AEs are grouped by similar preferred term as indicated 
in the appendix. 
Treatment-emergent AEs Grouped 
by Similar Preferred Term Leading 
to Treatment Discontinuation – 
Safety Analysis Set – Pralatrexate 
Arm  
Summary by preferred term. 
Treatment-emergent AEs by Age 
Group – Safety Analysis Set 
 
Summary by SOC and preferred term for each age group 
(< 65, ≥ 65). 
Treatment-emergent AEs by Gender 
– Safety Analysis Set 
Summary by SOC and preferred term for each gender. 
Treatment-emergent AEs by Race – 
Safety Analysis Set 
Summary by SOC and preferred term for each race (if feasible). 
Time to worsening of 
B-symptoms/Pruritus – Safety 
Analysis Set 
Analysis using the Cox model of time to worsening of 
B-symptoms/pruritus. 
Hematology – Safety Analysis Set 
Summary of hematology parameters at baseline, last observed 
value, maximum observed value, and minimum observed value.  
Include change from baseline to maximum observed value, 
minimum observed value and last observed value.  
Hematology Shift in Severity – 
Safety Analysis Set 
Tables of shifts in severity from baseline for selected laboratory 
parameters and selected time points. 
Serum Chemistry – Safety Analysis 
Set 
Summary of serum chemistry parameters at baseline, last 
observed value, maximum observed value, and minimum 
observed value.  Include change from baseline to maximum 
observed value, minimum observed value, and last observed 
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Title 
Description 
Chemistry Shift in Severity – Safety 
Analysis Set 
Tables of shifts in severity from baseline for selected laboratory 
parameters and selected time points. 
ECOG Performance Status – Safety 
Analysis Set 
Summary of ECOG performance status results at each scheduled 
time-point and the change from baseline. 
Concomitant Medications – Safety 
Analysis Set 
Summary of administered concomitant medications by ATC 
code and preferred term. 
FAS = full analysis set 
HR = hazard ratio 
SOC = system organ class 
PFS = progression-free survival 
K-M = Kaplan Meier 
SAE = serious adverse event 
OS = overall survival 
ORR = objective response rate ATC = Anatomical Therapeutic Chemical 
CI = confidence interval 
AE = adverse event 
ECOG = Eastern Cooperative Oncology Group 
Table 9.2. 
Planned Listings 
Title 
Description 
Patient Accountability 
Listing of all patients and the analysis set inclusion information. 
Patient Withdrawal 
Listing of all patients who withdraw from the study, including the 
reason for withdrawal and the time of withdrawal. 
Protocol-specified Treatment 
Administration 
Listing of all patient protocol-specified treatment administration 
information. 
Adverse Events 
Listing of all reported AEs by patient. 
Serious Adverse Events 
Listing of all patients with at least 1 reported SAE.  Only the AEs 
identified as serious will be included.  Listing will include patient 
number, SOC, and preferred term of AE, date of onset, date of 
resolution, CTCAE Grade, action taken, and outcome. 
Deaths – Safety Analysis Set  
Listing of deaths that occur within 30 days of the last dose of 
protocol specified treatment, including cause of death. 
Adverse Events Leading to 
Protocol-specified Treatment 
Discontinuation 
Listing of all patients who discontinue protocol-specified 
treatment due to an AE.  The listing will include the AE, date of 
onset of the AE, date of resolution of the AE, severity of AE, and 
the CTCAE severity grade of the AE. 
Hematology 
Listing of all hematology parameters. 
Serum Chemistry 
Listing of all serum chemistry parameters. 
Electrocardiograms 
Listing of all ECG results, including heart rate, QRS, PR, QT, 
and QTc intervals. 
Concomitant Medications 
Listing of all concomitant medications including the ATC code 
and preferred term. 
ECOG Performance Status 
Listing of ECOG performance status at each assessment. 
Lesion Measurements 
Listing of all lesions at each time-point, including the sum of all 
target lesions and change from baseline and percent change from 
baseline. 
Efficacy Parameters 
Listing of all efficacy parameters for each patient, including 
survival time, objective response, and PFS time. 
AE = adverse event 
ECG = electrocardiogram 
PFS = progression-free survival 
SAE = serious adverse event 
SOC = system organ class 
ATC = Anatomical Therapeutic Chemical 
QTc = QT interval corrected for heart rate 
ECOG = Eastern Cooperative Oncology Group 
CTCAE = Common Terminology Criteria for Adverse Events  
 


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Table 9.3. 
Planned Figures 
Title 
Description 
Progression Free Survival – FAS 
Kaplan-Meier plot of PFS. 
Overall Survival – FAS 
Kaplan-Meier plot of OS. 
FAS = full analysis set 
PFS = progression-free survival 
OS = overall survival 
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10 REFERENCES 
1. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-
cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 
2008;26(25):4124-30. 
2. Rudiger T, Weisenburger DD, Anderson JR, et al. Peripheral T-cell lymphoma 
(excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma 
Classification Project. Ann Oncol 2002;13(1):140-9. 
3. Gallamini A, Zaja F, Patti C, et al. Alemtuzumab (Campath-1H) and CHOP 
chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL 
(Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood 
2007;110(7):2316-2323. 
4. Gallamini A, Stelitano C, Calvi R, et al. Peripheral T-cell lymphoma unspecified (PTCL-
U): a new prognostic model from a retrospective multicentric clinical study. Blood 
2004;103(7):2474-9. 
5. Mercadal S, Briones J, Xicoy B, et al. Intensive chemotherapy (high-dose CHOP/ESHAP 
regimen) followed by autologous stem-cell transplantation in previously untreated patients 
with peripheral T-cell lymphoma. Ann Oncol 2008. 
6. Kim JG, Sohn SK, Chae YS, et al. CHOP plus etoposide and gemcitabine (CHOP-EG) as 
front-line chemotherapy for patients with peripheral T cell lymphomas. Cancer Chemother 
Pharmacol 2006;58(1):35-9. 
7. Abouyabis AN, Shenoy PJ, Lechowicz MJ, et al. Incidence and outcomes of the 
peripheral T-cell lymphoma subtypes in the United States. Leuk Lymphoma 
2008;49(11):2099-107. 
8. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70(3):659-63. 
9. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 
1979;35:549-56. 
10. Kittelson JM, Emerson SS. A unifying family of group sequential test designs. 
Biometrics 1999;55(3):874-82. 
11. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol 2007;25(5):579-86. 
12. SAS Institute, Inc.  SAS Statistical Analysis System. Cary, NC: SAS Publishing; 1996. 
13. Prentice RL, Gloeckler LA. Regression analysis of grouped survival data with application 
to breast cancer data. Biometrics 1978;34(1):57-67. 
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11 APPENDICES 
11.1 Table/Figure/Listing Shells 
Table, listing, and figure shells will be provided in a separate document prior to final analysis 
of study data.   
11.2 Reference Values/Severity Grades 
Severity grades for AEs are provided by the investigator.  Severity grades for laboratory 
values will be derived programmatically based on the CTCAE grading scale – Version 4.0.  
For laboratory values requiring a clinical assessment for determination of severity, severity 
will not be derived programmatically. 
11.3 Handling of Dates, Incomplete Dates, and Missing Dates for 
Adverse Events and Concomitant Medications 
Imputation Rules for Partial or Missing Stop Dates 
If a partial or complete stop date is present and the “ongoing” or “continuing” box is 
checked, then it will be assumed that the AE or concomitant medication stopped and the stop 
date will be imputed if partial. 
Imputation Rules for Partial or Missing Start Dates for AEs and Concomitant Medications 
Several different date variables are kept in the standard analysis datasets for AEs and 
concomitant medications because the start and stop dates may be incomplete and data 
processing requires different assumptions about incomplete dates for different purposes.  
The standard AE analysis datasets have the following date variables: 
aestdc – character variable for AE start date.  It may be partial date (eg, 20MAY07, 
MAY07, 07) 
aestdt – numeric date variable for AE start date.  Missing for partial date. 
aefstdt – first possible AE start date.  For missing day of month, set to first day of month.  
For missing month, set to first day of year.  For missing year, set to missing value. 
aespdc – character variable for AE stop date.  May be partial date.  (See aestdc above.) 
aespdt – numeric date variable for AE stop date.  Missing if partial date. 
aelspdt – last possible AE stop date.  For missing day of month, set to last day of month.  For 
missing month, set to last day of year.  For missing year, set to missing value. 
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Aestrsp - first possible AE start date minus the treatment stop day.  Positive values are the 
number of days the AE started after treatment stopped and are used to set post-treatment 
cutoffs.  
Aestdc and aespdc are used for the main AE listings. Aefstdt and aelspdt are used for 
ordering records in chronological order. 
The standard concomitant medication analysis datasets have the following date variables: 
cmstdc – character variable for concomitant medication (CM) start date.  May be partial date 
(eg, 20MAY07, MAY07, 07) 
cmstdt – numeric date variable for CM start date.  Missing for partial date. 
cmfstdt – first possible CM start date.  For missing day of month, set to first day of month.  
For missing month, set to first day of year.  For missing year, set to missing value. 
cmlstdt – last possible CM start date.  For missing day of month, set to last day of month.  
For missing month, set to last day of year.  For missing year, set to missing value. 
cmspdc – character variable for CM stop date.  May be partial date.  (See cmstdc above.) 
cmspdt – numeric date variable for CM stop date.  Missing for partial date. 
cmfspdt – first possible CM stop date.  (See cmfstdt above.) 
cmlspdt – last possible CM stop date.  (See cmlstdt above.) 
cmstrsp – first possible CM start date minus the treatment stop day.  Positive values are the 
number of days the CM started after treatment stopped and are used to set post treatment 
cutoffs. 
Cmstdc and cmspdc are used for the main CM listings.  Cmfstdt and cmlspdt are used for 
ordering records in chronological order.  


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11.4 Preferred Terms for Adverse Events Grouped by Similar Preferred 
Term 
Listed in Table 11.1 below are the AEs identified for the pralatrexate program.  The AEs 
grouped by similar preferred term are evolving over time as the coding dictionary is updated 
(there could be changes to the already identified events) and as the pralatrexate program 
expands (additional AEs may be added and others may be removed).  AEs included in the 
data summary will be based on the current list identified by the clinical study team at the 
time of the analysis.  
Table 11.1. Adverse Events Grouped by Similar Preferred Term 
Category 
Preferred Term 
Mucosal Inflammation  
Mucosal inflammation 
Stomatitis 
Anal Inflammation 
Mucositis Anal 
Vaginal Inflammation 
Rectal Mucositis 
Esophagitis 
Mouth Ulceration 
Oral Mucosal Erythema 
Oesophagitis 
Gingivitis 
Balanoposthitis 
Pharyngeal Inflammation 
Pharyngitis 
Stomatitis Haemorrhagic 
Thrombocytopenia  
Thrombocytopenia  
Platelet Count Decreased 
Anemia 
Anemia 
Hemoglobin Decreased 
Hypokalemia 
Hypokalemia 
Blood Potassium Decreased 
Neutropenia  
Neutropenia 
Neutrophil Count Decreased 
Dermatitis Exfoliative 
Dermatitis Exfoliative 
Exfoliative Rash 
Rash 
Rash 
Dermatitis Acneiform 
Rash Maculo-papular 
Rash Macular 
Rash Papular 
Dermatitis 
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Category 
Preferred Term 
Dry Skin 
Rash Erythematous 
Skin Disorder 
Liver Function Test Abnormal  
Liver Function Test Abnormal 
Alanine Aminotransferase Increased  
Alanine Aminotransferase 
Aspartate Aminotransferase 
Aspartate Aminotransferase Increased 
Transaminases Increased 
Oedema 
Oedema 
Oedema Peripheral 
Pitting Oedema 
Dry Mouth 
Dry Mouth 
Lip Dry 
Dry Throat 
Dyspepsia 
Dyspepsia  
Gastritis 
Gastrooesophageal Reflux Disease 
Odynophagia 
Odynophagia 
Oesophageal Pain 
Pruritus 
Pruritus 
Pruritus Generalized 
Anorexia 
Anorexia 
Decreased Appetite 
Leukopenia  
Leukopenia  
White Blood Cell Count Decreased