A Phase 1 Open-Label Study of the Safety, Tolerability and Efficacy of KPT-9274, a Dual Inhibitor of PAK4 and NAMPT, in Patients With Advanced Solid Malignancies or Non-Hodgkin's Lymphoma
Phase: PHASE1
Conditions: Solid Tumors, NHL
Sponsor: Karyopharm Therapeutics Inc

K P T -9 2 7 4  
 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1  Marc h 2 0 2 0  
 
C o nfi de ntial  
Pa ge 1  
Versi o n 5. 0  
 
C LI NI C A L S T U D Y P R O T O C O L  
K C P -9 2 7 4 -9 0 1  
A P H A S E 1 O P E N -L A B E L  S T U D Y O F T H E S A F E T Y , 
T O L E R A BI LI T Y A N D E F F I C A C Y O F K P T-9 2 7 4, A  D U A L 
I N HI BI T O R O F P A K 4 A ND N A M P T, I N P A TI E N T S  WI T H 
A D V A N C E D S O LI D M A LI G N A N CI E S O R N O N -H O D G K I N’ S 
L Y M P H O M A  
St u d y N a me: P A N A M A: P A K 4 a n d N A M P T i n P atie nts wit h S oli d M A li g n a ncies or 
N H L  
St u d y N u m ber:  
K C P -9 2 7 4 -9 0 1  
St u d y P h ase:  
1  
I n vesti g ati o n al Pr o d uct: 
K P T -9 2 7 4  
I N D N u m ber: 
  
I n dic ati o n: 
A d va nce d s oli d mali g na ncies a n d n o n -H o d g ki n’s l y m p h o ma  
S p o ns or:  
Kar y o p har m T hera pe utics I nc.  
8 5 Wells A ve n ue  
Ne wt o n, M A 0 2 4 5 9 U S A  
Tel. + ( 6 1 7) 6 5 8 -0 6 0 0  
Pr ot oc ol D ate a n d Versi o n:  
1 6 Dece m ber 2 0 1 5, Versi o n 1. 0  
2 6 Fe br uar y 2 0 1 6, Versi o n 2. 0  
0 2 Ma y 2 0 1 6, Versi o n 3. 0  
1 5  J u ne 2 0 1 7, Versi o n 4. 0 
1 3 Dece m ber 2 0 1 7 , Versi o n 4. 1  
0 2 Fe br uar y 2 0 1 8, Versi o n 4. 2 ( Ca na da S pecific A me n d me nt)  
1 1 Marc h  2 0 2 0,  Versi o n 5. 0  
C O N D U C T  
I n acc or da nce wit h t he et hical pri nci ples t hat ori gi nate fr o m t he Declarati o n of Helsi n ki a n d 
t hat are c o nsiste nt wit h I nter nati o nal C o nfere nce o n Har m o nizati o n (I C H) g ui deli nes o n G o o d 
Cli nical Practice ( G C P) a n d re g ulat or y re q uire me nts as a p plica ble.  
C O N FI D E N TI A L I N F O R M A TI O N  
T his d oc u me nt is t he s ole pr o pert y of Kar y o p har m T hera pe utics I nc. ( Kar y o p har m). T his 
d oc u me nt a n d a n y a n d all i nf or mati o n c o ntai ne d herei n has t o be c o nsi dere d a n d treate d as 
strictl y c o nfi de ntial. T his d oc u me nt s hall be use d o nl y f or t he p ur p ose of t he discl os ure herei n 
pr o vi de d. N o discl os ure or p u blicati o n s hall be ma de wit h o ut t he pri or writte n c o nse nt of 
Kar y o p har m.  
C CI

K P T -9 2 7 4  
 
 
Kar y o p har m T hera p e utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1  Marc h 2 0 2 0   
C o nfi de ntial  
Pa ge 2  
Versi o n 5. 0  
 
S P O N S O R I N F O R M A TI O N  
S p o ns or C o nt acts:  
, M D 
 
Kar y o p har m T hera pe utics I nc . 
 
, P h D, M B A 
 
Kar y o p har m T hera pe utics I nc.  
 
 
 
 
 
 
 
P P D
P P D
P P D
P P D

K P T- 9 2 7 4 
Cli ni c al St u d y Pr ot o c ol: K C P- 9 2 7 4- 9 0 I 
K ar y o p h ar m T h er a p e uti cs I n c. 
11 M ar c h 2 0 2 0 
P R O T O C O L A P P R O V A L SI G N A T U R E P A G E 
S P O N S O R: K A R Y O P H A R M T H E R A P E U TI C S I N C. 
I h a v e r e a d a n d u n d erst a n d t h e c o nt e nts of t his cli ni c al pr ot o c ol f or St u d y N o. K C P- 9 2 7 4- 9 0 1 
d at e d 1 1 M ar c h 2 0 2 0 a n d a gr e e t o m e et all o bli g ati o ns of K ar y o p h ar m T h er a p e uti c s I nc. , as 
d et ail e d i n all a p pli c a bl e r e g ul ati o ns a n d g ui d eli n es. I n a d diti o n , I will i nf or m t h e Pri n ci pal 
I n v esti g at or a n d all ot h er I n v esti g at ors of all r el e v a nt i nf or m ati o n t h at b e c o m es a vai l abl e d ur i n g 
t h e c o n d u ct of t his St u d y. 
A p p r o v e d B y: 
K a r y o p h a r m T h e r a p e uti cs I n c. 
, P h D, M B A 
K a r y o p h a r m T h e r a p e uti cs I nc. 
C o nfi d e nti al 
P a g e 3 
1 1 M ar c h 2 0 2 0 
D at e 
1 1 M ar c h 2 0 2 0 
D at e 
V ersi o n 5. 0 
P P D
P P D
P P D
P P D
P P D
P P D
P P D

KPT-9274 
 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901  
 
11 March 2020  
Confidential 
Page 4 
Version 5.0 
 
INVESTIGATORS’ AGREEMENT 
I have read and understand the contents of this clinical protocol for Study No. KCP-9274-901 
dated 11 March 2020 and will adhere to the study requirements as presented, including all 
statements regarding confidentiality. In addition, I will conduct the Study in accordance with 
current Good Clinical Practice, ICH E6, and applicable FDA regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institution 
 
 
 
 
 
 
 
 
Date 

KPT-9274 
 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901  
 
11 March 2020  
Confidential 
Page 5 
Version 5.0 
 
PROTOCOL SYNOPSIS 
 
Sponsor: 
Karyopharm Therapeutics Inc. 
Investigational Product: 
KPT-9274 
Study Phase: 
Phase 1 
Title of Study:  
A Phase 1 Open-Label Study of the Safety, Tolerability and Efficacy of KPT-9274, a Dual Inhibitor of 
PAK4 and NAMPT, in Patients with Advanced Solid Malignancies or Non-Hodgkin’s Lymphoma  
Study Name: PANAMA: PAK4 and NAMPT in Patients with Solid MAlignancies or NHL 
Name of Active Ingredient: 
(E)-3-(6-aminopyridin-3-yl)-N-((5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)-7-(4-
fluorophenyl)benzofuran-2-yl)methyl)acrylamide 
Protocol Number: KCP-9274-901 
Study Center(s):  Multi-center 
Patient Population: Patients with advanced solid malignancies (including sarcoma, colon, lung, etc.) or 
non-Hodgkin’s lymphoma for which all standard therapeutic options considered useful by the 
investigator have been exhausted and with progressive disease on study entry. 
Objectives and Endpoints: 
This study will evaluate the safety, tolerability, and efficacy of oral KPT-9274 for the treatment of 
patients with advanced solid malignancies or non-Hodgkin’s lymphoma (NHL).  
 
Objectives 
Endpoints 
Primary 
Parts A and B 
• 
To assess the maximum tolerated 
dose (MTD) in each Part 
• 
To establish a recommended phase 
2 dose (RP2D) 
 
 
Dose Expansion (if conducted) 
• 
Preliminary evidence of anti-tumor 
activity of KPT-9274 at the RP2D ± 
niacin ER 
 
 
Parts A and B 
• 
MTD/RP2D  
• 
Dose limiting toxicities (DLTs) 
• 
The occurrence of Grade ≥3 adverse 
events (AE), all serious adverse 
events (SAEs), and all AEs leading to 
treatment discontinuation 
 
Dose Expansion (if conducted) 
• 
Overall response rate (ORR), duration 
of response (DOR), disease control 
rate (DCR), duration of disease 
control, progression-free survival 
(PFS), overall survival (OS), time to 
progression (TTP) 
I 
I 

K P T -9 2 7 4  
 
 
Kar y o p har m T hera p e utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1  Marc h 2 0 2 0   
C o nfi de ntial  
Pa ge 6  
Versi o n 5. 0  
 
P art C  
•  
Safet y, t olera bilit y, a n d R P 2 D 
P art C  
•  
 M T D/ R P 2 D  
•  
D ose li miti n g t o xicities ( D L Ts)  
•  
T he occ urre nce of Gra de ≥3 a d verse 
e ve nts ( A E), all seri o us a d verse 
e ve nts ( S A Es), a n d all A Es lea di n g t o 
treat me nt disc o nti n uati o n 
Sec o n d ar y  
P arts A a n d B  
•  
Preli mi nar y e vi de nce of a nti -t u m or 
acti vit y of K P T -9 2 7 4 at t he R P 2 D ± 
niaci n E R  
•  
P har mac o ki netics ( P K)  
 
 
D ose Ex p a nsi o n (if c o n d ucte d)  
•  
P har mac o ki netics ( P K)  
 
 
 
P art C  
•  
Preli mi nar y e vi de nce of a nti -t u m or 
acti vit y of K P T -9 2 7 4 +  ni v ol u ma b  
•  
P har mac o ki netics ( P K)  
P arts A a n d B  
•  
O R R, D O R, D C R, d urati o n of disease 
c o ntr ol, P F S, O S, T T P  
•  
M a xi m u m plas ma c o nce ntrati o n, 
ti me-t o-pea k plas ma c o nce ntrati o n, 
ter mi nal half-life, a n d plas ma 
cleara nce  
D ose Ex p a nsi o n (if c o n d ucte d)  
•  
M a xi m u m plas ma c o nce ntrati o n, 
ti me-t o-pea k plas ma c o nce ntrati o n, 
ter mi nal half-life, a n d plas ma 
cleara nce  
P art C  
•  
O R R, D O R, D C R, d urati o n of disease 
c o ntr ol, P F S, O S, T T P  
•  
Area u n der t he c ur ve ( A U C) a n d 
Ma xi m u m c o nce ntrati o n ( C ma x)  
E x pl or at or y  
 
R ati o n ale f or t he St u d y:  
C CI

K P T -9 2 7 4  
 
 
Kar y o p har m T hera p e utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1  Marc h 2 0 2 0   
C o nfi de ntial  
Pa ge 7  
Versi o n 5. 0  
 
K P T -9 2 7 4 is a first -i n-class orall y bi oa vaila ble, n o n -c o m petiti ve, s mall m olec ule, d ual m o d ulat or of p 2 1 
pr otei n ( C dc 4 2/ Rac) -acti vate d ki nase 4 ( P A K 4) a n d nic oti na mi de p h os p h ori b os yltra nsferase 
/ P B E F/ visfati n ( N A M P T). P A K 4 is a ke y d o w nstrea m effect or f or R A S a n d f or ms a critical li n k 
bet wee n R A S -dri ve n o nc o ge nic tra nsf or mati o n a n d acti vati o n of t he W N T/ β -cate ni n si g nali n g pat h wa y. 
N A M P T is t he rate -li miti n g e nz y me i n t he meta b olic sca ve n gi n g pat h wa y t hat utilizes nic oti na mi de t o 
re ple nis h nic oti na mi de a de ni ne di n ucle oti de ( N A D), a n esse ntial meta b olic c of act or a n d sec o n d 
messe n ger.  
He mat ol o gic a n d s oli d t u m or cells are s usce pti ble t o si n gle -a ge nt c yt ot o xicit y b y K P T -9 2 7 4 as t he y 
bec o me de pe n de nt o n b ot h t he P A K 4 a n d N A M P T pat h wa ys. K P T -9 2 7 4 de m o nstrate d p ot e nt a nti-
pr oliferati ve acti vit y a gai nst ca ncer cell li nes wit h mi ni mal t o xicit y t o n or mal cells. I n m o use xe n o graft 
st u dies, K P T-9 2 7 4 was well t olerate d a n d res ulte d i n a mar ke d re d ucti o n/eli mi n ati o n of t u m ors, t u m or 
gr o wt h i n hi biti o n or disease c o ntr ol ac r oss a variet y of t u m ors, i ncl u di n g c ol o n, pa ncreatic, l u n g, 
sarc o ma, m ulti ple m y el o ma, le u ke mia, a n d l y m p h o ma. I n a p pr o xi matel y half of t he t u m or t y pes st u die d, 
c o m plete eli mi nati o n of t u m ors i n as s h ort as 3 wee ks was o bser ve d wit h n o re gr o wt h after cess ati o n of 
treat me nt (f or u p t o 3 a d diti o nal wee ks). M ore o ver, K P T-9 2 7 4 has s h o w n preli mi nar y efficac y i n 
c o m pa ni o n d o gs wit h s p o nta ne o us a d va nce d l y m p h o mas a n d m ulti ple m y el o ma.  
R ati o n ale f or a d di n g ni aci n E R:  N A D ca n be ge nerate d b y cata b olis m of tr y pt o p ha n, sal va ge of 
nic oti na mi de t hr o u g h N A M P T or sal va ge of e x o ge n o us niaci n t hr o u g h N A P R T 1 ( nic oti nate 
p h os p h ori b os yltra nsferase; a niaci n utilizi n g e nz y me). S o me ca ncers lac k t he e nz y me(s) necessar y f or 
t he de n ov o  s y nt hesis of N A D fr o m tr y pt o p ha n, w hile N A P R T 1 acti vit y is fre q ue ntl y d o w n -re g ulate d b y 
e pi ge netic m o d ulati o n or is ocitrate de h y dr o ge nase 1 ( N A D P +), s ol u ble (I D H 1) m ut ati o n lea vi n g t hese 
ca ncers de pe n de nt o n N A M P T acti vit y. If t u m ors ha ve re d uce d or a b se nt N A P R T 1 f u ncti o n, t he n t his 
tiss ue ma y n ot be a ble t o utilize niaci n t o ma ke N A D. T heref ore, patie nts wit h N A P R T 1 i n n or mal 
tiss ue, b ut n ot i n t heir t u m ors, mi g ht be nefit fr o m a niaci n c o-d osi n g strate g y i n or der t o re d uce si de 
effects. Pi v otal G L P a n d  e x pl orat or y n o n -G L P st u dies ha ve de m o nstrate d t hat c o -d osi n g niaci n wit h 
K P T -9 2 7 4 ca n i ncrease t olera bilit y; t heref ore, K P T -9 2 7 4 c o -a d mi nistere d orall y a d mi nistere d wit h 
niaci n e xte n de d release ( E R) will be e val uate d i n t he c urre nt st u d y.
R ati o n ale f or c o m bi ni n g K P T -9 2 7 4 wit h Ni v ol u m a b:  K P T -9 2 7 4 bi n ds t o a n d re d uces t he stea d y state 
le vel of t he P A K 4 pr otei n ki nase as well as bl oc ki n g t he acti vit y of N A M P T. I n a d diti o n, t hr o u g h P A K 4 
i n hi biti o n, K P T -9 2 7 4 re d uces t he sta bilit y , n uclear tra ns p ortati o n a n d f u ncti o n  of β -cate ni n b y i n hi biti n g  
its p h os p h or ylati o n o n S 6 7 5. T his is c o nsiste nt wit h β-cate ni n bei n g a tar get of P A K 4. Ni v ol u ma b is a 
m o n ocl o nal a nti b o d y directe d a gai nst t he pr o gra m me d cell deat h 1 rece pt or ( P D -1) o n l y m p h oc ytes. 
A nti -P D -1 treat me nt i ncreases t he i m m u ne res p o nse, all o w i n g T cell killi n g of t u m or cells. Ni v ol u ma b 
has bee n F D A -a p pr o ve d f or use i n patie nts wit h a d va nce d  mela n o ma. T here is e vi de nce s u g gesti n g t hat 
patie nts m ost li kel y t o res p o n d t o a nti -P D -1 treat me nt are t h ose w h o ha ve a n ele vate d baseli ne of C D 8 + 
T cell i nfiltrati o n wit hi n t he t u m or micr oe n vir o n me nt ( T M E ) (A bril -R o dri g uez 2 0 2 0 ). T h ose w h o lac k a 
T cell i nfiltrate res p o n d p o orl y. A c orrelati o n was re p orte d bet wee n h y peracti vati o n of t he W N T/ β -
cate ni n si g nali n g pat h wa y a n d T cell e xcl usi o n i n mela n o ma patie nt t u m or sa m ples ( S pra n ger et al 
2 0 1 5). Rece ntl y, t his c orrelati o n has bee n e xte n de d t o P A K 4 o vere x pressi o n (A bril -R o dri g uez 2 0 2 0 ). 
T hese data s u g gest t hat c o m bi nati o n t hera pies i n w hic h acti vate d β -cate ni n is i n hi bite d t hr o u g h P A K 4 
i n hi biti o n si m ulta n e o usl y wit h tar geti n g P D-1, ma y be partic ularl y effecti ve t hera p y. I n dee d, i n vi v o 
m o dels of mice e n grafte d wit h mela n o ma cells t hat were treate d wit h K P T -9 2 7 4 + a n a nti -P D -1 
a nti b o d y s h o we d mar ke d t u m or gr o wt h i n hi biti o n c o m p are d t o eit her a ge nt al o ne (A bril -R o dri g uez 
2 0 2 0 ). T heref ore, c o m bi nat orial treat me nt wit h K P T -9 2 7 4, w hic h bl oc ks β -cate ni n , wit h ni v ol u ma b ma y 
be be neficial t o patie nts wit h mela n o ma  w h o pr o gresse d o n pri or a nti -P D -1 or a nti -P D -L 1 treat me nt.  
C CI
C CI

KPT-9274 
 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901  
 
11 March 2020  
Confidential 
Page 8 
Version 5.0 
 
 
Methodology:  
This is a first-in-human, multi-center, open-label clinical study with separate Dose Escalation and 
Expansion Phases to assess preliminary safety, tolerability, and efficacy of KPT-9274, a dual inhibitor 
of PAK4 and NAMPT, in patients with advanced solid malignancies (including sarcoma, colon, lung, 
etc.) or NHL for which all standard therapeutic options considered useful by the investigator have been 
exhausted and with progressive disease on study entry.  
The Dose Escalation Phase will include two parts, Part A and Part B. 
• 
Part A will be performed to determine the RP2D and MTD of KPT-9274 alone (note that the 
RP2D may be ≤ the MTD and will be used for the Dose Expansion Phase of the study). 
• 
Part B will be performed to determine the RP2D and MTD of KPT-9274 co-administered with 
starting dose of 500 mg niacin ER (may be titrated to 2,000 mg of daily dose, per label); the 
starting dose of KPT-9274 for Part B will be a dose and schedule that has cleared DLT 
assessment in Part A. 
The Dose Escalation and Expansion Phases of the study will be comprised of Screening, Treatment, and 
Follow-up periods. 
DOSE ESCALATION PHASE 
Based on repeat-dose toxicology studies in dogs and rats, a starting dose of 10 mg of KPT-9274 was 
selected. This provides a 6-fold safety window relative to the expected highest non-severely toxic dose 
(HNSTD) in dogs. 
Patients will receive oral KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 
19, 22, 24, and 26) during each 28-day cycle. During Part B of the Dose Escalation Phase, patients will 
receive a starting dose of 500 mg niacin ER (may be titrated to 2,000 mg of daily dose, per label) 
co-administered with each dose of KPT-9274. For the purposes of dose escalation decisions, a standard 
3+3 dose escalation design will be used during both Part A and Part B.  
Based on preclinical and early clinical data, patients will be enrolled according to their NAPRT1 status 
at a ratio of 2:1 (NAPRT1 negative:NAPRT1 positive). The NAPRT1 status must be determined prior to 
enrollment based on evaluation of a fresh tumor biopsy or archival tissue taken ≤ 6 months of screening. 
 
Part A:  KPT-9274 
The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 10 mg. If these 
patients do not experience a DLT during Cycle 1, the KPT-9274 dose will be escalated to 20 mg for 
another group of 3 patients (Cohort 2) upon approval during a dose decision meeting. Dose escalation 
will continue based on a standard 3+3 design at the dose levels specified in the table below.  
Part B:  KPT-9274 + Niacin ER 
The initial cohort, Cohort 1 + niacin ER (Cohort 1B), will consist of 3 enrolled patients who will be 
treated at a dose and schedule of KPT-9274 that has cleared DLT assessment in Part A, co-administered 
with a starting dose of 500 mg niacin ER (may be titrated to 2,000 mg of daily dose, per label).  
Part A and Part B: 
Dose escalation will continue independently in Parts A and B until the MTD in each part is determined. 
The MTD is defined as the highest dose at which ≤1 patient experiences a DLT in Cycle 1. A RP2D 
equal to or less than the MTD will be declared for each part and used for the Dose Expansion Phase.  
In both Parts A and B, patients must complete a minimum of 1 cycle of treatment, defined as receiving 
≥ 75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a 
DLT within the first cycle of treatment to be evaluable for dose escalation decisions. Dose escalation 
decisions will occur when the cohort of patients has met these criteria. 

KPT-9274 
 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901  
 
11 March 2020  
Confidential 
Page 9 
Version 5.0 
 
The table below describes the starting dose of KPT-9274 and the dose cohorts that may be evaluated 
during Part A of the Dose Escalation Phase of this study. A similar dose escalation plan will be used in 
Part B; however, the starting dose of KPT-9274 will be based on a dose and schedule that has cleared 
DLT assessment in Part A. To better evaluate the safety, tolerability, and PK of KPT-9274, additional 
cohorts of patients may be enrolled on alternate dosing schedules, at preceding dose levels, or to 
intermediate dose levels before or while proceeding with further dose escalation.  
 
Part A:  KPT-9274 Dose Escalation Levels  
Cohort 
KPT-9274 
Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 in a 28-day cycle 
1 
(starting dose) 
10 mg 
2 
20 mg 
3 
30 mg 
4 
40 mg 
5+ 
Increases at 20 mg per cohort 
Three patients will be enrolled in each cohort, if 1 of 3 patients in a cohort experiences a DLT, the 
number of patients in that cohort will be expanded to 6 patients. A maximum of 6 patients will be 
enrolled per cohort. If ≥ 2 patients in a cohort experience a DLT, the MTD will be defined as 1 dose 
level lower. 
A DLT is defined as an AE or abnormal laboratory value that occurs within the first 28 days of 
treatment with KPT-9274, except for those that are clearly and incontrovertibly due to underlying 
disease, disease progression, or extraneous causes, and meets any of the criteria for defining dose-
limiting toxicities as described in the table below. The CTCAE, Version 4.03 will be used for grading. 
In addition, > 3 missed (consecutive or nonconsecutive) doses of KPT-9274 in the first 28 days due to a 
drug related toxicity will be considered to be a DLT. 
Other events may occur which do not meet the definition of a DLT but are of concern to the 
Investigators and Karyopharm and may be considered to be DLTs. 
Criteria for Defining Dose-Limiting Toxicities 
Toxicity 
Any of the following criteria (based on CTCAE [Version 4.03]): 
Non-
Hematologic 
Grade ≥3 nausea/vomiting, dehydration or diarrhea while taking optimal supportive 
medications. 
Any other Grade ≥3 non-hematological toxicity except alopecia or electrolyte 
abnormalities correctable with supportive therapy. 
Hematologic 
Grade 4 neutropenia lasting more than 5 days. 
Febrile neutropenia of any duration (ANC < 1.0 ×109 with single temperature 
>38.3°C or a sustained temperature ≥ 38°C for more than 1 hour). 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding, or any 
requirement for platelet transfusion. 
Grade 4 anemia, unexplained by underlying disease. 
CTCAE Version 4.03 will be used for grading AEs and laboratory abnormalities. Patients may 
receive supportive care as per local institutional guidelines. 
DOSE EXPANSION PHASE 

KPT-9274 
 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901  
 
11 March 2020  
Confidential 
Page 10 
Version 5.0 
 
After completion of the Dose Escalation Parts A and B, Dose Expansion in up to 65 additional patients 
with advanced solid malignancies and NHL may be conducted to further explore safety, tolerability and 
preliminary evidence of anti-tumor activity of the RP2D of KPT-9274 ± niacin ER. Note that 
preliminary clinical results may define the patient population (i.e., specific indications) selected for 
enrollment in the Dose Expansion Phase. 
After declaring the RP2D for KPT-9274 single agent and KPT-9274 + niacin ER, based on the safety 
and tolerability results of the Dose Escalation Phase, a decision will be made whether expansion 
(4 groups, ~45 patients total) will be conducted at the RP2D of KPT-9274 single agent or at the RP2D 
of KPT-9274 + niacin ER. If the ~45 patient expansion is conducted at the RP2D of KPT-9274 + niacin 
ER, an optional expansion with < 20 patients at the RP2D of KPT-9274 single agent may also be 
initiated.  
At least 1 clinical response (minimum of stable disease ~16 weeks) must be seen in any of the first 
10 patients treated at the RP2D in order to fully enroll either expansion cohort. These 10 patients include 
the patients enrolled under the 3+3 design for DLT assessment; if necessary, additional patients will be 
enrolled to a maximum of 10 patients. If no clinical responses are observed, the study will be stopped 
for futility. If a clinical response is observed at any time, then enrollment of the full expansion cohort 
may proceed. Initiation of the KPT-9274 + niacin ER escalation will not be dependent upon 
demonstration of clinical benefit of the single agent, but futility at the KPT-9274 + niacin ER RP2D will 
be assessed prior to full expansion using the same criterion as described above for the single agent KPT-
9274.  
The KPT-9274 ± niacin ER expansion cohort will consist of 4 groups of approximately 45 patients 
(please note that these expansion groups may change based on escalation results) including: 
• I. NAPRT1 deficient tumor group, approximately 10 patients 
• II. NAPRT1 positive tumor group, approximately 10 patients 
• III. Either NAPRT1 deficient or positive tumor group, approximately 10 patients 
• IV. IDH1 mutant tumor group, approximately 15 patients 
Please note that the composition of the expansion groups (e.g., number of patients with NAPRT1 
positive vs NAPRT1 deficient tumors) may change based on the results from the escalation phase. An 
additional, optional KPT-9274 single agent expansion cohort will consist of ~ 20 patients with any 
tumor mutational status. 
Patients in the Dose Expansion Phase may be treated with the RP2D of KPT-9274 ± niacin ER 
according to the same schedule administered in the Dose Escalation Phase of the study.  
Patients who are in Part A or Part B of the Dose Escalation Phase being treated at the RP2D ± niacin ER 
dose chosen for expansion will be included in the efficacy and safety analyses of the Dose Expansion 
Phase. 
Part C:  KPT-9274 + Nivolumab 
After sufficient data from Part A is available, Dose Finding with the potential for Expansion in patients 
with melanoma will be conducted to further explore safety, tolerability and preliminary evidence of anti-
tumor activity of the RP2D (or any DLT-cleared dose) of KPT-9274 + nivolumab.  
 
DOSE FINDING  PHASE 
This Arm will treat approximately 20 patients with melanoma who progressed on an anti-PD-1 or anti-
PD-L1 antibody in a prior line of therapy. Two dose levels of KPT-9274 (30 and 40 mg) in combination 
with nivolumab will be tested in parallel. Patients will be enrolled first into the 30 mg cohort. Patients 
will be treated with 30 or 40 mg KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 

K P T -9 2 7 4  
 
 
Kar y o p har m T hera p e utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1  Marc h 2 0 2 0   
C o nfi de ntial  
Pa ge 1 1  
Versi o n 5. 0  
 
1 5, 1 7, 1 9, 2 2, 2 4, a n d 2 6) d uri n g eac h 2 8 -da y c y cle i n c o m bi nati o n wit h a sta n dar d d ose a n d sc he d ule 
of ni v ol u ma b  ( 4 8 0 m g o n Da y 1 of eac h 2 8-da y c y cle) . A ma xi m u m of 1 0 patie nts ma y be e nr olle d at 
eac h d ose le vel. Treat me nt will c o nti n ue u ntil disease pr o gressi o n, u nacce pta ble A Es or t o xicit y t hat 
ca n n ot be ma na ge d b y s u p p orti ve care, patie nt’s wit h dra wal of c o nse nt, I n vesti gat or decisi o n t o 
disc o nti n ue st u d y treat me nt, pre g na nc y, deat h, or S p o ns or decisi o n t o ter mi nate t he st u d y. A safet y 
re vie w c o m mittee will e val uate all a vaila ble data fr o m b ot h c o h orts after t he last patie nt e nr olle d has 
bee n  o bser ve d f or at least 2 c y cles t o deter mi ne t he R P 2 D. A d diti o nal d ose le vels ( 2 0 m g or 6 0 m g) 
mi g ht be e val uate d if a n o pti mal d ose is n ot i de ntifie d a n d t he safet y re vie w c o m mittee is i n a gree me nt. 
T he defi niti o n of a D L T is t he sa me as descri be d i n Part s A  a n d B. Res p o nse will be assesse d e ver y 8  
wee ks per R E CI S T 1. 1 criteria.  
 
K P T -9 2 7 4 D ose Fi n di n g  ( P art C ) 
C o h ort  
K P T -9 2 7 4  
Ni v ol u m a b  
D ays 1, 3, 5, 8, 1 0, 1 2, 1 5, 1 7, 1 9, 2 2, 2 4, 2 6 i n a 2 8 -d ay cycle  
D ay 1 i n a 2 8 -d ay cycle  
1  
3 0 m g  
4 8 0 m g  
2  
4 0 m g  
4 8 0 m g  
 
P h ar m ac o ki netic 
 S a m ples  
Bl o o d sa m ples f or p har mac o ki netic ( P K) a n d 
 assess me nts will be c ollecte d 
d uri n g b ot h t he D ose Escalati o n a n d D ose E x pa nsi o n P hases of t he st u d y. Bi o psies f or Part C will be 
c ollecte d at baseli ne a n d at t he first res p o nse assess me nt.  
N u m ber of P atie nts ( pl a n ne d):  
A p pr o xi matel y 1 7 5 patie nts ma y be e nr olle d. H o we ver, t he n u m ber of patie nts re q uire d f or c o m pl eti o n 
of st u d y e nr oll me nt ca n n ot be defi ne d a pri ori si nce t his de pe n ds o n t he n u m ber of patie nts nee de d f or 
t he d ose escalati o ns i n Parts A an d B. Ass u mi n g t hat 9 d ose le vels of K P T -9 2 7 4 are e val uate d d uri n g 
b ot h Part A ( K P T -9 2 7 4 si n gle a ge nt) a n d Part B ( K P T -9 2 7 4 + niaci n E R) of t he D ose Escalati o n P hase 
a n d u p t o 6 5 a d diti o nal patie nts are e nr olle d i n t he D ose E x pa nsi o n P hase t he t otal c o m bi n e d e nr oll me nt 
is esti mate d t o be 1 7 5 patie nts. 
D ose Escalati o n P hase: Eac h c o h ort i n Parts A a n d B of t he escalati o n p hase w ill c o nsist of 3 or 
6  patie nts  at eac h d ose le vel .  
D ose E x pa nsi o n P hase: U p t o 6 5 a d diti o nal patie nts ( u p t o 4 5 patie nts i n t he K P T -9 2 7 4 ± niaci n E R 
c o h ort; if D ose E x pa nsi o n is c o n d ucte d wit h K P T -9 2 7 4 + niaci n E R t he n a n o pti o nal c o h ort of u p t o 
2 0  a d diti o nal patie nts i n t he K P T -9 2 7 4 si n gle a ge nt c o h ort ) ma y be e nr olle d. 
D ose Fi n di n g  i n Part C ma y i ncl u de a p pr o xi matel y  2 0 patie nts  wit h mela n o ma.  
C CI
C CI

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Inclusion/Exclusion Criteria (Part A and B):  
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible to enroll in this study. 
1. Written informed consent obtained prior to any screening procedures and in accordance with 
federal, local, and institutional guidelines. 
2. Age ≥18 years. 
3. Patients with advanced solid malignancies or NHL for which all standard therapeutic options 
considered useful by the investigator have been exhausted.  
4. Patients must have objective evidence of progressive disease on study entry: 
a. Advanced solid malignancies: Measurable disease as defined by RECIST 1.11. 
b. NHL: Measurable disease including target lesion(s) as defined by the Lugano 
Classification2 for initial evaluation and staging. 
5. Patients must have a site of disease amenable to biopsy and be a candidate for biopsy according 
to the treating institution’s guidelines.  
6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1. 
7. Adequate hepatic function: 
a. Total bilirubin < 1.5 times the upper limit of normal (ULN) (except patients with Gilbert’s 
syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of 
≤ 3 times ULN),  
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN 
(except patients with known liver involvement of their advanced solid malignancy or NHL 
who must have their AST and ALT ≤ 5.0 times ULN). 
8. Adequate renal function: estimated creatinine clearance of ≥ 60 mL/min, calculated using the 
formula of Cockroft and Gault (140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 
if female. 
9. Female patients of child-bearing potential must agree to use dual methods of contraception 
(including one highly effective and one effective method of contraception) and have a negative 
serum pregnancy test at Screening, and male patients must use an effective barrier method of 
contraception if sexually active with a female of child-bearing potential. For both male and 
female patients, effective methods of contraception must be used throughout the study and for 
3 months following the last dose. 
10. Adequate hematopoietic function: total white blood cell (WBC) count ≥ 1500/mm3, absolute 
neutrophil count (ANC) ≥ 1000/mm3, hemoglobin (Hb) ≥ 10.0 g/dL, and platelet count 
≥ 75,000/mm3.  
11. Dose Escalation Phase: Patients will be enrolled according to their NAPRT1 status at a ratio of 
2:1 (NAPRT1 negative:NAPRT1 positive). The NAPRT1 status must be determined prior to 
enrollment based on evaluation of a fresh tumor biopsy or archival tissue taken ≤ 6 months of 
screening. 
12. Dose Expansion Phase (KPT-9274 ± niacin ER cohort only): Patient tumors NAPRT1 and 
IDH1 tumor status must be determined at the central laboratory prior to enrollment.  
a. Confirmation of NAPRT1 expression and IDH1 mutation based on evaluation of a fresh 
tumor biopsy or archival tumor biopsy taken ≤ 6 months of screening tests as follows: 
i. NAPRT1 positive for expansion cohort I or III 
ii. NAPRT1 negative for expansion cohort II or III 
iii. IDH1 mutation status for expansion cohort IV 

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13. Life expectancy of ≥ 3 months. 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not eligible to enroll in this study. 
1. Female patients who are pregnant or lactating. 
2. Time since the last prior therapy for treatment of advanced solid malignancies or NHL**: 
a. Radiation, chemotherapy, immunotherapy or any other anticancer therapy, including 
investigational anti-cancer therapy ≤ 2 weeks prior to C1D1. 
b. Palliative steroids for disease related symptoms < 7 days prior to C1D1.  
**Patients must have recovered or stabilized (Grade 1 or to their baseline for non-hematologic 
toxicities, ≤ Grade 2 or to their baseline for hematologic toxicities) from toxicities related to their 
previous treatment except for alopecia. In specific cases, patients with Grade 2 non-hematologic 
toxicities will be allowed following approval by the Karyopharm medical monitor. 
3. Patients with known central nervous system (CNS) disease or leptomeningeal involvement, 
regardless of response to prior therapy, are excluded.  
4. Major surgery within four weeks before C1D1. 
5. Impaired cardiac function or clinically significant cardiac diseases, including any of the 
following: 
a. Unstable angina or acute myocardial infarction ≤ 3 months prior to C1D1; 
b. Clinically significant heart disease (e.g., symptomatic congestive heart failure; uncontrolled 
arrhythmia, or hypertension; history of labile hypertension or poor compliance with an 
antihypertensive regimen). 
6. Active infection with completion of therapeutic antibiotics, antivirals, or antifungals within one 
week prior to C1D1. Prophylactic antibiotics, antivirals or antifungals are permitted. 
7. Patients with a known history of Human Immunodeficiency Virus (HIV); HIV testing is not 
required as part of this study. 
8. Known, active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg 
(HBV surface antigen). Testing is not required. 
9. Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting 
or diarrhea that could interfere with the absorption of KPT-9274.  
10. Serious psychiatric or medical conditions that, in the opinion of the Investigator, could interfere 
with treatment, compliance, or the ability to give consent. 
11. Active peptic ulcer disease or other active gastrointestinal bleeds. 
 
Inclusion/Exclusion Criteria (Part C):  
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible to enroll in this study. 
1. Written informed consent obtained prior to any screening procedures and in accordance with 
federal, local, and institutional guidelines. 
2. Age ≥18 years. 
3. Patients must have objective and measurable melanoma by RECIST 1.1 after disease 
progression on a prior anti-PD-1 or anti-PD-L1 therapy. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 
5. Adequate hepatic function:  

KPT-9274 
 
 
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a. Total bilirubin < 1.5 times the upper limit of normal (ULN) (except patients with 
Gilbert’s syndrome [hereditary indirect hyperbilirubinemia] who must have a total 
bilirubin of ≤ 3 times ULN), 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times 
ULN (except patients with known liver involvement of their advanced solid malignancy 
who must have their AST and ALT ≤ 5.0 times ULN). 
6. Adequate renal function: Estimated creatinine clearance of ≥ 60 mL/min, calculated using the 
formula of Cockroft and Gault (140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 
if female. 
7. Female patients of child-bearing potential must agree to use dual methods of contraception 
(including one highly effective and one effective method of contraception) and have a negative 
serum pregnancy test at Screening, and male patients must use an effective barrier method of 
contraception if sexually active with a female of child-bearing potential. For both male and 
female patients, effective methods of contraception must be used throughout the study and for 
3 months following the last dose. 
8. Adequate hematopoietic function: total white blood cell (WBC) count ≥ 1500/mm3, absolute 
neutrophil count (ANC) ≥ 1000/mm3, hemoglobin (Hb) ≥ 10.0 g/dL, and platelet count 
≥ 100,000/mm3. 
9. Life expectancy of ≥ 3 months. 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not eligible to enroll in this study: 
1. Female patients who are pregnant or lactating. 
2. ≤ 2 weeks since the last prior therapeutic regimen for melanoma. Palliative steroids for disease 
related symptoms < 7 days prior to C1D1, unless physiologic doses of steroids are used.  
3. Patients who have not recovered or stabilized (Grade 1 or to their baseline for non-hematologic 
toxicities, ≤ Grade 2 or to their baseline for hematologic toxicities) from toxicities related to 
their previous treatment except for alopecia. In specific cases, patients with Grade 2 non-
hematologic toxicities will be allowed following approval by the Karyopharm medical monitor. 
4. Patients with untreated central nervous system (CNS) disease or leptomeningeal involvement 
are excluded. Patients without active brain or leptomeningeal metastases after prior treatment 
with local therapies are eligible provided that the treatment had been done ≥ 2 weeks prior to 
enrollment. 
5. Major surgery within four weeks before C1D1. 
6. Active infection with completion of therapeutic antibiotics, antivirals, or antifungals within one 
week prior to C1D1. Prophylactic antibiotics, antivirals or antifungals are permitted. 
7. Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting 
or diarrhea that could interfere with the absorption of KPT-9274. 
8. Serious psychiatric or medical conditions that, in the opinion of the Investigator, could interfere 
with treatment, compliance, or the ability to give consent. 
9. Active peptic ulcer disease or other active gastrointestinal bleeds. 
10. Patients requiring treatment with corticosteroids at doses higher than substitute therapy (> 10 
mg prednisone), are unstable with substitute hormonal therapy, or are deemed to be likely to re-
occur by the treating physician when administered nivolumab. 
Investigational product, dosage and mode of administration:  
KPT-9274 is an orally bioavailable small molecule and a tablet solid dosage form for oral administration 
is being used for clinical studies.  

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Clinical Study Protocol: KCP-9274-901  
 
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KPT-9274 tablets are designed for immediate-release oral administration and will be supplied in high-
density polyethylene (HDPE) bottles with induction seals. KPT-9274 tablets will be film coated for ease 
of handling and provided in tablet strengths of 5 mg and 20 mg. KPT-9274 will be supplied by 
Karyopharm. Additional details on KPT-9274 are provided in the Investigator’s Brochure. The 
investigational treatments will be administered as a flat dose and not by body weight or body surface 
area. 
Patients enrolled in Part B of the Dose Escalation Phase and potentially in the Dose Expansion phase 
will also receive 500 mg of any FDA approved prescription, generic niacin ER for oral use 
co-administered with each dose of KPT-9274. The starting dose of 500 mg niacin ER may be titrated up 
to 2,000 mg of daily dose, per label. A list of approved generic niacin ER will be provided in the 
Pharmacy Manual. 
Patients enrolled in Part C (KPT-9274 + nivolumab) will receive nivolumab (480 mg) intravenously on 
Day 1 of each 28 day cycle per the FDA approved package insert. 
Permitted Concomitant Medications: 
No significant inhibition of any of the CYP450 enzymes were observed after KPT-9274 treatment. 
Weak induction of CYPs 1A2, 2B6, and 3A4 were observed in an exploratory pre-clinical study after 
KPT-9274 treatment. There were no DDIs noted in the first 50 patients treated in Parts A and B. 
Therefore, the use of any concomitant medication/therapy (except for the medications listed in the 
prohibited concomitant medication section), including over-the-counter (OTC) medications (excluding 
herbal supplements, dietary supplements), deemed necessary for the care of the patient is permitted 
during the study. Medications required to treat AEs, manage cancer symptoms, concurrent stable 
diseases and supportive care agents (e.g., blood product transfusions, antibiotics with [if appropriate] 
granulocyte-colony stimulating factors [G-CSF] for neutropenic infection), pain medications, anti-
emetics, and anti-diarrheals are allowed. Concurrent therapy with growth factors is allowed. The use of 
any immunosuppressive agents must be discussed between the Investigator and the Karyopharm 
Medical Monitor on a case-by-case basis.  
Hormonal contraceptives are permitted in women of child-bearing potential. Hormonal contraceptives 
include any marketed contraceptive agent that includes an estrogen and/or a progestational agent. 
Additionally, the nivolumab product label will be consulted to obtain the permitted concomitant 
medications for patients in Part C (KPT-9274 + nivolumab). 
Supportive Care:   
Patients are expected to be aggressively treated to minimize the likelihood and/or severity of side effects 
at the discretion of the Investigator (consultation with the Karyopharm Medical Monitor is strongly 
encouraged), particularly GI symptoms and hematopoietic toxicities as observed in KPT-9274 animal 
toxicology studies. Supportive care including anti-nausea/anti-emetic therapy, acid suppression (e.g., 
proton pump inhibitors [PPIs] ± H2-blockers), anti-diarrheal therapy, and other standard treatments may 
be administered as per institutional guidelines for symptomatic patients. For additional options, see 
NCCN Supportive Care Clinical Practice Guidelines in Oncology. Note: the use of PPIs is allowed in all 
patients, but the Investigator must consult with the Karyopharm Medical Monitor prior to their use in 
patients receiving niacin ER. Supportive care recommendations for events such as anemia, arthralgias, 
and myalgias include the following; (1) anemia: dose interruption, dose reduction, use of growth factors 
(i.e., erythropoietins), and transfusions; (2) arthralgia: non-steroidal anti-inflammatory drugs (NSAIDs), 
cyclooxygenase-2 (COX-2) inhibitors, acetaminophen, tramadol, and low-dose steroids; and (3) myalgia 
and flu-like illness: KPT-9274 dosing at night, acetaminophen (including pre-treatment with 
acetaminophen), NSAIDs, COX-2 inhibitors, and low-dose steroids. For patients in Part A, the addition 
of niacin ER (up to 2,000 mg daily dose, per label) is allowed after completion of the DLT period in 
cycle 1 (first 28 days) in an attempt to offset potential side effect (i.e. anemia, arthralgias, myalgias, etc.) 

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Clinical Study Protocol: KCP-9274-901  
 
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of KPT-9274. Consultation with the Karyopharm Medical Monitor is recommended for questions 
regarding these recommendations. 
Prohibited Concomitant Medications: 
The use of niacin or niacin-containing supplements (e.g., multivitamins and energy drinks) is not 
allowed in the KPT-9274 only cohorts in the Dose Escalation or Expansion Phases. However, for 
patients in these cohorts that have cleared DLT in cycle 1, niacin ER (up to 2,000 mg co-administered 
with KPT-9274) may be used as supportive care in an attempt to offset potential side effects (e.g. 
anemia, arthralgias, myalgias, etc.) of KPT-9274. Prior to initiating niacin ER, patient symptoms and 
laboratory values should be reviewed and discussed with the Medical Monitor for this study. 
Investigational or commercial anticancer agents other than KPT-9274 are not allowed during the study. 
The initiation of any non-protocol specific anti-tumor treatment is considered an indication of disease 
relapse/progression and should be recorded appropriately in the eCRFs.  
There are exceptions including localized palliative radiation, hormonal therapy for patients with prostate 
cancer, hormonal contraception for the prevention of pregnancy, and blood products/growth factors. For 
other possible cases, consult the Karyopharm Medical Monitor.  
Treatment Duration: 
Treatment cycles are 28 days long. A patient may continue to receive KPT-9274 ± niacin ER (Parts A 
and B) or KPT-9274 + nivolumab (Part C) until the patient experiences progressive disease, withdraws 
consent or decides to withdraw from further treatment, is lost to follow-up, experiences intolerable 
toxicity which precludes further treatment with KPT-9274, or treatment is discontinued at the discretion 
of the Investigator or the Karyopharm Medical Monitor. 
Criteria for Evaluation: 
Safety Endpoints: 
The safety and tolerability of KPT-9274 ± niacin ER as well as KPT-9274 + nivolumab will be 
evaluated by means of DLTs, AE reports, physical examination results, electrocardiogram results and 
laboratory safety evaluations. The National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03, will be used for grading of AEs. 
A DLT is defined as an AE or abnormal laboratory value that occurs within the first 28 days of 
treatment with KPT-9274, except for those that are clearly and incontrovertibly due to underlying 
disease, disease progression, or extraneous causes, and meets any of the criteria for defining dose-
limiting toxicities. 
Efficacy Endpoints: 
The secondary endpoint of disease response will be evaluated according to RECIST 1.11 (advanced solid 
malignancies) or Lugano Classification2 (NHL) and will include the following: 
• 
Overall response rate (ORR): ORR = proportion of patients who have a response of partial 
response (PR) or complete response (CR)  
• 
Duration of response (DOR): the duration of time from first meeting CR or PR measurement 
criteria (whichever occurs first) until the first date that PD recurrence is objectively 
documented.  
• 
Disease control rate (DCR): DCR = proportion of patients who have a response of CR, PR, 
and Stable Disease (SD) ≥ 16 weeks.  
• 
Duration of disease control: the duration of time from date of first study treatment until the 
first date that PD is objectively documented. 
• 
Progression-free survival (PFS): the duration of time from date of first study treatment until 
the first date that PD is objectively documented or death due to any cause.  

K P T -9 2 7 4  
 
 
Kar y o p har m T hera p e utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1  Marc h 2 0 2 0   
C o nfi de ntial  
Pa ge 1 7  
Versi o n 5. 0  
 
•  
O ver all s ur vi v al ( O S): t he d urati o n of ti me fr o m date of first st u d y treat me nt u ntil deat h fr o m 
a n y ca use.  
•  
Ti me t o Pr o gressi o n  (T T P):  the  d urati o n of ti me fr o m date of first st u d y treat me nt u ntil t he 
first date t hat P D is o bjecti vel y d oc u me nte d or deat h d ue t o P D .  
P h ar m ac o ki netic E n d p oi nts:  
K P T -9 2 7 4 P K para meters ma y i ncl u de, b ut are n ot li mite d t o, ma xi m u m plas ma c o nce ntrati o n ( C ma x ), 
area u n der t he c ur ve ( A U C), ti me -t o-pea k plas ma c o nce ntrati o n (t ma x ), ter mi nal plas ma half-life (t½ ), 
a p pare nt v ol u me of distri b uti o n ( V d/ F), a n d a p pare nt plas ma cleara nce  (C L / F). 
St atistic al Met h o ds:  
S a m ple size j ustific ati o n  
C CI

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Part A and Part B:The sample size for Dose Escalation Phase is based on a standard 3+3 design for the 
purpose of determining the RP2D and MTD (Part A) and the RP2D and MTD of KPT-9274 co-
administered with niacin ER (Part B). Each cohort in Parts A and B of the Escalation Phase will consist 
of 3 or 6 patients per cohort.  
For the Dose Expansion Phase, up to 65 additional patients may be enrolled at the RP2D for KPT-9274 
single agent or KPT-9274 + niacin ER (up to 45 patients in the KPT-9274 ± niacin ER cohort; if Dose 
Expansion is conducted with KPT-9274 + niacin ER then an optional cohort of up to 20 additional 
patients in the KPT-9274 single agent cohort).  
Assuming that 9 dose levels of KPT-9274 are evaluated during both Part A and Part B of the Dose 
Escalation Phase and up to 65 additional patients are enrolled in the Dose Expansion Phase, the total 
combined enrollment is estimated to be 175 patients. 
Part C: 
For Part C, two dose levels of KPT-9274 (30 and 40 mg) + nivolumab will be tested. A maximum of 10 
patients may be enrolled at each dose level. Additional dose levels (20 mg or 60 mg) might be evaluated 
if an optimal dose is not identified and the safety review committee is in agreement.  
 
Analysis methods for efficacy endpoints:Disease response will be assessed according to RECIST 1.11 
(advanced solid malignancies) and the Lugano Classification for response assessment2 (NHL). ORR, 
DOR, DCR, duration of disease control, PFS, OS, and TTP will be evaluated separately for Part A, B 
and C. The 2-sided, exact 95% confidence interval (CI) of ORR and DCR will be estimated for each 
arm. The median duration of DOR, duration of diseae control, PFS, OS, and TTP with the 95% CI will 
be estimated for each arm using the Kaplan-Meier (KM) method. 
 
Analysis methods for safety endpoints 
Standard safety analyses will be performed. Details will be described in the Statistical Analysis Plan. 

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Clinical Study Protocol: KCP-9274-901  
 
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Version 5.0 
Table 1: Schedule of Assessments: Screening and Cycle 1 (Parts A and B) 
If an in-clinic visit is missed during Cycle 1 due to a national or local holiday, the patient should come to the clinic on their next dosing day to complete the visit assessments. Patient is to be instructed 
that dose is to be taken in the clinic. 
 
 
Screening 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Day -30 to 
Day -1 
Day -14 to 
Day -1 
Day 1 
Day 2 
Day 3 
D4 
+1 day 
D8 
D11  
±1 day 
D15 
D18  
±1 day 
D22 
D24 
D25 
D26 
Visit Type 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Activity/Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determination of NAPRT1 and 
IDH1 status2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient weight 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Vital Signs (BP, pulse, temp)4 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Complete physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed physical 
exam 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
12-lead ECG5,8 
X5 
 
 
X5 
(Pre-dose 
and 4 hours 
post-dose) 
 
 
 
 
 
 
 
 
 
 
X5 
(Pre-dose 
and 
4 hours 
post-dose) 
Echocardiogram or MUGA6,8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmic exam7, 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG8 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Rheumatology consultation and 
testing23 
 
 
As clinically indicated 
Hematology consultation and 
testing24 
 
 
As clinically indicated 
Clinical Labs 
 
 
 
 
 
 
 
 
 
 
 
 
 

K P T -9 2 7 4  
 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 2 0  
Versi o n 5. 0  
 
Scree ni n g  
C ycle 1  
Wee k 1  
Wee k 2  
Wee k 3  
Wee k 4  
D a y -3 0 t o 
D a y -1  
D a y -1 4 t o 
D a y  -1  
D a y 1  
D a y 2  
D a y 3  
D 4  
+ 1 d a y  
D 8  
D 1 1  
± 1 d a y  
D 1 5  
D 1 8  
± 1 d a y  
D 2 2  
D 2 4  
D 2 5  
D 2 6  
Visit T y pe  
Cli nic  
Visit  
Cli nic  
Visit  
Cli nic  
Visit  
Cli nic 
Visit  
Cli nic 
Visit  
P h o ne  
C all  
Cli nic 
Visit  
P h o ne  
C all  
Cli nic  
Visit  
P h o ne  
C all  
Cli nic  
Visit  
Cli nic  
Visit  
Cli nic  
Visit  
Cli nic  
Visit  
Uri nal ysis 8 
 
X  
X 2 1 
 
X   
 
X  
 
X  
 
X  
 
 
X  
C B C wit h differe ntial 8 
 
X  
X 2 1 
 
X  
 
X  
 
X  
 
X  
 
 
X  
T S H 8, 9 
 
X  
X 2 1 
 
X  
 
X  
 
X  
 
X  
 
 
X  
C o m plete ser u m c he mistr y 8 
 
X  
X 2 1 
 
X  
 
X  
 
X  
 
X  
 
 
X  
A m ylase a n d li pase 8, 9 
 
X  
X 2 1 
 
 
 
 
 
 
 
 
 
 
 
C oa g ulati o n tests 8 
 
X  
 
 
 
 
 
 
X  
 
 
 
 
 
Ser u m h C G pre g na nc y test 1 0 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Vita mi n B 1 2, f olate, ir o n, 
er yt hr o p oieti n, ha pt o gl o bi n, 
a n d tra nsferri n le vels a n d 
retic ul oc yte c o u nt2 5 
X  
 
As cli nicall y i n dicate d  
N H L O nl y Pr oce d ures  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease ris k assess me nt 1 1 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
P E T -C T or C T sca n 1 2 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
L y m p h n o de c ore bi o ps y 2 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
± 7 da ys  
B o ne marr o w as pirate a n d/ or 
bi o ps y 1 3 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
E O R T C Q L Q -C 3 0 a n d F A C T -
L y m q uesti o n naires 1 4 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
A d va nce d S oli d Mali g na nc y O nl y 
Pr oce d ures  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C T or M RI or P E T -C T 1 5 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
T u m or bi o ps y 2 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
± 7 da ys  
E O R T C Q L Q -C 3 0 1 4 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
St u d y treat me nt d osi n g i n -cli nic 2 0  
 
 
X  
 
X  
 
X  
 
X  
 
X  
X  
 
X  
P K/
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bl o o d dra ws f or P K a nal ysis 1 6 
 
 
X  
X  
X  
 
X  
 
X  
 
 
X  
X  
X  
A d verse e ve nts  
C o nti n u o us  
C o nc o mita nt me dicati o ns  
C o nti n u o us  
Tele p h o ne c o ntact 1 8 
 
 
 
 
 
X  
 
X  
 
X  
 
 
 
 
C CI
C CI

KPT-9274 
 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901  
 
11 March 2020 
 
Confidential 
Page 21 
Version 5.0 
Table 2: Schedule of Assessments: Cycles 2 and Beyond (Parts A and B) 
If an in-clinic visit is missed during Cycle 2 and beyond, the patient should come to the clinic on their next dosing day to complete the visit assessments. Patient is to be instructed that dose is to be 
taken in the clinic. 
 
 
Cycle 2 
Cycle 3 and Beyond 
Week 1 
Week 2 
Week 3 
Week 4 
Week 1 
Week 2 
Week 3 
Week 4 
D1 
D4  
±1 day 
D8 
D11 
±1 day 
D15 
D18 
 ±1 day 
D22 
D25 
 ±1 day 
D1 
D4  
±1 day 
D11  
±1 day 
D15 
D18 
 ±1 day 
D25 
 ±1 day 
Visit Type 
Clinic Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Phone 
Call 
Activity/Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient weight 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Vital Signs (BP, pulse, temp)4 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Symptom-directed physical exam 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
12-lead ECG5 
X 
 
 
 
 
 
 
 
X 
(Odd cycles 
only) 
 
 
 
 
 
ECOG 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Rheumatology consultation and 
testing23 
As clinically indicated 
Hematology consultation, testing, 
and biopsy24 
As clinically indicated 
Clinical Labs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
CBC with differential 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
TSH9 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Complete serum chemistry 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Amylase and lipase9 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Coagulation tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitamin B12, folate, iron, 
erythropoietin, haptoglobin, and 
transferrin levels and reticulocyte 
count25 
As clinically indicated 
NHL Only Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET-CT or CT scan12 
 
 
 
 
 
 
 
 
X 
(±7 days; odd 
cycles only) 
 
 
 
 
 

K P T -9 2 7 4  
 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 2 2  
Versi o n 5. 0  
 
C ycle 2  
C ycle 3 a n d Be y o n d  
Wee k 1  
Wee k 2  
Wee k 3  
Wee k 4  
Wee k 1  
Wee k 2  
Wee k 3  
Wee k 4  
D 1  
D 4  
± 1 d a y  
D 8  
D 1 1  
± 1 d a y  
D 1 5  
D 1 8  
 ± 1 d a y  
D 2 2  
D 2 5  
 ± 1 d a y  
D 1  
D 4  
± 1 d a y  
D 1 1  
± 1 d a y  
D 1 5  
D 1 8  
 ± 1 d a y  
D 2 5  
 ± 1 d a y  
Visit T y pe  
Cli nic Visit  
P h o ne 
C all  
Cli nic 
Visit  
P h o ne 
C all  
Cli nic 
Visit  
P h o ne 
C all  
Cli nic 
Visit  
P h o ne 
C all  
Cli nic  
Visit  
P h o ne 
C all  
P h o ne  
C all  
Cli nic  
Visit  
P h o ne  
C all  
P h o ne  
C all  
L y m p h n o de c ore bi o ps y 2 
 
 
 
 
 
 
 
 
X  
( ± 7 da ys; C 6 
o nl y)  
 
 
 
 
 
E O R T C Q L Q -C 3 0 a n d F A C T -L y m 
q uesti o n naires 1 4 
X  
 
 
 
 
 
 
 
X  
 
 
 
 
 
A d va nce d S oli d Mali g na nc y O nl y 
Pr oce d ures  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C T or M RI or P E T -C T 1 5 
 
 
 
 
 
 
 
 
X  
( ± 7 da ys; o d d 
c ycles o nl y) 
 
 
 
 
 
T u m or bi o ps y 2 
 
 
 
 
 
 
 
 
X  
( ± 7 da ys; C 6 
o nl y)  
 
 
 
 
 
E O R T C Q L Q -C 3 0 1 4 
X  
 
 
 
 
 
 
 
X  
 
 
 
 
 
St u d y treat me nt  d osi n g i n -cli nic 2 0 
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
 
P K/
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bl o o d dra ws f or P K a nal ysis 1 6 
 
 
 
 
X  
 
 
 
X  
( O d d c ycles 
o nl y)  
 
 
 
 
 
A d verse e ve nts  
C o nti n u o us  
C o nc o mita nt me dicati o ns  
C o nti n u o us  
Tele p h o ne c o ntact 1 8 
 
X  
 
X  
 
X  
 
X  
 
X  
X  
 
X  
X  
 
 
 
 
C CI
C CI

K P T -9 2 7 4  
 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 2 3  
Versi o n 5. 0  
T a ble  3 : Sc he d ule of Assess me nts:  E n d -of -Tre at me nt a n d Be y o n d  ( P arts A a n d B)
Acti vit y/ Assess me nt  
E n d -of -Tre at me nt ( E o T) Visit  
S afet y F oll o w -u p C all 2 2 
D ur a bilit y of Res p o nse a n d S ur vi v al  
F oll o w -u p 1 9 
≤ 1 4 D a ys P ost L ast D ose  
3 0 D a ys P ost -L ast D ose  
E ver y 3 m o nt hs f or 1 ye ar after t he s afet y 
f oll o w-u p c all  
+ 7 d a ys  
± 7 d a ys  
Cli nical Assess me nts  
Patie nt wei g ht  
X  
 
 
Vital Si g ns ( B P, p ulse, te m p) 4 
X  
 
 
C o m plete p h ysical e xa m  
X  
 
 
1 2 -lea d E C G5 
X  
 
 
Ec h ocar di o gra m or M U G A 6 
X  
 
 
O p ht hal mic e xa m 7  
X  
 
 
E C O G  
X  
 
 
R he u mat ol o g y c o ns ultati o n a n d testi n g 2 3 
As cli nicall y i n dicate d  
 
 
He mat ol o g y c o ns ultati o n, testi n g, a n d bi o ps y 2 4 
As cli nicall y i n dicate d  
 
 
Cli nical La bs  
Uri nal ysis  
X  
 
 
C B C wit h differe ntial  
X  
 
 
T S H 9 
X  
 
 
C o m plete ser u m c he mistr y  
X  
 
 
A m ylase a n d li pase 9 
X  
 
 
C oa g ulati o n tests  
X  
 
 
Ser u m h C G pre g na nc y test 1 0 
X  
 
 
Vita mi n B 1 2, f olate, ir o n , er yt hr o p oieti n, ha pt o gl o bi n, a n d 
tra nsferri n le vels a n d retic ul oc yte c o u nt 2 5 
X  
 
 
N H L O nl y Pr oce d ures  
P E T -C T or C T sca n 1 2 
X  
 
X  
E O R T C Q L Q -C 3 0 a n d F A C T -L y m q uesti o n naires 1 4 
X  
 
 
A d va nce d S oli d Mali g na nc y O nl y Pr oce d ures  
C T or M RI or P E T -C T 1 5 
X  
 
X  
E O R T C Q L Q -C 3 0 1 4 
X  
 
 
P K/
 
Bl o o d dra ws f or P K a nal ysis 1 6 
X  
 
 
A d verse e ve nts  
X  
X  
 
C CI
C CI

K P T -9 2 7 4  
 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 2 4  
Versi o n 5. 0  
Acti vit y/ Assess me nt  
E n d -of -Tre at me nt ( E o T) Visit  
S afet y F oll o w -u p C all 2 2 
D ur a bilit y of Res p o nse a n d S ur vi v al  
F oll o w -u p 1 9 
≤ 1 4 D a ys P ost L ast D ose  
3 0 D a ys P ost -L ast D ose  
E ver y 3 m o nt hs f or 1 ye ar after t he s afet y 
f oll o w-u p c all  
+ 7 d a ys  
± 7 d a ys  
C o nc o mita nt me dicati o ns  
X  
X  
 
Tele p h o ne c o ntact 1 8 
 
X  
X  
(If i n pers o n visit is n ot perf or me d) 
A nti ne o plastic t hera p y after E o T  
 
X  
X  
Sites s h o ul d a d here t o t he 2 8 -da y c ycle.  
Pr oce d ures t o be p erf or me d d uri n g cli nic visits will be d o ne pri or t o t he a d mi nistrati o n of st u d y treat me nt o n t h ose da ys.  
A b bre viati o ns: A E = a d verse e ve nt; B S A = b o d y s urface area; C B C = c o m plete bl o o d c o u nt; C T = c o m p ute d t o m o gra p h y; D = Da y; E C G = electr ocar di o gra m; E C O G = Easte r n C o o perati ve O nc ol o g y 
Gr o u p; E O R T C Q L Q = E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y o f Life Q uesti o n naire; E o T = E n d of Treat me nt; F A C T-L y m = F u ncti o nal Assess me nt of Ca ncer T hera p y -
L y m p h o ma; M RI = ma g netic res o na nce i ma gi n g; P E T = p ositr o n e missi o n t o m o gra p h y; 
; P K =  P har mac o ki netic; T S H = t h yr oi d sti m ulati n g h or m o ne  
1 
Pri or t o a n y st u d y -s pecific meas ure.  
2 
F or e x pl orati ve a nal ysis researc h pr o ce d ure, t u m or tiss ue (l y m p h n o de c ore bi o ps y f or N H L patie nts or t u m or bi o ps y f or patie n ts wit h a d va nce d s oli d mali g na nc y) will be o btai ne d pre- treat me nt 
( Da y -3 0 t o Da y 7 ), C 1 D 2 6 ( ± 7 da ys), a n d at C 6 D 1 ( ± 7 da ys) a n d/ or at t he ti me of pr o gressi o n. Eac h bi o ps y will be di vi de d i nt o 3 p orti o ns, res ulti n g i n  t w o fres h bi o psies a n d o ne f or mali n fi xe d 
bi o ps y. D ose Escalati o n P hase: Patie nts will be e nr olle d acc or di n g t o t heir  N A P R T 1 stat us at a rati o of 2: 1 ( N A P R T 1 ne gati ve: N A P R T 1 p ositi ve). T he N A P R T 1 stat us m ust be deter mi ne d pri or t o 
e nr oll me nt. N A P R T 1  a n d I D H 1 t u m or stat us m ust be deter mi ne d f or all patie nts pri or t o e nr oll me nt i n t he K P T -9 2 7 4 ± niaci n E R e x pa nsi o n c o h ort.  Prescree ni n g t o deter mi ne N A P R T 1 a n d I D H 1 
t u m or stat us will be perf or me d o n arc hi val bi o ps y material o btai ne d ≤6 m o nt hs pri or t o scree ni n g, f oll o we d b y c o nfir mati o n of N A P R T 1 a n d I D H 1 t u m or stat us d uri n g scree ni n g peri o d. F or t he 
bi o psies o n C 1 D 2 6 a n d C 6 D 1 o nly, p atie nts will be all o we d t o c o nti n ue tre at me nt if: 1) a p atie nt ref uses t he bi o psy, 2) i n t he o pi ni o n of t he tre ati n g  p hysici a n or p hysici a n perf or mi n g t he 
bi o psy t h at t he bi o psy will p ose si g nific a nt ris k t o t he p atie nt, or 3) if t he bi o psy s a m ple  o bt ai ne d o n t he first atte m pt is n ot a de q u ate.  
3 
A c o m plete me dical hist or y will be o btai ne d fr o m eac h patie nt. Me dical hist or y will i ncl u de baseli ne s y m pt o ms of t he disease u n der st u d y as well as a detaile d hist or y of pri or pr oce d ures f or t he 
patie nt’s N H L  or a d va nce d s oli d mali g na nc y a n d ot her pri or ca ncer t hera pi es (i.e., c he m ot hera p y, h or m o nal t hera p y, i m m u n ot hera p y, bi ot hera p y, ra di ot hera p y, a n d s ur ger y), i ncl u di n g start a n d 
e n d dates, best res p o nse, disease pr o gressi o n d uri n g or after t hera p y, as well as disc o nti n uati o ns d ue t o i nt olera bilit y, t o xicit y, or a n y ot her seri o us ill ness; T u m or N o des Metastasis ( T N M ) sta gi n g 
will be c ollecte d o n f or patie nts wit h a d va nce d s oli d mali g na ncies. S m o ki n g hist or y will be rec or de d. A detaile d hist or y of d isease-specific dia g n ostic a n d pr o g n ostic testi n g a n d test res ults (s uc h 
as p he n ot y pic a n d c yt o ge netic pr ofiles) will als o be c ollecte d.  
4 
Vital si g ns: bl o o d press ure, p ulse a n d b o d y te m perat ure; see  Secti o n  7. 5. 1. 2  f or a detaile d descri pti o n of vital si g n assess me nts.  
5 
1 2 -Lea d E C G t o be c o m plete d at Scree ni n g ( Da y -3 0 t o Da y -1), C 1 D 1 ( pre -d ose a n d 4 h o urs p ost -d ose), C 1 D 2 6 ( pre -d ose a n d 4 h o urs p ost -d os e), C 2 D 1, Da y 1 of o d d n u m bere d c ycles starti n g at 
C ycle 3, at t he E o T visit, a n d as cli nicall y i n dicate d at t he discreti o n of t he I n vesti gat or.  See Secti o n  9. 6. 1. 3 f or a detaile d descri pti o n of electr ocar di o gra p h y.  
6 
Ec h ocar di o gra m or M U G A sca n at Scree ni n g  ( Da y -3 0 t o Da y -1), E o T a n d as cli nicall y i n dicate d at t he discreti o n of t he  I n vesti gat or d uri n g t he st u d y. See Secti o n  7. 5. 1. 3  f or a detaile d desc ri pti o n 
of ec h ocar di o gra p h y.  
7 
A f ull o p ht hal mic e xa mi nati o n at Scree ni n g ( Da y -3 0 t o Da y -1) a n d E o T will i ncl u de, pri or t o dilati o n, best c orrecte d vis ual ac uit y, slit la m p e xa mi n ati o n i ncl u di n g t o n o metr y, f oll o wi n g dilati o n; 
f u n d osc o p y a n d slit la m p t o d oc u me nt le ns clarit y. See Secti o n  7. 5. 1. 4  f or a detaile d descri pti o n of o p ht hal mic e xa mi nati o n.  
8 
T he f oll o wi n g pr oce d ures m ust be perf or me d at S cree ni n g ( Da y -3 0 t o Da y -1) a n d pre -d ose o n C 1 D 1 (a n d as s h o w n i n  Ta ble 1  , Ta ble  2  , a n d Ta bl e  3  d uri n g t he st u d y): E C O G perf or ma nce 
assess me nt, ec h ocar di o gra m or M U G A sca n ( Scree ni n g o nl y), 1 2 -lea d E C G, a n d o p ht hal mic e xa m ( Scree ni n g o nl y). T he f oll o wi n g pr oce d ures m ust be perf or me d at Scree ni n g ( Da y -1 4 t o Da y -1) 
a n d pre -d ose o n C 1 D 1 (a n d as s h o w n i n  Ta ble 1 , Ta ble  2 , a n d Ta ble  3  d uri n g t he st u d y): uri nal ysis, C B C wit h differe ntial, T S H, c o m plete ser u m c he mistr y, c oa g ulati o ns tests ( Scree ni n g o nl y), 
a m ylase, a n d li pase.  
9 
T S H, a m ylase a n d li pase d o n ot nee d t o be re peat e d se paratel y if i ncl u de d i n ser u m c he mistr y.  
C CI

K P T -9 2 7 4  
 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 2 5  
Versi o n 5. 0  
1 0 
F or fe males of c hil d beari n g p ote ntial, ne gati ve ser u m h C G pre g na nc y test m ust be perf or me d ≤ 3 da ys of C 1 D 1 a n d t he E o T Visit . Re peat testi n g d uri n g t he st u d y as cli nicall y a p pr o priate. Test 
se nsiti vit y f or h C G m ust be ≥ 2 5 mI U/ m L.  
1 1 
Disease ris k assess me nt: See Secti o n  7. 2. 3  f or a d diti o nal details. 
1 2 
N H L disease assess me nt is prefera bl y base d o n P E T/ C T f or F D G -a vi d l y m p h o mas, or C T f or n o n -F D G -a vi d l y m p h o mas. P E T/ M RI or M RI ma y be s u bstit ute d if C T is c o ntrai n dicate d. S ca ns are 
perf or me d at Scree ni n g  a n d after e ver y 8 wee ks ± 7 da ys (e. g., Da y 1 of o d d  n u m bere d c ycles) u ntil disease pr o gressi o n or t he E o T visit a n d D ura bilit y of Res p o nse a n d S ur vi val F oll o w -u p. E o T 
sca n is o nl y re q uire d f or patie nts w h o e n d treat me nt f or reas o ns ot her t ha n di sease pr o gressi o n. T he sa me sca n m o dalit y s h o ul d be use d f or a ll assess me nts. D ura bilit y of Res p o nse a n d S ur vi val 
F oll o w -u p sca n is o nl y f or patie nts w h o ha ve n ot pr o gresse d.  
1 3 
B o ne marr o w bi o psies a n d/ or as pirates will be ta ke n wit hi n 3 0 da ys pri or t o first d ose ( baseli ne) t o assess N H L i n v ol ve me nt i n b o ne marr o w. T he  b o ne marr o w bi o ps y will be re pe ate d w he ne ver 
cli nicall y i n dicate d, at t he discreti o n of t he I n vesti gat or, t o c o nfir m C R/ P R i n o nl y t h ose patie nts w h o ha d N H L wit h k n o w n b o ne marr o w i n v ol ve me nt pri or t o d osi n g (see Secti o n  7. 3. 2. 2 ). 
1 4 
Patie nt will c o m pl ete Q o L q uesti o n naires bef ore t he y ha ve a n y st u d y pr oce d ures (i ncl u di n g disc ussi o ns wit h me dical pers o n nel a n d a d mi nistrati o n of st u d y treat me nt) at t hes e visits (s ee  
Secti o n  7. 3. 1. 1 ). 
1 5 
A d va nce d s oli d mali g na ncies: C T, M RI, or P E T -C T s ca ns will be perf or me d at scree ni n g ( Da y -3 0 t o Da y -1), t he n e ver y 8 wee ks ± 7 da ys (e. g., Da y 1 of o d d n u m bere d c ycles), u ntil disease 
pr o gressi o n or t he E o T visit a n d D ura bilit y of Res p o nse a n d S ur vi val F oll o w -u p. E o T sca n is o nl y re q uire d f or patie nts w h o e n d treat me nt f or reas o ns ot her t ha n disease pr o gressi o n. T he sa me 
sca n m o dalit y s h o ul d be use d f or all assess me nts. D ura bilit y of Res p o nse a n d S ur vi val F oll o w -u p sca n is o nl y f or patie nts w h o ha ve n ot pr o gresse d.  
1 6 
See Secti o n  7. 4  f or ti mi n g of bl o o d sa m pl es t o be c ollecte d f or P K a nalysis. Please n ote t hat if a patie nt’s d ose is c ha n ge d, bl o o d sa m pli n g f or P K (as re q ueste d f or C 1 D 1) s h o ul d be re peate d o n t h e 
first da y of d ose c ha n ge at t he sa me ti mes as descri be d f or C 1 D 1, C 1 D 2, a n d C 1 D 3. If t he d ose is misse d, P K bl o o d dra ws will n ot be c ollecte d o n t hat da y.  
1 8 
Tele p h o ne call ( or visit) wit h patie nt t o e val uate s u p p orti ve care me dicati o ns, c o nc o mi ta nt me dicati o ns, a d verse e ve nts, a n d seri o us a d verse e ve nts, a n d t o a dj ust s u p p orti ve care as a p pr o priate. T he 
tele p h o ne c o ntact wit h t he patie nt m ust ta ke place C ycle 1 Da ys 4 + 1 da y, 1 1 a n d 1 8 ± 1 da y; C ycle 2 a n d be y o n d –  Da ys 4, 1 1, 1 8, a n d 2 5 ± 1 da y; Saf et y F oll o w -u p p h o ne call + 7 da ys; a n d 
d ura bili t y of res p o nse ± 7 da ys if t he i n pers o n visit is n ot perf or me d.  
1 9 
If feasi ble a n d cli nicall y i n dicate d, t h e f oll o wi n g assess me nts s h o ul d be perf or me d e ver y 3 m o nt hs f or 1 year after t he Safet y F oll o w -u p Visit/ Call  f or patie nts w h o ha ve n ot pr o gresse d t o assess 
d ura bilit y of res p o nse: P E T/ C T f or F D G -a vi d l y m p h o mas, or C T f or n o n -F D G -a vi d l y m p h o mas ( or P E T/ M RI or M RI, res pecti vel y, if C T is c o ntrai n dicate d) sca ns f or N H L patie nts a n d C T, M RI, 
or P E T -C T sca ns f or s oli d mali g na nc y patie nts. If t hese assess me nts ca n n ot be perf or me d, a n d f or patie nts wit h P D, a tele p h o ne call will be ma de t o t he patie nt ( or t he p atie nt’s fa mil y) e ver y 3 
m o nt hs f or 1 year t o i n q uire a b o ut t he patie nt’s s ur vi val, disease stat us, a n d o verall  me dical c o n diti o n, a n d i nf or mati o n o n a n y a nti ne o plastic t hera pies utilize d si nce disc o nti n uati o n of K P T -9 2 7 4 
st u d y treat me nt.  
2 0 
See  Ta ble 4  f or at h o me vers us i n-cli nic visit d osi n g. 
2 1 
T hese assess me nts are t o be c o m plete d pre -d ose o n C 1 D 1 a n d are t o be use d t o esta blis h baseli ne val ues, n ot t o rec o nfir m eli gi bilit y. H o we ver, if a safet y c o ncer n is n ot e d, c o ntact Kar y o p har m.  
2 2 
Safet y f oll o w -u p te le p h o ne call [ 3 0 da ys p ost-last d ose ( + 7 da ys)] wit h patie nt after t heir last d ose of st u d y treat me nt t o e val uate t h eir o verall me dical c o n diti o n a n d stat us of disease, A Es, 
i ncl u di n g f oll o w-u p o n a n y A Es t hat were n ot res ol ve d at t he E o T Visit, a n d c olle cti o n of i nf or mati o n o n a n y a nti ne o plastic t hera pies use d after disc o nti n uati o n of st u d y treat me nt.  
2 3 
At t he I n vesti gat or’s discreti o n, i n c o ns ultati o n wit h t he Kar y o p har m Me di cal M o nit or, pati e nts wit h cli nicall y si g nifica nt j oi nt or m uscl e -relate d A Es ma y ha ve a r he u mat ol o g y  c o ns ultati o n. 
R he u mat ol o g y testi n g ma y be c o m plete d as cli nicall y i n dicate d per i nstit uti o nal sta n dar ds (e. g., a nti n uclear a nti b o dies, r he u mat oi d fact or, C -reacti ve pr otei n, er ythr oc yte se di me ntati o n rate, uric 
aci d [if n ot alrea d y a vaila ble], or ot her a ut oa nti b o dies base d o n s y m pt o ms ). 
2 4 
At t he I n vesti gat or’s discreti o n, i n c o ns ultati o n wit h t he Kar y o p har m Me di cal M o nit or, pati e nts wit h cli nicall y si g nif ica nt he mat ol o gical A Es, i ncl u di n g a n y gra de of treat me nt-e mer ge nt  a ne mia or 
a b n or mal reti c ul oc yte c o u nts , ma y ha ve a he mat ol o g y c o ns ultati o n. He mat ol o gical testi n g (i ncl u di n g b ut n ot li mite d t o sta n dar d he mat ol o gical e val uati o ns a n d er yt hr o p oieti n le vel) ± b o ne marr o w 
bi o ps y ma y be perf or me d as cli nicall y  i n dicate d per i nstit uti o nal sta n dar ds. 
2 5 
Patie nts wit h treat me nt -e mer ge nt a ne mia s h o ul d ha ve bl o o d le vels of vita mi n B 1 2, f olate, ir o n, er yt hr o p oieti n, ha pt o gl o bi n, a n d tra nsferri n a n d reti c ul oc yte c o u nts  assesse d as s o o n as p ossi ble after 
o nset. Patie nts wit h ≤ Gra de 1 a ne mi a s h o ul d ha ve t heir l e vels /c o u nts assesse d n o less t ha n o nce a m o nt h a n d patie nts wit h ≥ Gra de 2 a ne mia s h o ul d ha ve t heir le vels / c o u nts assesse d e ver y 
2  wee ks.  
 
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KPT-9274 
 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901  
 
11 March 2020 
 
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Version 5.0 
Table 4: Dosing Schedule (Parts A and B) 
Treatment 
Week 1 
Week 2 
Week 3 
Week 4 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15 
D16 
D17 
D18 
D19 
D20 
D21 
D22 
D23 
D24 
D25 
D26 
D27 
D28 
KPT-9274 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
Niacin ER11 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
1 Patients in the Dose Escalation Phase or in the potential Dose Expansion Phase of KPT-9274 + niacin ER cohort will receive niacin ER (500 mg – 2,000 mg 
co-administered with each dose of KPT-9274). 
Niacin ER=Niacin (vitamin B3/nicotinic acid) extended release. 
Note:  Study treatment dosing will occur in the clinic during Cycle 1 on Days 1, 3, 8, 15, 22, 24, and 26, during Cycle 2 on Days 1, 8, 15, and 22, 
and during > Cycle 3 on Days 1 and 15. Study treatment dosing will occur at home during Cycle 1 on Days 5, 10, 12, 17, and 19, during Cycle 2 
on Days 3, 5, 10, 12, 17, 19, 24, and 26 and during Cycles ≥3 on Days 3, 5, 8, 10, 12, 17, 19, 22, 24, and 26. 
 
 

KPT-9274 
 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901  
 
11 March 2020 
 
Confidential 
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Version 5.0 
Table 5: Schedule of Assessments for Screening and Cycle 1 (Part C) 
If an in-clinic visit is missed during Cycle 1 due to a national or local holiday, the patient should come to the clinic on their next dosing day to complete the visit assessments. Patient is to be instructed 
that dose is to be taken in the clinic. 
 
Screening 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Day -30 to 
Day -1 
Day -14 to 
Day -1 
Day 1 
Day 2 
Day 3 
D4 
+1 day 
D8 
D11  
±1 day D15 
D18  
±1 day 
D22 
Visit Type 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Activity/Assessment 
 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
Determination of Melanoma that 
Has Progressed on Prior Anti-PD-1 
or Anti-PD-L1 Treatment2 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Patient History 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history3 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
Patient height  
X 
 
 
 
 
 
 
 
 
 
 
Patient weight 
X 
 
X 
 
 
 
X 
 
X 
 
X 
Vital Signs (BP, pulse, temp)4 
X 
 
X 
 
 
 
X 
 
X 
 
X 
Complete physical exam 
X 
 
 
 
 
 
 
 
 
 
 
Symptom-directed physical 
exam 
 
 
X 
 
 
 
X 
 
X 
 
X 
12-lead ECG5,7 
 
 
 
X5 
(Pre-dose 
and 4 hours 
post-dose) 
 
 
 
 
 
 
 
 
Echocardiogram or MUGA6,7 
X 
 
 
 
 
 
 
 
 
 
 
ECOG7 
X 
 
X 
 
 
 
 
 
 
 
 
Hematology consultation and 
testing17 
 
 
As clinically indicated 
Clinical Labs 
 
CBC with differential7 
 
X 
X15 
 
 
 
X 
 
X 
 
X 
TSH7,8 
 
X 
X15 
 
 
 
X 
 
X 
 
 
Complete serum chemistry7 
 
X 
X15 
 
 
 
X 
 
X 
 
X 
Amylase and lipase7,8 
 
X 
X15 
 
 
 
 
 
 
 
 

K P T -9 2 7 4  
 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 2 8  
Versi o n 5. 0  
 
 
 
 
Ser u m h C G pre g na nc y test 9 
 
X  
 
 
 
 
 
 
 
 
 
Vita mi n B 1 2, f olate, ir o n, 
er yt hr o p oieti n, ha pt o gl o bi n, 
a n d tra nsferri n le vels a n d 
retic ul oc yte c o u nt1 8 
X  
 
As cli nicall y i n dicate d  
P K/
 
 
Bl o o d dra ws f or P K a nal ysis 1 0 
 
 
X  
X  
X  
 
 
 
 
 
 
A d verse e ve nts  
C o nti n u o us  (starti n g at C 1 D 1) 
C o nc o mita nt me dicati o ns  
C o nti n u o us  (starti n g at Scree ni n g) 
Tele p h o ne c o ntact 1 2 
 
 
 
 
 
X  
 
X  
 
X  
 
T u m or bi o ps y 1 9 
X  
 
 
 
 
 
 
 
 
 
 
Disease Assess me nt  
 
C T , M RI , P E T -C T  or   
i ma gi n g met h o d ol o g y per 
i n vesti gat or discreti o n2 0 
X  
 
 
 
 
 
 
 
 
 
 
St u d y treat me nt d osi n g i n -cli nic 1 4 
 
 
See Ta ble 8  
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K P T -9 2 7 4  
 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 2 9  
Versi o n 5. 0  
T a ble 6 : Sc he d ule of Assess me nts f or C ycles 2 a n d Be y o n d  ( P art C) 
If a n i n-cli nic visit is misse d d uri n g C ycle 2 a n d be y o n d, t he patie nt s h o ul d c o me t o t he cli nic o n t heir ne xt d osi n g da y t o c o m plete t he visit assess me nts. Patie nt is t o be i n str ucte d t hat d ose is t o be 
ta ke n i n t he cli nic. 
 
 
C ycle 2  
C ycle 3 a n d Be y o n d  
Wee k 1  
Wee k 
2  
Wee k 3  
Wee k 4  
Wee k 1  
Wee k 2  
Wee k 3  
Wee k 4  
D 1  
D 4  
± 1 d a y  
D 1 1  
± 1 d a y  D 1 5  
D 1 8  
 ± 1 d a y  
D 2 5  
 ± 1 d a y  
D 1  
D 4  
± 1 d a y  
D 1 1  
± 1 
d a y  
D 1 5  
D 1 8  
 ± 1 d a y  
D 2 5  
 ± 1 d a y  
Visit T y pe  
Cli nic 
Visit  
P h o ne 
C all  
P h o ne 
C all  
Cli nic 
Visit  
P h o ne 
C all  
P h o ne C all  
Cli nic  
Visit  
P h o ne 
C all  
P h o ne  
C all  
Cli nic  
Visit  
P h o ne  
C all  
P h o ne  
C all  
Acti vit y/ Assess me nt  
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical Assess me nts  
 
 
 
 
 
 
 
 
 
 
 
 
Patie nt wei g ht  
X  
 
 
X  
 
 
X  
 
 
X  
 
 
Vital Si g ns ( B P, p ulse, te m p) 4 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
S y m pt o m -directe d p h ysical 
e xa m 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
E C O G  
X  
 
 
 
 
 
X  
 
 
 
 
 
He mat ol o g y c o ns ultati o n, 
testi n g, a n d bi o ps y1 7 
As cli nicall y i n dicate d  
Cli nical La bs  
 
 
 
 
 
 
 
 
 
 
 
 
C B C wit h differe ntial  
X  
 
 
X  
 
 
X  
 
 
X  
 
 
T S H 8 
X  
 
 
 
 
 
X  
 
 
 
 
 
C o m plete ser u m c he mistr y  
X  
 
 
X  
 
 
X  
 
 
X  
 
 
A m ylase a n d li pase 8 
X  
 
 
 
 
 
X  
 
 
 
 
 
C oa g ulati o n tests  
X  
 
 
 
 
 
 
 
 
 
 
 
Vita mi n B 1 2, f olate, ir o n, 
er yt hr o p oieti n, ha pt o gl o bi n, 
a n d tra nsferri n le vels a n d 
retic ul oc yte c o u nt1 8 
As cli nicall y i n dicate d  
P K/
 
 
 
 
 
 
 
 
 
 
 
 
 
Bl o o d dra ws f or P K a nal ysis –  
K P T -9 2 7 4 + ni v ol u ma b 1 0 
X  
 
 
 
 
 
 
 
 
 
 
 
A d verse e ve nts  
C o nti n u o us  
C o nc o mita nt me dicati o ns  
C o nti n u o us  
Tele p h o ne c o ntact 1 2 
 
X  
X  
 
X  
X  
 
X  
X  
 
X  
X  
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KPT-9274 
 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901  
 
11 March 2020 
 
Confidential 
Page 30 
Version 5.0 
 
Cycle 2 
Cycle 3 and Beyond 
Week 1 
Week 
2 
Week 3 
Week 4 
Week 1 
Week 2 
Week 3 
Week 4 
D1 
D4  
±1 day 
D11 
±1 day D15 
D18 
 ±1 day 
D25 
 ±1 day 
D1 
D4  
±1 day 
D11  
±1 
day 
D15 
D18 
 ±1 day 
D25 
 ±1 day 
Visit Type 
Clinic 
Visit 
Phone 
Call 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Phone Call 
Clinic 
Visit 
Phone 
Call 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Phone 
Call 
Tumor biopsy19 
 
 
 
 
 
 
X 
±7 days 
 
 
 
 
 
CT, MRI, PET-CT, imaging 
methodology per investigator 
discretion20 
 
 
 
 
 
 
X (±7 days; odd 
cycles only) 
 
 
 
 
 
Study treatment dosing in-clinic14 
See Table 8 
 
Table 7: Schedule of Assessments for End-of-Treatment and Beyond (Part C) 
Activity/Assessment 
End-of-Treatment (EoT) Visit 
Safety Follow-up Call16 
Durability of Response and Survival  
Follow-up13 
≤ 14 Days Post Last Dose 
30 Days Post-Last Dose 
Every 3 months for 1 year after the safety 
follow-up call 
+ 7 days 
± 7 days 
Clinical Assessments 
Patient weight 
X 
 
 
Vital Signs (BP, pulse, temp)4 
X 
 
 
Complete physical exam  
X 
 
 
12-lead ECG5 
X 
 
 
ECOG 
X 
 
 
Hematology consultation, testing, and biopsy17 
As clinically indicated 
 
 
Clinical Labs 
CBC with differential 
X 
 
 
TSH9 
X 
 
 
Complete serum chemistry 
X 
 
 
Amylase and lipase8 
X 
 
 
Coagulation tests 
X 
 
 
Serum hCG pregnancy test9 
X 
 
 
Vitamin B12, folate, iron, erythropoietin, haptoglobin, and 
transferrin levels and reticulocyte count18 
X (Optional)18 
 
 

KPT-9274 
 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901  
 
11 March 2020 
 
Confidential 
Page 31 
Version 5.0 
Activity/Assessment 
End-of-Treatment (EoT) Visit 
Safety Follow-up Call16 
Durability of Response and Survival  
Follow-up13 
≤ 14 Days Post Last Dose 
30 Days Post-Last Dose 
Every 3 months for 1 year after the safety 
follow-up call 
+ 7 days 
± 7 days 
Adverse events 
X 
X 
 
Concomitant medications 
X 
X 
 
Telephone contact12 
 
X 
X 
(If in person visit is not performed) 
Antineoplastic therapy after EoT 
 
X 
X 
Tumor biopsy19 
X 
 
 
CT, MRI, PET-CT, imaging methodology per investigator 
discretion20 
X 
 
X 
Sites should adhere to the 28-day cycle.  

K P T -9 2 7 4  
 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1   
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 3 2  
Versi o n 5. 0  
Pr oce d ures t o be perf or me d d uri n g cli nic visits will be d o ne pri or t o t he a d mi nistr ati o n of st u d y tre at me nt o n t h ose d a ys.  
A b bre viati o ns: A E = a d verse e ve nt; B S A = b o d y s urface area; C B C = c o m plete bl o o d c o u nt; C T = c o m p ute d t o m o gra p h y; D = Da y; E C G = electr ocar di o gra m; E C O G = Easter n C o o p erati ve O nc ol o g y 
Gr o u p; E O R T C Q L Q = E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life Q uesti o n naire; E o T = E n d of Tre at me nt; F A C T -L y m = F u ncti o nal Assess me nt of Ca ncer T hera p y -
L y m p h o ma; M RI = ma g netic res o na nce i ma gi n g; P E T = p osit r o n e missi o n t o m o gra p h y; 
; P K =  P har mac o ki netic; T S H = t h yr oi d sti m ulati n g h or m o ne  
1 
Pri or t o a n y st u d y -s pecific meas ure.  
2 
C o nfir mati o n patie nts wit h mela n o ma  w h o pr o gresse d o n pri or a nti -P D -1 or a nti -P D -L 1 treat me nt . 
3 
A c o m plete me dical hist or y will be o btai ne d fr o m eac h patie nt. Me dical hist or y will i ncl u de baseli ne s y m pt o ms of t he disease u n der st u d y as well as a detaile d hist or y of pri or pr oce d ures f or t he 
p atie nt’s mela n o ma  a n d ot her pri or ca ncer t hera pies (i.e., c he m ot hera p y, h or m o nal t hera p y, i m m u n ot hera p y, bi ot hera p y, ra di ot hera p y, a n d s ur ger y) , i ncl u di n g start a n d e n d dates, best res p o nse, 
disease pr o gressi o n d uri n g or aft er t hera p y, as w ell as disc o nti n uati o ns d ue t o i nt olera bilit y, t o xicit y, or a n y ot h er seri o us ill ness; T u m or N o des Metastasis  ( TN M ) sta gi n g will be c ollecte d o n f or 
patie nts . S m o ki n g hist or y will be rec or de d. A detaile d hist or y of disease-s pecific dia g n ostic a n d pr o g n ostic testi n g a n d test res ults (s uc h as p he n ot y pic a n d c yt o ge netic pr ofiles) will als o be 
c ollecte d. 
4 
Vital si g ns: bl o o d press ure, p ulse a n d b o d y te m perat ure; see Secti o n  7. 5. 1. 2  f or a detaile d descri pti o n of vital si g n assess me nts. 
5 
1 2 -Lea d E C G (i n  tri plicate) t o be c o m pl ete d at C 1 D 1 ( pre-d ose a n d 4 h o urs p ost -d ose), at t h e E o T visit, a n d as cli nicall y i n dicate d at t he discreti o n of t he I n vesti gat or. See Secti o n  9. 6. 1. 3 f or a 
detaile d descri pti o n of electr ocar di o gra p h y.  
6 
Ec h ocar di o gra m or M U G A sca n at Scree ni n g ( Da y -3 0 t o Da y -1), an d as cli nicall y i n dicate d at t he discreti o n of t he I n vesti gat or d uri n g t he st u d y. Se e Secti o n 7. 5. 1. 3  f or a detaile d descri pti o n of 
ec h ocar di o gra p h y.  
7 
T he f oll o wi n g pr oce d ures m ust be perf or me d at S cr ee ni n g ( Da y -3 0 t o Da y -1) a n d / or pre -d ose o n C 1 D 1 (a n d as s h o w n i n Ta ble 5  , Ta ble 6  , a n d Ta ble 7) d uri n g t he st u d y: E C O G perf or ma nce 
assess me nt, ec h ocar di o gra m or M U G A sca n ( Scree ni n g o nl y), 1 2 -lea d E C G. T he f oll o wi n g pr oce d ures m ust b e perf or me d at Scree ni n g ( Da y -1 4 t o Da y -1) a n d pre -d ose o n C 1 D 1 (a n d as s h o w n 
i n Ta ble 5 , Ta ble 6 , a n d Ta ble 7  d uri n g  t he st u d y): uri nal ysis, C B C wit h differe ntial, T S H, c o m plete ser u m c he mistr y, c oa g ulati o ns tests ( Scree ni n g o nl y), a m ylase, an d li pase  per  Ta ble 1 9 . 
8 
T S H, a m ylase a n d li pase d o n ot nee d t o be re peate d se paratel y if i ncl u de d i n ser u m c he mistr y. 
9 
F or fe males of c hil d beari n g p ote ntial, ne gati ve ser u m h C G pre g na nc y test m ust be perf or me d ≤ 3 da ys of C 1 D 1 a n d t he E o T Visit . Re peat testi n g d uri n g t he st u d y as cli nicall y a p pr o priate. Test 
se nsiti vit y f or h C G m ust be ≥ 2 5 mI U/ m L. 
1 0 
See Secti o n  7. 4  f or ti mi n g of bl o o d sa m pl es t o be c ollecte d f or P K a nal ysis.  
1 2 
Tele p h o ne call ( or visit) wit h patie nt t o e val uate s u p p orti ve care me dicati o ns, c o nc o mita nt me dicati o ns, a d verse e ve nts, a n d seri o us a d verse e ve nts, a n d t o a dj ust s u p p orti ve care as a p pr o priate. T he 
tele p h o ne c o ntact wit h t he patie nt m ust ta ke place C ycle 1 Da ys 4 + 1 da y, 1 1 a n d 1 8 ± 1 da y; C ycle 2 a n d be y o n d –  Da ys 4, 1 1, 1 8, a n d 2 5 ± 1 da y; Safet y F oll o w -u p p h o ne call + 7 da ys; a n d 
d ura bilit y of res p o nse ± 7 da ys if t he i n pers o n visit is n ot perf or me d.  
1 3 
If feasi ble a n d cli nicall y i n dicate d, t h e f oll o wi n g assess me nts s h o ul d be perf or me d e ver y 3 m o nt hs f or 1 year after t he Safet y F oll o w -u p Visit/ Call f or patie nts w h o ha ve n ot pr o gresse d t o assess 
d ura bilit y of res p o nse: C T, M RI, or P E T -C T sca n s f or s oli d mali g na nc y patie nts. If t hese assess me nts ca n n ot be perf or me d, a n d f or patie nts wit h P D, a tele p h o ne call will be  ma de t o t he p atie nt ( or 
t he patie nt’s fa mil y) e ver y 3 m o nt hs f or 1 year t o i n q uire a b o ut t he patie nt’s s ur vi val, disease stat us, an d o verall me dical c o n diti o n, a n d i nf or mati o n o n a n y a nti ne o plastic t hera pies utilize d si nce 
disc o nti n uati o n of K P T -9 2 7 4 st u d y treat me nt.  
1 4 
See  Ta ble 8  f or at h o me vers us i n-cli nic visit d osi n g. 
1 5 
T hese assess me nts are t o be c o m plete d pre -d ose o n C 1 D 1 a n d are t o be use d t o esta blis h baseli ne val ues, n ot t o rec o nfir m eli gi bilit y. H o we ver, if a safet y c o ncer n is n ot e d, c o ntact Kar y o p har m.  
1 6 
Safet y f oll o w -u p te le p h o ne call [ 3 0 da ys p ost-last d ose ( + 7 da ys)] wit h patie nt after t heir last d ose of st u d y treat me nt t o e val uate t h eir o verall me dical c o n diti o n a n d stat us of disease, A Es, 
i ncl u di n g f oll o w-u p o n a n y A Es t hat were n ot res ol ve d at t he E o T Visit, a n d c olle cti o n of i nf or mati o n o n a n y a nti ne o plastic t hera pies use d after disc o nti n uati o n of st u d y treat me nt.  
1 7 
At t he I n vesti gat or’s discreti o n, i n c o ns ultati o n wit h t he Kar y o p har m Me di cal M o nit or, pati e nts wit h cli nicall y si g nifica nt h e mat ol o gical A Es, i ncl u di n g a n y  gra de of treat me nt -e mer ge nt a ne mia or 
a b n or mal reti c ul oc yte c o u nts, ma y ha ve a he mat ol o g y c o ns ultati o n. He mat ol o gical testi n g (i ncl u di n g b ut n ot li mite d t o sta n dar d he mat ol o gical e val uati o ns a n d er yt hr o p oieti n  le vel) ± b o ne marr o w 
bi o ps y ma y be perf or me d as cli nicall y i n dicate d per i nstit uti o nal sta n dar ds.  
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18 
Patients with treatment-emergent anemia should have blood levels of vitamin B12, folate, iron, erythropoietin, haptoglobin, and transferrin and reticulocyte counts assessed as soon as possible after 
onset. Patients with ≤ Grade 1 anemia should have their levels/counts assessed no less than once a month and patients with ≥ Grade 2 anemia should have their levels/counts assessed every 
2 weeks. 
19 
For explorative analysis research procedure, tumor tissue will be obtained pre- treatment (Day -30 to Day 1) , C3D1 (±7 days), and at the time of progression. Each biopsy will be divided into 3 
portions, resulting in two fresh biopsies and one formalin fixed biopsy. For the biopsies on C3D1 and EoT, patients will be allowed to continue treatment if: 1) a patient refuses the biopsy, 2) in 
the opinion of the treating physician or physician performing the biopsy that the biopsy will pose significant risk to the patient, or 3) if the biopsy sample obtained on the first attempt is not 
adequate. 
20 
Advanced solid malignancies: CT, MRI, or PET-CT scans will be performed at screening (Day -30 to Day -1), then every 8 weeks ± 7 days (e.g., Day 1 of odd numbered cycles), until disease 
progression or the EoT visit and Durability of Response and Survival Follow-up. EoT scan is only required for patients who end treatment for reasons other than disease progression. The same 
scan modality should be used for all assessments. Durability of Response and Survival Follow-up scan is only for patients who have not progressed. 
 
 
Table 8: Dosing Schedule for Patients with Melanoma Who Progressed on Prior Anti-PD-1 or Anti-PD-L1 Treatment (Part C) 
Treatment 
Week 1 
Week 2 
Week 3 
Week 4 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15 
D16 
D17 
D18 
D19 
D20 
D21 
D22 
D23 
D24 
D25 
D26 
D27 
D28 
KPT-9274 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
Nivolumab1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Every 4 weeks 
Note:  KPT-9274 dosing will occur in the clinic during Cycle 1 on Days 1, 3, 8, 15, 22, 24, and 26, during Cycle 2 on Days 1, 8, 15, and 22, and during > Cycle 3 
on Days 1 and 15. KPT-9274 dosing will occur at home during Cycle 1 on Days 5, 10, 12, 17, and 19, during Cycle 2 on Days 3, 5, 10, 12, 17, 19, 24, and 26 and 
during Cycles ≥3 on Days 3, 5, 8, 10, 12, 17, 19, 22, 24, and 26. Nivolumab treatment will occur in the clinic on Day 1 of each cycle. 
 
 

Investigational Product (KPT-9274) 
 
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Figure 1: 
Study Flow Chart 
 
 
The starting dose of KPT-9274 for Part B will be a dose and schedule that has cleared DLT 
assessment during Part A.  
Dose Expansion Phase may be completed; patients may be treated with the RP2D of KPT-9274 
± niacin ER according to the same schedule administered in the Dose Escalation Phase of the 
study.  
If Dose Expansion patients are to be treated with KPT-9274 + niacin ER, then an optional Dose 
Expansion of KPT-9274 single agent at RP2D (n ≤ 20) may also be conducted. Note that 
preliminary clinical results may define the patient population (i.e., specific indications) selected 
for enrollment in the Dose Expansion Phase. 
In Part C, a starting dose of KPT-9274 will be a dose and schedule that has cleared DLT 
assessment in Part A.  

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 3 5  
Versi o n  5 . 0 
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S  
1.  
I N T R O D U C TI O N ......................................................................................................4 8  
1. 1.  
I n dicati o n ....................................................................................................................4 8  
1. 2.  
K P T -9 2 7 4  ...................................................................................................................4 8  
1. 2. 1.  
P ote ntial Ris ks  ............................................................................................................4 9  
1. 2. 2.  
Re pr o d ucti ve Ris ks of K P T -9 2 7 4  ...............................................................................5 2  
1. 3.  
St u d y Rati o nale  ...........................................................................................................5 2  
1. 3. 1.  
Rati o nale f or t he K P T -9 2 7 4 D o se ..............................................................................5 2  
1. 3. 2.  
Rati o nale f or A d di n g Niaci n  .......................................................................................5 2  
1. 3. 3.  
Rati o nale f or C o m bi ni n g K P T -9 2 7 4 wit h Ni v ol u ma b i n Mela n o ma  .........................5 3  
2.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S  ..............................................................5 4  
2. 1.  
O bjecti ves  ...................................................................................................................5 4  
2. 1. 1.  
Pri mar y O bjecti ves  .....................................................................................................5 4  
2. 1. 2.  
Sec o n dar y O bjecti ves  .................................................................................................5 4  
2. 1. 3.  
E x pl orat or y O bjecti ves  ...............................................................................................5 5  
2. 2.  
E n d p oi nts  ....................................................................................................................5 5  
2. 2. 1.  
Safet y E n d p oi nts  .........................................................................................................5 5  
2. 2. 2.  
Efficac y E n d p oi nts  ......................................................................................................5 5  
2. 2. 3.  
P K E n d p oi nts  ..............................................................................................................5 6  
5 6  
3.  
I N V E S TI G A TI O N A L P L A N .....................................................................................5 8  
3. 1.  
O verall St u d y Desi g n a n d Pla n  ...................................................................................5 8  
3. 2.  
Re place me nt P olic y  ....................................................................................................6 0  
3. 3.  
Treat me nt D urati o n  .....................................................................................................6 0  
4.  
S T U D Y P O P U L A TI O N S E L E C TI O N  ......................................................................6 1  
4. 1.  
St u d y P o p ulati o n  .........................................................................................................6 1  
4. 2.  
I ncl usi o n Criteria ( Parts A a n d B) ..............................................................................6 1  
4. 3.  
E xcl usi o n Criteria ( Parts A a n d B)  .............................................................................6 2  
4. 4.  
I ncl usi o n Criteria ( Part C) ..........................................................................................6 3  
4. 5.  
E xcl usi o n Criteria ( Part C)  .........................................................................................6 4  
4. 6.  
Scree ni n g a n d Re gistrati o n  .........................................................................................6 4  
4. 6. 1.  
St u d y Patie nt N u m ber  .................................................................................................6 5  
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4.6.2. 
Rescreening .................................................................................................................65 
4.6.3. 
Screen Failures ............................................................................................................65 
5. 
DISCONTINUATION CRITERIA ............................................................................66 
5.1. 
Early Termination of the Study ..................................................................................66 
5.2. 
Discontinuation of Study Treatment and/or Withdrawal of Patients from the 
Study ...........................................................................................................................66 
6. 
STUDY TREATMENTS ............................................................................................67 
6.1. 
Treatments Administered ............................................................................................67 
6.1.1. 
KPT-9274 ...................................................................................................................67 
6.1.2. 
Niacin ER (Part B) ......................................................................................................67 
6.1.3. 
Nivolumab (Part C) .....................................................................................................67 
6.1.4. 
Placebo or Control ......................................................................................................67 
6.2. 
Study Treatment Dose Schedules and Administration ...............................................67 
6.2.1. 
Labeling ......................................................................................................................67 
6.2.2. 
Dispensing Directions .................................................................................................68 
6.2.3. 
Dosing Information .....................................................................................................68 
6.2.4. 
Dosing Instructions for Patients ..................................................................................68 
6.2.5. 
Dose Schedules for Evaluation During the Dose Escalation Phase ...........................69 
6.2.6. 
Dose Escalation Guidelines ........................................................................................69 
6.2.6.1. 
Dose Escalation Procedures ........................................................................................69 
6.2.6.2. 
Dose-Limiting Toxicity ..............................................................................................71 
6.2.6.3. 
Dose Decision Meeting or Teleconference .................................................................71 
6.2.7. 
Dose Schedule for Evaluation During the Dose Expansion Phase (Parts A 
and B) ..........................................................................................................................72 
6.2.8. 
KPT-9274 Dose Reduction Guidelines for Toxicity ..................................................73 
6.2.9. 
Missed or Vomited Doses ...........................................................................................77 
6.2.9.1. 
Missed Doses of Study Treatments ............................................................................77 
6.2.9.2. 
Vomited Doses of Study Treatments ..........................................................................77 
6.3. 
Study Treatment Storage ............................................................................................77 
6.4. 
Study Treatment Accountability .................................................................................77 
6.5. 
Selection and Timing of Dose for Each Patient ..........................................................77 
6.6. 
Method of Assigning Patients to Treatment Groups ..................................................78 
6.7. 
Blinding ......................................................................................................................78 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 3 7  
Versi o n  5 . 0 
6. 8.  
C o m plia nce  .................................................................................................................7 8  
6. 9.  
S u p p orti ve Care, C o ntrace pti o n Re q uire me nts, a n d C o nc o mita nt 
Me dicati o ns  .................................................................................................................7 8  
6. 9. 1.  
S u p p orti ve Care  ..........................................................................................................7 8  
6. 9. 2.  
N o n -st u d y Relate d C o nc o mita nt Me dicati o n a n d Treat me nt .....................................7 9  
6. 9. 2. 1.  
Per mitte d C o nc o mita nt Me dicati o n  ............................................................................7 9  
6. 9. 2. 2.  
Pre ve nti o n of Pre g na nc y  .............................................................................................8 0  
6. 9. 2. 3.  
Ra diati o n T hera p y  ......................................................................................................8 1  
6. 9. 2. 4.  
H or m o ne A blati o n T hera p y t o Treat A d va nce d Pr ostate Ca ncer  ...............................8 1  
6. 9. 2. 5.  
Gl uc oc ortic oi d T hera p y  ..............................................................................................8 1  
6. 9. 2. 6.  
Use of Bl o o d Pr o d ucts  ................................................................................................8 1  
6. 9. 3.  
Pr o hi bite d C o nc o mita nt Me dicati o ns  .........................................................................8 1  
7.  
A S S E S S M E N T S  .........................................................................................................8 3  
7. 1.  
I nf or me d C o nse nt .......................................................................................................8 3  
7. 2.  
De m o gra p hic a n d Baseli ne C haracteristics Assess me nts  ...........................................8 3  
7. 2. 1.  
De m o gra p hics  .............................................................................................................8 3  
7. 2. 2.  
Me dical Hist or y  ..........................................................................................................8 3  
7. 2. 3.  
Disease Ris k Assess me nt ( N H L patie nts o nl y)  ..........................................................8 3  
7. 2. 4.  
Baseli ne C haracteristics a n d Deter mi nati o n of Eli gi bilit y  .........................................8 3  
7. 2. 5.  
Deter mi nati o n of N A P R T 1 a n d I D H 1 T u m or Stat us  .................................................8 3  
7. 2. 6.  
Deter mi nati o n of Patie nts wit h Mela n o ma W h o Pr o gresse d o n Pri or A nti -
P D -1 or A nti -P D -L 1 Treat me nt  ..................................................................................8 4  
7. 3.  
Efficac y Assess me nts  .................................................................................................8 4  
7. 3 . 1. 
N o n -H o d g ki n’s L y m p h o ma a n d A d va nce d S oli d Mali g na nc y Assess me nts  .............8 4  
7. 3. 1. 1.  
Q ualit y of Life  ............................................................................................................8 4  
7. 3. 2.  
N o n -H o d g ki n’s L y m p h o ma O nl y Assess me nts  .........................................................8 4  
7. 3. 2. 1.  
P E T -C T ( or C T) Sca n  .................................................................................................8 4  
7. 3. 2. 2.  
B o ne Marr o w As pirat e a n d/ or Bi o ps y  ........................................................................8 5  
7. 3. 3.  
A d va nce d S oli d Mali g na nc y O nl y Assess me nts  ........................................................8 5  
7. 3. 3. 1.  
C T, M RI, P E T -C T, or I ma gi n g Met h o d ol o g y Per I n vesti gat or Discreti o n  ................8 5  
7. 4.  
P har mac o ki netic Assess me nts  ....................................................................................8 5  
7. 4. 1.  
P K Sa m pli n g f or K P T -9 2 7 4  .......................................................................................8 5  
8 6  
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
C o nfi de ntial  
P a ge 3 8  
Versi o n  5 . 0 
9 2  
9 2  
9 2  
9 2  
7. 5.  
Safet y Assess me nts  .....................................................................................................9 3  
7. 5. 1.  
Cli nical Safet y Assess me nts  .......................................................................................9 3  
7. 5. 1. 1.  
Wei g ht a n d Hei g ht  ......................................................................................................9 3  
7 . 5. 1. 2. 
P h ysical E xa mi nati o n, Vital Si g ns, a n d E C O G Perf or ma nce Stat us  ..........................9 3  
7. 5. 1. 3.  
Ec h ocar di o gra p h y a n d Electr ocar di o gra p h y  ...............................................................9 3  
7. 5. 1. 4.  
O p ht hal mic E xa mi nati o n  ............................................................................................9 4  
7. 5. 1. 5.  
C o nc o mita nt Me dicati o ns  ...........................................................................................9 4  
7. 5. 2.  
R he u mat ol o g y C o ns ultati o n a n d Testi n g ....................................................................9 5  
7. 5. 3.  
He mat ol o g y C o ns ultati o n, Testi n g, a n d Bi o ps y  .........................................................9 5  
7. 5. 3. 1.  
A d verse E ve nts  ...........................................................................................................9 5  
7. 5. 4.  
La b orat or y Safet y Assess me nts  ..................................................................................9 5  
7. 5. 4. 1.  
Cli nical La b orat or y Tests  ...........................................................................................9 5  
7. 5. 4. 2.  
Vita mi n B 1 2, F olate, Ir o n, Er yt hr o p oieti n, Ha pt o gl o bi n, a n d Tra nsferri n 
Le vels a n d Retic ul oc yte C o u nts  .................................................................................9 7  
7. 5. 4. 3.  
Pre g na nc y Testi n g  ......................................................................................................9 7  
7. 6.  
Ot her Assess me nts  ......................................................................................................9 7  
7. 6. 1.  
C ollecti o n of I nf or mati o n o n A nti ne o plastic T hera p y  ................................................9 7  
8.  
S A F E T Y D E FI NI TI O N S, R E C O R DI N G, A N D R E P O R TI N G  ................................9 8  
8. 1.  
A d v erse E ve nts ...........................................................................................................9 8  
8. 1. 1.  
Defi niti o ns  ..................................................................................................................9 8  
8. 1. 2.  
Rec or di n g of A d verse E ve nts  .....................................................................................9 8  
8. 1. 2. 1.  
La b orat or y Te st A b n or malities ...................................................................................9 9  
8. 1. 3.  
A d verse E ve nt Se verit y  ..............................................................................................9 9  
8. 1. 4.  
A d verse E ve nt Ca usalit y  .............................................................................................9 9  
8. 2.  
Seri o us A d verse E ve nts  ............................................................................................1 0 0  
8. 2. 1.  
Rec or di n g of Seri o us A d verse E ve nts  ......................................................................1 0 0  
8. 2. 2.  
Re p orti n g of Seri o us A d verse E ve nts  .......................................................................1 0 1  
8. 2. 3.  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns  ..................................................1 0 1  
8. 3.  
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns  .............................................................1 0 1  
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 3 9  
Versi o n  5 . 0 
8. 3. 1.  
Pre g na nc y  .................................................................................................................1 0 1  
8. 3. 2.  
A b use, Mis use, Me dicati o n Err ors, O ver d ose, a n d Occ u pati o nal E x p os ure  ............1 0 2  
8. 3. 2. 1.  
O ver d ose  ...................................................................................................................1 0 2  
8. 3. 2. 2.  
A b use, Mis use, or Me dicati o n Err or  .........................................................................1 0 2  
8. 3. 2. 3.  
Occ u pati o nal E x p os ure  .............................................................................................1 0 3  
9.  
S T A TI S TI C A L M E T H O D S  .....................................................................................1 0 4  
9. 1.  
Ge neral C o nsi derati o ns  .............................................................................................1 0 4  
9. 2.  
Deter mi nati o n of Sa m ple Size  ..................................................................................1 0 4  
9. 2. 1.  
Sa m ple size f or Part A a n d B:  ...................................................................................1 0 4  
9. 2. 2.  
Sa m ple size f or Part C:  .............................................................................................1 0 4  
9. 3.  
A nal ysis P o p ulati o ns  ................................................................................................1 0 5  
9. 3. 1.  
I nte nt-t o-Treat P o p ulati o n  ........................................................................................1 0 5  
9. 3. 2.  
Per Pr ot oc ol P o p ulati o n  ............................................................................................1 0 5  
9. 3. 3.  
Safet y P o p ulati o n  ......................................................................................................1 0 5  
9. 3. 4.  
P har mac o ki netic P o p ulati o n  .....................................................................................1 0 5  
9. 3. 5.  
D L T E val ua ble P o p ulati o n  .......................................................................................1 0 5  
9. 4.  
Data A nal ysis a n d Prese ntati o n  ................................................................................1 0 5  
9. 4. 1.  
Dis p ositi o n of Patie nts  ..............................................................................................1 0 5  
9. 4. 2.  
De m o gra p hic C haract eristics ....................................................................................1 0 6  
9. 4. 3.  
Baseli ne C haracteristics a n d Me dical Hist or y  ..........................................................1 0 6  
9. 5.  
Efficac y A nal ysis  ......................................................................................................1 0 6  
9. 5. 1.  
F utilit y Testi n g  ..........................................................................................................1 0 7  
9. 6.  
P har mac o ki netic A nal ysis  ........................................................................................1 0 7  
1 0 7  
9. 8.  
Safet y A nal ysis  .........................................................................................................1 0 8  
9. 8. 1.  
A d verse E ve nts  .........................................................................................................1 0 8  
9. 8. 2.  
Cli nical La b orat or y Dat a ..........................................................................................1 0 9  
9. 8. 3.  
Vital Si g ns a n d E xa mi nati o ns  ...................................................................................1 0 9  
9. 8. 4.  
C o nc o mita nt Me dicati o ns  .........................................................................................1 0 9  
1 0.  
A D MI NI S T R A TI V E A N D R E G U L A T O R Y R E Q UI R E M E N T S  ..........................1 1 0  
1 0. 1.  
G o o d Cli nical Practice ( G C P)  ..................................................................................1 1 0  
1 0. 2.  
I nstit uti o nal Re vie w B oar d .......................................................................................1 1 0  
C CI

Investigational Product (KPT-9274) 
 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-9274-901 
 
11 March 2020 
 
Confidential  
Page 40 
Version 5.0 
10.3. 
Ethical Considerations ..............................................................................................110 
10.4. 
Patient Information and Informed Consent ..............................................................110 
10.5. 
Patient Confidentiality ..............................................................................................110 
10.6. 
Protocol Compliance ................................................................................................111 
10.7. 
Direct Access to Source Data ...................................................................................111 
10.8. 
Electronic Case Report Form Completion ................................................................112 
10.9. 
Record Retention ......................................................................................................112 
11. 
LIST OF REFERENCES ..........................................................................................113 
12. 
APPENDICES ..........................................................................................................114 
APPENDIX 1. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS CRITERIA ................................................................................................115 
APPENDIX 2. THE LUGANO CLASSIFICATION FOR INITIAL EVALUATION 
AND STAGING OF NHL ........................................................................................116 
APPENDIX 3. THE LUGANO CLASSIFICATION FOR RESPONSE 
ASSESSMENT OF NHL (CHESON, 2014) ............................................................118 
APPENDIX 4. RECIST VERSION 1.1 ....................................................................................122 
APPENDIX 5. EORTC-QLQ-C30 ...........................................................................................125 
APPENDIX 6. PROTOCOL AMENDMENTS: RATIONALES AND SUMMARIES 
OF CHANGES .........................................................................................................126 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 4 1  
Versi o n  5 . 0 
LI S T O F T A B L E S  
Ta ble 1: Sc he d ule of Assess me nts: Scree ni n g a n d C ycle 1 ( Parts A a n d B)  .................................1 9  
Ta ble  2: Sc he d ule of Assess me nts: C ycles 2 a n d Be y o n d ( Parts A a n d B)  ...................................2 1  
Ta ble  3: Sc he d ule of Assess me nts:  E n d -of -Treat me nt a n d Be y o n d ( Parts A a n d B)  ...................2 3  
Ta ble  4: D osi n g Sc he d ule ( Parts A a n d B)  ....................................................................................2 6  
Ta ble 5: Sc he d ule of Assess me nts f or Scree ni n g a n d C ycle 1 ( Part C)  ........................................2 7  
Ta ble 6: Sc he d ule of Assess me nts f or C ycles 2 a n d Be y o n d ( Part C)  ..........................................2 9  
Ta ble 7: Sc he d ule of Assess me nts f or E n d -of -Treat me nt a n d Be y o n d ( Part C)  ...........................3 0  
Ta ble  8: D osi n g Sc he d ule f or Patie nts wit h Mela n o ma W h o Pr o gress e d o n Pri or A nti -
P D -1 or A nti -P D -L 1 Treat me nt ( Part C)  ....................................................................3 3  
Ta ble 9: A b bre viati o ns a n d Defi niti o ns of Ter ms  .........................................................................4 3  
Ta ble 1 0: D ose Le vels a n d Sc he d ules Teste d as of 0 2 Marc h 2 0 1 9  ..............................................5 0  
Ta ble 1 1: Treat me nt Relate d A d verse E ve nts Occ uri n g i n ≥ 1 0 % of All Patie nts  ........................5 0  
Ta ble 1 2: Treat me nt Relate d A d verse E ve nts Occ uri n g i n ≥ 1 0 % of Patie nts b y D ose 
Le vel a n d Sc he d ule  .....................................................................................................5 1  
Ta ble  1 3: Part A - K P T -9 2 7 4 D ose Escalati o n Le vels  ..................................................................6 9  
Ta ble  1 4: Criteria f or Defi ni n g D ose -Li miti n g T o xicities  .............................................................7 1  
Ta ble  1 5: Pre -s pecifie d D ose M o dificati o ns f or A d verse E ve nts ..................................................7 4  
Ta ble  1 6: K P T -9 2 7 4 D ose M o dificati o n a n d S u p p orti ve Care G ui deli nes  ...................................7 5  
Ta ble  1 7: C ollecti o n Ti me P oi nts a n d Sa m ple V ol u mes f or P K a n d  
 f or Parts A a n d 
B  ..................................................................................................................................8 7  
Ta ble  1 8: C ollecti o n Ti me P oi nts a n d Sa m ple V ol u mes f or P K a n d  
 f or f or Part C  ..............9 1  
Ta ble  1 9: Cli nical La b orat or y Tests ( Parts A, B, a n d C U nless I n dicate d)  ...................................9 6  
Ta ble  2 0: Classificati o n of A d verse E ve nts b y Ca usalit y  ............................................................1 0 0  
Ta ble  2 1: E C O G Perf or ma nce Stat us Scale  .................................................................................1 1 5  
Ta ble  2 2: Criteria f or I n v ol ve me nt of Site  ...................................................................................1 1 6  
Ta bl e 2 3: Re vise d Sta gi n g S yste m f or Pri mar y N o dal L y m p h o mas  ...........................................1 1 7  
Ta ble  2 4: Re vise d Criteria f or Res p o nse Assess me nt  .................................................................1 1 8  
 
C CI
C CI

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LIST OF FIGURES 
Figure 1: 
Study Flow Chart ........................................................................................................34 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 9: Abbreviations and Definitions of Terms 
Abbreviation or Specialist Term 
Explanation 
°C 
degrees Celsius 
°F 
degrees Fahrenheit 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
B-ALL 
B-cell acute lymphoblastic leukemia 
BP 
blood pressure 
BSA 
body surface area 
CBC 
complete blood count 
CBR 
clinical benefit rate 
 
CI 
confidence interval 
CL/F 
plasma clearance  
Cmax  
maximum plasma concentration 
cm 
centimeter 
CNS 
central nervous system 
COX-2 
cyclooxygenase-2 
CR 
complete response 
CrCl 
creatinine clearance 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXDX (e.g., C1D1) 
Cycle X Day X (e.g., Cycle 1 Day 1) 
DAP 
Data Analysis Plan 
DCR 
disease control rate 
DDA 
deoxyribonucleic acid damaging agent 
DLT 
dose-limiting toxicity 

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Abbreviation or Specialist Term 
Explanation 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC QLQ 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire 
EoT 
end of treatment 
ER 
extended release 
FACT-G 
Functional Assessment of Cancer Therapy 
FACT-Lym 
Functional Assessment of Cancer Therapy-Lymphoma 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FLC 
free light chain 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
HAT 
hormone ablation therapy 
Hb 
hemoglobin 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
HPLC/MS-MS 
high performance liquid chromatography/tandem mass 
spectrometry 
hr 
hour 
IB 
Investigator’s Brochure 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 4 5  
Versi o n  5 . 0 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
I C5 0 
5 0 % i n hi bit or y c o nce ntrati o n  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I D H 1 
is ocitrate de h y dr o ge nase 1 ( N A D P +), s ol u ble 
I H C 
i m m u n o hist oc he mistr y 
I N R 
I nter nati o nal n or malize d rati o 
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
i nte nt-t o-treat  
I V 
i ntra ve n o us 
Kar y o p har m  
Kar y o p har m T hera pe utics I nc.  
k g  
kil o gra m  
L L N  
l o wer li mit of n or mal 
L V E F  
left ve ntric ular ejecti o n fracti o n 
M D R  
m ulti ple dr u g resista nce  
mI U  
m illi-i nter nati o nal u nits 
m L  
m illiliter  
M M  
m ulti ple m y el o ma  
M RI  
ma g netic res o na nce i ma gi n g  
M T D  
ma xi m u m t olerate d d ose  
M U G A  
m ulti ple gate d ac q uisiti o n 
N  
n u m ber of patie nts  
N A D  
nic oti na mi de a de ni ne di n ucle oti de  
N A M P T  
nic oti na mi de p h os p h ori b os yltra nsferase/ P B E F/ visfati n  
N A P R T 1  
nic oti nate p h os p h ori b os yltra nsferase  
N CI  
Nati o nal Ca ncer I nstit ute  
N H L  
n o n -H o d g ki n’s l y m p h o ma  
Niaci n  
vita mi n B 3/ nic oti nic aci d  
N S AI D  
n o n -ster oi dal a nti-i nfla m mator y dr u g  
O R R  
o verall res p o nse rate  
O S  
o verall s ur vi val  
O T C  
o ver t he c o u nter  
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 4 6  
Versi o n  5 . 0 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
P A K 4  
p 2 1 pr otei n ( C dc 4 2/ Rac) -acti vate d ki nase 4  
P D  
pr o gressi ve disease  
P E T  
p ositr o n e missi o n t o m o gra p h y  
P F S  
p r o gressi o n-free s ur vi val 
P K  
p har mac o ki netic(s)  
P P  
per pr ot oc ol  
P PI  
pr ot o n p u m p i n hi bit or  
P R  
partial res p o nse  
Q O D  
ever y ot her da y  
Q o L  
q ualit y of life 
R A S  
rat sarc o ma viral o nc o ge ne h o m ol o g 
R B C  
re d bl o o d cell 
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
R N A  
ri b o n ucleic aci d 
R P 2 D  
Rec o m me n de d P hase 2 D ose  
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical A n al ysis Pla n  
S D  
sta ble disease 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
t½   
ter mi nal plas ma half -life 
T E A E  
treat me nt-e mer ge nt  a d verse e ve nt  
tma x   
ti me t o pea k plas ma c o nce ntrati o n 
T N M  
t u m or n o des metastasis  
T OI  
trial o utc o mes i n de x 
T S H  
t h yr oi d sti m ulati n g h or m o ne 
T T P  
ti me t o pr o gressi o n 
U L N  
u p per li mit of n or mal  
V d/ F 
v ol u me of distri b uti o n  
C CI
C CI
C CI
C CI

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Abbreviation or Specialist Term 
Explanation 
WBC 
white blood cell 

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1. 
INTRODUCTION 
1.1. 
Indication  
This study will enroll patients with advanced solid malignancies (including sarcoma, colon, lung, 
etc.) or non-Hodgkin’s lymphoma for which all standard therapeutic options considered useful by 
the investigator have been exhausted and with progressive disease on study entry. 
1.2. 
KPT-9274 
KPT-9274 is a first-in-class orally bioavailable small molecule that is a non-competitive dual 
modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide 
phosphoribosyltransferase/PBEF/visfatin (NAMPT). Co-inhibition of these targets leads to 
synergistic anti-tumor effects through energy depletion, inhibition of deoxyribonucleic acid 
(DNA) repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis. Normal cells 
are more resistant to inhibition by KPT-9274 due in part to their relative genomic stability and 
lower metabolic rates. 
KPT-9274 demonstrated potent anti-proliferative activity against cancer cell lines (solid tumor 
cells MTT median IC50: 135 nM, range 0.007 to >10 µM; hematological cancer cells MTT median 
IC50: 40 nM, range 0.003 to >10 µM) with minimal toxicity to normal cells (median MTT IC50: 
~0.9 µM, range 0.033 to >10 µM). In mouse xenograft studies, KPT-9274 (oral 50-200 mg/kg 
twice daily for 5 days/week) was well tolerated and resulted in a marked reduction in tumor size 
across a variety of tumors, including colon, pancreatic, lung, multiple myeloma, leukemia, and 
lymphoma. In approximately half of the tumor types studied, complete elimination of tumors in as 
short as 3 weeks was observed with no regrowth after cessation of treatment (up to 3 weeks). In 
other cell types tumor growth inhibition was observed. KPT-9274 was able to control systemic 
acute B lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML) tumor growth and 
significantly extended overall survival. Moreover, KPT-9274 has shown preliminary efficacy in 
companion dogs with spontaneous advanced lymphomas and multiple myeloma (MM).  
Unlike the Pan-PAK inhibitor (PF-3758309), or the NAMPT inhibitors (APO866 and 
GMX1777/GMX1778) that advanced to human clinical trials, the dual NAMPT/PAK inhibitor 
KPT-9274 demonstrates consistent pharmacokinetic (PK) properties (e.g., oral absorption), 
exhibits minimal brain penetration, and does not inhibit any of the cytochrome P450 (CYP450) 
enzymes. The nonclinical toxicity profile of KPT-9274 recapitulates the expected class level 
gastrointestinal (GI) and hematopoietic toxicities but not the retinal and cardiac effects observed 
preclinically with some NAMPT inhibitors. The lack of retinal and cardiac effects of KPT-9274 
may be attributed to its minimal permeability and decreased potency compared to other NAMPT 
inhibitors. Furthermore, no orally available PAK4 selective inhibitors have been developed to date. 
Thus, KPT-9274 captures many of the favorable therapeutic aspects of targeting both NAMPT and 
PAK4 with the potential for reduced adverse effects.  
Preliminary two-week non-good laboratory practices (GLP) toxicology studies in rats and dogs 
suggest that KPT-9274 has an acceptable tolerability profile. The dog has been identified as the 
most sensitive species for KPT-9274 GI toxicity, with rats also showing GI toxicity at significantly 
higher doses. The primary KPT-9274 toxicity that has been observed in dogs is gastrointestinal 

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hemorrhages in the small intestine, colon, and rectum. Other target organ effects include 
hypocellularity in the bone marrow and lymphoid depletion in the lymphoid tissues.  
Nicotinamide adenine dinucleotide (NAD) regeneration pathways can bypass NAMPT inhibition 
by utilizing niacin (vitamin B3/nicotinic acid) through nicotinate phosphoribosyltransferase 
(NAPRT1). Supplemented niacin can alleviate adverse events due to NAMPT inhibition when 
tissues express NAPRT1. However, NAPRT1 is frequently repressed in tumors (through 
epigenetic modulation or isocitrate dehydrogenase 1 (NADP+), soluble [IDH1] mutation) while 
remaining intact in surrounding normal tissue potentially increasing therapeutic index in the 
presence of niacin. Additional exploratory studies and data from 4-week GLP studies indicate that 
co-administration of niacin can increase tolerability of KPT-9274 in dogs. These data demonstrate 
that a dose of KPT-9274 previously shown to have an adverse toxicologic profile was tolerable 
and had minimal GI macroscopic findings. For this reason, co-administration of KPT-9274 with 
niacin in patients with or without NAPRT1 or IDH1 mutation in their tumors is planned. 
KPT-9274 demonstrated anti-tumor activity in dogs with spontaneous advanced lymphomas and 
multiple myeloma. Patient dog #1 was given 4 doses of 2 mg/kg KPT-9274 and had progressive 
disease after 1 week. This patient dog was given 25 mg/kg doxorubicin (Adriamycin) on Day 8 
(~24 hours post-final KPT-9274 dose). The bulk disease responded shortly thereafter with a partial 
response (PR) at the end of week 2 that transitioned into a complete response (CR). As of October 
2015, the patient dog remains in complete remission for >4 months off all therapy with no AEs 
reported to date. A T-cell lymphoma dog experienced a ~1 week PR at 2 mg/kg of KPT-9274 
every other day (QOD) × 3 but subsequently progressed. A patient dog with refractory multiple 
myeloma (4 lines of previous therapy) treated with 3 mg/kg of KPT-9274 QOD x 3 plus prednisone 
had a PR with decreases in globulins and resolution of anemia and thrombocytopenia for ~5 weeks, 
but progressed during Week 6. Two additional B-cell lymphoma dogs did not respond to 2 mg/kg 
or 3 mg/kg of KPT-9274 QOD × 3 in which one dog (2 mg/kg dose) had low drug levels in the 
plasma. These preliminary results suggest that KPT-9274 show anti-tumor activity both as a single 
agent and in combination with DNA damaging agents (DDA) with minimal or no side effects 
observed. Dose escalation evaluation in patient dogs with lymphoma and solid tumors is on-going. 
KPT-9274 has clear preclinical anti-tumor activity (in vitro and in vivo) as well as an encouraging 
safety profile (compared to previously described Pan-PAK and NAMPT inhibitors) making it an 
attractive novel drug candidate. Since both solid tumor and hematologic malignancies were seen 
to be susceptible to single-agent cytotoxicity with KPT-9274, development is planned in both 
areas. 
1.2.1. 
Potential Risks 
As of 02 March 2019, 47 patients had received KPT-9274 alone or with niacin ER in Parts A and 
B of this study. Dose levels and schedules are outlined in Table 10, along with the number of 
patients enrolled in each cohort. The most common AEs occurring across all patients in Parts A 
and B, were anemia (68%), nausea (34%), arthralgia (32%), fatigue (32%), and myalgia (23%) 
(Table 11; Table 12). AEs were largely dose dependent and increased with higher doses of KPT-
9274. There were 2 DLTs reported among the first 47 patients. These included one case of grade 
4 anemia, which occurred in the 40 mg KPT-9274 qodX3 cohort, and one case of grade 3 fatigue 
which occurred in the 80 mg KPT-9274 qodX3 + niacin cohort. Both dose levels enrolled 

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additional patients per the 3+3 study design, and both dose levels ultimately cleared DLT 
evaluation. To date, a MTD has not been reached.  
Table 10: Dose Levels and Schedules Tested as of 02 March 2019 
Cohort 
Dose / Schedule 
Patients Enrolled 
1 
10 mg / qodx3 
3 
2 
20 mg / qodx3 
3 
3 
30 mg / qodx3 
5 
4 
40 mg / qodx3 
7 
5 
40 mg / qodx2 
5 
3B 
30 mg / qodx3 + 500 mg niacin ER 
3 
4B 
40 mg / qodx3 + 500 mg niacin ER 
4 
5B 
60 mg / qodx3 + 500 mg niacin ER 
10 
6B 
80 mg / qodx3 + 500 mg niacin ER 
6 
7B 
100 mg / qodx3 + 500 mg niacin ER 
1 
 
Table 11: Treatment Related Adverse Events Occuring in ≥ 10% of All Patients 
Adverse 
Events 
All Dose Levels 
(N=47) 
G1 
G2 
G3 
G4 
Total 
Anemia 
2 
7 
22 
1 
32 (68%) 
Nausea 
13 
3 
 
 
16 (34%) 
Arthralgia 
11 
4 
 
 
15 (32%) 
Fatigue 
7 
6 
2 
 
15 (32%) 
Myalgia 
7 
4 
 
 
11 (23%) 
Diarrhea 
6 
3 
1 
 
10 (21%) 

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Vomiting 
7 
1 
1 
 
9 (19%) 
Dyspnea 
4 
2 
2 
 
8 (17%) 
AST increase 
2 
3 
 
 
5 (11%) 
Peripheral edema 
3 
2 
 
 
5 (11%) 
 
Table 12: Treatment Related Adverse Events Occuring in ≥ 10% of Patients by Dose Level 
and Schedule 
10 mg 
(N=3) 
20 mg 
(N=3) 
30 mg 
(N=5) 
30 mg + 
Niacin 
(N=3) 
40 mg 
(N=7) 
40 mg + 
Niacin 
(N=4) 
40 mg 
BIW (N=5) 
60 mg + 
Niacin 
(N=11) 
80 mg + 
Niacin 
(N=5) 
100 mg + 
Niacin 
(N=1) 
All 
G1/2 G3+ G1/2 G3+ G1/2 G3+ G1/2 G3+ G1/2 G3+ G1/2 G3+ G1/2 G3+ G1/2 G3+ G1/2 G3+ 
No Events 
1 
1 
1 
2 
1 
 
 
6 
 
2 
3 
2 
2 
5 
1 
4 
 
1 
 
 
 
 
 
 
3 
 
3 
 
1 
 
5 
 
3 
 
1 
 
 
 
2 
 
2 
 
5 
 
1 
 
1 
 
2 
 
1 
 
1 
 
 
 
1 
1 
1 
 
2 
 
1 
 
2 
 
4 
 
2 
1 
 
 
1 
 
2 
 
1 
 
1 
 
1 
 
2 
 
2 
 
 
 
1 
 
 
 
1 
 
1 
 
2 
 
 
 
1 
1 
1 
 
2 
 
1 
 
 
 
 
 
 
 
1 
 
2 
 
 
 
2 
1 
2 
 
1 
 
 
 
 
 
1 
 
1 
1 
 
 
 
 
1 
1 
3 
 
 
 
 
 
1 
 
1 
 
 
 
1 
 
1 
 
1 
 
 
 
 
 
1 
 
1 
 
 
 
1 
 
 
 
 
 
1 
 
1 
 
 
 
 
 
2 
 
1 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
1 
 
1 
 
 
 
 
 
1 
 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
1 
 
 
1 
 
 

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1.2.2. 
Reproductive Risks of KPT-9274 
It is unknown whether KPT-9274 might have reproductive toxicity in humans; therefore, all 
patients in this study must agree to use effective contraception (see Prevention of Pregnancy, 
Section 6.9.2.2) during the study, and for 3 months after their last dose of KPT-9274. 
1.3. 
Study Rationale 
KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator 
of PAK4 and NAMPT. PAK4 is a key downstream effector for RAS and forms a critical link 
between RAS-driven oncogenic transformation and activation of the WNT/β-catenin signaling 
pathway. NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes 
nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic 
cofactor and second messenger. 
Hematologic and solid tumor cells are susceptible to single-agent cytotoxicity by KPT-9274 as 
they become dependent on both the PAK4 and NAMPT pathways. KPT-9274 demonstrated potent 
anti-proliferative activity against cancer cell lines with minimal toxicity to normal cells. In mouse 
xenograft studies, KPT-9274 was well tolerated and resulted in a marked reduction/elimination of 
tumors, tumor growth inhibition or disease control across a variety of tumors, including colon, 
pancreatic, lung, sarcoma, multiple myeloma, leukemia, and lymphoma. In approximately half of 
the tumor types studied, complete elimination of tumors in as short as 3 weeks was observed with 
no regrowth after cessation of treatment (for up to 3 additional weeks). Moreover, KPT-9274 has 
shown preliminary efficacy in companion dogs with spontaneous advanced lymphomas and 
multiple myeloma.  
1.3.1. 
Rationale for the KPT-9274 Dose 
The first-in-human starting dose was calculated based on a pivotal GLP 4-week repeat-dose 
toxicology study in male and female dogs, the most sensitive species, where the highest non-
severely toxic dose (HNSTD) is 2 mg/kg/dose (40 mg/m2) for KPT-9274 when administered orally 
on a QODx3 weekly schedule. Using a conservative estimate of average human body surface area 
(BSA) of 1.7 m2, this is equivalent to an oral dose of 68 mg, and application of a 6-fold safety 
factor results in a 10 mg starting dose for humans. Additionally, Karyopharm Therapeutics has 
conducted a pivotal GLP 4-week repeat-dose toxicology study in rats where the severely toxic 
dose in 10% of the animals (STD10) is 80 mg/kg/dose (460 mg/m2). Similarly, using the same flat 
dose calculation as above, a 460 mg/m2 (~782 mg) dose and a safety factor of 10, results in a 
starting dose of 80 mg for humans. Based on these data, the dog is the more sensitive species, and 
therefore the appropriate starting dose for humans is 10 mg orally.  
1.3.2. 
Rationale for Adding Niacin 
NAD can be generated by catabolism of tryptophan, salvage of nicotinamide through NAMPT or 
salvage of exogenous niacin through NAPRT1. Some cancers lack the enzyme(s) necessary for 
the de novo synthesis of NAD from tryptophan, while NAPRT1 (a niacin utilizing enzyme) activity 
is frequently down-regulated by epigenetic modulation or IDH1 mutation leaving these cancers 
dependent on NAMPT activity. If tumors have reduced or absent NAPRT1 function, then this 
tissue may not be able to utilize niacin to make NAD. Therefore, patients with NAPRT1 in normal 
tissue, but not in their tumors, might benefit from a niacin co-dosing strategy in order to reduce 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 5 3  
Versi o n  5 . 0 
si de effects. Pi v otal G L P a n d e x pl orat or y n o n-G L P st u dies ha ve de m o nstrate d t hat c o -d osi n g 
niaci n wit h K P T -9 2 7 4 ca n i ncrease t olera bilit y; t heref ore, K P T -9 2 7 4 c o -a d mi nistere d wit h orall y 
a d mi nistere d niaci n e xte n de d release ( E R ) will be e val uate d i n t he c urre nt st u d y. I n a d diti o n, lac k 
of N A P R T 1 or I D H 1 m utati o n i n t he t u m or ma y be use d as a pr o g n ostic mar ker of K P T -9 2 7 4 
res p o nse a n d t heref ore ma y be use d t o c haracterize patie nt p o p ulati o ns. 
 
 
  
1. 3. 3.  
R ati o n ale f or C o m bi ni n g K P T -9 2 7 4 wit h Ni v ol u m a b i n Mel a n o m a 
K P T -9 2 7 4 bi n ds t o a n d re d uces t he stea d y state le vel  of t he P A K 4 pr otei n ki nase as well as 
bl oc ki n g t he acti vit y of N A M P T. I n a d diti o n, t hr o u g h P A K 4 i n hi biti o n , K P T -9 2 7 4 re d uces t he 
sta bilit y, n uclear tra ns p ortati o n a n d f u ncti o n  of β -cate ni n b y i n hi biti n g  its p h os p h or ylati o n o n 
S 6 7 5. T his is c o nsiste nt wit h β -cate ni n bei n g a tar get of P A K 4. Ni v ol u ma b is a m o n ocl o nal 
a nti b o d y directe d a gai nst t he pr o gra m me d cell deat h 1 rece pt or ( P D -1) o n l y m p h oc ytes. A nti -P D -
1 treat me nt i ncreases t he i m m u ne res p o nse, all o w i n g T cell killi n g of t u m or cells. Ni v ol u ma b has 
bee n F D A -a p pr o ve d f or use i n patie nts wit h a d va nce d  mela n o ma. T here is e vi de nce s u g gesti n g 
t hat patie nts m ost li kel y t o res p o n d t o a nti-P D -1 treat me nt are t h ose w h o ha ve a n ele vate d baseli ne 
of C D 8 + T cell i nfiltrati o n wit hi n t he t u m or micr oe n vir o n me nt ( T M E) (A bril -R o dri g uez , 2 0 2 0 ). 
T h ose w h o lac k a T cell i nfiltrate res p o n d p o orl y. A c orrelati o n was re p orte d bet wee n 
h y peracti vati o n of t he W N T/ β -cate ni n si g nali n g pat h wa y  a n d T cell e xcl usi o n i n mela n o ma patie nt 
t u m or sa m ples (S pra n ger 2 0 1 5 ). Rece ntl y, t his c orrelati o n has bee n e xte n de d t o P A K 4 
o vere x pressi o n (A bril -R o dri g uez , 2 0 2 0 ). T hese data s u g gest t hat c o m bi nati o n t hera pies i n w hic h 
acti vate d β -cate ni n is i n hi bite d t hr o u g h P A K 4 i n hi biti o n si m ulta ne o usl y wit h tar geti n g P D -1, ma y 
be partic ularl y effecti ve t hera p y. I n dee d, i n vi v o m o dels of mice e n grafte d wit h mela n o ma cells 
t hat were treate d wit h K P T-9 2 7 4 + a n a nti -P D -1 a nti b o d y s h o we d mar ke d t u m or gr o wt h i n hi biti o n 
c o m pare d t o eit her a ge nt al o ne ( A bril -R o dri g uez , 2 0 2 0 ). T heref ore, c o m bi nat orial treat me nt wit h 
K P T -9 2 7 4, w hic h bl oc ks β -cate ni n, wit h ni v ol u ma b ma y be be neficial t o patie nts wit h mela n o ma 
w h o pr o gresse d o n pri or a nti -P D -1 or a nti -P D -L 1 . 
C CI

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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
Parts A and B 
Dose Escalation 
• To determine the Recommended Phase 2 Dose (RP2D)* and the maximum tolerated dose (MTD)* 
for KPT-9274 administered alone (Part A) and with co-administration of niacin ER (Part B). 
*A RP2D equal to or less than the MTD will be declared based on safety and tolerability data 
and used for expansion. 
• To evaluate the safety and tolerability, including dose-limiting toxicities (DLT), of KPT-9274 ± 
niacin ER. 
Dose Expansion 
• To evaluate the safety and tolerability of the RP2D and schedule(s) for KPT-9274 ± niacin ER. 
• To determine preliminary evidence of anti-tumor activity of KPT-9274 at the RP2D* ± niacin ER 
in patients with advanced solid malignancies or NHL according to Response Evaluation Criteria 
in Solid Tumors, Version 1.1 (RECIST 1.1 - Appendix 4])) or Lugano Classification (Appendix 3), 
respectively. 
Part C 
• To evaluate the safety, tolerability, and RP2D of KPT-9274 + nivolumab in patients with 
melanoma. 
2.1.2. 
Secondary Objectives 
Parts A and B 
Dose Escalation 
• To define the preliminary evidence of anti-tumor activity of KPT-9274 alone (Part A) and with 
co-administration of niacin ER (Part B) in patients with advanced solid malignancies or NHL. 
Dose Escalation and Dose Expansion 
• To determine the pharmacokinetic (PK) profile of KPT-9274, including, but not limited to, 
maximum plasma concentration, time-to-peak plasma concentration, terminal half-life, and plasma 
clearance. 
Part C 
• To determine the preliminary evidence of anti-tumor activity of KPT-9274 + nivolumab in 
patients with melanoma. 
• To characterize the PK of KPT-9274 when administered with nivolumab in patients with 
melanoma. 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
1 1 Marc h  2 0 2 0  
C o nfi de ntial 
P a ge 5 5  
Versi o n  5 . 0 
2. 1. 3.  
E x pl or at or y O bjecti ves  
2. 2.  
E n d p oi nts  
2. 2. 1.  
S afet y E n d p oi nts  
T he safet y a n d t olera bilit y of K P T- 9 2 7 4 ± niaci n E R a n d K P T- 9 2 7 4 + ni v ol u ma b will be e val uate d 
b y mea ns of D L Ts, A E re p orts, p h ysical e xa mi nati o n res ults, electr ocar di o gra m res ults a n d 
la b orat or y safet y e val uati o ns. T he Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts ( C T C A E), Versi o n 4. 0 3, will be use d f or gra di n g of A Es. 
2. 2. 2.  
Effic ac y E n d p oi nts  
Disease res p o nse will be e val uate d acc or di n g t o R E CI S T 1. 1 (a d va nce d s oli d mali g na ncies a n d 
mela n o ma (A p pe n di x  4 )) or L u ga n o Classificati o n ( N H L) (A p pe n di x  3 ) a n d will i ncl u de t he 
f oll o wi n g: 
•
O ver all res p o nse r ate ( O R R):  = pr o p orti o n of patie nts w h o ha ve a res p o nse of partial
res p o nse ( P R) or c o m plete  res p o nse ( C R).
•
D ur ati o n of res p o nse ( D O R):  t he d urati o n of ti me fr o m first meeti n g C R or P R
meas ure me nt criteria ( w hic he ver occ urs first) u ntil t he first date t hat P D rec urre nce is
o bjecti vel y .
•
Dise ase c o ntr ol r ate ( D C R): D C R =  pr o p orti o n of patie nts w h o ha ve a res p o nse of  C R, P R,
a n d Sta ble Disease ( S D) ≥ 1 6 wee ks.
•
D ur at i o n of dise ase c o ntr ol: t he d urati o n of ti me fr o m date of first st u d y treat me nt u ntil t he
first date t hat P D is o bjecti vel y d oc u me nte d.
•
Pr o gressi o n -free s ur vi v al ( P F S): t he d urati o n of ti me fr o m date of first st u d y treat me nt
u ntil t he first date t hat P D is o bjecti vel y d oc u me nte d or deat h d ue t o a n y ca use .
•
O ver al l s ur vi v al ( O S): t he d urati o n of ti me fr o m date of first st u d y treat me nt u ntil deat h
fr o m a n y ca use .
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 5 6  
Versi o n  5 . 0 
•  Ti me t o Pr o gressi o n ( T T P):  T he d urati o n of ti me fr o m date of first st u d y treat me nt u ntil t he 
first date t hat P D is o bjecti vel y d oc u me nte d or deat h d ue t o P D .  
2. 2. 3.  
P K E n d p oi nts  
K P T -9 2 7 4 P K para meters ma y i ncl u de, b ut are n ot li mite d t o, ma xi m u m plas ma c o nce ntrati o n 
( Cma x ), area u n der t he c ur ve ( A U C), ti me-t o-pea k plas ma c o nce ntrati o n (t ma x ), ter mi nal plas ma 
half -life (t½ ), a p pare nt v ol u me of distri b uti o n ( V d/ F), a n d ap pare nt plas ma cleara nce  (C L / F). 
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 5 7  
Versi o n  5 . 0 
C CI

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a first-in-human, multi-center, open-label clinical study with separate Dose Escalation 
and Expansion Phases to assess preliminary safety, tolerability, and efficacy of KPT-9274, a dual 
inhibitor of PAK4 and NAMPT in patients with advanced solid malignancies or NHL for which 
all standard therapeutic options considered useful by the investigator have been exhausted and 
with progressive disease on study entry. 
The Dose Escalation Phase will include two parts, Part A and Part B. Patients will be enrolled 
according to their NAPRT1 status at a ratio of 2:1 (NAPRT1 negative:NAPRT1 positive). The 
NAPRT1 status must be determined prior to enrollment. For the purposes of dose escalation 
decisions, a standard 3+3 dose escalation design will be used during both Part A and Part B.  
• Part A will be performed to determine the RP2D and MTD of KPT-9274 alone (note that 
the RP2D may be ≤ the MTD and will be used for the Dose Expansion Phase of the 
study). 
• Part B will be performed to determine the RP2D and MTD of KPT-9274 co-
administered with 500 mg up to 2,000 mg niacin ER; the starting dose of KPT-9274 for 
Part B will be a dose and schedule that has cleared DLT assessment during Part A. 
A Dose Expansion Phase may be completed; this phase will determine the safety, tolerability, 
and preliminary evidence of anti-tumor activity of KPT-9274 at the RP2D ± niacin ER in 
patients with advanced solid malignancies or NHL according to RECIST 1.1 (advanced solid 
malignancies [Appendix 4]) or the Lugano Classification for response assessment of NHL 
(Appendix 3) and described in terms of best overall response, ORR, DOR, DCR, duration of 
disease control, PFS, OS, and TTP. Note that preliminary clinical results may define the patient 
population (i.e., specific indications) selected for enrollment in the Dose Expansion Phase. 
After declaring the RP2D for KPT-9274 single agent and KPT-9274 + niacin ER, based on the 
safety and tolerability results, a decision will be made whether expansion (4 groups, ~45 patients 
total) will be conducted at the RP2D of KPT-9274 single agent or at the RP2D of KPT-9274 + 
niacin ER. If the ~45 patient expansion is conducted at the RP2D of KPT-9274 + niacin ER, an 
additional, optional expansion with < 20 patients at the RP2D of KPT-9274 single agent may 
also be initiated.  
In Part C, a cohort of patients with melanoma that have progressed on an anti-PD1 or anti-PD-L1 
antibody will be treated with KPT-9274 (at a dose that cleared DLT evaluation in Part A) + 
nivolumab. Two dose levels of KPT-9274 (30 and 40 mg) in combination with nivolumab will 
be tested in parallel. Patients will be enrolled first into the 30 mg cohort. Patients will be treated 
with 30 or 40 mg KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 
19, 22, 24, and 26) during each 28-day cycle in combination with a standard dose and schedule 
of nivolumab (480 mg on Day 1 of each 28-day cycle). A maximum of 10 patients may be 
enrolled at each dose level. Treatment will continue until disease progression, unacceptable AEs 
or toxicity that cannot be managed by supportive care, patient’s withdrawal of consent, 
Investigator decision to discontinue study treatment, pregnancy, death, or Sponsor decision to 
terminate the study. A safety review committee will evaluate all available data from both cohorts 
after the last patient enrolled has been observed for at least 2 cycles to determine the RP2D. 

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Additional dose levels (20 mg or 60 mg) might be evaluated if an optimal dose is not identified 
and the safety review committee is in agreement. The definition of a DLT is the same as 
described in Parts A and B. Response will be assessed every 8 weeks per RECIST 1.1 criteria 
(Appendix 4). 
All phases of the study will be comprised of Screening, Treatment, and Follow-up periods. 
Screening will be performed within 30 or 14 days prior to the start of therapy (i.e., Day -30 to 
Day -1, Day -30 to Day -14, or Day -14 to Day -1), as summarized in Table 1 and Table 5. 
During the Treatment period, procedures are to be performed during clinic visits prior to the 
administration of study treatment on those days as presented in Table 1, Table 2, Table 5 and 
Table 6. The Follow-up period includes the EOT visit, the Safety Follow-up visit, and Durability 
of Response and Survival Follow-up; see Table 3 and Table 7 for assessments to be completed 
during the Follow-up period. 
Enrollment is estimated at 175 patients. However, the number of patients required for completion 
of study enrollment cannot be defined a priori since this depends on the number of patients 
needed for the dose escalations in Parts A and B. Assuming that 9 dose levels of KPT-9274 are 
evaluated during both Part A (KPT-9274 single agent) and Part B (KPT-9274 + niacin ER) of the 
Dose Escalation Phase and up to 65 additional patients are enrolled in the Dose Expansion Phase 
the total combined enrollment is estimated to be 175 patients. Each cohort in Parts A and B of 
the Escalation Phase will consist of 3 or 6 patients per cohort. The Dose Expansion Phase may 
include up to 65 additional patients (up to 45 patients in the KPT-9274 ± niacin ER cohort; if 
Dose Expansion is conducted with KPT-9274 + niacin ER then an optional cohort of up to 
20 additional patients in the KPT-9274 single agent cohort). 
The KPT-9274 ± niacin ER expansion cohort will consist of 4 groups of approximately 
45 patients (please note that the composition of the expansion groups [e.g., number of patients 
with NAPRT1 positive vs NAPRT1 deficient tumors] may change based on the results from the 
escalation phase) including the following: 
I.
NAPRT1 deficient tumor group, approximately 10 patients
II.
NAPRT1 positive tumor group, approximately 10 patients
III.
Either NAPRT1 deficient or positive tumor group, approximately 10 patients
IV.
IDH1 mutant tumor group, approximately 15 patients
An additional, optional KPT-9274 single agent expansion cohort will consist of < 20 patients 
with any tumor mutational status. 
Patients will receive oral KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 
15, 17, 19, 22, 24, and 26) during each 28-day cycle. During Part B of the Dose Escalation 
Phase, patients will receive 500 mg up to 2,000 mg niacin ER co-administered with each dose of 
KPT-9274. 
Patients in the Dose Expansion Phase may be treated with the RP2D of KPT-9274 ±niacin ER 
according to the same schedule administered in the Dose Escalation Phase of the study. 
Further details on the Dose Escalation phase are provided in Section 6.2.5 and Section 6.2.6 and 
additional details on the Dose Expansion phase are provided in Section 6.2.7. 

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3.2. 
Replacement Policy 
Patients who complete the first cycle of therapy will not be replaced during the Escalation Phase 
of the study. However, if a patient is considered as non-evaluable for DLT (i.e., did not complete 
the first cycle of therapy and did not experience a DLT), enrollment of a new patient to the 
current cohort will be considered if there is less than the required number of evaluable patients. 
During the Dose Expansion Phase, patients who have not completed 1 cycle will be replaced 
unless they were discontinued from the study due to a drug-related toxicity, PD, or death. 
3.3. 
Treatment Duration 
Treatment cycles are 28 days long. A patient may continue to receive KPT-9274 until that patient 
experiences PD, withdraws consent, is lost to follow-up, experiences intolerable toxicity which 
precludes further treatment with KPT-9274, or treatment is discontinued at the discretion of the 
Investigator or the Karyopharm Medical Monitor. 

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4. 
STUDY POPULATION SELECTION 
4.1. 
Study Population 
This study will enroll adult patients with advanced solid malignancies (including sarcoma, colon, 
lung, etc.) or non-Hodgkin’s lymphoma for which standard therapeutic options considered useful 
by the investigator have been exhausted and with progressive disease on study entry, and meet 
all of the inclusion criteria and none of the exclusion criteria. 
4.2. 
Inclusion Criteria (Parts A and B) 
Patients must meet all of the following inclusion criteria to be eligible to enroll in this study: 
1. Written informed consent obtained prior to any screening procedures and in accordance 
with federal, local, and institutional guidelines. 
2. Age ≥ 18 years. 
3. Patients with advanced solid malignancies or NHL for which all standard therapeutic 
options considered useful by the investigator have been exhausted. 
4. Patients must have objective evidence of progressive disease on study entry: 
a. Advanced solid malignancies:  Measurable disease as defined by RECIST 1.1 
(Appendix 4). 
b. NHL:  Measurable disease including target lesion(s) as defined by the Lugano 
Classification for initial evaluation and staging (Appendix 3). 
5. Patients must have a site of disease amenable to biopsy and be a candidate for biopsy 
according to the treating institution’s guidelines.  
6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1. 
7. Adequate hepatic function: 
a. Total bilirubin < 1.5 times the upper limit of normal (ULN) (except patients with 
Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total 
bilirubin of ≤ 3 times ULN),  
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times 
ULN (except patients with known liver involvement of their advanced solid 
malignancy or NHL who must have their AST and ALT ≤ 5.0 times ULN). 
8. Adequate renal function: estimated creatinine clearance of ≥ 60 mL/min, calculated using 
the formula of Cockroft and Gault (140-Age) • Mass (kg)/(72 • creatinine mg/dL); 
multiply by 0.85 if female. 
9. Female patients of child-bearing potential must agree to use dual methods of 
contraception (including one highly effective and one effective method of contraception 
[as defined in Section 6.9.2.2]) and have a negative serum pregnancy test at Screening, 
and male patients must use an effective barrier method of contraception if sexually active 
with a female of child-bearing potential. For both male and female patients, effective 
methods of contraception must be used throughout the study and for 3 months following 
the last dose. 

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10. Adequate hematopoietic function: total white blood cell (WBC) count ≥ 1500/mm3, 
absolute neutrophil count (ANC) ≥ 1000/mm3, hemoglobin (Hb) ≥ 10.0 g/dL, and platelet 
count ≥ 75,000/mm3. 
11. Dose Escalation Phase: Patients will be enrolled according to their NAPRT1 status at a 
ratio of 2:1 (NAPRT1 negative:NAPRT1 positive). The NAPRT1 status must be 
determined prior to enrollment based on evaluation of a fresh tumor biopsy or archival 
tissue taken ≤6 months of screening. 
12. Dose Expansion Phase (KPT-9274 ± niacin ER cohort only): Patient tumors NAPRT1 
and IDH1 status must be determined at the central laboratory prior to enrollment.  
a. Confirmation of NAPRT1 expression and IDH1 mutation based on evaluation of a 
fresh tumor biopsy or archival tumor biopsy taken ≤ 6 months of screening tests as 
follows: 
i. NAPRT1 positive for expansion cohort I or III 
ii NAPRT1 negative for expansion cohort II or III 
iii. IDH1 mutation status for expansion cohort IV 
13. Life expectancy of ≥ 3 months. 
4.3. 
Exclusion Criteria (Parts A and B) 
Patients meeting any of the following exclusion criteria are not eligible to enroll in this study: 
1. Female patients who are pregnant or lactating. 
2. Time since the last prior therapy for treatment of advanced solid malignancies or NHL**: 
a. Radiation, chemotherapy, immunotherapy or any other anticancer therapy, including 
investigational anti-cancer therapy ≤ 2 weeks prior to C1D1. 
b. Palliative steroids for disease related symptoms < 7 days prior to C1D1.  
**Patients must have recovered or stabilized (Grade 1 or to their baseline for non-
hematologic toxicities, ≤ Grade 2 or to their baseline for hematologic toxicities) from 
toxicities related to their previous treatment except for alopecia. In specific cases, patients 
with Grade 2 non-hematologic toxicities will be allowed following approval by the 
Karyopharm medical monitor. 
3. Patients with known central nervous system (CNS) disease or leptomeningeal 
involvement, regardless of response to prior therapy, are excluded.  
4. Major surgery within four weeks before C1D1. 
5. Impaired cardiac function or clinically significant cardiac diseases, including any of the 
following: 
a. Unstable angina or acute myocardial infarction ≤ 3 months prior to C1D1; 
b. Clinically significant heart disease (e.g., symptomatic congestive heart failure; 
uncontrolled arrhythmia, or hypertension; history of labile hypertension or poor 
compliance with an antihypertensive regimen). 

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6. Active infection with completion of therapeutic antibiotics, antivirals, or antifungals 
within one week prior to C1D1. Prophylactic antibiotics, antivirals or antifungals are 
permitted. 
7. Patients with a known history of Human Immunodeficiency Virus (HIV); HIV testing is 
not required as part of this study. 
8. Known, active hepatitis A, B, or C infection; or known to be positive for HCV RNA or 
HBsAg (HBV surface antigen). Testing is not required. 
9. Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled 
vomiting or diarrhea that could interfere with the absorption of KPT-9274.  
10. Serious psychiatric or medical conditions that, in the opinion of the Investigator, could 
interfere with treatment, compliance, or the ability to give consent. 
11. Active peptic ulcer disease or other active gastrointestinal bleeds. 
 
4.4. 
Inclusion Criteria (Part C) 
Patients must meet all of the following inclusion criteria to be eligible to enroll in this study. 
1. Written informed consent obtained prior to any screening procedures and in accordance 
with federal, local, and institutional guidelines. 
2. Age ≥18 years. 
3. Patients must have objective and measurable melanoma by RECIST 1.1 after disease 
progression on a prior anti-PD-1 or anti-PD-L1 therapy. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 
5. Adequate hepatic function:  
a. Total bilirubin < 1.5 times the upper limit of normal (ULN) (except patients with 
Gilbert’s syndrome [hereditary indirect hyperbilirubinemia] who must have a total 
bilirubin of ≤ 3 times ULN), 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 
times ULN (except patients with known liver involvement of their advanced solid 
malignancy who must have their AST and ALT ≤ 5.0 times ULN). 
6. Adequate renal function: Estimated creatinine clearance of ≥ 60 mL/min, calculated using 
the formula of Cockroft and Gault (140-Age) • Mass (kg)/(72 • creatinine mg/dL); 
multiply by 0.85 if female. 
7. Female patients of child-bearing potential must agree to use dual methods of 
contraception (including one highly effective and one effective method of contraception) 
and have a negative serum pregnancy test at Screening, and male patients must use an 
effective barrier method of contraception if sexually active with a female of child-bearing 
potential. For both male and female patients, effective methods of contraception must be 
used throughout the study and for 3 months following the last dose. 

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8. Adequate hematopoietic function: total white blood cell (WBC) count ≥ 1500/mm3, 
absolute neutrophil count (ANC) ≥ 1000/mm3, hemoglobin (Hb) ≥ 10.0 g/dL, and platelet 
count ≥ 100,000/mm3. 
9. Life expectancy of ≥ 3 months. 
 
4.5. 
Exclusion Criteria (Part C) 
Patients meeting any of the following exclusion criteria are not eligible to enroll in this study: 
1. Female patients who are pregnant or lactating. 
2. ≤ 2 weeks since the last prior therapeutic regimen for melanoma. Palliative steroids for 
disease related symptoms < 7 days prior to C1D1, unless physiologic doses of steroids 
are used.  
3. Patients who have not recovered or stabilized (Grade 1 or to their baseline for non-
hematologic toxicities, ≤ Grade 2 or to their baseline for hematologic toxicities) from 
toxicities related to their previous treatment except for alopecia. In specific cases, patients 
with Grade 2 non-hematologic toxicities will be allowed following approval by the 
Karyopharm medical monitor. 
4. Patients with untreated central nervous system (CNS) disease or leptomeningeal 
involvement are excluded. Patients without active brain or leptomeningeal metastases 
after prior treatment with local therapies are eligible provided that the treatment had been 
done ≥ 2 weeks prior to enrollment. 
5. Major surgery within four weeks before C1D1. 
6. Active infection with completion of therapeutic antibiotics, antivirals, or antifungals 
within one week prior to C1D1. Prophylactic antibiotics, antivirals or antifungals are 
permitted. 
7. Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled 
vomiting or diarrhea that could interfere with the absorption of KPT-9274. 
8. Serious psychiatric or medical conditions that, in the opinion of the Investigator, could 
interfere with treatment, compliance, or the ability to give consent. 
9. Active peptic ulcer disease or other active gastrointestinal bleeds. 
10. Patients requiring treatment with corticosteroids at doses higher than substitute therapy (> 
10 mg prednisone), are unstable with substitute hormonal therapy, or are deemed to be 
likely to re-occur by the treating physician when administered nivolumab. 
 
4.6. 
Screening and Registration 
The Screening period starts once a patient has provided written informed consent to participate in 
the study and ends on the day of study entry (C1D1). 

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Patient eligibility (inclusion/exclusion criteria) will be reviewed for each patient participating in 
the study by the Karyopharm Medical Monitor before the patient receives study treatment on 
C1D1. The procedure used to check eligibility and registration of patients is the same in the Dose 
Escalation Phase and the Dose Expansion Phase of the study, as follows: 
The eligibility check form/Patient Registration Form will be sent from the site to Karyopharm for 
evaluation either by fax or email. Upon confirmation of eligibility, Karyopharm will return the 
signed eligibility check form/Patient Registration Form via fax or email to the site. The Patient 
Registration Form will indicate the dose group to which the patient has been assigned (see 
Section 4.6.1).  
4.6.1. 
Study Patient Number 
Upon screening, each patient will be assigned a unique patient number and will keep this number 
for the duration of the study. Patient numbers will not be reassigned or reused for any reason. 
Patients will be identified to Karyopharm by their assigned number, initials, date of birth, and 
sex. The Investigator must maintain a patient master log. 
4.6.2. 
Rescreening 
Rescreening is permitted in this study following discussion with the Karyopharm Medical 
Monitor. If a patient fails any of the inclusion or exclusion criteria, that patient may be 
rescreened after a suitable period of time (the exact length is dependent upon the reason for the 
screen failure) at the agreement of the Karyopharm Medical Monitor and the Investigator. Any 
patient who is rescreened must be re-consented. A patient may only be re-screened once. 
4.6.3. 
Screen Failures 
Patients who sign an informed consent but fail to start on treatment for any reason will be 
considered a screen failure. Date of consent and reason for ineligibility will be entered into the 
clinical database. No other data will be entered into the clinical database for patients who are 
screen failures, unless those patients experience serious adverse event (SAE) during the 
Screening Phase. 

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5. 
DISCONTINUATION CRITERIA 
5.1. 
Early Termination of the Study 
This study may be discontinued at the sole discretion of Karyopharm for any reason, including 
medical or ethical reasons affecting the continued performance of the study, or difficulties in the 
recruitment of patients. If this occurs, Karyopharm will notify ethics committees, Investigators, 
and regulatory authorities, as applicable. 
5.2. 
Discontinuation of Study Treatment and/or Withdrawal of Patients 
from the Study 
The Investigator may remove a patient from study treatment after consultation with the 
Karyopharm Medical Monitor for any of the following reasons: 
• Unacceptable AEs or toxicity that cannot be managed by supportive care 
• Any medically appropriate reason (e.g., clinical progression) or significant protocol violation, in 
the opinion of the Investigator 
The Investigator must remove a patient from study treatment for any of the following reasons: 
• Disease progression per response criteria 
• Patient withdraws consent to continue study treatment 
• Pregnancy 
Patients who are removed from study treatment by the Investigator are not permitted to restart 
study treatment. 
Patients may discontinue study treatment for any reason. Patients who choose to discontinue 
study treatment should be encouraged to continue in the study so that follow-up information on 
disease progression and survival status may be obtained. Patients may elect to withdraw consent 
and decline further participation in the study at any time. If a patient withdraws consent after 
completing Cycle 1, he/she may request to re-enter the study, if it occurs within 28 days since the 
last dose, by re-signing consent. This is permitted based on the Investigator's discretion and after 
consultation with the Karyopharm Medical Monitor. 
The reason for the patient’s discontinuation of study treatment/withdrawal from the study must 
be recorded on the eCRF. 
All patients will be followed until PD, withdrawal of consent, occurrence of any withdrawal 
criteria, intolerable toxicity precluding further treatment with study treatment, death or loss to 
follow up. 

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6. 
STUDY TREATMENTS 
6.1. 
Treatments Administered 
6.1.1. 
KPT-9274 
KPT-9274 is an orally bioavailable small molecule prepared in a tablet solid dosage form for oral 
administration. 
KPT-9274 tablets are designed for immediate-release oral administration and will be supplied in 
high-density polyethylene (HDPE) bottles with induction seals and polypropylene caps.  
KPT-9274 tablets will be film coated for ease of handling and provided in tablet strengths of 
5 mg and 20 mg. KPT-9274 will be supplied by Karyopharm. Additional details on KPT-9274 
are provided in the IB. The investigational treatments will be administered as a flat dose and not 
by body weight or body surface area. 
6.1.2. 
Niacin ER (Part B)  
Patients enrolled in Part B of the Dose Escalation Phase or in the Dose Expansion cohort with 
co-administration of niacin will also receive 500 mg of any FDA approved prescription, generic 
niacin ER for oral use co-administered with each dose of KPT-9274. The starting dose of 500 mg 
niacin ER may be titrated up to 2,000 mg of daily dose, per label. A list of approved generic 
niacin ER will be provided in the Pharmacy Manual. The niacin ER study treatment will be 
obtained by the site pharmacy.  
6.1.3. 
Nivolumab (Part C)  
Nivolumab will begin on the first day (C1D1) and will be administered through an intravenous 
(IV) line on Day 1 of each cycle (once every 4-week cycle] at 480 mg according to the current 
prescribing information. Nivolumab will be given per standard of care.  
All dosages prescribed to the patient and all dose changes during the study must be recorded on 
the eCRF. 
6.1.4. 
Placebo or Control 
Not applicable. This is not a placebo-controlled study and the active treatment will not be 
compared to a control treatment. 
6.2. 
Study Treatment Dose Schedules and Administration 
6.2.1. 
Labeling 
All labels will include conditions for storage, lot number, and other pertinent information such as 
Sponsor and a caution statement. Medication labels for KPT-9274 will be in the local language 
of the site and comply with the legal requirements of each country. 

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6.2.2. 
Dispensing Directions 
The Investigator or responsible site personnel must instruct the patient or caregiver to take the 
study treatment(s) as per protocol. Study treatment(s) will be dispensed to the patient by 
authorized site personnel only.  
6.2.3. 
Dosing Information 
Patients will receive oral KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 
15, 17, 19, 22, 24, and 26) during each 28-day cycle.  
Study treatment will be administered in the clinic and at home as indicated in Table 4. Study 
treatment dosing will occur in the clinic during Cycle 1 on Days 1, 3, 8, 15, 22, 24, and 26, 
during Cycle 2 on Days 1, 8, 15, and 22, and during ≥ Cycle 3 on Days 1 and 15. Study treatment 
dosing will occur at home during Cycle 1 on Days 5, 10, 12, 17, and 19, during Cycle 2 on 
Days 3, 5, 10, 12, 17, 19, 24, and 26 and during Cycles ≥ 3 on Days 3, 5, 8, 10, 12, 17, 19, 22, 
24, and 26. 
During Part B of the Dose Escalation Phase, patients will receive 500 mg niacin ER 
co-administered with each dose of KPT-9274. The starting dose of 500 mg niacin ER may be 
titrated to 2,000 mg of daily dose, per label. The starting dose for KPT-9274 in Part B will be a 
dose and schedule that cleared DLT assessment during Part A. For the purposes of dose 
escalation decisions, a standard 3+3 dose escalation design will be used during both Part A and 
Part B. 
A total of ~65 patients with advanced solid malignancies and NHL may be enrolled to further 
explore safety, tolerability and preliminary evidence of anti-tumor activity of the RP2D of 
KPT-9274 ± niacin ER. After declaring the RP2D ± niacin ER (see Section 6.2.6), based on the 
safety and tolerability results of the Dose Escalation Phase, a decision will be made whether 
expansion (4 groups, ~45 patients total) will be conducted at the RP2D of KPT-9274 single agent 
or at the RP2D of KPT-9274 + niacin ER. If the 45 patient expansion is conducted at the RP2D 
of KPT-9274 + niacin ER, an optional expansion with < 20 patients at the RP2D of KPT-9274 
single agent may be initiated. Futility analyses based on clinical efficacy will be conducted in a 
maximum of 10 patients dosed at the RP2D ± niacin ER (see Section 6.2.7 for additional details).  
Dose escalation will occur according to the Dose Escalation Guidelines provided in 
Section 6.2.6. 
Patients with melanoma enrolled in Part C, KPT-9274 + nivolumab, cohort will receive 
nivolumab (480 mg once per 28 day cycle) according to the current prescribing information. 
6.2.4. 
Dosing Instructions for Patients 
Study medications will be dosed according to the schedules provided in Table 4. For doses of 
oral medication to be taken on non-clinic days, patients will be provided with an adequate supply 
of study treatment for self-administration at home until at least their next scheduled study visit. 
Patients will be provided with a take home diary to complete on home dosing days; the patient 
diary will be reviewed at each clinic visit.  
Oral KPT-9274 should be given with food, or within 30 minutes after the patient has eaten, 
together with 240-355 mL (8-12 ounces) of fluids.  

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KPT-9274 tablets should be swallowed whole (not crushed). 
Nivolumab (anti-PD-1) will be administered at the site based on the product label.  
6.2.5. 
Dose Schedules for Evaluation During the Dose Escalation Phase 
The dose schedule for evaluation during the Dose Escalation Phase in Part A is presented in 
Table 13. A similar dose escalation plan will be used in Part B; however, the starting dose of 
KPT-9274 will be a dose and schedule that has cleared DLT assessment during Part A. 
To better evaluate the safety, tolerability, and PK of KPT-9274, additional cohorts of patients 
may be enrolled on alternate dosing schedules (e.g. dosing on 2 days per week), at preceding 
dose levels, or to intermediate dose levels before or while proceeding with further dose 
escalation. Assessments at clinic visits may need to be adjusted based on the dosing schedule. 
Table 13: Part A - KPT-9274 Dose Escalation Levels 
Cohort 
KPT-9274 
Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 in a 
28-day cycle 
1 
(starting dose) 
10 mg 
2 
20 mg 
3 
30 mg 
4 
40 mg 
5+ 
Increases at 20 mg per cohort 
Three patients will be enrolled in each cohort, if 1 of 3 patients in a cohort experiences a DLT, 
the number of patients in that cohort will be expanded to 6 patients. A maximum of 6 patients 
will be enrolled per cohort. If ≥ 2 patients in a cohort experience a DLT, the MTD will be 
defined as 1 dose level lower. 
6.2.6. 
Dose Escalation Guidelines 
6.2.6.1. 
Dose Escalation Procedures 
The Dose Escalation Phase will include two parts, Part A and Part B. 
• Part A will be performed to determine the RP2D and MTD of KPT-9274 alone (note that the 
RP2D may be ≤ the MTD and will be used for the Dose Expansion Phase of the study). 
• Part B will be performed to determine the RP2D and MTD of KPT-9274 co-administered 
with a starting dose of 500 mg niacin ER (and may be titrated up to 2,000 mg daily dose, per 
label); the starting dose of KPT-9274 for Part B will be a dose and schedule that has cleared 
DLT assessment in Part A. 
For the purposes of dose escalation decisions for both Part A and Part B, a standard 3+3 dose 
escalation design will be used. Based on preclinical and early clinical data, patients will be 
enrolled according to their NAPRT1 status at a ratio of 2:1 (NAPRT1 negative:NAPRT1 

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positive). The NAPRT1 status must be determined prior to enrollment based on evaluation of a 
fresh tumor biopsy or archival tissue taken ≤ 6 months of screening. 
Part A (KPT-9274 single agent):   
The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 10 mg. If 
these patients do not experience a DLT during Cycle 1, the KPT-9274 dose will be escalated to 
20 mg for another group of 3 patients (Cohort 2) upon approval during a dose decision meeting. 
Dose escalation will continue based on a standard 3+3 design at the dose levels specified in the 
Table 13 and as further described for both parts below. 
Part B (KPT-9274 + niacin ER):   
The initial cohort, Cohort 1 + niacin ER (Cohort 1B), will consist of 3 enrolled patients who will 
be treated at a dose and schedule of KPT-9274 that has cleared DLT assessment in Part A, 
co-administered with a starting dose of 500 mg niacin ER (and may be titrated to 2,000 mg daily 
dose, per label) with each dose of KPT-9274.  
Part A and Part B: 
Dose escalation will continue independently in Parts A and B until the MTD in each part is 
determined. A RP2D equal to or less than the MTD will be declared for each part and used for 
the Dose Expansion Phase. The MTD is defined as the highest dose at which ≤ 1 patient 
experiences a DLT in Cycle 1. 
Patients must complete a minimum of 1 cycle of treatment, defined as receiving ≥ 75% of 
KPT-9274 doses during Cycle 1 (e.g., ≥ 9 of 12 doses in the 3 doses/week schedule), or have a 
DLT within the first cycle of treatment to be evaluable for dose escalation decisions. Dose 
escalation decisions will occur when the cohort of patients has met these criteria. 
Dose escalation decisions will be made by enrolling Investigators and Karyopharm study 
personnel. Decisions will be based on an evaluation of all relevant data available from all dose 
levels evaluated in the ongoing study including safety information, DLTs, all CTCAE 
(Version 4.03) toxicity data during Cycle 1 and PK data (if available) from evaluable patients 
(see Section 6.2.6.3) 
Table 13 describes the starting dose and the dose cohorts that may be evaluated in Part A. A 
similar dose escalation plan will be used in Part B. To better evaluate the safety, tolerability and 
PK of KPT-9274, additional cohorts of patients may be enrolled on alternate dosing schedules, at 
preceding dose levels, or to intermediate dose levels before or while proceeding with further 
dose escalation.  
Dose escalation for Part A and Part B will be conducted as follows: 
• If 0 of 3 patients experiences a DLT, escalate to next higher dose cohort. 
• If 1 of 3 patients experiences a DLT, that cohort will be expanded to 6 patients. If 1 of 6 
patients experiences a DLT, escalate to the next higher dose cohort; 
• If ≥ 2 of 3 or ≥ 2 of 6 patients experience a DLT, MTD is exceeded. If the MTD is exceeded, 
the patients will be de-escalated to the next lower dose level (the MTD). 
 

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Part C (KPT-9274 + nivolumab):   
The initial cohort will consist of 3 enrolled patients who will be treated at a dose of 30 mg KPT-
9274, co-administered with a dose of 480 mg nivolumab. If these patients do not experience a 
DLT during Cycle 1, the KPT-9274 dose will be escalated to 40 mg for another cohort of 3 
patients upon approval during a dose decision meeting. A maximum of 10 patients may be 
enrolled at each dose level. 
Additional KPT-9274 dose levels (e.g., 20 mg or 60 mg) may be evaluated if an optimal dose is 
not identified and the safety review committee is in agreement. 
6.2.6.2. 
Dose-Limiting Toxicity 
A DLT is defined as an AE or abnormal laboratory value that occurs within the first 28 days of 
treatment with KPT-9274, except for those that are clearly and incontrovertibly due to 
underlying disease, disease progression, or extraneous causes, and meets any of the criteria 
included in Table 14. The CTCAE, Version 4.03 will be used for grading. In addition, > 3 
missed (consecutive or non-consecutive) doses of KPT-9274 in the first 28 days due to a drug 
related toxicity will be considered to be a DLT. 
Other events may occur which do not meet the definition of a DLT, but are of concern to the 
Investigators and Karyopharm, and may then be considered to be DLTs. 
Table 14: Criteria for Defining Dose-Limiting Toxicities 
Toxicity 
Any of the following criteria (based on CTCAE [Version 4.03]): 
Non-
Hematologic 
Grade ≥ 3 nausea/vomiting, dehydration or diarrhea while taking optimal supportive 
medications. 
Any other Grade ≥ 3 non-hematological toxicity except alopecia or electrolyte 
abnormalities correctable with supportive therapy. 
Hematologic 
Grade 4 neutropenia lasting more than 5 days. 
Febrile neutropenia of any duration (ANC < 1.0 ×109 with single temperature >38.3°C 
or a sustained temperature ≥ 38°C for more than 1 hour). 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding, or any 
requirement for platelet transfusion. 
Grade 4 anemia, unexplained by underlying disease. 
CTCAE Version 4.03 will be used for grading AEs and laboratory abnormalities. Patients may receive 
supportive care as per local institutional guidelines. 
6.2.6.3. 
Dose Decision Meeting or Teleconference 
To implement dose escalation decisions, available toxicity information (including all AEs and all 
laboratory abnormalities regardless of DLT assessment) will be evaluated by the enrolling 
Investigators and Karyopharm study personnel during a dose decision meeting or teleconference. 
Decisions will be based on an evaluation of all relevant data available from all dose cohorts 
evaluated in the ongoing study including safety information, DLTs, all NCI CTCAE 
(Version 4.03), toxicity data during Cycle 1 and PK data (if available) from evaluable patients. 

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Drug administration at the next higher dose cohort may not proceed until the Investigator 
receives written confirmation from Karyopharm indicating that the results of the previous dose 
cohort were evaluated and that it is permissible to proceed to the next higher dose cohort. 
Interim safety data will be examined on an ongoing basis to ensure patient safety and to comply 
with the clinical study dose escalation rules (see Section 9.8). In addition, Karyopharm will 
conduct regular safety meetings with investigators and other site staff where all AEs are shared 
across the study, and appropriate management of toxicities fully reviewed and, as needed, 
implemented. 
6.2.7. 
Dose Schedule for Evaluation During the Dose Expansion Phase (Parts A and B) 
After completion of the Dose Escalation Parts A and B, Dose Expansion in up to 65 additional 
patients with advanced solid malignancies and NHL may be conducted to further explore safety, 
tolerability and preliminary evidence of anti-tumor activity of the RP2D of KPT-9274 ± niacin 
ER. Note that preliminary clinical results may define the patient population (i.e., specific 
indications) selected for enrollment in the Dose Expansion Phase. 
After declaring the RP2D for KPT-9274 single agent and KPT-9274 + niacin ER, based on the 
safety and tolerability results of the Dose Escalation Phase, a decision will be made whether 
expansion (4 groups, ~45 patients total) will be conducted at the RP2D of KPT-9274 single agent 
or at the RP2D of KPT-9274 + niacin ER. If the ~45 patient expansion is conducted at the RP2D 
of KPT-9274 + niacin ER, an optional expansion with < 20 patients at the RP2D of KPT-9274 
single agent may also be initiated.  
At least 1 clinical response (minimum of stable disease ~8 weeks) must be seen in any of the first 
ten patients treated at the RP2D in order to fully enroll either expansion cohort. These 10 patients 
include the patients enrolled under the 3+3 design for DLT assessment; if necessary, additional 
patients will be enrolled to a maximum of 10 patients. If no clinical responses are observed, the 
study will be stopped for futility. If a clinical response is observed at any time, then enrollment 
of the full expansion cohort may proceed. Initiation of the KPT-9274 + niacin ER escalation will 
not be dependent upon demonstration of clinical benefit of the single agent, but futility at the 
KPT-9274 + niacin ER RP2D will be assessed prior to full expansion using the same criterion as 
described above for the single agent KPT-9274.  
The KPT-9274 ± niacin ER expansion cohort will consist of 4 groups of approximately 
45 patients (please note that these expansion groups may change based on escalation results) 
including: 
• NAPRT1 deficient tumor group, approximately 10 patients 
• NAPRT1 positive tumor group, approximately 10 patients 
• Either NAPRT1 deficient or positive tumor group, approximately 10 patients 
• IDH1 mutant tumor group, approximately 15 patients 
Please note that the composition of the expansion groups (e.g. number of patients with NAPRT1 
positive vs NAPRT1 deficient tumors) may change based on the results from the escalation 
phase. 
An additional, optional KPT-9274 single agent expansion cohort will consist of < 20 patients 
with any tumor mutational status. 

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Patients in the Dose Expansion Phase may be treated with the RP2D of KPT-9274 ± niacin ER 
according to the same schedule administered in the Dose Escalation Phase of the study.  
Patients who are in Part A or Part B of the Dose Escalation Phase being treated at the RP2D 
± niacin ER dose chosen for expansion will be included in the efficacy and safety analyses of the 
Dose Expansion Phase. 
6.2.8. 
KPT-9274 Dose Reduction Guidelines for Toxicity 
For Grade 2 toxicities present at baseline, the drug will not be held and the treating investigator 
will closely monitor and support the patient. 
Patients are expected to be aggressively treated to minimize the likelihood and/or severity of side 
effects at the discretion of the Investigator (consultation with the Karyopharm Medical Monitor 
is strongly encouraged), particularly GI symptoms and hematopoietic toxicities as observed in 
KPT-9274 animal toxicology studies. See Section 6.9.1 for supportive care details. 
For patients who do not tolerate the protocol-specified dosing schedule, KPT-9247 dose 
adjustments are permitted in order to allow the patient to continue the study treatment. The criteria 
for dose modifications of KPT-9274 for toxicities are outlined in Table 15. These changes must 
be recorded on the eCRF. If a patient requires a dose delay of more than 28 days (> 28 days) from 
the intended day of the next scheduled dose, then the patient should be discontinued from the study 
(in exceptional situations, if the patient is clearly benefiting from the study treatment, and in the 
opinion of the Investigator no safety concerns are present, after discussion with the Karyopharm 
Medical Monitor, the patient may remain in the study). 
If, after interruption of treatment and resolution of the event, treatment is resumed at the same dose 
and the same toxicity reoccurs with the same severity, the next treatment re-initiation must resume 
at the next lower dose level, irrespective of duration. Patients who do not recover (i.e., ≤ Grade 1 
or baseline) within 28 days (≤ 28 days) of discontinuation of study treatment will not be permitted 
to re-start study treatment and will be discontinued from the study. 
In the event of a DLT (Cycle 1) during the Dose Escalation Phase the patient must discontinue 
KPT-9274. 
In the event of any other toxicity (< Grade 3) during the Dose Escalation Phase, one of the 
following actions may be taken at the Investigator’s discretion after consulting with the 
Karyopharm Medical Monitor: 
• Patients can continue treatment with KPT-9274 without a dose delay or reduction. 
• If the decision is made to hold KPT-9274: 
o Patients may be re-started on KPT-9274 either at the original dose OR at one dose 
level lower upon recovery to Grade ≤ 1 or baseline (see Table 15 for pre-specified 
dose modifications for AEs and Table 16 for dose modification guidelines for 
KPT-9274). 
For the Dose Expansion Phase, if an event meeting the definition of a DLT, but without 
necessarily occurring within the first 28 days, is observed in > 33% of patients at any time, or if 
> 33% of treated patients have withdrawn consent due to toxicity, enrollment will be held and a 
meeting with all investigators and Karyopharm/Medical Monitor will take place to review the 

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events and discuss their clinical significance. Based on this review, the sponsor may elect to 
reduce the dose for enrolled patients and to resume enrollment of the expansion cohort at this 
lower dose, or the enrollment into the expansion cohort will may be stopped. 
Table 15 summarizes the pre-specified dose modifications (i.e., Dose Levels 1 through 5+) for 
AEs listed in Table 16. 
Table 15: Pre-specified Dose Modifications for Adverse Events  
Dose Level 
KPT-9274 Dose (mg) (Dose Escalation, Part A and Part B)* 
5+ 
Increase in 20 mg increments 
4 
40 mg 
3 
30 mg 
2 
20 mg 
1 
10 mg 
*From the RP2D, patients will be dose reduced by 1 dose level increments as needed as in 
Table 16. 
For dose reduction, find the current dose in Table 15 and reduce as indicated in Table 16.  

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Table 16: KPT-9274 Dose Modification and Supportive Care Guidelines 
Toxicity and 
Intensity 
Dose Modification 
Non-hematologic Toxicity 
Grade 1 
Maintain dose. 
Consider instituting supportive care medications per institutional guidelines. For 
additional options, see NCCN Clinical Practice Guidelines in Oncology for Fatigue, 
Palliative Care, and Antiemesis, also refer to Benson guidelines). 
Grade 2 
Institute supportive care medications per institutional guidelines. For additional options, 
see NCCN Clinical Practice Guidelines in Oncology for Fatigue, Palliative Care, and 
Antiemesis, (also refer to Benson Guidelines). 
For Grade 2 toxicities, the Investigator should consult with the Karyopharm Medical 
Monitor when deciding on treatment delays or modifications. If modifications are 
desired, guidelines for AEs ≥ Grade 3 should be followed. At the Investigator’s 
discretion after consulting with the Karyopharm Medical Monitor, patients may continue 
on KPT-9274 uninterrupted at their current dose. 
 Grade 3 
Optimal supportive care medications according to institutional guidelines or NCCN 
Clinical Practice Guidelines in Oncology should already be instituted. Also refer to 
Benson Guidlines. 
Hold KPT-9274 until the event resolves to ≤ Grade1 or baseline (as appropriate): 
• 
First occurrence of  Grade 3: 
o 
If supportive care results in the AE improving to Grade 1 or baseline 
within 3 days ( 3 days), restart KPT-9274 at the current dose. 
o 
If the improvement to Grade  1 or baseline takes longer than 3 days 
(> 3 days), KPT-9274 should be resumed at one dose level lower (see 
Table 15). 
• 
Second or greater occurrence of  Grade 3, restart KPT-9274 at one dose level 
lower (see Table 15) upon improvement to Grade  1 or baseline irrespective of 
duration. 
**If the toxicity does not resolve to ≤ Grade 1 or baseline within 28 day ( 28 days), 
study treatment will be discontinued permanently. 
**If, after interruption of treatment and resolution, treatment is resumed at the same 
dose and the same toxicity reoccurs with the same severity, next treatment re-initiation 
must resume at the next lower dose level, irrespective of duration. 

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Toxicity and 
Intensity 
Dose Modification 
Hematological Toxicity 
Thrombocytopenia 
Grade 2 
Maintain dose  
 Grade 3 without 
bleeding 
Follow institutional guidelines for Grade 3 or 4 thrombocytopenia without bleeding. 
Transfusions are allowed per institutional guidelines.  
Hold KPT-9274 until resolves to ≤ Grade 1 or baseline (maximum of 28 days, 
 28 days): 
• 
First occurrence of  Grade 3: 
o 
If improves within 7 days ( 7 days), restart KPT-9274 at the current 
dose. 
o 
If the improvement takes longer than 7 days (> 7 days), KPT-9274 
should be resumed at one dose level lower. (see Table 15). 
• 
Second or greater occurrence of  Grade 3, restart KPT-9274 at one dose level 
lower (see Table 15) upon improvement to Grade 1 or baseline irrespective of 
duration. 
**If the toxicity does not resolve to ≤ Grade 1 or baseline within 28 days ( 28 days), 
study treatment will be discontinued permanently. 
**If, after interruption of treatment and resolution, treatment is resumed at the same 
dose and the same toxicity reoccurs with the same severity, next treatment re-initiation 
must resume at the next lower dose level (see Table 15), irrespective of duration.  
 Grade 3 with 
bleeding 
Follow institutional guidelines for Grade 3 or 4 thrombocytopenia with bleeding. 
Transfusions are allowed per institutional guidelines.  
Hold KPT-9274 until resolves to Grade  1 or baseline and restart at one dose level 
lower (see Table 15). 
Neutropenia 
 Grade 3 
neutropenia without 
fever 
Implement growth factors per institutional guidelines. 
Hold KPT-9274 until resolves to Grade  1 or baseline and restart at one dose level 
lower (see Table 15). 
 Grade 3 
neutropenia with 
fever (febrile 
neutropenia) 
Implement growth factors and broad anti-microbial coverage per institutional guidelines. 
Hold KPT-9274 until the event resolves to Grade  1 or baseline and restart at one dose 
level lower (see Table 15). 
All other hematologic Toxicity 
Grade 1 or 2 
Maintain dose 
 Grade 3 
Implement growth factors and broad anti-microbial coverage per institutional guidelines. 
Transfusions (e.g., RBCs for anemia) are allowed per institutional guidelines. 
Consider holding KPT-9274 until the event resolves to Grade  1 or baseline and restart 
at one dose level lower (see Table 15). At the discretion of the Investigator after 
consulting with the Karyopharm Medical Monitor, patient may be treated with 
KPT-9274 without dose delays or modifications while receiving transfusions and/or 
growth factor support per institutional guidelines. 
All dose modifications should be based on the worst preceding toxicity. 
*Isolated values of ≥ Grade 3 alkaline phosphatase values will NOT require dose interruption. Determination of 
liver vs. bone etiology should be made, and evaluation of gamma-glutamyl transferase (GGT), 5'-nucleotidase 
(5’NT), or other liver enzymes should be performed. 
Note: for combinations of Grade 1 or 2 adverse events (e.g., nausea, fatigue, anorexia) that significantly impair 
the patient’s quality of life, 1-2 doses of study treatment may be skipped after consultation with the Karyopharm 
Medical Monitor and supportive care per institutional guidelines has been implemented. Study treatment may 
then be restarted after consultation with the Karyopharm Medical Monitor. 
Benson AB, Ajani JA, Catalano RB, et al. 

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6.2.8.1.1. Conditions Not Requiring KPT-9274 Dose Reduction 
The following conditions are exceptions to the dose-modification guidelines. KPT-9274 does not 
need to be held in the following cases: 
• Alopecia of any grade. 
• Electrolyte or serum analyte (e.g., urate) abnormalities that are reversible with standard 
interventions. 
6.2.8.1.2. Dose Holds or Reductions for Nivolumab (Part C) 
• Dose reductions are not allowed for nivolumab. Consult the product label for dose holds. 
6.2.9. 
Missed or Vomited Doses   
6.2.9.1. 
Missed Doses of Study Treatments 
If a dose must be skipped (e.g., due to recommendation of Investigator), the next dose will be 
taken as per schedule; all missed doses should be documented. 
6.2.9.2. 
Vomited Doses of Study Treatments 
If a dose is vomited within 1 hour of ingestion, it will be replaced. If vomiting occurs more than 
1 hour after dosing, it will be considered a complete dose. 
6.3. 
Study Treatment Storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, KPT-9274 and niacin ER should be stored according to 
the instructions specified on the drug labels and in the IB for KPT-9274. Nivolumab should be 
stored according to the package label. 
6.4. 
Study Treatment Accountability 
The Investigator or designee must maintain an accurate record of the shipment and dispensing of 
study treatment in a drug accountability log. Study treatment accountability will be noted by the 
clinical research associate during site visits and at the completion of the study. Patients will be 
asked to return all unused study treatment and packaging on a regular basis, at the end of the 
study or at the time of study treatment discontinuation. 
KPT-9274 should not be used for any purpose outside the scope of this protocol, nor may 
KPT-9274 be transferred or licensed to any party not participating in the clinical study. 
6.5. 
Selection and Timing of Dose for Each Patient 
The rationale for the dose to be used is provided in Section 1.3.1. Guidelines for modifying the 
dose of KPT-9274, if needed due to AEs, are given in Table 16. 

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6.6. 
Method of Assigning Patients to Treatment Groups 
During the Dose Escalation Phase, assignment of a patient to a particular cohort will be 
coordinated by Karyopharm. Patients will be enrolled in the Dose Expansion Phase based on 
Investigator judgment and availability within the cohort. Patients may be enrolled in any actively 
enrolling cohort. 
6.7. 
Blinding 
Not applicable, this is an open-label study. 
6.8. 
Compliance 
The Investigator or other study staff will either directly administer or supervise study treatment 
given in the clinic and instruct the patient on study medication self-administration, as 
appropriate. Patients will be provided with a take home diary to complete on home dosing days; 
the patient diary will be reviewed at each clinic visit. 
Patients will be asked to bring their study medication containers with them at each visit and 
compliance with protocol-defined study treatment intake will be checked by tablet count.  
Compliance to study medication will be assessed by the Investigator at each visit and recorded in 
source documents after discussion with the patient and performing drug accountability. Dates 
will be recorded as per study treatment schedule. The Investigator will account for the number of 
tablets dispensed against those returned by the patient. Any deviations and missed doses will be 
recorded in the eCRF.  
The Investigator will try to ensure complete compliance with the dosing schedule by providing 
timely instructions to the patients. In case of non-compliance, the patients will be instructed 
again. 
6.9. 
Supportive Care, Contraception Requirements, and Concomitant 
Medications 
6.9.1. 
Supportive Care 
Patients are expected to be aggressively treated to minimize the likelihood and/or severity of side 
effects at the discretion of the Investigator (consultation with the Karyopharm Medical Monitor 
is strongly encouraged), including hematologic and musculoskeletal (arthralgias and myalgias) 
symptoms observed in humans. 
Supportive care including anti-nausea/anti-emetic therapy, acid suppression (e.g., PPIs ± H2 
blockers), anti-diarrheal therapy, and other standard treatments may be administered as per 
institutional guidelines for symptomatic patients. For additional options, please see NCCN 
Supportive Care Clinical Practice Guidelines in Oncology. Note: the use of PPIs is allowed in all 
patients but the Investigator must consult with the Karyopharm Medical Monitor prior to their use 
in patients receiving niacin ER. If any deficiencies in vitamin B12, folate, iron, erythropoietin, or 
transferrin are observed, then standard medical practice for their replacement should be instituted. 

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Anemia appears to be dose dependent and should be treated with dose interruption, dose 
reduction, use of growth factors (i.e., erythropoietins), and/or transfusions.  The addition of 
niacin ER (up to 2,000 mg daily dose, per label) willwill be allowed after completion of the DLT 
period in cycle 1 (first 28 days) in an attempt to offset potential side effect (i.e. anemia, 
arthralgias, myalgias, etc.) of KPT-9274. After Week 8, niacin may be titrated, as per label, to 
patient response and tolerance. If response to 1000 mg daily is inadequate, increase dose to 1500 
mg daily; may subsequently increase dose to 2000 mg daily. Daily dose should not be increased 
more than 500 mg in a 4-week period, and doses above 2000 mg daily are not recommended. 
Women may respond at lower doses than men.  
Arthralgia should be treated with non-steroidal anti-inflammatory drug (NSAIDs), 
cyclooxygenase-2 (COX-2) inhibitors, acetaminophen, tramadol, and/or low-dose steroids. 
Myalgia and flu-like illness should be treated with KPT-9274 dosing at night, acetaminophen 
(including pre-treatment with acetaminophen), NSAIDs, COX-2 inhibitors, and/or low-dose 
steroids. Consultation with the Karyopharm Medical Monitor is recommended for questions 
regarding these recommendations. 
For additional information on supportive care recommendations for events such as anemia, 
arthralgias, and myalgias see the current version of the IB as well as Section 7.5.2 and 
Section 7.5.3). 
6.9.2. 
Non-study Related Concomitant Medication and Treatment 
No significant inhibition of any of the CYP450 enzymes were observed after KPT-9274 
treatment. Weak induction of CYPs 1A2, 2B6, and 3A4 were observed in an exploratory 
pre-clinical study after KPT-9274 treatment; however, it is unlikely that a potential drug-drug 
interaction will occur in a clinical setting. Therefore, the use of any concomitant 
medication/therapy (except medications listed in the prohibited medications section, see 
Section 6.9.3), including over-the-counter (OTC) medications (excluding herbal supplements, 
dietary supplements), deemed necessary for the care of the patient is permitted during the study.  
6.9.2.1. 
Permitted Concomitant Medication 
Medications required to treat AEs, manage cancer symptoms, concurrent stable diseases and 
supportive care agents (e.g., blood product transfusions [see Section 6.9.2.6], antibiotics with [if 
appropriate] granulocyte-colony stimulating factors [G-CSF] for neutropenic infection), pain 
medications, anti-emetics, and anti-diarrheals are allowed. Concurrent therapy with growth 
factors is allowed. The use of any immunosuppressive agents must be discussed between the 
Investigator and the Karyopharm Medical Monitor on a case-by-case basis. The addition of 
niacin ER (up to 2,000 mg daily dose, per label) is allowed after completion of the DLT period in 
cycle 1 (first 28 days) in an attempt to offset potential side effect (i.e. anemia, arthralgias, 
myalgias, etc.) of KPT-9274. 
Note: the use of PPIs is allowed in all patients, but the Investigator must consult with the 
Karyopharm Medical Monitor prior to their use in patients receiving niacin ER. 
Hormonal contraceptives are permitted in women of child-bearing potential. Hormonal 
contraceptives include any marketed contraceptive agent that includes an estrogen and/or a 

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progestational agent. Since the effect of KPT-9274 on oral contraceptives is unknown at this 
time, it is recommended that patients use at least 2 forms of contraceptives while on study. 
Additionally, the nivolumab product label will be consulted to obtain the permitted concomitant 
medications for patients in Part C (the KPT-9274 + nivolumab). 
6.9.2.2. 
Prevention of Pregnancy 
Patients should not become pregnant or father a child while on this study because it is unknown 
whether KPT-9274 can affect an unborn baby. Women should not breastfeed a baby while on this 
study. It is important that patients understand the need to use birth control while on this study. 
Female patients of child-bearing potential must agree to use dual methods of contraception and 
have a negative serum pregnancy test at Screening; male patients must use an effective barrier 
method of contraception if sexually active with a female of child bearing potential. 
The use of two forms of contraception are required, including one highly effective and one 
effective method of contraception, from the following lists. 
• Highly effective methods include:  
− Hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, 
injectables, and implants)  
− Intrauterine device (IUD) or intrauterine system (IUS)  
− Vasectomy and tubal ligation 
• Effective methods include:  
− Barrier methods of contraception (e.g., male condom, female condom, cervical cap, 
diaphragm, contraceptive sponge)  
Notes: 
o No barrier method by itself achieves a highly effective standard of 
contraception 
o The proper use of diaphragm or cervical cap includes use of spermicide and is 
considered one barrier method. 
o The cervical cap and contraceptive sponge are less effective in parous women. 
o The use of spermicide alone is not considered a suitable barrier method for 
contraception. 
o When used consistently and correctly, “double barrier” methods of 
contraception (e.g., male condom with diaphragm, male condom with cervical 
cap) can be used as an effective alternative to the highly effective contraception 
methods described above. 
o Male and female condoms should not be used together as they can tear or 
become damaged. 
Acceptable methods of contraception also include: 
• A sexual partner who is surgically sterilized or post-menopausal.  
• Total (true) abstinence (when this is in line with the preferred and usual lifestyle of the 
patient), is an acceptable method of contraception. Periodic abstinence (e.g., calendar, 

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ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  
For both male and female patients, effective methods of contraception must be used throughout 
the study and for 3 months following the last dose. 
See Section 1.2.2 for additional safety information related to pregnancy. 
6.9.2.3. 
Radiation Therapy 
Palliative radiation therapy to non-target lesions is permitted but study treatment should be held 
for ≥1 day before the start of palliative radiation therapy and ≥1 day following each dose of 
palliative radiation therapy. Treatment with KPT-9274 shall not be discontinued solely due to 
palliative radiation. 
6.9.2.4. 
Hormone Ablation Therapy to Treat Advanced Prostate Cancer 
Conventional hormone ablation therapy (HAT) is permitted while on study; however, patients 
receiving HAT prior to the start of the study must not terminate HAT within 6 weeks prior to 
C1D1; termination of HAT during this study must be discussed with the sponsor. 
6.9.2.5. 
Glucocorticoid Therapy 
Glucocorticoids ≥10 mg oral prednisone (or equivalent) per day are not permitted at baseline; 
however physiological doses 10 mg oral prednisone (or equivalent) for non-malignant 
conditions (e.g., asthma, IBD, etc.) are permitted as needed.  
As part of supportive care (e.g., for nausea or anorexia), oral dexamethasone, up to 40 mg/week, 
may be given to patients. 
6.9.2.6. 
Use of Blood Products 
During treatment, patients may receive RBC or platelet transfusions per institutional guidelines. 
Patients who require repeated transfusion support should be discussed with the Karyopharm 
Medical Monitor. 
Appropriate anti-coagulation is allowed during the study (e.g., low molecular weight heparin, 
direct factor Xa inhibitors, etc.). Warfarin is allowed during the study provided patients are 
monitored for international normalized ratio (INR) twice a week during the first 2 cycles of 
therapy, then weekly to biweekly thereafter. 
Patients may receive supportive care with erythropoietin, darbepoetin, G-CSF or granulocyte 
macrophage-colony stimulating factor (GM-CSF), pegylated growth factors, and platelet 
stimulatory factors, in accordance with clinical practice or institutional guidelines prior to entry 
and throughout the study. 
6.9.3. 
Prohibited Concomitant Medications 
The use of niacin or niacin-containing supplements (e.g., multivitamins and energy drinks) is not 
allowed in cycle 1 of the Part A KPT-9274 only cohorts in the Dose Escalation or Expansion 
Phases. However, for patients in these cohorts that have cleared DLT in cycle 1, niacin ER (up to 
2,000 mg co-administered with KPT-9274) may be used as supportive care in an attempt to 

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offset potential side effects (e.g. anemia, arthralgias, myalgias, etc.) of KPT-9274. Prior to 
initiating niacin ER, patient symptoms and laboratory values should be reviewed and discussed 
with the Medical Monitor for this study. 
Investigational or commercial anticancer agents other than KPT-9274 are not allowed during the 
study. The initiation of any non-protocol specific anti-tumor treatment is considered an 
indication of disease relapse/progression and should be recorded appropriately in the eCRFs. 
There are exceptions including localized palliative radiation (see Section 6.9.2.3), hormonal 
contraception for the prevention of pregnancy (see Section 6.9.2.2), hormonal therapy for 
patients with prostate cancer (see Section 6.9.2.4), and blood products/growth factors (see 
Section 6.9.2.6). For other possible cases, please consult the Karyopharm Medical Monitor. 

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7. 
ASSESSMENTS 
7.1. 
Informed Consent 
Study-specific assessments may not be performed until the patient provides written informed 
consent (see Section 10.4). 
7.2. 
Demographic and Baseline Characteristics Assessments 
7.2.1. 
Demographics 
Patient demographics (including date of birth, sex, race, ethnicity, and age at time of consent) 
will be collected at study entry. 
7.2.2. 
Medical History 
A complete medical history will be obtained from each patient. Medical history will include 
baseline symptoms of the disease under study as well as a detailed history of prior procedures for 
the patient’s NHL or advanced solid malignancy and other prior cancer therapies (i.e., 
chemotherapy, hormonal therapy, immunotherapy, biotherapy, radiotherapy, and surgery), 
including start and end dates, best response, disease progression during or after therapy, as well 
as discontinuations due to intolerability, toxicity, or any other serious illness; Tumor Nodes 
Metastasis (TMN) staging will be collected on for patients with advanced solid malignancies. 
Smoking history will be recorded. A detailed history of disease-specific diagnostic and 
prognostic testing and test results (such as phenotypic and cytogenetic profiles) will also be 
collected. 
7.2.3. 
Disease Risk Assessment (NHL patients only) 
Disease risk assessment will be performed according to the Revised International Prognostic 
Index (R-IPI; Sehn, 2007) for NHL patients only. 
7.2.4. 
Baseline Characteristics and Determination of Eligibility 
Baseline characteristics will include ECOG performance status, duration from initial diagnosis, 
response to previous therapy, types of prior therapy, and height/weight. 
Inclusion/exclusion criteria will be reviewed to determine eligibility. 
Patients with known active HAV, HBV, HBC, or HIV infection will be excluded from this study. 
However, testing for these viruses is not required as part of this study. 
7.2.5. 
Determination of NAPRT1 and IDH1 Tumor Status 
NAPRT1 and IDH1 tumor status for Parts A and B must be determined prior to enrollment in the 
KPT-9274 ± niacin ER escalation and expansion cohorts. Archival biopsy material obtained ≤ 6 
months prior to screening may be used to prescreen patients for NAPRT1 and IDH1 tumor 
status. A fresh biopsy will be collected during screening to determine or confirm that NAPRT1 
and IDH1 tumor status. Screening period includes Day -30 to Day 7 prior to C1D1. Additional 
details are provided in Section 7.4.3.3. 

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7.2.6. 
Determination of Patients with Melanoma Who Progressed on Prior Anti-PD-1 
or Anti-PD-L1 Treatment  
Patients with melanoma who progressed on prior anti-PD-1 or anti-PD-L1 treatment must be 
determined prior to enrollment in Part C - KPT-9274 + nivolumab. Screening period includes 
Day -30 to Day -1 prior to C1D1. 
 
7.3. 
Efficacy Assessments 
7.3.1. 
Non-Hodgkin’s Lymphoma and Advanced Solid Malignancy Assessments 
7.3.1.1. 
Quality of Life 
QoL will be assessed using the European Organization for Research and Treatment of Cancer 
(EORTC) QLQ-C30 Questionnaire for all patients and the Functional Assessment of Cancer 
Therapy and Lymphoma (FACT-Lym) Questionnaire (Webster, 2005) for patients with NHL. 
The QoL assessments will be performed at Screening before undergoing any study procedures 
(including discussions with medical personnel and administration of study treatment) on Day 1 
of each cycle and at the EoT Visit. 
The EORTC QLQ-C30 is a validated, patient self-administered instrument for assessing the 
health-related QoL of cancer patients participating in international clinical trials. It is a 
questionnaire containing both multi-item and single scales, including five functional scales 
(physical, role, emotional, social and cognitive), three symptom scales (fatigue, nausea & 
vomiting and pain) and a global health status/QoL scale and six single items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties). 
NHL patients only: The FACT-Lym combines the General version of the Functional Assessment 
of Cancer Therapy (FACT-G) with a lymphoma-specific subscale (15 items). The subscales for 
the FACT-G are Physical Well-Being (7 items), Social/Family Well-Being (7 items), Emotional 
Well-Being (6 items), and Functional Well-Being (7 items). The trial outcomes index (TOI; total 
of 29 items) will be the primary measurement of interest, comprised of the Physical and 
Functional subscales plus the lymphoma-specific subscale. Each item is rated on a 5-point Likert 
scale, ranging from 0 (=“Not at all”) to 4 (=”Very much”), therefore the TOI has a score ranging 
from 0 to 116. 
7.3.2. 
Non-Hodgkin’s Lymphoma Only Assessments 
Patient response will be assessed by the procedures described in the following subsections and 
graded according to the Lugano Classification (NHL) summarized in Appendix 3. 
7.3.2.1. 
PET-CT (or CT) Scan 
Disease response will be preferably based on tumor measurement using PET/CT for FDG-avid 
lymphomas, or CT for non-FDG-avid lymphomas (or PET/MRI or MRI if CT is contraindicated) 
scans. Scans will be conducted at Screening (Day -30 to Day -1) and after every 8 weeks ± 

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7 days (e.g., Day 1 of odd numbered cycles) until disease progression or the EoT visit. EoT scan 
is only required for patients who end treatment for reasons other than disease progression. The 
same scan modality should be used for all assessments. PET/CT for FDG-avid lymphomas or CT 
for non-FDG-avid lymphomas (or PET/MRI or MRI if CT is contraindicated) is strongly 
preferred. 
7.3.2.2. 
Bone Marrow Aspirate and/or Biopsy 
Bone marrow biopsies and/or aspirates will be taken within 30 days prior to first dose (baseline) 
to assess NHL involvement in bone marrow. The bone marrow biopsy will be repeated whenever 
clinically indicated, at the discretion of the Investigator, to confirm CR/PR only in those patients 
who had NHL with known bone marrow involvement prior to dosing. 
7.3.3. 
Advanced Solid Malignancy Only Assessments 
Patient response will be assessed by the procedures described in the following subsections and 
graded according to RECIST 1.1 (Appendix 4). 
7.3.3.1. 
CT, MRI, PET-CT, or Imaging Methodology Per Investigator Discretion 
Disease response is based on tumor measurement using computed tomography (CT) scans or, 
magnetic resonance imaging (MRI) scans, or PET-CT, or imaging methodology per Investigator 
discretion. Scans will be performed at Screening (Day -30 to Day -1), then every 8 weeks ± 7 
days (e.g., Day 1 of odd numbered cycles) until disease progression or the EoT visit. EoT scan is 
only required for patients who end treatment for reasons other than disease progression. 
The same scan modality should be used for all assessments. 
7.4. 
Pharmacokinetic Assessments 
7.4.1. 
PK Sampling for KPT-9274 
Parts A and B 
PK sampling will be performed in all patients receiving KPT-9274. 
•
PK samples will be collected for all patients at PK time points listed in Table 17 except
on C1D24 at 4, 12, 18, and 32 hours post-dose; PK samples on C1D24 at 4, 12, 18, and
32 hours post-dose will only be collected for the first 18 patients enrolled in the
expansion phase (see Section 3.1).
Blood draws (using 2 mL/K2EDTA purple top tubes) for PK analysis will be performed as 
described in Table 17. 
Details of PK sample collection and processing can be found in the Laboratory Manual. 
Plasma samples will be analyzed via validated high performance liquid chromatography/tandem 
mass spectrometry (HPLC/MS-MS) methods for plasma KPT-9274 concentrations. 
PK parameters may include, but are not limited to, estimations of Cmax, AUC, tmax, t½, Vd/F, and 
CL/F.  
Patients must attend the clinic for PK sampling that occurs on non-dosing days. 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 8 6  
Versi o n  5 . 0 
If t he d ose is misse d, P K bl o o d dra ws will n ot be c ollecte d o n t hat da y.  
If a patie nt’s d ose is c ha n ge d, bl o o d sa m pli n g f or P K (as re q ueste d f or C 1 D 1) s h o ul d be re peate d 
o n t he first da y of d ose c ha n ge at t he sa me ti me p oi nts as descri be d f or C 1 D 1, C 1 D 2, a n d C 1 D 3.  
If a patie nt e x perie nces a n A E t hat fits t he criteria of a D L T as deter mi ne d b y t he I n vesti gat or i n 
eit her t he D ose Escalati o n or D ose E x pa nsi o n P hase, a n u nsc he d ule d P K bl o o d sa m ple s h o ul d be 
c ollecte d f or meas ure me nt of dr u g c o nce ntrati o ns. If a patie nt e x perie nces a st u d y treat me nt -
relate d A E t hat fits t he criteria of a S A E or disc o nti n ues fr o m t he st u d y treat me nt d ue t o st u d y 
treat me nt relate d t o xicities, a n u nsc he d ule d P K bl o o d sa m ple m ust be o btai ne d as s o o n as 
p ossi ble after t he last d ose of K P T -9 2 7 4 a n d t he date a n d ti me of last d ose rec or de d. 
A d diti o nall y, if at a n y ti me d uri n g t he st u d y a Q Tc > 5 0 0 msec has bee n de m o nstrate d b y 1 2 -lea d 
E C G, t he n a n u nsc he d ule d P K dra w s h o ul d be o btai ne d as cl ose t o t he ti me of t he re peat E C G as 
p ossi ble.  
P art C  
Starti n g fr o m C ycle 1 Da y 1  ( C 1 D 1), bl o o d will be dra w n at 0 h ( < 1 5 mi ns pri or t o d osi n g),  3  h 
± 1 5 mi ns, 6  h ± 3 0 mi ns , 8 h ± 3 0 mi ns, 2 4 h ± 6 0 mi ns, a n d 4 8 h ± 6 0 mi ns . C ycle 2 Da y 1  
( C 2 D 1), bl o o d will be dra w n at 0 h ( < 1 5 mi ns pri or d osi n g), 3  h ± 1 5  mi ns, , 6  h ± 3 0 mi ns , 8 h ± 
3 0 mi ns , 2 4 h ±  6 0 mi ns , a n d 4 8 h ± 6 0 mi ns  after C 2 D 1 d ose.  Ti me si nce last meal a n d a 
descri pti o n of t he meal c o nte nts will be re p orte d b y t he patie nt t o t he treati n g p h ysicia n pri or t o 
eac h P K bl o o d dra w. P K assess me nts are o utli ne d i n  Ta ble 1 8 . 
C CI
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 8 7  
Versi o n  5 . 0 
T a ble  1 7 : C ollecti o n Ti me P oi nts a n d S a m ple V ol u mes f or P K a n d 
 f or P art s A a n d B  
Ti me P oi nt  
T ot al 
V ol u me of 
Bl o o d 
( m L) 
N u m ber of T u bes b y V ol u me of Bl o o d  
Bi o ps y  
P K  
L y m p h N o de 
Bi o ps y a n d/ or 
T u m or Bi o ps y  
1 t u be x 2. 0 
m L  
 
Scree ni n g  
 
 
 
Bet wee n D -3 0 a n d 
D 7   
-- 
-- 
2 fres h 
bi o psies a n d 1 
f or mali n fi xe d 
bi o ps y  
C 1 D 1 (re pe at if 
p atie nt d ose 
c h a n ges)  
 
 
 
Pre -d ose ( < 1 0  mi n 
bef ore K P T -9 2 7 4 
d osi n g)  
1 3  
X  
-- 
0. 5 hr ( ± 5 mi n) 
p ost -d ose  
2  
X  
-- 
1 hr ( ± 1 0 mi n) 
p ost -d ose  
2  
X  
-- 
2  hr ( ± 1 0 mi n) 
p ost -d ose  
2  
X  
-- 
4 hr ( ± 2 0 mi n) 
p ost -d ose  
1 3  
X  
 
8 hr ( ± 3 0 mi n) 
p ost -d ose  
1 3  
X  
-- 
C 1 D 2 (re pe at if 
p atie nt d ose 
c h a n ges)  
 
 
 
2 4 hr ( ± 2 h o urs) 
after i nta ke of first 
d ose o n C 1 D 1  
1 3  
X  
-- 
C 1 D 3 (re pe at if 
p atie nt d ose 
c h a n ges)  
 
 
 
4 8 hr ( ± 2 h o urs) 
after i nta ke of first 
d ose o n C 1 D 1, 
pri or t o C 1 D 3 d ose  
1 3  
X  
-- 
C 1 D 8  
 
 
 
Pre -d ose ( < 1 0  mi n 
bef ore K P T -9 2 7 4 
d osi n g)  
1 3  
X  
-- 
2 hr ( ± 1 0  mi n) 
p ost -d ose  
2  
X  
-- 
C 1 D 1 5  
 
 
 
C CI
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 8 8  
Versi o n  5 . 0 
Ti me P oi nt  
T ot al 
V ol u me of 
Bl o o d 
( m L) 
N u m ber of T u bes b y V ol u me of Bl o o d  
Bi o ps y  
P K  
L y m p h N o de 
Bi o ps y a n d/ or 
T u m or Bi o ps y  
1 t u be x 2. 0 
m L  
 
Pre -d ose ( < 1 0 mi n 
bef ore K P T -9 2 7 4 
d osi n g)  
1 3  
X  
-- 
2 hr ( ± 1 0 mi n) 
p ost -d ose  
2  
X  
-- 
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 8 9  
Versi o n  5 . 0 
Ti me P oi nt  
T ot al 
V ol u me of 
Bl o o d 
( m L) 
N u m ber of T u bes b y V ol u me of Bl o o d  
Bi o ps y  
P K  
L y m p h N o de 
Bi o ps y a n d/ or 
T u m or Bi o ps y  
1 t u be x 2. 0 
m L  
 
C 1 D 2 4  
 
 
 
Pre -d ose ( < 1 0 mi n 
bef ore K P T -9 2 7 4 
d osi n g)  
1 3  
X  
-- 
2 hr ( ± 1 0 mi n) 
p ost -d ose  
2  
X  
-- 
4 hr ( ± 2 0 mi n) 
p ost -d ose 
( E x pa nsi o n P hase 
o nl y)  2 
2  
X  
 
8 hr ( ± 3 0 mi n) 
p ost -d ose  
1 3  
X  
-- 
1 2 hr ( ± 6 0  mi n) 
p ost -d ose 
( E x pa nsi o n P hase 
o nl y)  2 
2  
X  
 
1 8 hr ( ± 6 0  mi n) 
p ost -d ose 
( E x pa nsi o n P hase 
o nl y)  2 
2  
X  
 
C 1 D 2 5  
 
 
 
2 4 hr ( ± 2 h o urs) 
after i nta ke of d ose 
o n C 1 D 2 4  
1 3  
X  
-- 
3 2 hr ( ± 2 h o urs) 
after i nta ke of d ose 
o n C 1 D 2 4 
( E x pa nsi o n P hase 
o nl y) 2 
2  
X  
 
C 1 D 2 6  
 
 
 
4 8 hr ( ± 2  h o urs) 
after i nta ke of d ose 
o n C 1 D 2 4, pri or t o 
C 1 D 2 6 d ose  
1 3  
X  
2 fres h 
bi o psies a n d 1 
f or mali n fi xe d 
bi o ps y 1 
1 hr ( ± 1 0 mi n) 
p ost -d ose  
2  
X  
-- 
2 hr ( ± 1 0 mi n) 
p ost -d ose  
2  
X  
-- 
4 hr ( ± 2 0 mi n) 
p ost -d ose  
1 3  
X  
-- 
8 hr ( ± 3 0 mi n) 
p ost -d ose  
1 3  
X  
-- 
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 9 0  
Versi o n  5 . 0 
Ti me P oi nt  
T ot al 
V ol u me of 
Bl o o d 
( m L) 
N u m ber of T u bes b y V ol u me of Bl o o d  
Bi o ps y  
P K  
L y m p h N o de 
Bi o ps y a n d/ or 
T u m or Bi o ps y  
1 t u be x 2. 0 
m L  
 
C 2 D 1 5  
 
 
 
Pre -d ose ( < 1 0  mi n 
bef ore K P T -9 2 7 4 
d osi n g)  
2  
X  
-- 
2 hr ( ± 1 0 mi n) 
p ost -d ose  
2  
X  
-- 
C 3 D 1  
 
 
 
Pre -d ose ( < 1 0  mi n 
bef ore K P T -9 2 7 4 
d osi n g)  
1 3  
X  
-- 
2 hr ( ± 1 0  mi n) 
p ost -d ose  
2  
X  
-- 
2 4 hr ( ± 2 h o urs) 
after i nta ke of first 
d ose o n D 1  
1 3  
X  
-- 
D a y 1  of C ycle 5  
a n d Be y o n d O d d 
C ycles O nl y  
 
 
 
Pre -d ose ( < 1 0 mi n 
bef ore K P T -9 2 7 4 
d osi n g)  
1 3  
X  
-- 
2 4 hr ( ± 2 h o urs) 
after i nta ke of first 
d ose o n D 1  
1 3  
X  
-- 
C ycle 6 D a y 1 
a n d/ or at t he ti me 
of pr o gressi o n  
 
 
 
± 7 da ys  
-- 
 
2 fres h 
bi o psies a n d 1 
f or mali n fi xe d 
bi o ps y 1 
E n d -of -t her a p y 
 
 
 
± 7 da ys  
1 3  
X  
-- 
1 
F or t he bi o psies o n C 1 D 2 6 ( ±  7 da ys) a n d C 6 D 1 ( ±  7 da ys), patie nts will be all o we d t o c o nti n ue treat me nt if: 1) 
a patie nt ref uses t he bi o ps y, 2) i n t he o pi ni o n of t he treati n g p h ysicia n or p h ysicia n perf or mi n g t he bi o ps y t hat t he 
bi o ps y will p ose si g nifica nt ris k t o t he patie nt, or 3) if t he bi o ps y sa m p le o btai ne d o n first atte m pt is n ot a de q uate. 
2 
P K sa m ples  at t hese ti me p o i nts will o nl y be c ollecte d f or t he first 1 8 patie nts e nr olle d i n t he e x pa nsi o n p hase  
(see Secti o n 3. 1 ). 
 
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 9 1  
Versi o n  5 . 0 
T a ble  1 8 : C ollecti o n Ti me P oi nts a n d S a m ple V ol u mes f or P K a n d 
 f or f or P art C  
Ti me P oi nt  
T ot al V ol u me 
of Bl o o d ( m L)  
N u m ber of T u bes b y V ol u me of Bl o o d  
Bi o ps y  
P K  
T u m or Bi o ps y  
1 t u be x 2. 0 m L  
 
Scree ni n g  
 
 
 
Bet wee n D -3 0 
a n d D -1  
-- 
-- 
2 fres h bi o psies a n d 1 f or mali n 
fi xe d bi o ps y 
C 1 D 1  
 
 
 
Pre -d ose ( < 
1 5  mi n bef ore 
K P T -9 2 7 4 d osi n g)  
4. 5  
X  
-- 
3  hr ( ± 1 5  mi n) 
p ost -d ose  
2  
X  
-- 
6  hr ( ± 3 0  mi n) 
p ost -d ose  
2  
X  
-- 
8 hr ( ± 3 0  mi n) 
p ost -d ose  
2  
X  
-- 
C 1 D 2  
 
 
 
2 4 hr ( ±  6 0  mi n ) 
after i nta ke of first 
d ose o n C 1 D 1  
2  
X  
-- 
C 1 D 3  
 
 
 
4 8 hr ( ±  6 0  mi n ) 
after i nta ke of first 
d ose o n C 1 D 1, 
pri or t o C 1 D 3 
d ose  
2  
X  
-- 
C 2 D 1  
 
 
 
Pre -d ose ( < 1 5  
mi n bef ore K P T -
9 2 7 4 d osi n g)  
4. 5  
X  
2 fres h bi o psies a n d 1 f or mali n 
fi xe d bi o ps y1 
3 hr ( ± 1 5  mi n) 
p ost -d ose  
2  
X  
-- 
6  hr ( ± 3 0  mi n) 
p ost -d ose  
2  
X  
-- 
8 hr ( ± 3 0  mi n) 
p ost -d ose  
2  
X  
-- 
2 4 hr ( ±  6 0  mi n ) 
after i nta ke of first 
d ose o n D 1  
2  
X  
-- 
4 8  hr ( ±  6 0  mi n ) 
after i nta ke of first 
d ose o n D 1  
2  
X  
-- 
E n d -of -t her a p y 
 
 
2 fres h bi o psies a n d 1 f or mali n 
fi xe d bi o ps y1 
C CI
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 9 2  
Versi o n  5 . 0 
1.     F or t he bi o psies o n C 2 D 1  (±  7 da ys) a n d E o T  (±  7 da ys), patie nts will be all o we d t o c o nti n ue treat me nt if: 1) a 
patie nt ref uses t he bi o ps y, 2) i n t he o pi ni o n of t he treati n g p h ysicia n or p h ysicia n perf or mi n g t he bi o ps y t hat t he 
bi o ps y will p ose si g nifica nt ris k t o t he patie nt, or 3)  if t he bi o ps y sa m ple o btai ne d o n first atte m pt is n ot a de q uate. 
 
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
1 1 Marc h  2 0 2 0  
C o nfi de ntial 
P a ge 9 3  
Versi o n  5 . 0 
7. 5.  
S afet y Assess me nts  
Safet y e val uati o ns will be c o n d ucte d as descri be d bel o w. Refer t o  Ta ble 1 , Ta ble  2 , a n d Ta ble  3  
f or t he ti mi n g of all safet y assess me nts. 
7. 5. 1.  
Cli nic al S afet y Assess me nts  
7. 5. 1. 1.  
Wei g ht a n d Hei g ht   
Hei g ht ( wit h o ut s h oes) i n ce nti meters (c m) a n d wei g ht (i n d o or cl ot hi n g wit h o ut s h oes) i n 
kil o gra ms ( k g) will be meas ure d.  
7. 5. 1. 2.  
P h ysic al E x a mi n ati o n, Vit al Si g ns, a n d E C O G Perf or m a nce St at us  
P h ysical e xa mi nati o n m ust be perf or me d f or Parts A a n d B  as i n dicate d i n Ta ble 1, Ta ble 2, a n d 
Ta ble 3 a n d f or Part C as i n dicate d i n Ta ble 5, Ta ble 6, a n d Ta ble 7.  
T hese e xa mi nati o ns will be perf or me d acc or di n g t o t he sta n dar ds at eac h i nstit uti o n. T he 
p h ysical e xa mi nati o n will be perf or me d o n t he sche d ule d da y, e ve n if st u d y treat me nt is bei n g 
wit h hel d. M ore fre q ue nt e xa mi nati o ns ma y be perf or me d at t he discreti o n of t he i n vesti gat or a n d 
if me dicall y i n dicate d. If baseli ne/scr ee ni n g e xa mi nati o ns a re perf or m e d wit hi n 3 cale n dar da ys 
pri or t o t he first d ose of st u d y treatme nt, t he y nee d n ot be repeate d o n C 1 D 1 (e xce pt vital si g ns, 
w hic h m ust be c o n d ucte d o n C 1 D 1). 
C o m plete p h ysical e xa mi nati o ns s h o ul d i ncl u de ge neral a p peara nce, s ki n, nec k, e yes, ears, n ose, 
t hr oat, l u n gs, heart, a b d o me n, bac k, l y m p h n o des, e xtre mities, a n d ne ur ol o gica l e xa mi nati o ns.  
S y m pt o m- directe d p h ysical e xa mi nati o ns s h o ul d i ncl u de b o d y s yste ms as a p pro priate . T hese 
e xa mi nati o ns wi ll be perf or me d acc or di n g t o t he sta n dar ds at eac h i nstit uti o n. 
I nf or mati o n a b o ut t he p h ysical e xa mi nati o ns m ust be pre se nt i n t he so urce d oc u me ntati o n at t he 
st u d y site. T he res ults of t he p h ysical e xa mi nati o n pri or t o t he start of st u d y d osi n g m ust be 
i ncl u de d o n t he Me dical Hist or y e C R F. Cli nicall y rele va nt fi n di n gs m a de after t he start of st u d y 
d osi n g, w hic h meet t he defi niti o n of a n A E, m ust be rec or de d o n t he A E e C RF. 
Vital si g ns i ncl u de s yst olic a n d diast olic B P, p ulse me as ure me nts, a n d b o d y te m perat ure (° C or 
° F). Vital si g ns s h o ul d be assesse d pre- d ose o n t he sc he d ule d visit da y, if p ossi ble. B P a n d p ulse 
rate s h o ul d be meas ure d after t he patie nt ha s bee n i n a s u pi ne or sitti n g p ositi o n f or 5 mi n utes. 
B P s h o uld be assesse d o n t he sa me ar m t hro u g h o ut t he st u d y. 
E C O G perf or ma nce stat us assess me nts ( O ke n 1 9 8 2) will be perf or me d d uri n g t he st u d y t o assess 
h o w t he disease affects t he dail y li vi n g a bilities of t he pati e nts ( A p pe n di x 1). 
7. 5. 1. 3.  
Ec h oc ar di o gr a p h y a n d Electr oc ar di o gr a p h y  
A n ec h ocar di o gra m or m ulti ple gate d ac q uisiti o n ( M U G A) sca n t o assess car diac f u ncti o n a n d 
ris k of car diac d ysf u ncti o n, i ncl u di n g car di o m y o pat h y is re q uire d at Scree ni n g ( Da y -3 0 t o 
Da y -1) a n d at t he E o T Visit. A d diti o nal ec h ocar di o gra m or M U G A sca ns ma y be perf or me d 
C CI

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throughout the study if clinically indicated at the discretion of the Investigator. The same 
procedure (either MUGA or echocardiogram) should be performed at screening/baseline and 
subsequent visits. Preferably the same cardiologist/radiologist should read and report the 
outcome to minimize variability in results. Copies of all transthoracic echocardiograms and/or 
MUGA scans performed on subjects who experience a greater than or equal to 20% decrease in 
left ventricular ejection fraction (LVEF) from baseline and whose cardiac ejection fraction is 
below the institution’s lower limit of the normal range (LLN) will be required by Karyopharm 
for review. 
A single standard 12-lead ECG will be performed for patients in Part A and B. Patients must rest 
for at least 5 minutes prior to the ECG recording. The Investigator will interpret the ECG using 
one of the following categories: normal, abnormal but not clinically significant, or abnormal and 
clinically significant. The date and time the ECG is performed and the following parameters will 
be recorded in the eCRF: heart rate, PR interval, QT interval, QRS interval, and QT corrected 
using Bazett’s formula. 
7.5.1.4. 
Ophthalmic Examination 
For Parts A and B, an ophthalmic examination by an optometrist or ophthalmologist is required 
at Screening and the EoT Visit, and if clinically indicated (at the discretion of the Investigator) 
during the study (e.g., monitoring of pre-existing cataracts, visual disturbances). 
Patient reporting de novo or worsening of visual symptoms should immediately be referred for 
further examination. 
The ophthalmic examination is to include the following:  
• Prior to dilation: 
− best corrected visual acuity  
− slit lamp examination (for cataracts or other abnormalities) 
− tonometry 
• Following dilation:  
− fundoscopy 
− slit lamp examination to document lens clarity 
If a cataract/lens opacity is seen during the examination, the cataract/lens opacity will be graded 
according to a Grade 1-4 system.  
An ophthalamic examination is not required for patients enrolled in Part C, but may be 
performed at any time during the study if clinically indicated (at the discretion of the 
Investigator).  
7.5.1.5. 
Concomitant Medications 
Concomitant medications will be documented for each patient at each scheduled visit during the 
treatment phase. A detailed history of medications will be documented during Screening and 
C1D1. Subsequently, at each study visit, patients will be asked whether they have taken any 
medication other than the study treatment (from Screening through the EoT Visit). All 

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concomitant medications including dietary supplements, over-the-counter medications, and oral 
herbal preparations, as well as changes in medication, will be recorded on the eCRFs. 
Necessary supportive care such as appetite stimulants, anti-emetics, and anti-diarrheals, etc., are 
allowed (see Table 16 and Section 6.9.1). 
7.5.2. 
Rheumatology Consultation and Testing 
At the Investigator’s discretion, in consultation with the Karyopharm Medical Monitor, a 
rheumatological consultation is recommended for patients with clinically significant joint or 
muscle-related AEs. Rheumatology testing is recommended as clinically indicated and may be 
completed as clinically indicated per institutional standards (e.g., antinuclear antibodies, 
rheumatoid factor, C-reactive protein, erythrocyte sedimentation rate, uric acid [if not already 
available], or other autoantibodies based on symptoms). 
7.5.3. 
Hematology Consultation, Testing, and Biopsy 
At the Investigator’s discretion (after the screening assessment), in consultation with the 
Karyopharm Medical Monitor, a hematology consultation is recommended for patients with 
clinically significant hematological AEs, including any grade of treatment-emergent anemia or 
abnormal reticulocyte counts. Hematological testing (including but not limited to standard 
hematological evaluations and erythropoietin level) ± bone marrow biopsy may be performed as 
clinically indicated per institutional standards. In addition, assessments for vitamin B12, folate, 
iron, erythropoietin, haptoglobin, and transferrin levels and reticulocyte counts will be completed 
as described in Section 7.5.4.2. 
7.5.3.1. 
Adverse Events 
Information regarding AEs and SAEs will be collected. See Section 8. 
It is the responsibility of the Investigator to record and document all SAEs (occurring from the 
signing of the informed consent form [ICF]) and all AEs (occurring from the first dose of study 
treatment on C1D1) throughout the study and for 30 days after the last dose of study treatment. 
Each AE will be graded according to the CTCAE v4.03 at every visit (Section 8.1.3).  
7.5.4. 
Laboratory Safety Assessments 
7.5.4.1. 
Clinical Laboratory Tests 
Table 19 presents the clinical laboratory tests that will be performed during the study. 

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Table 19: Clinical Laboratory Tests (Parts A, B, and C Unless Indicated) 
Complete Blood Count with Differential (Blood sample: whole blood; ethylenediaminetetraacetic acid) tests 
including) 
Hemoglobin 
Hematocrit 
Mean corpuscular 
volume 
Mean corpuscular 
hemoglobin 
Mean corpuscular 
hemoglobin 
concentration 
WBC count 
WBC differential1
(Parts A and B 
Only) 
RBC count 
Lymphocytes 
Monocytes 
Neutrophils 
Band neutrophils 
(Parts A and B 
Only) 
Eosinophils 
Basophils 
Platelets 
Reticulocyte count 
Complete Serum Chemistry (Blood sample: serum) 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen 
Creatinine 
Glucose 
Calcium 
Phosphate 
Magnesium 
ALT 
AST 
Alkaline 
Phosphatase 
Total bilirubin2 
Lactate 
dehydrogenase 
Total protein 
Albumin 
Amylase3 
Lipase3 
Creatinine kinase 
Urate 
Thyroid-stimulating hormone3 
Coagulation 
Prothrombin time 
(Parts A and B 
Only) 
International 
normalization ratio 
(Parts A and B 
Only) 
Activated 
thromboplastin time 
(Parts A and B 
Only) 
Urinalysis4 
Appearance (Parts 
A and B Only) 
Color (Parts A and 
B Only) 
Urine bilirubin 
(Parts A and B 
Only) 
Glucose (Parts A 
and B Only) 
Hemoglobin (Parts 
A and B Only) 
Ketones (Parts A 
and B Only) 
pH (Parts A and B 
Only) 
Protein (Parts A and 
B Only) 
Specific gravity 
(Parts A and B 
Only) 
Urobilinogen (Parts 
A and B Only) 
1
2
3
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; RBC = red blood cell; ULN: 
upper limit of normal; WBC = white blood cell. 
 WBC differential may be automated or manual as per institutional standards. Blasts should be included. 
 If the total bilirubin concentration is increased > 1.5 × ULN, total bilirubin should be differentiated into the direct 
and indirect reacting bilirubin. 
 If not included in the complete serum chemistry panel at the site, amylase, lipase, and TSH must be performed 
at the time points indicated in Table 1, Table 2, and Table 3 for Parts A and B and Table 5, Table 6, and Table 7 
for Part C.  

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4 Microscopy will only be performed if clinically indicated at the discretion of the Investigator. Urinalysis is only 
required for Parts A and B. 
All laboratory safety assessments will be performed and analyzed at each site by a certified local 
laboratory. The Investigator or designee will review the laboratory results and assess the clinical 
significance of all abnormal values. Appropriate action will be taken for any clinically significant 
abnormal values. Values will be documented on the laboratory report until stabilized, or the 
laboratory value returns to a clinically acceptable range (regardless of relationship to study 
treatment) or baseline. 
In addition, laboratory safety assessments will be collected and analyzed on the scheduled day, 
even if study treatment is being withheld. More frequent assessments may be performed if 
clinically indicated, or at the Investigator’s discretion and these should be recorded on the 
Unscheduled Visit eCRFs. 
Any laboratory value that remains abnormal at the EoT Visit and that is considered clinically 
meaningful will be followed according to accepted medical standards for up to 30 days or until 
resolution of the abnormality or return to baseline. Toxicity will be graded using 
CTCAE Version 4.03.  
Karyopharm must be provided with a copy of the laboratory certification and normal ranges for 
each parameter measured. In addition, if at any time a patient has laboratory parameters obtained 
from a different outside laboratory, Karyopharm must be provided with a copy of the 
certification and normal ranges for that laboratory. 
7.5.4.2. 
Vitamin B12, Folate, Iron, Erythropoietin, Haptoglobin, and Transferrin Levels 
and Reticulocyte Counts 
Vitamin B12, folate, iron, erythropoietin, haptoglobin, and transferrin levels and reticulocyte 
counts will be assessed at Screening and the EoT Visit. Additionally, patients with treatment-
emergent anemia should have these analyte levels/counts assessed as soon as possible after onset. 
Patients with ≤ Grade 1 anemia should have their levels/counts assessed no less than once a 
month from and patients with ≥ Grade 2 anemia should have their levels/counts assessed every 
2 weeks from onset. A hematology consultation is recommended as appropriate (see 
Section 7.5.3). Supportive care recommendations for deficiencies in these analytes are noted in 
Section 6.9.1.  
7.5.4.3. 
Pregnancy Testing 
For females of childbearing potential, a negative serum human chorionic gonadotropin (hCG) 
pregnancy test must be obtained < 3 days prior to Cycle 1 Day 1 and at the EoT Visit. Test 
sensitivity for hCG must be ≥ 25 mIU/mL. Pregnancy testing is to be performed as clinically 
indicated at the discretion of the Investigator during the study. 
7.6. 
Other Assessments 
7.6.1. 
Collection of Information on Antineoplastic Therapy 
Information on any antineoplastic therapies used after discontinuation of study treatment will be 
collected.  

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8. 
SAFETY DEFINITIONS, RECORDING, AND REPORTING 
Note: For urgent medical issues in which the Karyopharm Medical Monitor should be contacted, 
please refer to the Study Manual for complete contact information. 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
• Adverse event (AE): Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of 
study treatment, whether or not considered related to the study treatment.  
• Treatment-emergent adverse event (TEAE): Any event that was not present prior to 
the initiation of study treatment or any event already present that worsens in either 
intensity or frequency following exposure to study treatment.  
• Serious adverse event (SAE): Any untoward medical occurrence that, at any dose, 
results in death; is life threatening (i.e., an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe); requires inpatient hospitalization or 
prolongation of existing hospitalization; results in persistent or significant 
disability/incapacity; or is a congenital anomaly/birth defect. (See Section 8.2.2 for 
additional information about SAE reporting.)  
8.1.2. 
Recording of Adverse Events 
Adverse Events will be reported and recorded in the eCRF from the time of the first dose of 
study drug through 30 days after the last dose of study drug or until the start of subsequent 
antineoplastic therapy, whichever occurs first. That is, if a patient begins a new antineoplastic 
therapy, the AE reporting period for nonserious AEs ends at the time the new treatment is 
started.  
Adverse events (including laboratory abnormalities that constitute AEs) should be described 
using a diagnosis whenever possible, rather than individual underlying signs and symptoms. 
When a clear diagnosis cannot be identified, each sign or symptom should be recorded as a 
separate AE. 
The Investigator should ask the patient non-leading questions to determine if any AEs have 
occurred during the study, since the last study visit. Adverse events may also be recorded when 
they are volunteered by the patient, or through physical examination, laboratory tests, or other 
clinical assessments. 
An AE should be followed, and an assessment should be made at each visit (or more frequently, 
if necessary) for any changes in severity of the event, the suspected relationship to the study 
treatment, the interventions required to treat the event, and the outcome.  

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All AEs occurring during the study are to be followed up in accordance with good medical 
practice until they are resolved, stabilized or judged no longer clinically significant or, if a 
chronic condition, until fully characterized. 
8.1.2.1. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (i.e., are considered to be 
clinically significant, induce clinical signs or symptoms, require concomitant therapy, or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever possible, 
a diagnosis, rather than a symptom should be provided (e.g., anemia instead of low hemoglobin). 
Laboratory abnormalities that meet the criteria for an AE should be followed until they have 
returned to normal or an adequate explanation of the abnormality is identified. When an 
abnormal laboratory or test result corresponds to a sign/symptom of an already reported AE, it is 
not necessary to separately record the laboratory/test result as an additional event. 
A laboratory abnormality that does not meet the definition of an AE should not be reported as an 
AE. A Grade 3 or 4 event (severe per NCI CTCAE v4.03) does not automatically indicate an 
SAE unless it meets the definition of serious as defined in Section 8.1.1 and/or as per 
Investigator’s discretion. A laboratory abnormality that results in a dose being held or modified 
would, by definition, be an AE and must be recorded as such in the eCRFs. 
8.1.3. 
Adverse Event Severity 
The severity of the AE will be graded by the Investigator according to the NCI CTCAE Grading 
Scale, v. 4.03 (the NCI CTCAE files can be accessed online at the following URL: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
If NCI CTCAE grading does not exist for an AE, the severity will be characterized as “mild,” 
“moderate,” “severe,” or “life-threatening (corresponding to Grades 1 to 4) according to the 
following definitions: 
•
Mild events are usually transient and do not interfere with the patient’s daily
activities.
•
Moderate events introduce a low level of inconvenience or concern to the patient and
may interfere with daily activities.
•
Severe events interrupt the patient’s usual daily activities.
•
Life-threatening.
The term “severe” is used to describe the intensity of an AE; the event itself could be of 
relatively minor clinical significance (e.g., ‘severe’ headache). This is not the same as a “serious” 
AE. 
8.1.4. 
Adverse Event Causality 
The Investigator will make a judgment regarding the relationship of the AE to study treatment, as 
outlined in Table 20. 

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Table 20: Classification of Adverse Events by Causality 
Not related 
The lack of a temporal relationship of the event to the study treatment makes a 
causal relationship not reasonably possible, or other drugs, therapeutic 
interventions, or underlying conditions provide a sufficient explanation. 
Related 
The temporal relationship of the event to the study treatment makes a definitive 
relationship, and the event is more likely explained by exposure to the study 
treatment than by any other drugs, therapeutic interventions, or underlying 
conditions. 
8.2. 
Serious Adverse Events 
See Section 8.1.1 for the definition of an SAE. Please note that SAEs that occur at any time 
between the signing of the ICF up to the first dose of study treatment, must be reported (in 
addition to SAEs that occur after the first dose of study treatment). 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in in-patient hospitalization, or the development of drug dependency or drug 
abuse. 
Hospitalizations for elective surgery or other medical procedures that are not due to an AE are 
not considered SAEs. A hospitalization meeting the regulatory definition for ‘serious’ is any 
inpatient hospital admission that includes a minimum of an overnight stay in a health care 
facility. An emergency room visit is not considered a hospitalization unless it results in an 
official admission to the hospital. 
Progression of the malignancy (including fatal outcomes) should not be reported as an SAE 
during the study or within the safety reporting period (see Section 8.2.2). Sudden and 
unexplained death should be reported as an SAE. If there is any uncertainty about a finding being 
due solely to progression of malignancy, the finding should be reported as an AE or SAE, as 
appropriate.  
8.2.1. 
Recording of Serious Adverse Events 
It is the responsibility of the Investigator to record and document all SAEs occurring from the 
signing of the ICF until at least 30 days after the patient has stopped study treatment. All SAEs 
must be reported on an SAE report form, in addition to being recorded in the eCRF. The original 
SAE report form must be retained in the Investigator’s site file. 
All applicable sections of the form must be completed in order to provide a clinically thorough 
report. The Investigator must assess and record the relationship of each SAE to study treatment 
and complete the SAE Report Form (in English). 
See ICH E2A (Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Attachment 1) for key data elements that are required for expedited reporting. 

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8.2.2. 
Reporting of Serious Adverse Events 
Every SAE, regardless of the causal relationship to the study treatment, occurring after the 
patient has signed informed consent, until at least 30 days after the patient has stopped study 
treatment, must be reported to the Karyopharm Pharmacovigilance Department within 24 hours 
of learning of its occurrence. The investigational site personnel must use the SAE Report Form 
provided by Karyopharm for reporting any SAE to the Karyopharm Pharmacovigilance 
Department. 
Upon completion, the SAE Report Form must be immediately emailed or faxed to: 
Pharmacovigilance Department 
Karyopharm Therapeutics Inc. 
Email: pharmacovigilance@karyopharm.com 
Fax: 
+1-617-334-7617 (USA) 
Any SAE observed after the 30-day follow-up period should only be reported to Karyopharm if 
the Investigator suspects that the SAE has a causal relationship to study treatment. Recurrent 
episodes, complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the Investigator receiving the follow-up information.  
An SAE should be followed until its resolution or until it is judged to be permanent, and 
assessment should be made at each visit (or more frequently, if necessary) of any changes in 
severity of the event, the suspected relationship to the study treatment, the interventions required 
to treat the event, and the outcome. 
8.2.3. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Karyopharm to be related to the study treatment administered. 
SUSARs will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with the FDA’s “Safety Reporting Requirements for Investigational 
New Drugs and Bioanalytical/Bioequivalence Studies” or as per national regulatory requirements 
in participating countries. 
In addition, Karyopharm will communicate all cases of cerebellar toxicity, Grade 3 or higher, to 
regulatory authorities, central ethics committees (e.g., IRBs), and Investigators, in the format of 
an expedited Safety Report, within 7 days of awareness of the event.  
If required by local regulations, the Investigator is responsible for notifying his/her IRB or local 
ethics committee of all SAEs. 
8.3. 
Procedures for Handling Special Situations 
8.3.1. 
Pregnancy 
Note: Pregnancy per se is not considered to be an AE; however, it is discussed here because of 
the importance of reporting pregnancies that occur during studies and because a medical 
occurrence observed in the mother or fetus/newborn would be classified as an AE. 

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To ensure patient safety, a pregnancy occurring while the patient is on study treatment must be 
reported to Karyopharm Pharmacovigilance by email or fax within 24 hours of first knowledge 
of its occurrence. A pregnancy report form is provided by Karyopharm. 
The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancies must be reported to Karyopharm, regardless of whether the patient withdraws from 
the study or the study is completed, for 3 months after the patient receives his/her last dose of 
study treatment. Patients should be instructed to inform the Investigator regarding any 
pregnancies.  
Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, birth defect) and reported within 24 hours in accordance with the procedure 
for reporting SAEs. 
A pregnancy in a female partner of a male patient must be reported to Karyopharm within 
24 hours of learning of its occurrence. Pregnancies in female partners should only be followed if 
the male patient is being treated with a KPT-9274-containing regimen. 
8.3.2. 
Abuse, Misuse, Medication Errors, Overdose, and Occupational Exposure 
All incidences of abuse, misuse, medication errors, overdose, and occupational exposure are 
required to be reported to Karyopharm Pharmacovigilance on an SAE report form, faxed to 
pharmacovigilance@karyopharm.com, regardless of whether or not there is an associated AE or 
SAE.  
8.3.2.1. 
Overdose 
An overdose is a deliberate or accidental administration of any study treatment to a study patient, 
at a dose greater than that which was assigned to that patient per the study protocol. If an 
overdose occurs, the Investigator and Karyopharm should be notified immediately, and the 
patient should be observed closely for AEs. Resulting symptoms should be treated, as 
appropriate, and the incident of overdose and related AEs and/or treatment should be 
documented in the patient’s medical record and in the eCRF. Overdose is to be reported on an 
SAE report form to Karyopharm Pharmacovigilance regardless of whether or not an AE or SAE 
has occurred due to the overdose. If the overdose is associated with an SAE, the SAE report form 
must be submitted to Karyopharm Pharmacovigilance within 24 hours of awareness. If there is 
no AE or SAE, the report must be submitted as soon as possible. 
8.3.2.2. 
Abuse, Misuse, or Medication Error 
Abuse is the persistent or sporadic, intentional excessive use of the study treatment which is 
accompanied by harmful physical or psychological effects.  
A medication error is any preventable incident that may cause or lead to inappropriate study 
treatment use or patient harm while the study treatment is in the control of the health care 
professionals or patients. Such incident may be due to health care professional practice, product 
labeling, packaging and preparation, procedures for administration, and systems, including the 

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following: prescribing, order communication, nomenclature, compounding, dispensing, 
distribution, administration, education, monitoring, and use. 
All occurrences of abuse, misuse, or medication error with any study treatment are to be reported 
on an SAE report form to Karyopharm Pharmacovigilance regardless of whether or not an AE or 
SAE has occurred due to the abuse, misuse, or medication error. If the abuse, misuse, or 
medication error is associated with an SAE, the SAE report form must be submitted to 
Karyopharm Pharmacovigilance within 24 hours of awareness. If there is no AE or SAE, the 
report must be submitted as soon as possible.  
8.3.2.3. 
Occupational Exposure 
Occupational exposure is the exposure to a study treatment as a result of one’s professional or 
non-professional occupation. For this protocol, please follow the instructions for preparation and 
administration of the bortezomib and dexamethasone. 
All occurrences of occupational exposure with any study treatment are to be reported on an SAE 
report form to Karyopharm Pharmacovigilance regardless of whether or not an AE or SAE has 
occurred due to the occupational exposure. If the occupational exposure is associated with an 
SAE, the SAE report form must be submitted to Karyopharm Pharmacovigilance within 24 hours 
of awareness. If there is no AE or SAE, the report must be submitted as soon as possible. 

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9. 
STATISTICAL METHODS 
A statistical analysis plan (SAP) will be finalized prior to database lock. Any changes from the 
statistical analyses described in this document will be described in the SAP, and any deviation 
from the final SAP will be described in the final report. 
9.1. 
General Considerations 
Tabulations will be produced for appropriate disposition, demographic, baseline, efficacy, and 
safety parameters. For categorical variables, summary tabulations of the number and percentage 
of patients within each category (with a category for missing data) of the parameter will be 
presented. For continuous variables, the number of patients, mean, median, standard deviation, 
minimum, and maximum values will be presented. Time-to-event data will be summarized using 
Kaplan-Meier methodology with median event time and associated 2 sided 95% confidence 
intervals, as well as number and percentage of patients with events and censored patients. 
Patients who are in Part A or Part B of the Dose Escalation Phase being treated at the RP2D 
± niacin ER dose chosen for expansion will be included in the efficacy and safety assessment of 
the Dose Expansion Phase. 
Efficacy and safety endpoints will be presented separately for Part A, B and two dose levels of 
Part C. 
9.2. 
Determination of Sample Size 
9.2.1. 
Sample size for Part A and B: 
The sample size for the Dose Escalation Phase is based on a standard 3+3 design for the purpose 
of determining the RP2D and MTD (Part A) and the RP2D and MTD of KPT-9274 
co-administered with niacin ER (Part B). Each cohort in Parts A and B of the Escalation Phase 
will consist of 3 or 6 patients per cohort.  
For the Dose Expansion Phase, up to 65 additional patients may be enrolled at the RP2D for 
KPT-9274 single agent or KPT-9274 + niacin ER (up to 45 patients in the KPT-9274 ± niacin 
ER cohort; if Dose Expansion is conducted with KPT-9274 + niacin ER then an optional cohort 
of up to 20 additional patients in the KPT-9274 single agent cohort).  
Assuming that 9 dose levels of KPT-9274 are evaluated during both Part A and Part B of the 
Dose Escalation Phase and up to 65 additional patients are enrolled in the Dose Expansion Phase, 
the total combined enrollment is estimated to be 175 patients. 
9.2.2. 
Sample size for Part C: 
Two dose levels of KPT-9274 (30 and 40 mg) + nivolumab will be tested. A maximum of 10 
patients may be enrolled at each dose level. Additional dose levels (20 mg or 60 mg) might be 
evaluated if an optimal dose is not identified and the safety review committee is in agreement.  

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9.3. 
Analysis Populations 
9.3.1. 
Intent-to-Treat Population 
The intent to treat (ITT) population for Part A and Part B will consist of all patients who receive 
at least one dose of the RP2D ± niacin ER chosen for expansion.  Note that patients who are in 
the Dose Escalation Phase being treated at the RP2D ± niacin ER dose will be included.  
The ITT population for Part C will consist of all patients who receive at least one dose of study 
treatment. 
ITT population will be used for primary analyses of efficacy. 
9.3.2. 
Per Protocol Population 
The per-protocol (PP) population will consist of all ITT patients who have received at least 2 
cycles of study treatment, are compliant with study assessments, have received at least 80% of 
their prescribed study medication, and have no major protocol violations that would compromise 
the assessment of efficacy. Major violations will be determined independently of knowledge of 
response to therapy, and prior to database lock and study analysis. This population will be used 
for supportive inferences concerning efficacy, however, if there are major differences between 
the results in this population and those obtained in the mITT population, this will be taken into 
consideration in the assessment of efficacy. 
9.3.3. 
Safety Population 
All patients who receive any amount of the study treatment will be included in the safety 
population for analysis. All safety analyses will be performed on the safety population.  
9.3.4. 
Pharmacokinetic Population 
All subjects who received at least 1 dose of study medication and had adequate sampling will be 
included in the PK population. All PK analyses will be performed on the PK population. 
9.3.5. 
DLT Evaluable Population 
All patients who complete a minimum of 1 cycle of treatment, defined as having received ≥ 75% 
of KPT-9274 doses during Cycle 1 (e.g., ≥ 9 of 12 doses in the 3 doses/week schedule), or who 
have a DLT within the first cycle of treatment, will be included in the DLT evaluable population. 
9.4. 
Data Analysis and Presentation 
Summary tabulations will be provided for disposition, demographic, baseline, efficacy, PK, and 
safety data as noted in the following sections. All data collected on the eCRF will be provided in 
by-patient data listings.  
9.4.1. 
Disposition of Patients 
A tabulation of patient disposition will be presented including the number in each analysis 
population, the number lost to follow-up, the number that withdrew, and reason(s) for 
withdrawal. 

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9.4.2. 
Demographic Characteristics 
Demographic characteristics will be summarized by dose cohort, as well as overall, and will 
include date of birth, sex, race, ethnicity, and age at time of consent. For sex, race, and ethnicity, 
the summary statistics will be the number and percentage of patients within each category. The 
categories for race will be those recorded in the database. For age at time of consent, the mean, 
median, minimum, maximum, and standard deviation will be provided for each arm and the total 
sample. No formal hypothesis testing of differences among dose cohorts will be performed. 
9.4.3. 
Baseline Characteristics and Medical History 
Baseline characteristics include ECOG performance status, duration from initial diagnosis, 
response to previous therapy, types of prior therapy, and height/weight/BSA. Baseline data will 
be tabulated for the same categories as used for demographics, using summary statistics; no 
formal hypothesis testing of dose cohort differences will be performed. Medical history and 
physical examination results at baseline will be tabulated by treatment cohort. 
9.5. 
Efficacy Analysis 
Disease response will be evaluated according to RECIST 1.1 (advanced solid malignancies) 
Appendix 4]) or Lugano Classification (NHL) (Appendix 3) and will include the following 
endpoints: Time-to-event efficacy endpoints will be performed using the same Kaplan-Meier 
method for estimation of summary statistics, and will include the 25th, 50th (median) and 75th 
percentiles, associated two-sided 95% Cis (if estimable), and number of events and censored 
observations. 
• Overall response rate (ORR): The analysis of ORR will be performed by calculating the point 
estimate of the percentage of patients who have either CR or PR, presented as the number 
and percentage of patients, including a two-sided 95% CI. 
• Duration of response (DOR): the duration of time from first meeting CR or PR measurement 
criteria (whichever occurs first) until the first date that Progressive Disease (PD) recurrence 
is objectively documented. Patients without documented PD will be censored on the date of 
last disease assessment. 
• Disease control rate (DCR): The analysis of DCR will be similar to that described for ORR, 
for patients who achieve CR, PR, or SD for ≥ 16 weeks.  
• Duration of disease control: the duration of time from date of first study treatment until the 
first date the PD is objectively documented. Patients without documented disease progression 
will be censored on the date of last disease assessment. 
• Progression-free survival (PFS): the duration of time from date of first dose of study 
treatment until the first date that PD is objectively documented or death due to any cause. 
Patients without documented PD will be censored on the date of last disease assessment. 
• Overall survival (OS): the duration of time from date of first dose of study treatment until 
death from any cause. Patients who withdraw from the study or are alive at the time of data 
analysis will be censored on the date of last contact. 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
1 1 Marc h  2 0 2 0  
C o nfi de ntial 
P a ge 1 0 7  
Versi o n  5 . 0 
•
T T P: T he d urati o n of ti me fr o m date of first d ose of st u d y treat me nt t o date of P D. Patie nts
w h o wit h dra w fr o m t he st u d y or are ali ve at t he ti me of data a nal ysis per Secti o n  2. 2. 2
wit h o ut d oc u me nte d D D will be ce ns ore d o n t he date of last c o ntact.
9. 5. 1.  
F utilit y Testi n g  
F or Part A or Part B, at least o ne cli nical res p o nse ( mi ni m u m of sta ble disease ~1 6  wee ks) m ust 
be see n i n a n y of t he first te n patie nts treate d at t he R P 2 D i n or der t o f ull y e nr oll eit her 
e x pa nsi o n c o h ort. T hese 1 0  patie nts i ncl u de t he patie nts e nr olle d u n der t he 3 + 3 desi g n f or D L T 
assess me nt; if necessar y, a d diti o nal patie nts will be e nr olle d t o a ma xi m u m of 1 0 patie nts. If n o 
cli nical res p o nses are o bser ve d, t he st u d y  will be st o p pe d f or f utilit y. If a cli nical res p o nse is 
o bser ve d at a n y ti me, t he n e nr oll me nt of t he f ull  e x pa nsi o n c o h ort ma y pr ocee d. I nitiati o n of t he 
K P T -9 2 7 4 + niaci n escalati o n will n ot be de pe n de nt u p o n de m o nstrati o n of cli nical be nefit of t he 
si ngle a ge nt, b ut f utilit y at t he K P T -9 2 7 4 + niaci n R P 2 D will be assesse d pri or t o f ull e x pa nsi o n 
usi n g t he sa me criteri o n as descri be d a b o ve f or t he si n gle a ge nt K P T -9 2 7 4.  
9. 6.  
P h ar m ac o ki netic A n al ysis  
P K Para meters f or K P T -9 2 7 4  will be deter mi ne d f oll o wi n g a d mi nistrati o n of K P T -9 2 7 4 
(Secti o n  7. 4 ). 
K P T -9 2 7 4 P K para meters ma y i ncl u de, b ut are n ot li mite d t o, C ma x , A U C, tma x , t½ , Vd/ F, a n d 
C L / F. I nteri m P K a nal yses ma y be perf or me d t hr o u g h o ut t he st u d y o n draft, u na u dite d plas ma 
K P T -9 2 7 4 c o nce ntrati o n data.  
T he P K pr o perties of K P T -9 2 7 4 will be e val u ate d a n d data c ollecte d o ver ti me will be 
s u m marize d. P K e n d p oi nts will be c o m p ute d usi n g n o n-c o m part me ntal met h o ds. S u m mar y 
statistics s uc h as mea n, sta n dar d de viati o n, me dia n, ra n ge, etc., will be c o m pile d a n d re p orte d. A  
se parate Data A nal ysis Pla n ( D A P ) mi g ht  be pre pare d  pri or t o i nitiati o n of t he fi nal P K a nal ysis. 
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 1 0 8  
Versi o n  5 . 0 
9. 8.  
S afet y A n al ysis  
All safet y a nal yses will be ma de o n t he Safet y P o p ulati o n. Details  of t he a nal yses  will be 
descri be d i n t he S A P.  
T he safet y a n d t olera bilit y of K P T -9 2 7 4 ± niaci n E R will be e val uate d b y mea ns of D L Ts, A E 
re p orts, p h ysical e xa mi nati o n res ults, electr ocar di o gram res ults a n d la b orat or y safet y 
e val uati o ns. N CI C T C A E, Versi o n 4. 0 3 will be use d f or gra di n g of A Es.  
T he M T D will be base d o n t he assess me nt of D L Ts d uri n g t he first c ycle of t hera p y a n d will be 
defi ne d as t he hi g hest d ose at w hic h ≤1 patie nt e x perie nces D L Ts wit hi n C ycle 1. If t he tr ue 
D L T rate is 3 3 % f or eac h d ose c o h ort, t he pr o ba bilit y of halti n g d ose escalati o n at a gi ve n d ose 
c o h ort is 0. 5 7.  
9. 8. 1.  
A d verse E ve nts  
A d verse E ve nts ( A Es) will be c o de d usi n g t he Me d D R A dicti o nar y  a n d dis pla ye d i n ta bles a n d 
listi n gs usi n g S yste m/ Or ga n/ Class ( S O C) a n d Preferre d Ter m. A nal yses of A Es will be 
perf or me d f or t h ose e ve nts t hat are c o nsi dere d t o be treat me nt-e mer ge nt  A Es ( T E A Es), defi ne d 
as a n y A E wit h o nset or w ors e ni n g of a pre -e xisti n g c o n diti o n o n or after t he first a d mi nistrati o n 
of st u d y me dicati o n t hr o u g h 3 0 da ys f oll o wi n g last d ose or a n y e ve nt c o nsi dere d dr u g -relate d b y 
t he I n vesti gat or t hr o u g h t he e n d of t he st u d y. A d verse e ve nts wit h partial dates will be assesse d 
usi n g t he a vaila ble date i nf or mati o n t o deter mi ne if treat me nt -e mer ge nt; A Es wit h c o m pletel y 
missi n g dates will be ass u me d t o be treat me nt -e mer ge nt. 
A d verse e ve nts will be s u m marize d b y fre q ue nc y c o u nts at patie nt le vel . T a b ulati o ns will be 
pr o vi de d f or all T E A Es, f or T E A Es assesse d b y t he I n vesti gat or as at least p ossi bl y relate d t o 
treat me nt, f or ≥ Gra de 3 T E A Es, a n d f or seri o us A Es ( S A Es).  
N o f or mal h y p ot hesis -testi n g a nal ysis of A E i nci de nce rates will be perf or me d. 
C CI

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All AEs (treatment-emergent and post-treatment) will be listed in patient data listings. Separate 
by-patient listings will be provided for the following: patient deaths, SAEs, and AEs leading to 
withdrawal. 
9.8.2. 
Clinical Laboratory Data 
Clinical laboratory values will be expressed using conventional SI units. 
The actual value and change from Baseline for each on study evaluation will be summarized for 
each clinical laboratory parameter, including hematology and clinical chemistry. 
Severity of select clinical lab measures will be determined using CTCAE criteria (i.e. those 
measures that have a corresponding CTCAE grade classification). Shift tables that present 
changes from baseline to worst on-study and baseline to last on-study values relative to CTCAE 
classification ranges will be produced.  
9.8.3. 
Vital Signs and Examinations 
The actual value and change from baseline to each on-study evaluation will be summarized.  
Physical examination results at Screening will be summarized; all other abnormal physical 
examination data are to be recorded on the AE eCRF. All examination findings will be presented 
in a data listing. 
ECOG performance status scores, 12-lead ECG results, and ophthalmic examination results will 
be summarized. 
9.8.4. 
Concomitant Medications 
Concomitant medications will be coded and tabulated based on the current version of the World 
Health Organization (WHO) Drug Dictionary.  
 

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10. 
ADMINISTRATIVE AND REGULATORY REQUIREMENTS 
10.1. 
Good Clinical Practice (GCP) 
The study will be conducted in accordance with the ICH Guideline for GCP and the appropriate 
regulatory requirement(s). The Investigator will be thoroughly familiar with the appropriate use 
of the study treatment as described in the protocol and IB. Essential clinical documents will be 
maintained to demonstrate the validity of the study and the integrity of the data collected. Master 
files should be established at the beginning of the study, maintained for the duration of the study 
and retained according to the appropriate regulations. 
10.2. 
Institutional Review Board 
The protocol, ICF(s), recruitment materials, and all subject materials will be submitted to the 
IRB for review and approval. Approval of both the protocol and the consent form must be 
obtained before any subject is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented in the study. 
10.3. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the patients. The study will only be conducted at a site where 
IRB/IEC approval has been obtained. The protocol, IB, ICF, advertisements (if applicable), 
written information given to the patients, safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB/IEC by the Investigator. 
10.4. 
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
patient, guardian or legal representative prior to study participation, on the appropriate IRB/EC 
approved consent form. The method of obtaining and documenting the informed consent and the 
contents of the consent will comply with ICH-GCP and all applicable regulatory requirement(s). 
10.5. 
Patient Confidentiality 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. 
In order to maintain patient privacy, all eCRFs, study treatment accountability records, study 
reports, and communications will identify the patient only by initials and the assigned patient 
number. The Investigator will grant monitor(s) and auditor(s) from Karyopharm or its designee 
and regulatory authorities access to the patient’s original medical records for verification of data 
gathered on the eCRFs and to audit the data collection process. The patient’s confidentiality will 
be maintained and will not be made publicly available to the extent permitted by applicable laws 
and regulations. 

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In the event that a patient revokes authorization to collect or use protected health information 
(PHI), the Investigator, by regulation, retains the ability to use all information collected prior to 
the revocation of patient authorization. For patients who have revoked authorization to collect or 
use PHI, attempts should be made to obtain permission to collect follow-up safety information 
(e.g., whether patients experienced any new or worsened AEs) at the end of their scheduled study 
period. 
Karyopharm may request medical records in order to obtain additional details on subject safety. 
Any medical records must be de-identified to remove all PHI. 
If a site indicates that country rules or ethics committee standards do not permit collection of key 
sensitive personally identifiable information (e.g., patient initials and exact Date of Birth), Year 
of birth will be solicited (in the place of exact date of birth) to establish that the patient satisfies 
protocol age requirements and to enable appropriate age-related normal ranges to be used in 
assessing laboratory test results. 
10.6. 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by 
Karyopharm, and given approval/favorable opinion by the IRB and the appropriate regulatory 
authority(ies). Modifications to the protocol should not be made without agreement of both the 
Investigator and Karyopharm. Changes to the protocol will require written IRB 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to patients. The IRB may provide expedited review and 
approval/favorable opinion for minor change(s) in ongoing studies that have the 
approval/favorable opinion of the IRB. Karyopharm will submit all protocol modifications to the 
regulatory authority(ies) in accordance with the governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact Karyopharm, if circumstances permit, to discuss the 
planned course of action. Any deviation from the protocol must be fully documented in the eCRF 
and source documentation. 
10.7. 
Direct Access to Source Data 
Monitoring and auditing procedures will be followed in compliance with ICH-GCP guidelines. 
The study will be monitored by Karyopharm or its designee. Monitoring will be done by 
personal visits from a representative of Karyopharm (site monitor) and will include on-site 
review of the eCRFs for completeness and clarity, verification with source documents, and 
confirmation of compliance with the study protocol and applicable regulations. The review of 
medical records will be performed in a manner to ensure that patient confidentiality is 
maintained. 
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, e-mail, telephone, and fax). 
Regulatory authorities, the IEC/IRB, and/or Karyopharm’s clinical quality assurance group may 
request access to all source documents, eCRFs, and other study documentation for on-site audit 
or inspection. Direct access to these documents must be guaranteed by the Investigator, who 
must provide support at all times for these activities. 

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10.8. 
Electronic Case Report Form Completion 
Required study data will be captured on eCRFs via electronic data capture (EDC) unless 
otherwise specified in this document. 
It is the Investigator’s responsibility to ensure the accuracy, completeness, and timeliness of the 
data reported in the patient’s eCRF. Source documentation supporting the eCRF data should 
indicate the patient’s participation in the study and should document the dates and details of 
study procedures, adverse events, and patient status. 
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected, preferably on the same day that a study patient is seen for an 
examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
10.9. 
Record Retention 
The Investigator will maintain all study records according to ICH GCPs and applicable 
regulatory requirement(s). Records will be retained for at least 2 years after the last marketing 
application approval or 2 years after formal discontinuation of the clinical development of the 
investigational product or according to applicable regulatory requirement(s). If the Investigator 
withdraws from the responsibility of keeping the study records, custody must be transferred to a 
person willing to accept the responsibility. Karyopharm must be notified in writing if a custodial 
change occurs. 
Karyopharm has full rights over any invention, discovery, or innovation, patentable or not, that 
may occur when performing the study. 

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11. 
LIST OF REFERENCES 
Abril-Rodriguez G, Torrejon DY, Liu W et al. PAK4 inhibition improves PD-1 blockade 
immunotherapy. Nature Cancer; 2020; 1:46-58. 
Benson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer 
treatment-induced diarrhea. J Clin Onc 2004; 22:2918. 
Cheson B, Fisher R, Barrington S, et al. Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma:  The Lugano Classification. J 
Clin Oncol. 2014 Sep 20;32(27):3059-67. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2): 228–47 
National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines®): Available online at 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. 
National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines®): Fatigue, version 2.2015. Available at 
http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. Published 22 January 2015.  
National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines®): Antiemesis, version 1.2015. Available at 
http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. Published 01 April 2015.  
National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines®): Palliative Care, version 2.2015. Available at 
http://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf. Published 18 May 2015.  
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a 
better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma 
treated with R-CHOP. Blood 2007;109:1857-1861. 
Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signaling prevents anti-tumour 
immunity. Nature. 2015 Jul 9;523(7559):231-5. 
Webster K, Cashy J, Cella D, et al. Measuring quality of life (QoL) in patients with non-
Hodgkin’s lymphoma (NHL): The Functional Assessment of Cancer Therapy-Lymphoma 
(FACT-Lym). Qual Life Res. 2005; 14:1650. 
 
 

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12. 
APPENDICES 
 

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APPENDIX 1. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS CRITERIA 
Table 21: ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655). 

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APPENDIX 2. THE LUGANO CLASSIFICATION FOR INITIAL 
EVALUATION AND STAGING OF NHL 
Table 22: Criteria for Involvement of Site 
Tissue Site 
Clinical 
FDG Avidity 
Test 
Positive Finding 
Lymph nodes 
Palpable 
FDG-avid 
histologies 
PET-CT 
Increased FDG uptake 
Nonavid 
disease 
CT 
Unexplained node enlargement 
Spleen 
Palpable 
FDG-avid 
histologies 
PET-CT 
Diffuse uptake, solitary mass, 
miliary lesions, nodules 
Nonavid 
disease 
CT 
> 13 cm in vertical length, mass, 
nodules 
Liver 
Palpable 
FDG-avid 
histologies 
PET-CT 
Diffuse uptake, mass 
Nonavid 
disease 
CT 
Nodules 
CNS 
Signs, 
symptoms 
 
CT 
Mass lesion(s) 
MRI 
Leptomeningeal infiltration, mass 
lesions 
CSF 
assessment 
Cytology, flow cytometry 
Other (e.g., skin, lung, GI tract, 
bone, bone marrow) 
Site 
dependent 
 
PET-CTa, 
biopsy  
Lymphoma involvement 
Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic 
resonance imaging; PET, positron emission tomography.  
a PET-CT is adequate for determination of bone marrow involvement and can be considered highly suggestive for 
involvement of other extralymphatic sites. Biopsy confirmation of those sites can be considered if necessary. 

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Table 23: Revised Staging System for Primary Nodal Lymphomas 
Stage 
Involvement 
Extranodal (E) Status 
Limited 
I 
One node or a group of adjacent nodes 
Single extranodal lesions without nodal 
involvement 
II 
Two or more nodal groups on the same side of the 
diaphragm 
Stage I or II by nodal extent with limited 
contiguous extranodal involvement 
II 
bulkya 
II as above with “bulky” disease 
Not applicable 
Advanced 
III 
Nodes on both sides of the diaphragm; nodes above 
the diaphragm with spleen involvement 
Not applicable 
IV 
Additional noncontiguous extralymphatic 
involvement 
Not applicable 
•NOTE. Extent of disease is determined by positron emission tomography–computed tomography for avid 
lymphomas and computed tomography for nonavid histologies. Tonsils, Waldeyer's ring, and spleen are considered 
nodal tissue. 
a Whether stage II bulky disease is treated as limited or advanced disease may be determined by histology and a 
number of prognostic factors. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 3. THE LUGANO CLASSIFICATION FOR RESPONSE 
ASSESSMENT OF NHL (CHESON, 2014) 
Table 24: Revised Criteria for Response Assessment 
Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of 
the following) 
Lymph nodes 
and 
extralymphatic 
sites 
Score 1, 2, or 3a with or without a residual mass on 
5PSb 
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi 
It is recognized that in Waldeyer's ring or extranodal 
sites with high physiologic uptake or with activation 
within spleen or marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the 
tissue has high physiologic uptake  
No extralymphatic sites of disease 
Nonmeasured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if 
indeterminate, IHC negative 

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Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
Partial 
Partial metabolic response 
Partial remission (all of the 
following) 
Lymph nodes 
and 
extralymphatic 
sites 
Score 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size  
≥ 50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites 
 
At interim, these findings suggest responding disease 
When a lesion is too small to measure 
on CT, assign 5 mm × 5 mm as the 
default value 
 
At end of treatment, these findings indicate residual 
disease 
When no longer visible, 0 × 0 mm 
 
 
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by > 50% 
in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow 
but reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, 
consideration should be given to further evaluation 
with MRI or biopsy or an interval scan  
Not applicable 
No response or 
stable disease 
No metabolic response 
Stable disease 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
Score 4 or 5 with no significant change in FDG 
uptake from baseline at interim or end of treatment 
< 50% decrease from baseline in SPD 
of up to 6 dominant, measurable 
nodes and extranodal sites; no criteria 
for progressive disease are met  
Nonmeasured 
lesions 
Not applicable 
No increase consistent with 
progression 
Organ 
enlargement 
Not applicable 
No increase consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 

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Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
Progressive 
disease 
Progressive metabolic disease 
Progressive disease requires at least 1 
of the following 
Individual 
target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity of uptake 
from baseline and/or 
PPD progression: 
Extranodal 
lesions 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
An individual node/lesion must be 
abnormal with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir 
and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior increase 
beyond baseline (e.g, a 15-cm spleen 
must increase to > 16 cm). If no prior 
splenomegaly, must increase by at 
least 2 cm from baseline 
New or recurrent splenomegaly  
Nonmeasured 
lesions 
None 
New or clear progression of 
preexisting nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather 
than another etiology (e.g., infection, inflammation). 
If uncertain regarding etiology of new lesions, biopsy 
or interval scan may be considered  
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma  
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, 
positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions.  
 
a. A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to 
consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to 6 of the 
largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. 
Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal 
and retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI 
involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as 
measured, dominant disease and truly assessable disease should be considered not measured. These sites include 
any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the 
requirements for measurability but are still considered abnormal, as well as truly assessable disease, which is any 

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site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural 
effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be 
confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (e.g., GI tract, liver, bone marrow), 
FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no higher 
than surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid 
growth factors). 
b. PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma. 
 

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APPENDIX 4. RECIST VERSION 1.1 
(Modified from Eisenhauer 2009)  
All patients will have their BEST RESPONSE on study classified as outlined below: 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non target) 
must have reduction in the short axis to <10mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline 
sum diameters. 
Stable Disease (SD) 
Steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of measured lesions taking as references the 
smallest sum of diameters recorded since the treatment started. In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
Appearance of one or more new lesions will also constitute progressive disease.  
Response Duration 
Response duration will be measured from the time measurement criteria for CR/PR (whichever 
is first recorded) are first met until the first date that recurrent or progressive disease is 
objectively documented, taking as reference the smallest measurements recorded since the 
treatment started. 
Stable Disease Duration 
Stable disease duration will be measured from the time of start of therapy until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment 
started. 
Evaluation of Best Overall Response – Patient with Target (± non-target) disease 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR-Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD/or not all 
evaluated 
No 
PR 
SD 
Non-PD/or not all 
evaluated 
No 
SD 

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Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Evaluation of Best Overall Response – Patient with Non-Target Disease 
Non-Target lesions 
New Lesions 
Overall response 
CR 
No 
CR 
Non-CR-Non-PD 
No 
Non-CR/Non-PD1 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
Method of Measurement 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is recommended.  
Chest X-ray 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
CT, MRI.  
CT and MRI might be the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed with 
cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 
5 mm contiguous reconstruction algorithm. This applies to the chest, abdomen and pelvis. Head 
& neck and extremities usually require specific protocols. 

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Ultrasound 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should 
not be used to measure tumour lesions that are clinically not easily accessible. It is a possible 
alternative to clinical measurements for superficial palpable nodes, subcutaneous lesions and 
thyroid nodules. US might also be useful to confirm the complete disappearance of superficial 
lesions usually assessed by clinical examination. 
Cytology, Histology 
These techniques can be used to differentiate between PR and CR in rare cases (for example, 
residual lesions in tumour types such as germ cell tumours, where known residual benign 
tumours can remain). The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumour has met criteria for response 
or stable disease is mandatory to differentiate between response or stable disease (an effusion 
may be an adverse drug reaction of the treatment) and progressive disease. 

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APPENDIX 5. EORTC-QLQ-C30 
The EORTC-QLQ-C30 contains 30 questions and includes 5 functional scales (Physical, Role, 
Emotional, Social, and Cognitive Functioning), 3 symptom scales (Fatigue, Nausea/Vomiting 
and Pain) and a Global Health Status/QoL scale at the following uniform resource locator (URL) 
http://groups.eortc.be/qol/. 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
P a ge 1 2 6  
Versi o n  5 . 0 
A P P E N DI X  6.  P R O T O C O L A M E N D M E N T S:  R A TI O N A L E S A N D 
S U M M A RI E S O F C H A N G E S  
 
Cli nic al St u d y Pr ot oc ol  
S u m m ar y of C h a n ges  
 
T his pri mar y r eas o n f or a me n di n g t his pr ot oc ol is t o a d d a n a d diti o nal ar m a d mi nisteri n g K P T -
9 2 7 4 + ni v ol u ma b t o patie nts wit h mela n o ma  a n d assessi n g t he f oll o wi n g para meters:  
 
•  Safet y, t olera bilit y, a n d R P 2 D  
•  A ntit u m or acti vit y  
•  P K  
•  
 
 
T he re vise d pr ot oc ol Versi o n 5. 0  date d 1 1  Marc h  2 0 2 0  will be s u b mitte d t o all a p plica ble 
I nstit uti o nal Re vie w B oar ds (I R Bs), I n de pe n de nt Et hics C o m mittees (I E Cs), or Researc h Et hics 
B oar ds ( R E Bs), a n d b y Kar y o p har m T hera pe utics I nc. t o all a p plica ble Re g ulat or y A ut h orities.  
A s u m mar y of t he ke y c ha n ges t hat were ma de t o Versi o n  4. 1  o f t he pr ot oc ol , i ncl u di n g t he 
rati o nale f or t hese c ha n ges i n Versi o n 5. 0  is pr o vi de d i n t he ta ble bel o w.   Gl o bal c ha n ges or 
m o dificati o n of lar ge a m o u nts of te xts are n ot descri be d i n detail, rat her, a ge neral descri pti o n of 
t he c ha n ge is pr o vi de d.  W he n a p pr o priate, e xact c ha n ges t o t he te xt are pr o vi de d.  I n t hese 
i nsta nces, re d f o nt i n dicates te xt t hat was delete d.  Te xt t hat was a d de d is pr o vi de d i n bl ue f o nt . 
C ha n ges  t hat were pri maril y e dit orial or  a d mi nistrati ve  i n nat ure or were ma de f or rea da bilit y 
a n d clarit y  are n ot detaile d i n t he ta ble . 
C CI

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Section(s) 
Description of Change 
Rationale for the Change 
Global 
Revised text referring to Version 4.1 to include any Version 5.0. 
Administrative 
Global 
Minor wording changes to improve clarity and conciseness 
Administrative 
Synopsis 
A new table was added to clearly and concisely present the objectives and 
endpoints of the study.  
Administrative 
Protocol Synopsis 
Figure 1: Study 
Flow Chart 
Section 2.1 
Objectives 
Section 3.1 
Overall Study 
Design and Plan 
Section 6.1.1. 
Study Treatments 
Section 9.2 
Determination of 
Sample Size 
Addition of a new arm (Part C) to include patients with melanoma. Study Flow 
Chart has been updated to reflect the addition of Part C including patients with 
melanoma that will receive KPT-9274 + nivolumab. The following details were 
added throughout. 
 
Patients enrolled in Part C (KPT-9274 + nivolumab) will receive nivolumab (480 
mg) intravenously on Day 1 of each 28 day cycle per the FDA approved package 
insert. 
Nivolumab (anti-PD-1) will be administered at the site based on the product label. 
Patients with melanoma (up to 20) who progressed on prior anti-PD-1 or anti-PD-
L1 treatment starting at the RP2D or a DLT-cleared dose of KPT-9274 in 
combination with nivolumab (anti-PD-1) will be enrolled for dose finding (Part C). 
--- 
Primary 
Part C 
To evaluate the safety, tolerability, and RP2D of KPT-9274 + nivolumab in 
patients with melanoma. 
 
Secondary 
Part C 
• 
To determine the preliminary evidence of anti-tumor activity of KPT-9274 + 
nivolumab in patients with melanoma 
• 
To characterize PK of KPT-9274 + nivolumab in patients with melanoma 
 
Exploratory 
Changes in trial arms relative to 
tested doses and their 
administration were undertaken 
based on promising published data 
demonstrating marked tumor 
growth inhibition by KPT-9274 + 
an anti-PD-1 antibody compared to 
either agent alone. 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 1 2 8  
Versi o n 5. 0  
Secti o n(s)  
Descri pti o n of C h a n ge  
R ati o n ale f or t he C h a n ge  
--- 
Secti o n 3. 1 O verall St u d y Desi g n a n d Pla n  
I n Part C, a c o h ort of patie nts wit h mela n o ma t hat ha ve pr o gresse d o n a n a nti-P D 1 
or a nti -P D -L 1 a nti b o d y will be treate d wit h K P T -9 2 7 4 (at a d ose t hat cleare d D L T 
e val uati o n i n Part A) + ni v ol u ma b. T w o d ose le vels of K P T -9 2 7 4 ( 3 0 a n d 4 0 m g) 
i n c o m bi nati o n wit h ni v ol u ma b will be teste d i n parallel. Patie nts will be e nr olle d 
first i nt o t he 3 0 m g c o h ort. Patie nts will be treate d wit h 3 0 or 4 0 m g K P T-9 2 7 4 
t hree ti mes a wee k e ver y ot her da y ( Da ys 1, 3, 5, 8, 1 0, 1 2, 1 5, 1 7, 1 9, 2 2, 2 4, a n d 
2 6) d uri n g eac h 2 8 -da y  c ycle i n c o m bi nati o n wit h a sta n dar d d ose a n d sc he d ule of 
ni v ol u ma b ( 4 8 0 m g o n Da y 1 of eac h 2 8 -da y c y cle). A ma xi m u m of 1 0 patie nts 
ma y be e nr olle d at eac h d ose le vel. Treat me nt will c o nti n ue u ntil disease 
pr o gressi o n, u nacce pta ble A Es or t o xicit y t hat c a n n ot be ma na ge d b y s u p p orti ve 
care, patie nt’s wit h dra wal of c o nse nt, I n vesti gat or decisi o n t o disc o nti n ue st u d y 
treat me nt, pre g na nc y, deat h, or S p o ns or decisi o n t o ter mi nate t he st u d y. A safet y 
re vie w c o m mittee will e val uate all a vaila ble data fr o m b ot h co h orts after t he last 
patie nt e nr olle d has bee n o bser ve d f or at least 2 c y cles t o deter mi ne t he R P 2 D. 
A d diti o nal d ose le vels ( 2 0 m g or 6 0 m g) mi g ht be e val uate d if a n o pti mal d ose is 
n ot i de ntifie d a n d t he safet y re vie w c o m mittee is i n a gree me nt. T he defi n iti o n of a 
D L T is t he sa me as descri b e d i n Parts A a n d B. Res p o nse will be assesse d e ver y 8  
wee ks per R E CI S T 1. 1 criteria ( A p pe n di x 4).  
--- 
C CI

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Section(s) 
Description of Change 
Rationale for the Change 
Section 9.2  Determination of Sample Size 
Section 9.2.1 Sample size for Part A and B: 
For the Dose Expansion Phase, up to 65 additional patients may be enrolled at the 
RP2D for KPT-9274 single agent or KPT-9274 + niacin ER (up to 45 patients in 
the KPT-9274 ± niacin ER cohort; if Dose Expansion is conducted with KPT-9274 
+ niacin ER then an optional cohort of up to 20 additional patients in the KPT-9274 
single agent cohort).  
Assuming that 9 dose levels of KPT-9274 are evaluated during both Part A and 
Part B of the Dose Escalation Phase and up to 65 additional patients are enrolled in 
the Dose Expansion Phase, the total combined enrollment is estimated to be 175 
patients. 
Section 9.2.2 Sample size for Part C: 
Two dose levels of KPT-9274 (30 and 40 mg) + nivolumab will be tested. A 
maximum of 10 patients may be enrolled at each dose level. Additional dose levels 
(20 mg or 60 mg) might be evaluated if an optimal dose is not identified and the 
safety review committee is in agreement. 
For the Dose Expansion Phase, up to 65 additional patients may be enrolled at the 
RP2D for KPT-9274 single agent and KPT-9274 + niacin ER (up to 45 patients in 
the KPT-9274 ± niacin ER cohort; if Dose Expansion is conducted with KPT-9274 
+ niacin ER then an optional cohort of up to 20 additional patients in the KPT-9274 
single agent cohort) to further explore safety, tolerability, and efficacy of the RP2D 
of KPT-9274 ± niacin ER. Patients with melanoma (up to 20) who progressed on 
prior anti-PD-1 or anti-PD-L1 treatment starting at the RP2D or a DLT-cleared 
dose of KPT-9274 in combination with nivolumab (anti-PD-1) will be enrolled for 
dose dose finding (Part C). Safety will be continuously monitored. No formal 
statistical calculations were performed for the number of patients to be included. 
Protocol Synopsis 
Section 1.3.3: 
Rationale for 
Combining KPT-
9274 with 
Rationale has been provided for combining KPT-9273 with nivolumab: 
Rationale for combining KPT-9274 with Nivolumab: KPT-9274 binds to and 
reduces the steady state level of the PAK4 protein kinase as well as blocking the 
activity of NAMPT. In addition, through PAK4 inhibition, KPT-9274 reduces the 
stability, nuclear transportation and function of β-catenin by inhibiting its 
phosphorylation on S675. This is consistent with β-catenin being a target of PAK4. 
Rationale was provided as 
justification for the addition of an 
additional arm of the study.  

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Nivolumab in 
Melanoma 
Nivolumab is a monoclonal antibody directed against the programmed cell death 1 
receptor (PD-1) on lymphocytes. Anti-PD-1 treatment increases the immune 
response, allowing T cell killing of tumor cells. Nivolumab has been FDA-
approved for use in patients with advanced melanoma. There is evidence 
suggesting that patients most likely to respond to anti-PD-1 treatment are those 
who have an elevated baseline of CD8+ T cell infiltration within the tumor 
microenvironment (TME) (Abril-Rodriguez 2020). Those who lack a T cell 
infiltrate respond poorly. A correlation was reported between hyperactivation of 
the WNT/β-catenin signaling pathway and T cell exclusion in melanoma patient 
tumor samples (Spranger et al 2015). Recently, this correlation has been extended 
to PAK4 overexpression (Abril-Rodriguez 2020). These data suggest that 
combination therapies in which activated β-catenin is inhibited through PAK4 
inhibition simultaneously with targeting PD-1, may be particularly effective 
therapy. Indeed, in vivo models of mice engrafted with melanoma cells that were 
treated with KPT-9274 + an anti-PD-1 antibody showed marked tumor growth 
inhibition compared to either agent alone (Abril-Rodriguez 2020). Therefore, 
combinatorial treatment with KPT-9274, which blocks β-catenin, with nivolumab 
may be beneficial to patients with melanoma who progressed on prior anti-PD-1 or 
anti-PD-L1 treatment.  
Protocol Synopsis 
Section 6.2.6.2 
Dose-Limiting 
Toxicity  
Table 14: Criteria 
for Defining Dose 
Limiting 
Toxicities 
Clarification of fever has been adjusted in the DLT table.  
Febrile neutropenia of any duration (ANC < 1.0 ×109 with single temperature 
>38.3°C, fever >38.5°C or a sustained temperature ≥ 38°C for more than 1 hour). 
Corrected typo to be consistent with 
CTCAE v4.03 guidelines for febrile 
neutropenia. 
Protocol Synopsis 
Explanation of Dose Escalation Phase for Part C is included.  
 
Part C:  KPT-9274 + Nivolumab 
After sufficient data from Part A is available, Dose Finding with the potential for 
Expansion in patients with melanoma will be conducted to further explore safety, 
With the addition of a new arm 
(Part C), dosing information has 
been provided.  

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Rationale for the Change 
tolerability and preliminary evidence of anti-tumor activity of the RP2D (or any 
DLT-cleared dose) of KPT-9274 + nivolumab.  
 
DOSE ESCALATION PHASE 
This Arm will treat approximately 20 patients with melanoma who progressed on 
an anti-PD-1 or anti-PD-L1 antibody in a prior line of therapy. Two dose levels of 
KPT-9274 (30 and 40 mg) in combination with nivolumab will be tested. Patients 
will be enrolled first into the 30 mg cohort. Patients will be treated with 30 or 40 
mg KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 
19, 22, 24, and 26) during each 28-day cycle in combination with a standard dose 
and schedule of nivolumab (480 mg on Day 1 of each 28-day cycle). A maximum 
of 10 patients may be enrolled at each dose level. Treatment will continue until 
disease progression, unacceptable AEs or toxicity that cannot be managed by 
supportive care, patient’s withdrawal of consent, Investigator decision to 
discontinue study treatment, pregnancy, death, or Sponsor decision to terminate the 
study. A safety review committee will evaluate all available data from both cohorts 
after the last patient enrolled has been observed for at least 2 cycles to determine 
the RP2D. Additional dose levels (20 mg or 60 mg) might be evaluated if an 
optimal dose is not identified and the safety review committee is in agreement. The 
definition of a DLT is the same as described in Parts A and B. Response will be 
assessed every 8 weeks per RECIST 1.1 criteria. 
1. 
 
KPT-9274 Dose Finding (Part C) 
Cohort 
KPT-9274 
Nivolumab 
Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 
22, 24, 26 in a 28-day cycle 
Day 1 in a 28-day cycle 
1 
30 mg 
480 mg 
2 
40 mg 
480 mg 
 
--- 

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Rationale for the Change 
Dose Finding and Expansion in Part C may include approximately 20 patients with 
melanoma. 
Protocol Synopsis 
Section 4.4/4.5: 
Study Population, 
Inclusion / 
Exclusion Criteria 
(Part C) 
Inclusion and exclusion criteria specific to Part C have been added. 
Inclusion/Exclusion Criteria (Part C):  
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible to enroll in 
this study. 
1. Written informed consent obtained prior to any screening procedures and in 
accordance with federal, local, and institutional guidelines. 
2. Age ≥18 years. 
3. Patients must have objective and measurable melanoma by RECIST 1.1 after 
disease progression on a prior anti-PD-1 or anti-PD-L1 therapy. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 
5. Adequate hepatic function:  
a. Total bilirubin < 1.5 times the upper limit of normal (ULN) 
(except patients with Gilbert’s syndrome [hereditary indirect 
hyperbilirubinemia] who must have a total bilirubin of ≤ 3 times 
ULN), 
b. Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 2.5 times ULN (except patients with known liver 
involvement of their advanced solid malignancy who must have 
their AST and ALT ≤ 5.0 times ULN). 
6. Adequate renal function: Estimated creatinine clearance of ≥ 60 mL/min, 
calculated using the formula of Cockroft and Gault (140-Age) • Mass (kg)/(72 
• creatinine mg/dL); multiply by 0.85 if female. 
7. Female patients of child-bearing potential must agree to use dual methods of 
contraception (including one highly effective and one effective method of 
contraception) and have a negative serum pregnancy test at Screening, and 
male patients must use an effective barrier method of contraception if sexually 
active with a female of child-bearing potential. For both male and female 
Separate inclusion and exclusion 
criteria were developed and 
included for the additional arm to 
administer KPT-9274 + nivolumab 
to patients with melanoma.  

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Rationale for the Change 
patients, effective methods of contraception must be used throughout the study 
and for 3 months following the last dose. 
8. Adequate hematopoietic function: total white blood cell (WBC) count ≥ 
1500/mm3, absolute neutrophil count (ANC) ≥ 1000/mm3, hemoglobin (Hb) ≥ 
10.0 g/dL, and platelet count ≥ 100,000/mm3. 
9. Life expectancy of ≥ 3 months. 
 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not eligible to enroll in 
this study: 
1. Female patients who are pregnant or lactating. 
2. ≤ 2 weeks since the last prior therapeutic regimen for melanoma. Palliative 
steroids for disease related symptoms < 7 days prior to C1D1, unless 
physiologic doses of steroids are used.  
3. Patients who have not recovered or stabilized (Grade 1 or to their baseline 
for non-hematologic toxicities, ≤ Grade 2 or to their baseline for 
hematologic toxicities) from toxicities related to their previous treatment 
except for alopecia. In specific cases, patients with Grade 2 non-
hematologic toxicities will be allowed following approval by the 
Karyopharm medical monitor. 
4. Patients with untreated central nervous system (CNS) disease or 
leptomeningeal involvement are excluded. Patients without active brain or 
leptomeningeal metastases after prior treatment with local therapies are 
eligible provided that the treatment had been done ≥ 2 weeks prior to 
enrollment. 
5. Major surgery within four weeks before C1D1. 
6. Active infection with completion of therapeutic antibiotics, antivirals, or 
antifungals within one week prior to C1D1. Prophylactic antibiotics, 
antivirals or antifungals are permitted. 
7. Patients with significantly diseased or obstructed gastrointestinal tract or 
uncontrolled vomiting or diarrhea that could interfere with the absorption 
of KPT-9274. 

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Rationale for the Change 
8. Serious psychiatric or medical conditions that, in the opinion of the 
Investigator, could interfere with treatment, compliance, or the ability to 
give consent. 
9. Active peptic ulcer disease or other active gastrointestinal bleeds. 
10. Patients requiring treatment with corticosteroids at doses higher than 
substitute therapy (> 10 mg prednisone), are unstable with substitute 
hormonal therapy, or are deemed to be likely to re-occur by the treating 
physician when administered nivolumab. 
Protocol Synopsis 
DLT has been more stringently defined: 
 
A DLT is defined as an AE or abnormal laboratory value that occurs within the 
first 28 days of treatment with KPT-9274, except for those that are clearly and 
incontrovertibly due to underlying disease, disease progression, or extraneous 
causes, and meets any of the criteria for defining dose-limiting toxicities as 
described in the table below. 
 
Definitions for DLTs have been 
updated and clarified. 
Protocol Synopsis 
Section 2.2.2 
Efficacy 
Endpoints 
 
Section 9.5 
Efficacy Analysis 
Definitions of efficacy endpoints have been updated.  
 
Efficacy Endpoints: 
The secondary endpoint of disease response will be evaluated according to 
RECIST 1.11 (advanced solid malignancies) or Lugano Classification2 (NHL) and 
will include the following: 
• 
Overall response rate (ORR): ORR = Complete response (CR) + Partial 
Response (PR) proportion of patients who have a response of partial 
response (PR) or complete response (CR)  
• 
Duration of response (DOR): the duration of time from first meeting CR 
or PR measurement criteria (whichever occurs first) until the first date that 
PD recurrence is objectively documented. Patients without documented PD 
will be censored on the date of last disease assessment. the duration of time 
Definitions for efficacy endpoints 
have been updated and clarified. 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 1 3 5  
Versi o n 5. 0  
Secti o n(s)  
Descri pti o n of C h a n ge  
R ati o n ale f or t he C h a n ge  
fr o m first meeti n g C R or P R meas ure me nt criteria ( w hic he ver occ urs first) 
u ntil t he first date t hat P D rec urre nce is o bjecti vel y d oc u me nte d.  
•  
Dise ase c o ntr ol r ate ( D C R):  D C R = pr o p orti o n of patie nts  w h o ha ve a 
res p o nse of C R, P R, a n d Sta ble Disease ( S D) ≥ 1 6 wee ks.   
•  
D ur ati o n of dise ase c o n tr ol: t he d urati o n of ti me fr o m date of first st u d y 
treat me nt u ntil t he first date t hat P D is o bjecti vel y d oc u me nte d. Patie nts 
wit h o ut d oc u me nte d P D will be ce ns ore d o n t he date of last disease 
assess me nt. t he d urati o n of ti me fr o m date of first st u d y treat me nt u ntil t he 
first date t hat P D is o bjecti vel y d oc u me nte d. 
•  
Pr o gressi o n -free s ur vi v al ( P F S): t he d urati o n of ti me fr o m date of first 
d ose of st u d y treat me nt u ntil t he first date t hat P D is o bjecti vel y 
d oc u me nte d or deat h d ue t o a n y ca use. Patie nts wit h o ut d oc u me nt e d P D 
will be ce ns ore d o n t he date of last disease assess me nt  t he d urati o n of ti me 
fr o m date of first st u d y treat me nt u ntil t he first date t hat P D is o bjecti vel y 
d oc u me nte d or deat h d ue t o a n y ca use .  
•  
O ver all s ur vi v al ( O S):  t he d urati o n of ti me fr o m date of first st u d y 
treat me nt u ntil deat h fr o m a n y ca use. Patie nts w h o wit h dra w fr o m t he 
st u d y or are ali ve at t he ti me of data a nal ysis will be ce ns ore d o n t he date 
of last c o ntact.  
•  
Ti me t o Pr o gressi o n  (T T P):  T he d urati o n of ti me fr o m d ate of first d ose 
of st u d y treat me nt t o date of P D. Patie nts wit h o ut d oc u me nte d P D will be 
ce ns ore d o n t he date of last disease assess me nt.  t he d urati o n of ti me fr o m 
date of first st u d y treat me nt u ntil t he first date t hat P D is o bjecti vel y 
d oc u me nte d or deat h d ue t o P D . Patie nts wit h o ut d oc u me nte d P D will be 
ce ns ore d o n t he date of last disease assess me nt . 
Pr ot oc ol S y n o psis  
Secti o n 2. 2. 4: 
 
Ta ble 1 8: C ollecti o n Ti me P oi nts a n d Sa m pl e V ol u mes f or P K a n d  
 f or Part C 
was a d de d.  
 
 
 
C CI
C CI
C CI
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 1 3 6  
Versi o n 5. 0  
Secti o n(s)  
Descri pti o n of C h a n ge  
R ati o n ale f or t he C h a n ge  
Ta ble 1 8: 
C ollecti o n Ti me 
P oi nts a n d Sa m pl e 
V ol u mes f or P K 
a n d  
 f or Part 
C  
Ta ble 5: Sc he d ule 
of Assess me nts 
f or Scree ni n g a n d 
C y cle 1 ( Part C)  
T a ble 6: Sc he d ule 
of Assess me nts 
f or C y cles 2 a n d 
Be y o n d ( Part C)  
Ta ble of Assess me nts has bee n i ncl u de d f or Part C a n d i ncl u des rele va nt acti vities, 
ti me p oi nts, a n d f o ot n otes.  
A s e parate Sc he d ule of 
Assess me nts  w as de vel o pe d a n d 
i ncl u de d f or t he a d diti o nal ar m t o 
a d mi nister K P T -9 2 7 4 + ni v ol u ma b 
t o patie nts wit h mela n o ma. 
Secti o n 1. 2. 1 
P ote ntial Ris ks  
Ta ble 1 0: D ose 
Le vels a n d 
Sc he d ules Teste d 
as of 0 2 Marc h 
2 0 1 9  
Ta ble 1 1: 
Treat me nt Relate d 
A d verse E ve nts 
Occ u rri n g i n ≥ 
1 0 % of All 
Patie nts  
Secti o n has bee n u p date d t o i ncl u de t he m ost rece nt i nf or mati o n a vaila ble o n 
e nr olle d patie nts t o date.  
 
As of 0 2 Marc h 2 0 1 9, 4 7 patie nts ha d recei ve d K P T -9 2 7 4 al o ne or wit h niaci n E R 
i n Parts A a n d B of t his st u d y. D ose le vels a n d sc he d ules are o utli ne d i n Ta ble 1 0, 
l o n g wit h t he n u m ber of patie nts e nr olle d i n eac h c o h ort. T he m ost c o m m o n A Es 
occ urri n g acr oss all patie nts i n Parts A a n d B, were a ne mia ( 6 8 %), na usea ( 3 4 %), 
art hral gia ( 3 2 %), fati g ue ( 3 2 %), a n d m y al gia ( 2 3 %) ( Ta ble 1 1; Ta ble 1 2). A Es 
were la r gel y d ose de pe n de nt a n d i ncrease d wit h hi g her d oses of K P T-9 2 7 4. T here 
were 2 D L Ts re p orte d a m o n g t he first 4 7 patie nts. T hese i ncl u de d o ne case of 
gra de 4 a ne mia, w hic h occ urre d i n t he 4 0 m g K P T -9 2 7 4 q o d X 3 c o h ort, a n d o ne 
case of gra de 3 fati g ue w hic h oc c urre d i n t he 8 0 m g K P T -9 2 7 4 q o d X 3 + niaci n 
c o h ort. B ot h d ose le vels e nr olle d a d diti o nal patie nts per t he 3 + 3 st u d y desi g n, a n d 
b ot h d ose le vels ulti matel y cleare d D L T e val uati o n. T o date, a M T D has n ot bee n 
reac he d. 
U p date d i nf or mati o n was a vaila ble 
a n d t heref ore i ncl u de d.  
C CI
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Table 12: 
Treatment Related 
Adverse Events 
Occurring in ≥ 
10% of Patients 
by Dose Level 
and Schedule 
 
Section 6.2.6.1 
Section 6.2.8.1.2 
Dose Holds or 
Reductions for 
Nivolumab (Part 
C) 
Section 6.3 Study 
Treatment Storage 
Instructions for dose levels, dose holds, reductions and storage for nivolumab were 
added. 
 
Part C (KPT-9274 + nivolumab):   
The initial cohort will consist of 3 enrolled patients who will be treated at a dose of 
30 mg KPT-9274, co-administered with a dose of 480 mg nivolumab. If these 
patients do not experience a DLT during Cycle 1, the KPT-9274 dose will be 
escalated to 40 mg for another cohort of 3 patients upon approval during a dose 
decision meeting. A maximum of 10 patients may be enrolled at each dose level. 
Additional KPT-9274 dose levels (e.g., 20 mg or 60 mg) may be evaluated if an 
optimal dose is not identified and the safety review committee is in agreement. 
 
Section 6.2.8.1.2 
Dose reductions are not allowed for nivolumab. Consult the product label for dose 
holds. 
 
Section 6.3 
Nivolumab should be stored according to the package label. 
Separate instructions were 
developed and included for the 
additional arm to administer KPT-
9274 + nivolumab to patients with 
melanoma. 
Section 6.9.1 
Supportive Care 
Instructions for increasing the dose of niacin were clarified. 
After Week 8, niacin may be titrated, as per label, to patient response and 
tolerance. If response to 1000 mg daily is inadequate, increase dose to 1500 mg 
daily; may subsequently increase dose to 2000 mg daily. Daily dose should not be 
Updated information to clarify 
potential changes in niacin dosing. 

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increased more than 500 mg in a 4-week period, and doses above 2000 mg daily 
are not recommended. Women may respond at lower doses than men. 
Section 6.9.2.1 
Permitted 
Concomitant 
Medication 
Section 9.8.4 
Concomitant 
Medications 
 
Additional clarification on contraceptives was added, in addition to details to 
obtain information on nivolumab concomitant medication.  
 
Since the effect of KPT-9274 on oral contraceptives is unknown at this time, it is 
recommended that patients use at least 2 forms of contraceptives while on study. 
Additionally, the nivolumab product label will be consulted to obtain the permitted 
concomitant medications for patients in Part C (the KPT-9274 + nivolumab). 
Separate instructions were 
developed and included for the 
additional arm to administer KPT-
9274 + nivolumab to patients with 
melanoma. 
Section 6.9.2.5 
Glucocorticoid 
Therapy 
 
Updates were made to administration of glucocorticoids. 
 
6.9.2.5 Glucocorticoid Therapy 
Glucocorticoids ≥≤10 mg oral prednisone (or equivalent) per day are not permitted 
at baseline; however physiological doses 10 mg oral prednisone (or equivalent) 
for non-malignant conditions (e.g., asthma, IBD, etc.) are permitted as needed.  
Corrected typo, however allowed 
for physiological doses 10 mg oral 
prednisone (or equivalent) in Part C 
as this may be common in the 
treatment population. 
Section 7.2.6 
Determination of 
Patients with 
Melanoma Who 
Progressed on 
Prior Anti-PD-1 
or Anti-PD-L1 
Treatment  
 
An additional section on assessments of patients in Part C has been added.  
 
Section 7.2.6 Determination of Patients with Melanoma Who Progressed on Prior 
Anti-PD-1 or Anti-PD-L1 Treatment 
Patients with melanoma who progressed on prior anti-PD-1 or anti-PD-L1 
treatment must be determined prior to enrollment in Part C - KPT-9274 + 
nivolumab. Screening period includes Day -30 to Day -1 prior to C1D1. 
 
Separate information was 
developed and included for the 
additional arm to administer KPT-
9274 + nivolumab to patients with 
melanoma. 
Section 8.1.2 
Recording of 
Adverse Events 
Updated section on recording of adverse events was included.  
 
Section 8.1.2 Recording of Adverse Events 
Adverse Events will be reported and recorded in the eCRF from the time of the 
first dose of study drug through 30 days after the last dose of study drug or until the 
Instructions for recording of 
adverse events have been updated 
and clarified.  

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start of subsequent antineoplastic therapy, whichever occurs first.  That is, if a 
patient begins a new antineoplastic therapy, the AE reporting period for nonserious 
AEs ends at the time the new treatment is started.  
Adverse events (including laboratory abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying 
signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be recorded as a separate AE. 
The Investigator should ask the patient non-leading questions to determine if any 
AEs have occurred during the study, since the last study visit. Adverse events may 
also be recorded when they are volunteered by the patient, or through physical 
examination, laboratory tests, or other clinical assessments. 
An AE should be followed, and an assessment should be made at each visit (or 
more frequently, if necessary) for any changes in severity of the event, the 
suspected relationship to the study treatment, the interventions required to treat the 
event, and the outcome.  
All AEs occurring during the study are to be followed up in accordance with good 
medical practice until they are resolved, stabilized or judged no longer clinically 
significant or, if a chronic condition, until fully characterized. 
Section 9.1 
General 
Considerations 
Clarification to statistical section 
Section 9.1 General Considerations 
 
Descriptive statistics will be provided to summarize safety and efficacy 
endpoints by study phase, dose cohort, and niacin ER use. In the Dose 
Expansion Phase, data will also be presented by NAPRT1 and IDH1 status 
(positive vs. deficient) and test methodology. For categorical variables, 
summary tabulations of frequency and percentage of patients within each 
category will be presented along with two-sided 95% exact confidence 
intervals where appropriate. For continuous variables, the number of 
patients, mean, median, standard deviation, minimum, and maximum values 
Clarification to the considerations 
for the method and manner of 
application of statistical analysis for 
the study 

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will be presented. Time-to-event data will be summarized using Kaplan-
Meier methodology with associated 2-sided 95% confidence intervals (if 
estimable), as well as percentage of censored observations at dose cohort of 
interest (e.g., RP2D) as appropriate.  
Tabulations will be produced for appropriate disposition, demographic, 
baseline, efficacy, and safety parameters. For categorical variables, 
summary tabulations of the number and percentage of patients within each 
category (with a category for missing data) of the parameter will be 
presented. For continuous variables, the number of patients, mean, median, 
standard deviation, minimum, and maximum values will be presented. 
Time-to-event data will be summarized using Kaplan-Meier methodology 
with median event time and associated 2 sided 95% confidence intervals, as 
well as number and percentage of patients with events and censored 
patients. 
 
Section 9.8.2 
Clinical 
Laboratory 
Values 
Changes made to data tabulation 
Section 9.8.2 Clinical Laboratory Values 
Shift tables that present changes from baseline to worst on-study and baseline to 
last on-study values relative to CTCAE classification ranges will be produced. 
Labs with CTCAE ≥ Grade 3 will be presented in a data listing. Shift tables that 
present changes from baseline to worst on-study values relative to CTCAE 
classification ranges will be produced. 
 
 
Clarification of analysis of selected 
clinical laboratory values to 
enhance understanding of changes 
in lab values. 
 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 1 4 1  
Versi o n 5. 0  
A me n d me nt 4. 0, Versi o n 4. 1  
Versi o n 4. 1 i nc or p or ates c h a n ges t o 4. 0  
A me n d me nt R ati o n ale  
T he pri mar y p ur p ose f or t his a me n d me nt is t o clarif y d osi n g of niaci n E R as a starti n g le vel of 
5 0 0 m g w hic h ma y be titrate d u p t o a dail y d ose of 2, 0 0 0 m g, per la bel.  
T he re vise d pr ot oc ol Versi o n 4. 1 date d 1 3 Dece m ber 2 0 1 7 will be s u b mitte d b y t he Pri nci pal 
I n vesti gat or(s) t o all a p plica ble I nstit uti o nal Re vie w 
B oar ds (I R Bs), I n de pe n de nt Et hics 
C o m mittees (I E Cs), or Researc h Et hics B oar ds ( R E Bs), a n d b y Kar y o p har m T hera pe utics I nc. t o 
all a p plica ble Re g ulat or y A ut h orities.  
A s u m mar y of t he c ha n ges t hat were ma de t o Versi o n 4 . 0 of t he pr ot oc ol i n Versi o n 4.1  is pr o vi de d 
bel o w.  
C h a n ges t o t he pr ot oc ol  
A d mi nistr ati ve  
•  U p date d t he versi o n n u m ber a n d date t o Versi o n 4. 1  a n d 1 3 Dece m ber 2 0 1 7  t hr o u g h o ut 
t o reflect t he c ha n ges ma de i n t his versi o n (M o difie d secti o ns:  Gl o bal).  
•  Ma de i nter nal c ha n ges t o i m pr o ve clarit y a n d eli mi nate i nc o nsiste ncies bet wee n secti o ns 
(M o difie d secti o ns:  Gl o bal).  
Pr ot oc ol A p pr o ver Si g n at ure P a ge  
•  
 t o re place 
, 
M D, P h D, 
 
St u d y R ati o n ale  
•  
o  M o difie d Secti o ns:  S y n o psis, Secti o n  3. 1   
Met h o d ol o g y Secti o n  
•  Re vise d t he te xt f or patie nts i n Part B t o rea d, “..starti n g d ose of 5 0 0 m g niaci n E R ( ma y 
be titrate d t o 2, 0 0 0 m g of dail y d ose, per la bel)  
o  R ati o n ale : T o clarif y t hat niaci n E R ma y d ose ma y i ncrease as necessar y, per t he 
la bel. 
o  M o difie d Secti o ns: S y n o psis, Secti o n 3. 1, Secti o n 4. 2 , Secti o n 6. 1. 1, a n d Secti o n 
6. 2. 6. 1 . 
•  A d de d t he f oll o wi n g te xt f or e nr ol me nt of patie nts acc or di n g t o t heir N A P R T 1 stat us, 
“Base d o n precli nical a n d earl y cli nical data, patie nts will be e nr olle d acc or di n g t o t heir 
N A P R T 1 stat us at a rati o of 2: 1 ( N A P R T 1 ne gati v e: N A P R T 1 p ositi ve). T he N A P R T 1 
P P D
P P D
P P D
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status must be determined prior to enrollment based on evaluation of a fresh tumor biopsy 
or archival tissue taken ≤6 months of screening.” 
o Rationale: To clarify the enrolment of patients based on their NAPRT1 status 
o Modified Sections: Synopsis, Section 3.1 
Dose Expansion Phase 
• Added a statement noting that the composition of the expansion groups may change 
based on the results from the escalation phase. 
o Rationale: To allow for the group(s) in the expansion phase to be defined by the 
results from the escalation phase rather than be pre-defined.  
o Modified Sections: Synopsis, Section 3.1 
Inclusion/Exclusion Criteria 
• New inclusion criteria #11 for patient enrolment according to their NAPRT1 status which 
is specific for the Dose Escalation Phase 
o Rationale: To clarify the enrolment of patients based on their NAPRT1 status 
o Modified Sections: Synopsis, Section 4.2 
• Clarification text added to inclusion #12a for confirmation of NAPRT1 based on the 
evaluation of a fresh tumor biopsy in addition to an archival tumor biopsy 
o Rationale: To provide the investigators with an additional confirmation of 
NAPRT1 status in patients if they do not have an archival tumor biopsy 
o Modified Sections: Synopsis, Section 4.2 
Supportive Care 
• Added the following clarifying statement, “For Part A patients, the addition of niacin ER 
(up to 2,000 mg daily dose) is allowed after completion of the DLT period in cycle 1 
(first 28 days) in an attempt to offset potential side effect (i.e. anemia, arthralgias, 
myalgias, etc.) of KPT-9274.” 
o Rationale: To provide the investigators with dosing guidance in order to offset 
the potential side effects of KPT-9274 
o Modified Sections: Synopsis, Section 6.9.1 
Prohibited Concomitant Medications 
• Added the following statement, “However, for patients in these cohorts that have cleared 
DLT in cycle 1, niacin ER (up to 2,000 mg co-dosed with KPT-9274) may be used as 
supportive care in an attempt to offset potential side effects (e.g. anemia, arthralgias, 
myalgias, etc.) of KPT-9274. Prior to initiating niacin ER, patient symptoms and 
laboratory values should be reviewed and discussed with the Medical Monitor for this 
study.” 
o Rationale: To provide the investigators with dosing guidance in order to offset 
the potential side effects of KPT-9274 

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o Modified Sections: Synopsis, Section 6.9.3 
Schedule of Assessments, Table 1 
• Added the following statement, “If an in-clinic visit is missed during Cycle 1 due to a 
national or local holiday, the patient should come to the clinic on their next dosing day to 
complete the visit assessments. Patient is to be instructed that dose is to be taken in the 
clinic.” 
o Rationale: To clarify the procedure for missed doses during Cycle 1 
o Modified Sections: Table 1 
Schedule of Assessments, Table 1 
• Revised footnote #2 to verify that pre-treament period is Day -30 to Day 7) and added the 
following text, “Dose Escalation Phase: Patients will be enrolled according to their 
NAPRT1 status at a ratio of 2:1 (NAPRT1 negative:NAPRT1 positive). The NAPRT1 
status must be determined prior to enrollment. NAPRT1.” 
o Rationale: To clarify the timeframe for pre-treatment and to clarify the enrolment 
of patients based on their NAPRT1 status 
o Modified Sections: Table 1, footnote #2 
Introduction 
• Added KPT-9274 to Section 1.3.1 to clarify this is the rationale for the KPT-9274 dose. 
 
 
 

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Amendment 3.0, Version 4.0 
Version 4.0 incorporates changes to 3.0. 
Amendment Rationale 
The primary purpose for this amendment is to add assessments to better understand the safety 
profile of KPT-9274.  
These changes have been made to address treatment-emergent adverse events. This includes 
determining the etiology of anemia, arthralgias, and myalgias and courses of treatment to 
alleviate the conditions that emerge. Minor changes that were addressed in memos to the sites are 
also incorporated in this amendment. 
The revised protocol Version 4.0 dated 15 June 2017 will be submitted by the Principal 
Investigator(s) to all applicable Institutional Review Boards (IRBs), Independent Ethics 
Committees (IECs), or Research Ethics Boards (REBs), and by Karyopharm Therapeutics Inc. to 
all applicable Regulatory Authorities. 
A summary of the changes that were made to Version 3.0 of the protocol in Version 4.0 is provided 
below. 
Changes to the protocol 
Administrative 
• Updated the version number and date to Version 4.0 and 15 June 2017 throughout to 
reflect the changes made in this version (Modified sections: Global). 
• Made internal changes to improve clarity and eliminate inconsistencies between sections 
(Modified sections: Global).  
• Updated the potential risks based on the v2.0 of the KPT-9274 Investigator’s Brochure, 
dated 25APR2017 (Modified section: Section 1.2.1). 
Study Population Selection 
• Revised inclusion criterion #10 to increase the hemoglobin level for inclusion from 
≥9.0 g/dL to ≥10 g/dL. 
o Rationale: To reduce the potential for patients to develop life-threatening 
treatment-emergent anemia. 
o Modified Sections: Synopsis, Section 4.2. 
• Removed exclusion criterion #12 (prohibition of use of proton pump inhibitors [PPIs] in 
patients in niacin ER cohorts). 
o Rationale: PPIs are not contraindicated in patients receiving niacin ER according to 
niacin prescribing information 
o Modified Sections: Synopsis, Section 4.3. 
Study Activities 
• Removed Section 5.0 Study Activities and added an overview of the timing for study 
activities and references to the schedule of assessments tables in Section 3.1. Section 

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numbers for Sections 6.0 through 13 of protocol version 3.0 were renumbered, 
accordingly (i.e., to Sections 5.0 through 12). 
o Rationale: Reduce length and complexity of the protocol. 
o Modified Sections: Section 3.1 and Section 5.0 (deleted section from protocol 
version 3.0). 
Study Treatments 
• Revised the starting dose for Part B from “the RP2D defined during Part A” to “a dose 
and schedule that has cleared DLT assessment in Part A.” 
o Rationale: Co-administration of KPT-9274 with niacin to determine if adverse events 
with single agent can be mitigated will be started without having determined the 
MTD with single agent (Part A). 
o Modified Sections: Synopsis, Sections 3.1, 6.2.3, 6.2.5, and 6.2.6.1. 
• Specified the minimum number of KPT-9274 doses during Cycle 1 that patients must 
receive to be evaluable for dose escalation decisions. 
o Rationale: In both Parts A and B, patients must complete a minimum of 1 cycle of 
treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 
12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of 
treatment to be evaluable for dose escalation decisions. 
o Modified Sections: Synopsis, Sections 6.2.6.1, 9.3.3, and 9.3.5 (new section). 
• Revised the volume of fluids required for dosing from at least 4 ounces to 8 to 12 ounces. 
o Rationale: The current volume (4 ounces) of fluids noted in protocol version 3.0 for 
dosing has not demonstrated linear PK with increasing doses. The current KPT-9274 
formulation requires aqueous media for disintegration, dissolution, and absorption. 
The revised recommendation to take KPT-9274 tablets with 8 to 12 ounces of fluids 
may help to provide a more consistent and dose dependent PK profile. 
o Modified Section: Section 6.2.4. 
Supportive Care 
• Added supportive care recommendations for treatment-emergent anemia, arthralgia, and 
myalgia. 
o Rationale: Treatment-emergent anemia, arthralgia, and myalgia are the most 
common AEs reported with KPT-9274 treatment. 
o Modified Sections: Synopsis and Section 6.9.1. 
• Clarified that the use of niacin or niacin-containing supplements includes multivitamins 
and energy drinks. 
o Rationale: To control the amount of niacin consumed by patients on the KPT-9274 + 
niacin cohort. 
o Modified Sections: Synopsis, Section 6.9.3. 

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• Modified to allow patients to receive proton pump inhibitors (removal of PPIs as a 
prohibited medication in patients receiving niacin).  
o Rationale: To be consistent with removal of exclusion criterion #11. 
o Modified Sections: Synopsis, Sections 6.9.1 and 6.9.2.1. 
Assessments 
• Added rheumatology consult and testing for patients with clinically significant joint or 
muscle-related AEs. 
o Rationale: To investigate the mechanism of treatment-emergent arthralgia. 
o Modified Sections: Schedule of Assessments (Table 1, Table 2, and Table 3) and 
Section 7.6.2 (new section). 
• Added hematology consultation and testing for patients with clinically significant 
hematological AEs.  
o Rationale: To further assess the safety profile of KPT-9274 concerning observations 
of non-hemolytic anemia. 
o Modified Sections: Schedule of Assessments (Table 1, Table 2, and Table 3) and 
Section 7.6.3 (new section). 
• Added testing for blood levels of vitamin B12, folate, iron, erythropoietin, haptoglobin, 
and transferrin and reticulocyte counts at Screening and the EoT Visit for all patients. 
This testing may also be performed throughout the study as clinically indicated. For 
patients who develop treatment-emergent anemia, this testing should be performed as 
soon as possible after onset. Patients with ≤ Grade 1 anemia should have their 
levels/counts assessed no less than once a month and patients with ≥ Grade 2 anemia 
should have their levels/counts assessed every 2 weeks. 
o Rationale: To further assess the mechanism of the treatment-emergent non-hemolytic 
anemia observed when patients are dosed with KPT-9274. 
o Modified Sections: Schedule of Assessments (Table 1, Table 2, and Table 3) and 
Section 7.6.4.2 (new section). 
• Added PK sampling time points at C1D24 at 4, 12, 18, and 32 hours post dose for the 
first 18 patients enrolled in the expansion phase. 
o Rationale: To accurately determine the t½ and clearance rate of KPT-9274. 
o Modified Sections: Section 7.4.1 and Table 10. 
Safety Definitions, Recording, and Reporting 
• Revised start time for recording of AEs from “from the first dose of study treatment on 
C1D1 “to “after the patient has provided informed consent” to ensure compliance with 
regulations. 
o Rationale: To ensure compliance with regulations. 
o Modified Sections: Section 8.1 and Table 1. 

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• Updated the safety section with the current standard Karyopharm safety definitions and 
recording/reporting procedures. 
o Rationale: To ensure compliance and consistency across Karyopharm clinical 
studies. 
o Modified Section: Section 8. 
 
 
 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 1 4 8  
Versi o n 5. 0  
A me n d me nt 2. 0, Versi o n 3. 0  
Versi o n 3. 0 i nc or p or ates c h a n ges t o 2. 0.  
A me n d me nt R ati o n ale  
T he pri mar y p ur p ose f or t his a me n d me nt is t o re d uce t he n u m ber of cli nic visits i n res p o nse t o 
i n vesti gat or fee d bac k o btai ne d d uri n g a n I n vesti gat or Meeti n g date d 2 2 Marc h 2 0 1 6.  
A d diti o nal c ha n ges ha ve bee n ma de f or c o nsiste nc y a n d clarit y, i ncl u di n g mi n or a dj ust me nts t o 
t he fre q ue nc y of s o me cli nical la b orat or y assess me nts, ali g n me nt of c ollecti o n of P K sa m ples 
wit h  
 sa m ples, t y pe of disease ass ess me nt sca ns f or N H L t u m or patie nts, i ncl usi o n of 
arc hi val bi o ps y material t o pre -scree n patie nts f or N A P R T 1 a n d I D H 1 t u m or m utati o n stat us, 
a n d creati o n of a n e nr oll me nt all ocati o n i n t he K P T -9 2 7 4 ± niaci n E R d ose e x pa nsi o n ar m t o 
all o w f or a n “eit her” c ate g or y a n d mi ni mize t he p ossi bilit y of a patie nt n ot bei n g e nr olle d i n t he 
trial, a n d clarificati o n of t he defi niti o n of a D L T.  
T he re vise d pr ot oc ol Versi o n 3. 0 date d 0 2 
Ma y 2 0 1 6 will be s u b mitte d b y t he Pri nci pal 
I n vesti gat or(s) t o all a p plica ble I nstituti o nal Re vie w 
B oar ds (I R Bs), I n de pe n de nt Et hics 
C o m mittees (I E Cs), or Researc h Et hics B oar ds ( R E Bs), a n d b y Kar y o p har m T hera pe utics I nc. t o 
all a p plica ble Re g ulat or y A ut h orities.  
A s u m mar y of t he c ha n ges t hat were ma de t o Versi o n 2. 0 of t he pr ot oc ol i n Ve rsi o n 3. 0 is pr o vi de d 
bel o w.  
C h a n ges t o t he pr ot oc ol  
A d mi nistr ati ve  
•  U p date d t he versi o n n u m ber a n d date t o Versi o n 3. 0 a n d 0 2 Ma y 2 0 1 6 t hr o u g h o ut t o 
reflect t he c ha n ges ma de i n t his versi o n (M o difie d secti o ns:  Gl o bal).  
•  I nter nal c ha n ges t o i m pr o ve clarit y an d eli mi nate i nc o nsiste ncies bet wee n secti o ns 
(M o difie d secti o ns:  Gl o bal).  
Re visi o ns t o t he n u m ber of Cli nic Visits t o A d dress I n vesti g at or Fee d b ac k.  
•  N u m ber of cli nic visits were re d uce d:  
o  C h a n ge Fr o m : Scree ni n g assess me nts occ urre d bet wee n Da ys -3 0 t o -1. Cli nic visits 
occ urre d i n C ycle 1 o n Da ys 1, 2, 3, 8, 1 2, 1 5, 1 9, 2 2, 2 6, 2 7, a n d 2 8, C ycle 2 o n Da ys 
1, 5, 8, 1 2, 1 5, 1 9, 2 2, a n d 2 6, a n d C ycles > 3 Da ys 1, 2, 8, 1 2, 1 5, 1 9, 2 2, a n d 2 6.  
o  C h a n ge T o :  Scree ni n g assess me nt ca n occ ur bet wee n eit her Da ys -3 0 t o -1, or Da ys 
-1 4 t o -1. Cli nic visits occ ur i n C ycle 1 o n Da ys 1, 2, 3, 8, 1 5, 2 2, 2 4, 2 5, 2 6, C ycle 2 
Da ys 1, 8, 1 5, a n d 2 2, a n d C ycles > 3 Da ys 1 a n d 1 5.  
•  If d osi n g were t o occ ur o n a M o n d a y, t he n C ycle 1 D a ys 2 7 a n d 2 8 cli nic visits w o ul d 
occ ur o n a wee ke n d a n d w as t h us c h a n ge d t o C ycle 1 D a ys 2 4 a n d 2 5 t o eli mi n ate 
wee ke n d visits.  
•  P h o ne c all d a ys were m o ve d t o T h urs d a ys (if d osi n g occ urs o n a M o n d a y d osi n g) 
a n d a wi n d o w of ±  1 d a y a d de d, e xce pt C ycl e 1 D a y 4 w here wi n d o w w as + 1 d a y t o 
a v oi d c o nflicti n g wit h C ycle 1 D a y 3 i n -cli nic visit. 
•  A dj uste d all c ollecti o n wi n d o ws fr o m ±  5 d a ys t o ±  7 d a ys f or l y m p h n o de c ore 
bi o psies, t u m or bi o psies, a n d M RI, P E T -C T or C T sc a ns.  
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• Comment added to Table 2 to account for in clinic visits that fall on a holiday or 
missed for other reasons, “If an in-clinic visit is missed during Cycle 2 and beyond the 
patient should come in to the clinic on their next dosing day to complete the visit 
assessments. Patient is to be instructed that dose is to be taken in the clinic.” 
• Clarified in-clinic versus at home dosing in Table 4: “Study treatment dosing will 
occur in the clinic during Cycle 1 on Days 1, 3, 8, 15, 22, 24, and 26, during Cycle 2 on 
Days 1, 8, 15, and 22, and during ≥Cycle 3 on Days 1 and 15. Study treatment dosing 
will occur at home during Cycle 1 on Days 5, 10, 12, 17, and 19, during Cycle 2 on Days 
3, 5, 10, 12, 17, 19, 24, and 26 and during Cycles ≥3 on Days 3, 5, 8, 10, 12, 17, 19, 22, 
24, and 26.” 
• Added urinalysis on Cycle 1 Day 3 to be consistent with other clinical assessments. 
• Aligned TSH timepoints with complete serum chemistry. 
• Modified Sections:  Schedule of Assessments, Table 4, Section 6.2, Section 8.2.3, 
Section 8.2.4, Table 10. 
 
Clarified the definition of a DLT with addition of underlined text, “A DLT is defined as an 
AE or abnormal laboratory value that occurs within the first 28 days of treatment with 
KPT-9274, except for those that are clearly and incontrovertibly due to underlying disease, 
disease progression, or extraneous causes, and meets any of the criteria for defining dose-
limiting toxicities as described in the table below. The CTCAE, Version 4.03 will be used 
for grading. In addition, >3 missed (consecutive or nonconsecutive) doses of KPT-9274 in 
the first 28 days due to a drug related toxicity will be considered to be a DLT. 
• The definition of a DLT was revised after consultation with investigators and 
confirmation from the FDA. 
• Modified Sections: Synopsis, Section 8.2.6.2. 
 
Revision to the Dose Expansion Study Flow where dose expansion of KPT-9274 will not be 
run in parallel with Dose Escalation of KPT-9274 + niacin ER and instead a decision will 
be made whether to initiate the Dose Expansion of KPT-9274 + niacin ER. If Dose 
Expansion of KPT-9274 + niacin ER is initiated, then an optional Dose Expansion with 
KPT-9274 single agent may be initiated.  
• Changed From: After declaring the RP2D ± niacin ER, based on the safety and 
tolerability results of the Dose Escalation Phase, at least one clinical response 
(minimum of stable disease ~8 weeks) must be seen in any of the first ten patients 
treated at the RP2D in order to fully enroll the expansion cohort. These 10 patients 
include the patients enrolled under the 3+3 design for DLT assessment; if necessary, 
additional patients will be enrolled to a maximum of 10 patients. If no clinical 
responses are observed, the study will be stopped for futility. If a clinical response is 
observed at any time, then enrollment of the full expansion cohort may proceed. 
Initiation of the KPT-9274 + niacin escalation will not be dependent upon 
demonstration of clinical benefit of the single agent, but futility at the KPT-9274 + 
niacin RP2D will be assessed prior to full expansion using the same criterion as 
described above for the single agent KPT-9274. During the Dose Expansion Phase, 

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up to 65 additional patients (up to 20 patients in the KPT-9274-only cohort and up to 
45 patients in the KPT-9274 + niacin ER cohort) with advanced solid malignancies 
and NHL may be enrolled to further explore safety, tolerability and preliminary 
evidence of anti-tumor activity of the RP2D of KPT-9274 ± niacin ER. Each cohort 
may be expanded at the time the RP2D for that cohort is declared. Note that 
preliminary clinical results may define the patient population (i.e., specific 
indications) selected for enrollment in the Dose Expansion Phase. 
The KPT-9274 + niacin ER expansion cohort will consist of 3 groups of approximately 
15 patients each including: 
o NAPRT1 deficient tumor group 
o NAPRT1 positive tumor group 
o IDH1 mutant tumor group 
Patients in the Dose Expansion Phase may be treated with the RP2D of KPT-9274 ± 
niacin ER according to the same schedule administered in the Dose Escalation Phase of 
the study.  
• Changed To: After completion of the Dose Escalation parts A and B, Dose 
Expansion in up to 65 additional patients with advanced solid malignancies and NHL 
may be conducted to further explore safety, tolerability and preliminary evidence of 
anti-tumor activity of the RP2D of KPT-9274 ± niacin ER. Note that preliminary 
clinical results may define the patient population (i.e., specific indications) selected 
for enrollment in the Dose Expansion Phase. 
After declaring the RP2D for KPT-9274 single agent and KPT-9274 + niacin ER, based 
on the safety and tolerability results of the Dose Escalation Phase, a decision will be 
made whether expansion (4 groups, ~45 patients total) will be conducted at the RP2D of 
KPT-9274 single agent or at the RP2D of KPT-9274 + niacin ER. If the ~45 patient 
expansion is conducted at the RP2D of KPT-9274 + niacin ER, an optional expansion 
with <20 patients at the RP2D of KPT-9274 single agent may also be initiated. 
At least one clinical response (minimum of stable disease ~8 weeks) must be seen in any 
of the first ten patients treated at the RP2D in order to fully enroll either expansion 
cohort. These 10 patients include the patients enrolled under the 3+3 design for DLT 
assessment; if necessary, additional patients will be enrolled to a maximum of 10 
patients. If no clinical responses are observed, the study will be stopped for futility. If a 
clinical response is observed at any time, then enrollment of the full expansion cohort 
may proceed. Initiation of the KPT-9274 + niacin ER escalation will not be dependent 
upon demonstration of clinical benefit of the single agent, but futility at the KPT-9274 + 
niacin ER RP2D will be assessed prior to full expansion using the same criterion as 
described above for the single agent KPT-9274.  
The KPT-9274 ± niacin ER expansion cohort will consist of 4 groups of approximately 
45 patients including: 
I. NAPRT1 deficient tumor group, approximately 10 patients 
II. NAPRT1 positive tumor group, approximately 10 patients 
III. Either NAPRT1 deficient or positive tumor group, approximately 10 patients 

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 1 5 1  
Versi o n 5. 0  
I V. I D H 1 m uta nt t u m or gr o u p, a p pr o xi matel y 1 5 patie nts 
A n a d diti o nal, o pti o nal K P T -9 2 7 4 si n gle a ge nt e x pa nsi o n c o h ort will c o nsi st of 
< 2 0  patie nts wit h a n y t u m or m utati o nal stat us.  
•  M o difie d Secti o ns : S y n o psis, Fi g ure 1, Secti o n 3. 1, Secti o n 8. 2. 3, Secti o n 8. 2. 7, 
Secti o n 1 1. 2 . 
P K a n d  
 s a m ple c ollecti o ns were ali g ne d a n d a dj ust me nts were m a de t o acc o m m o d ate 
t he re d ucti o n i n n u m ber of cli nic visits. P K a n d  
 c ollecti o n ti me p oi nts a n d bl o o d 
v ol u mes were c o ns oli d ate d i nt o o ne t a ble.  
•  C h a n ge Fr o m : P K bl o o d dra ws: C ycle ( C) 1 Da y ( D) 1 ( pre -d ose; 0. 5, 1, 2, 4, a n d 8 
h o urs p ost -d ose), C ycle 1 Da y 2 ( 2 4 h o urs p ost first d ose o n C 1 D 1), C ycle 1 Da y 3 
( 4 8 h o urs p ost first d ose o n C 1 D 1, pri or t o C 1 D 3 d ose), C ycle 1 Da y 1 5 ( pre-d ose; 1, 
2, 4, 8 h o urs p ost -d ose), C ycle 1 Da y 2 6 ( pre -d ose, 1, 2, 4, 8 h o urs p ost -d ose), a n d 
C ycle 2 Da y 1 5 ( pre -d ose a n d 2 h o urs p ost -d ose).  
•  C h a n ge T o : P K bl o o d dra ws: C ycle ( C) 1 Da y ( D) 1 ( pre -d ose, 0. 5, 1, 2, 4, a n d 8 
h o urs p ost -d ose), C ycle 1 Da y 2 ( 2 4 h o urs p ost first d ose o n C 1 D 1), C ycle 1 Da y 3 
( 4 8 h o urs p ost first d ose o n C 1 D 1, pri or t o C 1 D 3 d ose), C ycle 1 Da y 8 ( pre-d ose a n d 
2 h o urs p ost -d ose),  C ycle 1 Da y 1 5 ( pre -d ose a n d 2 h o urs p ost -d ose), C ycle 1 Da y 2 4 
( pre-d ose, 2 a n d 8 h o urs p ost -d ose), C ycle 1 Da y 2 5 ( 2 4 h o urs p ost first d ose o n 
C 1 D 2 4), C ycle 1 Da y 2 6 ( pre -d ose, 1, 2, 4, a n d 8 h o urs p ost -d ose), C ycle 2 Da y 1 5 
( pre-d ose a n d 2 h o urs p ost -d ose), C ycle 3 Da y 1 ( pre -d ose, 2 a n d 2 4 h o urs p ost -d ose), 
C ycle 5 a n d be y o n d Da y 1 of o d d c ycles o nl y ( pre -d ose a n d 2 4 h o urs p ost -d ose), a n d 
E n d -of -T hera p y visit.  
•  M o difie d Secti o n : S y n o psis, Sc he d ule of Assess me nts, Secti o n 6. 2, Secti o n 9. 4. 1, 
Secti o n 9. 5. 1, Ta ble 1 0.  
 
Cl arifie d sc a ns f or dise ase assess me nt f or N H L.  
•  C h a n ge Fr o m : Disease res p o nse will be base d o n t u m or meas ure me nt usi n g c o m p ute d 
t o m o gra p h y ( C T) sca ns ( prefera bl y P E T/ C T) or, if C T is c o ntrai n dicate d, ma g netic 
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resonance imaging (MRI) scans [preferably PET/MRI]. Scans will be conducted at 
Screening and after every 8 weeks ± 1 week (e.g., Day 1 of odd numbered cycles) until 
disease progression or the EoT visit. EoT scan is only required for patients who end 
treatment for reasons other than disease progression. The same scan modality should be 
used for all assessments. CT or MRI acceptable, however, PET-CT or PET MRI is 
strongly preferred 
• Change To: Disease response will be preferably based on tumor measurement using 
PET/CT for FDG-avid lymphomas, or CT for non-FDG-avid lymphomas (or PET/MRI or 
MRI if CT is contraindicated) scans. Scans will be conducted at Screening (Day -30 to 
Day -1) and after every 8 weeks ± 7 days (e.g., Day 1 of odd numbered cycles) until 
disease progression or the EoT visit. EoT scan is only required for patients who end 
treatment for reasons other than disease progression. 
Modified Sections: Schedule of Assessments Footnotes 12 and 19, Section 6.2, Section 9.3.2.1. 
Additional text to Inclusion Criteria #11: 
a. Confirmation of NAPRT1 expression and IDH1 mutation based on evaluation of 
archival tumor biopsy taken ≤6 months of screening tests as follows: 
i. NAPRT1 positive for expansion cohort I or III 
ii NAPRT1 negative for expansion cohort II or III 
iii. IDH1 mutation status for expansion cohort IV 
Modified Sections: Synopsis, Section 4.2. 
 
Modified Exclusion Criteria #2 and #3: 
• 
Change From:  
2. Time since the last prior therapy for treatment of advanced solid malignancies or 
NHL**: 
a. Radiation, chemotherapy, immunotherapy or any other anticancer therapy, including 
investigational anti-cancer therapy ≤2 weeks prior to C1D1. 
b. Palliative steroids for disease related symptoms <7 days prior to C1D1.  
**Patients must have recovered or stabilized (≤Grade 2 or to their baseline) from 
toxicities related to their previous treatment except for alopecia. 
3. Patients with central nervous system (CNS) disease or leptomeningeal involvement, 
regardless of response to prior therapy, are excluded. 
• 
Change To: 
2. Time since the last prior therapy for treatment of advanced solid malignancies or 
NHL**: 
a. Radiation, chemotherapy, immunotherapy or any other anticancer therapy, including 
investigational anti-cancer therapy ≤2 weeks prior to C1D1. 
b. Palliative steroids for disease related symptoms <7 days prior to C1D1.  
**Patients must have recovered or stabilized (Grade 1 or to their baseline for non-
hematologic toxicities, ≤Grade 2 or to their baseline for hematologic toxicities) from 
toxicities related to their previous treatment except for alopecia. In specific cases, patients 

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with Grade 2 non-hematologic toxicities will be allowed following approval by the 
Karyopharm medical monitor. 
3. Patients with known central nervous system (CNS) disease or leptomeningeal 
involvement, regardless of response to prior therapy, are excluded. 
Modified Sections: Synopsis, Section 4.3. 
 
Removed lymph node and tumor biopsies from EoT Visit 
Modified Section: Section 6.2.3.1. 
 
Clarified determination of NAPRT1 and IDH1 mutational status: Archival tumor biopsy 
taken ≤6 months of screening tests: 1. positive or deficient for NAPRT1 expression status 
for the Dose Expansion cohorts I-III; 2. positive for IDH1 mutation status for Dose 
Expansion cohort IV. If a patient's archival tumor biopsy is NAPRT1 positive and the 
NAPRT1 positive cohort is fully enrolled (10 patients) then patient is added to the NAPRT1 
positive or deficient cohort (10 patients). If the NAPRT1 positive or deficient cohort is full 
then the patient will be excluded. If the IDH1 mutation cohort is full (15 patients) then the 
patient will be excluded. Under all circumstances a fresh biopsy will be taken during 
screening to verify NAPRT1 or IDH1 status. If a patient's tumor NAPRT1 or IDH1 status 
has changed and as a result no longer qualify for any cohorts, then the patient will be 
excluded.  
• Change:  Prescreening to determine NAPRT1 and IDH1 tumor status will be performed 
on archival biopsy material obtained ≤6 months prior to Screening for Dose Expansion 
Phase.  
• Modified Sections:  Synopsis, Schedule of Assessments, Figure 1. Study Flow Chart, 
Section 3.1, Section 4.3, Section 6.2, Section 8.2.7, Section 9.2.5. 
 
Revised language to control for niacin bioequivalency: language was added to specify that 
niacin ER will be administered as a fixed dose of 500 mg and must be any FDA approved 
prescription generic extended release niacin, a list of which will be provided by 
Karyopharm in the Pharmacy Manual.  
• Modified Section: Section 8.1.1. 
 
Removed Section 8.2.8.2 because no adjustments will be made to the dose of niacin.  
• Modified Section: Section 8.2.8.2. 
 

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Amendment 1.0, Version 2.0 
Version 2.0 incorporates changes to 1.0. 
Amendment Rationale 
The primary purpose for this amendment is to address clinical deficiency items identified by the 
FDA in the Clinical Information Request dated 19 February 2016 and in the Clinical Information 
Request #2 dated 25 February 2016.  
Additional changes have been made for consistency and clarity, including minor adjustments to 
the frequency of some clinical laboratory assessments and standardization of the timing of 
disease assessment scans for NHL and solid malignancy patients (every 8 weeks until disease 
progression).  
The revised protocol Version 2.0 dated 26 February 2016 will be submitted by the Principal 
Investigator(s) to all applicable Institutional Review Boards (IRBs), Independent Ethics 
Committees (IECs), or Research Ethics Boards (REBs), and by Karyopharm Therapeutics Inc. to 
all applicable Regulatory Authorities. 
A summary of the changes that were made to Version 1.0 of the protocol in Version 2.0 is provided 
below. 
Changes to the protocol 
Administrative 
• Updated the version number and date to Version 2.0 and 26 February 2016 
throughout to reflect the changes made in this version (Modified sections: Global). 
• Internal changes to improve clarity and eliminate inconsistencies between sections 
(Modified sections: Global).  
Changes to Address Clinical Deficiencies identified by FDA: 
1. All patients with CNS disease or leptomeningeal involvement, regardless of response 
to prior therapy, should be excluded. 
• Change:  A new exclusion criterion (#3) has been inserted: “Patients with central 
nervous system (CNS) disease or leptomeningeal involvement, regardless of response to 
prior therapy, are excluded.” 
• Modified Sections:  Synopsis, Section 4.3. 
 
2. Regarding infection in the exclusion criteria (item #6): This item should read 
“Active infection with completion of therapeutic antibiotics, antivirals, or 
antifungals within one week prior to C1D1. Prophylactic antibiotics, antivirals or 
antifungals are permitted.” 
• Change:  Exclusion criteria #6 has been revised with the requested language.  
• Modified Sections:  Synopsis, Section 4.3. 
 

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3. If an adverse event meets criteria for a DLT, it should be considered a DLT 
regardless of attribution or “clinical meaningfulness”. Remove the following 
language and any reference to this language: “In rare instances, an event may fall 
within the definition of a DLT as defined above but the event may be considered not 
to be a DLT (e.g., not clinically meaningful/significant). If this occurs, a Dose 
Decision Meeting with all investigators and Karyopharm/Medical Monitor will take 
place to thoroughly review the event and supporting data and the reasons for not 
considering the event to be a DLT will be clearly documented with supporting 
rationale.” 
• Change:  The definition of a DLT has been changed in the revised protocol (Version 
2.0). 
Change From: 
A DLT is defined as an AE or abnormal laboratory value that occurs within the first 
28 days of treatment with KPT-9274 and meets any of the criteria included in the table 
below. The CTCAE, Version 4.03 will be used for grading. In addition, >3 missed 
(consecutive or non-consecutive) doses of KPT-9274 in the first 28 days due to a drug 
related toxicity will be considered to be a DLT. 
In rare instances, an event may fall within the definition of a DLT as defined above but 
the event may be considered not to be a DLT (e.g., not clinically meaningful/significant). 
If this occurs, a Dose Decision Meeting with all investigators and Karyopharm/Medical 
Monitor will take place to thoroughly review the event and supporting data and the 
reasons for not considering the event to be a DLT will be clearly documented with 
supporting rationale. In addition, other events may occur which do not meet the definition 
of a DLT, but are of concern to the Investigators and Karyopharm, and may e then be 
considered to be DLTs. 
Change To: 
A DLT is defined as an AE or abnormal laboratory value that occurs within the first 
28 days of treatment with KPT-9274 and meets any of the criteria included in the table 
below. The CTCAE, Version 4.03 will be used for grading. In addition, >3 missed 
(consecutive or non-consecutive) doses of KPT-9274 in the first 28 days due to a drug 
related toxicity will be considered to be a DLT. 
Other events may occur which do not meet the definition of a DLT, but are of concern to 
the Investigators and Karyopharm and may be considered to be DLTs. 
• Modified Sections:  Synopsis, Section 8.2.6.2. 
 
4. Remove language allowing resumption of KPT-9274 following a DLT (in the first 
28 days). Under no circumstances should a patient resume KPT-9274 following a 
DLT regardless of attribution or response to treatment. 
• Change:  The requested change has been made and incorporated into the revised protocol 
(Version 2.0).  
Change From: 

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In the event of a DLT (Cycle 1) during the Dose Escalation Phase: 
• Discontinue KPT-9274 
• KPT-9274 may be re-introduced upon recovery to Grade ≤1 or baseline at one 
dose level lower at the discretion of the Investigator after consulting the 
Karyopharm Medical Monitor. (see Table 8) 
Change To: 
In the event of a DLT (Cycle 1) during the Dose Escalation Phase the patient must 
discontinue KPT-9274. 
• Modified Section: Section 8.2.8. 
 
5. Remove attribution from the dose reduction schema. Doses of KPT-9274 should be 
reduced if subjects experience AEs regardless of investigator attribution. 
• Change:  The requested change has been made to the title of Table 8 and the headings 
and applicable text within Table 9.  
Change From: 
For patients who do not tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to allow the patient to continue the study treatment 
(see Section 8.2.8.2 for niacin ER dose adjustments). The criteria for dose 
modifications of KPT-9274 for toxicities considered at least possibly related to the 
study medication treatment are outlined in  Table 8. These changes must be recorded on 
the eCRF. If a patient requires a dose delay of more than 28 days (>28 days) from the 
intended day of the next scheduled dose, then the patient should be discontinued from 
the study (in exceptional situations, if the patient is clearly benefiting from the study 
treatment, and in the opinion of the Investigator no safety concerns are present, 
after discussion with the Karyopharm Medical Monitor, the patient may remain in the 
study). 
Change To: 
For patients who do not tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to allow the patient to continue the study treatment 
(see Section 8.2.8.2 for niacin ER dose adjustments). The criteria for dose 
modifications of KPT-9274 for toxicities are outlined in Table 8. These changes must 
be recorded on the eCRF. If a patient requires a dose delay of more than 28 days 
(>28 days) from the intended day of the next scheduled dose, then the patient should be 
discontinued from the study (in exceptional situations, if the patient is clearly benefiting 
from the study treatment, and in the opinion of the Investigator no safety concerns 
are present, after discussion with the Karyopharm Medical Monitor, the patient may 
remain in the study). 
• 
Modified Section: Section 8.2.8. 
 

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6. Provide formal stopping criteria in the dose expansion cohorts for safety. The 
following statement is inadequate: “Interim safety data will be examined on an 
ongoing basis to ensure patient safety and to comply with the clinical study dose 
escalation rules.” 
• Change:  Addition of specific guidance for safety assessment of dose expansion cohorts 
(KPT-9274 ± niacin ER, evaluated separately).  
Change From:    
For the Dose Expansion Phase, if an event meeting the definition of a DLT, but 
without necessarily occurring within the first 28 days, is observed in >33% of 
patients at any time, the sponsor may elect to reduce the dose for enrolled patients 
and to resume enrollment of the expansion cohort at this lower dose, or the 
enrollment into the expansion cohort will may be stopped. Since the target patient 
population is patients who are not candidates for anti-tumor regimens known to 
provide clinical benefit, no formal futility monitoring is planned for the expansion 
cohort. 
Change To: 
For the Dose Expansion Phase (KPT-9274 ± niacin ER, evaluated separately), if an 
event meeting the definition of a DLT, but without necessarily occurring within the 
first 28 days, is observed in >33% of patients at any time, or if >33% of treated 
patients have withdrawn consent due to toxicity, enrollment will be held and a 
meeting with all investigators and Karyopharm/Medical Monitor will take 
place to review the events and discuss their clinical significance. Based on this 
review, the sponsor may elect to reduce the dose for enrolled patients and to resume 
enrollment of the expansion cohort at this lower dose, or the enrollment into the 
expansion cohort will may be stopped. Since the target patient population is patients 
who are not candidates for anti-tumor regimens known to provide clinical benefit, 
no formal futility monitoring is planned for the expansion cohort. 
• Modified Sections: Synopsis, Section 11.8  
 
7. Provide futility stopping criteria after the dose escalation phases. Subjects should 
not be enrolled in the dose expansion cohorts if there is no evidence of clinical 
benefit. 
• Change:  The protocol has been modified to require at least one clinical response in the 
first 10 patients in the RP2D cohort prior to full dose expansion.  
Change From:    
After declaring the RP2D ± niacin ER, based on the safety and tolerability results 
of the Dose Escalation Phase, up to 65 additional patients (up to 20 patients in the 
KPT-9274-only cohort and up to 45 patients in the KPT-9274 + niacin ER cohort) 
with advanced solid malignancies and NHL may be enrolled to further explore 
safety, tolerability and preliminary evidence of anti-tumor activity of the RP2D of 
KPT-9274 ± niacin ER. Each cohort may be expanded at the time the RP2D for that 

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Version 5.0 
cohort is declared. Note that preliminary clinical results may define the patient 
population (i.e., specific indications) selected for enrollment in the Dose Expansion 
Phase. 
Change To: 
After declaring the RP2D ± niacin ER, based on the safety and tolerability results of 
the Dose Escalation Phase, at least one clinical response (minimum of stable 
disease ~8 weeks) must be seen in any of the first ten patients treated at the 
RP2D in order to fully enroll the expansion cohort. These 10 patients include the 
patients enrolled under the 3+3 design for DLT assessment; if necessary, 
additional patients will be enrolled to a maximum of 10 patients. If no clinical 
responses are observed, the study will be stopped for futility. If a clinical 
response is observed at any time, then enrollment of the full expansion cohort 
may proceed. Initiation of the KPT-9274 + niacin escalation will not be 
dependent upon demonstration of clinical benefit of the single agent, but futility 
at the KPT-9274 + niacin RP2D will be assessed prior to full expansion using the 
same criterion as described above for the single agent KPT-9274. During the 
Dose Expansion Phase, up to 65 additional patients (up to 20 patients in the 
KPT-9274-only cohort and up to 45 patients in the KPT-9274 + niacin ER cohort) 
with advanced solid malignancies or NHL may be enrolled to further explore safety, 
tolerability, and preliminary evidence of anti-tumor activity of the RP2D of 
KPT-9274 ± niacin ER. Each cohort may be expanded at the time the RP2D for that 
cohort is declared. Note that preliminary clinical results may define the patient 
population (i.e., specific indications) selected for enrollment in the Dose Expansion 
Phase. 
• Modified Sections:  Synopsis, Section 8.2.7. 
 
8. For the biopsies on C1D26 and C6D1, include a clause that will allow patients to 
continue treatment if (1) a patient refused biopsy or (2) if it is the opinion of the 
treating physician or physician performing biopsy that the biopsy would pose 
significant risk to the patient or (3) if the biopsy sample obtained on first attempt 
was inadequate for analysis. Commensurate language should be included in the 
informed consent document as well. 
• Change:  The requested change has been made and incorporated into the revised protocol 
(Version 2.0).  
• Modified Sections:  Synopsis, Table 1-3, footnote 2, Sections 4.2, 9.5.1.  
Indication  
• Sarcomas have been added as an example of the advanced solid malginancy indication  
o Rationale:  Sarcomas are an indication of interest to Karyopharm Therapeutics, 
as Ph1 and Ph2/3 studies in sarcoma patients treated with a different compound 
(selinexor) are in progress.  
o Modified Sections:  Synopsis, Sections 1.1, 4.1. 
Inclusion Criteria  

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 1 5 9  
Versi o n 5. 0  
•  A d diti o n  of ne w i ncl usi o n criteri o n # 5: “Patie nts m ust ha ve a site of disease a me na ble t o 
bi o ps y a n d be a ca n di date f or bi o ps y acc or di n g t o t he treati n g i nstit uti o n’s g ui deli nes.”  
o  R ati o n ale :  Bi o ps y tiss ue will be nee de d f or st u dies t o i de ntif y  
 of 
res p onse, t o better u n dersta n d t he K P T -9 2 7 4 mec ha nis ms of acti o n a n d resista nce, 
a n d t o deter mi ne tar get e n ga ge me nt b y meas uri n g P A K 4, N A M P T or c ha n ges i n 
d o w nstrea m si g nali n g pat h wa ys. W hile eac h patie nt m ust be a ca n di date f or 
bi o ps y at e nr oll me nt, t he decisi o n a b o ut t he safet y a n d feasi bilit y of perf or mi n g 
a n y bi o ps y is left t o i n vesti gat or a n d patie nt per g ui da nce else w here i n t he 
pr ot oc ol.  
o  M o difie d Secti o ns:   S y n o psis, Secti o n 4. 2.  
•  I ncl usi o n criteri o n # 7:  decrease d ma xi mal all o wa ble t otal bilir u bi n fr o m ≤2 ti mes t he 
u p per li mit of n or mal t o < 1. 5 ti mes t he u p per li mit of n or mal.  
o  R ati o n ale :  Re q uest fr o m F D A i n St u d y Ma y Pr ocee d Letter date d 0 3 Marc h 
2 0 1 6.  
o  M o difie d Secti o ns:   S y n o psi s, Secti o n 4. 2. 
•  I ncl usi o n criteri o n # 8:  i ncrease d mi ni mall y acce pta ble creati ni ne cleara nce fr o m ≥4 0 
m L/ mi n t o ≥6 0 m L/ mi n.  
o  R ati o n ale :  Re q uest fr o m F D A i n St u d y Ma y Pr ocee d Letter date d 0 3 Marc h 
2 0 1 6.  
o  M o difie d Secti o ns:   S y n o psis, Secti o n 4. 2.   
Assess me nt s 
•  M o difie d t he fre q ue nc y of select cli nical safet y assess me nts ( wei g ht, s y m pt o m -directe d 
p h ysical e xa m) a n d cli nical la b orat or y assess me nts ( uri nal ysis, c o m plete bl o o d c o u nt 
wit h differe ntial, c o m plete ser u m c he mistr y).  
o  R ati o n ale :  Mi n or a dj ust me nts t o reflect a p pr o priate fre q ue nc y of assess me nts 
relati ve t o t he fre q ue nc y of cli nic visits, a n d f or c o nsiste nc y bet wee n sc he d ule of 
assess me nt ta bles a n d secti o n 6. 2.   
o  M o difie d Secti o ns:   Sc he d ule of As sess me nts ( Ta bles 1-3), Secti o n  6. 2 . 
•  A d de d a pre -d ose E C G o n C ycle 1 Da y 2 6, res ulti n g i n c oi nci de nt pre -d ose a n d 4 h o ur 
p ost -d ose (esti mate d K P T -9 2 7 4 T ma x ) E C Gs a n d P K bl o o d sa m ples.  
o  R ati o n ale : A d dress re q uest fr o m F D A i n Stu d y Ma y Pr ocee d Letter date d 
0 3  Marc h 2 0 1 6 t o i ncl u de sa m pli n g t o ca pt ure  lar ge car diac safet y si g nals. T he 
ti me matc he d C 1 D 2 6 pre- a n d p ost-d ose P K sa m ples a n d E C Gs will all o w pre - 
a n d p ost -d ose (at esti mate d K P T-9 2 7 4 T ma x ) assess me nt of car diac c ha n ges after 
4  wee ks of d osi n g. T hese data will all o w c o m paris o n of car diac c ha n ges  after o ne 
d ose ( C 1 D 1) a n d after 4 wee ks of d osi n g ( C 1 D 2 6).  
o  M o difie d Secti o ns:  Sc he d ule of Assess me nts ( Ta ble 1 a n d f o ot n ote # 5), 
Secti o n  6. 2. 2. 5 . 
C CI

I n vesti gati o nal Pr o d uct ( K P T-9 2 7 4 ) 
 
Kar y o p har m T hera pe utics I nc.  
Cli nical St u d y Pr ot oc ol: K C P -9 2 7 4 -9 0 1  
 
1 1 Marc h  2 0 2 0  
 
C o nfi de ntial  
Pa ge 1 6 0  
Versi o n 5. 0  
•  C ha n ge d fre q ue nc y of disease assess me nt sca ns f or s oli d mali g na nc y patie nts fr o m e ver y 
6 wee ks t o e ver y 8 we e ks; i n dicate d t hat E o T sca ns are o nl y re q uire d f or patie nts w h o 
e n d treat me nt f or reas o ns ot her t ha n disease pr o gressi o n.  
o  R ati o n ale : Sta n dar dize fre q ue nc y of disease assess me nts f or s oli d mali g na nc y 
a n d N H L patie nts; eli mi nate E o T sca n f or patie nts w h o h a d a disease assess me nt 
sca n at t he ti me of t heir disease pr o gressi o n pri or t o E o T visit.  
o  M o difie d Secti o ns:  Sc he d ule of Assess me nts ( Ta bles 1 -3), Secti o ns 6. 2, 9. 3. 2, 
9. 3. 3 . 
Refere nces  
•  Re m o ve d t w o refere nces t hat d o n ot a p pear i n t he pr ot oc ol.  
o  R ati o n ale :  C orrecti o n of te xt err ors.  
o  M o difie d Secti o n:   Secti o n 1 3 . 
 
 
C CI