Clinical trial NCT02923531
Conditions: Clear Cell Renal Cell Carcinoma
Sponsor: X4 Pharmaceuticals
Start date: 2016-12-07; Completion date: 2018-08-08
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine if the combination of X4P-001 plus nivolumab is safe and tolerable. Secondly, the study will investigate if adding X4P-001 to nivolumab treatment has an effect on the body and the cancer tumor, in participants receiving nivolumab but not exhibiting a radiological response.

Detailed description:

Arms: arm 1: Participants will receive X4P-001 400 milligrams (mg) (as 4 capsules of 100 mg each) orally once daily in combination with nivolumab 240 mg intravenous (IV) infusion (over 60 minutes) every 2 weeks. Study medication will be administered in 28-day cycles and will continue until treatment-limiting toxicity or disease progression.
Interventions: intervention 1: X4P-001 intervention 2: Nivolumab
Intervention descriptions: intervention 1: X4P-001 will be administered as per the dose and schedule specified in the arm. intervention 2: Nivolumab will be administered as per the dose and schedule specified in the arm.

Protocol documents:
Prot_000.pdf: 
C O N FI D E N TI A LI T Y N O T E:  
T he i nf or m ati o n c o nt ai ne d i n t his d oc u me nt is privile ge d a n d c o nfi de nti al. A ny distri b uti o n, 
c o pyi n g, or discl os ure is strictly pr o hi bite d u nless s uc h discl os ure is re q uire d by re g ul ati o ns or 
l oc al l a w. Pers o ns t o w h o m t he i nf or m ati o n is discl ose d m ust k n o w t h at it is c o nfi de nti al a n d 
t h at it m ay n ot be f urt her discl ose d by t he m. 
T his st u dy will be c o n d ucte d acc or di n g t o t he pr ot oc ol a n d i n c o m pli a nce wit h  
G o o d Cli nic al Pr actice, t he et hic al pri nci ples st ate d i n t he Decl ar ati o n of Helsi nki, 
a n d ot her a p plic a ble re g ul at ory re q uire me nts. 
St u d y Title : 
A P hase 1 b/ 2a Trial A d di n g X 4 P- 0 0 1 i n Patie nts Recei vi n g 
Ni v ol u ma b f or Treat me nt of A d va nce d Clear Cell Re nal Cell 
Carci n o ma  
I n vesti g ati o n al Dr u g: 
X 4 P - 0 0 1 
I N D #: 
1 2 4 1 9 4 
Cli nic al Tri als. g o v I D 
N C T 0 2 9 2 3 5 3 1 
S p o ns or:  
X 4 P har mace uticals, I nc.  
9 5 5 Massac h us etts A ve, 4 t h Fl o or 
Ca m bri d ge, M A 0 2 1 3 9 
Pr ot oc ol N u m ber:  
X 4 P - 0 0 1-R C C B  
Pr ot oc ol V ersi o n , D ate : 
3. 0 ( 0 5 J ul 2 0 1 7) 
Re pl aces Versi o n , D ate:  
2. 0 ( 2 0 Fe b  2 0 1 7) 
N C T # : N C T 0 2 9 2 3 5 3 1


X4 Pharmaceuticals, Inc. 
Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
Confidential 
Page 2 of 98 
INVESTIGATOR STATEMENT 
I understand that all documentation provided to me by X4 Pharmaceuticals, Inc. (X4), or its 
designated representative(s) concerning this study that has not been published previously will 
be kept in the strictest confidence. This documentation includes the study protocol, 
investigator brochure, case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board/Independent Ethics Committee (IRB/IEC). No changes will be 
made to the study protocol without the prior written approval of X4 and the IRB/IEC, except 
where necessary to eliminate an immediate hazard to the patient. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to X4 as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform X4 immediately that this request has been made. 
I have read, understood, and agree to abide by all the conditions and instructions contained in 
this protocol. 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
Printed Name 
 
 
 


X 4 P har mace uticals, I n c.  
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C o nfi de ntial  
P a ge 3  of 9 8  
T A B L E O F C O N T E N T S  
I N V E S TI G A T O R S T A T E M EN T  .................................................................................................. 2  
T A B L E O F C O N T E N T S  ................................................................................................................ 3  
LI S T O F T A B L E S I N T H E T E X T  ................................................................................................. 8  
LI S T O F A B B R E VI A TI O N S  ......................................................................................................... 9  
P R O T O C O L S U M M A R Y  ............................................................................................................ 1 3  
1.  
K E Y R O L E S  ..................................................................................................................... 2 4  
2.  
I N T R O D U C TI O N:  B A C K GR O U N D I N F O R M A TI O N A N D S CI E N TI FI C 
R A TI O N A L E  .................................................................................................................... 2 5  
2. 1.  
Bac k gr o u n d I nf or mati o n  ....................................................................................... 2 5  
2. 1. 1.  
Re nal Cell Carci n o ma  .......................................................................... 2 5  
2. 1. 2.  
Ni v ol u ma b i n t he treat me nt of R C C  .................................................... 2 5  
2. 1. 3.  
C X C R 4 ( C -X -C C he m o ki ne Rece pt or T y p e 4)  ................................... 2 6  
2. 2.  
O ver vie w of X 4 P -0 0 1  ........................................................................................... 2 7  
2. 2. 1.  
Pri or Cli nical St u dies C o n d ucte d Usi n g X 4 P -0 0 1  ............................... 2 7  
2. 2. 2.  
Cli nical P har mac ol o g y of X 4 P -0 0 1  ..................................................... 2 9  
2. 2. 3.  
Cli nical Safet y E x perie n ce wit h X 4 P -0 0 1  ........................................... 3 1  
2. 2. 4.  
Treat me nt Effect of X 4 P -0 0 1 i n Pri or Cli nical St u dies  ....................... 3 2  
2. 2. 5.  
N o ncli nical T o xicit y St u dies of X 4 P -0 0 1  ............................................ 3 2  
2. 3.  
Cli nical E x perie nce wit h Relate d C o m p o u n ds  ..................................................... 3 3  
2. 4.  
Rati o nale  ............................................................................................................... 3 3  
3.  
O BJ E C TI V E S A N D P U R P O S E  ....................................................................................... 3 5  
3. 1.  
Pri mar y O bj ecti ve  ................................................................................................. 3 5  
3. 2.  
Sec o n dar y O bj ecti ves ............................................................................................ 3 5  
3. 3.  
E x pl orat or y O bjecti ves  ......................................................................................... 3 5  
4.  
S T U D Y D E SI G N A N D E N D P OI N T S  ............................................................................. 3 6  
4. 1.  
Descri pti o n of t he St u d y Desi g n  ........................................................................... 3 6  
4. 1. 1.  
Rati o nale f or t he St u d y  Desi g n, I ncl u di n g t he C h oice of C o ntr ol 
Gr o u ps  .................................................................................................. 3 6  
4. 2.  
E n d p oi nts  .............................................................................................................. 3 7  
4. 2. 1.  
Safet y E n d p oi nts  .................................................................................. 3 7  
4. 2. 2.  
Efficac y E n d p oi nts  ............................................................................... 3 7  
4. 2. 3.  
P har mac o ki netic E n d p oi nts  .................................................................. 3 8  
4. 2. 4.  
E x pl orat or y E n d p oi nts  ......................................................................... 3 8  


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5.  
S T U D Y E N R O L L M E N T A N D  WI T H D R A W A L  .......................................................... 3 9  
5. 1.  
I n cl usi o n Criteria .................................................................................................. 3 9  
5. 2.  
E x cl usi o n Criteria  ................................................................................................. 3 9  
5. 3.  
Strate gies f or Recr uit me nt a n d Rete nti o n  ............................................................. 4 1  
5. 4.  
Partici pa nt Wit h dra wal or Ter mi nati o n  ................................................................ 4 1  
5. 4. 1.  
Reas o ns  f or Wit h dra wal or Ter mi nati o n .............................................. 4 1  
5. 4. 2.  
Ha n dli n g of Partici pa nt Wit h dra wals or Ter mi nati o n  .......................... 4 2  
5. 5.  
Pre mat ure Ter mi nati o n or S us pe nsi o n of St u d y  ................................................... 4 2  
5. 6.  
Defi niti o ns of Treat me nt -Li miti n g T o xicit y  ......................................................... 4 3  
5. 7.  
Defi niti o ns a n d Pr oce d ures Relate d t o Diseas e Pr o gressi o n  ................................ 4 4  
5. 7. 1.  
C o nti n uati o n of Treat me nt  Be y o n d Ra di ol o gic Disease Pr o gressi o n  .. 4 4  
6.  
S T U D Y D R U G( S)  ............................................................................................................ 4 6  
6. 1.  
St u d y Dr u g(s) a n d C o ntr ol Descri pti o n  ................................................................ 4 6  
6. 1. 1.  
Ac q uisiti o n  ........................................................................................... 4 6  
6. 1. 2.  
F or m ulati o n, A p peara n ce, Pac ka gi n g, a n d La b eli n g  ........................... 4 6  
Please ref er t o t he p ac ka ge i nsert f or a descri pti o n of ni v ol u ma b.  ....................... 4 7  
6. 1. 3.  
Pr o d uct St ora ge a n d Sta bilit y  ............................................................... 4 7  
6. 1. 4.  
Pre parati o n  ........................................................................................... 4 7  
6. 1. 5.  
D osi n g a n d A d mi nistrati o n  .................................................................. 4 7  
6. 1. 6.  
R o ute of A d mi nistrati o n  ....................................................................... 4 8  
6. 1. 7.  
D ose A dj ust me nts/ M o dificati o ns/ Dela ys  ............................................ 4 8  
6. 1. 8.  
D urati o n of T hera p y  ............................................................................. 5 0  
6. 1. 9.  
Treat me nt C o m plia nce  ......................................................................... 5 0  
6. 2.  
St u d y Dr u g A cc o u nta bilit y Pr oce d ures  ................................................................ 5 1  
7.  
S T U D Y P R O C E D U R E S A N D  S C H E D U L E  ................................................................... 5 2  
7. 1.  
St u d y Pr o ce d ur es/ E val uati o ns  .............................................................................. 5 2  
7. 1. 1.  
Baseli ne a n d Safet y Ass ess me nts  ........................................................ 5 2  
7. 1. 2.  
P har mac o ki netic Assess me nts  ............................................................. 5 5  
7. 1. 3.  
P har mac o d y na mic Ass ess me nts  .......................................................... 5 5  
7. 1. 4.  
Efficac y Assess me nts  ........................................................................... 5 6  
7. 2.  
La b orat or y Pr o ce d ur es/ E val uati o ns  ...................................................................... 5 9  
7. 2. 1.  
Cli nical La b orat or y E val uati o ns  .......................................................... 5 9  
7. 2. 2.  
Ot her Assa ys or Pr o ce d ures  ................................................................. 6 0  
7. 2. 3.  
S peci me n Pre parati o n, H a n dli n g, a n d St ora ge  ..................................... 6 0  
7. 2. 4.  
S peci me n S hi p me nt  .............................................................................. 6 0  
7. 3.  
St u d y Sc h e d ule ...................................................................................................... 6 0  
7. 3. 1.  
E xte nsi o n P hase  ................................................................................... 6 1  
7. 4.  
C o nc o mita nt Me dicati o ns, Treat me nts, a n d Pr oce d ures ....................................... 6 1  


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7. 4. 1.  
Preca uti o nar y M e dicati o ns, Treat me nts, a n d Pr oce d ures  .................... 6 2  
7. 4. 2.  
Pr o hi bite d Me dicati o ns, Treat me nts, a n d Pr o ce d ures  .......................... 6 3  
7. 4. 3.  
Pr o p h ylactic Me dicati o ns, Tre at me nts, a n d Pr oce d ures  ...................... 6 3  
7. 4. 4.  
Resc ue Me dicati o ns, Treat me nts, a n d Pr oce d ures  ............................... 6 3  
7. 4. 5.  
Preca uti o ns Re gar di n g Ni v ol u ma b  ...................................................... 6 4  
7. 4. 6.  
Patie nt Restricti o ns d uri n g t he C o n d uct of t h e St u d y  .......................... 6 4  
7. 5.  
A p pr o priate n ess of Meas ure me nts  ........................................................................ 6 4  
8.  
A D V E R S E E V E N T S  ........................................................................................................ 6 5  
8. 1.  
Defi niti o ns ............................................................................................................. 6 5  
8. 1. 1.  
A d verse E v e nts ( A E) ............................................................................ 6 5  
8. 1. 2.  
Seri o us A d verse E v e nts ( S A E)  ............................................................ 6 5  
8. 1. 3.  
A d verse Dr u g Reacti o n  ........................................................................ 6 6  
8. 1. 4.  
S us pecte d, U ne x pecte d S eri o us A d vers e Reacti o n ( S U S A R)  ............. 6 6  
8. 1. 5.  
Cli nical La b orat or y A d v erse E ve nts  .................................................... 6 7  
8. 2.  
Classificati o n of A d verse E ve nts  .......................................................................... 6 7  
8. 2. 1.  
Se verit y  ................................................................................................ 6 7  
8. 2. 2.  
Gra di n g of La b orat or y S afet y Tests f or Re p orti n g a n d A nal ysis  ........ 6 8  
8. 2. 3.  
Relati o ns hi p t o St u d y Dr u g  .................................................................. 6 8  
8. 2. 4.  
E x pecte d ness  ........................................................................................ 6 9  
8. 2. 5.  
D ate a n d Ti me of O nset  ....................................................................... 6 9  
8. 2. 6.  
Acti o ns Ta ke n f or Ma na ge m e nt of A E  ................................................ 6 9  
8. 2. 7.  
F oll o w -u p a n d O ut c o me of A Es  .......................................................... 7 0  
8. 2. 8.  
Date a n d Ti me of O utc o me  .................................................................. 7 0  
8. 3.  
Ti me Peri o d a n d Fr e q ue n c y f or E ve nt Assess me nt a n d F oll o w -U p  ..................... 7 0  
8. 4.  
Re p orti n g Pr oce d ures  ............................................................................................ 7 1  
8. 4. 1.  
A d verse E v e nt Re p orti n g  ..................................................................... 7 1  
8. 4. 2.  
Seri o us A d verse E v e nt Re p orti n g  ........................................................ 7 1  
8. 4. 3.  
E ve nts of S pecial I nterest  ..................................................................... 7 2  
8. 4. 4.  
Re p orti n g of Pre g na nc y ........................................................................ 7 3  
8. 5.  
St u d y Halti n g R ules  .............................................................................................. 7 3  
8. 6.  
Safet y O versi g ht .................................................................................................... 7 3  
8. 6. 1.  
A d diti o nal Pr oce d ures f or M o nit ori n g Patie nt Safet y  .......................... 7 4  
8. 6. 2.  
Data Re vie w C o m mittee ( D R C)  .......................................................... 7 5  
9.  
C L I NIC A L  M O N IT O R IN G  ............................................................................................. 7 6  
9. 1.  
E xter nal Re vie w of t he St u d y C o n d uct at Partici pati n g Sites  ............................... 7 6  
9. 2.  
St u d y M o nit ori n g Visits  ........................................................................................ 7 7  
9. 2. 1.  
Site Q ualificati o n a n d I nitiati o n Visits  ................................................. 7 7  
9. 2. 2.  
I nteri m M o nit ori n g Visits .................................................................... 7 7  


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9. 2. 3.  
St u d y Cl ose o ut Visit  ............................................................................ 7 7  
1 0.  
S T A TI S TI C A L C O N SI D E R A TI O N S .............................................................................. 7 9  
1 0. 1.  Statistical a n d A nal ytical Pla ns  ............................................................................. 7 9  
1 0. 2.  Statistical H y p ot heses  ........................................................................................... 7 9  
1 0. 3.  A nal ysis D atasets  .................................................................................................. 7 9  
1 0. 4.  Descri pti o n of Statistical Met h o ds  ........................................................................ 7 9  
1 0. 4. 1.  
Ge ner al A p pr oac h  ................................................................................ 7 9  
1 0. 4. 2.  
Baseli ne Descri pti ve Statistics  ............................................................. 8 0  
1 0. 4. 3.  
A nal ys es of Safet y Data  ....................................................................... 8 0  
1 0. 4. 4.  
Pla n ne d I nteri m A nal yses  .................................................................... 8 1  
1 0. 4. 5.  
A nal ys es of t he Efficac y E n d p oi nts  ..................................................... 8 1  
1 0. 4. 6.  
M ulti ple C o m paris o n/ M ulti plicit y  ....................................................... 8 2  
1 0. 4. 7.  
Ta b ulati o n of I n di vi d ual Res p o nse Data  .............................................. 8 2  
1 0. 4. 8.  
E x pl orat or y A nal yses  ........................................................................... 8 2  
1 0. 4. 9.  
P har mac o ki netic A n al ys es.  .................................................................. 8 2  
1 0. 5.  Sa m ple Size  ........................................................................................................... 8 2  
1 0. 6.  Meas ures t o Mi ni mize Bias  .................................................................................. 8 3  
1 0. 6. 1.  
E nr oll me nt/ Ra n d o mizati o n/ Mas ki n g Pr oce d ures  .............................. 8 3  
1 0. 6. 2.  
E val uati o n of S uccess of Bli n di n g  ....................................................... 8 3  
1 0. 6. 3.  
Brea ki n g t he St u d y Bli n d/ Partici pa nt C o de  ......................................... 8 3  
1 1.  
S O U R C E D O C U M E N T S A N D  A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  .......... 8 4  
1 1. 1.  Me dical Rec or ds  ................................................................................................... 8 4  
1 1. 2.  St u d y -S pecific S o ur ce D oc u me nts  ....................................................................... 8 4  
1 1. 3.  S o urce D oc u m e nts Re q uire me nts  ......................................................................... 8 5  
1 1. 4.  Electr o nic Case Re p ort F or ms (e C R Fs)  ................................................................ 8 5  
1 2.  
Q U A LI T Y A S S U R A N C E A N D Q U A LI T Y C O N T R O L  ................................................ 8 6  
1 2. 1.  St u d y M o nit ori n g  .................................................................................................. 8 6  
1 2. 2.  Case Re p ort F or m C o m pleti o n  ............................................................................. 8 6  
1 2. 3.  C o m p uterize d S yste ms / Me dical Rec or ds as S o urce Dat a  .................................. 8 6  
1 2. 4.  A u dits a n d I ns p ecti o ns  .......................................................................................... 8 6  
1 2. 5.  Res ol uti o n of Deficie nci es  .................................................................................... 8 6  
1 3.  
E T HI C S/ P R O T E C TI O N O F  H U M A N S U BJ E C T S  ........................................................ 8 8  
1 3. 1.  Et hical Sta n dar d  .................................................................................................... 8 8  
1 3. 2.  I nstit uti o nal Re vie w B oar d ................................................................................... 8 8  
1 3. 3.  I nf or me d C o nse nt Pr ocess .................................................................................... 8 8  


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1 3. 3. 1.  
C o nse nt/asse nt a n d Ot her I nf or mati o nal D oc u m e nts Pr o vi de d t o 
Partici pa nts  ........................................................................................... 8 8  
1 3. 3. 2.  
C o nse nt Pr oce d ures a n d D oc u me ntati o n  ............................................. 8 9  
1 3. 4.  Partici pa nt a n d Data C o nfi de ntialit y  ..................................................................... 8 9  
1 4.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ............................................................ 9 0  
1 4. 1.  Data C ollecti o n a n d Ma n a ge me nt Res p o nsi bilities  .............................................. 9 0  
1 4. 2.  St u d y R ec or ds Rete nti o n ....................................................................................... 9 0  
1 4. 3.  Pr ot oc ol De viati o ns  ............................................................................................... 9 0  
1 4. 4.  P u blicati o n a n d Data S hari n g P olic y  .................................................................... 9 0  
1 5.  
S T U D Y A D MI NI S T R A TI O N .......................................................................................... 9 2  
1 6.  
C O N F LI C T O F I N T E R E S T  P O LI C Y .............................................................................. 9 3  
1 7.  
LI T E R A T U R E R E F E R E N C E S  ........................................................................................ 9 4  
1 8.  
A P P E N DI C E S  .................................................................................................................. 9 7  
1 8. 1.  Re visi o n Hist or y a n d S p o ns or Si g nat ure  .............................................................. 9 7  
1 8. 2.  P ote ntial C Y P -Relate d Dr u g -Dr u g I nt eracti o ns  ................................................... 9 8  
 


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P a ge 8  of 9 8  
LI S T O F T A B L E S I N T H E T E X T  
Ta ble 1 -1:  
Sc he d ule of E ve nts  ...................................................................................................2 3  
Ta ble 2 -1:  
Pri or Cli nical St u dies C o n d ucte d usi n g X 4 P -0 0 1 –  Pr ot oc ol N u m ber, St u d y Title, 
a n d P u blicati o n 1 ........................................................................................................2 8  
Ta ble 2 -2:  
Pri or Cli nical St u dies C o n d ucte d usi n g X 4 P -0 0 1 –  St u d y P o p ulati o n, O bjecti ves, 
a n d E x p os ures  ..........................................................................................................2 9  
Ta ble 5 -1:  
Defi niti o ns of T L Ts  ..................................................................................................4 3  
Ta ble 6 -1:  
P h ysical a n d C he mical Pr o perties of X 4 P -0 0 1 Acti ve I n gre die nt ( Dr u g S u bsta nce)
 ..................................................................................................................................4 6  
Ta ble 6 -2:  
F or m ulati o n of X 4 P -0 0 1 Dr u g Pr o d uct  ....................................................................4 6  
Ta ble 6 -3:  
Rec o m me n de d Tr eat me nt M o dificati o ns f or Ni v ol u ma b a n d X 4 P -0 0 1  ..................4 9  
Ta ble 7 -1:  
E C O G P S Defi niti o ns  ...............................................................................................5 4  
Ta ble 7 -2:  
Ca n di date  Bl o o d Bi o mar kers  ...................................................................................5 5  
Ta ble 7 -3:  
R E CI S T –  Defi niti o ns of Res p o nse Cate g ories f or Tar get a n d N o n -Tar get Lesi o ns
 ..................................................................................................................................5 8  
Ta ble 7 -4:  
R E CI S T –  O ver all Res p o nses Bas e d o n Tar get Lesi o ns, N o ntar get Lesi o ns, a n d 
Ne w Lesi o ns  .............................................................................................................5 8  
Ta ble 7 -5:  
Safet y La b or at or y Tests  ...........................................................................................5 9  
Ta ble 8 -1:  
Re p orti n g t he D ate a n d Ti me of O nset of A E f or Differe nt T y p es of E ve nts  ..........6 9  
Ta ble 8 -2:  
Date a n d Ti me of O utc o me f or A E b y O ut c o me Class ............................................7 0  
Ta ble 8 -3:  
M o nit ori n g Pr oce d ures f or Ris ks I de ntifie d i n Pri or St u dies of X 4 P -0 0 1 
( A M D 1 1 0 7 0) ............................................................................................................7 4  
Ta ble 1 8 -1:  Pr ot oc ol Re visi o n Hist or y  ........................................................................................9 7  
 


X4 Pharmaceuticals, Inc. 
Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
Confidential 
Page 9 of 98 
LIST OF ABBREVIATIONS 
Abbreviation  Explanation 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-versus-time curve 
BID 
Twice daily 
BP 
Blood pressure 
ccRCC 
Clear cell renal cell carcinoma 
CE 
Clinically Evaluable 
CI 
Confidence interval 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRA 
Clinical research associate 
CRO 
Contract research organization 
CS 
Clinically significant 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CV 
Coefficient of variation 
CXCL12 
C-X-C chemokine ligand type 12 (also designated SDF-1) 
CXCR4 
C-X-C chemokine receptor type 4 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DCR 
Disease control rate 
DRC 
Data Review Committee 
EC50 
Half-maximal effective concentration 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 


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Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
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Page 10 of 98 
Abbreviation  Explanation 
EDC 
Electronic data capture 
EHR 
Electronic health records 
Emax 
Maximum exposure 
EOS 
End-of-study 
EOT 
End-of-treatment 
FDA 
Food and Drug Administration (US) 
FFPE 
Formalin fixed paraffin embedded 
FGFR 
Fibroblast growth factor receptor 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
Ig 
Immunoglobin 
IND 
Investigational New Drug Application 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
kit 
Cytokine receptor 
LFT 
Liver function tests 
MDSC 
Myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
mTOR 
Mechanistic target of Rapamycin 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NCS 
Not clinically significant 


X4 Pharmaceuticals, Inc. 
Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
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Page 11 of 98 
Abbreviation  Explanation 
NOAEL 
No observed adverse effect level 
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death-ligand 1 
PD-L2 
Programmed death-ligand 2 
PE 
Physical Exam 
PFS 
Progression-free survival 
PDGFR 
Platelet-derived growth factor receptor 
PHB 
p-hydroxybenzoate salt 
PHI 
Protected health information 
PK 
Pharmacokinetics 
PO 
By mouth 
PR 
Partial response 
QD 
Once daily 
RCC 
Renal cell carcinoma 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Stable disease 
SDF-1 
Stromal-derived-factor 1 (also designated CXCL12) 
SOD 
Sum of diameters 
SUSAR 
Suspected unexpected serious adverse reaction 
T1/2 
Half-life 
TBIL 
Total bilirubin 
TKI 
Tyrosine kinase inhibitor 
TLT 
Treatment-limiting toxicity 
Tmax 
Time to maximum concentration 
TME 
Tumor microenvironment 


X4 Pharmaceuticals, Inc. 
Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
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Page 12 of 98 
Abbreviation  Explanation 
TMF 
Trial master file  
Treg 
T regulatory 
TTP 
Time to progression 
ULN 
Upper limit of normal 
US 
United States 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cell 
WOCP 
Women of childbearing potential 
 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 1 3  of 9 8  
P R O T O C O L S U M M A R Y  
St u d y title  
A P hase 1 b/ 2a Trial A d di n g X 4 P -0 0 1 i n Patie nts Recei vi n g Ni v ol u ma b f or 
Treat me nt of A d va nce d Clear Cell Re nal Cell Carci n o ma  
St u d y n u m ber  
X 4 P -0 0 1 -R C C B  
S p o ns or  
X 4 P har mace uticals, I nc.  
9 5 5 Massac h u setts A ve, 4 t h Fl o or  
Ca m bri d ge, M A 0 2 1 3 9  
P h ase  
1 b/ 2a  
St u d y ce nters  / 
c o u ntries 
M ulti ple Ce nters i n t he U nite d States ( U S ). 
Pl a n ne d st u d y peri o d  
 
First patie nt  e nr olle d:  Q 1 2 0 1 7  
Last patie nt  e nr olle d:   Q 4  2 0 1 7  
Last patie nt  last visit:  Q 2  2 0 1 8  
St u d y o bjecti ves  
T he pri mar y o bjecti ve is:  
•  
T o c haracterize t he safet y a n d t olera bilit y of X 4 P -0 0 1 use d i n 
c o m bi nati o n wit h ni v ol u ma b i n patie nts t olerati n g ni v ol u ma b b ut 
n ot e x hi biti n g ra di ol o gic res p o nse.  
Sec o n dar y o bj ecti ves are:  
•  
T o c haracterize t he p har mac o ki netics ( P K) of X 4 P -0 0 1 w he n use d 
i n c o m bi nati o n wit h ni v ol u ma b. 
•  
T o c haracterize t he a ntit u m or acti vit y of t he c o m bi nati o n of 
X 4 P -0 0 1 a n d ni v ol u ma b.  
T he e x pl orat or y o bj ecti ves are:  
•  
T o i n vesti gate selecte d peri p heral bl o o d bi o mar kers of i m m u ne 
acti vati o n d uri n g treat me nt wit h X 4 P-0 0 1 pl us ni v ol u ma b.  
•  
T o e val uate arc hi ve d t u m or tiss ue f or bi o mar kers t hat ma y c orrelate 
wit h res p o nse t o c o m bi nati o n treat me nt wit h X 4 P -0 0 1 a n d 
ni v ol u ma b.  
•  
T o a ssess t he treat me nt effect (cli nical acti vit y) of t he c o m bi nati o n 
of X 4 P -0 0 1 a n d ni v ol u ma b i n patie nts wit h a d va nce d  ccR C C  usi n g 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 1 4  of 9 8  
m o difie d  Res p o nse E val uati o n  Criteria  i n S oli d T u m o urs f or 
i m m u ne-base d t hera pe utics (i RE CI S T ) [Se y m o ur  2 0 1 7 ]. 
St u d y desi g n a n d pl a n  T his si n gle -ar m, o pe n-la bel, m ulti-ce nter st u d y is desi g ne d t o c haracterize 
t he safet y a n d t olera bilit y of a d di n g X 4 P-0 0 1 t o ni v ol u ma b treat me nt i n 
patie nts wit h a d va nce d clear cell re nal cell carci n o ma (cc R C C). T o be 
eli gi ble, patie nts m ust ha ve recei ve d ni v ol u ma b a n d ha ve de m o nstrate d a 
c o nfir me d best res p o nse of sta ble disease ( S D) or ra di ol o gic pr o gressi o n  
( P D) wit h o ut cli nical deteri orati o n, as assesse d b y t heir I n vesti gat or.  
C o nfir me d S D or c o nfir me d P D refers t o a res p o nse t hat is c o nfir me d b y a 
2 n d sca n w hic h is at least 4 wee ks a part fr o m t he pre vi o us sca n. 
U p t o 2 0 patie nts ma y recei ve t he pr ot oc ol -s pecifie d c o m bi nati o n treat me nt 
a n d c o nti n ue u ntil eit her: 
•  
Treat me nt -Li miti n g T o xicit y ( T L T), as defi ne d f or X 4 P -0 0 1 a n d as 
p er a p pr o ve d la bel f or ni v ol u ma b.  
•  
Pr o gressi ve disease ( P D ), base d o n eit her cli nical or ra di ol o gic 
assess me nts, usi n g fi n di n gs at st u d y e ntr y t o defi ne t he baseli ne.  
Patie nts t hat meet ra di ol o gic criteria f or pr o gressi o n c o m pare d wit h st u d y 
baseli ne , as defi ne d b y t he Res p o nse E val u ati o n Criteria f or S oli d T u m ors, 
versi o n 1. 1 ( R E CI S T v 1. 1) [ Eise n ha uer 2 0 0 9 ], ma y c o nti n ue i n t he st u d y if 
t heir I n vesti gat or j u d ges t hat b ot h of t he f oll o wi n g a p pl y: (a) t he patie nt is 
li kel y t o be nefit fr o m o n g oi n g treat me nt wit h the st u d y re gi me n; a n d ( b) t he 
patie nt d oes n ot ha ve cli nicall y si g nifica nt s y m pt o ms  of P D . A n y patie nt 
wit h s u bse q ue nt i ma gi n g de m o nstrati n g i m m u ne c o nfir me d pr o gressi ve 
disease (i C P D) base d o n i R E CI S T criteria [ Se y m o ur 2 0 1 7 ] m ust 
di sc o nti n ue st u d y treat me nt.  
After t he first 3 patie nts c o m plete 2 8 da ys of c o m bi nati o n treat me nt 
( C ycle 1), a Data Re vie w C o m mittee ( D R C) will re vie w all a vaila ble safet y 
data a n d ma ke a rec o m me n dati o n o n t he pr o gress of t he st u d y.  T o f urt her 
pr otect patie nts’ safet y, T L Ts will c o nti n ue t o be m o nit ore d d uri n g t he 
re mai n der of t he st u d y.  
If e xcessi ve T L Ts are o bser ve d a n yti me d uri n g t he trial, a d ose de -
escalati o n ca n be e nf orce d f oll o wi n g D R C re vie w or t he trial ca n be 
st o p pe d at t he s p o ns or’s discreti o n. S pecificall y, if less t ha n or e q ual t o 4 
T L Ts are o bser ve d i n t he first 1 2 patie nts, t he trial will c o nti n ue wit h t he 
sa me d ose le vel f or t he re mai ni n g patie nts. If 5 or m or e T L Ts are o bser ve d, 
t he trial ma y c o nti n ue wit h d ose de -escalati o n, i.e., t he rest  of t he patie nts 
will be d ose d at 2 0 0 m g Q D.  
Wit h t he de -escalati o n r ule, t he trial wit h a hi g her T L T rate at t he starti n g 
d ose  ( 4 0 0 m g Q D) will i ncrease t he pr o ba bilit y of t he de -escalati o n t o 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 1 5  of 9 8  
pr otect patie nts’ safet y. F or i nsta nce, if t he T L T rate i n t he first 1 2  patie nts 
is 3 0 %, t he pr o ba bilit y of de-escalati o n is 2 8 %; if t he T L T rate is 4 0 %, t he 
pr o ba bilit y of de -escalati o n is 5 6 %; if t he T L T rate is 5 0 %, t he pr o ba bilit y 
of de -escalati o n is 8 1 %.  
Pl a n ne d n u m ber of 
p atie nts  
U p t o 2 0 patie nts are pla n ne d t o be e nr olle d.  
Sc he d ule of visits a n d 
assess me nts  
Patie nts will be scree ne d f or st u d y eli gi bilit y wit hi n 2 8 da ys pri or t o Da y 1 
(t he first d ose of st u d y dr u g). Eli gi ble patie nts will be e nr olle d a n d start 
c o m bi nati o n st u d y treat me nt o n C ycle 1, Da y 1. D uri n g treat me nt, 
assess me nts f or treat me nt res p o nse ( or P D) are sc he d ule d e ver y 8 wee ks 
d uri n g t he first 1 2 m o nt hs of treat me nt a n d e ver y 1 2 wee ks t hereafter.  
A n E n d -of -Treat me nt ( E O T) visit will be perf or me d wit hi n 6 da ys after t he 
last d ose of st u d y dr ug or t he decisi o n t o ter mi nate treat me nt pre mat urel y .  
A n E n d -of -St u d y ( E O S) visit (i.e., t he fi nal st u d y e ve nt) will be perf or me d 
3 0 da ys  (± 4 cale n dar da ys)  after t he last d ose of st u d y dr u g. I n t he e ve nt t he 
E O T visit is dela ye d, t he E O S visit will be pe rf or me d at least 1 4 da ys after 
t he E O T visit. 
Pr o visi o n is ma de f or t he S p o ns or t o a nal yze t he st u d y data after all 
e nr olle d patie nts ha ve c o m plete d at least 1 2 m o nt hs of treat me nt. Patie nts 
recei vi n g st u d y treat me nt at t hat ti me ma y c o nti n ue t o recei ve treat me nt 
d uri n g a n e xte nsi o n p hase of t he pr ot oc ol, wit h a n a dj uste d sc he d ule of 
assess me nts a n d li mite d ce ntral data c ollecti o n.  
Di a g n osis a n d m ai n 
i ncl usi o n criteri a 
Patie nts m ust meet all of t he f oll o wi n g criteria t o be eli gi ble f or st u d y 
partici pati o n:  
1.  Be at least 1 8 years of a ge.  
2.  Ha ve si g ne d t he c urre nt a p pr o ve d i nf or me d c o nse nt f or m.  
3.  Ha ve a hist ol o gicall y c o nfir me d dia g n osis of re nal cell carci n o ma 
wit h a d oc u me nte d clear cell c o m p o ne nt (i.e., cc R C C).  
4.  Be c urre ntl y recei vi n g ni v ol u ma b a n d be c o nsi dere d  b y t heir 
I n vesti gat or t o ha ve t he p ote ntial t o deri ve cli nical be nefit fr o m 
c o nti n ui n g treat me nt wit h ni v ol u ma b.  
5.  Has a best res p o nse of c o nfir me d S D or c o nfir me d P D * ( base d o n 
R E CI S T v 1. 1 [ Eise n ha uer 2 0 0 9 ]) o n c urre nt ni v ol u ma b treat me nt 
pri or t o i nitiati o n of t his st u d y.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 1 6  of 9 8  
* c o nfir me d S D or c o nfir me d P D refers t o a res p o nse t hat is 
c o nfir me d b y a 2 n d sca n w hic h is at least 4 wee ks a part fr o m t he 
pre vi o us sca n.  
 
6.  Ha ve o n c o m p ute d t o m o gra p h y ( C T) i ma gi n g d o ne wit hi n 2 8 da ys 
of Da y 1 fi n di n gs c o nsiste nt wit h a d va nce d cc R C C, i ncl u di n g at 
least o ne e xtra-re nal meas ura ble tar get lesi o n meeti n g t he criteria of 
R E CI S T v 1. 1.  
7.  A gree t o use c o ntrace pti o n fr o m scree ni n g, t hr ou g h t he st u d y, a n d 
f or at least 5 m o nt hs after t he last d ose of ni v ol u ma b as f oll o ws: 
•  F or w o me n of c hil d beari n g p ote ntial ( W O C P, see Secti o n 
7. 4. 1. 2  f or defi niti o n) a gree t o use  hi g hl y  effecti ve c o ntrace pti ve 
met h o ds.  Acce pta ble met h o ds are descri be d i n Secti o n 7. 4. 1. 3 . 
•  F or males, a gree t o use a c o n d o m wit h a n y W O C P se x ual 
part ner . 
8.  A grees t o per mit s u b missi o n of arc hi ve d t u m or tiss ue t o S p o ns or 
f or a nal ysis, if a vaila ble. 
9.  Be willi n g a n d a ble t o c o m pl y wit h t his pr ot oc ol. 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 1 7  of 9 8  
E xcl usi o n criteri a  
Patie nts wit h a n y of t he f oll o wi n g will be e xcl u de d fr o m partici pati o n i n t he 
st u d y: 
1.  Is pre g na nt or n ursi n g.  
2.  Has life e x pecta nc y of less t ha n 3 m o nt hs.  
3.  Has perf or ma nce stat us ≥2 ( Easter n C o o perati ve O nc ol o g y Gr o u p 
[ E C O G] criteria). 
4.  Has cli nicall y si g nifica nt a n d/ or u nc o ntr olle d heart disease s uc h as 
c o n gesti ve heart fail ure re q uiri n g treat me nt (Ne w Y or k Heart 
Ass ociati o n Class III or I V ), u nc o ntr olle d h y perte nsi o n , or 
cli nicall y si g nifica nt arr h yt h mia .  
5.  Has pre vi o usl y rec ei ve d X 4 P -0 0 1.  
6.  Has a  sec o n d mali g na nc y. E xce pt: mali g na ncies t hat were treate d 
c urati vel y a n d ha ve n ot rec urre d wit hi n 2 years pri or t o st u d y 
treat me nt; c o m pletel y resecte d basal cell a n d s q ua m o us cell s ki n 
ca ncers; a n y mali g na nc y c o nsi dere d t o be i n d ole n t a n d t hat has 
ne ver re q uire d t hera p y; a n d c o m pletel y resecte d carci n o ma i n sit u 
of a n y t y pe . 
7.  Has acti ve ce ntral ner v o us s yste m (C N S) metasta ses (i ncl u di n g 
e vi de nce of cere bral e de ma b y M RI, or pr o gressi o n fr o m pri or 
i ma gi n g st u d y, or a n y re q uire me nt f or ster oi ds, or cli nical 
s y m pt o ms of/fr o m C N S metastases) wit h i n 2 8 da ys pri or t o  st u d y 
treat me nt. S u bjects wit h k n o w n C N S metastases m ust ha ve a  
baseli ne M RI  sca n wit hi n 2 8 da ys of st u d y treat me nt . 
8.  Has o n g oi n g cli nical a d verse e ve nts Nati o nal Ca ncer I nstit ute 
C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts ( N CI C T C A E) 
Gra de > 2 res ulti n g fr o m pri or ca ncer t hera pies, i ncl u di n g 
ni v ol u ma b (e xce pt al o pe cia or h y p ot h yr oi dis m). 
9.  Has a k n o w n hist or y of a p ositi ve ser ol o g y or viral l oa d f or h u ma n 
i m m u n o deficie nc y vir us ( HI V) or a k n o w n hist or y of ac q uire d 
i m m u n o deficie nc y dis or der.  
1 0.  Has ha d wit hi n t he past 6 m o nt hs t he occ urre nce or persiste nce of 
o ne or m ore  of t he f oll o wi n g me dical c o n diti o ns t hat c o ul d n ot be 
c o ntr olle d wit h us ual me dical care (e. g., re q uire d e mer ge nc y care 
or h os pitalizati o n): h y perte nsi o n, a n gi na, c o n gesti ve heart fail ure, 
dia betes, seiz ure dis or der.  
1 1.  Has ha d wit hi n t he past 6 m o nt hs t he occ urre nce of o ne or m ore of 
t he f oll o wi n g e ve nts: m y oc ar dial i nfarcti o n, cere br o vasc ular 
acci de nt, dee p vei n t hr o m b osis, p ul m o nar y e m b olis m, he m orr ha ge 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 1 8  of 9 8  
( N CI C T C A E Gra de 3 or 4), c hr o nic li ver disease ( meeti n g criteria 
f or C hil d-P u g h Class B or C), or or ga n tra ns pla ntati o n.  
1 2.  Has ha d wit hi n t he 4 wee ks pri or t o i nitiati o n of st u d y dr u g s ur ger y 
re q uiri n g ge neral a nest hesia.  
1 3.  Has, at scree ni n g, ser ol o gic la b orat or y tests meeti n g o ne or m ore of 
t he f oll o wi n g criteria: 
•  
A n i n deter mi nate or p ositi ve test f or a nti b o d y t o he patitis C 
vir us ( H C V), u nless d oc u me nte d t o ha ve n o detecta ble viral 
l oa d o n t w o i n de pe n de nt sa m ples.  
•  
A p ositi ve test f or he patitis B s urface a nti ge n ( H Bs A g).  
1 4.  Has, at scree ni n g, safet y la b orat or y tests meeti n g o ne or m ore of t he 
f oll o wi n g criteria: 
•  
He m o gl o bi n < 8. 0 g/ d L  (tra nsf usi o n is all o we d) 
•  
A bs ol ute ne utr o p hil c o u nt ( A N C ) < 1, 5 0 0/ µ L  
•  
Platelets < 7 5, 0 0 0/ µ L  
•  
Creati ni ne > 2. 0 x u p per li mit of n or mal ( U L N)  
•  
Ser u m as partate tra nsa mi nase ( A S T)  or ala ni ne tra nsa mi nase 
( A L T) > 2. 5 x U L N  
o  A S T a n d A L T > 5 x U L N f or patie nts wit h li ver metastasis  
•  
T otal bilir u bi n > 1. 5 x U L N ( u nless d ue t o Gil bert's S y n dr o me , 
t otal bilir u bi n > 3. 0 x U L N a n d direct bilir u bi n > 1. 5 x U L N) 
•  
I nter nati o nal n or malize d rati o (I N R) > 1. 5 x U L N 
1 5.  Has, wit hi n 4 wee ks pri or t o Da y  1, recei ve d s yste mic 
c ortic oster oi ds e xcee di n g pre d nis o ne 1 0 m g per da y ( or e q ui vale nt). 
T o pical, i n hale d, nasal a n d o p ht hal mic ster oi ds are all o we d; f or 
ot her i m m u n os u p pressi ve a ge nts, t he e xcl usi o nar y d ose a n d 
d urati o n will be deter mi ne d i n c o ns ultati o n  wit h t he Me dical 
M o nit or.  
1 6.  Has, wit hi n t hree ( 3) wee ks pri or t o Da y 1, recei ve d a nti -ca ncer 
t hera p y ot her t ha n ni v ol u ma b, i ncl u di n g a t yr osi ne ki nase i n hi bit or 
( T KI), be vaciz u ma b, c he m ot hera p y (e. g., mit o m yci n-C, 
nitr os o urea), i m m u n ot hera p y, or ra diati o n t hera p y. F or 
i n vesti gati o nal a nti-ca ncer t hera pies, t he i nter val will be deter mi ne d 
i n c o ns ultati o n wit h t he Me dical M o nit or. 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 1 9  of 9 8  
1 7.  Has, wit hi n 2 wee ks pri or t o Da y 1, recei ve d a me dicati o n 
pr o hi bite d base d o n c yt oc hr o me P 4 5 0 ( C Y P ) 3 A 4 i nteracti o n.  
1 8.  Has, at t he p la n ne d i nitiati o n of st u d y dr u g, a n u nc o ntr olle d 
i nfecti o n.  
1 9.  Has a n y ot her me dical or pers o nal c o n diti o n t hat, i n t he o pi ni o n of 
t he I n vesti gat or, ma y p ote ntiall y c o m pr o mise t he safet y or 
c o m plia nce of t he patie nt, or ma y precl u de t he patie nt's s uccessf ul 
c o m pleti o n of t he cli nical st u d y.  
I n vesti g ati o n al 
Me dici n al P r o d uct: 
d ose/ m o de of 
a d mi nistr ati o n/ d osi n g 
sc he d ule 
All patie nts will recei ve t he i n vesti gati o nal a ge nt X 4 P -0 0 1 i n c o m bi nati o n 
wit h ni v ol u ma b ( O P DI V O ® ), a pr o gra m me d cell deat h pr otei n 1 ( P D-1) 
bl oc ki n g a nti b o d y a p pr o ve d f or t he treat me nt of patie nts wit h a d va nce d 
cc R C C.  
X 4 P -0 0 1 will be pr o vi de d as 1 0 0  m g ca ps ules . (Ma n ufact uri n g of a  2 0 0 m g 
ca ps ule f or m ulati o n is u n der de vel o p me nt a n d ma y be i ntr o d uce d  i nt o t he 
cli nic w he n release d.)  All patie nts will recei ve X 4 P -0 0 1 4 0 0 m g o nce dail y 
( Q D) orall y ( P O). X 4 P -0 0 1 is t o be a d mi nistere d at a c o nsiste nt ti me eac h 
m or ni n g ( ± 2 h o urs) wit h n o f o o d or dri n k (e xce pt water) f or at least 1  hr 
pre -d ose a n d c o nti n ui n g f or at least 2  hr p ost -d ose.  
Al l patie nts will ha ve recei ve d ni v ol u ma b as per sta n dar d of care pri or t o 
e nr oll me nt t o t he st u d y. E nr olle d patie nts will c o nti n ue treat me nt wit h 
ni v ol u ma b at 2 4 0 m g e ver y 2  wee ks b y i ntra ve n o us (I V) i nf usi o n o ver 
6 0  mi n utes usi n g  a sterile, n o n-p yr o ge nic, l o w pr otei n bi n di n g i n -li ne filter 
wit h p ore size of 0. 2 t o 1. 2 micr o meter. O t her dr u gs s h o ul d n ot be 
a d mi nistere d c o nc urre ntl y t hr o u g h t he sa me I V li ne. 
Ref ere nce t her a p y: 
d ose/ m o de of 
a d mi nistr ati o n/ d osi n g 
sc he d ule 
N o ne.   
Pl a n ne d tre at me nt 
d ur ati o n per  p atie nt  
Patie nts are e x pecte d t o recei ve st u d y treat me nt u ntil t he earliest of:  
•  
T L T e ve nt:  
-  F or a n y T L T e ve nt  occ urr i n g i n C ycle 1, st u d y treat me nt will 
be disc o nti n ue d per ma ne ntl y.  
-  F or T L T e ve nts  occ urr i n g after C ycle 1, pr o visi o n is ma de f or 
d ose i nterr u pti o n.  
•  
P D  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 2 0  of 9 8  
E n d p oi nts:  
Safet y e n d p oi nts are:  
•  
A d verse e ve nts ( A Es).  
•  
Cli nical o bser vati o ns (e. g., vital si g ns, p h ysical e xa mi nati o n).  
•  
La b orat or y test res ults (e. g., cli nical c he mistr y, he mat ol o g y).  
•  
Electr ocar di o gra m ( E C G) fi n di n gs.  
•  
O p ht hal m ol o gic e xa mi nati o n  fi n di n gs. 
Efficac y e n d p oi nts are:  
•  
O bjecti ve res p o nse rate ( O R R), w here res p o nse is defi ne d as 
ac hie vi n g eit her c o m plete res p o nse ( C R) or partial res p o nse ( P R).  
•  
Ti me t o o bjecti ve res p o nse.  
•  
D urati o n of o bjecti ve res p o nse.  
•  
Disease c o ntr ol rate ( D C R; C R + P R + S D).  
•  
Pr o gressi o n -free s ur vi val ( P F S), defi ne d as t he ti me fr o m first 
a d mi nistrati o n of c o m bi nati o n re gi me n u ntil o bjecti ve t u m or 
pr o gressi o n or deat h fr o m a n y ca use.  
•  
Ti me t o pr o gressi o n ( T T P), defi ne d as t he ti me fr o m first 
a d mi nistrati o n of c o m bi nati o n re gi me n u ntil o bjecti ve t u m or 
pr o gressi o n.  
P K e n d p oi nts are:  
•  
Area u n der t he c o nce ntrati o n -vers us -ti me-c ur ve ( A U C).  
•  
Ma xi m u m c o nce ntrati o n ( C
ma x ). 
•  
Ti me t o reac h m a xi m u m c o nce ntrati o n (T ma x ). 
E x pl orat or y e n d p oi nts are: 
•  
Effect of st u d y treat me nt o n w hite b l o o d cell c o u nts ( W B Cs), 
i ncl u di n g A N C a n d a bs ol ute l y m p h oc yte c o u nts ( A L C), i n bl o o d. 
•  
Effect of st u d y treat me nt o n treat me nt - a n d t u m or -relate d 
bi o mar kers i n peri p heral bl o o d m o n o n uclear cells ( P B M Cs), 
i ncl u di n g T re g ulat or y ( Tre g) l y m p h oc ytes, acti vate d T cells, a n d 
m yel oi d -deri ve d s u p press or cells ( M D S Cs), a n d i n ser u m, 
i ncl u di n g C X C L 1 2 . 
•  
Effect of st u d y treat me nt o n e x pl orat or y bi o mar kers i n t u m or 
tiss ue. 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 2 1  of 9 8  
•  
E fficac y e n d p oi nts ma y be e x pl ore d usi n g t he i R E CI S T assess me nt . 
St atistic al met h o ds 
(i ncl u des s a m ple size 
c alc ul ati o n) 
S a m ple Size:  
Wit h a sa m ple size of 2 0 patie nts, t here is a n esti mate d 9 5 % pr o ba bilit y of 
o bser vi n g at least o nce a n y A E (i ncl u di n g T L T) t hat has a n i nci de nce rate 
of 1 4 % or hi g her.  
Alt h o u g h t he sa m ple size is base d o n feasi bilit y rat her t ha n statistical 
p o wer, t he res ults of t he st u d y will be use d t o pr o vi de a preli mi nar y 
esti mate of t he effect size. T he sa m ple size of 2 0 patie nts will be s ufficie nt 
t o e xcl u de a l o w t hres h ol d rate of res p o nse t o treat me nt. S pecificall y, if a n 
O R R o f 2 0 % or hi g her is o bser ve d, t he n t he l o wer b o u n d of t he 9 5 % e xact 
c o nfi de nce i nter val f or t he pr o p orti o n of res p o n ders e xcee ds t he t hres h ol d 
rate of 5 %. T his w o ul d s u p p ort f urt her st u dies of t he c o m bi nati o n of 
ni v ol u ma b a n d X 4 P -0 0 1.  
 
St atistic al Met h o ds:  
T he pri mar y o bjecti ve of t he st u d y is safet y a n d t olera bilit y. A Es will be 
c o de d usi n g Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
versi o n 1 6. 0 ( or later) a n d ta b ulate d b y s yste m or ga n class a n d preferre d 
ter m, se verit y, a n d relati o ns hi p t o st u dy t hera p y. La b orat or y res ults, vital 
si g ns, E C O G perf or ma nce stat us, a n d E C G para meters will be s u m marize d 
usi n g descri pti ve statistics. La b orat or y val ues will als o be gra de d acc or di n g 
t o t he N CI C T C A E, Versi o n 4. 0 3, a n d s u m marize d i n s hift ta bles. T L T 
e vents will be s u m marize d descri pti vel y.  
All safet y data will be prese nte d i n listi n gs.  
Best res p o nse per R E CI S T v 1. 1 a n d O R R will be s u m marize d. Patie nts 
w h o d o n ot ha ve data s ufficie nt f or res p o nse assess me nt will be c o nsi dere d 
treat me nt fail ures. T he n u m ber a n d pr o p orti o ns of res p o n ders will be 
s u m marize d as a perce nt of t he a nal ysis p o p ulati o n. T he I nte nt -t o-Treat 
(I T T) will be t he pri mar y p o p ulati o n f or a nal ysis a n d t he cli nicall y 
e val ua ble ( C E) p o p ulati o n will be c o nsi dere d s u p p orti ve.  
T he D C R  will be calc ulate d as t he n u m ber of patie nts w h o ha d C R, P R, or 
S D di vi de d b y t he I T T p o p ulati o n.  
P F S, d urati o n of res p o nse, a n d T T P will be s u m marize d usi n g Ka pla n 
Meier met h o ds. Me dia n, 2 5t h, a n d 7 5t h perce ntiles will be re p orte d. T he 
9 5 % c o nfi de nce i nter vals o n t he me dia n a n d pr o p orti o n of ce ns ore d data 
als o will be prese nte d. F urt her details r e gar di n g ce ns ori n g will be descri be d 
i n t he Statistical A nal ysis Pla n ( S A P).  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 2 2  of 9 8  
P K data will be a nal yze d usi n g descri pti ve statistics f or A U C, C ma x , a n d 
T ma x .  
P har mac o d y na mic data will be a nal yze d as descri be d i n t he S A P.  
Sc he d ule of e ve nts:  
T he sc he d ule of e ve nts is prese nte d i n Ta ble 1 -1 . 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 2 3  of 9 8  
T a ble 1 -1 : 
Sc he d ule of E ve nts  
E ve nt 1 
Scree n 2 
C y cle 1  
E ve n -
n u m bere d 
c y cles ≥# 2 
O d d -
n u m bere d 
c y cles ≥# 3 
E O T 3 
E O S 4 
D a y # wit hi n C y cle 5 
 
1  
8  
1 5  
2 2  
1  
1 5  
1  
1 5  
 
 
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y , i n cl u di n g R C C 
X  
 
 
 
 
 
 
 
 
 
 
E C O G P erf or ma n ce Stat us  
X  
X  
 
 
 
X  
 
X  
 
X  
X  
P E , b o d y wei g ht, b o d y h ei g ht6 , 7 
X 7 
X  
 
 
 
X  
 
X  
 
X  
X  
Vital si g ns 8 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C T i ma gi n g 9 
X  
 
 
 
 
 
 
X  
 
X  
 
He mat ol o g y & C h e mistr y 1 0 
X 1 1 
X  
X  
X  
X  
X  
 
X  
 
X  
X  
T F Ts, C oa g ulati o n & U/ A 1 2 
X 1 1 
X 1 2 
 
 
 
 
 
X 1 2 
 
X 1 2 
 
1 2 -lea d E C G 
X  
X  
 
 
X 2 3 
 
 
X  
 
X  
X  
O p ht hal m ol o gic E xa m i n ati o n1 3 
X 1 4 
 
 
 
 
 
 
X  
 
X  
 
Pre g na nc y test1 5 
X  
X  
 
 
 
 
 
X  
 
X  
X  
Pre -d ose P K Sa m ple  
 
X  
X  
X  
 
 
 
X 1 6 
 
 
 
De nse P K & P D Sa m pli n g 1 7 
 
 
 
 
X  
 
 
 
 
 
 
Bl o o d bi o mar ker c ollecti o n 1 8 
 
X  
 
 
X  
 
 
X  
 
X  
X  
Arc hi ve d tiss ue 1 9 
X  
 
 
 
 
 
 
 
 
 
 
A d mi nistrati o n of ni v ol u ma b 2 0 
 
X 2 1 
 
X  
 
X  
X  
X  
X  
 
 
X 4 P -0 0 1 d ose d i n cli nic 2 2 
 
X 2 3 
X  
X  
X  
 
 
X 1 6 
 
 
 
A E & C o n Me d M o nit ori n g  
Fr o m scree ni n g t o E n d of St u d y Visit  
1.  T h e sc h e d ule is prese nte d relati ve t o C ycle a n d Da y wit hi n C ycle. T he cale n dar da y of t he first a d mi nistrati o n of st u d y dr u g is desi g nate d 
Da y 1. Eac h C ycle re pres e nts 4 wee ks ( 2 8 da ys). Pre - a n d p ost -d ose i nter vals are relati ve t o t he ti me of oral a d mi nis trati o n of st u d y dr u g, 
d esi g n ate d 0 hr. See Secti o n 7. 3. 1  f or e ve nts d uri n g E xte nsi o n P hase.  
2.  Scree ni n g ma y be i nitiate d u p t o 2 8 da ys pri or t o Da y 1. C o nfir mati o n of eli gi bilit y will be d o ne b y S p o ns or  re vie w pri or t o e nr oll me nt  (see 
Secti o n 7. 1. 1. 1 ). 
3.  T h e E O T visit will be perf or me d ≤6 da ys after t he last d ose of st u d y dr u g or t he decisi o n t o ter mi nate treat me nt.  
4.  T h e E O S visit is sc h e d ule d f or 3 0 da ys  (± 4 cale n dar da ys)  after t he last d ose of st u d y dr u g. I n t he e ve nt t he E O T visit is dela ye d, t he E O S 
visit will b e perf or me d at least 1 4 da ys after t he E O T visit.  
5.  T o all o w f or sc he d uli n g fle xi bilit y, o n -treat me nt visits ma y be d o ne wit hi n ±3 cale n dar da ys of t he da y i n dicate d.  
6.  At Scree ni n g, E O T, a n d E O S, c o m plete p h ysical e xa m  ( P E); at ot her visits, e xa ms f oc use d o n areas of disease or A Es. 
7.  B o d y h ei g ht is c ollecte d at scree ni n g o nl y . 
8.  Vital si g ns c o m prise heart rate, bl o o d press ure, a n d te m perat ure. F or patie nts d ose d i n cli nic f or P K c ollecti o ns, vital si g ns will be perf or me d 
pre -d ose.  
9.  C T (c h est, a b d o me n, a n d pel vis) –  f or scree ni n g p ur p oses, i ma gi n g perf or me d as sta n dar d of care may be use d if d o ne ≤2 8  da ys pri or t o Da y 
1; w hile o n -treat me nt, i ma gi n g ma y be perf or m e d wit h a wi n d o w of ± 4 cale n dar da ys ; at E O T, i ma gi n g is n ot re q uire d if perf or me d i n t he 
pri or 4 wee ks; see Secti o n 7. 1. 4. 1  f or details.  
1 0.  H e mat ol o g y a n d c he mistr y la b orat or y  tests ma y be o btai ne d u p t o 3 da ys pri or t o visit; perf or me d at l ocal la b; F or patie nts d ose d i n cli nic f or 
P K c ollecti o ns, safet y la b orat o r y tests will be c ollecte d pre-d ose .  
1 1.  Safet y la b orat or y testi n g f or eli gi bilit y s h o ul d be perf or me d wit hi n 1 4 da ys pri or t o C ycle 1 Da y 1 ; perf or me d at l ocal la b. 
1 2.  T F Ts, T h yr oi d F u ncti o n Tests; C oa g ulati o n st u dies  a n d U/ A (uri nal ysis ) perf or me d at Scree ni n g a n d E O T o nl y  (s ee S ecti o n 7. 2. 1  f or details); 
p erf or me d at l ocal la b orat or y .  
1 3.  O p ht hal m ol o gic e xa m i nati o n (see Secti o n 7. 1. 1. 5  f or details) ma y be perf or me d wit h a wi n d o w of ± 4 cale n dar da ys . 
1 4.  Scree ni n g o p ht hal m ol o gic e xa m re p orts a n d reti nal p h ot os m ust be s u b mitte d t o t he s p o ns or at least 5 b usi ness da ys pri or t o C ycle 1 Da y 1 t o 
all o w ce ntral re vie w f or eli gi bilit y. See st u d y p perati o n al m a n ual f or a d diti o nal details. 
1 5.  Pre g n a n c y tests, a p p lica ble o nl y t o w o me n of c hil d beari n g p ote ntial (see Secti o n  7. 4. 1. 2 ), ma y be uri ne or ser u m test. O n Da y 1, t he test 
res ults will b e o btai ne d pri or t o d osi n g. Perf or m e d at l ocal la b.  
1 6 . Pre -d ose P K sa m ple a n d X 4 P -0 0 1 d osi n g i n cli nic o nl y at C ycle 3.  
1 7 . Se e S ecti o n s 7. 1. 2  a n d 7. 1. 3. 1  f or details of sa m ple c ollecti o n ti mes f or de nse P K (ce ntral la b ) a n d P D (l ocal la b). 
1 8 . Bl o o d sa m ples f or bi o mar kers ; pr ocesse d at site a n d s hi p pe d t o ce ntral la b orat or y –  see Secti o n 7. 1. 3. 1  f or details. 
1 9 . Site t o c o nfir m a vaila bilit y of arc hi ve d t u m or tiss ue.  
2 0 . A d mi nistrati o n of ni v ol u ma b –  see Secti o n 6. 1. 5. 2  f or details. 
2 1 . Patie nts s h o ul d be o bser ve d f or at least 1 h o ur after t heir 1 st d ose of X 4 P -0 0 1 bef ore r ecei vi n g ni v ol u ma b, t he n o bser ve d f or at least 1 h o ur 
after ni v ol u ma b i nf usi o n o n C ycl e 1 Da y 1.  
2 2 . X 4 P -0 0 1 will be self -a d mi nistere d b y t he patie nt, e xce pt at P K visits, w he n it will be a d mi nistere d i n t he cli nic.  
2 3 . O n Da y 1, dis pe nse e ye dr o ps a n d nasal s pra y  (see S ecti o n 7. 4. 4. 1 ).  
2 4 . E C G assess me nt perf or me d at 2 hr p ost -d ose ( ±  1 5 mi n).   


X4 Pharmaceuticals, Inc. 
Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
Confidential 
Page 24 of 98 
1. 
KEY ROLES 
Study Sponsor: 
X4 Pharmaceuticals, Inc. 
955 Massachusetts Ave, 4th Floor 
Cambridge, MA 02139 
Primary Sponsor Contact: 
 
 
X4 Pharmaceuticals, Inc. 
  
 
Sponsor Signatory: 
 
 
X4 Pharmaceuticals, Inc.  
  
 
 
 
X4 Pharmaceuticals, Inc.  
 
 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 2 5  of 9 8  
2.  
I N T R O D U C TI O N:  B A C K GR O U N D I N F O R M A TI O N A N D 
S CI E N TI FI C R A TI O N A L E  
2. 1.  
B ac k gr o u n d I nf or m ati o n  
2. 1. 1.  
Re nal Cell Carci n o ma  
Re nal Cell Carci n o ma  ( R C C) is t he m ost c o m m o n mali g na nt lesi o n of t he ki d ne y, wit h a n 
esti mate d a n n ual i nci de n ce i n t he U nite d States ( U S ) of o ver 5 0, 0 0 0 n e w cases a n d 1 3, 0 0 0 
deat hs per year [Sie gel 2 0 1 5 ; Ric hie 2 0 0 6 ]. Wit h c urre n tl y a v aila ble treat me nts, t he me dia n 
o verall s ur vi val ( O S) is a p pr o xi matel y 2 8 m o nt hs [M otzer 2 0 1 3 ].  
Se veral diff ere nt classes of t hera p e utic a ge nts are a vaila ble f or patie nts wit h  a d va nce d 
(u nresecta ble ) disease . First-li ne treat ment is t y pi call y a s mall m olec ul e t yr osi ne ki nase i n hi bit or 
( T KI) tar geti n g t he vas c ular e n d ot helial gr o wt h fact or rece pt or ( V E G F R) si g nali n g pat h w a y. 
A d diti o nal a ge nts f or sec o n d -li ne t hera p y i ncl u d e a nti-V E G F a nti b o dies, mec ha nistic tar get of 
ra pa m yci n [m T O R ] i n hi bit ors, as well as a ge nts acti ve a gai nst m ulti ple t yr osi ne ki nases. I n m ost 
st u dies, these a ge nts re d u ce t u m or size a n d pr ol o n g pr o gressi o n -free s ur vi val ( P F S), b ut t heir 
i m pact o n O S is less clear. T w o a ge nts rece ntl y a p pr o ve d b y U S F o o d a n d Dr u g  A d mi nistrati o n 
(F D A ), ni v ol u ma b (a n a nti-pr o gr a m me d cell deat h pr otei n 1 [ P D -1 ] i m m u n ot hera p y) a n d 
ca b oza nti ni b (a T KI tar geti n g m ulti ple rece pt ors, i ncl u di n g V E G F R a n d M E T ) ha ve s h o w n O S 
be nefits relati ve t o m T O R i n hi biti o n i n patie nts wit h pri or V E G F R T KI t h era p y [ Ni v ol u ma b 
prescri bi n g i nf or mati o n, 2 0 1 7 ; Ca b oza nti n i b prescri bi n g i nf or mati o n, 2 0 1 6].  
2. 1. 2.  
Ni v ol u ma b i n t he treat me nt of R C C  
N o ncli n ical a n d cli nical st u dies o ver t he past deca de ha ve i de ntifie d critical mec ha nis ms b y 
w hic h ca n cers s u b v ert n or mal i m m u n o m o d ulat or y mec ha nis ms (referre d t o as “c hec k p oi nts”) t o 
bl oc k eff ecti ve a nti -t u m or i m m u ne s ur veilla nce. T hese i nsi g hts ha v e le d t o t he de vel o p me nt of a 
ne w class of i m m u n ot her a pe utics referre d t o as “c hec k p oi nt i n hi bit ors,” w hic h i ncl u de 
ni v ol u ma b, a h u ma n i m m u n o gl o b uli n (I g) G 4 m o n ocl o nal a nti b o d y t h at bi n ds t o P D -1  a n d 
bl oc ks its i nteracti o n wit h pr o gra m me d deat h -li ga n d 1 a n d 2 [P D -L 1 a n d P D -L 2 ], releasi n g P D-1 
pat h wa y -me diat e d i n hi biti o n of t he i m m u ne res p o nse, i ncl u di n g  t he a nti-t u m or i m m u ne 
res p o nse.  
Ni v ol u ma b [ O P DI V O® ] was a p pr o v e d i n N o ve m ber 2 0 1 5 b y t he U S F D A  f or use i n patie nts 
wit h a d va nce d R C C w h o ha ve recei ve d pri or a nti-a n gi o ge nic t hera p y [Ni v ol u ma b prescri bi n g 
i nf or mati o n, 2 0 17 ]. T he a p pr o val was b ase d o n a ra n d o mize d ( 1: 1) o pe n -la bel st u d y of 
ni v ol u ma b vers us  e ver oli m us , a n m T O R i n hi bit or i n dicate d f or t he treat me nt of patie nts wit h 
a d va nce d R C C after f ail ure of s u niti ni b or s orafe ni b. Ni v ol u ma b de m o nstrate d a statisticall y 
si g nifica nt i m pr o ve m e nt i n O S c o m pare d t o e ver oli m us, wit h a me dia n s ur vi val of 2 5. 0 vs. 
1 9. 6  m o nt hs ( hazar d rati o 0. 7 3, p < 0. 0 0 2) a n d c o nfir me d o bjecti ve res p o ns e rates ( O R R) of 
2 1. 5 % vs 3. 9 %, res p ecti v el y .  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 2 6  of 9 8  
H o we ver, des pite t he i m pr o ve me nts i n O S a n d O R R, n o differe nce was o bser ve d i n o verall 
pr o gressi o n -free s ur vi val [M otzer 2 0 1 5 ]. Ma n y patie nts de m o nstrate d i nitial peri o ds of sta ble 
disease ( S D) or ra di ol o gi c  pr o gressi o n wit h o ut cli nical deteri orati o n, b ut di d n ot e x perie nce 
s ustai ne d be nefit, i ncl u di n g a p pr o xi matel y 3 5 % of patie nts w h ose best res p o nse t o treat me nt was 
pr o gressi ve disease  ( P D). T h us, t here re mai ns a n u n met nee d f or a ge nts t hat i m pr o ve o utc o mes 
b y i ncr easi n g earl y r es p o nse rate or b y pre v e nti n g or dela yi n g treat me nt resista nce, tra nslati n g 
i nt o a d diti o nal i ncreases i n O S. 
2. 1. 3.  
C X C R 4  ( C-X -C C he m o ki ne R ece pt or T y p e 4)  
C X C R 4  ( C-X -C c he m o ki ne rece pt or t y pe 4)  is t he rece pt or f or C X C L 1 2  ( C-X -C c he m o ki ne  
li ga n d t y pe 1 2; als o r eferre d t o as S D F -1 α, str o mal -deri ve d -fact or 1 α). C X C L 1 2  has p ote nt 
c he m otactic acti vit y f or l y m p h oc ytes a n d m yel oi d -deri ve d s u p press or cells ( M D S Cs), a n d is 
i m p orta nt i n c o ntr olli n g t he traffi c ki n g of b ot h he mat o p oietic ste m cells an d e n d ot helial 
pr o ge nit or cells. C X C R 4  is als o e x presse d a n d acti ve o n m ulti ple t y pes of h u ma n ca ncers, 
i ncl u di n g clear cell re nal cell car ci n o ma (cc R C C ), o varia n ca ncer, a n d mela n o ma, a n d i ncrease d 
e x pressi o n of C X C R 4  o n t u m or cells has bee n ass ociate d wi t h si g nifi ca ntl y decrease d O S 
[Staller 2 0 0 3 ; Se ki ya 2 0 1 2 ; E htes ha m 2 0 0 8 ; Maréc hal 2 0 0 9 ].  
I n m uri n e  ca n cer m o d els i nterfer e nce wit h  C X C R 4  f u ncti o n has bee n d e m o nstr ate d t o disr u pt t he 
t u m or micr oe n vir o n me nt ( T M E) a n d u n mas k t he t u m or t o i m m u ne attac k b y m ulti ple 
mec ha nis ms, i nc l u di n g: 
•  Decr easi n g t he i nfiltrati o n of M D S Cs [ O ber majer 2 0 1 1 ; Gil 2 0 1 4; Pa n ka 2 0 1 6 ] 
•  I n creasi n g t h e rati o of C D 8 + T cells t o T re g ulat or y ( Tre g ) cells [ Ri g hi 2 0 1 1 ; Fei g 2 0 1 3 ; 
Fear o n 2 0 1 4 ]  
•  Eli mi nati n g t u m or re -vas c ularizati o n [ Ri g hi 2 0 1 1 ; Fear o n 2 0 1 4 ] 
T h ese effects res ult i n si g nifica ntl y d ecrease d t u m or b ur de n a n d i n crease d o verall s ur vi val i n 
x e n o graft, s y n ge neic , as well as tra ns ge nic, ca n cer m o dels [ Ri g hi 2 0 1 1 ; Fei g 2 0 1 3 ; Ki oi 2 0 1 0 ].  
We p ost ulate t hat effecti ve C X C R 4  a nta g o nis m b y X 4 P -0 0 1 w o ul d b e of p ote ntial be nefit i n 
patie nts wit h a d va nce d cc R C C a n d ot her ca n cers b y m ulti ple mec ha nis ms:   
•  Decr ease d recr uit me nt of M D S C, res ulti n g i n i ncrease d a nti-t u m or i m m u ne attac k. 
•  S ustai ne d decrease i n ne oa n gi o ge nesis a n d t u m or vasc ular s u p pl y . 
•  I nterfere n ce wit h t he a ut ocri ne effect of i ncrease d e x pressi o n b y cc R C C of b ot h C X C R 4  
a n d C X C L 1 2 , its o nl y li ga n d, t here b y, p ote ntiall y re d uci n g ca ncer cell metastasis. 
T his cli nical st u d y i n pati e nts wit h a d va nce d cc R C C will e val uate t he a d diti o n of X 4 P-0 0 1 i n 
patie nts w h o are recei vi n g ni v ol u ma b a n d h a ve n ot ac hie ve d a ra di ol o gic res p o nse. We 
h y p ot hesize t hat t he c o m bi nati o n has t he p ote ntial t o i m pr o ve o u tc o mes b y f urt her e n h a nci n g 
a ntit u m or i m m u ne acti vit y.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 2 7  of 9 8  
2. 2.  
O ver vie w of X 4 P -0 0 1  
X 4 P -0 0 1 is a p ote nt,  orall y bi oa vaila bl e C X C R 4  a nta g o nist [ St o ne 2 0 0 7 ], t hat has de m o nstrate d 
acti vit y i n s oli d a n d  li q ui d t u m or m o dels [Para mes wara n 2 0 1 1 , a n d u n p u blis he d data]. We 
p ost ulate t hat effecti ve C X C R 4  a nta g o nis m b y X 4 P -0 0 1 w o ul d be of p ote ntial be nefit i n patie nts 
wit h a d va nce d cc R C C a n d ot her ca n cers b y m ulti ple mec ha nis ms:   
•  Decr eas e d recr uit me nt of M D S C, res ulti n g i n i ncrease d a nti -t u m or i m m u ne attac k. 
•  S ustai ne d decrease i n ne oa n gi o ge nesis a n d t u m or vasc ular s u p pl y.  
•  I nterfere n ce wit h t he a ut ocri ne effect of i ncrease d e x pressi o n b y cc R C C of b ot h C X C R 4  
a n d C X C L 1 2 , its o nl y li ga n d, t here b y, p ote ntiall y re d uci n g ca ncer cell metastasis. 
T his cli nical st u d y i n pati e nts wit h a d va nce d cc R C C will e val uate t he a d diti o n of X 4 P -0 0 1 i n 
patie nts w h o are recei vi n g ni v ol u ma b a n d h a ve n ot ac hie ve d a ra di ol o gic res p o nse. We 
h y p ot hesize t hat t he c o m bi n ati o n has t he p ote ntial t o i m pr o ve o utc o mes b y f urt her e n h a nci n g 
a ntit u m or i m m u ne acti vit y.  
X 4 P -0 0 1 was pre vi o usl y u n der de vel o p me nt f or t h e treat me nt of HI V i nfecti o n base d o n t he r ole 
of C X C R 4  i n viral e ntr y i nt o t he cell. T hat pr o gra m, w hic h is prese nted i n detail i n t he 
I n v esti gat or Br oc h ur e, i n cl u de d n o ncli nical t o xic ol o g y st u dies a n d cli nical st u dies usi n g t he free 
base f or m ulati o n, t he n desi g nate d A M D 1 1 0 7 0 a n d here X 4 P -0 0 1. T hr o u g h o ut t he pri or cli nical 
de vel o p me nt pr o gr a m, t he dr u g pr o d uct us e d was ca ps ules c o ntai ni n g 1 0 0  m g of t he free base. 
T he sa me f or m ulati o n will be use d i n t his pr ot oc ol (see Secti o n  6. 1. 2. 1 ). 
C o nc urre nt p har mace utical de vel o p me nt w or k i de ntifie d t he p -h y dr o x y be n z oate salt  (P H B ) salt 
f or m of t he dr u g ( desi g nate d A M D 1 1 0 7 0 P H B) f or f ut ure ma n ufact uri n g a n d de vel o p me nt 
p ur p oses . A ni mal t o xic ol o g y st u dies ( 1 3- a n d 2 6-wee k d urati o n) c o n d uct e d wit h 
A M D 1 1 0 7 0 P H B de m o nstrate d u ne x pecte d fi n di n gs, i ncl u di n g reti nal c ha n ges i n al bi n o rats 
treate d f or 2 6 wee ks a n d n ota ble gastr oi ntesti nal ( GI) i nt olera n ce a n d li ver c ha n ges i n Bea gl e 
d o gs  treate d f or 1 3 wee ks (see I n v esti gat or’s Br oc h ure).  
Alt h o u g h A M D 1 1 0 7 0 P H B was n e ver a d mi nistere d t o h u ma ns a n d is n ot pr o p ose d f or use i n a n y 
cli nical st u dies i n t his pr o gr a m, t hese o bser vati o ns were caref ull y c o nsi dere d i n t he safet y 
m o nit ori n g pla ns f or  cli nical st u dies of X 4 P ‑ 0 0 1.  
2. 2. 1.  
Pri or Cli nical St u dies C o n d ucte d Usi n g X 4 P -0 0 1  
T here are n o pri or cli nical st u dies of X 4 P -0 0 1 i n patie nts wit h a d va nce d cc R C C or a n y ot her 
mali g na n c y.  
T he 4 cli nical st u dies c o n d ucte d u n der t he pri or de vel o p me nt pr o gra m i ncl u de d P hase 1 a n d 2 a 
st u dies i n v ol ve d a t otal of 5 5 healt h y v ol u nteers [Ca o 2 0 0 8 ; N y u nt 2 0 0 8 ] a n d 1 6 HI V-i nfecte d 
patie nts [M o yle 2 0 0 9 ; A C T G ( DI AI D S) Pr ot oc ol A 5 2 1 0 ]. Ta ble 2 -1  s h o ws t he pr ot oc ol 
n u m bers, titles, a n d relat e d p u blicati o n s; Ta ble 2 -2  s u m marizes t he st u d y p o p ulati o ns, o bjecti ves, 
n u m bers, d ose a d mi nistere d, a n d d ur ati o n.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 2 8  of 9 8  
T hese st u dies de m o nstrat e d t he f oll o wi n g:  
•  Oral a d mi nistrati o n of u p t o 4 0 0 m g BI D f or 3. 5 d a ys ( healt h y v ol u nteers) a n d 2 0 0 m g 
BI D f or 8 -1 0  d a ys ( healt h y v ol u nteers a n d HI V p atie nts) was ge n erall y safe a n d well -
t olerate d wit h n o patter n of A Es or cli nicall y si g nifica nt la b orat or y c ha n ges.  
•  Oral a d mi nistrati o n of 2 0 0 m g BI D a n d 4 0 0 m g o n ce dail y ( Q D ) de m o nstrat e t he 
c o nsiste nt T 1/ 2 of 2 3  h o urs f or X 4 P -0 0 1, s u p p orti n g t he use of Q D d osi n g ( see 
I n v esti gat or’s Br oc h ure). 
•  P har mac o d y na mic acti vit y, as assesse d b y i ncreas es i n circ ulati n g W B C, w as relate d t o 
d ose a n d d urati o n of tr eat me nt .  
T a ble 2 -1 : 
Pri o r Cli nic al St u dies C o n d ucte d usi n g X 4 P -0 0 1 –  Pr ot oc ol N u m ber, St u d y 
Title, a n d P u blic ati o n 1  
Pr ot oc ol N o.  
St u d y Title  
P u blic ati o ns  
A C T G A 5 1 9 1  
A P hase I, D ose -Risi n g St u d y of A M D 1 1 0 7 0 I n HI V -Ser o ne gati ve Me n T o 
Assess t he Safet y a n d P har ma c o ki netics After Si n gle or M ulti ple D oses  
St o ne 2 0 0 7  
A M D -1 0 0 1 
( X A C T) 
M ultice nter, d ose -fi n di n g safet y a n d acti vit y st u d y of A M D 1 1 0 7 0 i n HIV -
i nfecte d patie nts carr yi n g X 4-tr o pic vir us 
M o yle 2 0 0 9  
A M D -1 0 0 2 
( XI S T) 
A St u d y of t he P har mac o ki netic I nteracti o n bet wee n A M D 1 1 0 7 0 a n d S u bstrates 
of C Y P  3 A 4 a n d 2 D 6 E nz y mes i n Healt h y V ol u nteers  
N y u nt 2 0 0 8  
A C T G A 5 2 1 0  
P hase I B/II A D ose -Fi n di n g Safet y a n d Acti vit y St u d y of A M D 1 1 0 7 0 ( A n Orall y 
A d mi nistere d C X C R 4 E ntr y I n hi bit or) i n HI V -I nfecte d S u bj ects 
( u n p u blis he d) 
1.  All st u dies were c o n d ucte d bet wee n 3 Se p 2 0 0 3 a n d 1 3 J ul 2 0 0 6.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 2 9  of 9 8  
T a ble 2 -2 : 
Pri o r Cli nic al St u dies C o n d ucte d usi n g X 4 P -0 0 1 –  St u d y P o p ul ati o n, 
O bjecti ves, a n d E x p os ures  
St u d y I D  
St u d y 
P o p ul ati o n  
St u d y  
O bje cti ve  
C o h ort  
( A 5 1 9 1 
o nl y)  
N  
Ge n de r  
M/ F
2 
D ose & R e gi me n  
( All or al) 
D ur ati o n  
A 5 1 9 1 1 
 
Healt h y 
V ol u nteers  
D ose escalati o n:  
Safet y, P K  
A -D  
1 2 1 
4 3 M, 0 F a 
Si n gle D ose  
5 0 t o 4 0 0 m g  
1 d a y  
 
 
F,  G, I  
1 8 1 
 
1 0 0 t o 4 0 0 m g, BI D  
3. 5 d a ys ( 7  d oses)  
 
 
Effect of f o o d,  
of rit o n a vir  
H, J, K  
3 2 1 
 
≤3 d oses, 2 0 0 m g or 
4 0 0 m g ea c h  
≤3 d oses o ver 6  t o 
1 7 d a ys  
A 5 2 1 0  
HI V -i nfecte d 
Safet y  
Viral l o a d 
re d u cti o n 
 
6  
3 M, 3 F  
2 0 0 m g, BI D  
1 0 d a ys  
A M D -1 0 0 1  
HI V -i nfecte d 
Safet y  
Viral l o a d 
re d u cti o n 
 
1 0  
9 M, 1 F  
1 0 0 m g, BI D ( N = 2)  
2 0 0 m g, BI D ( N = 8)  
1 0 d a ys  
A M D -1 0 0 2  
Healt h y 
V ol u nteers  
Safet y  
Dr u g -dr u g 
i nteracti o n 
 
1 2  
9 M, 3 F  
2 0 0  m g, BI D  
8 d a ys  
1.  St u d y A 5 1 9 1 e nr olle d 1 0 c o h orts t otali n g 6 8 s u bj ects re prese nti n g 4 3 u ni q ue i n di vi d uals. T here were 3 s u bj ects 
i n eac h of t he 4 si n gle d ose escalati o n c o h orts ( A-D) a n d 6 s u bj ects i n eac h of t he 3 m ulti ple d ose escalati o n 
c o h orts ( F,  G,  I). N o s u bj ect was e nr olle d i n m ore t ha n o ne of t he d ose escalati o n c o h ort. 
2.  Wit hi n eac h st u d y t he me dia n a ge was ~ 4 0 years; o verall a ge ra n ge was 1 9 t o 5 8 years.  
2. 2. 2.  
Cli nical P har mac ol o g y of X 4 P -0 0 1  
2. 2. 2. 1.  
Cli nic al P h ar m ac oki netics  
I n t h e 4 pr e vi o us  cli nical st u dies  c o n d ucte d b y A n or Me d a n d NI H ( St u dies A M D 1 0 0 1, A M D 1 0 0 2, 
A 5 1 9 1, a n d A 5 2 1 0) usi n g  t h e fr ee b ase f or m ulati o n i n n or mal h ealt h y v ol u nteers a n d patie nts wit h 
HI V . Dr u g w as a d mi nistere d P O  i n all st u dies; m ulti ple d ose st u dies were c o n d ucte d usin g BI D 
d osi n g . I n si n gle a n d m ulti ple d ose escalati o n st u dies, ma xi m u m c o nce ntrati o n ( Cma x ) a n d A U C 
i ncreas e d m ore t ha n d os e -pr o p orti o nall y o ver 5 0 - 4 0 0 m g d ose ra n ge. Mea n ter mi nal  half -life 
(T 1 / 2) was 2 2. 9  hr , s u p p orti n g t he Q D d osi n g re gi me n.  
Stea d y -st ate P K p ar a met ers w ere si milar i n h ealt h y v ol u nteers ( A M D -1 0 0 2) a n d i n HI V i nfecte d 
patie nts  ( A 5 2 1 0  a n d  A M D -1 0 0 1).  T he  res ults  ( mea n  ±  S D )  were  deri ve d  fr o m  2 6  s u bjects,  
i ncl u di n g b ot h healt h y v ol u nteers a n d HI V-i nfect e d s u bjects, w h o recei ve d X 4 P-0 0 1 at 2 0 0  m g 
BI D f or 8 t o 1 0 da ys.  
•  A U C ( 0-1 2 hr):  3 7 3 5 ± 1 7 5 5 n g⋅hr/ m L  
•  C ma x :  1 2 2 3 ± 6 0 0 n g/ m L 
•  Mi ni m u m c o nce ntrati o n ( C
mi n ) at 1 2 h o urs: 7 4. 3 ± 4 7. 3 n g/ m L 
•  Ti me t o ma xi m u m c o nce ntrati o n ( T ma x ):  2. 2 ± 0. 9 hr 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 3 0  of 9 8  
F or 1 3 s u bjects, dail y C mi n(tr o u g h)  c o nce ntrati o ns were deter mi ne d. O verall, s u bjects reac h e d stea d y 
state b y Da y 6, w hic h is c o nsiste nt wit h t he T 1 / 2 of ~ 2 3  hr. F urt her, C mi n  a n d A U C ( 0-1 2) were str o n gl y 
c orrel ate d s u g gesti n g t h at m o nit ori n g C mi n  ma y pr o vi de a practical mea ns f or assessi n g dr u g  
e x p os ure.  
X 4 P -0 0 1 -R E G A st u d y was a p hase I st u d y i n 1 5 healt h y v ol u nteers c o m pari n g t w o differe nt 
d osi n g r e gi me ns: 2 0 0 m g BI D a n d 4 0 0 m g Q D  ( 1 0-da y treat me nt). T h e st u d y w as pre m at urel y 
disc o nti n ue d o n Da y 3 d ue t o a n i ns ufficie nt n u m ber of patie nts re mai ni n g o n t he trial t o assess 
t he statistical e n d p oi nts. I n t his st u d y, P K sa m ples were c ollecte d fr o m 0-1 2 hr f or BI D d osi n g a n d 
0 -2 4 hr f or Q D d osi n g. Preli mi nar y P K res ults are liste d bel o w .  
F oll o wi n g a d mi nistrati o n  of X 4 P -0 0 1 2 0 0 m g BI D a n d 4 0 0 m g Q D o n Da y 1, t he mea n C ma x  were 
1 0 7 0 n g/ m L a n d 2 6 6 2 n g/ m L, res p ecti vel y; t he me dia n T ma x  were 2 . 5 hr a n d 1. 5 hr res pecti vel y. 
A U C 0 -1 2 was 3 6 8 2 n g * hr/ m L after  2 0 0 m g BI D d ose a n d A U C 0 -2 4 was 9 4 2 1  n g * hr/ m L after  
4 0 0  m g Q D d ose. C o m pari n g wit h res ults fr o m St u d y A 5 1 9 1, t he e x p os ure i n R E G A st u d y is 
hi g her.  
2. 2. 2. 2.  
Effect of F o o d o n A bs or pti o n  
I n a f o o d-eff ect st u d y ( A 5 1 9 1), 9 male s u bjects recei ve d X 4 P -0 0 1 i n t he faste d state d (fasti n g 
o ver ni g ht after mi d ni g ht u ntil 2 h o urs p ost -d ose) a n d i n t he fe d state (l o w -fat meal wit hi n 
3 0  mi n utes pri or t o d osi n g), f o o d ha d a si g nifica nt ne gati ve effect o n t he bi oa vaila bilit y of 
X 4 P -0 0 1. C ma x  a n d A U C 0 -1 2 i n t he fe d state was 0. 3 3 x a n d 0. 4 4 x of t hat o bser ve d i n t he faste d 
state, res pecti vel y. Tma x  was dela ye d fr o m 1 hr (faste d) t o 3 hr (fe d). T1/ 2  was n ot c ha n ge d.  
See Secti o n 6. 1. 5. 1  f or d etails of f o o d restri cti o ns wit h oral a d mi nistrati o n of X 4 P-0 0 1 i n t his 
pr ot oc ol.  
2. 2. 2. 3.  
P ote nti al f or Dr u g -Dr u g I nter acti o ns B ase d o n C Y P Met a b olis m  
T w o cli nical st u dies ( A 5 1 9 1, A M D-1 0 0 2) w ere c o n d ucte d t o assess t h e p ote ntial f or dr u g -dr u g 
i nteracti o ns ( D DI). Rit o na vir (a str o n g C Y P 3 A 4 i n hi bit or, P -g p  i n hi bit or) res ulte d i n a m o dest 
i ncreas e i n X 4 P-0 0 1 plas ma c o nce ntrati o ns [ A 5 1 9 1, Ca o 2 0 0 8 ]. T he m ea n C ma x  a n d A U C of 
X 4 P -0 0 1  c oa d mi nistere d  wit h  t he  first  d ose  of  rit o na vir  were  i ncrease d  b y  3 9 %  a n d  6 0 %,  
res pecti vel y, c o m p are d t o t he a d mi nistrati o n of X 4 P-0 0 1 al o ne. Si milar effects were see n after 
rit o na vir ha d bee n a d mi nistere d t wice d ail y f or 1 4 da ys.  
St u d y A M D -1 0 0 2 ass esse d t he eff ect  of X 4 P -0 0 1 o n meta b olis m  of C Y P 3 A 4 a n d C Y P 2 D 6 
s u bstrates, usi n g mi daz ola m a n d d e xtr o met h or p ha n as s u bstrat es [N y u nt 2 0 0 8 ]. A d mi nistrati o n of 
X 4 P -0 0 1 ha d t he f oll o wi n g effects.  
•  T he C ma x  f or mi daz ola m (a C Y P 3 A 4 s u bstrate) w as u naffecte d; A U C was 1. 3 3 x baseli ne. 
•  T he C ma x  f or de xtr o met h or p ha n (a C Y P 2 D 6 s u bstrate) w as 2 . 5 x baseli ne; t he A U C, 2 . 8 6 x.  
T he ma g nit u de of t he mi daz ola m i nteracti o n was m o dest. T he ma g nit u de of t he effect o n 
de xtr o met h or p ha n has si g nifica nt p ote ntial t o res ult i n c ha n ges i n cli nical dr u g res p o nse, 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 3 1  of 9 8  
affecti n g eit her efficac y or t o xicit y. T he cli nical st u d y pr ot oc ols i ncl u de d etaile d restricti o ns o n 
c o nc o mita nt me dicati o ns t o mi ni mize t he p ote ntial f or dr u g -dr u g i nteracti o ns.  
2. 2. 2. 4.  
Cli nic al P h ar m ac o dy n a mics  
A pri mar y p har mac o d y n a mic eff ect of C X C R 4  a nta g o nis m is m o bilizati o n of W B C (i ncl u di n g 
b ot h m yel oi d a n d l y m p h oi d cell li nes) fr o m t he b o ne marr o w i nt o t he p eri p heral circ ulati o n. T he 
relati o ns hi p bet wee n pl as ma dr u g l e vels a n d c o nc urre nt peri p h eral bl o o d W B C c o u nts was 
e x a mi ne d i n p hase 1 st u dies wit h de nse sa m pli n g [ St o ne 2 0 0 7 ]. After d osi n g , circ ulati n g W B C 
c o u nts i ncreas e d fr o m baseli ne i n all s u bjects, pea ki n g  bet w ee n 2 a n d 4 h f oll o wi n g d osi n g . T h e 
distri b uti o n of  c o nc urre nt W B C -f ol d c ha n ge fr o m baseli ne vers us dr u g  c o n ce ntrati o n best fit a 
si g m oi d ma xi m u m e x pos ure ( E ma x ) m o del.  
•  T he esti mate d E ma x  was W B C i ncrease t o 2. 0 3 x baseli ne ( 9 5 % c o nfi de n ce i nter val [ CI ], 
1. 9 5 x t o 2. 1 1 x).  
•  T he esti mate d half -ma xi mal effecti ve c o nce ntrati o n ( E C 5 0) was 3 9 n g/ m L ( 9 5 % CI, 2 8 t o 
5 0  n g/ m L) , w hic h is b el o w t he o bser ve d st ea d y-st ate Cmi n( 1 2 h)  f or X 4 P-0 0 1 at 2 0 0 m g 
BI D, t he st arti n g d os e i n t he pr o p ose d o nc ol o g y st u dies . 
2. 2. 3.  
Cli nical Safet y E x perie n ce wit h X 4 P -0 0 1  
2. 2. 3. 1.  
S afety Ex perie n ce –  X 4 P h ar m ace utic als Cli nic al Devel o p m e nt Pr o gr a m  
As of J ul y 0 5, 2 0 1 7, t he f oll o wi n g st u dies have b ee n i nitiate d or c o m plete d :   
•  X 4 P -0 0 1 -R C C A –  a st u d y of X 4 P -0 0 1 i n c o m bi nati o n wit h a xiti ni b f or t he treat me nt of 
patie nts wit h a d va nce d  cc R C C .  
•  X 4 P -0 0 1 -R C C B –  t he st u d y det aile d i n t his pr ot oc ol. 
•  X 4 P -0 0 1 -M E L A –  a p h ase 1 b st u d y of X 4 P -0 0 1 al o ne a n d i n  c o m bi nati o n wit h 
pe m br oliz u ma b i n patie nts wit h a d va nce d  mela n o ma.  
•  X 4 P -0 0 1 -M K K A –  a p h ase 2/ 3  ra n d o mize d, d o u ble -b li n d, p lace b o-co ntr oll e d trial of 
X 4 P -0 0 1 i n p atie nts w it h W HI M ( Warts, H y p o ga m ma gl o b uli ne mia, I nfecti o ns a n d 
M yel o kat h e xis) S y n dr o me  
•  X 4 P -0 0 1 -R E G A –  a p has e 1 st u d y i n healt h y v ol u nteers c o m pari n g t w o differe nt d osi n g 
re gi me ns: 2 0 0 m g BI D vers us 4 0 0 m g Q D.  
Please ref er t o t he c urr e nt I n vesti gat or’s Br oc h ure f or m ore i nf or mati o n rel ate d t o X 4 P -0 0 1’s 
cli nical safet y dat a . 
2. 2. 3. 2.  
S afety Ex perie n ce –  Pri o r Devel o p m e nt Pr o gr a m 
A t otal of 7 1 i n di vi d uals were e x p ose d t o X 4 P -0 0 1 i n 4 pri or cli nical st u dies. Acr oss t hes e 
4  st u dies: 
•  T he m ost c o m m o n A Es acr oss st u dies were mil d t o m o derate GI e ve nts.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 3 2  of 9 8  
•  T here w ere n o d eat hs a n d n o disc o nti n uati o ns d ue t o A Es. T w o s u bjects disc o nti n ue d f or 
pers o nal reas o ns aft er r ecei vi n g 1 or 2 d os es of X 4 P -0 0 1.  
•  T here w as o ne S A E, a gr a n d mal seiz ure i n a s u bject wit h a hist or y of e pile ps y; t here 
were n o e ve nts of seiz ure re p orte d i n ot her s u bj ects. T his S A E was t he o nl y cli nical A E 
assesse d as se v er e ( Gr a d e 3).  
•  T here w as o ne ot her cli nicall y n ot a ble A E. A s u bj ect wit h baseli ne bra d ycar dia 
e x perie nce d a n e pis o de of s y n c o pe u p o n sta n di n g ra pi dl y. T h e e pis o de res ol ve d pr o m ptl y 
wit h o ut l yi n g d o w n. T her e wer e n o e ve nts of s y n c o pe re p ort e d  i n ot her s u bjects. 
•  T here w ere n o l a b orat or y a b n or malities assesse d as cli nicall y si g nifica nt. T he pri mar y 
treat me nt-r elate d la b or at or y a b n or malities o bser v e d were t he p har mac ol o gicall y e x pecte d 
i ncreas e i n circ ulati n g ne utr o p hils a n d l y m p h oc ytes. Treat me nt-e mer ge nt ele vati o n i n 
li pase was o bser v e d i n o ne as y m pt o matic p atie nt; t he s o urce of t h e e nz y m e ( pa ncreas or 
sali var y gla n ds) w as u ncl ear. 
•  A detaile d b y -s u bject a nal ysis of a b n or m al li ver f u ncti o n tests ( L F Ts) re veale d n o patter n 
of treat me nt -e mer ge nt L FT a b n or m alities s u g gesti n g a dr u g effect.  
2. 2. 4.  
Treat me nt Effect of X 4 P -0 0 1 i n Pri or Cli nical St u dies  
As of J ul y 0 5, 2 0 1 7, t her e are n o effi cac y d ata wit h X 4 P-0 0 1 t o re p ort i n p atie nts wit h 
mali g na n c y (i ncl u di n g cc R C C or mela n o ma).   
2. 2. 5.  
N o ncli nical T o xicit y St u dies of X 4 P -0 0 1  
Pi v otal n o ncli nical t o xicit y st u dies were c o n d u cte d i n rats a n d B ea gle d o gs wit h X 4 P-0 0 1 
a d mi nistere d orall y i n di vi de d d oses, BI D . T he n o o bser ve d a d v erse effect l e vel ( N O A E L ) i n t he 
4 -wee k  rat st u d y was 1 2 5 m g/ k g/ da y . A d verse effects at 2 5 0 m g/ k g/ da y i ncl u de d decreas es i n 
f o o d c o ns u m pti o n, b o d y wei g ht, a n d retic ul oc yt e c o u nts a n d mi ni mal b o ne marr o w 
h y p ocell ularit y; all e x ce pt b o d y wei g ht w ere res ol ve d f oll o wi n g a 1 4 -da y rec o ver y p eri o d.  
T he d ose le vels i n t he 1 3 -wee k t o xicit y st u d y i n d o gs w e re 1 0, 2 0, 3 5, a n d 7 0 m g/ k g/ da y. 
Micr osc o pic li ver fi n di n gs of pi g me nt de p ositi o n a n d i nfla m mati o n were re p orte d i n all d ose 
gr o u ps a n d acr oss males a n d fe males; t hes e fi n di n gs w ere t y picall y assesse d as mi ni mal a n d n ot 
ass ociate d wit h hist o pat h ol o gic fi n d i n gs of necr osis or wit h L F T c ha n ges. T he N O A E L 
(< 1 0  m g/ k g/ da y ) reflect e d t he fi n di n g of a n is olate d f oc us of li ver necr osis (sli g ht) i n a si n gle 
male a ni mal  d ose d at 1 0 m g/ k g/ d a y. N o ne of  t he re mai ni n g 1 1 a ni mals (5  males a n d 6 fe m ales) 
i n t he 2 l o west d ose gr o u ps ha d ot her li ver -relate d fi n di n gs a n d no n e, i ncl u di n g t he male wit h  
f ocal necr osis, ha d treat me nt-e mer ge nt i ncreases i n  L F Ts . 
At t he 2  hi g hest d ose l e v els ( 3 5 a n d 7 0 m g/ k g/ d a y), 4  of 1 2 a ni mals were re p orte d t o ha ve 
micr osc o pic li ver c h a n ges of m u ltif ocal necr osis  ( mi ni mal t o sli g ht), f urt her c haracterize d as 
si n gle cell necr osis i n 2 a ni mals. T w o of t he 1 2 a ni mals i n t h ose d ose gr o u ps ( b ot h 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 3 3  of 9 8  
7 0   m g/ k g/ d a y) s h o w e d p ost-treat me nt i ncrease d ala ni ne a mi n otra nsferase ( A L T ), risi n g t o 1. 4x  
a b o ve t he u p pe r ra n ge of c o ntr ols i n a male wit h n o hist ol o gic fi n di n gs, a n d t o 2. 4x  i n a fe male 
wit h m ultif ocal si n gle cell necr osis (sli g ht). T h ere were n o ele vati o ns i n bilir u bi n i n a n y a ni mal.  
O ne male ( 3 5 m g/ k g/ da y) ha d “f o call y e xte nsi ve ( m o derate)” necr osis a n d i nfla m mati o n 
ass ociate d wit h macr osc o pic disc ol orati o n of t he li ver; tra nsa mi nas es were n or mal. O n re vie w, 
t his lesi o n was q ualitati vel y differ e nt fr o m t he mi cr osc o pic m ultif ocal lesi o ns i n ot her a ni mals 
a n d ha d a s u b ca ps ular l o cati o n, c o nsiste nt wit h bei n g  sec o n dar y t o e xter nal tra u ma.  
T he ori gi nal de vel o p me nt pr o gr a m of A M D 1 1 0 7 0 i de ntifie d a n alter n ati ve salt f or m of t he dr u g 
s u bsta nce f or m a n ufact uri n g p ur p ose, P H B salt ( d esi g nat e d A M D 1 1 0 7 0 P H B). T o xic ol o g y 
st u dies of A M D 1 1 0 7 0 P H B i ncl u de d u ne x pecte d fi n din gs of reti nal de ge n erati o n i n Al bi n o rats 
treate d f or 2 6 wee ks. T his was n ot see n i n Bea gles a d mi nistere d eit her P H B or free base ( X 4 P-
0 0 1) dr u g f or ms f or u p t o 1 3  wee ks.  A M D 1 1 0 7 0 P H B w as ne ver a d mi nistere d t o h u ma ns a n d is 
n ot pr o p ose d f or use i n a n y cli n ical st u dies i n t his pr o gra m. 
2. 3.  
Cli nic al E x perie nce wit h R el ate d C o m p o u n ds  
M oz o bil
®  ( pleri x af or) is t he o nl y a p pr o ve d a ge nt t hat bl oc ks t he C X C R 4 rece pt or , w hic h is a n 
i njecta ble dr u g wit h a v er y s h ort half -life, a n d is a p pr o ve d i n c o m bi nati o n wit h gra n ul oc yt e -
c ol o n y sti m ulati n g fact or ( G -C S F)  t o m o bilize  he mat o p oietic  ste m cells ( H S Cs) t o t he peri p heral 
bl o o d f or c ollecti o n a n d  s u bse q ue nt a ut ol o g o us tra ns pla ntati o n i n patie nts wit h n o n -H o d g ki n’s  
l y m p h o ma a n d m ulti ple m yel o ma.   
I n t u m or m o dels i n mice t he dr u g has bee n a d mi nistere d b y c o nti n u o us i nf usi o n usi n g 
s u bc uta ne o us os m otic res er v oirs. T he res ults of t h ose n o ncli nical st u dies i n dicate t hat C X C R 4  
rece pt or bl oc ka d e has a n a nti-t u m or treat me nt effect a n d t here b y s u p p ort t he h y p ot h esis t hat a n 
ora ll y a d mi nistere d a ge nt s uc h as X 4 P-0 0 1 c o ul d ha ve cli nical be n efit.   
2. 4.  
R ati o n ale  
T he c urr e nt sta n dar d of care tr eat me nt para di g m f or  patie nts wit h a d va nce d ccR C C  i ncl u des a 
m ulti -T KI, s uc h as s u niti ni b, as first -li ne t hera p y, f oll o we d b y a n i m m u n ot hera p y, alter nati ve 
T KI, or tar gete d t her a p y f or f ut ure t h era pies. T ar geti n g a nti -a n gi o ge nesis as a mec ha nis m f or 
bl oc ki n g t u m or gr o wt h is k n o w n t o be effecti ve i n cc R C C, wit h se veral a p pr o ve d a nti -
a n gi o ge nic a ge nts, s uc h as s u niti ni b, paz o pa ni b, a xiti ni b, a n d be vaciz u ma b. Tar gets of m ulti -
T KI s i ncl u de a n gi o ge ni c tar gets as well as ot h er gr o wt h fact ors, s uc h as V E G F R, platelet -
deri ve d gr o wt h fact or rece pt or  ( P D G F R), fi br o blast gr o wt h fact or rece pt or ( F G F R), a n d c yt o kin e 
rece pt or ( kit). Rece ntl y, ni v ol u ma b, a n i m m u ne c hec k p oi nt i n hi bit or, was a p pr o ve d as a sec o n d -
li ne treat me nt f or p atie nts f oll o wi n g pri or a nti-a n gi o ge nic t h era p y. Ni v ol u ma b is a n a nti b o d y t hat 
bl oc ks t he i nteracti o n of P D -1 o n T cells wit h its li ga n d, P D -L 1, res ulti n g i n t u m or -reacti ve 
C D 8 + T cells t ha t ca n acti vate a c yt ot o xic i m m u ne res p o nse. W hile a n O S b e nefit was 
de m o nstrate d wit h ni v ol u ma b treat me nt, it is u na ble t o i n d uce a t u m or res p o nse i n a maj orit y of 
patie nts. O nl y 2 1. 5 % of a d va nce d R C C patie nts ac hie ved  an o bjecti ve  ra di ol o gical res p o nse 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 3 4  of 9 8  
[M otzer 2 0 1 5 ]. T heref or e, it is i m p orta nt t o i de ntif y a d diti o nal t hera pies t h at c o ul d a u g me nt t he 
a nti-t u m or i m m u ne acti vit y of c h ec k p oi nt i n hi bit ors, res ulti n g i n a n i ncreas e i n t he n u m ber of 
patie nts a ble t o ac hie v e a d ura ble r es p o ns e t o treat me nt.  
It is h y p ot hesize d t hat a T M E t hat fa v ors i m m u ne s u p pressi o n res ults i n resista nce t o b ot h T KIs, 
as well as i m m u n ot hera pies. A ni mal s t u dies of  cc R C C x e n o grafts i m plicate i ncrease d i nfiltrati o n 
of M D S C s as a ce ntr al fact or i n ac q uir e d resis ta nce t o V E G F-tar gete d t hera pies [Pa n ka 2 0 1 3 ] as 
well as ot her a nti -ca ncer t hera pies [S h ojaei 2 0 0 7 ; Fi n ke 2 0 1 1 ]. M D S Cs als o i m pair t he e ntr y of 
C D -8 + c yt ot o xic T cells i nt o t he T M E a n d fa cilitate t he e ntr y of Tre g cells [ Zea 2 0 0 5 ; Na garaj 
2 0 0 7 ].  
C X C L 1 2  ( pr e vi o usl y d esi g nate d S D F-1), t h e s ole li ga n d f or C X C R 4 , is i ncrease d i n t he T M E, 
partic ularl y i n cc R C C, w here it is pr o d uce d b y t h e t u m or i n res p o nse t o h y p o xia i n a HI F-
de pe n de nt ma n n er . I n crease d C X C L 1 2  is c o nsi dere d i m p orta nt i n i ncreasi n g M D S C traffic ki n g 
i nt o t u m or tiss ue. T his h y p ot hesis is s u p p orte d b y rece nt m uri n e x e n o graft m o dels i n w hic h 
X 4 P -0 0 1 a nta g o nis m of  C X C L 1 2 /C X C R 4  si g nali n g decrease d t he n u m b er of M D S Cs i n t he 
T M E, a n d directl y i n hi bite d t he i ncrease i n M D S Cs ass ociate d wit h treat me nt wit h a xiti ni b, a 
T KI a nta g o nist.  
W hile c hec k p oi nt i n hi bit ors facilitate acti vati o n of c yt ot o xic T cells, t he a ge nts d o n ot i m pact 
T  cell traffic ki n g. A nal ys es of h u ma n t u m or bi o ps y sa m ples i n dicates t hat a cli nical res p o nse t o 
c hec k p oi nt i n hi bit ors ma y be pre dicte d b y i m m u n e mar kers, s uc h as t he rati o of effect or T cells 
t o re g ul at or y T cells, i nfla m mat or y ge ne e x pressi o n patter ns, or t he prese nce of C D 8 + T cells i n 
t he t u m or micr oe n vir o n me nt b ot h bef ore a n d s h ortl y after treat me nt [Mc D er m ott 2 0 1 6 ; Ji 2 0 1 2; 
Ri bas 2 0 1 5 ; T u me h 2 0 1 4 ]. I n mela n o ma, res p o nse t o treat me nt wit h a n a nti-P D -1 bl oc ki n g 
a nti b o d y (p e m br oliz u ma b ) was ass oci ate d wit h greater n u m bers of C D 8 + T cells at t he i n vasi ve 
t u m or mar gi n pri or t o treat me nt, wit h t h ose cells t he n de m o nstrati n g i ncrease d pr oliferati o n a n d 
t u m or i nfiltrati o n d uri n g t he c o urse of treat me nt [ T u me h 2 0 1 4 ].  
Ni v ol u ma b is c urre ntl y t he o nl y i m m u ne c h ec k p oi nt i n hi bit or a p pr o ve d i n R C C. T he a d diti o n of 
X 4 P -0 0 1  treat me nt is h y p ot hesize d t o i ncrease t h e cli nical res p o ns e t o ni v ol u ma b b y decreasi n g 
M D S Cs a n d i ncreasi n g c yt ot o xic T cells at t he t u m or, t here b y pr o vi di n g a n i nfl u x of cells t hat 
ca n be f urt her acti vate d b y t he c hec k p oi nt i n hi bit or. A d diti o nall y, C X C R 4  has a r ole i n 
traffic ki n g of e n d ot helial pr o ge nit or cells w hic h m e diate a n gi o ge n esis. R C C is k no w n t o be 
res p o nsi ve t o a nti-a n gi o ge nic a ge nts, a n d t h us X 4 P -0 0 1 tar gets a sec o n d mec ha nis m of t u m or 
gr o wt h i n hi biti o n.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 3 5  of 9 8  
3.  
O B J E C TI V E S A N D  P U R P O S E  
3. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve is:  
•  T o c har acterize t he safet y a n d t olera bilit y of X 4 P -0 0 1 use d i n c o m bi nati o n wit h 
ni v ol u ma b i n patie nts t olerati n g ni v ol u ma b b ut n ot e x hi biti n g ra di ol o gic res p o nse.  
3. 2.  
Sec o n d ar y  O bjecti ves  
Sec o n dar y o bjecti ves ar e:  
•  T o c har acterize t he P K  of X 4 P -0 0 1 w he n use d i n c o m bi nati o n wit h ni v ol u ma b.  
•  T o c har acterize t he a ntit u m or acti vit y of t h e c o m bi nati o n of X 4 P -0 0 1 a n d ni v ol u ma b.  
3. 3.  
E x pl or at or y O bjecti ves  
E x pl orat or y o bjecti ves ar e t o:  
•  T o i n vesti gate s electe d p eri p heral bl o o d bi o mar kers of i m m u ne acti vati o n d uri n g 
treat me nt wit h X 4 P-0 0 1 pl us ni v ol u ma b.  
•  T o e val uate arc hi ve d t u m or ti ss ue f or bi o mar kers t hat ma y c orrelate wit h res p o nse t o 
c o m bi nati o n treat me nt wit h X 4 P -0 0 1 a n d ni v ol u ma b.  
•  T o a ssess t he treat me nt effect (cli nical acti vit y) of t he c o m bi nati o n of X 4 P -0 0 1 a n d 
ni v ol u ma b i n patie nts wit h a d va nce d  ccR C C  usi n g m o difie d Res p o nse  E val uati o n 
Criteria i n S oli d T u m ors f or i m m u ne-base d t h era p e utics  (i R E CI S T) [Se y m o ur  2 0 1 7 ]. 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 3 6  of 9 8  
4.  
S T U D Y D E SI G N  A N D E N D P OI N T S  
4. 1.  
Descri pti o n of t he St u d y Desi g n  
T he pri mar y o bjecti ve of t his si n gle -ar m, o p e n-la b el, m ulti-ce nter st u d y is t o c haracterize t he 
safet y a n d t oler a bilit y of a d di n g X 4 P-0 0 1 t o ni v ol u ma b treat me nt i n patie nts wit h a d va nce d 
cc R C C. T o be eli gi ble, p atie nts m ust ha ve recei ve d ni v ol u ma b a n d ha ve de m o nstrate d a  
c o nfir me d  best r es p o nse of  S D  or ra di ol o gic pr o gressi o n ( P D) wi t h o ut cli nical deteri orati o n, as 
assesse d b y t heir I n v esti gat or.  C o nfir me d S D or c o nfir me d P D refers t o a res p o nse t hat is 
c o nfir me d b y a 2 n d s ca n w hic h is at least 4 wee ks a part fr o m t he pre vi o us s ca n.  
U p t o 2 0 patie nts ma y recei ve t he pr ot o c ol -s pecifie d c o m bi nati o n treat me nt a n d c o nti n ue u ntil 
eit her: 
•  Treat me nt -Li miti n g T o xicit y ( T L T), as d efi ne d f or X 4 P -0 0 1 a n d as p er a p pr o ve d la bel 
f or ni v ol u ma b (see Secti o n 5. 6 ). 
•  P D , base d o n eit her cli nical or ra di ol o gic assess m e nts, usi n g fi n di n gs at st u d y e ntr y t o 
defi ne t he bas eli ne.  
-  Patie nts t hat meet ra di ol o gic criteria f or pr o gressi o n c o m pare d wit h st u d y b aseli ne as 
defi ne d b y R E CI S T v 1. 1 [Eise n ha u er 2 0 0 9] ma y c o nti n ue i n t he st u d y if t h eir 
I n v esti gat or j u d ges t hat b ot h of t he f oll o wi n g a p pl y: (a) t he patie nt is li kel y t o be nefit  
fr o m o n g oi n g tr eat me nt wit h st u d y treat me nt; a n d ( b) t he patie nt d oes n ot h a ve 
cli nicall y si g nifica nt s y m pt o ms  of P D .  
-  A n y p atie nt wit h s u bse q ue nt i ma gi n g de m o nstrati n g i m m u ne c o nfir me d pr o gressi ve 
disease (i C P D) base d o n i R E CI S T criteria [Se y m o ur  2 0 1 7 ] m ust disc o nti n ue st u d y 
treat me nt (see Secti o n  5. 7. 1 ).  
T o pr otect patie nts’ safet y , a Data Re vie w C o m mittee ( D R C) will re vie w a vaila ble safet y d ata  
a n d ma ke a rec o m me n d ati o n o n t he pr o gress of t h e st u d y d uri n g st u d y treat me nt (see Secti o n  
8. 6. 2 ).  
4. 1. 1.  
Rati o nale f or t he St u d y Desi g n, I ncl u di n g t he C h oice of C o ntr ol Gr o u ps  
4. 1. 1. 1.  
R ati o n ale f or St u dy Str uct ure  
T he o pe n -la b el st u d y d esi g n is c o nsiste nt wit h b ot h t he st u d y o bjecti ves a n d c urre nt pri n ci ples 
f or t he earl y e val u ati o n of i n vesti gati o nal dr u gs i n patie nts wit h a d va nce d m ali g na n c y. T he 
si n gle d ose le v el of X 4 P-0 0 1 i n c o m bi nati o n wit h ni v ol u ma b, w hic h is  a p pr o ve d f or certai n 
patie nts wit h a d va nce d ccR C C will e na ble a f oc us e d assess me nt of t he s afet y a n d t olera bilit y of 
a n o vel c o m bi nati o n wit h t he p ote ntial t o pr o vi de i m pr o ve d o utc o mes b y pre ve nti n g or dela yi n g 
treat me nt resista n ce. 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 3 7  of 9 8  
4. 1. 1. 2.  
R ati o n ale f or Tre at me n t Re gi me n 
T he pr o p ose d d ose  of X 4 P -0 0 1 ( 4 0 0 m g Q D) is selecte d base d o n t h e f oll o wi n g e x perie n ce:  
•  I n pri or cli nical st u dies, t he sa me t otal dail y e x p os ure a d mi nistere d as 2 0 0 m g BI D w as 
(a) p har mac ol o gicall y acti ve ( Secti o n  2. 2. 2. 4 ) a n d ( b) well-t olerate d i n 2 6 h ealt h y 
v ol u nteers a n d HI V -i nf ecte d patie nts treate d f or 8 t o 1 0 da ys (Secti o n  2. 2. 1 ), wit h n o 
treat me nt-r elate d disc o nti n uati o ns a n d n o patter n of si g nifica nt la b orat or y a b n or malities.  
•  I n pri or d ose es calati o n st u dies, 4 0 0 m g BI D w as well t olerate d f or 3. 5 da ys.  
•  T he 4 0 0 m g d ail y d os e w as ge nerall y s afe a n d well t olerate d i n patie nts w h o were i n t he 
X 4 P -0 0 1 -R C C A st u d y as of N o ve m ber 3 0, 2 0 1 6  (Secti o n 2. 2. 3. 1 ). 
T 1/ 2 of X 4 P -0 0 1 is ~ 2 3 hr, s u p p orti n g o nce dail y d osi n g  (see Secti o n  2. 2. 2. 1 ).  
4. 2.  
E n d p oi nts  
4. 2. 1.  
Safet y E n d p oi nt s 
Safet y e n d p oi nt s are: 
•  A Es.  
•  Cli nical o bser vati o ns (e. g., vital si g ns, p h ysical e x a mi nati o n). 
•  La b orat or y test r es ults (e. g., cli nical c he mistr y, he mat ol o g y).  
•  Electr ocar di o gra m ( E C G ) fi n di n gs. 
•  O p ht hal m ol o gic e x a mi nati o n fi n di n gs.  
4. 2. 2.  
E fficac y E n d p oi nts  
Efficac y e n d p oi nts ar e:  
•  O R R, w here r es p o nse is defi ne d as ac hie vi n g eit h er c o m plete res p o nse ( C R) or partial 
res p o nse ( P R). 
•  Ti me t o o bjecti ve res p o nse.  
•  D urati o n of o bjecti ve res p o nse.  
•  Disease c o ntr ol rate ( D C R; C R + P R + S D )  
•  P F S, defi ne d as t he ti me fr o m first a d mi nistrati o n of c o m bi nati o n re gi me n u ntil o bjecti ve 
t u m or pr o gressi o n or deat h fr o m a n y ca us e.  
•  Ti me t o pr o gr essi o n ( T T P), defi ne d as t he ti me fr o m first a d mi nistrati o n of c o m bi nati o n 
re gi me n u ntil o bjecti ve t u m or pr o gressi o n. 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 3 8  of 9 8  
4. 2. 3.  
P har mac o ki netic E n d p oi nts  
P K e n d p oi nts are:  
•  A U C.  
•  C ma x . 
•  T ma x . 
4. 2. 4.  
E x pl orat or y E n d p oi nts  
E x pl orat or y e n d p oi nts ar e:  
•  Effect of st u d y tr eat me nt o n W B Cs, i ncl u di n g a bs ol ute ne utr o p hil c o u nts ( A N C) a n d 
a bs ol ute l y m p h oc yte c o u nts ( A L C) , i n bl o o d. 
•  Effect of st u d y tr eat me nt o n treat me nt - a n d t u m or -relate d bi o mar k ers i n peri p heral bl o o d 
m o n o n uclear cells ( P B M Cs), i ncl u di n g Tre g  l y m p h oc yt es, acti vate d T cells, a n d M D S Cs, 
a n d i n ser u m, i ncl u di n g C X C L 1 2 . 
•  I d e ntificati o n of p ote ntial bi o mar kers t hat ma y pre dict res p o nse t o c o m bi nati o n treat me nt 
wit h X 4 P -0 0 1 a n d ni v ol u ma b . 
•  T u m or res p o nse assess e d  p ossi bl y usi n g t he i R E CI S T. 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 3 9  of 9 8  
5.  
S T U D Y E N R O L L M E N T A N D WI T H D R A W A L  
5. 1.  
I ncl usi o n Criteri a 
Patie nts m ust meet all of t he f oll o wi n g criteria t o b e eli gi ble f or st u d y partici pati o n:  
1.  Be at least 1 8 years of a ge.  
2.  Ha ve si g ne d t he c urr e nt a p pr o ve d i nf or me d c o nse nt f or m.  
3.  Ha ve a hist ol o gicall y c o nfir me d dia g n osis of R C C wit h a d oc u me nte d cl ear cell 
c o m p o ne nt (i.e., cc R C C). 
4.  Be c urre ntl y r ecei vi n g ni v ol u ma b a n d be c o nsi dere d b y t h eir I n vesti gat or t o ha ve t he 
p ote ntial t o deri ve cli nical be nefit fr o m c o nti n ui n g treat me nt wit h ni v ol u ma b.  
5.  Has a best r es p o nse of c o nfir me d S D or c o nfir me d P D * ( base d o n R E CI S T v 1. 1 
[Eise n ha uer 2 0 0 9 ]) o n c urre nt ni v ol u ma b treat me nt  pri or t o i nitiati o n of t his st u d y . 
* c o nfir me d S D or c o nfir me d P D  refers t o a res p o nse t hat is c o nfir me d b y a 2 n d sca n 
w hic h is at le ast 4 wee ks a part fr o m t he pre vi o us  s ca n. 
6.  Ha ve o n c o m p ute d t o m o gr a p h y (C T ) i ma gi n g d o ne wit hi n 2 8 da ys of Da y 1 fi n di n gs 
c o nsiste nt wit h a d va nce d cc R C C, i ncl u di n g at least o ne e xtra -re nal meas ura ble tar get 
lesi o n meeti n g t he criteri a of R E CI S T v 1. 1 ( Secti o n 7. 1. 4. 2 ).  
7.  A gree t o use c o ntrace pti o n fr o m scree ni n g, t hr o u g h t he st u d y, a n d f or at least 5 m o nt hs 
after the l ast d ose of ni v ol u ma b as f oll o ws:  
•  F or w o me n of c hil d beari n g p ote ntial ( W O C P, see Secti o n 7. 4. 1. 2  f or defi niti o n) a gree 
t o use hi g hl y effecti ve c o ntrace pti ve met h o ds . A cce pta ble met h o ds are descri be d i n 
Secti o n 7. 4. 1. 3 . 
•  F or males, a gree t o use a c o n d o m wit h a n y W O C P se x ual part ner. 
8.  A grees t o per mit s u b missi o n of arc hi ve d t u m or tiss ue t o S p o ns or f or a nal ysis, if 
a vaila ble.  
9.  Be willi n g a n d a ble t o c o m pl y wit h t his pr ot oc ol. 
5. 2.  
E x cl usi o n Criteri a  
Patie nts meeti n g a n y of t he f oll o wi n g criteria are e x cl u de d fr o m st u d y partici pati o n:  
1.  Is pre g na nt or n ursi n g.  
2.  Has life e x pecta n c y of less t ha n 3 m o nt hs.  
3.  Has perf or ma nce stat us ≥2 ( Easter n C o o perati ve O nc ol o g y Gr o u p [ E C O G]  criteria).  
4.  Has cli nicall y si g nifi ca nt a n d/ or u nc o ntr olle d heart disease s uc h as c o n gesti ve heart 
fail ure r e q uiri n g treat me nt (Ne w Y or k Heart Ass ociati o n  Class III or I V ), u nc o ntr olle d 
h y perte nsi o n , or cli nicall y si g nifica nt arr h yt h mia.  
5.  Has pre vi o usl y rec ei ve d X 4 P -0 0 1.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 4 0  of 9 8  
6.  Has a sec o n d mali g n a nc y. E x ce pt: mali g na ncies t h at were treat e d c urati vel y a n d ha ve n ot 
rec urre d wit hi n 2 years pri or t o st u d y treat me nt; c o m pletel y resecte d basal cell a n d 
s q ua m o us cell s ki n ca ncers; a n y m ali g n a nc y c o nsi dere d t o be i n d ole nt a n d t hat has ne ver 
re q uire d t hera p y; a n d c o m pletel y resecte d carci n o ma i n sit u of a n y t y pe. 
7.  Has acti ve C N S metasta s es (i ncl u di n g e vi de nce of cere bral e d e ma b y M RI, or 
pr o gressi o n fr o m pri or i ma gi n g st u d y, or a n y re q uire me nt f or ster oi ds, or cli nical 
s y m pt o ms of/fr o m C N S metastases) wit hi n 2 8 da ys pri or t o  st u d y treat me nt. S u bjects 
wit h k n o w n C N S metastases m ust ha ve a b aseli ne M RI  sca n wit hi n 2 8 da ys of st u d y 
treat me nt. 
8.  Has o n g oi n g cli nical a d v erse e v e nts Nati o nal Ca n cer I nstit ute C o m m o n Ter mi n ol o g y 
C riteria f or A d v erse E v e nts (N CI C T C A E ) Gra d e > 2 res ulti n g fr o m pri or ca ncer 
t hera pies, i ncl u di n g ni v ol u ma b (e x ce pt al o peci a or h y p ot h yr oi dis m). 
9.  Has a k n o w n hist or y of a p ositi ve ser ol o g y or viral l oa d f or HI V or a k n o w n hist or y of 
ac q uire d i m m u n o defi cie nc y dis or d er .  
1 0.  Has ha d wit hi n t he past 6 m o nt hs t he occ urre n ce or persiste nce of o ne or m ore of t he 
f oll o wi n g me dical c o n diti o ns t hat c o ul d n ot be c o ntr olle d wit h us ual me dical care 
(e. g., re q uir e d e mer ge n c y care or h os pitalizati o n): h y pert e nsi o n, a n gi na, c o ngesti ve h eart 
fail ure, dia b etes, seiz ure dis or der.  
1 1.  Has ha d wit hi n t he past 6 m o nt hs t he occ urre n ce of o ne or m ore of t he f oll o wi n g e v e nts: 
m y ocar dial i nfarcti o n, cere br o vas c ular acci d e nt, dee p vei n t hr o m b osis, p ul m o nar y 
e m b olis m, he m orr ha ge ( N CI C T C A E  Gra de 3 or 4), c hr o nic li ver dis ease ( meeti n g 
criteria f or C hil d -P u g h Class B or C), or or ga n tra ns pla ntati o n.  
1 2.  Has ha d wit hi n t he 4 wee ks pri or t o i nitiati o n of st u d y dr u g s ur ger y re q uiri n g ge n eral 
a nest hesia.  
1 3.  Has, at scr ee ni n g, ser ol o gic la b orat or y tests me eti n g o ne or m ore of t he f oll o wi n g 
criteria:  
•  A n i n deter mi nate or p ositi ve test f or a nti b o d y t o h e patitis C vir us ( H C V), u nless 
d oc u me nte d t o ha ve n o d etecta ble viral l oa d o n t w o i n de pe n de nt sa m ples.  
•  A p ositi ve test f or he patitis B s urface a nti ge n ( H Bs A g).  
1 4.  Has, at scr ee ni n g, safet y la b orat or y tests meeti n g o ne or m ore of t he f oll o wi n g criteria:  
•  He m o gl o bi n < 8. 0 g/ d L  (tra nsf usi o n is all o we d) 
•  A N C < 1, 5 0 0/ µ L  
•  Platelets < 7 5, 0 0 0/ µ L  
•  Creati ni ne > 2. 0 x u p per li mit of n or mal ( U L N ) 
•  A S T  or A L T  > 2. 5 x U L N  
o  A S T a n d A L T > 5 x U L N f or patie nts wit h li ver metastasis   


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 4 1  of 9 8  
•  
T otal bilir u bi n ( T BI L) > 1. 5 x U L N ( u nless d ue t o Gil bert's S y n dr o me , t otal bilir u bi n > 
3. 0 x U L N a n d direct bilir u bi n > 1. 5 x U L N ) 
•  I nter nati o nal n or malize d rati o (I N R) > 1. 5 x U L N 
1 5.  Has, wit hi n 4 wee ks pri or t o Da y 1, recei v e d s yste mic c ortic oster oi ds e x cee di n g 
pre d nis o ne 1 0 m g per d a y ( or e q ui vale nt). T o pical, i n hale d, nasal a n d o p ht h al mic ster oi ds 
are all o w e d; for ot her i m m u n os u p pressi ve a ge nts, t he e x cl usi o nar y d ose a n d d urati o n will 
be deter mi ne d i n c o ns ult ati o n wit h t he Me dical M o nit or.  
1 6.  Has, wit hi n t hree ( 3) wee ks pri or t o Da y 1, recei ve d a nti -ca ncer t hera p y ot h er t ha n 
ni v ol u ma b, i ncl u di n g a T KI, be vaciz u ma b, c he m ot hera p y (e. g., mit o m yci n -C, 
nitr os o urea), i m m u n ot her a p y, or ra di ati o n t hera p y. F or i n vesti gati o nal a nti -ca ncer 
t hera pies, t he i nter v al will be deter mi ne d i n c o ns ultati o n wit h t he Me dical M o nit or. 
1 7.  Has, wit hi n 2 wee ks pri or t o Da y 1, recei ve d a me dicati o n pr o hi bite d base d o n C Y P 3 A 4 
i nteracti o n (see Secti o n 7. 4. 1. 1  f or details).  
1 8.  Has, at t he pla n ne d i nitiati o n of st u d y dr u g, a n u n c o ntr olle d i nfecti o n.  
1 9.  Has a n y ot her m e dical or pers o nal c o n diti o n t hat, i n t he o pi ni o n of t he I n vesti gat or, ma y 
p ote ntiall y c o m pr o mise t he safet y or c o m plia nce of t he patie nt, or ma y precl u de t he 
patie nt's s uccessf ul c o m pleti o n of t he cli nical st u d y. 
Patie nts ta ki n g me dicati o ns pr o hi bite d o n t he basis of C Y P 3 A 4 i nteracti o ns (see  Secti o n 
7. 4. 1. 1 ), ma y, after disc ussi o n wit h t he prescri bi n g p h ysicia n, b e c ha n ge d t o a f u ncti o nall y 
e q ui vale nt, n o n -pr o hi bite d me dicati o n, a n d, aft er at least t w o wee ks off t he pr o hi bite d 
me dica ti o n, reass esse d f or e nr oll me nt, i ncl u di n g rescree ni n g, if n ecess ar y.  
5. 3.  
Str ate gies f or Recr uit me nt a n d Rete nti o n  
F oll o wi n g recei pt of I R B/I E C a p pr o val , t he In v esti gat or ma y i nitiate p atie nt recr uit me nt (see  
Secti o n  1 3 ). T o reac h a n ec o n o micall y a n d s oci all y di vers e p o p ulati o n, t he st u d y ma y be 
a n n o u nce d p u blicl y, i ncl u di n g  o n r ele va nt I nter net we bsites; pri or t o use, t he f or m a n d c o nte nt of 
s uc h a n n o u nce me nts will be s u b mitte d t o t he I R B/I E C f or a p pr o v al (see Secti o n  1 3 ). 
5. 4.  
P a rtici p a nt  Wit h dr a w al  or T er mi n ati o n  
5. 4. 1.  
Reas o ns f or Wit h dra wal  or Ter mi nati o n  
T o pr o vi de f or c o nsiste nt acc o u nti n g of patie nt dis p ositi o n, w he n st u d y treat me nt is disc o nti n ue d 
i n a n i n di vi d ual patie nt f or a n y reas o n, t he In v esti gat or will c o m plete t he a p pr o priate  el ectr o nic 
case r e p ort f or m ( eC R F) a n d select t he pri mar y reas o n fr o m t he f oll o wi n g sta n dar d cate g ories:  
•  T L T eve nt  –  see Secti o n  5. 6 . 
•  P D  per R E CI S T v 1. 1  [Eise n ha uer 2 0 0 9 ] (see Secti o n 7. 1. 4. 2  f or details). 
•  Cli nic al Deteri or ati o n  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 4 2  of 9 8  
•  A dverse E ve nt, ot her t h a n T L T  –  T his i ncl u des a n y A E (cli nical or la b orat or y; seri o us or 
n o n -seri o us; re gar dless of relati o n t o st u d y dr u g), t hat re pres e nts t he reas o n st u d y dr u g 
was disc o nti n ue d, i ncl u di n g:  
-  T he me dical j u d g me nt of t he In v esti gat or bas e d o n t he best i nterests of t he patie nt .  
•  T he patie nt’s r e q uest bas e d o n a n y A E.  
•  Wit h dr a w al of C o nse nt  –  T he patie nt desire d t o wit h dra w fr o m f urt her p artici pati o n i n  t he 
st u d y i n t he a bse n ce of a cli nical iss ue. If t he p atie nt ga v e a reas o n f or wit h dra wi n g (e. g., 
lea vi n g area), it s h o ul d be rec or de d i n t he eC R F.  
•  L ost t o F oll o w -U p  –  T he patie nt st o p pe d c o mi n g f or visits .  
•  St u dy Ter mi n ati o n  –  b y t he S p o ns or, f or a n y reas o n.  
5. 4. 2.  
Ha n dli n g of Partici pa nt Wit h dra wals or Ter mi nati o n  
W he n st u d y treat me nt is disc o nti n ue d f or a n y reas o n, t h e E n d -of -Treat me nt ( E O T ) a n d E n d -of -
St u d y ( E O S ) visits will be perf or me d as s p ecifie d. If a patie nt ca n n ot be see n, atte m pts will be 
ma de t o c o ntact t he p atie nt b y tele p h o n e t o i n q uire a b o ut reas o ns f or st o p pi n g partici p ati o n a n d 
get u p d ate d i nf or mati o n o n  a n y u nres ol ve d A Es.   
5. 5.  
Pre m at ure Ter mi n ati o n or S us pe nsi o n of St u d y  
T he S p o ns or reser ves t he ri g ht t o ter mi nate t he st u d y or p artic ular st u d y ce nter at a n y ti me . If t h e 
S p o ns or or I n v esti gat or disc o vers c o n diti o ns arisi n g d uri n g t he st u d y t hat s u g gest t he s t u d y 
s h o ul d be halte d, t he n st u d y ter mi nati o n ca n occ ur o nl y aft er a p pr o priate c o ns ultati o n bet wee n 
t he S p o ns or a n d I n vesti gat ors. C o n diti o ns t hat ma y w arra nt st u d y or st u d y ce nter ter mi nati o n 
i ncl u de, b ut are n ot li mite d t o: 
•  T he disc o ver y of a n y u ne x pecte d, si g nifica nt, or u nacce pta ble ris k t o t he patie nts e nr olle d 
i n t he st u d y. 
•  Fail ure of t he I n vesti gat or t o e nter patie nts at a n acce pta bl e rate.  
•  I ns ufficie nt a d h ere n ce t o t he pr ot oc ol re q uire me nts. 
•  A decisi o n o n t he part of t he S p o ns or t o s us pe n d or disc o n ti n ue de vel o p me nt of st u d y 
dr u g.  
S h o ul d t he st u d y b e cl ose d pre mat urel y, all st u d y materials (st u d y dr u g, etc.) m ust be ret ur ne d t o 
t he S p o ns or or desi g n ee ( or dis p ose d of as directe d b y t he S p o ns or or d esi g n ee). 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 4 3  of 9 8  
5. 6.  
Defi niti o ns of Tre at me nt -Li miti n g T o xicit y  
A T L T e ve nt is defi n e d as a n a d vers e e ve nt t hat m eets  b ot h  of t he f oll o wi n g criteria  wit hi n t he 
first 2 8 da ys of treat me nt ( C ycl e 1) :  
a)  Is assesse d b y t he I n vesti gat or as p ossi bl y relate d or relate d t o st u d y dr u g ( X 4 P-0 0 1) (see 
Secti o n 8. 2. 3  f or details).  
b)  Re prese nts o ne of t he f oll o wi n g e v e nts ( gra di n g as defi ne d b y t he N CI C T C A E; Ver.  4. 0 3) 
(see Secti o n  8. 2. 1 ). La borat or y  val ues s h o ul d be re peate d 4 8 -7 2 hrs after t h e i nitial la b orat or y  
re p ort t o c o nfir m t he res ults.  
T a ble 5 -1 : 
Defi niti o ns of T L Ts  
T o x icit y 
T L T Criteri a  
He mat ol o g y  
Gra de 4 Ne utr o pe nia lasti n g m ore t ha n 7 c o nsec uti ve da ys 
 
Gra de 3 or 4 ne utr o pe nia wit h fe ver (te m perat ure of > 3 8. 5 °C)  
 
Gra de 4 t hr o m b oc yt o pe nia, or Gra de 3 t hr o m b oc yt o pe nia wit h blee di n g  
 
Gra de 4 a ne mia  
 
Gra de 4 l y m p h o pe nia 
N o n -he mat ol o g y 
e ve nts  
A n y ≥ Gra de 3 cli nical e ve nts or la b orat or y e ve nts, e xce pt f or t he e ve nts descri be d bel o w , 
w hic h are T L Ts o nl y if t he y meet t he criteria bel o w.  
Gastr oi ntesti nal  
Gra de 3 or 4 na usea, v o miti n g or diarr hea last i n g ≥ 4 8 hr des pite o pti mal me dical ma na ge me nt  
He pat o biliar y  
≥ Gra de 2 t otal bilir u bi n ele vati o n wit h ≥ gra de 2 A L T/ A S T ele vati o n  
 
≥ Gra de 3 A L T/ A S T ele vati o n lasti n g ≥ 5 da ys or Gra de 4 A L T/ A S T ele vati o n  
P ne u m o nitis  
Gra de 2 p ne u m o nitis lasti n g > 7 da ys des pite o pti mal treat me nt 
H y perte nsi o n  
Gra de 3 h y perte nsi o n lasti n g > 7 da ys des pite o pti mal treat me nt  
I nfecti o n 
Gra de 3 i nfecti o n or fe ver i n t he a bse nce of ne utr o pe nia lasti n g > 5 da ys  
Electr ol ytes  
Gra de 3 electr ol yte a b n or malities lasti n g > 7 da ys  
Ras h a n d/ or 
p h ot ose nsiti vit y  
≥ G ra de 3 ras h or p h ot ose nsiti vit y lasti n g > 7 da ys des pite o pti mal treat me nt  
 
Fati g ue  
Gra de 3 fati g ue  lasti n g > 7 da ys  
I m m u ne relate d 
t o xicities (e xce pt 
p ne u m o nitis)  
Gra de 3  i m m u ne relate d t o xicities lasti n g > 7 da ys  
des pite o pti mal treat me nt 
Ot hers  
A n y ot her ≥ Gra de 2 t o xicit y t hat i n t he o pi ni o n of t he i n vesti gat or a n d a gree d wit h t he 
Me dical M o nit or is c o nsi dere d t o be a cli nicall y u nacce pta ble ris k  
 
F or a n y T L T e ve nt o cc urri n g d uri n g t he first 4 wee ks of treat me nt, st u d y treat me nt will be 
disc o nti n ue d per ma ne ntl y. F or a n y T L T e ve nt o cc urri n g after s uccessf ul c o m pleti o n of 4 wee ks 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 4 4  of 9 8  
of treat me nt, pr o visi o n is ma de f or d os e m o difica ti o n (see Secti o n 6. 1. 7 ). If e x cessi ve T L Ts are 
o bser ve d a n yti me d uri n g t he trial, a d ose de -escalati o n ca n be e nf orce d f oll o wi n g D R C re vi e w or 
t he trial ca n be st o p p e d at t he s p o ns or’s discreti o n  (see Secti o n 8. 6. 2 ). 
5. 7.  
Defi niti o ns a n d Pr oce d ures Rel ate d t o Dise ase Pr o gressi o n  
Patie nts will be assesse d f or cli nical a n d/ or ra di ol o gic al pr o gressi o n t hr o u g h o ut t he st u d y usi n g 
t he scree ni n g assess me nts as t he baseli ne f or deter mi nati o n of c ha n ges. 
•  Patie nts will ha ve cli nical disease assess me nts (e. g., E C O G p erf or ma nce stat us a n d 
e val uati o n of A Es, i ncl u di n g ne w si g ns or s y m pt o ms of disea se) t hr o u g h o ut t he st u d y.  
-  Patie nts w h o de m o nstrate cli nical deteri orati o n s h o ul d be disc o nti n ue d fr o m st u d y 
treat me nt. 
•  Patie nts will ha ve ra di ol o gical disease assess me nts at st u d y e ntr y a n d e v er y 8 wee ks f or 
t he first 1 2 m o nt hs w hile o n treat me nt  a n d e v er y 1 2 wee ks t hereaft er; u nsc h e d ule d 
assess me nt s ma y be c o n d ucte d i n res p o nse t o ne w cli nical o bser vati o ns. Dis ease stat us 
will be classifie d acc or di n g t o R E CI S T v 1. 1 [Eise n ha uer 2 0 0 9 ] (see Secti o n 7. 1. 4. 2  f or 
details ).  
-  F or patie nts wit h ra di ol o gical e vi de nce of P D c o m pare d t o st u d y b aseli ne , st u d y 
treat me nt ma y be disc o nti n ue d; h o we ver, p atie nts ma y re mai n o n st u d y if t he 
I n v esti gat or deter mi nes t hat c o nti n ue d treat me nt wit h t he c o m bi nati o n of ni v ol u ma b 
a n d X 4 P -0 0 1 is i n t he patie nt’s best i nterests  (see re q uire me nts i n Secti o n 5. 7. 1 ). 
5. 7. 1.  
C o nti n uati o n of Treat me nt Be y o n d Ra di ol o gic Disease Pr o gressi o n  
Rece nt p u blicati o ns s u g gest t hat s o me patie nts treate d wit h i m m u n ot hera p y ma y b e nefit fr o m 
c o nti n ue d treat me nt des pite meeti n g t he ra di ol o gical criteria f or  P D  [W olc h o k 2 0 0 9 ]. I n 
c o nsi derati o n of t hes e o bser vati o ns, patie nts e nr olle d i n t he st u d y w h o meet ra di ol o gical criteri a 
f or P D will be all o we d t o c o nti n ue recei vi n g st u d y treat me nt if t he y meet all  of t he f oll o wi n g 
criteria:  
•  I n t he j u d g me nt of t heir I n vesti gat or, all  of t he f oll o wi n g a p pl y:  
-  T he patie nt is n ot de m o nstrati n g cli nicall y si g nifica nt s y m pt o ms  of P D .  
-  T he patie nt is t olerati n g st u d y treat me nt.  
-  T he patie nt has e x perie n ce d, or has t h e p ote ntial t o e x perie nce, cli nic al be n efit fr o m 
c o nti n ui n g t o recei ve st u d y treat me nt.  
•  B ot h t he I n vesti gat or’s rec o m me n dati o n t o c o nti n ue treat me nt a n d t h e c o nc urre nce of t he 
Me dical M o nit or ar e d oc u me nte d i n t he st u d y rec or ds.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 4 5  of 9 8  
Patie nts w h o c o nti n ue treat me nt u n der t his pr o visi o n will ha ve o n g oi n g, re g ularl y s c he d ule d 
cli nical a n d ra di ol o gic assess me nts as per pr ot o c ol. St u d y treat me nt s h o ul d be disc o nti n ue d if 
patie nt s meet eit her of t h e f oll o wi n g criteria:  
•  Cli nical e vi de nce of P D.  
•  F urt her ra di ol o gical pr o gressi o n, defi ne d as a n i m m u ne c o nfir me d pr o gressi ve disease 
(i C P D) base d o n i R E CI S T criteria [Se y m o ur  2 0 1 7 ]. Bel o w is a n o ver vie w of i R E CI S T 
assess me nt of pr o gr essi ve disease; refere nce Se y m o ur et al. f or m ore details . 
-  I m m u ne u n c o nfir me d pr o gressi ve disease (i U P D) is defi ne d b y R E CI S T 1. 1 criteria 
f or pr o gr essi ve disease.  
-  F or tar get lesi o ns, pr o gressi o n is c o nfir me d if t he ne xt i ma gi n g ass ess me nt after 
i U P D ( 4– 8 wee ks later) c o nfir ms a f urt her i ncreas e i n s u m of meas ures of tar get 
disease fr o m i U P D, wit h a n i ncrease of at least 5 m m.  
o  H o we ver, t he criteria f or i C P D (after i U P D) are n ot c o nsi dere d t o ha v e bee n met 
if c o m plete res p o ns e, partial res p o nse, or sta ble disease criteria (c o m pare d wit h 
baseli ne a n d as d efi ne d b y R E CI S T 1. 1) are met at t he ne xt assess m e nt after 
i U P D.  
-  F or n o n -tar get lesi o ns, pr o gressi ve diseas e is c o nfir me d if s u bse q ue nt i ma gi n g d o ne 
4 – 8 wee ks after i U P D, s h o ws a f urt her i ncrease fr o m i U P D.  
o  T he criteri a f or i C P D ar e n ot j u d ge d t o ha v e bee n met if R E CI S T 1. 1 criteria f or 
c o m plete res p o n se or n o n-i C R/ n o n-i U P D are met after a pre vi o us i U P D. 
-  F or ne w lesi o ns, p r o gressi ve disease is c o nfir m e d (i C P D) if t he ne xt i ma gi n g 
assess me nt, d o ne at  4 – 8 wee ks after i U P D, c o nfir ms a d diti o nal ne w lesi o ns  or a 
f urt her i ncreas e i n ne w lesi o n size fr o m i U P D (≥5 m m i ncrease i n s u m of m eas ures 
f or ne w tar get lesi o n, or a n y i n crease f or ne w n o n -tar get lesi o n). 


X4 Pharmaceuticals, Inc. 
Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
Confidential 
Page 46 of 98 
6. 
STUDY DRUG(S) 
6.1. 
Study Drug(s) and Control Description 
The investigational agent is X4P-001, which will be administered in combination with 
nivolumab (OPDIVO®), a PD-1 blocking antibody approved for the treatment of patients with 
advanced RCC who have received prior anti-angiogenic therapy.  
6.1.1. 
Acquisition 
X4P-001 will be supplied by the Sponsor. Nivolumab will be supplied by prescription from 
commercial supplies. 
6.1.2. 
Formulation, Appearance, Packaging, and Labeling 
All manufacture, packaging and labeling operations will be performed according to Good 
Manufacturing Practice (GMP) and Good Clinical Practice (GCP) guidelines, as well as US 
regulations.  
6.1.2.1. 
X4P-001 
Table 6-1: 
Physical and Chemical Properties of X4P-001 Active Ingredient (Drug 
Substance) 
Name 
X4P-001 
Drug Class 
Chemokine (C-X-C motif) receptor 4 (CXCR4) antagonist 
INN 
Not Assigned 
Molecular Formula 
C21H27N5 
Molecular Weight 
349.48 amu 
Appearance 
white to pale yellow solid 
Solubility 
X4P-001 is freely soluble in the pH range 3.0 to 8.0 (>100 mg/mL), sparingly soluble at pH 9.0 (10.7 
mg/mL) and slightly soluble at pH 10.0 (2.0 mg/mL). X4P-001 is only slightly soluble in water.  
Melting Point 
111.4°C 
 
Table 6-2: 
Formulation of X4P-001 Drug Product 
Name 
X4P-001 100 mg or 200 mg Capsule 
Active ingredient 
X4P-001 
Excipients 
Dibasic calcium phosphate dihydrate, microcrystalline cellulose, croscarmellose sodium, sodium 
stearyl fumarate, colloidal silicon dioxide, sodium lauryl sulfate 
How supplied 
Dispensing instructions will be provided in the Pharmacy Manual 
Storage 
5°C ± 3°C; Protect from light and humidity 
Administration 
Oral 
 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 4 7  of 9 8  
6. 1. 2. 2.  
Niv ol u m a b  
Please ref er t o t he p ac ka ge i nsert f or a descri pti o n of n i v ol u ma b.  
6. 1. 3.  
Pr o d uct St ora ge a n d Sta bilit y  
6. 1. 3. 1.  
X 4 P -0 0 1  
See Ta ble 6 -2 . 
6. 1. 3. 2.  
Niv ol u m a b  
Please refer t o t he pac ka ge i nsert f or n i v ol u ma b st ora ge c o n diti o ns. 
6. 1. 4.  
Pre parati o n  
6. 1. 4. 1.  
X 4 P -0 0 1  
N o ne.  
6. 1. 4. 2.  
Niv ol u m a b  
Ni v ol u ma b will be pre pare d a n d a d mi nistere d i n t he cli nic acc or di n g t o t he c urre nt p ac ka ge 
i nsert a n d i nstit uti o nal g ui deli nes. 
6. 1. 5.  
D osi n g a n d A d mi nistrati o n  
6. 1. 5. 1.  
X 4 P -0 0 1  
X 4 P -0 0 1  4 0 0 m g is a d mi nistere d P O Q D as f oll o ws:  
•  T he dail y d os e s h o ul d be ta ke n i n t he m or ni n g, at t he sa me ti me eac h da y ± 2 hr.  
•  T he i nter val bet w ee n s uccessi ve d oses  s h o ul d n ot be < 2 0 hrs. 
•  If t he i nter val b et wee n s u ccessi ve d oses is d ela ye d t o > 3 0 hrs, t he d ose s h o ul d be o mitte d 
a n d t he us ual sc he d ul e res u me d t he ne xt da y .  
•  T here s h o ul d be n o f o o d or dri n k (e x ce pt water) f or 1 h o ur pri or t o d osi n g a n d c o nti n ui n g 
u ntil  2  h o urs p ost -d ose.  
Patie nts f or w h o m t he sc he d uli n g r e q uire me nts a n d eati n g restricti o ns re prese nt si g nifica nt 
diffic ulties s h o ul d be disc usse d wit h t he Me dical M o nit or t o de vel o p t he m ost effecti ve re gi me n 
p ossi ble.   
6. 1. 5. 2.  
Niv ol u m a b  
I n v esti gat ors s h o ul d re vi e w a n d be fa miliar wit h t he c urre nt pres cri bi n g i nf or mati o n f or 
ni v ol u ma b ( Fe br u ar y 2 0 1 7 ). 
All patie nts will ha ve recei ve d ni v ol u ma b as per st a n dar d of care pri or t o e nr oll me nt t o t he st u d y. 
E nr olle d patie nts will c o nti n ue treat me nt wit h ni v ol u ma b at 2 4 0 m g e v er y 2  wee ks b y 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 4 8  of 9 8  
i ntra ve n o us (I V) i nf usi o n o ver 6 0 mi n utes usi n g  a sterile, n o n -p yr o ge ni c, l o w pr otei n bi n di n g i n -
li ne filter wit h p ore size of 0. 2 t o 1. 2 micr o meter. O t her dr u gs s h o ul d n ot be a d mi nistere d 
c o nc urr e ntl y t hr o u g h t h e sa me I V li ne.  
6. 1. 6.  
R o ute o f A d mi nistrati o n 
6. 1. 6. 1.  
X 4 P -0 0 1  
X 4 P -0 0 1 will be a d mi nistere d  P O . 
6. 1. 6. 2.  
Niv ol u m a b  
Ni v ol u ma b will be a d mi nistere d I V.  
6. 1. 7.  
D ose A dj ust me nts/ M o dificati o ns/ Dela ys  
T he pr oce d ures d etaile d bel o w s h o ul d be use d t o g ui de treat me nt m o dificati o ns i n res p o nse t o 
A Es, i ncl u di n g T L Ts a nd/ or i m m u ne -me diate d e v e nts. T he s pecifi c criteria a n d pr oce d ures 
reflect t he c urre nt ni v ol u ma b la bel, t he a vaila bl e cli nical a n d n o ncli nical e x perie nce wit h X 4 P-
0 0 1, a n d t he rec o g niti o n t hat b ot h c o m p o ne nts of t he st u d y treat me nt re gi m e n m o d ulate t he 
i m m une s yste m. Treat me nt m o dificati o ns s h o ul d be i m ple me nte d as des cri b e d. I n vesti gat ors a n d 
patie nts al wa ys ha v e t he o pti o n t o disc o nti n ue st u d y treat me nt base d o n t h eir j u d g me nt of t he 
patie nt’s best i nterests.   
N ote t hat t he Sc he d ules of E ve nts (Ta ble 1 -1 ), i ncl u di n g t he 2 8-d a y c ycl es,  are bas e d o n cale n dar 
da ys f oll o wi n g t he first d ose ( defi ne d as Da y 1). T hese sc he d ul es will n ot c ha n ge , t hat is, a d ose 
of ni v ol u ma b or X 4 P -0 0 1 t hat is hel d will be c o nsi dere d t o ha ve b ee n s ki p p e d; d ose dela ys are 
n ot per mitte d .  
F or d ose m o dificati o ns d ue t o c o nc o mita nt use of str o n g i n hi bit ors a n d i n d ucers of C Y P 3 A 4, see 
Secti o n 7. 4. 1. 1 . 
Ta ble 6 -3  dis pla ys t he treat me nt m o dificati o n g ui d eli nes i n res p o ns e t o s pecific a d vers e reacti o ns 
(A E s t hat ar e c o nsi der e d as treat me nt-relate d). T h ese g ui deli nes a p pl y t o b ot h st u d y treat me nts, 
X 4 P -0 0 1 a n d ni v ol u ma b. I n t he e ve nt of A E s, st u d y treat me nt ma y, wit h t he a gree me nt of t he 
p atie nt, t he I nvesti g at or, a n d t he Me dic al M o nit or , be ma na ge d as f oll o ws:  
•  If t he e v e nt d oes n ot  i m pr o ve t o Gra d e ≤1 wit hi n t he ne xt 6 wee ks , st u d y treat me nt will 
be per ma n e ntl y disc o nti n ue d .  
•  If t he e v e nt i m pr o ves t o Gra de ≤1 wit hi n 6 wee ks of h ol di n g st u d y treat me nt, t he patie nt 
ma y r es u me ni v ol u ma b a n d X 4 P -0 0 1 . X 4 P -0 0 1 ca n be res u me d i m me diatel y. Ni v ol u ma b 
d ose will be res u me d at t he ne xt sc he d ule d ti me. N ote t hat c o nsiste nt wit h c urre nt la b el 
rec o m me n dati o ns, ni v ol u ma b d ose re d u cti o ns are n ot per mitte d. F or A Es ≤ Gra de 2, 
X 4 P -0 0 1 ca n be  gi v e n at t he sa me d ose ( 4 0 0 m g Q D). F or A Es ≥ Gra d e 3, X 4 P -0 0 1 will 
be res u me d at a l o wer d ose ( 2 0 0 m g Q D).   


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 4 9  of 9 8  
-  If t he e v e nt rec urs t o t he sa me se verit y or great er at a ny ti me  after res u mi n g t he st u d y 
dr u gs , st u d y treat me nt will be disc o nti n ue d. 
C o nc o mit a nt m a n a ge m e nt of i m m u ne -m e di ate d re acti o ns , as defi ne d i n t he ni v ol u ma b la bel:  
•  If i m m u ne-me diate d reacti o ns occ ur, t he I n vesti gat or ma y  a d mi nister c ortic oster oi ds  at 
0. 5 t o 2 m g/ k g/ d a y pre d nis o ne e q ui vale nt , de pe n di n g o n t he n at ure a n d s e verit y of t he 
e ve nt. F or e n d ocri ne -r elate d e ve nts i nitiate h or m o ne-re pl ace m e nt t hera p y, if a p pr o priat e.  
-  U p o n i m pr o ve me nt t o Gr a de 1 or less, i nitiate c ortic oster oi d ta per a n d c o nti n ue t o 
ta per o ver at least 1 m o nt h.  
T a ble 6 -3 : 
Rec o m me n de d Tre at me nt M o dific ati o ns f or Ni v ol u m a b a n d X 4 P -0 0 1  
A d verse 
Re acti o n  
Se verit y  
Tre at me nt Re gi me n M o dific ati o n 1 
C olitis  
Gra d e 2 or 3 diarr h ea or c olitis  
Wit h h ol d d ose
2 
 
Gra d e 4 diarr h ea or c olitis  
P er ma n e ntl y disc o nti n u e  
P ne u m o nit is 
Gra d e 2 p n e u m o nitis  
Wit h h ol d d ose
2 
 
Gra d e 3 or 4 p n e u m o nitis  
P er ma n e ntl y disc o nti n u e  
He patitis  
A S T or A L T > 3 x u p t o 5 x U L N or   
t otal bilir u bi n > 1. 5 x u p t o 3 x U L N 
Wit h h ol d d ose
2 
 
A S T or A L T > 5 x U L N or   
t otal bilir u bi n > 3 x U L N 
P er ma n e ntl y disc o nti n u e  
H y p o p h ysitis  
Gra d e 2 or 3 h y p o p h ysitis  
Wit h h ol d d ose
2 
 
Gra d e 4 h y p o p h ysitis  
P er ma n e ntl y disc o nti n u e  
A dre nal 
I ns ufficie nc y 
Gra d e 2 a dre n al i ns ufficie n c y  
Wit h h ol d d ose
2 
Gra d e 3 or 4 a dre n al i ns ufficie n c y  
P er ma n e ntl y disc o nti n u e  
T y pe I Dia betes 
Mellit us  
Gra d e 3 h y p er gl yce mia  
Wit h h ol d d ose
2 
Gra d e 4 h y p er gl yce mia  
P er ma n e ntl y disc o nti n u e  
Ne p hritis / Re nal 
D ysf u ncti o n  
Ser u m creati ni n e > 1. 5 x u p t o 6 x U L N  
Wit h h ol d d ose
2 
Ser u m creati ni n e > 6 x U L N  
P er ma n e ntl y disc o nti n u e  
S ki n  
Gra d e 3 ras h  or s us p ecte d Ste ve ns -J o h ns o n 
s y n dr o me ( SJ S) or t o xic e pi d er mal n ecr ol ysis 
( T E N) 
Wit h h ol d d ose
2 
 
Gra d e 4 ras h  or c o nfir me d SJ S or T E N  
P er ma n e ntl y disc o nti n u e  
E nce p halitis  
Ne w o nset m o d erate or se vere n e ur ol o gic si g ns or 
s y m pt o ms 
Wit h h ol d d ose
2 
 
I m m u n e-me diate d e n ce p h alitis  
P er ma n e ntl y disc o nti n u e  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 5 0  of 9 8  
A d verse 
Re acti o n  
Se verit y  
Tre at me nt Re gi me n M o dific ati o n 1 
I nf usi o n 
Reacti o n  
Gra d e 1 a n d 2  
I nterr u pt or sl o w t h e rate of ni v ol u ma b i nf usi o n. Pr o vi de 
pr o p er me dicati o n a n d s y m p t o matic relief as n ee d e d. N o 
d ose m o dificati o n f or X 4 P -0 0 1 . 
Gra d e 3 a n d 4  
Disc o nti n u e ni v ol u ma b i nf usi o n i m me diatel y. Pr o vi de 
pr o p er me dicati o n a n d s y m pt o matic relief . N o d ose 
m o dific ati o n f or X 4 P -0 0 1 . 
Reti nal 
A b n or malit y  
Gra d e 1  
M o nit or cl osel y  ( N o d ose m o dific ati o ns). 
Gra d e 2  
Wit h h ol d d ose
 of X 4 P -0 0 1 . N o d ose m o dificati o n f or 
ni v ol u ma b.  
Gra d e 3 a n d 4  
P er ma n e ntl y disc o nti n u e  X 4 P -0 0 1 . N o d ose 
m o dific ati o n f or  ni v ol u ma b . 
Ot her E ve nts  
Ot h er Gra d e 3 A E  
First Occ urre n ce  
Rec urre n ce of sa me Gr a d e 3 A E  
 
Wit h h ol d d ose
2  
P er ma n e ntl y disc o nti n u e  
A n y Gra d e 4 (life -t hreate ni n g) A E  
P er ma n e ntl y disc o nti n u e  
A n y e ve nt t h at re q uires treat me nt f or > 1 2 wee ks 
wit h pre d nis o n e ≥1 0 m g/ d a y ( or e q ui vale nt)  
P er ma n e ntl y disc o nti n u e  
A n y Gra d e 2 or 3 A Es p ersisti n g ≥1 2 wee ks  
P er ma n e ntl y disc o nti n u e  
1 . Re gi me n m o dificati o ns a p pl y t o b ot h  ni v ol u ma b a n d X 4 P -0 0 1  u nless ot h er wise s p ecifie d .  
2 . See te xt f or d etails of pr o ce d ures f or res u mi n g st u d y treat me nt.  
6. 1. 8.  
D urati o n of T hera p y  
Patie nts are e x pecte d t o r ecei ve st u d y treat me nt u ntil t he earliest of:  
•  T L T eve nt  –  see Secti o n  5. 6 . 
-  F or a n y T L T e ve nt  o cc urr i n g wit hi n C ycle 1 , st u d y treat me nt will  be disc o nti n ue d  
per ma ne ntl y.  
-  F or T L T e ve nts  occ urri n g after C ycle 1 , pr o visi on is ma de f or d ose i nterr u pti o n (see 
Secti o n  6. 1. 7 ).  
•  P D –  see Secti o n  5. 7 . 
6. 1. 9.  
Tr eat me nt C o m plia nce  
Treat me nt c o m plia nce wit h X 4 P -0 0 1 will be m o nit ore d b y 2 pr oce d ures.  
•  Patie nts will be pr o vi de d wit h treat me nt diar y t o rec or d ti me a n d d ose le v el ta ke n f or 
b ot h X 4 P -0 0 1,  as well as ti me of last f o o d pri or t o a n d after d osi n g X 4 P -0 0 1. Diaries will 
be re vie w e d wit h t he pati e nt at eac h cli nic visit.  
•  X 4 P -0 0 1 will be dis pe nse d i n b ottles, w hic h will be e x a mi ne d vis uall y at eac h cli nic 
visit; n o n -destr ucti ve pill c o u nts will b e perf or m e d if i n dicate d.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 5 1  of 9 8  
6. 2.  
St u d y Dr u g  Acc o u nt a bilit y Pr o ce d ures  
T he U S F D A a n d ot her a p plica ble re g ulat or y a ut h orities re q uire acc o u nti n g of all i n vesti gati o nal 
dr u g recei ve d b y eac h st u d y ce nter . Rec or ds of dr u g dis p ositi o n re q uire d i ncl u de t he date 
receiv e d b y t he ce nter, d ate a d mi nistere d, q u a ntit y a d mi nistere d, a n d t he p atie nt t o w h o m st u d y 
dr u g was a d mi nistere d . T he I n vesti gat or is res p o nsi ble f or t he acc o u nta bilit y of all use d a n d 
u n use d st u d y dr u g c o ntai ners a n d u n use d st u d y dr u g . F or t he C o m bi nati o n  C o h ort(s), t he st u d y 
ce nter als o will mai ntai n rec or ds f or t he c o m bi nati o n a ntica ncer a ge nt, i ncl u di n g t he dat e 
a d mi nistere d, q ua ntit y a d mi nistere d, a n d t he patie nt t o w h o m t he a ge nt was a d mi nistere d.  
Eac h st u d y ce nt er is t o use a st u d y dr u g acc o u nta bilit y l o g t o d oc u m e nt st u d y dr u g dis p ositi o n . 
All ite ms o n t his f or m are t o be c o m plete d i n f ull . T he S p o ns or’s cli nical researc h ass oci ate 
( C R A) is t o a p pr o ve t he area w her e st u d y dr u g is t o be st ore d a n d acc o u nta bilit y rec or ds are t o 
be mai ntai ne d.  
T he i n ves ti gat or i de ntificati o n n u m ber a n d patie nt i nitials (as all o we d b y l o cal re g ulati o ns) a n d 
i de ntificati o n n u m ber ar e t o be rec or de d o n eac h st u d y dr u g acc o u nta bilit y l o g. Eac h ti me st u d y 
pers o n nel dis pe nse st u d y dr u g f or a p atie nt, he or s he is t o rec or d t he  d ate dis pe nse d, a m o u nt of 
st u d y dr u g dis pe nse d, a n d his or her i nitials. St u d y pers o n nel are t o m o nit or t he i n ve nt or y of 
cli nical s u p plies a n d mai ntai n a c o u nt of all use d a n d u n use d st u d y dr u g . T he C R A is t o re vie w 
st u d y dr u g acc o u nta bilit y rec or ds a n d re m ai ni n g dr u g s u p plies d uri n g r o uti ne m o nit ori n g visits.  
At t he c o m pleti o n of t he st u d y, t he site m ust o btai n writte n a ut h orizati o n fr o m t he S p o ns or 
re gar di n g t he fi nal dis p ositi o n of a n y re mai ni n g X 4 P -0 0 1 ; t hat dis p ositi o n m ust be a p pr o priatel y 
d oc u me nte d . T y pical pr o ce d ures f or ha n dli n g a n y re mai ni n g st u d y dr u g i n cl u de t he f oll o wi n g: 
•  Ret ur ni n g st u d y dr u g t o t he S p o ns or .  
•  Destr o yi n g st u d y dr u g at t he st u d y site acc or di n g t o t he site’s i nstit uti o nal sta n dar d 
o perati n g pr oce d ure . 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 5 2  of 9 8  
7.  
S T U D Y P R O C E D U R E S A N D S C H E D U L E  
7. 1.  
St u d y Pr oce d ures/ E v al u ati o ns  
Ta ble 1 -1  det ails t he sc he d ules f or all st u d y e val uati o ns.  
T he sc he d ule is pr ese nte d relati ve t o  c ycl e, d a y wit hi n cycle, a n d ti me of d osi n g . Eac h c ycl e 
re pres e nts 4 wee ks ( 2 8 d a ys). T he cale n dar da y o f t he first a d mi nistrati o n of X 4 P -0 0 1 is  
desi g nat e d C ycle  1, D a y 1.  Pre - a n d p ost -d ose i nter vals are  relati ve t o t he ti me of oral 
a d mi nistrati o n of X 4 P -0 0 1, desi g n ate d 0 hr.  
7. 1. 1.  
Baseli ne a n d Safet y Ass ess me nts  
Writte n i nf or me d c o nse nt will be o btai ne d a n d t he  c o nse nt pr oce d ure rec or de d i n s o urce 
d oc u me ntati o n bef or e a n y ot her st u d y -s p ecific pr oce d ures are p erf or me d.  
7. 1. 1. 1.  
E nr oll me nt Pr oce d ure  
E nr oll me nt i n t his pr ot oc ol will be o pe n acr oss all acti vate d sites. At t he dis creti o n of t he 
S p o ns or, a site t hat e nr olls ≥6 ( 3 0 %) of t he a ntici pate d 2 0 patie nts ma y be ca p pe d.  
T he f oll o wi n g pr oce d ure is i m ple me nte d t o ass ure t hat eli gi bilit y of all patie nts is re vie we d a n d 
a p pr o ve d b y t he S p o ns or ( or re prese ntati ve, e. g., Me dical M o nit or). Site pers o n nel will access a n 
i nteracti ve v oice- or w e b -base d e nr oll me nt s yste m, c o nfir m eli gi bilit y, a n d i n dicate t hat t he 
patie nt is bei n g pr o p os e d f or e nr oll me nt  (f or details, i ncl u di n g re q uire me nts f or e C R F dat a e ntr y, 
refere nce t he st u d y o per ati o n al m a n ual). I n t he e v e nt of a n y discre pa nci es or ot her iss ues, t he 
re q uest will be referre d t o t he Me dical M o nit or or desi g nat e d st u d y p ers o n nel f or re vi e w.  
After acce pta nce, t he I n v esti gat or a n d site p har m ac y will be pr o vi de d writt e n c o nfir mati o n ( b y 
e mail a n d/ or fa x) of t he p atie nt’s acce pta nce f or e nr oll me nt. E nr oll me nt will be defi ne d as 
c o m pleti n g bas eli ne e val uati o n a n d recei vi n g at least o ne d ose of X 4 P -0 0 1 . 
7. 1. 1. 2.  
De m o gr a p hics a n d M e dic al Hist ory  
Ge ner al Me dic al Hist or y  
A c o m plete me dical hist or y is t o be d o c u me nte d d uri n g Scree ni n g, i ncl u di n g rele va nt ge n eral 
me dical a n d s ur gical hist or y, c urr e nt or past a b n or malities or diseases of t h e f oll o wi n g s yste ms: 
aller gic (i ncl u di n g dr u g s e nsiti vit y), car di o vasc ular, der mat ol o gic, e n d o cri n e/ meta b olic, 
gastr oi ntesti nal, g y n ec ol o gic, h e mat ol o gi c/l y m p h atic, he patic/ biliar y, i m m u n ol o gic, i nfecti o us, 
m usc ul os keletal, ne ur ol o gic/ ps yc hiatric, re n al, a n d res pirat or y.  
T he me dical hist or y s h o ul d i ncl u de all si g nifica nt ill nesses a n d h os pitalizati o ns t hat occ urre d i n 
t he past 6 m o nt hs, w het her acti ve or res ol v e d. Ill nesses acti ve at t he ti me of i nf or me d c o ns e nt 
will be rec or d e d i n t he m e dical hist or y.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 5 3  of 9 8  
Hist or y of Re n al Cell C arci n o m a ( R C C)  
Detaile d hist or y of t he c o urse of t he patie nt’s R C C will be rec or d e d, i ncl u di n g:  
•  Pri or s ur gical  pr oce d ures, dia g n ostic or t h era p e utic.  
•  Res ults ( p ositi ve a n d ne gati ve) of pri or tiss ue bi o psies.  
•  Pri or me dical treat me nts (i ncl u di n g s u p p orti ve t hera p y) –  a ge nt, d urati o n, b est cli nical 
res p o nse, a d v erse e ve nts relate d t o treat me nt, a n d reas o n f or disc o nti n uati o n. 
•  H os pitalizati o ns f or cli nicall y si g nifica nt c o m plicati o ns of t he treat me nts or t he 
mali g na n c y, e. g., s yste mi c i nfecti o ns, blee di n g.  
•  Hist orical t u m or meas ure me nts fr o m pri or t o starti n g ni v ol u ma b t hr o u g h t h e scree ni n g 
peri o d.  
7. 1. 1. 3.  
Vit al Si g ns  
Vital si g ns i ncl u de heart rate ( H R), bl o o d press ure ( B P),  a n d t e m perat ure . W here feasi ble, vital 
si g ns s h o ul d be meas ure d bef ore bl o o d is dra w n a n d after t he p atie nt has b ee n sitti n g 
c o mf orta bl y f or 5 mi n utes wit h t he B P c uff i n place o n t he n o n -d o mi na nt ar m. B P a n d H R 
meas ure me nts will be ta k e n first a n d ma y be d o n e ma n uall y or b y a ut o mate d rec or d er. 
Te m perat ur e will be o btai ne d usi n g a n electr o ni c (ra pi d rea di n g) de vice.  
Vital si g n meas ur e me nts will be assesse d b y t he In vesti gat or as eit her ‘ n or mal’, ‘a b n or mal, n ot 
cli nicall y si g nifica nt’, or ‘a b n or mal, cli nicall y si g nifica nt’. Cli nicall y si g nifica nt a b n or m al vital 
si g n meas ure me nts will be re p ort e d as a n A E , a n d, if p ossi ble, s h o ul d be re peate d at cli nicall y 
rele va nt i nter v als u ntil res ol ve d or sta bilize d.  
7. 1. 1. 4.  
P hys ic al Ex a mi n ati o n a n d B o dy Wei g ht 
C o m plete p h ysical e x a mi nati o ns will i ncl u de meas ure me nt of b o d y w ei g ht a n d e x a mi nati o n of 
ge n eral a p peara n ce, s ki n, nec k (i ncl u di n g t h yr oi d), e yes, n ose, t hr o at, heart, l u n gs, a b d o me n, 
l y m p h n o des, e xtre mities, a n d ner v o us s yste m. B o d y hei g ht will be meas ure d at scree ni n g o nl y.  
•  F or pal pa ble l y m p h n o d es, t he l ocati o n a n d ma xi mal li near di me nsi o n will be  rec or de d at 
eac h e x a mi nati o n.  
•  E x a mi nati o n of t he re pr o d ucti ve s yste m will be p erf or me d if t here are relat e d s y m pt o ms, 
a d verse e ve nts, or rece nt hist or y; t he e x a m ma y be perf or me d b y t h e  I n vesti gat or or 
dele gate d t o a s p ecialist.  
P h ysical e x a mi nati o n fi n d i n gs will be assess e d b y t he In v esti gat or as eit her ‘ n or mal’, ‘a b n or mal, 
n ot cli nicall y si g nifica nt’, or ‘a b n or mal, cli nicall y si g nifica nt’. A n y cli nicall y si g nifica nt c h a n ges 
i de ntifie d after t h e baseli ne (scr ee ni n g) e x a mi nati o n will be rec or d e d as A E s (see Secti o n  8 ). 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 5 4  of 9 8  
7. 1. 1. 5.  
O p ht h al m ol o gic Ex a mi n ati o n  
O p ht hal m ol o gic e x a mi nati o n s will be perf or me d as sc he d ule d a n d i ncl u d e t he f oll o wi n g 
ele me nts: assess me nt of vis ual ac uit y ( usi n g S nell e n test), refracti o n (at sc ree ni n g o nl y), 
assess me nt of c ol or visi o n, slit la m p e x a mi nati o n, a n d reti nal e x a mi nati o n wit h p h ot o gra p hs. 
Please ref er t o t he st u d y o perati o nal ma n ual f or d etails. All e x a mi nati o n re p orts a n d p h ot o gra p hs 
will be s u b mitte d t o a ce ntral re p osit or y as s o o n as feasi ble after bei n g p erf or me d t o be re vi e we d 
f or q ualit y a n d c o m plete ness (see st u d y o perati o nal ma n ual f o r d etails). 
Reti nal a b n or malities n ote d at scr ee ni n g will be disc usse d wit h t he Me dical M o nit or. 
E x a mi nati o n b y a s ec o n d o p ht hal m ol o gist ma y b e re q ueste d t o c o nfir m t he descri pti o n of t he 
fi n di n gs a n d t he a de q u ac y of t he p h ot o gra p hs. E nr oll me nt ma y pr ocee d wit h t he a p pr o val of t h e 
Me dical M o nit or.  
A n y p atie nt re p ort e d t o ha ve treat me nt -e mer ge nt fi n di n gs of reti n o pat h y will be e x a mi ne d b y a 
sec o n d op ht hal m ol o gist.  
All e x a mi nati o n re p orts a n d p h ot o gr a p hs ma y be re vie we d b y a n i n de pe n d e nt, bli n de d 
o p ht hal m ol o gist desi g n ate d b y t h e S p o ns or.  
7. 1. 1. 6.  
E C O G Perf or m a nce St at us ( P S)  
T he E C O G P S will be o btai ne d b y q uesti o ni n g t he patie nt a b o ut t heir f u ncti o nal ca pa bi lities, 
acc or di n g t o  T a ble 7 -1 . 
T a ble 7 -1 : 
E C O G P S Defi niti o ns  
Gr a de  E C O G Perf or m a nce St at us  
0  
F ull y acti ve, a ble t o carr y o n all 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 -c are, 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 carr y o n a n y self -care. T otall y c o nfi ne d t o be d or c hair  
5  
Dea d  
 
7. 1. 1. 7.  
Electr oc ar di o gr a m  
Sta n dar d 1 2 -lea d E C G will be o btai ne d after t he p atie nt has bee n s e mi-rec u m be nt f or 
~ 1 0  mi n utes. T he f oll o wi n g E C G para meters will be rec or de d: ve ntri c ular  rate, R R i nter val, P R 
i nter val, Q R S i nter val, Q T i nter val, Q Tc i nter val, a n d Q Tc met h o d . 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 5 5  of 9 8  
7. 1. 2.  
P har mac o ki netic Assess me nts  
P K sa m ples will be o btai ne d o n all patie nts as f oll o ws:  
•  C ycle 1, Da y 1: pre -d ose o nl y  (-3 0 mi n)  
•  C ycle 1, Da y 8: pre -d ose o nl y (-1 0 mi n)  
•  C ycle 1, Da y 1 5: pre -d os e o nl y (-1 0 mi n)  
•  C ycle 1, Da y 2 2: pre -d os e  (-1 0 mi n) ; p ost-d ose at 6 0, 9 0 mi n (eac h ± 1 0 mi n) a n d 2, 3, 4, 
8 hr (eac h ± 1 5 mi n)  
•  C ycle 3, Da y 1: pre -d ose o nl y  (-1 0 mi n)  
T hese visits will be sc he d ule d f or earl y i n t he da y a n d patie nts will be i nstr ucte d t o arri v e at t he 
cli nic fasti n g a n d ha vi n g n ot ta ke n t heir d ose of X 4 P-0 0 1.  
If res ults s u g gest eit her ( a) o n g oi n g acc u m ulati o n or ( b) s pecific e x p os ures ass ociate d wit h 
a d verse eff ects, t he n a d diti o nal P K sa m ples ma y b e c ollecte d.  
Sa m ples will be a nal yze d f or X 4 P -0 0 1  c o n ce ntrati o n usi n g re v erse d-p hase hi g h perf or ma n ce 
li q ui d c hr o mat o gr a p h y wit h ta n de m mass s pectr o metr y d etecti o n.  
7. 1. 3.  
P har mac o d y na mic  Ass ess me nts  
In v esti gati o nal assa ys will be perf or me d b y a ce ntral la b orat or y d esi g nate d b y t he S p o ns or; t o 
ma xi mize c o nsiste nc y,  tests ma y be b atc he d. T h e cli nical si g nifica nce of t h ese tests is u n k n o w n 
at t his ti me, a n d t he res ults will n ot be assesse d b y t he In v esti gat or.  
7. 1. 3. 1.  
Bl o o d  S a m ples  
W h ole bl o o d sa m ples f or p har mac o d y n a mic  a nal ysis will be o btai ne d c o nc urre ntl y wit h 
sc he d ule d PK sa m ples o n C ycle 1 Da y  2 2 o nl y (s ee Secti o n 7. 1. 2 ) a n d s e nt t o t he l ocal 
la b orat or y f or W B C c o u nts, i ncl u di n g A N C a n d A L C .  
I n a d diti o n, P B M C a n d ser u m sa m ples will be c ollecte d as sc h e d ule d a n d assa ye d  b y a ce ntral 
la b orat or y f or p ote ntial tr eat me nt- a n d t u m or-relat e d bi o mar kers  (Ta ble 7 -2 ).  
T a ble 7 -2 : 
C a n di d ate Bl o o d Bi o m ar kers  
Ser u m  
P B M C [ T ar hi ni 2 0 1 4 ] 
C X C L 1 2  
V E G F  
Tre g l y m p h oc ytes  
Acti vate d T cells  
M D S Cs  
 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 5 6  of 9 8  
7. 1. 3. 2.  
Tiss ue  Bi o m arkers  
If a vaila bl e, u nstai ne d sli des pre pare d fr o m f or mali n fi x e d paraffi n e m be d d e d ( F F P E) t u m or 
sa m ples fr o m t he patie nt’s m ost rece nt t u m or sa m pli n g will be c ollecte d a n d a nal yze d f or 
bi o mar kers t hat are p ote ntiall y ass ociat e d wit h  se nsiti vit y a n d resista nce t o c o m bi nati o n 
treat me nt wit h X 4 P-0 0 1 a n d ni v ol u ma b. Ca n di date mar kers i ncl u de C X C R 4 , C X C L 1 2 , C D 3, 
C D 8, a n d m yel oi d mar kers; a d diti o nal or alter nati ve bi o mar kers ma y b e e x pl ore d usi n g t he 
sa m ples o btai ne d f or bi o mar ker a nal ysis.  
A p pr o xi matel y 1 2 5 μ m  of t u m or sa m ple is re q uire d f or t his p ur p ose. Directi o ns f or pr ocessi n g 
t he arc hi ve d F F P E  bl oc ks are i ncl u de d i n t he st u d y  la b orat or y ma n u al ; briefl y, 15 ( 5 micr o n 
sli des) a n d 5  ( 1 0 micr o n sli des) are r e q ueste d.  
7. 1. 4.  
Efficac y Assess me nts  
7. 1. 4. 1.  
R a di ol o gic Assess me nt  of cc R C C   
Ra di ol o gic i ma gi n g of c h est, a b d o me n a n d pel vis f or assessi n g t u m or stat us a n d treat me nt effect 
will be perf or me d as i n dicate d i n t he Sc he d ul es of E ve nts. I nteri m assess m e nts  ma y b e d o ne  at 
t he re q uest of t he I n vesti gat or b ase d o n n e w fi n di n gs. Patie nts e nr olle d wit h a hist or y or c urre nt 
e vi de nce of C N S disease will ha ve brai n i ma gi n g b y ma g n etic res o n a nce i ma gi n g ( M RI) wit h 
c o ntrast at baseli ne a n d, t hereafter, as cli nicall y i n dicate d.  
I ma gi n g will be i nter pret e d usi n g R E CI S T  v 1. 1 [Eise n ha uer 2 0 0 9 ] (see Secti o n  7. 1. 4. 2 ). T he 
e x pecte d i ma gi n g tec h n ol o g y is C T wit h slice t hic k ness ≤5 m m a n d c o ntrast. T he use of 
alter nati ve tec h n ol o gi e s ( e. g., C T s ca n wit h slice t hic k ness > 5  m m or M RI) re q uires t he a p pr o val 
of t he Me dical M o nit or  a n d m ust be perf or me d i n a ma n ner c o nsiste nt wit h R E CI S T. F or eac h 
patie nt, t he i ma gi n g m o d alit y s h o ul d be c o nsiste nt t hr o u g h o ut t he st u d y. If t here is a n ee d t o 
c ha n ge m o dalit y (e. g., a patie nt ca n n ot recei ve ra di ol o gic c o ntrast), a n alter nati ve m o dalit y ma y 
be use d wit h t he a p pr o v al of t he Me dical M o nit or.  
F or cli nical ma n a ge me nt d uri n g t he st u d y, i ma gi n g will be i nter prete d b y t he ra di ol o gist at t he 
site; h owe ver, patie nts w h o, i n t he j u d g me nt of t h e I n vesti gat or, ha v e deri ve d cli nical be nefit 
ma y c o nti n ue t o recei ve st u d y treat me nt u ntil cli nical deteri orati o n (see S ecti o n  5. 7. 1 ).  
7. 1. 4. 2.  
Ev al u ati o n of Res p o nse t o Tre at me nt a n d Dise ase St at us  
T u m or Res p o nse . Ra di ol o gic assess me nts  will be c o n d ucte d e v er y ei g ht ( 8) wee ks (e ver y ot her 
c ycle) d uri n g t h e first 1 2 m o nt hs; e ver y 1 2 wee ks (e ver y t hir d c ycle) t hereafter; at E O T (if n ot 
perf or me d i n t he pri or 4 wee ks);  or  as i n dicate d b ase d o n ne w si g ns, s y m pt o ms or la b orat or y 
fi n di n gs. Disease stat us, ti me t o pr o gr essi o n, d urati o n of res p o nse, a n d P F S will be deter mi ne d 
base d  o n R E C I S T v 1. 1 [Eise n ha uer 2 0 0 9 ]. Treat me nt decisi o ns will be ma de b y t he I n v esti gat or 
i nc or p orati n g t he l ocal ra di ol o g y i nter pretati o n a n d, if necessar y, c o ns ultati o n wit h t he Me dical 
M o nit or (see Secti o n 5. 7. 1 ). Patie nts e nr olle d wit h a hist or y or c urre nt e vi d e nce of C N S disease 
will ha ve brai n i ma gi n g b y M RI wit h c o ntrast at baseli ne a n d, t hereafter, as cli nicall y i n dicate d.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 5 7  of 9 8  
I n a d diti o n t o t he ra di ol o gic assess me nts c ollecte d w hile o n st u d y, a n eff ort will be ma de t o 
c ollect i ma gi n g st u dies a n d/ or t u m or meas ure me nts o ver t he peri o d fr o m t he start of treat me nt 
wit h ni v ol u ma b u ntil e nr oll me nt i n t his st u d y.  
T he c urr e nt ( v 1. 1) R E CI S T  pr o vi de a detaile d pr o cess f or usi n g se q u e ntial C T i ma gi n g t o 
classif y t u m or res p o nse [ Eise n ha uer 2 0 0 9 ]. Ke y ele me nts of t he pr ocess are s u m marize d bel o w; 
details pr o vi de d i n t he g ui deli ne  re mai n deter mi nati ve. N O T E: all s pecifica ti o ns ass u me use of 
C T wit h slice t hic k ness ≤5 m m.  M o dificati o ns are re q uire d f or ot her tec h n ol o gies.  
Defi niti o ns of ke y ter mi n ol o g y:  
•  Meas ura ble n o n -n o dal lesi o ns –  ≥1 0 m m i n l o n gest dia meter.  
•  Meas ura ble n o dal lesi o ns –  ≥1 5 m m i n s h ort a xis  
•  N o n meas ura bl e  lesi o ns –  lesi o ns t hat are s maller, i ncl u di n g t h ose t hat ca n n ot be 
meas ure d.  
•  Meas ura ble dis ease –  prese nce of at least o ne meas ura ble lesi o n. [ N O T E: E ntr y i nt o t his 
st u d y re q uires at least o ne meas ura ble e xtra -re nal lesi o n.] 
•  Tar get lesi o ns –  At baseli ne,  a ma xi m u m of 5 meas urea ble lesi o ns, n o m ore t ha n 2 f or 
a n y i n di vi d ual or ga n, s h o ul d be i de ntifie d, d oc u me nte d, a n d t he a p pr o priate dia meter of 
eac h r ec or de d. Lesi o ns s h o ul d be selecte d b ase d o n size, be re pres e ntati ve of disease, a n d 
be s uita ble f or r e pr o d uci ble re peat meas ure me nt. Tar get lesi o ns ma y i ncl u de meas ura ble 
l y m p h n o des. 
•  T he baseli ne s u m of  dia meter s ( S O D) –  T h e s u m of t he l o n gest dia meters f or all n o n -
n o dal tar get lesi o ns pl us t he s u m of t he s h ort a xis dia meter f or all n o dal tar get lesi o ns.  
•  N o n -tar get lesi o ns –  All ot her lesi o ns prese nt  at b aseli ne, i ncl u di n g p at h ol o gic n o d es 
( defi ne d as n o des > 1 0 m m i n s h ort a xis). T hese s h o ul d be d oc u me nte d ( q u a ntitati ve 
m eas ure me nts are n ot r e q uire d) s o t hat t he y ca n b e classifie d o n f oll o w -u p as prese nt, 
a bse nt, or u ne q ui v ocal pr o gr essi o n.  
•  Ne w lesi o ns –  a ne w lesi o n s h o ul d be u ne q ui v ocal (e. g., n ot attri b uta ble t o variati o n i n 
tec h ni q ue); i ncl u des lesi o ns i n a l ocati o n n ot  sca n n e d at baseli ne.  
•  Defi niti o ns of res p o nse criteria f or t ar get a n d n o n -tar get lesio ns are s u m marize d i n Ta ble 
7 -3 ; t hese ar e i nte grate d i nt o a n o verall res p o nse assess me nt as s u m marize d i n Ta bl e 7 -4 . 


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P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 5 8  of 9 8  
T a ble 7 -3 : 
R E CI S T –  Defi niti o ns of Res p o nse C ate g ories f or T ar get a n d N o n -T ar get 
Lesi o ns  
T ar get Lesi o ns  
 
C o m plete Res p o nse ( C R)  (a) Disa p peara nce of all n o n-n o dal lesi o ns, a n d  ( b) A bse nce of pat h ol o gic l y m p h n o des1. 
P artial Res p o nse ( P R)  
≥3 0 % decrease fr o m baseli ne i n t he S O D of t he tar get lesi o ns  
Sta ble Disease ( S D)  
P ersisti n g disease t hat d oes n ot meet criteria f or eit her P R o r P D 
Pr o gressi ve Disease ( P D)  a) ≥2 0 % i ncrease i n t he S O D of t he tar get lesi o ns, c o m pare d t o t he s mallest s u m o n st u d y, 
w hic h ma y be eit her at  baseli ne or  w hile o n treat me nt;  
a n d  ( b) a n a bs ol ute i ncrease of ≥5 m m i n t he S O D.  
N o n -T ar get Lesi o ns  
 
C o m plete Res p o nse ( C R)  (a) Disa p peara nce of all n o n-t ar get lesi o ns, a n d  ( b) A bse nce of pat h ol o gic l y m p h n o des1. 
N o n -C R/ n o n -P D  
P ersiste nce of o ne or m ore n o n -tar get lesi o ns 
Pr o gressi ve Disease ( P D)  U ne q uiv oc al pr o gressi o n  of e xisti n g n o n -tar get lesi o ns.  
1 . All l y m p h n o des, w het her or n ot desi g nate d tar get or n o n -tar get lesi o ns, ha ve s h ort a xis dia meter ≤1 0 m m 
T a ble 7 -4 : 
R E CI S T –  O ver all Res p o nses  B ase d o n T ar get Lesi o ns, N o nt ar get Lesi o ns, 
a n d Ne w Lesi o ns  
T ar get  
Lesi o ns  
N o n -t ar get  
Lesi o ns  
Ne w  
Lesi o ns  
O ver all  
Res p o nse  
C R  
C R  
N o  
C R  
C R  
N o n -C R/ n o n -P D  
N o  
P R  
C R  
N ot e val uate d  
N o  
P R  
N o n -P D or n ot all e val uate d  
N o  
S D  
N o n -P D or n ot all e val uate d  
N o  
S D  
N ot all e val uate d  
N o n -P D  
N o  
N o n -e val ua ble  
C R, P R, or S D  
P D 1 
N o  
 
P D  
A n y  
Yes or n o  
P D  
A n y  
A n y  
Yes  
 
1.  “ T he desi g n ati o n of o verall pr o gressi o n s olely o n t h e b asis of c h a n ge i n n o n -tar get disease” i n t h e face of C R, P R, or S D of 
tar get lesi o ns is e x p ecte d t o b e “e xtre mel y r are” [Eise n h a u er 2 0 0 9 ]. 
7. 1. 4. 3.  
Ex pl or at ory A n alysis of Effic acy Usi n g i R E CI S T  
T u m or res p o nse assess me nts ma y b e e x pl ore d b y usi n g t he i R E CI S T [Se y m o ur  2 0 1 7 ]. Details of 
t his assess me nt will be defi ne d i n statistical a nal ysis pla n ( S A P) a n d/ or stu d y  o perati o nal 
ma n ual . 


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C o nfi de ntial  
P a ge 5 9  of 9 8  
7. 2.  
L a b or at or y Pr oce d ures/ E v al u ati o ns  
7. 2. 1.  
Cli nical La b or at or y E val uati o ns  
T he la b orat or y s afet y tests liste d i n Ta ble 7 -5  will be perf or me d as s c he d ule d b y a ce ntral 
la b orat or y f acilit y. T h e I n vesti gat or m a y or der a d diti o nal l ocal la b orat or y t ests c o nsiste nt wit h 
t heir r o uti ne sta n dar d of care.  
T a ble 7 -5 : 
S af et y L a b or at or y Tests  
He m at ol o g y P a nel  
 
He mat ocrit  
W B C differe ntial  a n d a bs ol ute cell c o u nts: 
He m o gl o bi n  
Bas o p hils  
Platelet c o u nt  
E osi n o p hils  
W B C c o u nt  
L y m p h oc ytes  
 
M o n oc ytes  
 
Ne utr o p hils  
Cli nic al C he mistr y P a nel  
 
A L T  
Gl uc ose  
Al b u mi n  
I n or ga nic p h os p h or us 
Al kali ne p h os p hatase  
Li pase  
A m ylase  
Ma g nesi u m  
A S T  
P otassi u m  
Bicar b o nate  
S o di u m  
Calci u m  
T BI L * *  
C hl ori de  
T otal pr otei n  
Creati ne ki nase  ( C K) 
Urea  
Creati ni ne *  
Uric aci d  
* Creati ni ne cleara n ce will b e calc ulate d usi n g t h e met h o d of C o c kcr oft a n d Ga ult ( C o c kr oft, Ga ult, 1 9 7 6).  
* * If t he t otal bilir u bi n c o n ce ntrati o n is a b o ve 1. 5 ti mes t h e u p p er li mit of n or mal, direct a n d i n direct bilir u bi n s h o ul d b e  
differe ntiate d.  
C o a g ul ati o n P a nel  
 
Acti vate d partial t hr o m b o plasti n ti me  
I nter nati o nal n or malize d rati o 
Uri n al ysis  
 
Bl o o d (c o m mercial di pstic k ma y be use d)  
p H  
Gl uc ose  
Pr otei n  
Ket o nes  
S pecific gra vit y  
Micr osc o pic e xa mi nati o n, i ncl u di n g q ua ntitati o n of 
W B Cs, re d bl o o d cells, a n d casts  
 
T h yr oi d F u ncti o n Tests ( P arts A a n d B o nl y)  
 
Free t h yr o xi n  
T h yr oi d sti m ulati n g h or m o ne  


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C o nfi de ntial  
P a ge 6 0  of 9 8  
P re g n a nc y tests ( W O C P  o nl y)  
 
be ta-h u ma n c h ori o nic g o na d otr o pi n  
Ser ol o gic tests ( Scree ni n g o nl y)  
 
H Bs A g  
 
A nti b o d y t o H C V  
 
7. 2. 1. 1.  
Re p orti n g of S afety L a b or at ory Tests  
R es ults of safet y la b orat or y tests ( e x ce pt ser ol o g y) are e x pecte d t o b e a vaila ble t o t he 
In v esti gat or wit hi n 4 8 h o urs. Pr oce d ur es f or t he In vesti gat or assess me nt of t he res ults are 
detaile d i n Secti o n  8. 1. 5 . Pr oce d ures f or t he a nal ysis of la b orat or y dat a are descri be d i n Secti o n  
8. 2. 2 .  
7. 2. 1. 2.  
R e pe ati n g A b n or m al L a b or at ory Tests  
La b orat or y tests s h o wi n g a b n or mal or e x cl usi o nar y val u es at Scree ni n g  ma y be re peate d n o m ore 
t ha n o nce; h o we v er, e x cl usi o nar y s er ol o gic res ults ma y n ot be re peate d .  
After d osi n g, a b n or m al la b orat or y tests ass esse d as “cli nicall y si g nifica nt” val ues ma y be 
re peat e d as ofte n as dee me d cli nicall y n ecess ar y b y t he I n vesti gat or u ntil t he test val ues are 
cli nicall y acce pta ble or u ntil a n e x pla nati o n ot her t ha n  dr u g effect is gi ve n.  
7. 2. 2.  
Ot her Assa ys or Pr o ce d ures  
N o ne.  
7. 2. 3.  
S peci me n Pre par ati o n, H a n dli n g, a n d St ora ge  
La b orat or y s a m ples ar e t o be pre pare d, h a n dle d, a n d st ore d as i nstr ucte d i n t he la b orat or y 
ma n ual.  
7. 2. 4.  
S peci me n S hi p me nt  
La b orat or y s a m ples ar e t o be s hi p pe d as i nstr ucte d i n t he la b orat or y ma n u al. 
7. 3.  
S tu d y S c he d ule 
T he sc he d ule of e ve nts is prese nte d i n  Ta bl e 1 -1 . 
•  N ote: i n all c o nte xts, “ da ys ” ref ers t o cal e n dar d a ys.  
•  Scree ni n g will be d o ne wit hi n 2 8 da ys pri or t o Da y 1 (t he first d ose of st u d y dr u g). See 
Ta ble 1 -1  f or details of s cree ni n g a n d Secti o n 7. 1. 1. 1  f or details of t he e nr oll me nt 
pr ocess.  
•  Assess me nts f or treat me nt res p o nse ( or  P D ) are sc he d ule d e v er y 8 w ee ks (± 4 cale n dar 
da ys) d uri n g t he first 1 2 m o nt hs of treat me nt a n d e ver y 1 2 w ee ks (± 4 cale n dar da ys) 
t hereafter (s ee Secti o ns 5. 7  a n d 7. 1. 4 ). 


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C o nfi de ntial  
P a ge 6 1  of 9 8  
•  E O T visit will be perf or me d wit hi n 6 da ys a fter t he last d ose of st u d y dr u g or t he d ecisi o n 
t o ter mi nate treat me nt pr e mat urel y. 
•  E O S visit, t he fi nal st u d y e ve nt, will be perf or me d 3 0  da ys  (± 4 cale n d ar d a ys)   after t h e 
last d ose of st u d y dr u g. I n t he e ve nt t he E O T visit is dela ye d, t he E O S visit will be 
perf or me d at least 1 4 da ys after t he E O T visit.  
•  E xte nsi o n P hase: Pr o visi o n is ma de f or t he S p o ns or t o a nal yze t h e st u d y d ata after all 
e nr olle d patie nts ha v e c o m plete d at least 1 2 m o nt hs of treat me nt. Patie nts recei vi n g st u d y 
treat me nt at t hat ti me ma y c o nti n ue t o recei ve treat me nt d uri n g a n e xte nsi o n p hase of t he 
pr ot oc ol, wit h a n a dj uste d sc he d ule of assess me nts a n d li mite d ce ntral data c ollecti o n 
(see Secti o n 7. 3. 1  f or det ails). 
7. 3. 1.  
E xte nsi o n P hase  
Pr o visi o n is ma de f or perf or mi n g t he fi nal a nal ysis f or t he st u d y pr o vi de d all of t he f oll o wi n g 
criteria are met:  
•  E nr oll me nt has bee n cl os e d.  
•  All o n g oi n g patie nt s ha v e c o m plete d at least 1 2 m o nt hs of st u d y treat me nt.  
•  All o n g oi n g patie nt s ar e cli nicall y sta ble ( or i m pr o ve d) at t heir last e v al uati o n.  
If t he S p o ns or elects t o a nal yze t he st u d y data pri or t o t he disc o nti n uati o n of all patie nt s, o n g oi n g 
patie nt s will e nter t he e xte nsi o n p hase of t he st u d y a n d ma y c o nti n ue t o recei ve st u d y dr u g u ntil 
P D or u nacce pta ble t o xicit y, w hic he v er occ urs first (see S ecti o n 5. 4. 1  f or treat me nt termi nati o n 
criteria). T he patie nt’s p artici pati o n i n t he e xte nsi o n p hase will be c o m plete w he n st u d y 
treat me nt is disc o nti n ue d. 
T he f oll o wi n g pr oce d ures will a p pl y d uri n g t he e xte nsi o n p hase:  
•  F ull safet y r e p orti n g re q uire me nts as detaile d i n Secti o n 8. 4  will a p pl y t o t he f oll o wi n g 
e ve nts:  
-  All S A Es, as defi ne d i n Secti o n 8. 1. 2 . 
-  A n y A E w hic h i n t he I n v esti gat or’s j u d ge me nt occ urre d at greater i nci de n ce or 
se verit y t ha n pres e nte d i n t he I n v esti gat or Br oc h ure. 
•  F oll o w -u p f or s afet y a n d disease e v al uati o n will be c o n d uc te d as per r o uti ne sta n dar d of 
care.  
•  C ollecti o n of ot her data will be li mite d t o ra di ol o gic i ma gi n g a n d A Es.  
7. 4.  
C o nc o mit a nt Me dic ati o ns, Tre at me nts, a n d Pr oce d ures  
A n y c o nc o mita nt me dicati o n use d fr o m ti me of scree ni n g t hr o u g h last st u d y visit will be 
rec or d e d i n t he eC R F, i n cl u di n g d ose, re gi me n, a n d i n dicati o n (reas o n f or its prescri pti o n).  


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C o nfi de ntial  
P a ge 6 2  of 9 8  
7. 4. 1.  
Preca uti o nar y M e dicati o ns, Treat me nts, a n d Pr oce d ures  
7. 4. 1. 1.  
Restricti o ns rel ate d t o C Y P Inter acti o ns  
X 4 P -0 0 1 is meta b olize d t hr o u g h, a n d i nteracts wit h, t he C Y P meta b olic e nz y m es f o u n d i n t he 
he patic a n d i ntesti nal micr os o mes  (see Secti o n 2. 2. 2. 3  f or details). Base d o n t hese o bser v ati o ns, 
t he f oll o wi n g r estricti o ns are place d o n c o n c o mita nt me dicati o ns:  
•  Str o n g i n hi bit ors a n d i n d ucers of C Y P 3 A 4 are pr o hi bite d. If a str o n g i n hi bit or or i n d ucer 
ca n n ot  be a v oi d e d, t he d ose of X 4 P -0 0 1 ca n be re d uce d wit h a p pr o v al of  Me dical 
M o nit or.  
•  Gra pefr uit a n d/ or starfr uit pr o d ucts , varia ble i n hi bit ors of C Y P 3 A 4, are pr o hi bite d.  
•  M o derate i n hi bit ors a n d i n d ucers of C Y P 3 A 4 are t o be prescri be d o nl y wit h t he a p pr o val 
of t he Me dical M o nit or; a d diti o nal m o nit ori n g of X 4 P -0 0 1 dr u g l e v els ma y be re q uire d.  
•  Se nsiti ve C Y P 2 D 6 s u bstrates s h o ul d be a v oi de d a n d ot her C Y P 2 D 6 s u bstrates s h o ul d be 
a d mi nistere d o nl y wit h t he a p pr o val of t he Me dical M o nit or.  
A p pe n di x Secti o n 1 8. 2  pr o vi des a list of c o m m o nl y prescri be d dr u gs t hat are i n hi bit ors or 
i n d ucers of C Y P 3 A 4 a n d s u bstrates of C Y P 2 D 6. K n o w n str o n g i n d u cers a n d i n hi bit ors are 
i n dicate d. T his list of dr u gs ma y n ot be a c o m plete list, c o ns ultati o n wit h t he me dical m o nit or is 
re q ueste d f or a n y c o ncer ns a b o ut c o nc o mita nt me dicati o n use.  
7. 4. 1. 2.  
N o n -c hil d be ari n g P ote nti al  
N o n -c hil d beari n g p ot e ntial is defi ne d as a fe mal e w h o meets eit her of t he f oll o wi n g criteria:  
•  A ge ≥5 0 years a n d n o m e nses f or at least 1 year.  
•  D oc u me nte d h yster ect o m y, bilateral t u bal li gati o n, or bilateral o o p h orect o m y.  
7. 4. 1. 3.  
Effective B irt h C o ntr ol ( C o ntr ace pti o n) M et h o ds 
W o me n of c hil d beari n g p ote ntial ( W O C P) m ust use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
d uri n g t he st u d y, a n d t hr o u g h 5 m o nt hs after t he l ast d ose of ni v ol u ma b  or t hr o u g h 4 w ee ks after 
t he last d ose of X 4 P-0 0 1, w hic he ver is lat est. Acce pta ble met h o ds i ncl u de: 
•  h or m o nal c o ntrace pti ves w he n use d wit h a n a d diti o nal barrier met h o d (e . g., a male 
c o n d o m):  
-  c o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n:  
 oral  
 i ntra va gi nal 
 tra ns der mal 


X 4 P har mace uticals, I n c.  
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C o nfi de ntial  
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-  pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n:  
 oral  
 i njecta ble 
 i m pla nta ble 
•  i ntra uteri ne de vice (I U D). 
•  i ntra uteri ne h or m o ne-rel easi n g s yst e m (I U S). 
•  bilateral t u bal occl usi o n.  
•  vasect o mize d part ner w h o has recei ve d a m e dical assess me nt of s ur gical s uccess ( w he n 
t he part ner is t he s ole p art ner). 
•  se x ual a bsti ne nce ( w he n i n a gree me nt wit h t he lifest yle a n d prefere nce of t he W O C P). 
Fertile males are re q uir e d t o use a male c o n d o m wit h a n y W O C P se x ual part ner d uri n g t he st u d y, 
a n d t hr o u g h 5 m o nt hs after t he last d ose of ni v ol u ma b  or t hr o u g h 4 wee ks after t he l ast d ose of 
X 4 P -0 0 1, w hic he ver is latest. 
7. 4. 2.  
Pr o hi bite d Me dicati o ns, Treat me nts, a n d Pr o ce d ures  
T he e x cl usi o n criteria s p ecif y treat me nts pr o hi bite d at t he ti me of st u d y e ntr y (Secti o n  5. 2 ).  
W hile patie nts are recei vi n g st u d y treat me nt, ot her treat me nts f or ccR C C are pr o hi bite d. Patie nts 
w h o disc o nti n ue treat me nt pre mat urel y a n d h a ve c o m plete d t he E O T visit, ma y recei ve a v aila ble 
or i n vesti gati o nal tr eat me nt f or t heir disease at a n y ti me base d o n t he j u d g m e nt of t heir 
p h ysicia n. If s uc h tr eat m e nt is i nitiate d pri or t o t he E O S  visit, t his will be rec or de d i n 
c o nc o mita nt me dicati o ns a n d c o nsi dere d i n assess me nt of a n y ne w  A E . 
7. 4. 3.  
Pr o p h ylactic Me dicati o ns, Treat me nts, a n d Pr oce d ures  
N o ne.  
7. 4. 4.  
Resc ue Me dicati o ns, Treat me nts, a n d Pr oce d ures  
7. 4. 4. 1.  
Tre at me nt of Ex pecte d A dverse Eve nts  
Base d o n pri or cli nical e x perie nce (as d etaile d i n Secti o n  2. 2. 1 ), t he f oll o wi n g treat me nts are 
rec o m me n de d f or s y m pt o matic relief of “re d e ye”, “ dr y e ye”, nas al c o n gesti o n (i n s o me 
i nsta nces wit h n ose blee d), faci al pai ns, a n d diarr h ea w hic h ma y o cc ur wit h i n 4 8 h o urs of 
i nitiati o n of treat me nt:  
•  L u bri ca nt e ye dr o ps c o nt ai ni n g car b o x y met h ylcell ul ose s o di u m ( 0. 5 %), s uc h as 
Refres h ™ Tears  
•  N o n -me dicate d s ali ne nasal s pra y, s uc h as Si m pl y Sali ne ™ Nasal Mist ( Ar m & Ha m mer)  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 6 4  of 9 8  
•  Aceta mi n o p he n ( T yl e n ol ™)  
•  Diarr hea s h o ul d be ma na ge d acc or di n g t o i nstit uti o nal sta n dar d of care . 
7. 4. 5.  
Preca uti o ns Re gar di n g Ni v ol u ma b  
Please ref er t o n i v ol u ma b prescri bi n g i nf or mati o n  f or all war ni n gs a n d preca uti o ns relate d t o t his 
dr u g.  
7. 4. 6.  
Patie nt  Restricti o ns d uri n g t he C o n d uct of t h e St u d y  
I n t he i nterest of t heir s af et y a n d t o facilitate assess me nt of b ot h safet y a n d treat me nt effect, t he 
patie nts partici pati n g i n t his st u d y will be re q uest e d t o a gree t o t he f oll o wi n g restricti o ns d uri n g 
t he st u d y:  
•  N ot start a n y ne w prescri pti o n me dicati o ns, e x ce pt as prescri b e d or a p pr o v e d b y t h eir 
I n v esti gat or or if r e q uire d i n a n e mer ge n c y; 
•  N ot ta ke a n y o ver -t he-c o u nter me dicati o ns, e x ce pt as i nstr ucte d or a p pr o v e d b y t heir 
I n v esti gat or.  
•  N ot dri n k gr a pefr uit j uice or eat gra pefr uit /starfr uit.  
•  Use effecti ve c o ntrace pti o n as defi ne d i n Secti o n 7. 4. 1. 3 . 
7. 5.  
A p pr o pri ate ness of Me as ure me nts  
Pla n ne d assess me nts ar e sta n dar d meas ure me nts f or t his t y pe of st u d y a n d are c o nsi d ere d 
a p pr o priate. Per re g ul at or y g ui da n ce, d e m o gra p hi c data, c o m plete m e dical hist ories, i ncl u di n g 
ca ncer treat me nt hist or y, a n d Bas eli ne diseas e stat us are t o be d o c u me nte d  f or all patie nts at 
Baseli ne [F D A G ui da n ce f or I n d ustr y 2 0 0 1 ].  
A Es a n d S A Es ar e m o nit ore d i n t his st u d y i n acc or da nce wit h I nter nati o nal C o nfere nce o n 
Har m o nisati o n (I C H) G C P g ui deli nes t o e ns ure t h e safet y of p atie nts. F urt h er m ore , a d diti o nal 
safet y assess me nts c o n d u cte d d uri n g t his st u d y, i n cl u di n g p h ysical e x a mi nati o ns, E C Gs, vital 
si g ns assess me nts, a n d cli nical la b orat or y tests, are wi del y use d a n d ge nerall y rec o g nize d as 
relia ble, acc ur ate, a n d rel e va nt. T hese t ests a n d pr oce dures als o will be m o nit ore d i n acc or da nce 
wit h I C H G C P g ui deli nes.  
T u m or res p o nse a n d pr o gr essi o n will be assesse d usi n g sta n dar d criteri a f or t he assess me nt of 
disease res p o ns e i n s oli d t u m ors, R E CI S T, v 1. 1.  


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C o nfi de ntial  
P a ge 6 5  of 9 8  
8.  
A D V E R S E E V E N T S  
8. 1.  
Defi niti o ns  
8. 1. 1.  
A d verse E v e nts  ( A E) 
A n A E is a n y u nt o war d me dical occ urre n ce i n a patie nt or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct, a n d w hic h d oes n ot necess aril y h a v e t o ha ve a ca usal 
relati o ns hi p wit h t his treat me nt. A n A E ca n t heref ore 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 b n or mal la b orat or y fi n di n gs), s y m pt o m, or disease te m p orall y ass ociate d wit h t he 
use of a n i n vesti gati o nal pr o d uct, w het her or n ot relate d t o t he i n vesti gati o nal pr o d uct.  
A n A E i n a cli nical st u d y ma y b e a n y of t he f oll o wi n g:  
•  A n u nfa v or a ble a n d u ni nte n de d s y m pt o m re p orte d b y t he p atie nt . Patie nts will be 
e nc o ura ge d t o re p ort treat me nt -e mer ge nt A Es s p o nta ne o usl y; ge n eral, n o n -directe d 
q uesti o ni n g ma y als o be use d t o elicit re p orts of A Es.  
•  Cli nical si g n detecte d b y t he I n v esti ga t or. O bser vati o ns b y ot her st u d y pers o n nel will be 
re p orte d t o t he I n v esti gat or f or e v al uati o n. 
•  A b n or mal res ult fr o m a l a b orat or y st u d y or ot her dia g n ostic pr o ce d ure t hat meets at least 
o ne of t he f oll o wi n g criteria:  
-  Res ults i n ter mi nati o n of st u d y dr u g;  
-  Lea ds t o treat me nt;  
-  Lea ds t o f urt her dia g n ostic tests ( ot her t ha n a si n gle re peat f or c o nfir mati o n);  
-  Is assesse d as “cli nicall y si g nifica nt ” b y t he I n vesti gat or. 
8. 1. 2.  
Seri o us A d verse E v e nts  ( S A E) 
A n A E or s us pect e d a d verse reacti o n is c o nsi dere d seri o us if, i n t he vie w of eit her t he 
I n v esti gat or or S p o ns or, it: 
•  Res ults i n deat h.  
•  Is life-t hreate ni n g. Life -t hreate ni n g mea ns t hat t he patie nt was at i m me diat e ris k of deat h 
fr o m t he reacti o n as it occ urre d, i. e., it d oes n ot i ncl u de a reacti o n w hic h h y p ot heticall y 
mi g ht ha ve ca use d d eat h ha d it occ urre d i n a m ore se vere f or m.  


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P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
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P a ge 6 6  of 9 8  
•  Re q uires i n -patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n . 
H os pitalizati o n a d missi o ns a n d/ or s ur gical o perati o ns sc he d ule d t o occ ur d uri n g t he st u d y 
peri o d, b ut pla n ne d pr i or t o st u d y e ntr y are n ot c o nsi dere d A Es if t he ill ness or disease 
e xiste d bef ore t he patie nt was e nr olle d i n t he st u d y, pr o vi d e d t hat it di d n ot deteri orat e i n 
a n u ne x pecte d ma n ner d uri n g t he st u d y (e. g., s ur ger y perf or me d earlier t ha n pla n ne d) . 
A d diti o n al e x cl usi o ns t o S A E re p orti n g i ncl u de h os pitalizati o ns f or:  
-  Electi ve pr oce d ures.  
-  S ocial/a d mi nistrati ve reas o ns i n t he a bse nce of a n A E.  
-  E x p ecte d deteri orati o n ca use d b y pr o gressi o n of t h e disease u n d er st u d y . 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y . Disa bilit y is defi ne d as a 
s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life f u ncti o ns. 
•  Is a c o n ge nital a n o mal y/ birt h defect. 
•  Is a n i m p orta nt me dical e ve nt. A n i m p orta nt me dical e ve nt is a n e ve nt t hat ma y n ot res ult 
i n deat h, be life -t hr eate ni n g, or re q uire h os pitalizati o n b ut ma y be c o nsi dere d a n S A E 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, it ma y je o p ar dize t he pati e nt a n d ma y 
re q uire me di cal or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t he 
d efi niti o ns f or S A Es . E xa m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m 
re q uiri n g i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me, bl o o d d ys crasias or 
c o n v ulsi o ns t hat d o n ot res ult i n i n -patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g 
de pe n de n c y or dr u g a b us e .  
8. 1. 3.  
A d verse Dr u g Reacti o n  
All n o xi o us a n d u ni nte n de d res p o nses t o a m e dici nal pr o d uct rel ate d t o a n y d ose s h o ul d be 
c o nsi dere d a d vers e dr u g reacti o ns . T he p hrase "res p o nses t o a me dici nal pr o d ucts" mea ns t h at a 
ca usal r elati o ns hi p be t wee n a me dici nal pr o d u ct a n d a n a d vers e e v e nt is at least a reas o na ble 
p ossi bilit y, i.e., t he r elati o ns hi p ca n n ot be r ule d o ut.  
8. 1. 4.  
S us pecte d, U ne x pecte d S eri o us A d vers e Reacti o n ( S U S A R)  
A S U S A R is defi ne d as a n S A E t hat meets b ot h t he f oll o wi n g criteria wit h  res pect t o st u d y dr u g:  
•  S us pecte d —  is assesse d as relate d or p ossi bl y relate d t o st u d y dr u g (s ee Secti o n  8. 2. 2 );  
•  U ne x pecte d —  c o m par e d t o t he s t u d y dr u g-relate d A Es descri be d i n I n vesti gat or’s 
Br oc h ure, t he e ve nt meets a n y of t he f oll o wi n g criteria:  
-  T he e ve nt w as n ot pre vi o usl y descri be d;  
-  T he e ve nt is n o w c h aract erize d as m ore se v ere (see Secti o n 8. 2. 1 );  


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-  T he e ve nt is n o w c h aract erize d m ore s pecificall y (e. g., a n e v e nt of “i nterstitial 
ne p hritis” i n a patie nt recei vi n g a n a ge nt pre vi o usl y des cri be d as ass ociate d wit h 
“ac ute re nal fail ure” ). 
I n cli nical st u dies i n v ol vi n g ill patie nts, e ve nts c o nsi dere d rel ate d t o t he nat ural hist or y of t he 
disease u n der st u d y or t o lac k of efficac y (t hat is, t he e ve nt is c o nsi dere d m ore li kel y relate d t o 
t h ose fact ors t ha n t o ot her fact ors, i n cl u di n g st u d y dr u g) are n ot c o nsi dere d " u ne x pecte d".  
8. 1. 5.  
Cli nical La b or at or y A d v erse E ve nts  
T he I n vesti gat or will re vi e w t he res ults of all Safet y La b orat or y tests (s ee  S ecti o n  7. 2. 1 ) a n d 
desi g nat e a n y r es ults o utsi de of t he refere nce ra n ge as eit her of t he f oll o wi n g:  
•  A b n or mal, n ot cli nicall y si g nifica nt ( N C S)  
•  A b n or mal, cli nicall y si g nifica nt ( C S).  
I n ma ki n g t his j u d g me nt, t he I n v esti gat or will c o nsi der all a vaila ble i nf or mati o n, i ncl u di n g t he 
patie nt’s cli nical c o n diti o n, a ll a vaila ble la b orat or y res ults, a n d t he p ote ntial f or false p ositi ve 
test res ults. I n a d diti o n, la b orat or y st u dies t hat res ult i n t he acti o ns s pecifie d i n Secti o n 8. 1. 1  will 
be classifie d as “a b n or m al, cli nicall y si g nifica nt”.  
A n y res ult assesse d as “a b n or mal, cli nicall y si g nifica nt” will be rec or de d as a n A E u nless  it is 
c o nsiste nt wit h o ne or m ore of t he f oll o wi n g:  
•  Pr ocess n ote d i n t he me dical hist or y:  
•  O n g oi n g a d v erse e ve nt alrea d y rec or d e d;  
•  E x pecte d c o urse of t h e pri mar y disease u n der st u d y.  
8. 2.  
Cl assific ati o n of A d verse E ve nt s 
8. 2. 1.  
Se verit y  
T he i nte nsit y (s y n o n y m: se verit y) of cli nical A Es (i.e., s y m pt o ms re p orte d b y t he p atie nt a n d/ or 
si g ns o bser v e d b y t he In v esti gat or) will be assesse d b y t he I n vesti gat or usi n g t he N ati o nal 
Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteri a f or A d vers e E ve nts ( N C I C T C A E) ( v 4. 03 ) 
fi ve-le vel gr a di n g s yst e m, a vaila ble o n-li ne (see 
htt p://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0 -0 6 -1 4 _ Q uic k Refere nce _ 8. 5 x 1 1. p df ). 
If t he A E is n ot i ncl u de d i n t he N CI C T C A E, t he n t he I n v esti gat or is t o deter mi ne t he i nte nsit y 
of t he A E acc or di n g t o t h e f oll o wi n g criteria:  
•  Mil d ( Gr a de 1) :  A E t hat disa p pears or is easil y t olerate d o n c o nti n uati o n of st u d y dr u g.  
•  M o der ate ( Gr a de 2) :  A E s uffic ie ntl y disc o mf orti n g t o ca us e i nterfere n ce wit h us ual 
w or k acti vities.  


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•  Severe ( Gr a de 3):   A E t h at is i nca pacitati n g, wit h i na bilit y t o w or k or perf or m dail y 
acti vities. 
•  Life -T hre ate ni n g ( Gr a d e 4):   A E t hat is p ote ntiall y life t hreate ni n g.  
•  De at h ( Gr a de 5):   Deat h relate d t o A E.   
8. 2. 2.  
Gra di n g of La b orat or y S afet y Tests f or Re p orti n g a n d A nal ysis  
Treat me nt -e mer ge nt a b n or mal la b orat or y res ults will be re p orte d as A Es w he n assesse d as 
“cli nicall y si g nifica nt” usi n g t he pr o ce d ures a n d criteria detaile d i n  Secti o n  8. 1. 5 .  
F or p ur p os es of a n al yzi n g la b or at or y dat a, all la b orat or y res ults will be gra de d usi n g N CI 
C T C A E v 4. 0 3 a n d t he n s u m marize d as “s hift ta bles” c o m pari n g b aseli ne  a n d treat me nt -e mer ge nt 
res ults. T his pr ocess will ass ure t hat t he fi n al st u d y re p ort c o ntai ns c o m plet e a n d c o nsiste nt 
a nal ys es of safet y la b or at or y tests.  
8. 2. 3.  
Relati o ns hi p t o St u d y Dr u g  
T his deter mi nati o n is base d o n t he I n vesti gat or’s cli nical j u d g me nt re gar di n g t he li keli h o o d t hat 
t he st u d y dr u g ca use d t he A E a n d ma y i ncl u de c o nsi derati o n of s o me or all of t he f oll o wi n g 
fact ors:  
•  Alter nati ve p ossi ble ca us es of t he A E, i ncl u di n g t he pati e nt’s u n derl yi n g disease or 
c o-m or bi d c o n diti o ns, ot her dr u gs, ot her h ost a n d e n vir o n me ntal fact ors;  
•  Te m p oral se q ue n ce b et w ee n t he e x p os ure t o st u d y dr u g a n d t he A E;  
•  W het her t he cli nical or la b orat or y ma nifest ati o ns of t he A E are c o nsiste nt wit h k n o w n 
acti o ns or t o xicit y of t h e st u d y dr u g;  
•  W het her t he A E res ol v e d or i m pr o ve d wit h decreasi n g t he d ose or st o p pi n g t he st u d y 
dr u g (i.e., dec halle n ge); or rec urre d or w ors e ne d wit h re -e x p os ure t o t he dr u g 
(i.e., rec halle n ge).  
T he relati o ns hi p bet wee n t he st u d y dr u g a n d t he A E will be descri be d usi n g o ne of t he f oll o wi n g 
cate g ories:  
•  Rel ate d :  t he st u d y dr u g is m ore li kel y t he ca use of t he A E t ha n ot her fact ors;  
•  P ossi bly rel ate d :  t here is a re as o n a ble p ossi bilit y t hat t he st u d y dr u g is t he ca use of t h e 
A E, i ncl u di n g t hat t he st u d y dr u g a n d a n ot her fact or(s) are e q uall y li kel y as ca uses of t he 
A E;  
•  U nli kely rel ate d :  a n ot her fact or is c o nsi dere d m ore li kel y  t h e ca us e of t he A E t ha n t he 
st u d y dr u g;  
•  N ot rel ate d :  a n ot her fact or is c o nsi dere d t o be t h e ca use of t h e  A E.  


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C o nfi de ntial  
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Relate d a n d p ossi bl y relate d A Es ma y res ult d uri n g t he use of t he st u d y dr u g as pla n ne d ( p er 
pr ot oc ol), or fr o m a b use, wit h dra wal or o v er -d os a ge of t he a ge nt.  
 
8. 2. 4.  
E x pecte d ness  
A Es meeti n g t h e criteria i n Secti o n 8. 1. 4  are t o be c o nsi dere d u n e x pecte d.  
8. 2. 5.  
Date a n d Ti me of O nset  
T he date a n d ti me at w hic h t he e ve nt w as first a p p are nt . Ta bl e 8 -1  s u m mari zes t he basis f or 
re p orti n g t he date a n d ti me of o nset f or t he differe nt t y pes of A Es.  
T a ble 8 -1 : 
Re p orti n g t he D at e a n d Ti me of O nset of A E f or Differe nt T y pes of E ve nts  
T y pe of E ve nt  
E x a m ples  
S o ur ce of D at e a n d Ti me of O nset  
S y m pt o m  
Hea d ac h e, fe veris h, p arest h esia  
W h e n first e x p erie n ce d b y t h e p atie nt  
Si g n ( Fi n di n g)  
Ele vate d B P, e nlar ge d li ver o n p h ysical 
e xa m 
W h e n first o bser ve d b y t h e I n vesti gat or or ot h er st u d y 
staff 
La b orat or y / 
dia g n ostic res ult  
Ne utr o p e nia, h y p er gl yce mia,  
lesi o ns o n brai n sca n 
W h e n la b orat or y  sa m ple was o btai n e d or dia g n ostic 
st u d y p erf or me d 
 
T he ti me of o nset of s y m pt o ms ma y be a p precia bl y earlier t h a n t he date a n d ti me t he I n v esti gat or 
bec o mes a w ar e of t he e v e nt . S o me e ve nts ma y be a p pare nt t o t he p atie nt a n d I n v esti gat or 
i n de pe n de ntl y, a n d i nf or mati o n fr o m eac h m a y c o ntri b ute t o t he fi nal re p ort. F or e x a m ple, a 
patie nt ma y re p ort t he o nset of a ras h t w o d a ys bef ore bei n g see n b y a p h ysi cia n w h o ma kes a 
dia g n osis of h er pes z oster base d o n a p p eara nce a n d la b orat or y c o nfir mati o n . I n t hat case, t h ere is 
a si n gle A E, wit h t he dat e of o nset bas e d o n t he d ate o f t he i nitial o bser vati o n b y t he p atie nt a n d 
a s pecific d escri pti o n ( her pes z oster) base d o n t h e cli nical e x a mi nati o n a n d tests.  
8. 2. 6.  
Acti o ns Ta ke n f or Ma na ge m e nt of A E  
A Es will be f oll o we d a n d ma na ge d b y t he I n v esti gat or, i ncl u di n g o btai ni n g a n y s u p pl e me ntal 
st u dies nee de d t o defi n e t he nat ure a n d/ or ca use of t he e ve nt (e. g., l a b orat or y tests, dia g n ostic 
pr oce d ur es, c o ns ultati o n wit h ot her healt h care pr ofessi o nals).  
F o r eac h A E t h e I n vesti gat or will cate g orize as f oll o ws t he acti o ns ta ke n t o ma na ge t he A E:  
•  C o nc o mita nt me dicati o n —  o ne or m ore me di cati o ns ( prescri pti o n or o ver -t he-c o u nter) 
were starte d or i ncreas e d i n d ose; n o n -me dicati o n acti o ns ma y als o ha ve b ee n or dere d.  
•  Ot her acti o n —  o nl y n o n -me dicati o n acti o n(s) were or dere d as m a na ge m e nt of t he A E 
(e.g., be d place d i n Tr e n dele n b ur g p ositi o n, war m c o m presses a p plie d t o I V access site).  
•  N o acti o n —  n o acti o ns were or dere d f or ma n a ge me nt of t he A E.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 7 0  of 9 8  
8. 2. 7.  
F oll o w -u p a n d O ut c o me of A Es  
If p ossi ble, A Es will be f oll o we d u ntil res ol ve d (s y n o n y ms: rec o vere d, rec u perate d, e n de d) eit her 
wit h or wit h o ut se q uelae, i ncl u di n g f or p atie nts w h o pre mat urel y disc o nti n ue st u d y p artici pati o n . 
F or A Es t hat are assesse d as n ot dr u g -rel ate d a n d are n ot res ol ve d at t he E O S visit , f oll o w-u p 
ma y b e li mite d wit h t he a p pr o val of t he Me dical M o nit or.  
T he o utc o me of eac h e ve nt will be descri be d usi n g t he f oll o wi n g cate g ori es:  
•  Res ol ve d wit h o ut se q uelae —  t he e v e nt res ol ve d a n d patie nt ret ur n e d t o baseli ne;  
•  Res ol ve d wit h se q uelae —  t he e ve nt res ol v e d b ut t he patie nt is left wit h resi d ual 
pr o ble ms (e. g., f u n cti o nal deficits, pai n);  
•  Res ol vi n g —  at t he last o bser vati o n, t he e v e nt was i m pr o vi n g;  
•  N ot Res ol ve d —  at t he last o bser vati o n, t he e ve nt was u nc ha n ge d;  
•  Deat h ( Fatal) —  t o b e use d f or t he o n e A E w hic h, i n t he j u d g me nt of t he I n vesti gat or, 
was t he pri mar y ca use of deat h;  
•  U n k n o w n —  t here wer e n o o bser vati o ns after t he o nset (i nitial o bser vati o n or re p ort) of 
t he e ve nt.  
N ote: Res ol vi n g a n d N ot Res ol ve d ma y als o be us e d f or A Es t hat w ere u nres ol ve d at t he ti me a 
patie nt die d, b ut were n o t assesse d as t he pri mar y ca use of d eat h.  
8. 2. 8.  
Date a n d Ti me of O utc o me  
F or eac h cl ass of o utc o m e as defi n e d a b o ve, T a ble 8 -2  i n dicates t he dat e a n d ti me t o be rec or d e d. 
As disc usse d i n detail f or date / ti me of o nset (see Secti o n  8. 2. 5 ), deter mi ni n g t he d ate / ti me a n 
e ve nt res ol ve d (e n de d) s h o ul d reflect t he t y p e of e ve nt a n d t he s o urce of t he i nf or mati o n.  
T a ble 8 -2 : 
D ate a n d Ti me of O utc o me f or A E b y O utc o me Cl ass  
O utc o me assi g ne d t o A E  
D ate a n d Ti me t o be Re c or de d  
Res ol ve d ( wit h or wit h o ut se q u elae) 
Date a n d ti me e v e nt o bser ve d or re p orte d as res ol ve d  
Deat h  
Date a n d ti me of d eat h  
Res ol vi n g or N ot Res ol ve d  
Date a n d ti me of last o bser vati o n  
U n k n o w n  
N o n e (see d efi niti o n a b o ve)  
 
8. 3.  
Ti me Peri o d a n d Fre q ue nc y f or E ve nt Assess me nt a n d F oll o w -U p  
Pr oce d ures f or t he c ollecti o n a n d rec or di n g of A Es are as f oll o ws:  
•  Fr o m o btai ni n g i nf or me d c o nse nt t hr o u g h E O S , t here will be acti ve s ur veill a nce t o 
i de ntif y all A Es. E v e nts will be rec or d e d i n t he A E p orti o n of t he e C R F, wit h partic ular 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 7 1  of 9 8  
atte nti o n t o w het her t he o nset of t he e ve nt w as bef ore or after t he a d mi nistrati o n of t he 
first d ose of st u d y dr u g. 
•  After E O S , s ur v eilla nce will be passi ve ( o nl y e ve nts br o u g ht t o t he In vesti gat or’s 
atte nti o n will be c o nsi der e d) a n d o nl y e v e nts assesse d as S U S A Rs (see Sect i o n 8. 1. 4 ) 
will be rec or d e d.   
8. 4.  
Re p orti n g Pr oce d ures  
8. 4. 1.  
A d verse E v e nt Re p orti n g  
Eac h patie nt m ust be car ef ull y m o nit ore d f or t he de vel o p me nt of a n y A Es . T his i nf or mati o n 
s h o ul d be o btai ne d i n t he f or m of n o n-lea di n g q u esti o ns (e. g., “ H o w are y o u feeli n g? ”) a n d fr o m 
si g ns a n d s y m pt o ms detecte d d uri n g eac h e x a mi nati o n, o bser vati o ns of st u d y pers o n nel, a n d 
s p o nta ne o us re p orts fr o m patie nts.  
All A Es (seri o us a n d n o n -seri o us) s p o nta ne o usl y re p orte d b y t he patie nt a n d/ or i n res p o nse t o a n 
o pe n q uesti o n fr o m st u d y pers o n nel or re veale d b y o bser vati o n, p h ysical e x a mi nati o n, or ot her 
dia g n ostic pr o ce d ur es occ urri n g wit hi n t he ti me fra me s pecifi e d i n Secti o n 8. 3  will be 
d oc u me nte d i n t he patie nt’s s o urce d oc u m e nts a n d rec or d e d i n t he e C R F . A n y cli nicall y rele va nt 
(as deter mi ne d b y t h e I n v esti gat or) deteri orati o n i n la b orat or y ass ess me nts or ot her cli nical 
fi n di n gs is c o nsi der e d a n A E a n d m ust be rec or de d i n t he patie nt’s s o urce d oc u me nts a n d i n t he 
e C R F.  
T he A E ter m s h o ul d be r e p orte d i n sta n dar d m e dical ter mi n ol o g y w he n p ossi ble . Als o w he n 
p ossi ble, si g ns a n d s y m pt o ms i n dicati n g a c o m m o n u n derl yi n g p at h ol o g y s h o ul d be n ote d as o ne 
c o m pre he nsi ve e ve nt . F or eac h A E, t he i n vesti gat or will e val uate a n d re p ort t he o nset, 
res ol uti o n, i nte nsit y, ca us alit y, acti o n ta ke n, seri o us o utc o me (if a p plica bl e), a n d w het her or n ot 
it ca use d t he patie nt t o disc o nti n ue t he st u d y. 
8. 4. 2.  
Seri o us A d verse E v e nt Re p orti n g  
S A E re p orti n g , i ncl u di n g s u p p orti n g materi als, will be perf or m e d b y t he site usi n g a s yst e m 
a p pr o ve d b y t he S p o ns or; detaile d trai ni n g will be pr o vi de d d uri n g site  i nitiati o n. C o ntact 
i nf or mati o n f or g ui da nce a n d assista nce wit h S A E re p orti n g will be pr o vi de d i n t he st u d y 
o perati o nal m a n ual.  
8. 4. 2. 1.  
Pr oce d ures f or Re p orti n g S A Es t o t he S p o ns or  
T he i niti al n otific ati o n of eac h S A E will be re p ort e d wit hi n 2 4 h o urs of t he ti me t he I n v esti gat or 
( or t he I n vesti gat or's d esi g nee) bec o mes a ware t hat t he e ve nt has occ urre d a n d will i ncl u de t he 
f oll o wi n g ite ms of i nf or mati o n (a n y ite ms n ot a v aila ble s h o ul d be e x plicitl y n ote d):  
•  Pr ot oc ol n u m ber, st u d y site, patie nt n u m ber;  
•  I n v esti gat or’s na me, a d dr ess, a n d c o ntact i nf or mati o n ( p h o ne, fa x, e mail);  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 7 2  of 9 8  
•  Descri pti o n of t he e v e nt (i.e., date a n d ti me of o ns et, i nitial assess me nt, treat me nts a n d 
c o urse);  
•  C urre nt stat us of t he pati e nt a n d t he e v e nt;  
•  Criteria b y w hic h t he e v e nt was assesse d as seri o us;  
•  Date of t he first a d mi nistrati o n of st u d y dr u g;  
•  Date of t he last a d mi nistrati o n of st u d y dr u g pri or t he e ve nt;  
•  Assess me nt of relati o ns hi p of st u d y dr u g t o t he e v e nt;  
•  W het her t he st u d y dr u g was disc o nti n ue d or a dj uste d as a res ult of t he e ve nt.  
A  n arr ative s u m m ary  of t he e ve nt will be re p orte d wit hi n 2  da ys f or deat h a n d life -t hreat e ni n g 
e ve nts a n d wit hi n f o ur da ys f or all ot her S A Es . T h e narrati ve s u m mar y will i ncl u de  s pecific 
i nf or mati o n t hat will assist i n u n dersta n di n g t he e ve nt, e. g., rele v a nt me dical hist or y, c o-m or bi d 
c o n diti o ns, p h ysical e x a m, dia g n ostics, assess me nt, treat me nts (i ncl u di n g c o nc o mita nt 
me dicati o ns), res p o nse t o treat me nt,  c o urs e, a n d o utc o me (if k n o w n).  
T hereafter, si g ne d s u p ple m e nt al (f oll o w-u p) i nf or m ati o n  will be pr o vi de d as it bec o mes 
a vaila ble t o t he I n v esti gat or (eit her dir ectl y or as a res ult of i n vesti gati o n i nt o a q uer y) . S uc h 
i nf or mati o n i ncl u des b ut is n ot li mite d t o:  
•  C o pies of rele va nt me di cal re p orts —  i ncl u di n g dia g n ostic pr oce d ures (e. g., la b orat or y 
tests), s ur gi cal pr oce d ures, a n d c o ns ultati o ns  
•  M ore defi niti ve o utc o me f or e ve nts pre vi o usl y re p orte d  as o n g oi n g or u n k n o w n o utc o me  
8. 4. 2. 2.  
Re q uire me nts f or Ex pe dit e d a n d Peri o dic Re p orti n g of A dverse Eve nts  
S U S A Rs are re q uir e d t o be re p ort e d ra pi dl y t o re g ulat or y a ut h orities a n d t o I R B/I E Cs (t y picall y 
wit hi n 7  da ys f or fatal or life -t hreat e ni n g S U S A Rs; wit hi n 1 4 da ys f or all ot her S U S A Rs). T he 
S p o ns or a n d t he I n vesti gat or will w or k t o get her t o meet t hese re p orti n g re q uire me nts.  
8. 4. 2. 3.  
N otific ati o n of S A Es t o t he I nvesti g at or by t he S p o ns or  
I n acc or da n ce wit h re g ul at or y re q uir e me nts, t he S p o ns or will n otif y t he I n v esti gat or of t he 
occ urr e nce of S U S A Rs re p orte d b y ot her I n vesti gat ors i n t his or i n ot her st u dies i n v ol vi n g t he 
st u d y dr u g. T h e I n vesti gat or will pr o m ptl y i nf or m his/ her I R B/I E C of s uc h c o m m u nicati o ns 
fr o m t he S p o ns or a n d will d oc u me nt t hat n otificati o n i n t he I n v esti gat or’s R e g ul at or y Bi n d er.  
8. 4. 3.  
E ve nts of S pecial I nterest  
N o ne.  


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P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 7 3  of 9 8  
8. 4. 4.  
Re p orti n g of Pr e g na nc y  
Pre g n a ncies o cc urri n g i n t he patie nt or patie nt’s part ner w hile t he p atie nt is recei vi n g st u d y dr u g 
or wit hi n 1 m o nt h after t he patie nt’s last d ose of st u d y dr u g will n ot be c o nsi dere d seri o us, b ut 
are t o be re p orte d usi n g t he sa me pr o ce d u res as f or S A Es descri be d i n Secti o n 8. 4. 2 .  
St u d y dr u g m ust be disc o nti n ue d i m me diatel y i n t he e ve nt of a pre g n a nc y i n t he patie nt . T he 
patie nt s h o ul d be ref err e d t o a n o bstetricia n/ g y nec ol o gist e x perie nce d i n re pr o d ucti ve t o xicit y f or 
f urt her e v al uati o n a n d c o u nseli n g. 
T he I n vesti gat or will f oll o w t he patie nt / patie nt’s part ner u ntil c o m pleti o n of t he pre g n a nc y, a n d 
m ust n otif y t h e Me dical M o nit o r of t he o utc o me wit hi n 5 da ys. T he I n vesti gat or will pr o vi de t his 
i nf or mati o n as a f oll o w-u p t o t he i nitial re p ort.  
If t he o utc o me of t h e pre g na n c y meets t he criteria f or i m me diate classificati o n as a n S A E (i.e., 
s p o nta ne o us a b orti o n [ a n y c o n ge nital a n o mal y det ecte d i n a n a b orte d fet us is t o be d oc u me nte d], 
still birt h, ne o natal deat h, or c o n ge nital a n o mal y), t he n t he I n vesti gat or s h o ul d re p ort it as s uc h. 
F urt her m ore, all ne o n atal deat hs t hat occ ur wit hi n 3 0 da ys of birt h s h o ul d be re p ort e d, wit h o ut 
re gar d t o ca usalit y, as S A Es. I n a d diti o n, a n y i nfa nt deat h aft er 3 0 da ys t h at t he I n vesti gat or 
s us pects is relate d t o t he i n uter o e x p os ure t o t he st u d y dr u g s h o ul d als o be re p orte d.  
8. 5.  
St u d y H alti n g R ules  
St o p pi n g R ules ma y b e d e vel o pe d if u ne x pecte d S A Es wit h ca usal relati o ns hi p t o st u d y dr u g, 
i ncl u di n g deli ver y pr oce d ure, a p pear d uri n g t he st u d y.  
T he st u d y als o ma y b e st o p pe d base d o n a decisi o n o n t he part of t he S p o ns or t o s us pe n d or 
disc o nti n ue de vel o p me nt of st u d y dr u g.  
8. 6.  
S af et y O versi g ht  
Ta ble 8 -3  i n dicates s p ecific pr oce d ures i n t his pr ot oc ol f or ma na gi n g t hese pre vi o usl y i de ntifie d 
ris ks. 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 7 4  of 9 8  
T a ble 8 -3 : 
M o nit ori n g P r o ce d ures f or R is ks Ide nti fie d i n P ri or S t u dies of X 4 P-0 0 1 
( A M D 1 1 0 7 0) 
Pri or Fi n di n gs  
Cli nic al M o nit ori n g Pr oce d ures  
X 4 P -0 0 1 is pre d o mi n a ntl y meta b olize d t hr o u g h C Y P 3 A 4 1 
A v oi d c o n c o mita nt me dicati o ns t h at are str o n g C Y P -3 A 4 
i n hi bit ors or i n d u cers; if a str o n g i n hi bit or or i n d u cer ca n n ot 
b e a v oi d e d, t h e d ose of X 4 P -0 0 1 ca n b e re d u ce d wit h 
a p pr o val of Me dical M o nit or.  
X 4 P -0 0 1 is a m o d erate i n hi bit or of C Y P 2 D 6 1 
A v oi d se nsiti ve C Y P 2 D 6 s u bstrates. Cl osel y m o nit or ot her 
c o n c o mita nt me dicati o ns C Y P -2 D 6  s u bstrates. 
Bea gles, 1 3 -we e k t o xic ol o g y st u d y wit h X 4 P -0 0 1 (free -b ase) 2 
-- A L T: mil d ( 1. 4 x – 2. 4 x), e x p os ure -relate d i n creases  
-- T otal bilir u bi n: n o i n creases i n a n y a ni mal  
-- Micr osc o pic li ver fi n di n gs: m ultif o cal n ecr osis (si n gle cell) i n 4 
of 1 2 a ni mals d ose d at 3 5 or 7 0 m g/ k g/ d  
Safet y la b orat or y tests, i n cl u di n g as p artate tra nsa mi nase, 
ala ni n e tra nsa mi n ase, t otal bilir u bi n, e ver y 4 wee ks d uri n g 
treat me nt. 
Rats, 2 6 -wee k t o xic ol o g y st u d y wit h A M D 1 1 0 7 0 P H B (salt) 3 
-- reti nal de ge n erati o n ( 2 0, 5 0, 1 0 0 m g/ k g bi d) 
-- reti nal atr o p h y ( 1 0 0 m g/ k g BI D o nl y)  
A n o p ht h al m ol o g y e val u ati o n e ver y 1 2 we e ks:  
vis u al ac uit y assess me nt; c ol or visi o n assess me nt;  
slit la m p e xa m; reti n al e x a mi n ati o n wit h p h ot o gra p hs.  
1 . A detaile d listi n g of a ge nts wit h p ote ntial f or C Y P -relate d i nteracti o n is pr o vi de d i n A p pe n di x Secti o n  1 8. 2 .  
2 . T he li ver fi n di n gs i n bea gles treate d f or 1 3 wee ks wit h t he P H B salt were greater t ha n t h os e o bser ve d wit h t he 
free base dr u g. T his (a n d all pri or) cli nical st u dies use o nl y t he free base dr u g.  
3 . T he reti nal c ha n ges were o bser ve d o nl y i n al bi n o rats treate d f or 2 6 wee ks wit h t he P H B salt. N o reti nal c ha n ges 
were o bser ve d i n bea gles treat e d f or 1 3 wee ks wit h eit her t he  free base or t he P H B salt.  
8. 6. 1.  
A d diti o nal Pr oce d ures f or M o nit ori n g Patie nt Safet y  
A d diti o nal p r oce d ur es f or patie nt safet y are s u m m arize d bel o w; a detaile d s c he d ule of 
assess me nts is prese nte d i n Ta ble 1 -1 .  
•  T he first d ose of st u d y dr u g will be a d mi nistere d b y st u d y pers o n n el. Patie nts will t he n be 
o bser ve d f or at least 1 h o ur bef ore recei vi n g ni v ol u ma b (t y picall y a 1 h o ur i nf usi o n), a n d 
t he n obser ve d f or at least o ne h o ur p ost -i nf usi o n.  
•  O n g oi n g m o nit ori n g f or A Es.  
•  Re g ularl y s c he d ule d s afet y la b orat or y tests.  
•  O n g oi n g m o nit ori n g of all c o nc o mita nt me dicati o ns ( prescri pti o n a n d o ver -t he-c o u nter) 
t o a v oi d p ote ntial D DIs me diate d t hr o u g h alterati o ns i n C Y P-meta b olis m  
•  Detaile d pr oce d ur es f or m o nit ori n g a n d re vie w of data, i ncl u di n g D R C meeti n gs (see 
Secti o n  8. 6. 2 ) a n d re g ul arl y sc h e d ule d telec o nfere nces i ncl u di n g acti ve I n v esti gat ors, t he 
Me dical M o nit or, a n d t he S p o ns or, t o disc uss o verall cli nical e x perie nce i n cl u di n g safet y 
a n d o utc o mes.  
•  Detaile d pr o visi o ns (s u m marize d bel o w) f or m a na ge m e nt of st u d y dr u g i n i n di vi d ual 
patie nts base d o n saf et y a n d t olera bilit y (see  Secti o n  5. 6 ), a n d o n diseas e res p o nse (see 
Secti o n s 5. 7  a n d 7. 1. 4. 2 ).  


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C o nfi de ntial  
P a ge 7 5  of 9 8  
8. 6. 2.  
Data Re vie w C o m mittee ( D R C)  
A D R C w ill be c o n ve ne d t o assess t he safet y of t he c o m bi nati o n of X 4 P-0 0 1 a n d ni v ol u ma b . T he 
details of t he re vie w pr oce d ures will be d oc u m e nte d i n a D R C c harter . 
Me m bers of t he D R C will ha ve a p pr o priate e x peri e nce treati n g patie nts wit h a d va nce d cc R C C 
a n d/ or c o n d ucti n g earl y p hase st u dies of i n vesti gati o nal dr u gs a n d will i ncl u de t he f oll o wi n g: 
•  T he me dical m o nit or f or t he st u d y.  
•  P artici pati n g I n v esti gat or s. 
•  A p h ysici a n re prese ntati v e of t he S p o ns or.  
T he first f or mal D R C re vie w of saf et y data will occ ur aft er 3  patie nts ha v e c o m plete d 2 8 da ys 
( C ycl e 1) of tr eat me nt or disc o nti n ue d pre mat urel y d ue t o a n A E . T he D R C will be prese nte d all 
a vaila ble safet y data a n d will be e x pecte d , base d o n t heir j u d g me nt , t o ma k e a s pecific 
rec o m me n dati o n f or t he pr o gress of t he stu d y, t hat is, t o c o nti n ue e nr oll me nt, t o st o p e nr oll me nt, 
or t o c o n d uct a sec o n d safet y re vie w after a n a d diti o nal 3 patie nts c o m plete  C ycle 1 . 
T o f urt her pr ot ect patie nts’ safet y, T L Ts will c o nti n ue t o be m o nit ore d d uri n g t he re mai n der of 
t he st u d y, i ncl udi n g a sec o n d f or mal D R C re vie w of all a vaila ble safet y dat a after 1 2 patie nts 
ha ve c o m plete d 2 8 d a ys ( C ycle 1) of treat me nt or disc o nti n ue d pre mat urel y d ue t o a n A E . 
S pecificall y, if less t ha n or e q ual t o 4 T L Ts are o bser ve d i n t he first 1 2 pati e nts, t he trial will 
c o nti n ue wit h t he sa me d ose le vel f or t he re mai ni n g patie nts. If 5 or m ore T L Ts are o bser ve d, t he 
trial ma y c o nti n ue wit h d ose de-es calati o n, i.e., t h e rest of t he p atie nts will be d ose d at 2 0 0 m g 
Q D. If e x cessi ve T L Ts ar e o bser ve d a n yti me d uri ng t he trial, a d ose de -escalati o n ca n be 
e nf orce d f oll o wi n g D R C re vie w or t h e trial ca n b e st o p pe d at t he s p o ns or’s discreti o n.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 7 6  of 9 8  
9.  
C L I NIC A L  M O N IT O R IN G  
9. 1.  
E xter n al Re vie w of t he St u d y C o n d uct at P a rti ci p ati n g Sites  
All st u d y -r elate d materials at t he site are s u bject t o e xter nal re vie w t o e ns ure t he safet y of t he 
patie nts, t he i nte grit y of t he st u d y d ata, a n d c o m plia nce wit h all a p plica bl e re g ulat or y a n d 
o versi g ht re q uire m e nts.  
T here are s e ver al differe nt classes of r e vie w:  
•  M o nit ori n g —  re vie w b y t he S p o ns or or a uth orize d re pres e ntati ves, t y picall y fr o m t he 
c o ntract r esearc h or ga nizati o n ( C R O) c o or di nati n g t he cli nical c o n d uct of t he st u d y . As 
detaile d bel o w, visits ma y be c o n d ucte d b ef ore, d uri n g, a n d after t he c o n d uct of t he 
st u d y. 
•  A u dits —  s yste matic, i n d e pe n de nt re vie w b y t he q ualit y ass ura nce d e part me nt of t he 
S p o ns or or a ut h orize d re prese ntati ves, p ote ntiall y fr o m a n or ga nizati o n n ot i n v ol ve d i n 
t he cli nical c o n d uct of t h e st u d y;  
•  Re g ulat or y re vie w —  p erf or me d b y re prese ntati ves of re g ulat or y a ut h orities wit h 
res p o nsi bilit y f or o versi g ht of t he st u d y or a p pr o v al of t he i n vesti gati o nal a ge nt. T h ese 
a ut h orities ma y b e fr o m t he c o u ntr y w h ere t he site is l ocate d or fr o m a n ot her c o u ntr y.  
M o nit ori n g a n d a u diti n g visits o n be half of t he  S p o ns or will be sc he d ule d wit h t he I n v esti gat or 
i n a d va nce a n d will be c o n d ucte d at a reas o n a ble ti me. T o facilitate t hes e visits, t he I n vesti gat or 
will ass ure t hat t he f oll o wi n g are a v aila ble:  
•  A p pr o priate s p ace, facilities a n d access t o all s o urce d oc u me nts (i n cl u di n g access t o 
c o m p uterize d rec or ds eit her electr o nicall y or as c o m plete pri nt o uts).  
•  C o nse nt/asse nt f or ms, e C R Fs, S A E f or ms, a n d me dical rec or ds f or all scree ne d a n d 
e nr olle d patie nts.  
•  Ti mel y access t o site pers o n nel, i ncl u di n g t he I n v esti gat o r, s u b I n vesti gat or(s), a n d ot her 
st u d y pers o n n el o n t he da y of t he visit t o res ol ve a n y q uesti o ns t hat aris e. 
Re g ulat or y a ut h orities ma y visit a n d r e vie w t he site a n d/ or I n vesti gat or d uri n g or after t he st u d y 
a n d ma y or ma y n ot n otif y t he I n v esti gat or or t he S p o ns or i n a d va nce. T h e I n v esti gat or will f ull y 
c o o perat e wit h re g ulat or y a u dits c o n d u cte d at a reas o na ble ti me i n a reas o n a ble ma n ner . T he 
I n v esti gat or will n otif y t he S p o ns or i m me diatel y of a n y c o ntact b y or c o m m u nicati o n fr o m 
re g ulat or y a ut h orities r e gar di n g t h e st u d y.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 7 7  of 9 8  
9. 2.  
St u d y M o nit ori n g Visits  
9. 2. 1.  
Site Q ualificati o n a n d I nitiati o n Visits  
Bef ore a n i n v esti gati o nal site ca n e nter a patie nt i nt o t he st u d y, a re pres e ntati ve of X 4 will visit 
t he site t o perf or m t he f oll o wi n g: 
•  I ns p ect t he f acilities (e. g., cli nical a n d a d mi nistrati ve areas, p har m ac y, la b orat or y).  
•  Disc uss wit h t he I n v esti gat or(s) a n d ot h er pers o n n el t heir res p o nsi bilities wit h re gar d t o 
pr ot oc ol a d her e nce, as w ell as t he res p o nsi bilities of X 4 a n d its re prese nta ti ves.  
•  Re vie w t he site trial master file (T M F ), i ncl u di n g d oc u me ntati o n relate d t o t he pr ot oc ol, 
t he I n v esti gat or, a n d ot her st u d y site pers o n nel; c orres p o n de n ce t o a n d fr o m t he I R B/I E C,  
t he S p o ns or, a n d t heir re prese ntati ves.  
•  Re vie w t he sta n dar d o p er at i n g pr o ce d ures a n d c urre nt practices relati n g t o cli nical a n d 
p har mac y acti vities, data ha n dli n g, t he I R B/I E C o versi g ht a n d t he i nf or me d c o nse nt 
pr ocess.  
9. 2. 2.  
I nteri m M o nit ori n g Visits 
D uri n g t h e st u d y, a C R A fr o m or re prese nti n g X 4 will visit t he i n vesti gati o nal site, f or t he 
f oll o wi n g:  
•  Pr o vi de i nf or mati o n a n d s u p p ort t o t he I n v esti gat or(s).  
•  C o nfir m t hat facilities re mai n acce pta ble.  
•  C o nfir m t hat t he i n vesti gati o nal tea m is a d heri n g t o t he pr ot oc ol, t hat data are bei n g 
acc ur atel y r ec or d e d i n t he case re p ort f o r ms, a n d t hat i n vesti gati o nal pr o d u ct is bei n g 
a p pr o priatel y h a n dle d a n d acc o u nte d.  
•  Perf or m s o urce data v erificati o n, i ncl u di n g verif yi n g t he d ata i n t he e C R Fs a gai nst t he 
rele va nt s o ur ce d oc u m e nts (see Secti o n  1 1. 3 ) a n d res ol vi n g a n y discre p a nci es n ote d.  
•  Rec or d a n d r e p ort a n y pr ot oc ol de viati o ns.  
•  C o nfir m t hat A Es a n d S A Es ha ve bee n pr o p erl y d oc u me nte d o n e C R Fs; t hat a n y S A Es 
ha ve bee n f or w ar de d t o  X 4; a n d t hat S A Es meeti n g criteria f or re p orti n g h a ve bee n 
f or war de d t o t he I R B/I E C.  
Bet wee n visits t he C R A will be a vaila ble as n ee d e d t o pr o vi de i nf or mati o n or s u p p ort t o t he 
I n v esti gat or(s) or ot her st aff. 
9. 2. 3.  
St u d y Cl ose o ut Visit  
T he st u d y will be c o nsi d ere d c o m plet e w he n all of t he f oll o wi n g h a ve o cc urre d:  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 7 8  of 9 8  
•  All treate d patie nts ha v e c o m plete d all sc he d ule d visits pl us a n y u ns c he d ul e d f oll o w -u p 
re q uire d b y A Es;  
•  All e C R Fs ha ve bee n c o m plete d, s u b mitte d a n d all q ueries res ol ve d;  
•  T he st u d y d ata base h as b ee n l oc ke d.  
•  T he S p o ns or or desi g nee will t he n c o n d uct a st u d y cl ose o ut visit, w hic h ma y i ncl u de, b ut 
is n ot li mite d t o, t he f oll o wi n g:  
•  Re vie w t he site T M F t o ass ure all re q uire d re g ul at or y d o c u me nts are c urre nt a n d 
c o m plete.  
•  Res ol ve a n y o pe n iss ues fr o m p ri or m o nit ori n g, a u dit or i ns pecti o n visits.  
•  Re vie w t he site’s pr o visi o ns f or meeti n g t he re q uire me nts f or rete nti o n st u d y rec or ds.  
•  Disc uss p ossi ble f ut ure site a u dits.  
•  Re vie w t he S p o ns or’s p u blicati o n p olic y.  
•  C o nfir m c o m plia nce wit h re q uire me nts f or n otif yi n g t he I R B/I E C of st u d y e ve nts, 
i ncl u di n g cl os ur e.  
•  C ollect a n y u n us e d st u d y materials f or eit her ret ur n t o t he S p o ns or or dis p osal i n a 
ma n ner a p pr o ve d b y t he S p o ns or.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 7 9  of 9 8  
1 0.  
S T A TI S TI C A L C O N SI D E R A TI O N S   
1 0. 1.  
St atistic a l a n d A n al ytic al Pl a ns 
A detaile d statistical a nal ysis pla n ( S A P) will be d e vel o pe d. T he S A P will defi ne p o p ulati o ns f or 
a nal ysis, o utli ne all data ha n dli n g c o n v e nti o ns, i ncl u di n g s oft w are, a n d s pecif y a d diti o nal 
statistical met h o ds t o be use d f or a n al ysis of s afet y, efficac y a n d p h ar mac o ki netics.  
1 0. 2.  
St atistic al H y p ot heses  
N ot a p plica ble.  
1 0. 3.  
A n al ysis D at asets  
A nal ys es will be perf or m e d usi n g t he f oll o wi n g p o p ulati o ns:  
•  Safet y P o p ulati o n —  all patie nt s w h o recei ve d at l east o ne d ose of st u d y dr u g.  
•  I nte nt-t o-Treat (I T T) P o p ulati o n —  all patie nt s w h o recei v e d at least o ne d ose of st u d y 
dr u g  
Cli nicall y E val ua ble ( C E) P o p ulati o n –  all patie nts w h o ha ve a d e q uate d ata at baseli ne 
a n d at o ne or m or e p ost -treat me nt t u m or assess me nt, a n d n o maj or pr ot oc ol deviati o ns . 
T he cli nicall y e val u a ble  p o p ulati o n ma y be o mitte d fr o m t he fi nal a nal ysis if t he 
cli nicall y e v al ua ble  p o p ulati o n  a n d I T T p o p ulati o ns if t here are n o cli nicall y mea ni n gf ul 
differe n ces i n o utc o mes bet wee n t he 2  p o p ul ati o ns.  
1 0. 4.  
Descri pti o n of St atist ic al Met h o ds 
1 0. 4. 1.  
Ge ner al A p pr oac h  
St u d y e ve nts will be r ec or de d usi n g t h e cal e n dar d ate a n d ( w h ere a p plica bl e) t he ti me t o t he 
nearest mi n ute . F or p ur p oses of p ost -st u d y a nal ysis (e. g., t a bles a n d listi n gs), st u d y da ys will be 
desi g nat e d as f oll o ws:  
•  Da y 1 is defi ne d as t he cale n dar d a y of t he first d ose  of st u d y dr u g.  
•  T he da ys pri or t o D a y 1 are desi g nate d Da y – 1, D a y – 2, et c; t here is n o D a y 0.  
•  T he da ys f oll o wi n g t he d a y of t he first d ose  of st u d y dr u g are d esi g nate d D a y  2, Da y 3, 
etc.  
•  T he da y of t he l ast d ose  of st u d y dr u g is i n dicat e d b y a d di n g t he s uffi x " L", e. g., if t h e 
last d ose  is a d mi nistere d o n Da y 4 3, it will be dis pla ye d as " Da y 4 3 L". 
•  T he da ys f oll o wi n g t he last a d mi nistrati o n of st u d y dr u g are d esi g nate d D a y  1 P, Da y 2 P, 
etc.  


X4 Pharmaceuticals, Inc. 
Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
Confidential 
Page 80 of 98 
The times of events related to dosing of study drug will be designated as minutes or hours before 
or after the time of dosing, which is designated as t = 0 (zero). Thus, 15 minutes prior to dosing 
is t = –15 min; 2 hour after dosing is designated t = 2 h.  
Missing data will not be imputed. Further details for handling of missing, duplicated or 
unscheduled data will be given in the SAP.  
If changes are made to the SAP, then these will be listed in the Clinical Study Report (CSR), 
along with an explanation as to why they occurred.  
10.4.2. 
Baseline Descriptive Statistics 
10.4.2.1. Disposition 
The number of patients who were in each analysis population, the number who received any 
study drug, the number who completed the study, and the reasons for treatment discontinuation 
will be summarized. A by-patient listing of study completion information, including the reason 
for premature study withdrawal will be presented. 
10.4.2.2. Demographics and Medical History 
Disease history, baseline medical history, and demographic variables will be summarized using 
descriptive statistics (n, mean, standard deviation, median, range) for continuous variables and 
frequency and proportion for categorical variables. 
10.4.3. 
Analyses of Safety Data 
The primary objective of the study is safety and tolerability. AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) version 16.0 (or later) and tabulated by system 
organ class and preferred term, severity, and relationship to study therapy. TLT events will be 
summarized.  
Safety observations will be analyzed using descriptive statistics and tabulation. No formal 
statistical comparisons are planned. All safety data will be presented in listings.  
The incidence of treatment emergent adverse events (defined as events occurring on or after the 
first dose of study treatment through 30 days after the last dose), grade 3 or higher events, 
treatment-related events (defined as events indicated as possibly related or related to either study 
drug), TLTs, events leading to study discontinuation, and events leading to dose modifications, 
will be summarized by system organ class and preferred term for the safety population. Events 
will also be summarized by maximum severity and relationship. By-patient listings will be 
provided for deaths, SAEs, TLTs, and AEs leading to discontinuation of treatment. 
Vitals signs, quantitative laboratory tests, and quantitative ECG intervals will be summarized 
using descriptive statistics as reported value and change from baseline by timepoint. ECOG will 
be presented as a shift from baseline to the last value on study and the worst value on study. 
Laboratory tests with CTCAE grading (v 4.03) will be summarized by shifts from baseline to the 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 8 1  of 9 8  
last gr a de a n d w orst gra d e o n st u d y. La b orat or y v al ues wit h o ut gra des will be  s u m marize d as 
s hifts fr o m bel o w, wit hi n, a n d a b o ve n or mal ra n ges b y ti me p oi nt. O p ht hal m ol o gic e x a mi nati o ns 
a n d p h ysi cal e x a mi nati o n data will be liste d.  
E x p os ure t o ni v ol u ma b a n d X 4 P -0 0 1 will be s u m marize d a n d para meters will i ncl u de d urati o n 
of treat me nt, n u m ber of d oses of eac h t hera p y recei ve d, t he i nci de n ce of p atie nts w h o ha d d osi n g 
hel d or per ma n e ntl y disc o nti n ue d.  
C o nc o mita nt me dicati o ns will be liste d b y patie nt , me dicati o n start a n d st o p dates a n d 
me dicati o n na me.  
1 0. 4. 4.  
Pla n ne d I nteri m A nal yses  
T here is n o f or mal pr o visi o n f or a n i nteri m a nal ysis i n t his earl y p has e st u d y.  
1 0. 4. 5.  
A nal ys es of t he Efficac y E n d p oi nts 
A ntit u m or acti vit y will be e val uat e d usi n g R E CI S T v 1. 1  [Eise n ha uer 2 0 0 9 ], t o deter mi ne t he 
f oll o wi n g metrics:  
•  O bjecti ve res p o ns e rat e ( O R R), w here res p o nse is defi ne d as ac hie vi n g eit h er C R or P R.  
•  Ti me t o o bjecti ve res p o nse  
•  D urati o n of o bjecti ve res p o nse  
•  Disease c o ntr ol rate ( D C R; C R + P R + S D )  
•  P F S, defi ne d as t he ti me fr o m fir st a d mi nistrati o n of c o m bi nati o n re gi me n u ntil o bjecti ve 
t u m or pr o gressi o n or deat h fr o m a n y ca us e. 
•  T T P, defi ne d as t he ti me fr o m first a d mi nistrati o n of c o m bi nati o n re gi me n u ntil o bjecti ve 
t u m or pr o gressi o n (e x cl u di n g deat hs) 
Best res p o ns e per R E CI S T v 1. 1  a n d O R R will be s u m marize d . Patie nts w h o d o n ot ha ve data 
s ufficie nt f or res p o nse assess me nt will be c o nsi dere d treat me nt fail ures. T h e n u m ber a n d 
pr o p orti o ns of res p o n ders will be s u m marize d as a perce nt of t he a nal ysis p o p ulati o n. I T T will be 
t he pri mary p o p ulati o n f or a nal ysis a n d t he C E p o p ulati o n will be c o nsi dere d s u p p orti ve.  
Disease c o ntr ol rate will be calc ul ate d as t he n u m ber of patie nt s w h o h a d C R, P R, or S D at 
1 6  wee ks a n d 2 4 wee ks di vi de d b y t he I T T p o p ulati o n.  
P F S , d urati o n of res p o ns e, a n d T T P will be s u m marize d usi n g K a pla n Mei er met h o ds. Me dia n, 
2 5 t h, a n d 7 5t h perce ntiles will be re p orte d .  
P F S will be calc ulate d fr o m t he date of first d ose t o t he ti me of d oc u me nte d P D  or deat h d ue t o 
a n y ca use. Patie nts w h o are still ali ve a n d ha v e n ot ha d P D at t he data c ut off f or t he fi nal efficac y 
a nal ysis, or w h o dr o p o ut pri or t o st u d y e n d, will be ce ns ore d at t he d ate of l ast t u m or assess me nt 
t hat t he patie nt was pr o gr essi o n-free o n or pri or t o t he data c ut off. If a patie nt be gi ns a n e w a nti-


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 8 2  of 9 8  
ca ncer t her a p y pri or t o d oc u me nte d P D ( or d eat h), t he patie nt will be ce ns ore d at t he dat e of last 
assess me nt w he n t he p atie nt was d oc u me nte d as pr o gressi o n -free pri or t o t he i nter ve nti o n. 
Patie nts wit h t w o or m ore c o nsec uti ve missi n g res p o nse assess me nts pri or t o  a visit wit h 
d oc u me nte d pr o gr essi o n ( or deat h) will be ce ns ore d at t he last date of t u m or assess me nt w he n 
t he patie nt was d oc u me nt e d t o be pr o gressi o n free. Patie nts w h o d o n ot ha ve a n y res p o ns e 
assess me nts a n d ha v e n ot die d will be ce ns ore d o n t he da y of  first d ose.  
T he me dia n d ur ati o n of P F S will be esti mate d base d o n t he 5 0t h perce ntile of t he Ka pla n -Meier 
distri b uti o n; a d diti o nal s u m mar y statistics will be prese nte d, i ncl u di n g t he 2 5t h a n d 7 5t h 
perce ntiles, 9 5 % c o nfi de nce i nter vals o n t he m e dia n, a n d pr o p orti o n of ce ns ore d data . F urt her 
details re gar di n g ce ns ori n g will be des cri be d i n t h e S A P.  
D urati o n of res p o ns e will be calc ul ate d fr o m t he d ate of first res p o nse ( C R or P R) t o t he date of 
d oc u me nte d P D f or t he s u bset of patie nts w h o ha d a best res p o nse of C R or P R.  
T T P will be calc ulate d fr o m t he first d ose date u ntil t he date of d oc u me nte d P D f or all patie nt s. 
T T P a n d d urati o n of res p o nse  will use Ka pla n -M eier met h o ds i n t he sa me ma n ner as t he a nal ysis 
of P F S a n d will be descri be d i n t he S A P.  
T u m or  Res p o nse a n d e n d p oi nts liste d a b o ve ma y als o be e x pl ore d b y usi n g t he i R E CI S T 
[Se y m o ur  2 0 1 7 ]. Det ails of t he a nal ysis will be defi ne d i n S A P.  
1 0. 4. 6.  
M ulti ple C o m paris o n/ M ulti plicit y  
N ot a p plica ble.  
1 0. 4. 7.  
Ta b ulati o n of I n di vi d ual Res p o nse Data  
T he i n di vi d ual res p o nse data will be ta b ulate d a n d t he details will be descri be d i n S A P.  
1 0. 4. 8.  
E x pl orat or y A nal yses  
T he details of e x pl orat or y a n al ys es will be descri be d i n S A P.  
1 0. 4. 9.  
P har mac o ki netic A n al ys es.  
P K data will be a nal yz e d usi n g descri pti ve statistics f or  A U C, C ma x , a n d T ma x .  
1 0. 5.  
S a m ple Size  
Wit h a sa m ple size of 2 0 patie nt s, t here is a n esti m ate d 9 5% pr o b a bilit y of o b ser vi n g at least 
o nce a n y A E (i ncl u di n g T L T) t hat has a n i nci d e n ce rat e of  1 4 %  or hi g h er.   
Alt h o u g h t he sa m ple size is base d o n feasi bilit y rat h er t ha n statistical p o wer , t he res ults of t he 
st u d y will be use d t o pr o vi de a preli mi nar y esti mate of t he effect size. T he  sa m ple size of 
2 0  patie nt s will be s uffici e nt t o e x cl u de a l o w t hres h ol d rate of res p o nse t o 
treat me nt. S pecificall y, i f an O R R  of 2 0 % or hi g her is o bser ve d, t he n t he  l o wer b o u n d of t he 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 8 3  of 9 8  
9 5 % e x act c o nfi de n ce i nt er val f or t h e pr o p orti o n of res p o n ders e x cee ds t he t hres h ol d rate of 
5 %.  T his w o ul d s u p p ort f urt her st u dies of t he c o m bi nati o n of ni v ol u ma b a n d X 4 P -0 0 1.   
D ose de -escalati o n ma y occ ur d uri n g t he st u d y if e x cessi ve T L T is o bser ve d (see Secti o n  8. 6. 2 ). 
Wit h t he de -escalati o n r ule, t he trial wit h a hi g h er T L T rate at t he starti n g d ose ( 4 0 0  m g Q D) will 
i ncreas e t he pr o ba bilit y of t he de-escalati o n t o pr ot ect patie nts’ safet y. F or i nsta nce, if t he T L T 
rate i n t he first 1 2 patie nts is 3 0 %, t he pr o ba bilit y of de-es calati o n is 2 8 %; if t he T L T rat e is 
4 0 %, t he pr o ba bilit y of d e -escalati o n is 5 6 %;  if t he T L T rat e is 5 0 %, t he pr o ba bilit y of de-
escalati o n is 8 1 %. T he d e -escal ati o n r ule will ser v e as statistical g ui d a nce.  
1 0. 6.  
Me as ures t o Mi ni mize Bi as  
1 0. 6. 1.  
E nr oll me nt/ Ra n d o mizati o n/ Mas ki n g Pr oce d ures  
All patie nts will be treate d o pe n -la bel; n o bli n di n g met h o ds will be e m pl o ye d.  
1 0. 6. 2.  
E val uati o n of S uccess of Bli n di n g  
N ot a p plica ble.  
1 0. 6. 3.  
Brea ki n g t he St u d y Bli n d/ Partici pa nt  C o de  
N ot a p plica ble.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 8 4  of 9 8  
1 1.  
S O U R C E D O C U M E N T S A N D  A C C E S S T O S O U R C E 
D A T A/ D O C U M E N T S  
S o urce d oc u me nts are t h e ori gi n als of a n y d oc u m e nts use d b y t h e I n vesti gat or, h os pital, or 
i nstit uti o n t hat verif y t h e e xiste nce of t he patie nt a n d s u bsta ntiate t he i nte grit y of t he dat a 
c ollecte d d uri n g t he st u d y.  
1 1. 1.  
Me dic al Rec o r ds  
Me dical rec or ds r elate d t o t he patie nt’s r o uti ne cli nical care, i ncl u di n g pri or t o or d uri n g t he 
st u d y:  
•  I nf or mati o n o btai ne d fr o m t he patie nt’s pers o nal p h ysicia ns or ot her t hir d parties 
re gar di n g t he p atie nt’s m e dical hist or y or pri or p h ysical c o n diti o n. 
•  Me dicati o n prescri pti o n a n d a d mi nistrati o n rec or ds.  
•  La b orat or y re p orts, i ncl u di n g cli nical p at h ol o g y a n d dia g n ostic hist ol o gi c pat h ol o g y.  
•  Re p orts of i ma gi n g st u di es.  
•  Data a n d r e p orts fr o m a ut o mate d i nstr u me nts (e. g., vital si g ns).  
•  Me dical rec or ds r elat i n g t o sc he d ule d a n d u nsc h e d ule d cli nical visits 
1 1. 2.  
St u d y -S pecific S o urce D oc u me nts  
St u d y -s pecific so urce d o c u me nts i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  T he i nf or me d c o ns e nt f or m, si g ne d a n d d ate d b y t he patie nt.  
•  T he site scree ni n g l o g.  
•  A n y cli nic al re p orts n ote d a b o ve t hat are sc h e d ule d as part of t he pr ot oc ol a n d ha ve bee n 
a n n otate d t o i n dicate t he si g nifica n ce of a n y a b n or mal fi n di n gs.  
•  C o nc o mita nt me dicati o n prescri pti o n a n d a d mi nistrati o n rec or ds .  
•  Rec or ds rel ati n g t o sc h e d ule d a n d u nsc he d ule d st u d y visits, i ncl u di n g, b ut n ot li mite d t o, 
res ults of e x a mi nati o ns, o bser vati o ns relati n g t o A Es, a n d c o nc o mita nt m e dicati o ns.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 8 5  of 9 8  
1 1. 3.  
S o urce D oc u me nts R e q uire me nts  
T he f oll o wi n g d o c u me nt c haracteristics are ess e ntial t o ass uri n g d ata q ualit y a n d are re q uire d o f 
all d oc u me nts ge ner ate d b y t he I n vesti gat or a n d t h e st u d y tea m d uri n g t he c o urse of t he st u d y.  
•  Be pr e par e d at t he ti me of t he e ve nts or acti vities descri be d (i. e., c o nte m p ora ne o usl y);  
•  I n dicate b ot h t he dat e a n d ti me rec or d e d;  
•  I d e ntif y t he s o urce of all rec or d e d i nf or mati o n (e. g., t he p atie nt, direct o bs er vati o ns of t he 
rec or d er, la b orat or y r e p orts, e xter nal / hist orical s o urces).  
•  Te xt s h o ul d be rea da ble a n d u na m bi g u o us, i ncl u di n g a p plicati o n of best me dical rec or d 
practices (e . g., mi ni mal use of a b bre viati o ns; pr o per n u merical, d ose a n d p os ol o g y 
f or mats).  
Electr o nic healt h rec or d ( E H R) s yste ms m ust be c o m plia nt wit h c urre nt re g ulat or y re q uire m e nts 
f or s yst e ms c o ntai ni n g “pr otecte d healt h i nf or mati o n” ( P HI ), i ncl u di n g, b ut n ot li mite d t o: 
•  S ec urit y re q uire m e nts f or restricte d access a n d electr o nic si g n at ure s 
•  Electr o nic ti mesta m p  
•  A u dit trails f or a n y c h a n ges  or a me n d me nt  
P a per d oc u me nts m ust meet t he f oll o wi n g re q uire me nts:  
•  Be writte n le gi bl y i n dar k ( prefera bl y blac k ) i n k, i ncl udi n g si g n at ure a n d d ate.  
•  Be si g ne d ( or i nitiale d), wit h date a n d ti me, b y t he rec or der . T he site m ust mai ntai n a 
f or mal l o g s h o wi n g f or all st u d y pers o n n el pri nte d na me, f ull si g n at ures, a n d i nitials.  
•  I n t he e ve nt t hat a n y e ntr y nee ds t o be c h a n ge d, a sin gle li ne will be ma de t hr o u g h t h e 
ori gi nal e ntr y, t he c orrect i nf or mati o n e ntere d ( or refere nce d) o n t he sa m e p a ge , a n d t he 
acti o n i nitiale d, date d, a n d (if a p pr o pri ate) e x plai ne d . T he ori gi nal e ntr y m ust n ot be 
o bsc ure d or o bliter ate d b y m ulti ple cr oss -o ut, c orrecti o n fl ui d or o verla y of ot her 
material.  
S t u d y-s pecific s o urce d o c u me nt f or ms create d b y t he site  m ust be re vie we d b y t he S p o ns or pri or 
t o use. 
1 1. 4.  
Electr o nic C ase Re p ort F o r ms (e C R Fs)  
T he S p o ns or  will pr o vi de a re g ulat or y-c o m plia nt electr o nic data ca pt ure (E D C ) s yste m f or 
re p orti n g st u d y d ata t o a ce ntral f acilit y h ol di n g t h e st u d y d ata base . All st u d y pers o n nel will be 
trai ne d o n t he s yste m a n d eac h will ha v e a u ni q ue l o gi n pass w or d a n d el ectr o nic si g nat ure.  
T he I n vesti gat or ( or q ualifie d s u b -I n vesti gat or a p pr o ve d b y t he S p o ns or) will re vie w all eC R Fs 
a n d i n dicate t heir c o nc urre nce b y (electr o nic) si g n at ure.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 8 6  of 9 8  
1 2.  
Q U A LI T Y A S S U R A N C E A N D  Q U A LI T Y C O N T R O L  
1 2. 1.  
St u d y M o nit ori n g  
M o nit ori n g a n d a u diti n g pr oce d ur es de vel o p e d b y t he S p o ns or or desi g n ee will be f oll o we d, i n 
or der t o c o m pl y wit h IC H G C P g ui deli nes , as d escri be d i n Secti o n 9. 2 .  
1 2. 2.  
C ase Re p ort F or m C o m pleti o n  
T he S p o ns or or desi g nee will pr o vi de t he st u d y ce nters wit h e C R Fs f or eac h patie nt.  
e C R Fs will be c o m plete d f or eac h st u d y patie nt . It is t he I n v esti gat or’s res p o nsi bilit y t o e ns ure 
t he acc urac y, c o m plete ness, an d ti meli ness of t he data re p orte d i n t he patie nt’s e C R F . S o urce 
d oc u me ntati o n s u p p orti n g t he e C R F data s h o ul d i n dicate t he patie nt’s p arti ci pati o n i n t he st u d y 
a n d s h o ul d d oc u me nt t he dates a n d details of st u d y pr o ce d ures, A Es, a n d p atie nt stat us .  
T he I n vesti gat or, or d esi g nat e d re prese ntati ve, s h o ul d c o m plete t he e C R F as s o o n as p ossi ble 
after i nf or mati o n is c ollecte d, prefer a bl y o n t h e sa me da y t hat a patie nt is s ee n f or a n 
e x a mi nati o n, treat me nt, or a n y ot her st u d y pr o ce d ure . A n y o utsta n di n g e ntri es m u st be 
c o m plete d i m me diatel y after t he fi nal e x a mi nati o n . A n e x pla nati o n s h o ul d be gi v e n f or all 
missi n g data.  
T he I n vesti gat or m ust electr o nicall y si g n a n d date t he I n v esti gat or’s State m e nt at t he e n d of t he 
e C R F t o e n d orse t he rec or de d data .  
1 2. 3.  
C o m p uterize d  S yste ms / Me dic al Rec o r ds as S o urce D at a  
All st u d y data r ec or d e d o n s o urce d oc u m e nts are t o be tra nscri b e d i nt o t he e C R Fs . A n y 
electr o nic st u d y dat a ar e t o be e ntere d i nt o a s ec ure, vali date d data pr ocessi n g s yste m a n d a 
bac k u p mai ntai ne d . A n y c ha n ges t o electr o nic st u d y dat a will be d oc u me nt e d.  
1 2. 4.  
A u dits a n d I ns pecti o ns  
A ut h orize d re pres e ntati ves of S p o ns or or desi g nee, a re g ul at or y a ut h orit y, or I R B /I E C ma y visit 
t he st u d y ce nter t o perf or m a u dits or i ns pecti o ns, i ncl u di n g s o urce dat a verificati o n. T he p ur p os e 
of a S p o ns or  a u dit or i ns pecti o n is t o s yste maticall y a n d i n de p e n de ntl y e x a mi ne all st u d y -relate d 
acti vities a n d d oc u me nts t o deter mi ne w het her t hese acti vities were c o n d ucte d, a n d data w ere 
rec or d e d, a n al yze d, a n d acc urat el y re p ort e d acc or di n g t o t he pr ot oc ol, I C H G C P, a n d a n y 
a p plica ble r e g ulat or y r e q uire me nts.  
T he i n vesti gat or s h o ul d c o ntact t he S p o ns or i m me diatel y if c o ntacte d b y a re g ul at or y a ge n c y 
a b o ut a n i ns pecti o n.  
1 2. 5.  
Res ol uti o n of Deficie ncies  
T he I n vesti gat or a grees t o ta ke pr o m ptl y a n y reas o na ble ste ps re q u este d b y t he S p o ns or t o 
res ol ve a n y d eficie n cies i de ntifie d as a res ult of m o nit ori n g, a u dits, i ns pecti o ns, pr ot oc ol 


X4 Pharmaceuticals, Inc. 
Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
Confidential 
Page 87 of 98 
deviations, or review of any other study documentation. Failure to take adequate remedial action 
can result in suspension or termination of the study at the site. 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 8 8  of 9 8  
1 3.  
E T HI C S/ P R O T E C TI O N O F  H U M A N S U B J E C T S  
1 3. 1.  
E t hic al St a n d ar d 
T he S p o ns or a n d a n y t hir d part y t o w h o m as pects of t he st u d y ma n a ge me nt or m o nit ori n g ha v e 
bee n dele gate d will u n derta ke t heir assi g n e d r oles f or t his st u d y i n c o m plia nce wit h all a p plica ble 
i n d ustr y r e g ulati o ns, t he et hical pri nci ples state d i n t he Declarati o n of H elsi n ki, a n d I C H G C P 
G ui deli ne E 6 .  
I C H G C P G ui deli ne E 6 is a vaila ble at: 
htt p:// w w w.ic h. or g/filea d mi n/ P u blic _ We b _ Site/I C H _ Pr o d ucts/ G ui deli nes/ Efficac y/ E 6 _ R 1/ Ste
p 4/ E 6 _ R 1 _ _ G ui deli ne. p df   
1 3. 2.  
I nstit uti o n al Re view B o ar d  
T he I R B /I E C will re vi e w all a p pr o priate st u d y d oc u me ntati o n i n or der t o safe g uar d t h e ri g hts, 
safet y, a n d w ell-bei n g of t he patie nts . T he st u d y will o nl y b e c o n d uct e d at st u d y ce nters w h ere 
I R B/I E C a p pr o v al has bee n o btai ne d . T he pr ot oc ol, I n vesti g at or’s Br oc h ure, i nf or me d c o ns e nt, 
a d vertise me nts (if a p plica ble), writte n i nf or mati o n gi ve n t o t he p atie nts (i ncl u di n g diar y car ds), 
safet y u p dates, a n n ual pr o gr ess re p orts, a n d a n y re visi o ns t o t hese d oc u me nts will be pr o vi de d t o 
t he I R B/I E C b y t he I n v es ti gat or. 
T he fi nal st u d y pr ot oc ol, i ncl u di n g t he fi nal v ersi o n of t he I nf or m e d C o nse nt F or m, m ust be 
a p pr o ve d or gi v e n a f a v ora ble o pi ni o n i n writi n g b y a n I R B/I E C as a p pr o pri ate. Writte n I R B/I E C 
a p pr o val m ust be recei ve d b y t he S p o ns or or d esi g nee bef ore a site ca n e nr oll a n y patie nt i nt o t he 
st u d y. 
T he I n vesti gat or is r es p o nsi ble f or i nf or mi n g t h e I R B/I E C of a n y a m e n d me nt t o t he pr ot oc ol i n 
acc or d a nce wit h l ocal re q uire me nts . I n a d diti o n, t he I R B/I E C m ust a p pr o v e all a d vertisi n g use d 
t o recr uit patie nts for t h e st u d y . T he pr ot oc ol (a n d ot her a me n de d st u d y d o c u me nts) m ust be re -
a p pr o ve d b y t he I R B/I E C u p o n recei pt of a m e n d me nts a n d a n n uall y, as l o cal re g ulati o ns re q uire . 
T he I n vesti gat or is als o r es p o nsi ble f or pr o vi di n g t he I R B/I E C wit h re p orts of a n y re p o rta ble 
seri o us a d vers e dr u g r eacti o ns fr o m a n y ot her st u d y c o n d u cte d wit h t he i n v esti gati o nal pr o d u ct . 
T he S p o ns or will pr o vi de t his i nf or mati o n t o t he I n vesti gat or.  
Pr o gr ess re p orts a n d n otificati o ns of seri o us a d v erse dr u g reacti o ns will be pr o vi de d t o t he 
I R B/I E C acc or di n g t o l ocal re g ulati o ns a n d g ui d eli nes.  
1 3. 3.  
I nf or me d C o nse nt Pr ocess  
1 3. 3. 1.  
C o nse nt/asse nt a n d O t her Inf or mati o nal D oc u m e nts P r o vi de d t o P artici pa nt s 
T he I n vesti gat or(s) at eac h ce nter will e ns ure t hat t he patie nt is gi ve n f ull a n d a de q uate oral a n d 
writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris k a n d be nefit of t he st u d y . Patie nts 
m ust als o be n otifie d t hat t he y are free t o disc o nti n ue fr o m t he st u d y at a n y ti me . T he patie nt 


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 8 9  of 9 8  
s h o ul d be gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d all o we d ti me t o c o nsi der t he i nf or mati o n 
pr o vi de d . T his pr ocess s h o ul d be rec or de d i n t he p atie nt’s s o urce d o c u me nt ati o n.  
T he patie nt’s si g ne d a n d date d i nf or me d c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y st u d y 
pr oce d ur es . D oc u m e ntati o n of t he c o nse nti n g pr oces s m ust be rec or de d i n t he patie nt’s s o urce 
d oc u me nts.  
1 3. 3. 2.  
C o nse nt P r oce d ures a n d D oc u me ntati o n  
T he I n vesti gat or(s) m ust mai ntai n t he ori gi nal, si g ne d I nf or me d C o ns e nt F or m . A c o p y of t he 
si g ne d I nf or me d C o nse nt F or m m ust be gi ve n t o t he patie nt, a n d t his m ust be d oc u me nte d i n t he 
patie nt’s s o urce d o c u me nts.  
1 3. 4.  
P a rtici p a nt  a n d D at a C o nfi de nti alit y  
I n or der t o mai ntai n patie nt pri vac y, all e C R Fs, st u d y dr u g acc o u nta bilit y rec or ds, st u d y re p orts, 
a n d c o m m u nicati o ns will i de ntif y t he p atie nt b y i nitials (as all o we d b y l ocal re g ulati o ns) a n d t he 
assi g ne d p atie nt n u m ber . T he I n vesti gat or will gra nt m o nit or(s) a n d a u dit or(s) fr o m t he S p o ns or 
or its desi g nee a n d r e g ulat or y a ut h orit y(i es) access t o t he patie nt’s ori gi n al me dical rec or ds f or 
verificati o n of d ata gat here d o n  t he e C R Fs a n d t o a u dit t he data c ollecti o n pr ocess. T he p atie nt’s 
c o nfi de ntialit y will be m ai ntai ne d a n d will n ot be ma de p u blicl y a vaila ble t o t he e xte nt per mitte d 
b y t he a p plica ble la ws a n d re g ulati o ns.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 9 0  of 9 8  
1 4.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  
1 4. 1.  
D at a C o llecti o n a n d M a n a ge me nt Res p o nsi bilities  
All st u d y data r ec or d e d o n s o urce d oc u m e nts are t o be tra nscri b e d i nt o t he e C R Fs . A n y 
electr o nic st u d y dat a ar e t o be e ntere d i nt o a s ec ure, vali date d data pr ocessi n g s yste m a n d a 
bac k u p mai ntai ne d . A n y c ha n ges t o e lectr o nic st u d y dat a will be d oc u me nt e d. 
1 4. 2.  
St u d y Rec or ds Rete nti o n  
T he I n vesti gat or will mai ntai n all st u d y rec or ds acc or di n g t o I C H G C P a n d a p plica ble re g ulat or y 
re q uire me nt(s). Rec or ds will be retai ne d f or at least 2 years aft er t he last m ar keti n g a p plicat i o n 
a p pr o val or 2 years after f or mal disc o nti n uati o n of t he cli nical de vel o p me nt of t he i n vesti gati o nal 
pr o d uct or acc or di n g t o a p plica ble re g ulat or y re q uire me nt(s) . If t he I n vesti gat or wit h dra ws fr o m 
t he res p o nsi bilit y of kee pi n g t he st u d y rec or ds, c ust o dy m ust be tra nsferre d t o a pers o n willi n g t o 
acce pt t he res p o nsi bilit y. T he S p o ns or m ust be n otifie d i m me diatel y b y tel e p h o ne or e -m ail a n d 
t he n otificati o n c o nfir me d i n writi n g if a c ust o dial c ha n ge o cc urs. 
1 4. 3.  
Pr ot oc ol D e vi ati o ns  
A pr ot oc ol de viati o n is def i ne d as a n e ve nt i n w hi c h t he I n vesti gat or or site pers o n nel di d n ot 
c o n d uct t he st u d y acc or di n g t o t he Pr ot oc ol, i ncl u di n g c o m plia nce re q uire me nts a n d a gree me nts . 
G ui deli nes f or mi n or pr o ce d ural v ariati o ns (e. g., c ollecti o n ti me of bl o o d sa m ples) will be a gree d 
t o a n d d oc u me nte d b y t h e I n vesti gat or a n d t h e S p o ns or pri or t o starti n g t h e st u d y. E ve nts 
c o nf or mi n g t o t h ose g ui d eli nes will n ot be c o nsi dere d de viati o ns.  
F or pr ot oc ol d e viati o ns r elati n g t o i n di vi d ual patie nts, t he e ve nt a n d rele v a nt circ u msta nce s will 
be rec or de d o n s o ur ce d o c u me nts a n d o n t he a p pr o priate eC R F; re p orte d t o t he S p o ns or i n a 
ti mel y ma n ner; a n d pres e nte d i n t he Cli nical St u d y Re p ort .  
De viati o ns t hat are n ot p atie nt -s pecific (e. g., u n a ut h orize d use of a n i n vesti gati o nal a ge nt o utsi de 
t he pr ot oc ol, eit her h u ma n a d mi nistrati o n or la b orat or y us e) will be re p orte d t o t he S p o ns or i n 
writi n g a n d c o pies place d i n t he T M F.  
De viati o ns t hat ca n be a ntici pate d s h o ul d, if p ossi ble, be disc usse d wit h t he S p o ns or bef ore bei n g 
i m ple me nte d. 
1 4. 4.  
P u blic a ti o n a n d D at a S h ari n g P olic y 
X 4 rec o g nizes t he i m p ort a nce of c o m m u nicati n g t he res ults of scie ntific st u dies, i ncl u di n g 
cli nical st u dies, a n d, t her ef ore, e nc o ur a ges t heir p u blicati o n i n re p uta ble scie ntific j o ur nals a n d 
prese ntati o n at se mi nars or c o nfere n ces. X 4 als o h as le giti mate c or p orate a n d s hare h ol der 
res p o nsi bilities, i ncl u di n g, b ut n ot li mite d t o, pr otecti n g c o nfi de ntial i nf or mati o n a b o ut its 
pr o prietar y pr o d ucts a n d o btai ni n g pate nt pr ot ecti o n f or its i ntellect ual pr o pert y.  


X 4 P har mace uticals, I n c.  
P r ot oc ol X 4 P -0 0 1 -R C C B , Versi o n 3 . 0 (0 5  J ul 2 0 1 7 ) 
 
C o nfi de ntial  
P a ge 9 1  of 9 8  
T heref ore, t he f oll o wi n g pr oce d ur es a p pl y t o a n y c o m m u nicati o n (i ncl u di n g writte n, oral, or 
electr o nic; ma n us cri pt, a bstract, ot her p u blicati o n, or prese ntati o n) of res ults or i nf or mati o n 
arisi n g fr o m t his st u d y (i ncl u di n g a n y a ncillar y st u dies i n v ol vi n g st u d y p atie nts) t o a n y t hir d 
parties:  
•  T he pr o p ose d c o m m u nicati o n will be pre pare d i n c olla b orati o n wit h t he S p o ns or.  
•  T he fi nal pr o p ose d v ersi o n m ust be s u b mitte d t o X 4 f or re vie w a n d c o m me nt at least 
3 0  da ys pri or t o pres e ntati o n, s u b missi o n f or p u blicati o n or ot her disse mi nat i o n. 
•  I n t he e ve nt X 4 reas o n a bl y deter mi nes t hat a pr o p ose d c o m m u nicati o n c o ntai ns 
c o nfi de ntial or pat e nta ble material, t he y ma y re q uire eit her of t he f oll o wi n g:  
-  T he material be re m o ve d fr o m t he c o m m u nicati o n;  
-  T he c o m m u nicati o n be d ela ye d f or u p t o 6 0 a d d iti o nal da ys t o per mit fili n g t he 
a p pr o priate i ntellect ual pr o pert y pr otecti o n.  
T hese pr oce d ur es a p pl y r e gar dless of w het her t he st u d y is c o m plete d as pla n ne d or is ter mi nate d 
pre mat urel y f or a n y r eas o n.  


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Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
Confidential 
Page 92 of 98 
15. 
STUDY ADMINISTRATION 
Key personnel, along with relevant contact information, are provided in the study operational 
manual. 


X4 Pharmaceuticals, Inc. 
Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
Confidential 
Page 93 of 98 
16. 
CONFLICT OF INTEREST POLICY 
The conflict of interest policy is addressed in the Clinical Trial Agreement. 


X4 Pharmaceuticals, Inc. 
Protocol X4P-001-RCCB, Version 3.0 (05 Jul 2017) 
 
Confidential 
Page 94 of 98 
17. 
LITERATURE REFERENCES  
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X 4 P har mace uticals, I n c.  
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1 8.  
A P P E N DI C E S  
1 8. 1.  
Re visi o n Hist or y  a n d S p o ns or Si g n at ure  
T he re visi o n hist or y is s u m marize d i n  Ta ble 1 8- 1 . Si g nifica nt re visi o ns ma de i n eac h pr ot oc ol 
versi o n are pr o vi de d i n a se parat e S u m mar y of C ha n ges d oc u me nt. 
T a ble 1 8- 1: 
P r ot oc ol Re visi o n Hist or y  
Ver. N o.  
D ate  
C o m me nt  
1. 0 
0 6 Ma y 2 0 1 6 
I nitial s u b missi o n t o F D A 
2. 0 
2 0 Fe b 2 0 1 7 
Re -f or matte d d oc u me nt; a ll o w patie nts wit h hist or y of brai n met astases 
if sta ble; ad d st o p pi n g r ule wit h  D R C re vie w f oll o wi n g t he first 
1 2 patie nts; i nc or p orate c ha n ges as d oc u me nte d i n 1 3 Oct 1 6 N T F ; 
i nc or p orate d u p dates t o st u d y dr u g Refere nce Safet y I nf or mati o n 
( X 4 P- 0 0 1 I B v 4 & Fe br uar y 2 0 1 7 ni v ol u ma b  U S PI)  
3. 0 
0 5 J ul 2 0 1 7  
M o difie d e xcl usi o n criteria a n d mi n or a d mi nistrati ve c ha n ges 
 
T his pr ot oc ol Versi o n 3. 0 has bee n pr e pare d a n d a p pr o ve d b y t he S p o ns or.  
  
 
 
X 4 P har mace uticals, I nc.  
 
 
  
Si g nat ure  
Date  
 
 
 
  
  
X 4 P har mace uticals, I nc.  
 
 
  
Si g nat ure  
Date  


X 4 P har mace uticals, I n c.  
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1 8. 2.  
P ot e nti al C Y P -R el ate d D ru g -Dr u g Inter a cti o ns 
Str o n g C Y P 3 A  
i n hi bit or1 
Str o n g C Y P 3 A 
i n d ucer1 
M o der ate 
C Y P 3 A 
i n hi bit or2 
M o der ate 
C Y P 3 A 
i n d ucer2 
C Y P 2 D 6 se nsiti ve 
s u bstr ate 1 
C Y P 2 D 6 
m o der ate 
se nsiti ve 
s u bstr ate 2 
b oce pre vir, 
clarit hr o m yci n, 
c o bicistat, 
c o ni va pta n, 
da n o pre vir a n d 
rit o na vir, diltiaze m, 
el vite gra vir a n d 
rit o na vir, gra pefr uit 
j uice, i delalisi b, 
i n di na vir, 
itrac o naz ole, 
ket oc o naz ole, 
l o pi na vir a n d 
rit o na vir, 
mi befra dil, 
nefaz o d o ne, 
nelfi na vir, 
parita pre vir a n d 
rit o na vir, 
o m bitas vir a n d/ or 
dasa b u vir, 
p osac o naz ole, 
sa q ui na vir, 
tela pre vir, 
telit hr o m yci n, 
ti prana vir a n d 
rit o na vir, 
tr olea n d o m yci n, 
v oric o naz ole  
car ba maze pi ne, 
e nzal uta mi de, 
mit ota ne, 
p he n yt oi n, 
rifa m pi n, 
St. J o h n’s w ort  
a m pre na vir, 
a pre pita nt, 
ataza na vir, 
ci meti di ne, 
ci pr ofl o xaci n, 
cl otri maz ole, 
criz oti ni b, 
c ycl os p ori ne,  
dar u na vir a n d 
rit o na vir, 
d r o ne dar o ne, 
er yt hr o m yci n, 
fl uc o naz ole, 
fl u v o xa mi ne, 
f osa m pre na vir, 
i mati ni b, 
t ofis o pa m, 
vera pa mil  
b ose nta n, 
efa vire nz, 
etra viri ne, 
m o dafi nil,  
nafcilli n   
at o m o xeti ne, 
desi pra mi ne, 
de xtr o met h or p ha n, 
eli gl ustat, ne bi v ol ol, 
n ortri pt yli ne, 
per p he nazi ne, 
pi m ozi de, 
t hi ori dazi ne, 
t olter o di ne, 
ve nlafa xi ne  
a mitri pt yli ne, 
e ncai ni de, 
i mi pra mi ne, 
met o pr ol ol, 
pr o pafe n o ne, 
pr o pra n ol ol, 
tra ma d ol, 
tri mi pra mi ne 
1  Pr o hi bite d . 
2  Use wit h Me dical M o nit or a p pr o val o nl y . 
N ote: T his list of dr u gs ma y n ot be a c o m plete list, c o ns ultati o n wit h t he me dical m o nit or is re q ueste d f or a n y 
c o ncer ns a b o ut c o nc o mita nt me dicati o n use.  
S o urces:   
htt p:// w w w.f da. g o v/ Dr u gs/ De v el o p me nt A p pr o val Pr o cess/ De v el o p me nt Res o urces/ Dr u gI nteracti o ns La b eli n g/ u c m 0 8 0 4 9 9. ht m  
htt p://la beli n g. pfizer.c o m/ S h o w La b eli n g.as p x?i d = 7 5 9  
 

SAP_001.pdf: 
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S T A TI S TI C A L A N A L Y SI S P L A N  
A P h ase 1 b/ 2 a Tri al A d di n g X 4 P -0 0 1 i n P atie nts Recei vi n g Ni v ol u m a b 
f or Tre at me nt of A d v a nce d Cle ar Re n al Cell C arci n o m a 
Pr ot oc ol N u m ber:  
X 4 P -0 0 1 -R C C B  
Pr ot oc ol V ersi o n a n d D ate:  
V 3 . 0 J ul y 0 5, 2 0 1 7 
St u d y Dr u g N a me:  
X 4 P -0 0 1  
P h ase:  
P hase 1 b / 2a 
S p o ns or:  
X 4 P har mace uticals, I nc.  
A n al ysis Pl a n D ate:  
Se pte m ber  1 4 , 2 0 1 8  
A n al ysis Pl a n Versi o n:  
Versi o n 1. 1  
 
C o nfi de nti alit y St ate me nt  
All i nf or mati o n c o ntai ne d i n t his d oc u me nt is pri vile ge d a n d c o nfi d e ntial t o X 4 
P har mace uticals, I nc. A n y distri b uti o n, c o p yi n g, or discl os ure is strictl y pr o hi bite d wit h o ut 
pri or writte n a p pr o v al b y X 4. 
N C T # : N C T 0 2 9 2 3 5 3 1


 
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S P O N S O R SI G N A T U R E P A G E  
Pr ot oc ol Title:  
A P hase 1 b/ 2a Trial A d di n g X 4 P -0 0 1 i n Patie nts Recei vi n g 
Ni v ol u ma b f or Treat me nt of A d va nce d Clear Cell Re nal Cell 
Carci n o ma  
Pr ot oc ol N u m ber:  
X 4 P -0 0 1 -R C C B   
S p o ns or:  
X 4 P har mace uticals, I nc.  
9 5 5 Massac h usetts A ve, 4 t h Fl o or 
Ca m bri d ge, M A 0 2 1 3 9 
B y si g ni n g t his d oc u m e nt, I ac k n o wl e d ge t hat I ha ve rea d  t he d oc u me nt a n d a p pr o v e of t he 
pla n ne d statistical a nal ys es descri be d h erei n. I a gree t hat t he pla n ne d statistical a nal ys es are 
a p pr o priate f or t his st u d y, are i n acc or d a nce wit h t he st u d y o bjecti ves, a n d are c o nsiste nt wit h 
t he  statistical  met h o d ol o g y  descri be d  i n  t he  pr ot oc ol,  cli nical  de vel o p me nt  pla n,  a n d  all  
a p plica ble r e g ulat or y g ui da nce a n d g ui deli nes.   
A ut h or  
 
 
 
L L X  S ol uti o ns, L L C 
Si g nat ure:  
Date:  
 
A p pr o ver:  
 
 
 
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Si g nat ure:  
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T A B L E O F C O N T E N T S  
S P O N S O R SI G N A T U R E P A G E .................................................................................................................. 2  
T A B L E O F C O N T E N T S  .............................................................................................................................. 3  
LI S T O F T A B L E S I N C L U D E D I N T H E T E X T  ......................................................................................... 6  
A B B R E VI A TI O N S  ...................................................................................................................................... 7  
1  
I N T R O D U C TI O N ............................................................................................................................... 8  
2  
S T U D Y D E SI G N O V E R VI E W  .......................................................................................................... 9  
3  
S T U D Y O BJ E C TI V E S  ...................................................................................................................... 1 2  
4  
S T U D Y E N D P OI N T S A N D E V A L U A TI O N S  ................................................................................ 1 3  
5  
D E FI NI TI O N S A N D C O N V E N TI O N S F O R D A T A H A N D LI N G  ................................................. 1 5  
5. 5. 1  
Ha n dli n g of Re peate d Cli nical La b orat or y T ests  ................................................................ 1 6  
5. 5. 2  
Ha n dli n g of Partial Dates  .................................................................................................... 1 6  
6  
P L A N N E D A N A L Y SI S  .................................................................................................................... 1 7  


 
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7  
A N A L Y SI S P O P U L A TI O N S A N D A P P LI C A TI O N S  ..................................................................... 1 8  
8  
S T A TI S TI C A L C O N SI D E R A TI O N S  ............................................................................................... 1 9  
8. 4. 1  
De m o gra p hics a n d Baseli ne C haracteristics  ....................................................................... 2 0  
8. 4. 2  
Ser ol o g y T ests  ..................................................................................................................... 2 0  
8. 4. 3  
Me dical Hist or y ................................................................................................................... 2 0  
8. 4. 4  
Pri or Ca ncer Treat me nt/ Pr oce d ures f or Re nal Cell Carci n o ma  .......................................... 2 1  
8. 4. 5  
Pri or a n d C o nc o mita nt Me dicati o n  ..................................................................................... 2 1  
8. 4. 6  
Pr o g n osis Fact ors  ................................................................................................................ 2 1  
8. 5. 1  
A d verse E ve nts  ................................................................................................................... 2 1  
8. 5. 2  
Treat me nt E x p os ure  ............................................................................................................ 2 3  
8. 5. 3  
Cli nical La b orat or y T ests  .................................................................................................... 2 5  
8. 5. 4  
P h ysical E xa mi nati o n Fi n di n gs  ........................................................................................... 2 5  
8. 5. 5  
O p ht hal m ol o gic E xa mi nati o n  ............................................................................................. 2 5  
8. 5. 6  
Vital Si g ns  ........................................................................................................................... 2 5  
8. 5. 7  
E C O G perf or ma nce stat us  .................................................................................................. 2 5  
8. 5. 8  
Electr ocar di o gra m ( E C G)  ................................................................................................... 2 5  
8. 6. 1  
R E CI S T v 1. 1 Base d Assess me nt  ........................................................................................ 2 6  
8. 6. 2  
i R E CI S T Base d Assess me nt ............................................................................................... 2 7  


 
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9  
Refere nces  .......................................................................................................................................... 2 8  
 
 
 


 
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LI S T O F T A B L E S I N C L U D E D I N T H E T E X T  
T a ble 1: Sc he d ule of E ve nts  ....................................................................................................................... 1 0  
T a ble 2: A p plicati o n of P o p ulati o ns o n Ta bles a n d Fi g ures  ....................................................................... 1 8  
 
 
 


 
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A B B R E VI A TI O N S  
A b bre vi ati o n  
E x pl a n ati o n  
a C S R 
A b bre viate d Cli nical St u d y Re p ort  
A E  
A d verse E ve nt  
cc R C C 
Clear Cell Re nal Cell Carci n o ma  
C E  
Cli nicall y E val ua ble  
C R  
C o m plete Res p o nse  
C R F  
Case Re p ort F or m  
C S  
Cli nicall y si g nifica nt  
C X C L 1 2  
C -X -C C he m o ki ne Li ga n d T y pe 1 2 (als o desi g nate d S D F -1)  
D C R  
Disease C o ntr ol Rate  
E C G  
Electr ocar di o gra m  
i R E CI S T 
Res p o nse E val uati o n Criteria i n S oli d T u m ors f or i m m u ne -base d t hera pe utics  
I T T 
I nte nt-t o-Treat  
M D S Cs  
M yel oi d -deri ve d s u p press or cells  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
N C S  
N o n -Cli nicall y si g nifica nt  
O R R  
O bjecti ve Res p o nse Rate  
P B M C  
Peri p heral bl o o d m o n o n uclear cell  
P D  
Pr o gressi ve Disease  
P F S  
Pr o gressi o n Free S ur vi val  
P K  
P har mac o ki netics  
P R  
Partial Res p o nse  
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A nal ysis Pla n  
S D  
Sta ble Disease  
S O C  
S yste m Or ga n Class  
S T D  
Sta n dar d De viati o n  
T E A E  
Treat me nt E mer ge nt A d verse E ve nt  
T L T  
Treat me nt -Li miti n g T o xicit y  
Tre g  
T Re g ulat or y  
T T P  
Ti me t o Pr o gressi o n  
W B C  
W hite Bl o o d Cell  
W H O  
W orl d Healt h Or ga nizati o n  
 


 
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1  I N T R O D U C TI O N  
T his statistical a nal ysis pla n is desi g ne d t o o utli ne t he statistical met h o ds i n e val uati n g t he safet y 
a n d t olera bilit y of X 4 P-0 0 1 use d i n c o m bi nati o n wit h ni v ol u ma b i n patie nts t olerati n g ni v ol u ma b 
b ut n ot e x hi biti n g ra di ol o gic r es p o nse  i n st u d y pr ot oc ol X 4 P -0 0 1 -R C C B .  
T his d oc u me nt has b ee n pre par e d pr ot o c ol ve rsi o n 3. 0 date d 5t h J ul y 2 0 1 7 a n d Case Re p ort F or m 
( C R F) date d 1 2t h  Oct o ber 2 0 1 7.  X 4 P har mace uticals is ter mi nati n g t his st u d y earl y d ue t o t he p o or 
e nr oll me nt rate. A n a b br e viate d cli nical st u d y re p ort (a C S R) will be writte n f or t his st u d y.  T his 
re p ort will descri b e all t he safet y a n d t he selecte d efficac y i nf or m ati o n. 
Bi o mar ker s pecifi c a nal yses will be pr o vi de d i n a se parat e statistical a nal ysis pla n.   
 


 
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2  S T U D Y D E SI G N O V E R VI E W  
2. 1  
O ver all St u d y Desi g n  
T his is a si n gle-ar m, o pe n-la bel a n d m ultice nter  st u d y t o c haracterize t he safet y a n d t olera bilit y of 
a d di n g X 4 P -0 0 1 t o ni v ol u ma b treat me nt i n patie nts wit h a d va nce d cc R C C. Eli gi ble p atie nts w h o 
ha ve r ecei ve d ni v ol u ma b a n d ha v e de m o nstrate d a c o nfir m e d best res p o ns e of S D or ra di ol o gic 
pr o gressi o n ( P D) wit h o ut cli nical d eteri orati o n, as assesse d b y t heir I n vesti gat or , will be e nr olle d 
i nt o st u d y.  
U p t o 2 0 patie nts ma y r ecei ve t he pr ot o c ol -s pecifie d c o m bi nati o n treat me nt a n d c o nti n ue u ntil 
eit her:  
•  Treat me nt -Li miti n g T o xicit y ( T L T), as d efi ne d f or X 4 P -0 0 1 a n d as p er a p pr o ve d la bel f or 
ni v ol u ma b.  
•  P D, base d o n eit her cli nical or ra di ol o gi c assess me nts, usi n g fi n di n gs at st u d y e ntr y t o 
defi ne t he bas eli ne.  
•  Patie nts t hat meet ra di ol o gic criteria f or pr o gressi o n c o m pare d wit h st u d y baseli ne as 
defi ne d b y R E CI S T v 1. 1 ma y c o nti n ue i n t he st u d y if t heir I n v esti gat or j u d ges t hat b ot h of 
t he f oll o wi n g a p pl y: (a) t he patie nt is li kel y t o be n efit fr o m o n g oi n g treat me nt wit h st u d y 
treat me nt; a n d ( b) t h e patie nt d oes n ot ha ve cli nicall y si g nifi ca nt s y m pt o ms of P D.  
•  A n y  p atie nt  wit h  s u bse q ue nt  i ma gi n g  d e m o nstrati n g  i m m u ne  c o nfir m e d  pr o gressi ve  
disease (i C P D) base d o n i R E CI S T criteria m ust disc o nti n ue st u d y treat me nt .  
T o pr otect patie nts’ s afet y, a Data R e vie w C o m mittee will re vie w a vaila ble safet y dat a a n d ma k e 
a rec o m me n d ati o n o n t he pr o gress of t he st u d y d uri n g st u d y tr eat me nt.  
T he st u d y s c he d ule is prese nte d i n  Ta ble 1 . 
 
 


 
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T a ble 1 : Sc he d ule of E ve nts 
E ve nt 1 
Scree n 2 
C y cle 1  
E ve n -
n u m bere d 
c y cles ≥# 2 
O d d -
n u m bere d 
c y cles ≥# 3 
E O T 3 
E O S 4 
D a y # wit hi n C y cle 5 
 
1  
8  
1 5  
2 2  
1  
1 5  
1  
1 5  
 
 
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y, i n cl u di n g R C C  
X  
 
 
 
 
 
 
 
 
 
 
E C O G P erf or ma n ce Stat us  
X  
X  
 
 
 
X  
 
X  
 
X  
X  
P E, b o d y wei g ht, b o d y h ei g ht 6, 7 
X 7 
X  
 
 
 
X  
 
X  
 
X  
X  
Vital si g ns 8 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C T i ma gi n g 9 
X  
 
 
 
 
 
 
X  
 
X  
 
He mat ol o g y & C h e mistr y 1 0 
X 1 1 
X  
X  
X  
X  
X  
 
X  
 
X  
X  
T F Ts, C oa g ulati o n & U/ A 1 2 
X 1 1 
X 1 2 
 
 
 
 
 
X 1 2 
 
X 1 2 
 
1 2 -lea d E C G 
X  
X  
 
 
X 2 3 
 
 
X  
 
X  
X  
O p ht hal m ol o gic E xa mi n ati o n 1 3 
X 1 4 
 
 
 
 
 
 
X  
 
X  
 
Pre g na nc y test 1 5 
X  
X  
 
 
 
 
 
X  
 
X  
X  
Pre -d ose P K Sa m ple  
 
X  
X  
X  
 
 
 
X 1 6 
 
 
 
De nse P K & P D Sa m pli n g 1 7 
 
 
 
 
X  
 
 
 
 
 
 
Bl o o d bi o mar ker c ollecti o n 1 8 
 
X  
 
 
X  
 
 
X  
 
X  
X  
Arc hi ve d tiss ue 1 9 
X  
 
 
 
 
 
 
 
 
 
 
A d mi nistrati o n of ni v ol u ma b 2 0 
 
X 2 1 
 
X  
 
X  
X  
X  
X  
 
 
X 4 P -0 0 1 d ose d i n cli nic 2 2 
 
X 2 3 
X  
X  
X  
 
 
X 1 6 
 
 
 
A E & C o n Me d M o nit ori n g  
Fr o m scree ni n g t o E n d of St u d y Visit  
1.  T he sc he d ule is prese nte d relati ve t o C ycle a n d Da y wit hi n C ycl e. T h e cale n d ar d a y of t h e first a d mi nistrati o n of st u d y dr u g 
is desi g nate d Da y 1. Eac h C ycl e re prese nts 4 wee ks ( 2 8 d a ys). Pre - a n d p ost-d ose i nter vals are relati v e t o t h e ti me of oral 
a d mi nistrati o n of st u d y dr u g, d esi g n ate d 0 hr.  
2.  Scree ni n g ma y b e i nitiate d u p t o 2 8 d a ys pri or t o Da y 1. C o nfir mati o n of eli gi bilit y will b e d o n e b y S p o ns or re vie w pri or t o 
e nr oll me nt  
3.  T he E O T visit will b e p erf or me d ≤6 d a ys after t h e last d ose of st u d y dr u g or t h e d ecisi o n t o ter mi n ate treat me nt.  
4.  T he E O S visit is sc h e d ule d f or 3 0 d a ys ( ± 4 cale n d ar d a ys) after t h e last d ose of st u d y dr u g. I n t h e e ve nt t h e E O T visit is 
dela ye d, t he E O S visit will b e p erf or me d at least 1 4 d a ys after t h e E O T visit.  
5.  T o all o w f or sc h e d uli n g fle xi bilit y, o n -treat me nt visits ma y b e d o ne wit hi n ± 3 cale n d ar d a ys of t h e d a y i n dicate d.  
6.  At Scree ni n g, E O T, a n d E O S, c o m plete p h ysical e x a m ( P E); at ot her visits, e xa ms f o c use d o n areas of disease or A Es.  
7.  B o d y hei g ht is c ollecte d at scree ni n g o nl y.  
8.  Vital si g ns c o m prise h eart rate, bl o o d press ure, a n d te m p erat ure. F or p atie nts d ose d i n cli nic f or P K c ollecti o ns, vita l si g ns 
will be perf or me d pre -d ose.  
9.  C T (c hest, a b d o me n, a n d p el vis) –  f or scree ni n g p ur p oses, i ma gi n g p erf or me d as sta n d ar d of care ma y b e use d if d o n e 
≤2 8  da ys pri or t o Da y 1; w hile o n -treat me nt, i ma gi n g ma y b e p erf or me d wit h a wi n d o w of ± 4 cale n d ar d a ys; at  E O T, 
i ma gi n g is n ot re q uire d if p erf or me d i n t h e pri or 4 wee ks.  
1 0.  He mat ol o g y a n d c h e mistr y la b orat or y tests ma y b e o btai n e d u p t o 3 d a ys pri or t o visit; p erf or me d at l o cal la b; F or p atie nts 
d ose d i n cli nic f or P K c ollecti o ns, safet y la b orat or y te sts will b e c ollecte d pre-d ose.  
1 1.  Safet y la b orat or y testi n g f or eli gi bilit y s h o ul d b e p erf or me d wit hi n 1 4 d a ys pri or t o C ycle 1 Da y 1; p erf or me d at l o cal la b.  
1 2.  T F Ts, T h yr oi d F u n cti o n Tests; C o a g ulati o n st u dies a n d U/ A ( uri n al ysis) p erf or me d at Scree n i n g a n d E O T o nl y; p erf or me d 
at l ocal la b orat or y.  
1 3.  O p ht hal m ol o gic e xa mi n ati o n ma y b e p erf or me d wit h a wi n d o w of ± 4 cale n d ar d a ys.  
1 4.  Scree ni n g o p ht h al m ol o gic e xa m re p orts a n d reti n al p h ot os m ust b e s u b mitte d t o t h e s p o ns or at least 5 b usi n ess d a ys pri or t o 
C ycle 1 Da y 1 t o all o w ce ntral re vie w f or eli gi bilit y. See st u d y p p erati o n al ma n u al f or a d diti o n al d etails.  
1 5.  Pre g na nc y tests, a p plica ble o nl y t o w o me n of c hil d b eari n g p ote ntial, ma y b e uri n e or ser u m test. O n  Da y 1, t h e test res ults 
will be o bt ai n e d pri or t o d osi n g. Perf or me d at l o cal la b.  
1 6.  Pre -d ose P K sa m ple a n d X 4 P -0 0 1 d osi n g i n cli nic o nl y at C ycle 3.  
1 7.  See pr ot oc ol Secti o ns 7. 1. 2  a n d 7. 1. 3. 1  f or d etails of sa m ple c ollecti o n ti mes f or d e nse P K (ce ntral la b) a n d P D (l o cal la b). 
1 8.  Bl o o d sa m ples f or bi o mar kers; pr o cesse d at site a n d s hi p p e d t o ce ntral la b orat or y. 
1 9.  Site t o c o nfir m a vaila bilit y of ar c hi ve d t u m or tiss u e.  
2 0.  A d mi nistrati o n of ni v ol u ma b.  


 
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2 1.  P atie nts s h o ul d b e o bser ve d f or at least 1 h o ur after t h eir 1 st d ose of X 4 P -0 0 1 b ef ore recei vi n g ni v ol u ma b, t h e n o bser v e d f or 
at least 1 h o ur after ni v ol u ma b i nf usi o n o n C ycle 1 Da y 1.  
2 2. X 4 P -0 0 1 will b e self -a d mi nistere d b y t h e p atie nt, e xce pt at P K visits, w h e n it will b e a d mi nistere d i n t h e cli nic.  
2 3.  O n Da y 1, dis p e nse e ye dr o ps a n d n asal s pra y.  
2 4.  E C G assess me nt p erf or me d at 2 hr p ost -d ose ( ±  1 5 mi n).   
 
2. 2  
S a m ple Size  
U p t o 2 0 patie nts are pla n ne d t o be e nr olle d.  Wit h a sa m ple size of 2 0 patie nts, t here is a n esti mate d 
9 5 % pr o ba bilit y of o bser vi n g at least o nce a n y A E (i ncl u di n g T L T) t hat has a n i nci de nce rate of 
1 4 % or hi g h er.  
Alt h o u g h t he sa m ple size is base d o n feasi bilit y rat her t ha n statistical p o wer, t he res ults of t he 
st u d y will be use d t o pr o vi de a pr eli mi nar y esti mate of t he effect size. T he sa m ple size of 2 0 
patie nts will be s uffi cie nt t o e x cl u de a l o w t hres h ol d rate of res p o ns e t o treat me nt. S pecificall y, if 
a n O R R of 2 0 % or hi g her is o bser ve d, t he n t h e l o wer b o u n d of t h e 9 5 % e x act c o nfi d e nce i nter val 
f or t he pr o p orti o n of r es p o n ders e x cee ds t h e t hres h ol d rate of 5 %. T his w o ul d s u p p ort f urt her 
st u dies of t he c o m bi nati o n of ni v ol u ma b a n d X 4 P-0 0 1.  
2. 3  
R a n d o miz ati o n a n d Bli n di n g  
T his is a n o pe n -la bel P hase 1 b/ 2a st u d y. Patie nts will n ot be ra n d o mize d t o st u d y treat me nt.  
 
 
 


 
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3  S T U D Y O B J E C TI V E S  
3. 1  
Pri m ar y O bjecti ves  
•  T o c haracterize t he safet y a n d t olera bilit y of X 4 P -0 0 1 use d i n c o m bi nati o n wit h ni v ol u ma b 
i n patie nts t olerati n g ni v ol u ma b b ut n ot e x hi biti n g ra di ol o gic resp o nse.  
3. 2  
Sec o n d ar y O bjecti ves  
•  T o c har acterize t he p har mac o ki netics ( P K) of X 4 P -0 0 1 w he n use d i n c o m bi nati o n wit h 
ni v ol u ma b.  
•  T o c har acterize t he a ntit u m or acti vit y of t h e c o m bi nati o n of X 4 P -0 0 1 a n d ni v ol u ma b.  
3. 3  
E x pl or at or y O bjecti ves  
•  T o i n vesti gate selecte d per i p heral bl o o d bi o mar kers of i m m u ne acti vati o n d uri n g treat me nt 
wit h X 4 P -0 0 1 pl us ni v ol u ma b.  
•  T o e val uate ar c hi ve d t u m or tiss ue f or bi o mar kers t hat ma y c orrelate wit h res p o nse t o 
c o m bi nati o n treat me nt wit h X 4 P -0 0 1 a n d ni v ol u ma b.  
•  T o  a ssess  t he  treat me nt  effect  (cli nical  acti vit y) of  t he  c o m bi nati o n  of  X 4 P -0 0 1  a n d  
ni v ol u ma b i n patie nts wit h a d va nce d  ccR C C  usi n g m o difie d Res p o nse E val uati o n  Criteria 
i n S oli d T u m ors  f or i m m u ne-base d t h era p e utics (i R E CI S T)  
 


 
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Statistical A nal ysis Pla n  
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C o nfi de ntial  
 
 
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4  S T U D Y E N D P OI N T S A N D E V A L U A TI O N S  
4. 1  
S af et y E v al u ati o ns  
•  Treat me nt e mer ge nt a d v erse e ve nts ( T E A Es)  
•  Cli nical la b orat or y assess me nts  
− He mat ol o g y  
− Ser u m c he mistr y  
− C oa g ulati o n f act ors  
− P re g n a nc y tests 
− Uri nal ysis  
− T h yr oi d f u ncti o n  
•  P h ysical  e x a mi nati o n fi n di n gs  (i ncl u di n g wei g ht) 
•  O p ht hal m ol o gic ex a m i nati o n 
•  Vital si g ns  
•  E C O G perf or ma nce stat us  
•  E C G  fi n di n gs 
4. 2  
Effic ac y E n d p oi nts a n d E v al u ati o ns  
•  O R R, defi ne d as pr o p orti o n of patie nts wit h  best o verall res p o ns e of C R or P R  
•  Ti me t o o bjecti ve res p o nse , defi ne d as ti me fr o m first a d mi nistrati o n of c o m bi nati o n 
re gi me n t o first C R or P R w hic he ver c o mes first.  
•  D urati o n of res p o nse  ( D O R), defi ne d as t he ti me fr o m first C R or P R w hic he ver c o m es 
first u ntil t he ti me of disease pr o gressi o n b y R E CI S T v 1. 1 or deat h b y a n y ca use.  
•   Disease c o ntr ol rate  ( D C R), defi ne d as pr o p orti o n of patients wit h best o verall res p o nse 
of C R, P R or S D   
•  P F S, defi ne d as t he ti me fr o m first a d mi nistrati o n of c o m bi nati o n re gi me n u ntil o bjecti ve 
t u m or res p o nse or d eat h fr o m a n y ca us e 
•  Ti me t o pr o gressi o n ( T T P), defi ne d as t he ti me fr o m first a d mi nistrati o n of c o m bi nati o n 
re gi me n u ntil o bjecti ve t u m or pr o gressi o n 
4. 3  
Bi o m ar ker  E v al u ati o ns  
•  I d e ntificati o n of p ote ntial bi o mar kers t h at ma y pre dict res p o ns e t o c o m bi n ati o n treat me nt 
wit h X 4 P -0 0 1 a n d ni v ol u ma b  
Bi o mar ker a nal ysis will be pr o vi de d i n a se p arat e d a nal ysis pla n.   
 


 
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Statistical A nal ysis Pla n  
Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
C o nfi de ntial  
 
 
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4. 4  
P h ar m a c o ki netics E v al u ati o ns  
•  Plas ma or ser u m c o nce ntrati o ns  
•  P har mac o ki netics para m eters  
− Area u n d er t he c o nce ntr ati o n -vers us -ti me-c ur v e ( A U C)  
− Ma xi m u m c o nce ntrati o n ( C
ma x ) 
− Ti me t o reac h ma xi m u m c o nce ntrati o n ( T ma x ) 
4. 5  
P h ar m a c o d y n a mi c E v al u ati o ns  
•  Effect of st u d y tr eat me nt i n W B Cs i ncl u di n g a bs ol ute ne utr o p hil c o u nts a n d a bs ol ute 
l y m p h oc yte c o u nts i n bl o o d 
4. 6  
Ot her E v al u ati o ns  
•  Baseli ne a n d d e m o gr a p hic c haracteristics  
•  Ser ol o g y  test at b aseli ne  
•  Me dical hist or y  
•  Pri or ca ncer treat me nt / pr oce d ures  f or re nal cell carci n o ma  
•  Pre vi o us a n d c o nc o mita nt me dicati o ns  
•  Pr o g n osis fact ors  
 
 


 
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Statistical A nal ysis Pla n  
Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
C o nfi de ntial  
 
 
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5  D E FI NI TI O N S A N D C O N V E N TI O N S F O R D A T A H A N D LI N G  
5. 1  
Defi niti o n of B aseli ne  
F or all e v al uati o ns u nless ot her wise n ote d, b aseli ne is defi ne d as t he m ost rece nt n o n -missi n g 
meas ure me nt pri or t o t he first a d mi nistrati o n of st u d y dr u g.  
5. 2  
St u d y E ve nt D a ys a n d Ti mes   
St u d y e ve nts will be rec or de d usi n g t he cale n d ar d ate a n d ( w h ere a p plic a ble) t he ti me t o t he nearest 
mi n ute.  F or p ur p oses of p ost -st u d y a nal ysis (e. g., ta bles a n d listi n gs), st u d y d a ys will be desi g n ate d 
as f oll o ws:  
•  Da y 1 is defi ne d as t he cale n dar d a y of t he first d ose of st u d y dr u g.  
•  T he da ys pri or t o D a y 1 are desi g nate d Da y -1, Da y -2, etc.; t here is n o Da y 0.  
•  T he da ys f oll o wi n g t he d a y of t he first d ose of st u d y dr u g are desi g nate d D a y 2, Da y 3, etc.  
•  T he da y of t he d ose of st u d y dr u g is i n dicat e d b y a d di n g t he s uffi x " L", e. g., if t he last d os e 
is a d mi nistere d o n D a y 4 3, it will be dis pla ye d as " Da y 4 3 L".  T h e da ys f oll o wi n g t he last 
a d mi nistrati o n of st u d y dr u g are d esi g n ate d D a y 1 P, Da y 2 P, etc.  
T he ti mes of e ve nts relate d t o d osi n g of st u d y dr u g will be desi g nate d as mi n utes or h o urs bef ore 
or aft er t he ti me of d osi n g, w hic h is d esi g n ate d as t = 0 (zer o). T h us, 1 5 mi n utes pri or t o d osi n g is t 
= -1 5 mi n; 2 h o urs after d osi n g is desi g nate d t = 2 h.  
5. 3  
First D ose D ate of St u d y Tre at me nt  
T he date of first d ose of st u d y tr eat me nt is d efi ne d as t he earliest d ose dat e of st u d y dr u gs in t he 
treat me nt re gi me n. 
5. 4  
A n al ysis Visit Wi n d o w  
F or saf et y par a meters as descri be d i n Secti o n 4. 1  e x cl u di n g cli nical la b orat or y d ata , meas ure me nts 
c ollecte d fr o m u nsc he d ul e d visits will n ot be i ncl u de d i n t he b y -visit s u m mar y t a bles b ut will b e 
i ncl u de d i n t he listi n gs. Earl y ter mi nati o n visits f or safet y meas ure me nts will n ot be ma p p e d t o 
a n y s c he d ule d p ost -b aseli ne visit b ut will be use d as t he las t assess me nt d uri n g treat me nt peri o d.  
5. 5  
S af et y D at a H a n dli n g  
F or all safet y data, o nl y o bser ve d dat a will be use d f or a n al ys es, a n d missi n g data will n ot be 
i m p ute d. 
Missi n g val ues f or saf et y meas ures at baseli ne  s uc h as la b orat or y data, vital si g ns a n d E C G  data 
will be s u bstit ute d b y v al ues fr o m t he scree ni n g visit, w here a v aila ble.  


 
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5. 5. 1  H a n dli n g of Re pe ate d Cli nic al L a b or at or y Tests  
F or la b or at ories res ults at u nsc he d ule d visits, it will be treate d as re p eate d la b orat or y res ults f or 
t he cl osest pre vi o us visit. T he w orst  res ults wit hi n t he visit will be use d i n t he s u m mar y ta bles f or 
t hat visit.  
La b r es ults be y o n d t he detecta ble li mits will be re p orte d as detecta ble li mits f or calc ulati n g 
descri pti ve statistics.  
All t he la b orat or y test r es ults will be i ncl u de d i n t he data listi n gs as re p orte d.  
5. 5. 2  H a n dli n g of P arti al D ates  
Partial or missi n g dates will be ha n dle d as f oll o ws:  
•  F or  a d verse e v e nts,  i m p utati o n of missi n g or  partial dates will o nl y b e  perf or me d t o 
deter mi ne  treat me nt e mer ge n ce. U nl ess t he partial p orti o n of t he date  or t h e c orres p o n di n g 
e n d date i n dicat es ot her wise, partial a n d missi n g st art dates will be ass u me d t o be t he date 
of first d ose of st u d y me dicati o n t o c o nser vati vel y re p ort t he e ve nt as treat me nt e mer ge nt. 
If t he p artial date or t he c or res p o n di n g e n d date i n dicates ot her wise, t he r ules f or all ot her 
data t y p es s h o ul d be f oll o we d  as des cri be d b el o w.  
•  F or me dicati o ns, i m p utati o n of partial dates will o nl y b e perf or me d t o deter mi ne w het her 
a me dicati o n is c o n c o mita nt. U nless t he partial p or ti o n of t he date i n dicates ot her wise, 
partial start a n d e n d dates will be ass u me d t o be t he date of first d ose of st u d y me dicati o n 
t o  c o nser v ati vel y  re p ort  t he  me dicati o n  as  c o n c o mita nt.  If  t he  partial  dates  i n dicate  
ot her wise, t he r ules f or all ot her data  t y pes s h o ul d be f oll o we d as d escri be d bel o w.  
•  F or all ot her d ata t y p es ( e. g. d ate of i nitial dia g n osis), if t here are partial dates w hic h re q uire 
i m p utati o n  f or  calc ulati o ns,  t he  da y  a n d/ or  m o nt h  a n d/ or  year  will  be  i m p ute d  i n  a  
c o nser vati ve ma n n er; i.e. f or t he start dates, if o nl y t he da y is missi n g, it will be i m p ute d 
wit h t he first da y of t he m o nt h a n d if t he m o nt h is als o missi n g, it will be i m p ute d wit h t he 
1 st J a n uar y. F or t he e n d dates, if o nl y t he da y is missi n g, it will be i m p ute d wit h t he last 
da y of t he  m o nt h a n d if t he m o nt h is als o missi n g, it will be i m p ute d  wit h t he 3 1st 
Dece m b er.  


 
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Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
C o nfi de ntial  
 
 
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6  P L A N N E D A N A L Y SI S  
6. 1  
C h a n ges f r o m Pl a n ne d A n al yses i n t he Pr ot o c ol  
As X 4 P har mace uticals  h as deci de d t o ter mi nate t his st u d y earl y, a n d t o s u m marize t he st u d y wit h 
a n a C S R, n ot all data c ollecte d i n t his st u d y will be a nal yze d. S u m mar y statistics will o nl y b e 
prese nte d f or patie nt dis p ositi o n, baseli ne c haract eristics, e x p os ure of st u d y dr u g, A Es, la b orat or y 
val ues  ( he mat ol o g y,  cli nical  c he mistr y,  c o a g ulati o n  a n d  th yr oi d fu ncti o n ),  vital  si g ns,  E C G,  
o p ht hal m ol o gical e x a mi nati o n, O R R , D C R  a n d bi o mar kers .  
6. 2  
I nteri m A n al ysis 
T here is n o f or mal pr o visi o n f or a n i nteri m a nal ysis i n t his earl y p has e st u d y.  
6. 3  
Fi n al A n al yses a n d Re p orti n g  
All fi nal pla n ne d a nal yses per pr ot oc ol a n d t his a n al ysis pla n  will be perf or me d o nl y after data b ase 
l oc k. 
 


 
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Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
C o nfi de ntial  
 
 
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7  A N A L Y SI S P O P U L A TI O N S A N D A P P LI C A TI O N S  
7. 1  
All P atie nts P o p ul ati o n  
All Patie nts P o p ulati o n  i ncl u des all patie nts w h o si g n a n i nf or me d c o nse nt f or m (I C F).  
7. 2  
S af et y P o p ul ati o n  
T he S afet y P o p ulati o n is defi ne d as all patie nts w h o recei v e at least o ne d os e of st u d y me dicati o n.  
7. 3  
I nte nt-t o-Tre at  P o p ul ati o n  
T he I nt e nt -t o-Treat (I T T) p o p ulati o n is defi ne d as all patie nts w h o recei v e at least o ne d ose of 
st u d y me dicati o n. T his p o p ulati o n will be use d f or efficac y s u m mari es. 
T his p o p ulati o n is i de ntical t o t he S afet y P o p ulati o n.  
7. 4  
Cli nic all y E v al u a ble P o p ul ati o n   
T he Cli nicall y E v al ua ble ( C E) P o p ulati o n is defi ne d as all p atie nts w h o ha ve a d e q uate data at 
baseli ne a n d  at o n e or m ore p ost -treat me nt t u m or assess me nt, a n d n o maj or pr ot oc ol de viati o ns. 
7. 5  
A p plic ati o n of A n al ysis P o p ul ati o ns  
U nless ot her wise n ote d , t he a nal ysis p o p ulati o ns t hat will be use d f or creati n g t he s u m mar y ta ble(s) 
a n d fi g ures of eac h t y p e is pr o vi de d  i n Ta ble 2 .  Listi n g will be pr o vi de d f or all a vaila ble data.   
T a ble 2 : A p plic ati o n of P o p ul ati o ns o n T a bles a n d Fi g ures  
T y pe  
S af et y  
I T T 
C E  
Dis p ositi o n  
X  
 
X  
Pr ot oc ol de viati o ns  
X  
 
 
De m o gra p hics  
X  
 
 
Pri or ca ncer treat me nt f or re nal cell carci n o ma  
X  
 
 
Treat me nt e x p os ure  
X  
 
X  
Safet y e val uati o ns  
X  
 
 
Efficac y e val uati o ns  
 
X  
X  
 


 
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Statistical A nal ysis Pla n  
Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
C o nfi de ntial  
 
 
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8  S T A TI S TI C A L C O N SI D E R A TI O N S  
All a nal ys es des cri be d i n t his pla n are c o nsi dere d a pri ori a n al ys es i n t hat t he y ha ve b ee n d efi ne d 
pri or t o l oc ki n g t h e dat a base.  All ot her a nal ys es, if a n y, desi g ne d s u bse q ue ntl y t o l oc ki n g t he 
data base, will be c o nsi dere d p ost h o c a nal yses a n d will be d escri b e d as e x pl orat or y a nal yses i n t he 
Cli nical St u d y Re p ort.  
All s u m maries a n d statistical a nal ysis will be perf or me d b y S A S v 9. 3 or lat er.  
8. 1  
Ge ner al St atistic al Pr oce d ures  
Fre q u e nc y distri b uti o ns f or cate g orical varia bl es will be pr o vi de d as n u m ber of patie nts wit h a 
res p o nse i n t he cate g or y a n d t he perce nt a ges of t he t otal n u m ber of p atie nts i n t hat c ol u m n.  
Perce nta ges will be bas e d o n n u m ber of p atie nts i n t he gi ve n p o p ulati o n as n ote d. Perce nt a ges will 
be re p ort e d t o o ne deci mal place.  
A 2 -si de d 95 % e x act bi n o mial ( Cl o p per-Pears o n) c o nfi de nce i nter v al ( CI) f or cate g ori cal varia bl es 
wit h o ut m ulti plicit y a dj ust me nt will be pr o vi de d  w here a p pr o priat e f or efficac y a n al ysis. 
T he descri pti ve statistics f or c o nti n u o us varia bles will be n u m ber of patie nts, mea n, sta n dar d 
de viati o n ( S T D), me dia n, mi ni m u m a n d ma xi m u m.   Mea n  a n d me dia n will be re p orte d t o 1 m ore 
deci mal place t ha n t he ra w data, w hile t he S T D will be re p orte d t o 2 m ore deci mal places t ha n t he 
ra w data. Mi ni m u m a n d ma xi m u m will be re p orte d t he sa me as t he ori gi nal  data.  
I n ge ner al, all listi n gs will be or dere d b y st u d y treat me nt, patie nt I D a n d visit  f or a vaila ble data 
u nless ot her wise s pecifie d i n t he te xt.   
8. 2  
P ati e nts Dis p ositi o n  
N u m ber of p atie nts w h o c o m plete d t he st u d y, are still recei vi n g t reat me nt b y t he d ata l oc k d ate, 
a n d n u m ber of p atie nts w h o disc o nti n ue d  fr o m treat me nt a n d pri mar y reas o ns of disc o nti n uati o n 
will be ta b ulate d f or Saf et y P o p ulati o n a n d C E  P o p ulati o n.  
P atie nts’ dis p ositi o n will be pr o vi de d i n a dat a listi n g.  
8. 3  
Pr ot oc ol D e v i ati o ns 
O nl y m aj or pr ot oc ol d e vi ati o n will be c ollecte d i n t he st u d y. Maj or pr ot oc ol de viati o ns are defi n e d 
as t h ose de viati o ns fr o m t he st u d y pr ot o c ol t hat ma y ha v e t he a bilit y t o i m pact t he i nter pretati o n 
of t he safet y a n d efficac y res ults.  
Maj or pr ot oc o l de viati o ns f or all parts of t he st u d y i ncl u de ( b ut are n ot li mite d t o): 
•  Recei ve d st u d y treat me nt wit h o ut meeti n g eli gi bilit y criteria ( u nless a s pecific wai v er w as 
iss ue d pri or t o first d ose) 
•  Recei ve d wr o n g treat me nt or i nc orrect d ose  


 
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Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
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•  Fail ure t o c ollect data n ecessar y t o det er mi ne t he safet y/t olera bilit y of X 4 P -0 0 1  
•  Recei ve d e x cl u de d c o n c o mita nt treat me nt   
•  Met wit h dra wal criteri a a n d was n ot wit h dra w n b y t he site PI n or disc usse d wit h t he 
Me dical M o nit or  
If a r e p orte d pr ot oc ol d e viati o n  d oes n ot meet clas sificati o n criteria f or maj or d e viati o n , t he 
pr ot oc ol de viati o n  will be re p ort e d as a pr ot oc ol d e viati o n wit h o ut a classificati o n.   
All pr ot oc ol de viati o n s will be i de ntifie d a n d fi nalize d pri or t o data base l oc k a n d d oc u me nte d.   
N u m ber a n d per ce nta ge of p atie nts wit h a m aj or pr ot oc ol de viati o n  will b e ta b ulate d f or Safet y 
P o p ulati o n.  
P r ot oc ol de viati o ns will be liste d.  
8. 4  
De m o gr a p hics  a n d B aseli ne C h ar acteristics  
8. 4. 1  De m o gr a p hics a n d B aseli ne C h ar acteristics  
De m o gra p hic a n d baseli ne para meters will be ta b ulate d  usi n g descri pti ve statistics f or Safet y 
P o p ulati o n . T he f oll o wi n g varia bles will be i ncl u d e d i n t he s u m mar y ta ble:   
•  A ge ( years), calc ulat e d as ( date of scree ni n g - dat e of birt h) / 3 6 5. 2 5  
•  A ge cat e g or y ( 1 8 t o < 6 5, ≥ 6 5  a n d missi n g) 
•  Se x  
•  Race  
•  Et h nicit y  
•  Hei g ht ( c m)  
•  Scree ni n g w ei g ht ( k g)  
•  Scree ni n g E C O G stat us  
De m o gra p hics  a n d baseli ne c har acteristics  will be liste d.  
8. 4. 2  Ser ol o g y  Test s 
Bl o o d sa m ples will be c ollecte d f or a nal ysis of t he f oll o wi n g: He p atitis B s urface a nti ge n a n d  
a nti b o d y t o he p atitis C vir us. Ser ol o g y t ests will be liste d o nl y.  
8. 4. 3  Me dic al Hist or y  
Me dical hist or y  will be c o de d acc or di n g t o t he c urre nt versi o n of t he Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A) dicti o nar y v ersi o n i n effect at t he ti me of data base freeze.  
Me dical hist or y d ata will be liste d o nl y.  


 
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Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
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8. 4. 4  Pri o r C a ncer Tre at me nt /P r oce d ures  f or R e n al C ell C arci n o m a  
Pri or a ntica ncer tr eat me nt a n d pr oce d ures f or re nal cell carci n o ma will be ta b ulate d f or Safet y 
P o p ulati o n  i ncl u di n g:  
•  A n y pri or s yst e mic treat me nt f or re n al carci n o ma (incl u de ni v ol u ma b treat me nt)  
•  N u m ber of pri or s yste mic treat me nts f or re n al cell carci n o ma (i ncl u d e ni v ol u ma b treat me nt) 
•  D urati o n o n last ni v ol u ma b m o n ot hera p y ( m o nt hs)  
•  Res p o nse o n last ni v ol u ma b m o n ot hera p y bef ore e nteri n g st u d y  
•  Best res p o ns e t o ni v ol u ma b  
•  A n y p ri or p r oce d ures 
D urati o n of  last  ni v ol u ma b m o n ot hera p y  i n  m o nt hs is  calc ulate d  as ( date of  last  ni v ol u ma b 
treat me nt - date of first ni v ol u ma b treat me nt)/ 3 0. 4 3 7 5 f or patie nts’ last ni v ol u ma b m o n ot hera p y.  
A data listi n g of pri or a ntica ncer treat me nt a n d pr o ce d ures  will be pr o vi de d.  
8. 4. 5  Pri o r a n d C o nc o mit a nt Me dic ati o n   
All me dicati o ns as d oc u me nte d b y t h e i n vesti gat or will be c o de d usi n g A nat o mical T hera pe utic 
C he mical ( A T C) classifi cati o n base d o n t he W orl d Healt h Or ga nizati o n ( W H O) Dr u g Dicti o nar y 
( W H O-D D M arc h 2 0 1 6).  
Pri or a n d c o nc o mita nt m e dicati o n s will be liste d o nl y.   
8. 4. 6  Pr o g n osis F act ors  
Patie nts s ur vi val stat us bef ore e nteri n g t he st u d y will be classifie d i nt o t hree gr o u ps: p o or ( H e n g 
sc ore ≥ 3), i nter me diate ( He n g sc ore = 1 or 2), a n d fa v ora ble pr o g n osis ( H e n g sc ore = 0) [ Da niel 
Y. C. H 2 0 0 9 ].  Pr o g n osis will be s u m marize d f or Safet y P o p ulati o n, I T T a n d C E P o p ulati o ns, a n d 
a detaile d listi n g will be pr o vi de d.  
8. 5  
S af et y A n al ysis  
8. 5. 1  A d verse E ve nts  
A Es will be c o de d usi n g Me d D R A v 1 9 . 0 or later a n d will be classifi e d b y S O C a n d P T of 
Me d D R A. Se verit y of A Es will be assesse d b y i n vesti gat ors acc or di n g t o C T C A E ( v 4. 0 3).  
Relate d A Es are defi ne d as p ossi bl y r elate d or relate d t o st u d y dr u g as ass esse d b y t he I n vesti gat or, 
or wit h missi n g relati o ns hi p.  
A se par ate listi n g of d etails of a n y d eat hs will als o be prese nt e d.  
A n o verall A E s u m mar y will be prese nte d f or t he f oll o wi n g cate g ories:  


 
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•  A n y T E A Es  
•  Dr u g -r elate d T E A Es  
− A n y X 4 P -0 0 1 relate d T E A Es  
− A n y Ni v ol u ma b relate d T E A Es  
− A n y X 4 P -0 0 1 or Ni v ol u ma b  relate d T E A Es 
•  A n y Gra d e ≥ 3 T E A Es  
•  A n y  dr u g -r elate d Gr a de ≥ 3 T E A Es  
− A n y X 4 P -0 0 1 relate d Gr a de ≥ 3 T E A Es   
− A n y Ni v ol u ma b relate d Gra de ≥ 3 T E A Es   
− A n y X 4 P -0 0 1 or Ni v ol u ma b  relate d Gra d e ≥ 3 T E A Es   
•  A n y  T E A Es lea di n g t o d eat h   
•  A n y dr u g -r elate d T E A Es lea di n g t o d eat h  
− A n y X 4 P -0 0 1  relate d T E A Es lea di n g t o deat h  
− A n y Ni v ol u ma b relate d T E A Es lea di n g t o deat h  
− A n y X 4 P -0 0 1  or Ni v ol u ma b relate d T E A Es lea di n g t o deat h  
•  A n y  S A E  
•  A n y dr u g -r elate d S A Es  
− A n y X 4 P -0 0 1  relate d S A Es  
− A n y Ni v ol u ma b relate d S A Es  
− A n y X 4 P -0 0 1  or Ni v ol u ma b relate d S A Es  
•  A n y  T E A Es lea di n g t o st u d y dr u g disc o nti n uati o ns  
− A n y  T E A Es lea di n g t o X 4 P -0 0 1  disc o nti n uati o ns  
− A n y  T E A Es lea di n g t o Ni v ol u ma b  disc o nti n uati o ns  
− A n y T E A Es lea di n g t o X 4 P -0 0 1 or Ni v ol u ma b  disc o nti n uati o ns  
•  A n y dr u g relat e d T E A Es lea di n g t o st u d y dr u g dis c o nti n uati o n  
− A n y dr u g -r elate d T E A Es lea di n g t o X 4 P -0 0 1 disc o nti n uati o n  
− A n y dr u g -r elate d T E A Es lea di n g t o Ni v ol u ma b disc o nti n uati o n  
− A n y dr u g -r elate d T E A Es lea di n g t o X 4 P -0 0 1 or Ni v ol u ma b disc o nti n uati o n  
•  A n y T L Ts  o cc urri n g d uri n g c ycle 1  
B ot h n u m ber of e v e nts a n d n u m ber of patie nts will be ta b ulate d. F or p atie nts, perce nt a ges will be 
calc ulate d fr o m t he t otal n u m ber of patie nts per d ose gr o u p.  
S u m maries of T E A Es  b y S yste m Or ga n Class ( S O C ) a n d preferre d t er m s orte d b y decreasi n g 
fre q ue n c y of pr eferre d t er m wit hi n S O C i ncl u de t he f oll o wi n g:  
•  T E A Es  
•  Dr u g -r elate d T E A Es  
•  S A Es  


 
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Statistical A nal ysis Pla n  
Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
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•  Dr u g -r elate d S A Es  
•  T E A Es lea di n g t o disc o nti n uati o n of eit her st u d y dr u g  
•  T E A Es lea di n g t o deat h  
•  T E A Es lea di n g t o X 4 P -0 0 1 d ose i nterr u pti o n 
•  T L Ts  o cc urri n g d uri n g c ycl e 1  
B ot h n u m ber of e v e nts a n d n u m ber of patie nts will be ta b ulate d. F or p atie nts, perce nt a ges will be 
calc ulate d fr o m t he t otal n u m ber of patie nts per d ose gr o u p.  
A s u m mar y of T E A Es b y S O C, pref erre d ter m a n d ma xi m u m se verit y, s orte d  b y d ecreasi n g 
fre q ue n c y of pr eferre d t er m wit hi n S O C, will als o be pr o vi ded f or:  
•  T E A Es  
•  T E A Es wit h C T C A E  Gr a de ≥ 3 s plit b y ma xi m u m gra d e a n d o v erall  
•  Dr u g -r elate d T E A Es wit h C T C A E  Gra de ≥ 3 s plit b y ma xi m u m gra de a n d o verall  
S u m maries of T E A Es b y de creasi n g fre q ue nc y of preferre d t er m will be prese nte d f or: 
•  All T E A Es  
•  S A Es  
•  M ost Fre q ue nt T E A Es  ( > 1 0 %)  
•  C T C A E  G ra de ≥ 3 T E A Es  
•  Dr u g -r elate d T E A Es  
•  Dr u g -r elate d S A Es 
•  D r u g-r elate d C T CA E  Gr a de ≥ 3  T E A Es  
T he f oll o wi n g listi n g will be pr o vi de d:  
•  All A Es (fla g gi n g t h ose t hat are treat me nt e mer ge nt) 
•  R elate d A Es (fla g gi n g t h ose relate d t o X 4 P -0 0 1, relate d t o ni v ol u ma b  or b ot h)  
•  S eri o us a d verse e ve nts ( S A Es)  
•  A Es lea di n g t o disc o nti n uati o n (fla g gi n g t h ose lea di n g t o disc o nti n uati o n of X 4 P -0 0 1, 
ni v ol u ma b  or b ot h)  
•  A Es lea d i n g t o deat h 
•  T L Ts    
8. 5. 2  Tre at me nt E x p os ure  
Details of X 4 P -0 0 1 a n d ni v ol u ma b  a d mi nistrati o n will be liste d. T his will i ncl u de details of dr u g 
a d mi nistrati o n, treat me nt  dis pe nse d a n d ret ur n e d, a n d t he fre q ue nc y a n d ti mi n g of a n y d ose 
m o dificati o ns.  


 
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Statistical A nal ysis Pla n  
Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
C o nfi de ntial  
 
 
    Pa ge  2 4  | 2 8  
E x p os ure t o X 4 P -0 0 1 will be s u m marize d usi n g t h e f oll o wi n g para meters f or t he Safet y P o p ulati o n  
a n d C E P o p ulati o n:  
•  Ti me o n treat me nt (m o nt h s) defi ne d as  
            (Last d ose date of X 4 P -0 0 1 –  first d ose dat e X 4 P-0 0 1 + 1 )/ 3 0. 43 7 5  
•  Act ual ti me o n treat me nt (m o nt h s) defi ne d as  
            (T otal ti me o n treat me nt ( da ys) –  n u m ber of da ys of X 4 P -0 0 1 d ose i nterr u pti o ns )/ 3 0. 43 7 5  
D ose m o dificati o n f or X 4 P-0 0 1 i ncl u di n g n u m ber a n d perce nta ge of patie nts wit h a n y, 1, 2 a n d 3 
or m ore d ose i ncreas es, d ose decreases, d ose h ol ds a n d d ose m o dificati o ns (i ncreas es or decreases) 
will be prese nte d f or t he Safet y P o p ulati o n  a n d C E  P o p ulati o n . 
Details of st u d y tr eat me nt e x p os ure will be liste d.  
 
 


 
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Statistical A nal ysis Pla n  
Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
C o nfi de ntial  
 
 
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8. 5. 3  Cli nic al L a b or at or y Tests  
All  la b orat or y  p ara m eters  c ollecte d  at  eac h  ce n ter’s  l ocal  la b orat or y  will  be  n or malize d  b y  
c o n verti n g val u es i n ori gi nal u nits t o val ues i n SI u nits a n d classifie d as n or mal, l o w, or hi g h b ase d 
o n n or mal ra n ges s u p plie d b y t he l ocal la b orat ories a n d u p o n e m pl o yi n g sta n dar dizati o n.  
F or he mat ol o g y, c hemistr y, c oa g ul ati o n  a n d t h yr oi d f u ncti o n la b orat or y para meters w hic h are 
n or malize d  i n SI u nits, descri pti ve s u m mar y t a bles f or o bser v e d val ues a n d c ha n ges fr o m bas eli ne 
will be pr o vi de d b y st u d y treat me nt a n d visit f or S afet y P o p ulati o n.  
La b orat or y val u es will als o be cate g orize d acc or di n g t o t heir N CI -C T C A E ( V 4. 0 3) t o xicit y gra d e. 
F or a p plica ble para met ers, s hift ta bles will be prese nte d fr o m t he baseli ne t o xicit y gra d e t o t he 
w orst p ost -baseli ne visit val ue (sc h e d ule d or u nsc he d ule d).  
F or N o n -N CI -C T C  cli ni cal  c h e mistr y  a n d  he mat ol o g y  la b orat or y  para m eters,  s hift  ta bles  of  
n or mal , a b n or mal  N C S a n d a b n or mal  C S res ults will be prese nte d fr o m t he baseli ne val u e t o t he 
w orst p ost -baseli ne visit val ue (sc h e d ule d or u nsc he d ule d).  
Se parate listi n gs will be pr o vi de d f or all la b orat or y tests i ncl u di n g uri n al ysis a n d pre g na n c y 
testi n g.   
8. 5. 4  P h ysic al E x a mi n ati o n Fi n di n gs  
P h ysical e x a mi nati o n will be prese nte d i n listi n g visit.  
8. 5. 5  O p ht h al m ol o gic E x a mi n ati o n  
O p ht hal m ol o gic e x a mi nati o n will be perf or me d t hr o u g h o ut t h e st u d y. Det ails of o p ht hal m ol o gic 
res ults b y l ocal re vie w will be liste d. Shift ta bles of n or mal , a b n or mal  N C S a n d a b n or m al  C S 
res ults will  be  pr ese nte d  fr o m  b aseli ne  t o  t he  w orst  p ost -baseli ne visit  val ue  (sc he d ule d  or  
u nsc he d ule d).   
8. 5. 6  Vit al Si g ns  
Vitals si g ns will be c ollecte d t hr o u g h o ut t he st u d y. T he v al ue a n d c h a n ge fr o m bas eli ne f or vital 
si g n para meters will be liste d a n d s u m marize d des cri pti vel y f or eac h s c he d ule d ti me-p oi nt d uri n g 
t he st u d y. 
8. 5. 7  E C O G perf or m a nce st at us  
Details of E C O G perf or ma nce stat us will be liste d.  
8. 5. 8  Electr oc a r di o gr a m ( E C G)  
E C G data will be c ollect e d b y usi n g a di gital 1 2 -l ea d E C G mac hi n e t hr o u g h o ut t he st u d y. 


 
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Statistical A nal ysis Pla n  
Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
C o nfi de ntial  
 
 
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T he val ue a n d c ha n ge fr o m baseli ne i n E C G para meters ( heart rat e, R R, P R, Q R S, Q T a n d Q Tc) 
will be liste d a n d  s u m marize d descri pti vel y f or eac h sc he d ul e d ti me-p oi nt d uri n g t h e st u d y.  R R 
i nter val i n sec o n ds is cal c ulate d as 6 0 di vi de d b y H R i n beats/ mi n. B ot h Q Tc B a n d Q Tc F ma y be  
c ollecte d a n d t hese will be s u m marize d se paratel y, deri vi n g t hese if t he y are n ot c ollecte d f or a 
patie nt, usi n g t he f oll o wi n g e q u ati o ns:  
•  Q Tc B = Q T/ √R R  
•  Q Tc F = Q T/ 3√R R  
F or Q Tc B a n d Q Tc F, t a bles will be prese nte d t o i n dicate t he n u m ber of patie nts b y visit wit h 
val ues ≥ 4 5 0 msec, ≥ 4 8 0 msec, ≥ 5 0 0 msec, a n i ncreas e fr o m bas eli ne > 3 0 msec a n d a n i ncrease 
fr o m baseli ne > 6 0 ms ec. 
E C G data  will be liste d.  
8. 6  
Effic ac y A n al ysis  
T u m or res p o nse assess m e nts will be c o n d uct e d e v er y ei g ht ( 8) wee ks f or 8 0 wee ks ( 2 0 c ycl es) a n d 
t he n e ver y 1 2  wee ks  t hereafter, at  E n d of Treat me nt, a n d as i n dicate d  base d o n ne w si g ns,  
s y m pt o ms or la b orat or y fi n di n gs.  
8. 6. 1  R E CI S T v 1. 1 B ase d Assess me nt  
I ma gi n g will be i nter pr ete d usi n g R E CI S T v 1. 1. T u m or res p o ns e  i ncl u di n g b ot h c o nfir me d a n d 
u nc o nfir me d O R R  a n d D C R  will be ta b ulate d usi n g best o verall res p o nse, i n c or p orati n g 9 5 % e x act 
Cl o p per -Pears o n c o nfi de nce i nter vals f or b ot h I T T P o p ulati o n a n d C E P o p ulati o n.   
F or c o nfir m e d res p o nses, res p o nses m ust be c o nfir me d at least 2 8 da ys after t he ori gi nal res p o nse. 
A visit after 2 misse d visits will n ot be c o nsi dere d a c o nfir mati o n visit. A res p o nse of P R  f oll o w e d 
b y a res p o nse of C R will be c o nsi der e d as a c o nfir me d P R  if t here is n o s u bse q ue nt C R. 
I n a d diti o n, t he f oll o wi n g pl ots will be pr o vi de d f or b ot h I T T P o p ulati o n a n d C E P o p ulati o n: 
•  W aterfall pl ot s of t he best perce nta ge c ha n ge i n t u m or size (i.e. ma xi m u m t u m or re d ucti o n, 
or mi ni m u m i ncrease i n t he a bse nce of a n y  re d u cti o n) 
•  S pi der pl ot s of the perce nta ge c h a n ge fr o m baseli ne i n t he s u m of dia meters o ver ti m e 
c o n necte d wit h a li ne  
•  S wi m la ne pl ot s of ti me o n st u d y treat me nt a n d o n pri or n i v ol u ma b treat me nt wit h s y m b ols 
i n dicati n g r es p o nse start, pr o gressi o n, a n d wit h dra wal fr o m st u d y, w here a p plica ble.  
Details of tar get lesi o ns, n o n -tar get l esi o ns, ne w l esi o ns a n d o v erall t u m or res p o nse will be liste d.  
A b y -patie nt listi n g will als o be pr o vi de d f or d urati o n of st u d y treat me nt a n d pri or ni v ol u ma b 
treat me nt. 


 
X 4 P har mace uticals , I nc. 
 
Statistical A nal ysis Pla n  
Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
C o nfi de ntial  
 
 
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8. 6. 2  i R E CI S T B ase d Assess me nt  
i R E CI S T data will n ot be a vaila ble d ue t o t he earl y ter mi nati o n of t he st u d y . Tu m or  res p o ns e 
assess me nts will n ot be e x pl ore d usi n g i R E CI S T  criteria. 
8. 7  
P h ar m a c o ki netic A n al ysis  
Plas ma or ser u m c o nce ntrati o ns a n d p har mac o ki n etic para meters  will be n ot  s u m marize d i n t his 
S A P.  
8. 8  
P h ar m a c o d y n a mi c  A n al ysis  
P har mac o d y na mic d ata will be liste d o nl y .  
 
 
 


 
X 4 P har mace uticals , I nc. 
 
Statistical A nal ysis Pla n  
Pr ot oc ol N o: X 4 P -0 0 1 -R C C B                                
 
 
 
 
C o nfi de ntial  
 
 
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9  
Refere nces  
Da niel Y. C. H, Wa nli n g X, Mere dit h M. R, et al. Pr o g n ostic Fact ors f or O verall S ur vi val i n 
Patie nts wit h Metastatic Re nal Cell Carci n o ma Treate d w it h Vasc ular E n d ot helial Gr o wt h Fact or–
Tar gete d A ge nts: Res ults fr o m a Lar ge, M ultice nter St u d y. J o ur nal of Cli nical O nc ol o g y. 2 0 0 9; 
2 7: 3 4 -3 9.