Clinical trial NCT04854434
Conditions: Metastatic Colorectal Cancer
Sponsor: Karyopharm Therapeutics Inc
Start date: 2021-06-29; Completion date: 2022-06-24
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of selinexor alone or with pembrolizumab in participants with advanced or metastatic colorectal cancer (CRC). Approximately 78 participants with advanced or metastatic CRC will be enrolled, and randomized (1:1:1) into three arms A (selinexor only), B (selinexor and pembrolizumab), and C (standard of care \[Combination of trifluridine and tipiracil\]). Randomization will be based on stratification factors: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 versus 2. The end of treatment (EoT) visit will occur less than or equal to (\<=30) days post-treatment discontinuation. A survival follow-up visit will be performed every 3 months from EoT and will continue for 12 months.

Detailed description:

Arms: arm 1: Participants received a single dose of selinexor 80 mg (4 tablets of 20 mg) orally QW on Day 1 of each week of a 42-day cycle (i.e., on Days 1, 8, 15, 22, 29, and 36 of each 42-day cycle) until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 33 weeks). arm 2: Participants received a single dose of selinexor 80 mg (4 tablets of 20 mg) orally QW on Day 1 of each week of a 42-day cycle (i.e., on Days 1, 8, 15, 22, 29, and 36 of each 42-day cycle) in combination with pembrolizumab 400 mg IV once every 6 weeks of each 42-day cycle until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 30 weeks). arm 3: Participants received combination of trifluridine and tipiracil 35 mg/m\^2/dose tablets orally BID (maximum 80 mg per dose) as SOC on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 11 weeks).
Interventions: intervention 1: Selinexor intervention 2: Pembrolizumab intervention 3: Trifluridine intervention 4: Tipiracil
Intervention descriptions: intervention 1: Participants will receive selinexor oral tablets. intervention 2: Participants will receive pembrolizumab intravenously. intervention 3: Participants will receive trifluridine oral tablets as SOC. intervention 4: Participants will receive tipiracil oral tablets as SOC.

Protocol documents:
Prot_000.pdf: 
Cli nical St u d y Pr ot oc ol : X P O R T-C R C -0 4 1  
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C LI NI C A L S T U D Y P R O T O C O L  
X P O R T -C R C - 0 4 1 ( SeR A S ) 
 
A P h ase 2 O pe n - La bel M ultice nter S t u d y t o E v al u ate t he S afet y 
a n d E ffic ac y of S eli ne x or wit h or wit h o ut P e m br oliz u m a b vers us 
S t a n d ar d of C are i n P re vi o usl y tre ate d M et ast atic C ol orect al 
C a ncer wit h R A S m ut ati o n s  
St u d y N u m ber:  
X P O R T -C R C -0 4 1  
St u d y P h ase:  
P hase 2  
I n vesti g ati o n al Pr o d uct: 
Seli ne x or ( K P T -3 3 0)  
I N D N u m ber : 
I n dic ati o n: 
Pre vi o usl y treate d metastatic c ol orectal ca ncer wit h R A S 
m utati o n t y pe  
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. + 1  ( 6 1 7) 6 5 8-0 6 0 0  
Pr ot oc ol D ate a n d Versi o n:  
2 0  A pril  2 0 2 1, Versi o n 1. 0  
2 6 Ma y  2 0 2 1, Versi o n 2. 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 u ncil f or Har m o nisati 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 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 will be use d o nl y f or t he discl os ure herei n pr o vi de d. N o discl os ure 
or p u blicati o n will 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


Cli nical St u d y Pr ot oc ol: X P O R T- C R C- 0 4 1 
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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 
I h a ve rea d a n d u n dersta n d t he c o nte nts of t his cli nical pr ot ocol f or St u d y X P O R T- C R C- 0 4 1 
date d 2 6 Ma y 2 0 2 1 a n d a gree t o meet all o bli gati o ns of Kar y o p ha r m T hera pe utics I nc., as 
detaile d i n all a p plica ble re g ulati o ns a n d g ui deli nes. I n a d dit i o n, I will i nf or m t he Pri nci pal 
I n v esti gat or a n d all ot her I n v esti gat ors of all rele va nt i nf or mati o n t hat bec o mes a vaila ble d uri n g 
t he c o n d uct of t his St u d y. 
A p pr o ve d B y:  
 
 P h D 
K ar y o p h ar m T her a pe utics I nc.  
 
 
 
 
 
D ate  
 
, M D 
K ar y o p h ar m T her a pe utics I nc.  
 
 
 
D ate  
 
 
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D


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INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of this clinical protocol for Study XPORT-CRC-041 
dated 26 May 2021 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 
 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF FIGURES .........................................................................................................................8 
LIST OF TABLES ...........................................................................................................................8 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
PROTOCOL SUMMARY ..........................................................................................13 
1.1. 
Schedule of Assessments ............................................................................................20 
2. 
INTRODUCTION ......................................................................................................26 
2.1. 
Colorectal Cancer .......................................................................................................26 
2.2. 
Study Rationale ...........................................................................................................27 
2.3. 
Selinexor .....................................................................................................................28 
2.4. 
Dose Justification (Monotherapy and Combination) ..................................................33 
2.5. 
Benefit/Risk Assessment ............................................................................................34 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................35 
4. 
STUDY DESIGN .......................................................................................................37 
4.1. 
Overall Design ............................................................................................................37 
4.2. 
End of Treatment ........................................................................................................38 
4.3. 
Safety Follow-Up Visit and Survival Follow-Up Visit ..............................................38 
5. 
STUDY POPULATION .............................................................................................39 
5.1. 
Inclusion Criteria ........................................................................................................39 
5.2. 
Exclusion Criteria .......................................................................................................39 
5.3. 
Screen Failures ............................................................................................................41 
6. 
STUDY TREATMENT ..............................................................................................42 
6.1. 
Study Treatments Administered .................................................................................42 
6.2. 
Study Drug Dosing and Administration .....................................................................42 
6.2.1. 
Labeling ......................................................................................................................42 
6.2.2. 
Dispensing Directions .................................................................................................42 
6.2.3. 
Dosing Information .....................................................................................................43 
6.3. 
Preparation/Handling/Storage/Accountability ............................................................43 
6.4. 
Study Treatment Compliance .....................................................................................43 
6.5. 
Concomitant Medication ............................................................................................43 
6.5.1. 
Prohibited Concomitant Medications .........................................................................43 


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6. 5. 2.  
Per mitte d C o nc o mita nt Me dicati o ns  .......................................................................... 4 4 
6. 5. 2. 1.  
A nti -e metic A ge nts  ..................................................................................................... 4 4 
6. 6.  
N utriti o nal C o ns ultati o n  ............................................................................................. 4 5 
6. 7.  
Restricti o ns  ................................................................................................................. 4 5 
6. 7. 1.  
Diet  ............................................................................................................................. 4 5 
6. 8.  
D ose M o dificati o ns  ..................................................................................................... 4 5 
6. 8. 1.  
Seli ne x or D ose M o dificati o ns .................................................................................... 4 5  
6. 8. 2.  
Pe m br oliz u ma b D ose M o dificati o ns  .......................................................................... 4 9 
6. 8. 3.  
Trifl uri di ne a n d ti piracil D ose M o dificati o ns  ............................................................. 4 9 
6. 9.  
Misse d or V o mite d Seli ne x or D oses  .......................................................................... 4 9 
7.  
DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T A N D P A TI E N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  .................................................................. 5 0 
7. 1.  
Patie nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  .................................................. 5 0 
7. 2.  
L ost t o F oll o w- u p ....................................................................................................... 5 0  
7. 3.  
Earl y Ter mi nati o n of t he St u d y  .................................................................................. 5 1 
8.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ...................................................... 5 2 
8. 1.  
I nf or me d C o nse nt ....................................................................................................... 5 2 
8. 2.  
Baseli ne Assess me nts  ................................................................................................. 5 2 
8. 2. 1.  
De m o gra p hics ............................................................................................................. 5 2  
8. 2. 2.  
Me dical Hist or y  .......................................................................................................... 5 2 
8. 3.  
Efficac y Assess me nts  ................................................................................................. 5 3 
8. 3. 1.  
R es p o nse Criteria  ........................................................................................................ 5 3 
8. 3. 2.  
Carci n oe m br y o nic A nti ge n ......................................................................................... 5 3  
8. 5.  
Safet y Assess me nts  ..................................................................................................... 5 5 
8. 5. 1.  
P h ysical E xa mi nati o ns  ................................................................................................ 5 5 
8. 5. 2.  
Vital Si g ns  .................................................................................................................. 5 5 
8. 5. 3.  
E C O G Pe rf or ma nce Stat us ......................................................................................... 5 6 
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8.5.4. 
Electrocardiogram .......................................................................................................56 
8.5.5. 
Clinical Safety Laboratory Assessments ....................................................................56 
8.5.6. 
Adverse Events and Serious Adverse Events .............................................................57 
8.5.6.1. 
Pregnancy Testing ......................................................................................................57 
8.6. 
Other Assessments ......................................................................................................58 
8.6.1. 
Collection of Information on Antineoplastic Therapy ................................................58 
8.6.2. 
Telephone Contacts ....................................................................................................58 
8.7. 
Post-treatment Assessments ........................................................................................58 
9. 
ADVERSE EVENTS ..................................................................................................59 
9.1. 
Definitions ..................................................................................................................59 
9.1.1. 
Recording of Adverse Events .....................................................................................60 
9.1.2. 
Laboratory Test Abnormalities ...................................................................................60 
9.1.3. 
Adverse Event Severity ..............................................................................................61 
9.1.4. 
Adverse Event Causality .............................................................................................61 
9.2. 
Serious Adverse Events ..............................................................................................61 
9.2.1. 
Events that Do Not Meet the Definition of a Serious Adverse Event ........................61 
9.2.2. 
Recording of Serious Adverse Events ........................................................................62 
9.2.3. 
Reporting of Serious Adverse Events .........................................................................62 
9.2.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................63 
9.3. 
Procedures for Handling Special Situations ...............................................................63 
9.3.1. 
Pregnancy and Breastfeeding .....................................................................................63 
9.3.2. 
Abuse, Misuse, Medication Errors, Overdose, and Occupational Exposure ..............65 
9.3.2.1. 
Overdose .....................................................................................................................65 
9.3.2.2. 
Abuse, Misuse, or Medication Error ...........................................................................65 
9.3.2.3. 
Occupational Exposure ...............................................................................................66 
10. 
STATISTICAL CONSIDERATIONS .......................................................................67 
10.1. 
General Considerations ...............................................................................................67 
10.1.1. 
Procedures for Handling Missing Data .......................................................................67 
10.2. 
Statistical Hypotheses .................................................................................................67 
10.3. 
Sample Size Determination ........................................................................................67 
10.4. 
Populations for Analyses ............................................................................................68 
10.4.1. 
Intent to Treat Population ...........................................................................................68 
10.4.2. 
Safety Population ........................................................................................................68 


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1 0. 5.  
Statistical A nal yses  ..................................................................................................... 6 8 
1 0. 5. 1.  
Efficac y A nal yses  ....................................................................................................... 6 8 
1 0. 5. 2.  
Safet y A nal yses  .......................................................................................................... 6 8 
1 0. 5. 2. 1.  
A d verse E ve nts ........................................................................................................... 6 9  
1 0. 5. 2. 2.  
La b orat or y Data  .......................................................................................................... 6 9 
1 0. 5. 2. 3.  
Vital Si g ns a n d P h ysical E xa mi nati o ns  ...................................................................... 6 9 
1 0. 5. 2. 4.  
C o nc o mita nt Me dicati o ns  ........................................................................................... 7 0 
1 1.  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  .................................................................................................. 7 1 
1 1. 1.  
Et hical a n d A d mi nistrati ve O bli gati o ns  ...................................................................... 7 1 
1 1. 1. 1.  
Re g ulat or y a n d Et hical C o nsi derati o ns  ...................................................................... 7 1 
1 1. 1. 2.  
Res p o nsi bilities of t he I n vesti gat or a n d G o o d Cli nical Practice  ................................ 7 1 
1 1. 2.  
Fi na ncial Discl os ure  ................................................................................................... 7 1 
1 1. 3.  
I nf or me d C o nse nt Pr ocess .......................................................................................... 7 2 
1 1. 4.  
Data C ollecti o n a n d Ma na ge me nt  .............................................................................. 7 3 
1 1. 4. 1.  
Data C o nfi de ntialit y  .................................................................................................... 7 3 
1 1. 4. 2.  
Data C ollecti o n  ........................................................................................................... 7 3 
1 1. 4. 3.  
Site M o nit ori n g ........................................................................................................... 7 4  
1 1. 4. 4.  
Data Ca pt ures  .............................................................................................................. 7 4 
1 1. 4. 5.  
Data base Ma na ge me nt a n d Q ualit y C o ntr ol ............................................................... 7 4  
1 1. 5.  
Str uct ure of C o m mittees  ............................................................................................. 7 5 
1 1. 5. 1.  
Data Safet y M o nit ori n g B oar d  .................................................................................... 7 5 
1 1. 6.  
Disse mi nati o n of Cli nical St u d y Data  ........................................................................ 7 5 
1 1. 7.  
S o urce D oc u me nts ...................................................................................................... 7 5  
1 1. 8.  
St u d y a n d Site Cl os ure ................................................................................................ 7 6  
1 1. 9.  
P u blicati o n P olic y  ....................................................................................................... 7 6 
1 2.  
R E F E R E N C E S  ........................................................................................................... 7 7 
1 3.  
A P P E N DI C E S  ............................................................................................................ 8 3 
A P P E N DI X  1. R E CI S T  V E R SI O N 1. 1  ...................................................................................... 8 3 
A P P E N DI X  2. E A S T E R N C O O P E R A TI V E O N C O L O G Y G R O U P P E R F O R M A N C E 
S T A T U S C RI T E RI A  .................................................................................................. 8 6 
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A P P E N DI X  3. S T R O N G A N D M O D E R A T E C Y P 3 A I N HI BI T O R S A N D 
I N D U C E R S ................................................................................................................ 8 7 
 
 
LI S T O F FI G U R E S  
Fi g ure 1:  
T u m or Re d ucti o n i n C R C Patie nts ( St u d y K C P- 3 3 0- 0 2 7) ( A) .................................. 3 1  
Fi g ure 2:  
T u m or Re d ucti o n i n C R C Patie nts ( St u d y K C P- 3 3 0- 0 2 7) ( B) .................................. 3 2  
Fi g ure 3:  
St u d y Sc he ma ............................................................................................................. 3 7  
  
LI S T O F T A B L E S  
Ta ble 1:  
Ar m A ( Seli ne x or M o n ot hera p y) a n d Ar m B ( Seli ne x or a n d 
Pe m br oliz u ma b) ( 4 2 - da y C ycle) ................................................................................. 2 0 
Ta ble 2:  
Ar m C:  Sta n dar d of Care: trifl uri di ne a n d ti piracil ( 2 8 - da y C ycle) .......................... 2 3 
Ta ble  3: 
St u d y Treat me nt .......................................................................................................... 4 2  
Ta ble 4:  
Seli ne x or D ose M o dificati o n Ste ps f or A d verse Reacti o ns  ....................................... 4 5 
Ta ble 5:  
D ose M o dificati o n f or He mat ol o gic A d verse Reacti o ns  ............................................ 4 6 
Ta ble  6: 
Seli ne x or D ose M o dificati o n  G ui deli nes f or N o n-He mat ol o gic A d verse 
Reacti o ns  ..................................................................................................................... 4 7 
Ta ble  8: 
Cli nical Safet y La b orat or y Tests  ................................................................................ 5 6 
Ta ble  9: 
E val uati o n of Best O verall Res p o nse – Patie nt wit h Tar get ( ± N o n -tar get) 
Disease  ........................................................................................................................ 8 4 
Ta ble  1 0: E val uati o n of Best O verall Res p o nse – Patie nt wit h N o n -Tar get Disease  ................. 8 4 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ARC 
absolute reticulocyte count 
AST 
aspartate transaminase 
AUC 
area under the concentration-time curve 
BID 
twice daily 
BIW 
biweekly 
BOR 
best overall response 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
C 
cycle 
CEA 
carcinoembryonic antigen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CPI 
checkpoint inhibitor 
CR 
complete response 
CRC 
colorectal cancer 
CrCl 
creatinine clearance 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A 
cytochrome P450 3A 
D 
day 
DCR 
disease control rate 
DLBCL 
diffuse large B-cell lymphoma 
dMMR 
deficient mismatch repair 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 


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Abbreviation 
Definition 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
EGFR 
epidermal growth factor receptor 
EORTC-QLQ-C30 
The European Organization for Research and Treatment of 
Cancer quality of life questionnaire 
EOT 
end of treatment 
FCSI 
Functional Assessment of Cancer Therapy Colorectal Cancer 
Symptom Index 
FDA 
Food and Drug Administration 
5-FU 
fluorouracil 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
hCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Institutional Ethics Committee 
IkBα 
nuclear factor of kappa light polypeptide gene enhancer in B-
cells inhibitor, alpha 
ITT 
intent to treat 
IO 
immunotherapy 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
KRAS 
Kirsten rat sarcoma 
LDH 
lactate dehydrogenase 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minute 


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A b bre vi ati o n  
Defi niti o n  
m L  
milliliter  
M M  
m ulti ple m yel o ma  
M RI 
ma g netic res o na nce i ma gi n g  
M SI - H 
micr osatellite i nsta bilit y -hi g h  
M S S  
micr osatellite sta ble  
N A  
n ot a p plica ble  
N C C N 
Nati o nal C o m pre he nsi ve Ca ncer Net w or k ®  
N CI  
Nati o nal Ca ncer I nstit ute  
N F k B  
n uclear fact or ka p pa B  
N K 1  
Ne ur o ki ni n - 1 
N R A S  
ne ur o blast o ma rat sarc o ma  
N S C L C  
n o n -s mall cell l u n g ca ncer 
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O R R  
o bjecti ve res p o nse rate 
P D  
p r o gressi ve disease 
P D - 1 
pr o gra m me d cell deat h pr otei n  1 
P D -L 1  
pr o gra m me d deat h -li ga n d 1 
P F S  
pr o gressi o n -free s ur vi val 
P HI  
pr otecte d healt h i nf or mati o n  
P O  
orall y  
P R  
partial res p o nse  
Q o L  
q ualit y of life  
Q W  
o nce wee kl y  
R A S  
rat sarc o ma 
R E B 
researc h et hics b oar d 
R E CI S T 
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
SI  
I nter nati o nal S yste m of U nits  
C CI
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Abbreviation 
Definition 
SINE 
selective inhibitor of nuclear export 
SOA 
schedule of assessments 
SOC  
standard of care 
TEAE 
treatment-emergent adverse event 
TSP 
tumor suppressor protein 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WT 
wild type 
XPO1 
exportin 1 
 


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1. 
PROTOCOL SUMMARY 
Sponsor: 
Karyopharm Therapeutics Inc. 
Investigational Product: 
Selinexor (KPT-330) 
Study Phase: 
Phase 2 
Title of Study: A phase 2 open-label multicenter study to evaluate the safety and efficacy of selinexor 
with or without pembrolizumab versus standard of care in previously treated metastatic colorectal cancer 
with RAS mutations (SeRAS).  
Protocol Number: XPORT-CRC-041 
Study Location:  
Approximately 10-15 US sites in a multicenter study 
Study Rationale: 
In the US, colorectal cancer is the third leading cause of cancer-related deaths in men and in women, and 
the second most common cause of cancer deaths when men and women are combined (ACS 2020). More 
than 1.9 million new cases were diagnosed in 2020. Approximately 20% of new colorectal cancer patients 
have metastatic disease at the time of diagnosis. Another 20% of patients progress to have metastatic 
colorectal cancer (mCRC) and have a significant lower survival rate (Li 2020). Patients with advanced or 
mCRC are typically treated with 5-FU and oxaliplatin or irinotecan-based regimens in first- and second-
line disease management. Despite initial response rates around 60% with first line chemotherapy, mCRC 
remains incurable, with recurrence after 8-12 months and overall survival of approximately 30 months 
(Saltz 2008; Douillard 2010; Loupakis 2014; van Cutsem 2011; Venook 2017). Second line chemotherapy 
in recurrent mCRC yields considerably less efficacy with response rates of 5-36%, progression-free 
survival (PFS) of 5-7 months, and overall survival (OS) of 11-14 months (Giantonio 2007; Bennouna 
2013; Sobrero 2008; Peeters 2014).  
Mutations in RAS proteins (KRAS, NRAS, HRAS) occur in between 33-69% of patients with CRC (Prior 
2020; Tate 2019; Sanchez-Vega 2018; Serebriiskii 2019). The presence of oncogenic RAS alterations leads 
to poor response from conventional treatments and poor clinical outcomes. While options for the third line 
therapy of mCRC are very limited, patients who have RAS-mutated CRC lack effective therapies and are 
treated with agents that demonstrate only modest survival gains. Currently regorafenib (Stivarga®) and 
combination treatment of trifluridine and tipiracil (Lonsurf®) are the only third and later line treatments for 
patients with mCRC including those with RAS mutations. However, patients with KRAS mutant tumors 
had shorter median overall survival (OS) in the CORRECT and RECOURSE studies (Tabernero 2015; 
Van Cutsem 2018). Currently there are no approved therapies for targeting RAS mutations in cancer while 
several investigational agents are in development targeting KRASG12C mutation in patients with heavily 
pre-treated solid tumors including patients with CRC with RAS mutations (Hong 2020).  
Anti-EGFR targeted therapies, cetuximab and panitumumab, are indicated for EGFR expressing, RAS 
wild type mCRC but have shown poor results for mCRC in patients with KRAS mutations (Saif 2009; 
Lievre 2008; Amado 2008; Douillard 2013; Van Cutsem 2009). Pembrolizumab, an anti-PD-1 mAb, is 
approved as the first-line treatment of patients with unresectable, metastatic microsatellite instability-high 
(MSI-H), or deficient mismatch repair (dMMR) colorectal cancer, which includes approximately 5% of 
CRC patients (Overman 2018). It is the first immunotherapy approved for this patient population as a first-
line treatment and which is administered to patients without administering chemotherapy. Pembrolizumab 
demonstrated a statistically significant improvement in PFS compared with chemotherapy (16.5 months 
for pembrolizumab versus 8.2 months for chemotherapy) in patients with MSI-H/dMMR CRC in the 
KEYNOTE-177 study (Andre 2020). Among patients with treatment refractory CRC treated with immune 
checkpoint inhibitors, PFS is increased among patients with MSI-H/dMMR vs MSS/pMMR (~ 2 months 
to not reached in follow-up versus ~ 2 months) (Overman 2018; Le 2020; Le 2015).   


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Selinexor is a first-in-class, oral selective inhibitor of nuclear export. Preclinical data have demonstrated 
sensitivity of RAS-mutant NSCLC cell lines to exportin-1 (XPO1) inhibitors (Kim 2016). Inhibition of 
XPO1 leads to nuclear retention of IkBα, decreased NFkB target gene expression and selective lethality in 
RAS mutant tumors (Kim 2016). CRC is associated with alterations in the ubiquitin-proteosome system 
and associated with APC, p53, Fbw7, and Smad4. Additionally, XPO1 is highly co-expressed in CRC 
tumors as compared to the adjacent normal epithelium.  In vitro models demonstrated inhibition of CRC 
cell growth with the use of selinexor (Wu 2017; Aladhraei 2019). Furthermore, results from several 
nonclinical studies show that selinexor can upregulate immune function and sensitize tumors to PD-1/PD-
L1 blockade (Farren 2017; Elloul 2016; Trott 2016). Clinical activity of selinexor in KRAS mutant 
NSCLC and CRC has been observed in other studies (Abdul Razak 2016). Selinexor has shown single 
agent activity against heavily pretreated CRC with an ORR of 3% and a disease control rate (DCR) of 
47% in KRAS-mutant CRC (Abdul Razak 2016).  
In study KCP-330-027, the combination of selinexor 80 mg weekly with pembrolizumab, 200 mg every 
three weeks was used to treat patients with advanced or metastatic colorectal cancer (CRC) who have 
received 1-3 prior systemic treatments for KRAS wild-type (WT) CRC or 1-2 prior treatments for KRAS 
mutant CRC but have not received prior therapy with an anti-PD1/L1 mAb. The results to date (31 March 
2021) suggest that patients with RAS (KRAS and NRAS) mutant tumors have better clinical outcomes 
than those with wild type tumors and support further clinical evaluation of the combination of selinexor 
with a PD-1/PD-L1 inhibitor in CRC patients. These results indicate a potential for effective treatment 
using selinexor in combination with pembrolizumab in previously treated mCRC patients with RAS 
mutations.  
The activity of selinexor as monotherapy and the synergistic anti-tumor activity of selinexor and PD 1/L1 
blockade seen in nonclinical studies in the hard to treat patients with RAS mutated mCRC, make selinexor 
an ideal candidate to be evaluated for this unmet medical need. Selinexor demonstrated preliminary 
evidence of activity in patients with RAS mutant mCRC, both as monotherapy (Abdul Razak 2016) and in 
combination with pembrolizumab in KCP 330-027. In addition, selinexor has a manageable safety profile 
in monotherapy as well as a lack of overlapping toxicities in combination therapy. Based on these 
preliminary yet promising results, this study aims to evaluate the combination of selinexor with 
pembrolizumab in chemotherapy-refractory CRC with RAS mutations.  
 
Objectives and Endpoints: 
The following objectives will be assessed in patients with RAS mutated mCRC: 
Objectives 
Endpoints 
Primary 
• 
To evaluate preliminary anti-tumor activity of 
selinexor with pembrolizumab versus 
standard of care (SOC)  
• 
Progression-free survival (PFS), as assessed 
by the investigator per RECIST 1.1 assessed 
from randomization until disease progression 
or death from any cause, whichever occurs 
first 
 
Secondary 
• 
To evaluate preliminary anti-tumor activity of 
selinexor with pembrolizumab versus SOC  
 
 
 
 
• 
Overall survival (OS), defined as time to 
death due to any cause from the 
randomization date 
• 
ORR, defined as the proportion of patients 
who achieve complete response (CR) or 
partial response (PR), per RECIST 1.1 as 


Cli nical St u d y Pr ot oc ol : X P O R T-C R C -0 4 1  
Seli ne x or  
Versi o n 2. 0 
 
2 6  Ma y  2 0 2 1  
C O N FI D E N TI A L  
Pa ge 1 5  of 8 7  
 
 
defi ne d b y t he I n vesti gat or base d o n 
ra di ol o gic criteria 
•  
P F S at 6 m o nt hs, O S perce nt i n 6 m o nt hs, O S 
perce nt i n 1 2 m o nt hs, D O R, a n d D C R per 
R E CI S T 1. 1  
 
•  
T o e val uate preli mi nar y a nti -t u m or acti vit y of 
seli ne x or o nl y vers us S O C  
•  
O verall s ur vi val ( O S), defi ne d as ti me t o 
deat h d ue t o a n y ca use fr o m t he 
ra n d o mizati o n date 
•  
O R R, defi ne d as t he pr o p orti o n of patie nts 
w h o ac hie ve c o m plete res p o nse ( C R) or 
partial res p o nse ( P R), per R E CI S T 1. 1 as 
defi ne d b y t he I n vesti gat or base d o n 
ra di ol o gic criteria. 
•  
P F S at 6 m o nt hs, O S perce nt i n 6 m o nt hs, O S 
perce nt i n 1 2 m o nt hs, D O R, a n d D C R per 
R E CI S T 1. 1  
•  
Pr o gressi o n -free s ur vi val ( P F S) per RE CI S T 
1. 1 assesse d b y t he i n vesti gat or fr o m t he 
ra n d o mizati o n date 
 
•  
T o descri be  t he safet y a n d t olera bilit y of 
seli ne x or wit h a n d wit h o ut pe m br oliz u ma b  
•  
Safet y a n d t olera bilit y of st u d y treat me nt will 
be e val uate d base d o n A E re p orts, vital si g ns, 
cli nical la b orat or y res ults, electr ocar di o gra m 
( E C G) a n d p h ysical e xa mi nati o n fi n di n gs, b y 
t he occ urre nce, nat ure, a n d se verit y of A Es as 
cate g orize d b y t he 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) v 5. 0  
 
E x pl or at or y   
C CI


Cli nical St u d y Pr ot oc ol : X P O R T-C R C -0 4 1  
Seli ne x or  
Versi o n 2. 0 
 
2 6  Ma y  2 0 2 1  
C O N FI D E N TI A L  
Pa ge 1 6  of 8 7  
 
 
St u d y Sc he m a :  
 
 
BI D = t wice dail y; d M M R =  deficie nt mis matc h re pair; M SI -H = micr osatellite i nsta bilit y hi g h; P D = pr o gressi ve 
disease; Q W = o nce wee kl y , S O C =sta n dar d of care, C R C =  c ol orectal ca ncer . 
 
N u m ber of P atie nts ( pl a n ne d): A p pr o xi matel y  7 8 patie nts will be e nr olle d wit h 2 6 patie nts i n eac h of t he 
3 ar ms.  
 
 
 
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Eligible patients must fulfill all inclusion criteria and no exclusion criteria. 
Inclusion Criteria 
1. Patient has histologically proven diagnosis of unresectable metastatic colorectal cancer with a 
known RAS mutation 
2. Patient has measurable disease according to RECIST 1.1 criteria 
3. Has received 2-3 prior lines of systemic anticancer treatment (adjuvant or neoadjuvant therapy is 
not counted as one line of systemic therapy)  
4. Patients with stable previously treated brain metastases are allowed. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 at the time of screening 
6. Age ≥18 years at the time of signing informed consent.  
7. Life expectancy of at least 3 months. 
8. Female patients of childbearing potential must agree to use dual methods 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 throughout the study and for 4 months after the last 
dose of selinexor or pembrolizumab or 6 months after trifluridine and tipiracil.  
9. Written informed consent signed in accordance with federal, local, and institutional guidelines 
Exclusion Criteria  
1. Prior treatment with a SINE compound or selinexor   
2. Prior treatment with immune checkpoint inhibitors  
3. Patients with microsatellite instability high (MSI-H) or deficient mismatch repair (dMMR). 
4. Known allergy to any of study drugs (selinexor, pembrolizumab, and trifluridine and tipiracil) or 
the excipient of pembrolizumab 
5. Significant cardiovascular impairment, defined as: 
i. Left ventricular ejection fraction ≤40% 
ii. Active congestive heart failure (New York Heart Association [NYHA]) Class ≥3 
iii. Unstable angina or myocardial infarction within 3 months of enrollment 
iv. Serious and potentially life-threatening arrhythmia 
6. Impaired hematopoietic function (any of the following would result in exclusion): 
i. Absolute neutrophil count (ANC) <1500/mm3  
ii. Platelet count <100,000/mm3 
iii. Hemoglobin (Hb) <10 g/dL  
7. Significant renal impairment, defined as: calculated creatinine clearance (CrCl) of <30 mL/min 
using the formula of Cockcroft and Gault 
8. Impaired hepatic function defined as: total bilirubin > 1.5 × ULN and AST >2.5 x ULN, ALT > 
2.5 x ULN; for Arm B, unless bilirubin elevation is related to Gilbert’s Syndrome for which 
bilirubin must be ≤ 4 x ULN  
9. Patients with a diagnosis of immunodeficiency or are receiving systemic steroid therapy 
(>10 mg/day of prednisone or equivalent) or any other form of immunosuppressive therapy. 
Patients with active autoimmune disease requiring systemic treatment during the past 2 years. 
• 
Patients with controlled Type I and Type II diabetes mellitus, and endocrinopathies 
such as hypothyroidism on stable hormone replacement, skin disorders (such as 
vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 


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expected to recur in the absence of an external trigger are allowed  
Note: The Investigator needs to evaluate the patient’s medical history to confirm that they are 
eligible to receive the combination with pembrolizumab per these criteria. 
10. Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as: 
i. Not recovered from major surgery ≤21 days prior to Day 1 dosing. Minor 
procedures, such as biopsies, dental work, or placement of a port or intravenous 
(IV) line for infusion are permitted 
ii. Have ongoing clinically significant anti-cancer therapy-related toxicities CTCAE 
Grade >1. In specific cases, patients whose toxicity has stabilized or with Grade 2 
non-hematologic toxicities can be allowed following documented approval by the 
Sponsor’s Medical Monitor 
iii. Had last dose of previous anti-cancer therapy ≤14 days prior to Day 1 dosing 
iv. Palliative radiotherapy >14 days prior to the study is allowed 
v. Received investigational drugs in other clinical trials within 28 days, or 5 half-
lives of the investigational drug (whichever is shorter), prior to C1D1 
vi. Live-attenuated vaccine against an infectious disease (e.g., nasal spray influenza 
vaccine) ≤14 days prior to the intended C1D1 
11. Female patients who are pregnant or lactating 
12. Active, ongoing or uncontrolled active infection requiring parenteral antibiotics, antivirals, 
antifungals within 1 week of Screening 
13. Patients with autoimmune disease, a medical condition that requires systemic corticosteroids or 
other immunosuppressive medication; or a history of interstitial lung disease 
14. Any gastrointestinal dysfunctions that could interfere with the absorption of selinexor (e.g., bowel 
obstruction, inability to swallow tablets, malabsorption syndrome, unresolved nausea, vomiting, 
diarrhea CTCAE > grade 1) 
15. In the opinion of the Investigator, patients who are below their ideal body weight and would be 
unduly impacted by changes in their weight 
16. Serious psychiatric or medical conditions that could interfere with participation in the study or in 
the opinion of the Investigator would make study involvement unreasonably hazardous 
17. Concurrent therapy with approved or investigational anticancer therapeutic including topical 
therapies 
 
Study Treatment/Treatment Groups, Dose, and Mode of Administration:  
Selinexor will be provided in tablet formulations for oral administration. Pembrolizumab therapy, 400 mg 
IV once every 6 weeks, per the Keytruda® USPI.    
All patients will receive study drug as follows: 
Arm A: Selinexor 80 mg QW PO on Day 1 of each week (Days 1, 8, 15, 22, 29, and 36 of 42-day cycle) 
Arm B: Selinexor 80mg QW PO on Day 1 of each week (days 1, 8, 15, 22, 29, and 36) in combination 
with pembrolizumab 400 mg IV once every 6 weeks 
Arm C: Standard of care (28-day cycle) - trifluridine and tipiracil: 35 mg/m2 /dose orally twice daily (max 
80 mg / dose) on Days 1 through 5 and Days 8 through 12 of each 28-day cycle 
 


Cli nical St u d y Pr ot oc ol : X P O R T-C R C -0 4 1  
Seli ne x or  
Versi o n 2. 0 
 
2 6  Ma y  2 0 2 1  
C O N FI D E N TI A L  
Pa ge 1 9  of 8 7  
 
St atistic al Met h o ds:  
Gi ve n t h e a bo ve ass u m pti o ns, t he t otal sa m ple size is a p pr o xi matel y  7 8 patie nts wit h 2 6 i n eac h ar m.  
A n al ysis P o p ul ati o ns:  
I nte nt-t o-Tre at P o p ul ati o n (I T T) : All patie nts ra n d o mize d t o st u d y treat me nt. Patie nts will be a nal yze d i n 
t he treat me nt ar m t o w hic h t he y will be ra n d o mize d. 
S afety P o p ul ati o n:   All patie nts w h o ha ve bee n assi g ne d t o st u d y treat me nt a n d w h o ha ve recei ve d ≥1 d ose 
of st u d y dr u g. Patie nts will be a nal yze d acc or di n g t o t he treat me nt ar m recei ve d. 
Efficac y A nal yses:  
All efficac y a nal yses will be perf or me d usi n g t he I T T P o p ulati o n. T he a nal ysis of ti me -t o-e ve nt e n d p oi nts 
( P F S, O S) will be base d o n Ka pla n-Meier met h o d f or esti mati o n of s u m mar y statistics a n d will i ncl u de t he 
me dia n e ve nt ti mes a n d ass ociate d 9 5 % CIs, as well as t he n u m ber a n d perce nta ge of ce ns ore d patie nts.  I n 
a d diti o n, C o x pr o p orti o nal hazar ds re gressi o n m o dels will be use d t o esti mate a H R f or t he ris k of 
pr o gressi o n i n t he seli ne x or o nl y  ar m or seli ne x or a n d pe m br oliz u ma b ar m vers us  t he S O C c o ntr ol ar m. 
Safet y A nal yses:  
All safet y a nal yses will be perf or me d usi n g t he Safet y P o p ulati o n. T he safet y a n d t olera bilit y of t he t hree 
treat me nt ar ms will be e val uate d b y mea ns of dr u g-relate d a d verse e ve nts ( A E) re p orts, p h ysical 
e xa mi nati o ns, a n d la b orat or y safet y e val uati o ns. T he gra di n g of t he se verit y of t he A Es will be d o ne 
acc or di n g t o N CI C T C A E, v 5. 0. I n vesti gat ors will pr o vi de t heir assess me nt o n ca usalit y (i.e., w het her t he 
A E is relate d or n ot relate d t o seli ne x or). Treat me nt -e mer ge nt A Es, seri o us a d verse e ve nts ( S A Es), A Es of 
at least Gra de 3 i n se verit y, A Es relate d t o seli ne x or a n d ot her st u d y dr u gs, a n d A Es lea di n g t o wit h dra wal 
of treat me nt will be s u m marize d. Treat me nt -e mer ge nt A Es will be t h ose t hat start or w orse n o n or after t he 
first da y of st u d y treat me nt, t hr o u g h 3 0 da ys after last d ose. 
A nal ysis of efficac y, A Es, la b orat or y data, a n d vital si g ns will be o utli ne d i n t he statistical a nal ysis pla n. 
 
C CI






Cli nical St u d y Pr ot oc ol : X P O R T-C R C -0 4 1  
Seli ne x or  
Versi o n 2. 0 
2 6  Ma y  2 0 2 1  
C O N FI D E N TI A L  
Pa ge 2 2  of 8 7  
A Es will be gi n t o be rec or de d p ost -d osi n g a n d a n y A Es w hic h were e x perie nce d pri or t o d o si n g will be a d de d t o t he patie nt’s me dical hist or y. S A Es will be 
re p orte d o nce t he I C F is si g ne d. A d verse e ve nt m o nit ori n g s h o ul d be c o nti n ue d f or at least 3 0 da ys f oll o wi n g t he last d ose of st u d y dr u g (i.e., t hr o u g h 3 0 da ys 
f oll o wi n g last d ose or u ntil res ol uti o n or t hr o u g h t he e n d of t he st u d y f or e ve nts c o nsi dere d relate d t o st u d y dr u g b y t he I n vesti gat or). See  Secti o n 9. 1 for 
a d diti o nal details.  
h Tele p h o ne  c o ntact will be ma de o n C 1 D 3 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 n d 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. After disc o nti n uati o n of st u d y treat me nt, f oll o w -u p p h o ne ca lls will be perf or me d 3 0 da ys a n d e ver y 3 m o nt hs u ntil 1 2 m o nt hs d oc u me nti n g start 
of  ne w t her a p y an d s ur vi val stat us . 
j  Ser u m c he mistr y a n d he mat ol o g y m ust be c o n d ucte d ≤3 da ys bef ore t he first d ose. If t he res ults are wit hi n re q uire d le vels, he mat ol o g y a n d ser u m c he mistr y d o   
n ot nee d t o be re peate d o n D 1. See  Ta ble  8 f or a list of la b tests. La bs will be re peate d e ver y 2 wee ks f or 2 c ycles a n d t hereafter o nce per c ycle  
kFe male  patie nts of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m h C G pre g na nc y test ≤3 da ys bef o re first d ose C 1 D 1.  
oT he sa me met h o d of assess me nt ( C T or M RI of c hest, a b d o me n a n d pel vis [ ot her re gi o ns as cli nicall y i n dicate d f or t he ass ess me nt of disease]) s h o ul d be use d 
t hr o u g h o ut t he st u d y f or eac h tar get lesi o n. T u m or assess me nts at scree ni n g a n d e ver y 6 wee ks fr o m C 1 D 1 f or t he first 6 m o nt hs a n d t he n e ver y 9 wee ks  till 1 
y ear. After o ne year, t u m or assess me nt fre q ue nc y ca n be re d uce d t o o nce e ver y 3 m o nt hs at t he I n vesti gat or’s discreti o n. T u m or asse ss me nt s h o ul d be o btai ne d at 
E O T if p ossi ble, f or patie nts w h o disc o nti n ue treat me nt f or ot her t ha n P D  
p C E A s h o ul d be o btai ne d at  sa me ti me p oi nts as i ma gi n g assess me nts 
C CI
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Cli nical St u d y Pr ot oc ol : X P O R T-C R C -0 4 1  
Seli ne x or  
Versi o n 2. 0 
 
2 6  Ma y  2 0 2 1  
C O N FI D E N TI A L  
Pa ge 2 5  of 8 7  
 
 
m T he sa me met h o d of assess me nt ( C T or M RI of c hest, a b d o me n a n d pel vis [ ot her re gi o ns as cli nicall y i n dicate d f or t he assess me nt of disease]) s h o ul d be use d 
t hr o u g h o ut t he st u d y f or eac h tar get lesi o n. T u m or assess me nts at scree ni n g a n d e ver y 6 wee ks fr o m C 1 D 1 f or t he first 6 m o nt hs a n d t he n e ver y 9 wee ks till 1 
year . Af ter o ne year, t u m or assess me nt fre q ue nc y ca n be re d uce d t o o nce e ver y 3 m o nt hs at t he I n vesti gat or’s discreti o n. T u m or assess me nt s h o ul d be o btai ne d at 
E O T if p ossi ble, f or patie nts w h o disc o nti n ue treat me nt f or ot her t ha n P D  
n  C E A s h o ul d be o btai ne d at sa me ti me p oi nts as i ma gi n g assess me nts  
o Trifl uri di ne a n d ti pir acil 3 5 m g/ m 2 / d ose orall y t wice dail y ( ma x 8 0 m g / d ose) o n Da ys 1 t hr o u g h 5 a n d Da ys 8 t hr o u g h 1 2 of eac h 2 8-da y c ycle . Trifl uri di ne 
a n d ti piracil  s h o ul d be ta ke n wit h f o o d 
  
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2. 
INTRODUCTION 
2.1. 
Colorectal Cancer 
Colorectal cancer (CRC) is the third most common cancer worldwide and is the fourth leading 
cause of cancer-related deaths, with an estimated 850,000 deaths in 2018 (Bray 2018). More than 
1.9 million new cases were diagnosed in 2020. Approximately 20% of patients with CRC will 
have metastatic disease at the time of diagnosis and a further 25% will develop metastatic 
disease after curative resection of localized CRC. Over the last two decades, the development of 
treatment options has significantly improved the prognosis for metastatic CRC patients. 
Traditionally, systemic chemotherapy in this setting has been based on fluoropyrimidine 
regimens. By the introduction of cytotoxic agents, such as irinotecan and oxaliplatin, the 
response rate, time to progression, and overall survival have improved from 15-20%, 5-6 and 10-
12 months to 30-40%, 8 and 20-24 months, respectively (Tournigand 2004; Colucci 2005). 
Approximately 3.5% to 6.5% of stage IV CRCs are characterized as microsatellite instability-
high (MSI-H), which is the biologic footprint of deficiency in deoxyribonucleic acid (DNA) 
mismatch repair enzymes (dMMR). Immune checkpoint inhibitors are approved for 
approximately 5% of CRC patients with MSI-H/dMMR tumors and survival may be prolonged 
by adding biologic agents.  
While anti-EGFR targeted therapies, cetuximab and panitumumab, are indicated for EGFR 
expressing, RAS wild type mCRC, these therapies have shown poor results for mCRC in patients 
with KRAS mutations (Saif 2009). A recent meta-analysis demonstrated no clinically significant 
difference in PFS with anti-EGFR monoclonal antibody therapy between KRAS G13D and other 
KRAS mutant colorectal cancer tumors (Rowland 2016). It is now well established in the 
literature that KRAS mutations confer resistance to anti-EGFR targeted therapies (Lièvre 2008; 
Amado 2008; Douillard 2013; Van Cutsem 2009). Per NCCN guidelines, patients with RAS 
mutations should not be treated with cetuximab or panitumumab due to potential for toxicity 
without any expectation of benefit. Cetuximab or panitumumab are approved in RAS wild type 
only in the EU per Summary of Product Characteristics (SmPC). 
Current available options include monotherapy with an immune checkpoint inhibitor (CPI) that 
targets the programmed death receptor-1 (i.e., nivolumab or pembrolizumab). Pembrolizumab 
(intravenous injection) is approved as the first-line treatment of patients with unresectable or 
metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) 
colorectal cancer. It is the first immunotherapy approved for this patient population as a first-line 
treatment which is administered to patients without chemotherapy.  
Per NCCN guidelines, regorafenib or trifluridine and tipiracil with or without bevacizumab or 
participation in a clinical trial is recommended for patients with advanced/mCRC who have 
progressed after all standard therapies (NCCN 2020). Regorafenib (Stivarga®) and trifluridine 
and tipiracil  (Lonsurf®)were FDA approved based on the results of the CORRECT and 
RECOURSE studies respectively (Grothey 2013; Mayer 2015). Both studies met their primary 
survival endpoints with significant improvement in survival versus placebo (6.4 months for 
regorafenib versus 5.0 months for placebo and 7.1 months for trifluridine and tipiracil versus 5.3 


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months for placebo). Lacking alternatives, these modest gains in survival have become the 
standard of care (SOC) for most patients reflecting the poor prognosis for this indication. 
The KRAS mutation occurs in approximately 35%-45% of CRC. The presence of oncogenic 
KRAS alterations has been proposed to portend poor response to conventional treatment and 
poor clinical outcomes. To date, pharmacologic attempts to inhibit KRAS directly have proven 
unsuccessful. Recently, two KRAS inhibitors specifically targeting G12C mutation, AMG510 
and MRTX849, entered early clinical development and have demonstrated encouraging anti-
tumor activity in patients with KRASG12C tumors (Canon 2019; Hallin 2020). KRASG12C is 
present in only approximately 13% of lung adenocarcinoma, 3% of colorectal cancer, and 2% of 
other solid tumors (AACR Project GENIE Consortium). AMG510 and MRTX849 do not affect 
cancers with other type of KRAS mutations. Therefore, novel concepts are needed to improve 
treatment in KRAS mutant cancers.  
In the Cancer Genome Atlas data set, XPO1 expression is upregulated in CRC vs normal tissue, 
and high expression of XPO1 correlated with poor prognosis. Consistently, expression of XPO1 
in 4 CRC PDX models was elevated compared with normal colon epithelial cells (Inoue 2021; 
Aladhraei 2019). In 40 CRC samples from patients, XPO1 overexpression was observed in 
52.5% of CRC and was significantly apparent with strong intensity in tumor cells compared to 
the normal adjacent epithelium (P<0.001). XPO1 overexpression was significantly associated 
with advanced tumor stages (P=0.049) and had tendency towards moderate/poorly differentiated 
tumors (Aladhraei 2019).  
In PDX-derived cultures, increasing selinexor concentration correlated with increased p53 
protein levels in the nucleus and decreasing in XPO1 levels. In addition, levels of the DNA 
damage repair proteins RAD51 and RAD50 were also reduced (Inoue 2021).  
In other preclinical CRC models, XPO1 inhibition by SINE compounds or other XPO1 inhibitors 
resulted in inhibition of cell proliferation, nuclear localization of APC, reduced levels of β-
catenin, nuclear localization of nrf2 and enhancement of radiation response (Neufeld 2000, 
Velichkova 2005; Ki 2008; Neufeld 2009; Ferreiro-Neira 2016; Cheng 2018).  
In vitro screening of 278 cancer cell lines, XPO1 inhibition by KPT-207 (similar analog to 
selinexor), resulted in increased cytotoxicity of KRAS-mutant compared to RAS wild-type cells 
(KPTI internal information). 
Preclinical data have demonstrated sensitivity of KRAS-mutant melanoma (Yang 2014) and non-
small-cell lung carcinoma (NSCLC) cell lines to SINE molecules (Kim 2016) including BRAF 
mutated melanoma (Salas Fragomeni, 2013). In a multi-genomic, data driven approach obtained 
by analysis of 106 cell lines, it was identified that the nuclear transport machinery is an 
obligatory function required for cell survival. By application of selinexor, tumor cell growth was 
halted, and apoptotic cell death was induced at bioavailable concentrations (0.5 μM to 10 μM). 
Inhibition of XPO1 led to nuclear retention of IkBα, which resulted in dysregulation of crucial 
survival pathways via NFκB as the responsible mechanism of cell death induction and selective 
lethality in RAS mutant tumors (Kim 2016). 
2.2. 
Study Rationale 
Patients with advanced/metastatic CRC (mCRC) are typically treated with 5-FU and oxaliplatin 
or irinotecan-based regimens in first- and second-line disease management. Treatment selection 


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depends on clinical factors and molecular markers. Despite initial response rates around 60% 
with first line chemotherapy, mCRC remains incurable. After progression free survival (PFS) of 
about 8-12 months, the disease recurs with and overall survival (OS) remains poor around 30 
months (Saltz 2008; Douillard 2010; Loupakis 2014; Van Cutsem 2011; Venook 2017). Second 
line chemotherapy in recurrent mCRC yields considerably less efficacy with response rates of 5-
36%, PFS lasing 5-7 months, and OS of 11-14 months (Giantonio 2007; Bennouna 2013; 
Sobrero 2008; Peeters 2014). The options for the third line therapy of mCRC are very limited.  
Additionally, patients who have RAS-mutated CRC lack effective therapies and are treated with 
agents that demonstrate only modest survival gains. Response rate and survival in patients with 
mutations in RAS proteins remains an unmet medical need due to the poor antitumor responses, 
few treatment options, and the aggressive nature of the tumors leading to a shorter survival.  
Currently regorafenib and combination of trifluridine and tipiracil are third and later lines 
treatments for patients with mCRC including those with RAS mutations. Immune checkpoint 
inhibitors are approved for approximately 5% of CRC patients with MSI-H/dMMR tumors. Anti-
EGFR targeted therapies, cetuximab and panitumumab, are only indicated for EGFR-expressing 
KRAS wild-type mCRC in the EU per SmPC. Pembrolizumab, an anti-PD-1 mAb, is approved 
as the first-line treatment of patients with unresectable or metastatic microsatellite instability-
high (MSI-H) or deficient mismatch repair (dMMR) colorectal cancer. In a study of 
pembrolizumab in CRC, regardless of MSI status but with PD-L1-positive disease, the ORR was 
only 4% (1 out of 23 enrolled and treated).  In a review of the patient with a tumor response, it 
was noted that patient who responded was the only one with MSI-H disease. In the study 
KEYNOTE-016, patients with microsatellite stable (MSS) disease had an ORR of 0% (95% CI: 
0, 20), while those patients with mismatch repair–deficient colorectal adenocarcinomas had an 
ORR of 40% (95% confidence interval [CI], 12, 74) (Li 2015). Further studies using 
pembrolizumab have limited the population to MSI-H only; the population for which 
pembrolizumab received approval.  Results from study KCP-330-027 indicate a potential for 
effective treatment using selinexor in combination with pembrolizumab in previously treated 
mCRC patients with RAS mutations.  
This study aims to evaluate the combination of selinexor with pembrolizumab in chemotherapy-
refractory CRC with RAS mutations. The single agent activity of both selinexor and 
pembrolizumab in RAS mutant CRC, along with the safety and early indications of efficacy of 
this combination support the study design in this niche indication where there is acute need for 
effective treatment. 
2.3. 
Selinexor 
Selinexor (Xpovio®) is a first-in-class oral selective inhibitor of nuclear export (SINE) 
compound, specifically inhibiting exportin-1 (XPO1, also called Chromosome Region 
Maintenance protein 1/CRM1) and has been validated as a target for therapeutic intervention in 
cancer. Inhibition of XPO1 leads to the nuclear accumulation and re-activation of TSPs and other 
growth modulators. Selinexor reduces the expression of DNA damage repair proteins and 
therefore potentiate DNA damage-based therapies and increase cancer cell death (Kashyap 
2018). Selinexor is FDA approved as a treatment (80 mg twice weekly [BIW]) in combination 
with low-dose dexamethasone in patients with penta-refractory multiple myeloma, and as a 
monotherapy (60 mg BIW) for patients with relapsed or refractory diffuse large B-cell 
lymphoma (DLBCL) after at least 2 prior lines of therapy. Selinexor is also approved in 


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combination with bortezomib and dexamethasone for the treatment of adult patients with 
multiple myeloma who have received at least one prior therapy.  
Selinexor restores most of the known TSPs to the nucleus where they can carry out their normal 
regulatory and anti-tumor functions. Through the restoration of TSP function, selinexor is 
selectively cytotoxic for cells with genomic damage, i.e., for tumor cells, both in vitro and in 
vivo. All cell types exposed to SINE in vitro undergo G1 ± G2 cell cycle arrest, followed by a 
‘genomic fidelity’ review. Cells with damaged genomes are induced to undergo apoptosis. 
Normal cells with an intact genome remain in transient, reversible cell cycle arrest until the 
export block is relieved. Tumors of hematopoietic lineage are particularly susceptible to 
induction of apoptosis by XPO1 inhibition; normal hematopoietic cells including stem cells 
(Etchin 2013) and their functions are largely spared.  
Mutations in RAS proteins (KRAS, NRAS, HRAS) are very common in human cancer and occur 
in ~33% of patients with CRC, according to the COSMIC results, and up to ~69% according to 
The Cancer Genome Atlas (Prior 2020; Tate 2019; Sanchez-Vega 2018; Serebriiskii 2019). The 
presence of oncogenic RAS alterations leads to poor response from conventional treatments and 
poor clinical outcomes.  Pharmacologic attempts at inhibiting RAS directly have proven not so 
successful to date.  
Preclinical data have demonstrated sensitivity of RAS-mutant NSCLC cell lines to XPO1 
inhibitors (Kim 2016). Therapeutic activity of selinexor has been observed in cancers with RAS 
mutations. Clinical activity of selinexor in KRAS mutant NSCLC and CRC has been observed in 
other studies. Selinexor has shown single agent activity against heavily pretreated CRC with an 
ORR of 3% and a disease control rate (DCR) of 47% in KRAS-mutant CRC (Abdul Razak 
2016). 
Rationale for use of Selinexor in Combination with Pembrolizumab 
Several nonclinical studies show that selinexor can upregulate immune function and sensitize 
tumors to PD-1/PD-L1 blockade: (1) the combination of selinexor and anti-PD-1 or anti-PD-L1 
blockade has been assessed in in vivo studies and demonstrated synergistic anti-tumor activity in 
an aggressive murine colon cancer model (Elloul 2016) as well as other solid tumor models 
(Farren 2017; Trott 2016) (2) a combination of selinexor and anti-PD-1 or anti-PD-L1 mAb 
shows significant immunomodulatory activity, inducing changes in the frequency and phenotype 
of immune cell populations, including increased frequency of NK cells, increased frequency of 
differentiated TH1 cells, and increased frequency of activated T-cells (Farren 2017); (3) 
selinexor induces PD-1 and PD-L1 gene expression, sensitizing tumor cells to immunotherapy 
and synergizes with anti-PD-1 to inhibit tumor cell proliferation and to induce apoptosis in vitro 
(Farren 2017; Elloul 2016; Trott 2016) 
In study KCP-330-027 the combination of selinexor 80 mg weekly with pembrolizumab, 200 mg 
every three weeks was used to treat patients with advanced or metastatic colorectal cancer (CRC) 
who have received 1-3 prior systemic treatments for KRAS wild-type (WT) CRC or 1-2 prior 
treatments for KRAS mutant CRC but have not received prior therapy with an anti-PD1/L1 
mAb. As of 31 March 2021, there were 24 patients out of 30 patients who had at least one post 
baseline efficacy evaluation based on imaging. The median age was 57.5 years, 19 (63.3%) were 
male, and 16 (53.3%) had RAS mutations.  Median number of prior antineoplastic regimens was 
2. All patients entered the study with documented progression of disease. In this group, 11 


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patients had stable disease as their best overall response (BOR), and 8 of these 11 patients with 
stable disease (73%) had RAS mutant tumors (Figure 1, Figure 2). Notably none of the RAS 
mutated tumors were MSI-H. Disease stabilization was achieved in various RAS mutant tumors 
including NRAS mutant, KRAS G12V and G12D. The mPFS in patients with RAS mutated 
CRC was 12.9 weeks, 95% CI (8.3, NA) versus RAS WT 7.1 weeks, 95% CI: (5.7, NA) (p = 
0.20; HR 0.55 [95% CI 0.21, 1.41]). At least one TEAE and one treatment related adverse event 
(TRAE) were observed in at least 96.7% and 86.7% of patients respectively. The most frequent 
cause of discontinuation of treatment was due to disease progression (PD). Among patients with 
TRAEs, 20% had dose modifications and 20% dose interruptions. One patient withdrew consent 
in Cycle 1 for Grade 1 AEs (nausea, vomiting, headache) prior to on-study assessment; one 
patient withdrew consent after Cycle 3 with stable disease (+9% increase) and Grade 2 fatigue 
and nausea and Grade 1 loss of appetite and headache. The most common AEs observed were 
nausea (76.7%), fatigue and vomiting (43.3% each), decreased appetite and diarrhea (36.7% 
each), weight decrease (26.7%) and constipation (23%). Most AEs were grade 1 or 2. The most 
common grade 3 AE was fatigue in 13.3% of patients. Side effects were generally reversible and 
manageable with supportive care, dose holds and dose modifications. There were no deaths from 
drug-related toxicity. The increased PFS and disease stabilization observed among patients with 
RAS mutated CRC, whose tumors were notably also MSS, and treated with selinexor and 
pembrolizumab as contrasted with patients with RAS wild-type tumors indicates that this 
combination may be an effective treatment for patients with RAS mutant CRC who would 
otherwise have few options and be ineligible for checkpoint inhibitors and warrants further 
study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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previously for selinexor and pembrolizumab. No overlapping toxicities were identified (Glitza 
2020).  
In the above-described study (NCT02419495), a total of 31 melanoma patients were treated with 
combinations of selinexor 60-120 mg total weekly dose (once or twice weekly) and 
pembrolizumab 2 mg/kg or 200 mg IV once every three weeks (Q3W). Of those, 25 patients 
were treated with selinexor 60 mg BIW. 3 patients out of the 25 patients discontinued due to 
adverse events. Overall, these results demonstrate that selinexor in combination with 
pembrolizumab is well-tolerated.   
Selinexor appears to overcome resistance to IO, acquired resistance in IO refractory melanoma in 
the Phase 1b (NCT02419495) and innate resistance in MSS/pMMR CRC in KCP-330-027. 
Mechanisms of resistance may differ but the hypothesis that selinexor may sensitize IO 
refractory/resistant tumors is intriguing. Microsatellite instability is infrequent in RAS (Birgisson 
2015), and, therefore, patients with RAS mutant CRC will in most cases be deprived of the 
benefit of IO.  
The activity of selinexor as monotherapy and the synergistic anti-tumor activity of selinexor and 
PD 1/L1 blockade seen in nonclinical studies in the hard to treat patients with RAS mutated 
mCRC, make selinexor an ideal candidate to be evaluated for this unmet medical need. Selinexor 
demonstrated preliminary evidence of activity in patients with RAS mutant mCRC, both as 
monotherapy (Abdul Razak 2016) and in combination with pembrolizumab in KCP 330 027. In 
addition, selinexor has a manageable safety profile in monotherapy as well as a lack of 
overlapping toxicities in combination therapy. Based on these preliminary yet promising results, 
this study aims to evaluate the combination of selinexor with pembrolizumab in chemotherapy-
refractory CRC with RAS mutations. 
2.4. 
Dose Justification (Monotherapy and Combination) 
Selinexor has been evaluated as a single agent or in combination with other anti-cancer agents in 
>3700 patients with hematologic or solid-tumor malignancies who received at least 1 dose of 
selinexor. Among these patients, 2310 were treated on company-sponsored trials (CSTs) and 
1201 patients were treated on investigator-sponsored trials (ISTs). Based on the robust available 
clinical safety and efficacy data from these clinical trials, selinexor shows a reasonably wide 
therapeutic range, with single agent activity ranging from ~6 mg/m2 to ≥85 mg/m2 BIW 
(approximately 10 mg to 145 mg PO BIW) which was initially observed from the two phase 1 
studies and subsequently confirmed in multiple phase 2 and phase 3 clinical trials.  
In dose escalation studies in patients with advanced hematologic and solid tumor malignancies 
(Studies KCP-330-001 and KCP-330-002, respectively), selinexor was dosed once or twice 
weekly and exhibited linear PK and dose-proportional exposure (maximum plasma concentration 
[Cmax] and area under the concentration-time curve [AUC]). Based on the observation from the 
Phase 1 study (KCP-330-002) and several other phase 2 studies in solid tumors, the revised 
recommended Phase 2 dose (RP2D) of selinexor as single agent for many solid tumors is 60 mg 
BIW or 80 mg once weekly (QW). 
A dose of 80 mg selinexor QW in combination with pembrolizumab 400 mg every 6 weeks has 
been selected for this study based on the once weekly dosing regimen of 80 mg selinexor in 
combination with pembrolizumab at the standard approved dose 400 mg once every 6 weeks  in 
the KCP-330-027 study (NCT04256707). Five patients are ongoing on the combination 


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treatment as of 31Mar 2021. Median treatment duration is 3.2 cycles (21-day cycle) with the 
longest duration of treatment in 2 patients with KRAS and NRAS mutation (8 and 9 months, 
respectively, on the combination).  Overall, this combination regimen was well tolerated in the 
30 patients treated in this study with no dose limiting toxicities. Side effects were generally 
reversible and manageable with supportive care, dose holds and dose modifications. There were 
no deaths from drug-related toxicity. These findings indicate that selinexor 80 mg once weekly 
with pembrolizumab 400 mg once every six weeks is a tolerable regimen in patients with 
advanced, heavily pretreated CRC. 
2.5. 
Benefit/Risk Assessment 
Broad antitumor activity has been observed with selinexor treatment in preclinical and clinical 
studies. The information about selinexor’s mechanism of action and its efficacy observed in the 
KCP-330-027 study (NCT04256707) in patients with advanced or metastatic colorectal cancer 
(CRC), indicates that selinexor 80 mg once weekly with pembrolizumab 400 mg IV once every 
six weeks has activity in RAS mutated CRC; however, further investigation is warranted to 
elucidate clinical benefit.  Adverse events in the study were consistent with those reported 
previously for selinexor and pembrolizumab administered separately with no clear overlapping 
toxicities. AEs noted during the trial include hematological, fatigue, nausea/diarrhea, low 
sodium/potassium attributed as possible/definite to either selinexor or pembrolizumab or possible 
with both treatments. 
In addition, selinexor is currently being evaluated in combination with other agents (targeted 
therapies and chemo-/radiotherapy). As these clinical trials proceed, more data will become 
available to assess both the added efficacy and possible adverse events resulting from these 
combinations to better inform potential trials combining selinexor with immune checkpoint 
blockade. In ongoing clinical studies, the most common non-hematologic AEs reported as related 
to selinexor have been predominantly nausea, vomiting, diarrhea, fatigue, anorexia and weight 
loss, and these AEs were assessed as low-grade and manageable with dose modification or 
supportive care. Hyponatremia (typically asymptomatic), confused state and dizziness have also 
been reported. On the other hand, hematological AEs including thrombocytopenia, neutropenia 
and anemia, which can be higher grade, were reported primarily in patients with hematologic 
malignancies. Any potential overlapping toxicity, such as thrombocytopenia, will be monitored 
closely by careful physical examination and clinical laboratory testing on Day 1 and Day 15 of 
Cycle 1 and Cycle 2 with dose adjustments as per prespecified dose modifications (see Table 4).  
A summary of the clinical trials, antitumor responses observed, and anticipated adverse events 
(AEs) of selinexor are found in the Investigator’s Brochure. 
Pembrolizumab is approved for use in the treatment of patients with unresectable or metastatic 
MSI-H or dMMR CRC that has progressed following treatment with a fluoropyrimidine, 
oxaliplatin, and irinotecan as a result of an accelerated approval based upon the tumor response 
rate and durable response. Early studies using pembrolizumab did not demonstrate activity in 
CRC with RAS mutations or without microsatellite instability. Nonclinical models demonstrated 
combination activity of selinexor and pembrolizumab.  The results seen in Study KCP-330-027 
confirmed the activity of the combination in this otherwise pembrolizumab nonresponding 
population.   
Please refer to the Prescribing Information for more information regarding pembrolizumab. 






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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a phase 2, open-label, multicenter study that will evaluate the efficacy and safety of 
selinexor and pembrolizumab in patients with advanced or metastatic CRC. The study schema is 
depicted in Figure 3.   
Figure 3: 
Study Schema 
 
 
SOC = Standard of care, PD = progressive disease; MSI-H = microsatellite instability high; dMMR = 
deficient mismatch repair; QW = once weekly; BID=twice daily; CRC=colorectal cancer 
Approximately 78 patients with advanced or metastatic CRC will be enrolled, and randomized to 
Arm A, B or C based on the following stratification factor: 
• ECOG performance status 0 or 1 versus 2 
All eligible patients in Arm A will be treated with selinexor 80 mg QW orally as a monotherapy 
on Day 1 of each week of a 42-day cycle. Arm B patients will be treated with selinexor at the 
same dose as Arm A in combination with pembrolizumab 400 mg IV once every 6 weeks. Arm 
C patients will be administered the standard of care treatment trifluridine and tipiracil 35 
mg/m2/dose orally BID (max 80 mg / dose) on Days 1 through 5 and Days 8 through 12 of each 
28-day cycle. Trifluridine and tipiracil should be taken with food. 
Primary efficacy will be assessed by PFS, as assessed by the investigator per RECIST1.1 for 
selinexor plus pembrolizumab and for SOC assessed from randomization until disease 
progression or death from any cause, whichever occurs first. Objective response rate (ORR) 
defined as the proportion of patients who achieve complete response (CR) or partial response 


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(PR), per RECIST 1.1 as defined by the Investigator based on radiologic criteria. Assessments 
will be performed per timepoints as mentioned in SoA. 
Safety and tolerability of study treatment will be evaluated based on AE reports, vital signs, 
clinical laboratory results, electrocardiogram (ECG) and physical examination findings, by the 
occurrence, nature, and severity of AEs as categorized by the Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0. Timepoints will be performed as mentioned in SoA. 
Patients will receive study treatment until disease progression (PD), intolerable toxicity, or 
withdrawal from the study. Disease response/progression will be based on tumor assessments at 
timepoints specified in the SoA.  
4.2. 
End of Treatment 
The EOT visit will occur ≤30 days post-treatment discontinuation. After discontinuation of study 
treatment, patients will be followed for PFS approximately every 3 months after EOT visit until 
PD, death or initiation of the subsequent treatment (if a patient discontinues from the treatment 
due to reasons other than PD), and for survival every 3 months after end of treatment visit for 12 
months or until withdrawal of consent, death, or the end of study (i.e., when the last patient in the 
study has been followed up on study treatment for at least 1 year or completed at least 6 months 
of survival follow-up period after their last dose of study treatment, has withdrawn consent, has 
died, or has been lost to follow-up, whichever occurs first). The duration of the study will be 
approximately 3 years. 
4.3. 
Safety Follow-Up Visit and Survival Follow-Up Visit 
A safety follow-up visit must be performed within 30 days after EOT.  The purpose is to assess 
patient status, follow-up on any AEs that were not resolved at the EOT Visit.  
Survival follow-up visit will be performed every 3 months from EOT and will continue for 12 
months.  
AEs will be reported 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 new therapy, whichever occurs first. For 
events that are considered by the Investigator to be related to the study drug, the monitoring of 
the AE should be continued for at least 30 days following the last dose of study drug (30-Day 
Safety visit), or until the AE has resolved. 
 
 


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5. 
 STUDY POPULATION 
Eligible patients must fulfill all inclusion criteria and no exclusion criteria. 
5.1. 
Inclusion Criteria 
1. Patient has histologically proven diagnosis of unresectable metastatic colorectal cancer 
with a known RAS mutation. 
2. Patient has measurable disease according to RECIST 1.1 criteria. 
3. Has received 2-3 prior lines of systemic anticancer treatment (adjuvant or neoadjuvant 
therapy is not counted as one line of systemic therapy). 
4. Patients with stable previously treated brain metastases are allowed.        
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 at the time of 
screening. 
6. Age ≥ 18 years at the time of signing informed consent 
7. Life expectancy of at least 3 months. 
8. Female patients of childbearing potential must agree to use dual methods 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 throughout the study and for 4 
months after the last dose of  selinexor or pembrolizumab or 6 months after trifluridine 
and tipiracil. 
9. Written informed consent signed in accordance with federal, local, and institutional 
guidelines. 
5.2. 
Exclusion Criteria  
1. Prior treatment with a SINE compound or selinexor.   
2. Prior treatment with immune checkpoint inhibitors.  
3. Patients with microsatellite instability high (MSI-H) or deficient mismatch repair 
(dMMR). 
4. Known allergy to any of study drugs (selinexor, pembrolizumab, and trifluridine and 
tipiracil) or the excipient of pembrolizumab. 
5. Significant cardiovascular impairment, defined as: 
i. Left ventricular ejection fraction ≤40% 
ii. Active congestive heart failure (New York Heart Association [NYHA]) 
Class ≥3 
iii. 
 Unstable angina or myocardial infarction within 3 months of enrollment 
iv. Serious and potentially life-threatening arrhythmia 
6. Impaired hematopoietic function (any of the following would result in exclusion): 
i. Absolute neutrophil count (ANC) <1500/mm3  
ii. Platelet count <100,000/mm3 


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iii. Hemoglobin (Hb) <10 g/dL  
7. Significant renal impairment, defined as: calculated creatinine clearance (CrCl) of                  
<30 mL/min using the formula of Cockcroft and Gault. 
8. Impaired hepatic function defined as: total bilirubin > 1.5 × ULN and AST > 2.5 x ULN, 
ALT > 2.5 x ULN; for Arm B, unless bilirubin elevation is related to Gilbert’s Syndrome 
for which bilirubin must be ≤ 4 x ULN. 
9. Patients with a diagnosis of immunodeficiency or are receiving systemic steroid therapy 
(>10 mg/day of prednisone or equivalent) or any other form of immunosuppressive 
therapy. Patients with active autoimmune disease requiring systemic treatment during the 
past 2 years. 
• Patients with controlled Type I and Type II diabetes mellitus, and 
endocrinopathies such as hypothyroidism on stable hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external trigger 
are allowed.  
Note: The Investigator needs to evaluate the patient’s medical history to confirm that 
they are eligible to receive the combination with pembrolizumab per these criteria. 
10. Insufficient time since or not recovered from procedures or anti-cancer therapy, defined 
as: 
i. 
Not recovered from major surgery ≤21 days prior to Day 1 dosing. Minor 
procedures, such as biopsies, dental work, or placement of a port or intravenous 
(IV) line for infusion are permitted. 
ii. 
Have ongoing clinically significant anti-cancer therapy-related toxicities CTCAE 
Grade >1. In specific cases, patients whose toxicity has stabilized or with Grade 2 
non-hematologic toxicities can be allowed following documented approval by the 
Sponsor’s Medical Monitor. 
iii. 
Had last dose of previous anti-cancer therapy ≤14 days prior to Day 1 dosing. 
iv. 
Palliative radiotherapy >14 days prior to the study is allowed. 
v. 
Received investigational drugs in other clinical trials within 28 days, or 5 half-
lives of the investigational drug (whichever is shorter), prior to C1D1. 
vi. 
Live-attenuated vaccine against an infectious disease (e.g., nasal spray influenza 
vaccine) ≤14 days prior to the intended C1D1. 
11. Female patients who are pregnant or lactating. 
12. Active, ongoing or uncontrolled active infection requiring parenteral antibiotics, 
antivirals, antifungals within 1 week of Screening. 
13. Patients with autoimmune disease, a medical condition that requires systemic 
corticosteroids or other immunosuppressive medication; or a history of interstitial lung 
disease. 
14. Any gastrointestinal dysfunctions that could interfere with the absorption of selinexor 
(e.g., bowel obstruction, inability to swallow tablets, malabsorption syndrome, 
unresolved nausea, vomiting, diarrhea CTCAE > Grade 1). 


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15. In the opinion of the Investigator, patients who are below their ideal body weight and 
would be unduly impacted by changes in their weight. 
16. Serious psychiatric or medical conditions that could interfere with participation in the 
study or in the opinion of the Investigator would make study involvement unreasonably 
hazardous. 
17. Concurrent therapy with approved or investigational anticancer therapeutic including 
topical therapies. 
5.3. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently entered in the study as they did not meet the inclusion/exclusion criteria. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, reason for screen failure, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened one more time. Rescreened patients should be assigned the same patient number as 
for the initial screening. 
 
 


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6. 
STUDY TREATMENT 
6.1. 
Study Treatments Administered 
All study drugs must be dispensed only by a pharmacist or appropriately qualified site staff, 
including the investigator. 
Table 3: 
Study Treatment 
Treatment Name 
Selinexor (Xpovio®) 
Pembrolizumab 
(Keytruda™) 
Standard of Care 
 (Trifluridine and 
Tipiracil) 
Dose Formulation 
Tablet 
Solution 
Tablet 
Unit Dose Strength 
20 mg 
25 mg/mL 
15 or 20 mg 
Dosage Level 
80 mg, single dose once 
weekly on Day 1 
400 mg once every six 
weeks on Day 1 
35 mg/m2 /dose twice 
daily (max 80 mg / 
dose) on Days 1 
through 5 and Days 8 
through 12 of each 28-
day cycle 
Route of 
Administration 
PO 
IV 
PO 
PO=orally; IV=intravenous. 
6.2. 
Study Drug Dosing and Administration 
6.2.1. 
Labeling 
All labels (selinexor, pembrolizumab, and Lonsurf (trifluridine and tipiracil) will include 
conditions for storage, lot number, and other information required by the Food and Drug 
Administration (FDA), International Council for Harmonization (ICH), and/or Annex 13, and all 
local regulations for investigational medications. 
Medication labels for each blister pack or bottle of selinexor will be in the local language and 
comply with the legal and regulatory requirements of each country. They will include storage 
conditions for the drug. Additional information about selinexor labeling is in the Pharmacy 
Manual.  
Refer to the Pharmacy Manual for information on pembrolizumab and trifluridine and tipiracil 
labeling and additional information.  
6.2.2. 
Dispensing Directions 
The Investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drug as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. Additional dispensing instructions will be provided in the Pharmacy Manual. 


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6.2.3. 
Dosing Information 
Selinexor tablets should be taken orally with at least 120 mL (4 fluid ounces) of water. Selinexor 
can be taken with or without food. In order to avoid contact with skin, tablets must be swallowed 
whole and should not be crushed. For additional details on drug formulation, preparation, and 
administration, please refer to the Pharmacy Manual and the Investigator’s Brochure.  
Pembrolizumab (Arm B) will be administered at the site, only by authorized site personnel. 
Trifluridine and tipiracil (Arm C) should be taken with food and should be taken at home unless 
there is a site visit on the dosing day as appropriate. 
6.3. 
Preparation/Handling/Storage/Accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study medication accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study medications are 
provided in the Pharmacy Manual. 
6.4. 
Study Treatment Compliance 
Patient compliance with study treatment will be assessed at each visit. Deviation(s) from the 
prescribed dosage regimen should be recorded in the electronic case report form (eCRF). 
6.5. 
Concomitant Medication 
Concomitant medications include any prescription or over-the-counter preparation, including 
blood/blood products, vitamins, dietary supplements, over-the-counter medications, and oral 
herbal preparations taken during the study. Patients may continue their baseline medication(s). 
All concomitant medication(s) must be reported in the eCRF. Any diagnostic, therapeutic, or 
surgical procedure performed during the study period should be recorded, including the dates, 
description of the procedure(s), and any clinical findings, if applicable. 
6.5.1. 
Prohibited Concomitant Medications 
Concurrent therapy with any approved or investigative anticancer therapeutic outside of those 
included in this study is not allowed. Use of any immunosuppressive agents during the study 
must be confirmed by the Sponsor. Refer to the full prescribing information for treatment of 
patients receiving pembrolizumab for the most current information on prohibited concurrent 
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There are no restrictions on the use of acetaminophen (paracetamol) or acetaminophen-
containing products in combination with study drug, except on days of selinexor dosing, when 
acetaminophen must not exceed a total daily dose of 1 gram. 
6.5.2. 
Permitted Concomitant Medications 
Patients will receive concomitant medications as prophylaxis and to treat symptoms, AEs and 
intercurrent illnesses that are medically necessary as standard care. Medications to treat 
concomitant diseases like diabetes, hypertension, etc., are allowed. Supportive measures for 
optimal medical care should be provided to all patients in this study. Supportive care per 
institutional guidelines and/or the National Comprehensive Cancer Network® (NCCN) Clinical 
Practice Guidelines in Oncology (NCCN Guidelines®) should be used as clinically indicated at 
the discretion of the Investigator. Should the physician choose to use different antiemetics than 
what is described in this section, the treating physician should consult the Sponsor in order to 
ensure two different classes of antiemetics are administered prophylactically. Necessary 
supportive care such as appetite stimulants, and anti-diarrheals will be allowed. 
Based on our current limited clinical information, there are no known contraindications 
associated with selinexor and the available authorized COVID vaccines. While Karyopharm is 
unable to offer COVID vaccinations to patients at this time, patients are not prohibited to receive 
vaccination through available sources at any time while being treated with selinexor. If a patient 
receives the concomitant COVID vaccine, each dose, the manufacturer of the vaccine, and the 
date of vaccination should be recorded and the respective prescribing information of the 
authorized COVID vaccines should be referred. As always, all AEs, including their causalities, 
as well as noted laboratory abnormalities will be recorded. There may be concurrent known 
adverse events, such as fatigue and nausea associated with the authorized COVID vaccines and 
selinexor. All causalities associated with the treatment emergent events should be reported 
according to the clinical discretion of the investigator. Based on our current limited clinical 
information, there are no known contraindications associated with selinexor and the available 
authorized COVID- vaccines.    
6.5.2.1. 
Anti-emetic Agents 
In order to minimize nausea, unless contraindicated all patients must receive 2 anti-emetics 
initially. A 5-HT3 antagonist (ondansetron 8mg or equivalent), starting 30-60 minutes before 
administration of study drug and continued 2-3 times daily for at least 2 days after dosing, as 
needed.  
In addition to 5-HT3 antagonist, patients receiving selinexor, single agent and selinexor and 
pembrolizumab arms, should receive olanzapine 2.5-5.0 mg PO daily at night, starting on C1D1 
and continuing for the first 2 months of the study treatment and continue if needed. 
If the patient does not tolerate olanzapine well, or needs another antiemetic, an NK1 antagonist 
can be used daily together with ondansetron for the first 2 months or longer as deemed necessary 
per discussion with the medical monitor. An NK-1 antagonist, or another anti-emetic agent 
should be used as per the label per NCCN Guidelines Alternative; or an additional anti-emetic 
agent may be used if the patient does not tolerate or has inadequate anti-emetic effect with 5-
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6.6. 
Nutritional Consultation 
Patients must be given documented nutritional consultation to discuss any food 
recommendations and strategies for managing potential nausea and appetite changes experienced 
with study drug. This must be completed within the Screening period of the study and prior to 
administration of study drug on C1D1. The Investigator or any study staff can provide the 
nutritional consultation, in person or by telephone. Nutritional/supportive care is to be provided 
throughout, as needed, and per local guidance. 
6.7. 
Restrictions 
6.7.1. 
Diet  
There are no dietary restrictions during this study. Selinexor should be administered with about 4 
oz (120 mL) of water. Patients can drink water as desired. Throughout the study, patients on 
study drug should maintain adequate caloric and fluid intake. 
6.8. 
Dose Modifications 
6.8.1. 
Selinexor Dose Modifications 
All dose modifications will be captured in the eCRF. Dose modifications should be associated in 
the eCRF with the AE requiring the modification. 
If drug-related toxicity requires a treatment delay of more than 28 days, the patient will be taken 
off study treatment unless the investigator in consultation with the Medical Monitor believes that 
it is safe for the patient to resume therapy. 
For all Grade ≥3 hematological or non-hematological AEs that are NOT selinexor related, after 
consultation with the Medical Monitor and at the discretion of the Investigator, selinexor dosing 
may be maintained. 
Table 4 summarizes the selinexor dose levels for modification; Table 5 describes supportive care 
and dose adjustment guidelines for hematologic adverse reactions. Table 6 describes dose 
adjustment guidelines for non-hematologic adverse reactions. Deviations from the guidelines are 
permitted after discussion between the Sponsor and the treating physician. 
Table 4: 
Selinexor Dose Modification Steps for Adverse Reactions 
Recommended 
Starting Dosage 
First Reduction 
Second 
Reduction 
Third Reduction 
Fourth 
Reduction 
80 mg 
Once weekly 
60 mg 
Once weekly 
40 mg 
Once weekly 
20 mg 
Once weekly 
Discontinue 
 
 
 


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Table 5: 
Dose Modification for Hematologic Adverse Reactions 
Adverse Reactiona 
Occurrence 
Action 
Thrombocytopenia 
Platelet count < 50,000 μL  
(Grade 3-4) 
First 
Occurrence 
Hold selinexor until platelets recover to ≥ 75,000  
Restart selinexor at same dose level (see Table 4).  
Consider additional supportive care and discuss with Sponsor’s 
Medical Monitor  
  
2nd and 
subsequent 
Hold selinexor until platelets recover to ≥ 75,000  
Reduce selinexor by 1 dose level (see Table 4).  
Consider additional supportive care and discuss with Sponsor’s 
Medical Monitor 
Platelet count < 50,000 µL 
with concurrent bleeding 
Any 
Hold selinexor until platelets recover to ≥ 50,000 and bleeding 
has resolved. 
Restart selinexor at 1 lower dose level (see Table 4) 
Consider additional supportive care and discuss with Sponsor’s 
Medical Monitor 
Neutropenia 
ANC of 0.5 to 1.0 x 109 /L 
(Grade 3) 
First 
Occurrence 
Hold selinexor until ANC recover to ≥ 1.0  
Restart selinexor at same dose level (see Table 4).  
Consider additional supportive care and discuss with Sponsor’s 
Medical Monitor  
 ANC of 0.5 to 1.0 x 109 /L 
(Grade 3) 
2nd and 
subsequent 
Hold selinexor until ANC recover to ≥ 1.0 
Reduce selinexor by 1 dose level (see Table 4).  
Consider additional supportive care and discuss with Sponsor’s 
Medical Monitor 
ANC < 0.5 x 109/L 
(Grade 4) 
OR febrile neutropenia 
Any 
  
Hold selinexor until ANC recover to ≥ 1.0 
Reduce selinexor by 1 dose level (see Table 4).  
Consider additional supportive care and discuss with Sponsor’s 
Medical Monitor 
Anemia 


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Adverse Reactiona 
Occurrence 
Action 
Hemoglobin level < 8.0 g/dL 
Any 
Administer blood transfusions and/or other treatments per 
clinical guidelines. 
Life-threatening consequences 
(urgent intervention indicated) 
Any 
Interrupt selinexor.  
Monitor hemoglobin until levels return to 8 g/dL or higher. 
Restart selinexor at 1 dose level lower (see Table 4). 
Administer blood transfusions and/or other treatments per 
clinical guidelines. 
aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. 
 
Table 6: 
Selinexor Dose Modification Guidelines for Non-Hematologic Adverse Reactions 
Adverse Reactiona 
Occurrence 
Action 
Hyponatremia 
Grade 1 or 2 (sodium level 
< normal to 130 mmol/L) 
Any 
Maintain dose 
Rule out other causes including drug (e.g. diuretic) effects  
Be certain that reported sodium level is corrected for 
concurrent hyperglycemia (serum glucose > 150 mg/dL) 
Treat hyponatremia per institutional guidelines including 
dietary review 
Consider addition of salt tablets to patient’s diet 
Grade 3 (sodium levels 120 
to 129 mmol/L) without 
symptoms 
Any 
Rule out other causes including drug (e.g., diuretic) effects 
Be certain that reported sodium level is corrected for concurrent 
hyperglycemia (serum glucose > 150mg/dL) 
If (corrected) sodium is Grade ≤ 3 and continues to be 
asymptomatic, then patient may continue current dosing 
provided that IV saline and/or salt tablets are provided 
Grade 3 (sodium levels 120 
to 129 mmol/L) with 
symptoms  
OR Grade 4 (sodium levels 
< 120 mmol/L) 
Any 
Rule out other causes including drug (e.g., diuretic) effects 
Be certain that reported sodium level is corrected for concurrent 
hyperglycemia (serum glucose > 150 mg/dL) 


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Adverse Reactiona 
Occurrence 
Action 
Interrupt selinexor dosing until resolved to Grade 1 or baseline 
and without symptoms. Reduce selinexor by 1 dose level 
Fatigue 
Grade 2 lasting > 7 days  
OR Grade 3 
Any 
  
Interrupt selinexor. 
Monitor until fatigue resolves to Grade 1 or baseline. 
Restart selinexor at 1 dose level lower (see Table 4).  
Nausea and Vomiting 
Grade 1 or 2 nausea (oral 
intake decreased without 
significant weight loss, 
dehydration or malnutrition) 
OR Grade 1 or 2 vomiting 
(5 or fewer episodes per 
day) 
Any 
Maintain selinexor and initiate additional anti-nausea 
medications. 
Grade 3 nausea (inadequate 
oral caloric or fluid intake)  
OR Grade 3 or higher 
vomiting (6 or more 
episodes per day) 
Any 
Rule out other causes. Use additional anti-nausea medications 
to supplement the protocol-required 5-HT3 antagonists 
Additional options can be found in the National Comprehensive 
Cancer Network (NCCN) Clinical Practice Guidelines in 
Oncology (CPGO) for antiemesis and anorexia/cachexia 
(palliative care). 
Interrupt selinexor dosing. 
Initiate additional anti-nausea medications.  
Monitor until resolved to Grade ≤ 2 or baseline and reduce 
selinexor by 1 dose level (see Table 4). 
Diarrhea 
Grade 2 (increase of 4 to 6 
stools per day over baseline) 
1st  
Maintain selinexor and institute supportive care. 
  
2nd and 
subsequent 
Reduce selinexor by 1 dose level (see Table 4). 
Institute supportive care. 
Grade 3 or higher (increase 
of 7 stools or more per day 
over baseline; 
hospitalization indicated) 
Any 
  
Interrupt selinexor and institute supportive care. 
Monitor until diarrhea resolves to Grade 2 or lower. 
Restart selinexor at 1 dose level lower (see Table 4).  
Weight Loss and Anorexia 
Weight loss of 10% to less 
than 20%  
Any 
Interrupt selinexor and institute supportive care. 


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Adverse Reactiona 
Occurrence 
Action 
OR anorexia associated with 
significant weight loss or 
malnutrition 
Monitor until weight returns to more than 90% of baseline 
weight. 
Restart selinexor at 1 dose level lower (see Table 4). 
Other Non-Hematologic Adverse Reactions 
Grade 3 or 4 
Any 
Interrupt selinexor. 
Monitor until resolved to Grade 2 or lower, restart selinexor at 1 
dose level lower (see Table 4).  
aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. 
 
6.8.2. 
Pembrolizumab Dose Modifications 
For AEs related to pembrolizumab, refer to dose adjustment guidelines in the respective drug’s 
prescribing information. If an AE requires interruption of pembrolizumab but not selinexor, 
selinexor treatment may continue. Pembrolizumab dosing will be done on Day1 of any given 42-
day cycle. If an AE requires interruption of only pembrolizumab, but the AE does not require 
interruption of selinexor, then pembrolizumab may remain interrupted as long as is necessary to 
allow the patient to recover from the AE that caused the drug interruption. If it is determined that 
the patient should no longer receive pembrolizumab, the patient may continue treatment with 
single agent selinexor, at the discretion of the Investigator.  
6.8.3. 
Trifluridine and tipiracil Dose Modifications 
Trifluridine and tipiracil dose modifications will be determined based on dose adjustment 
guidelines in the drug’s prescribing information. 
6.9. 
Missed or Vomited Selinexor Doses 
If a dose was missed, the missed dose will be administered if the time for the next scheduled 
dose is ≥ 72 hours. The missed dose will not be administered if the time for the next scheduled 
dose is < 72 hours. The next dose will be taken as per the schedule. 
If a dose must be skipped (e.g., due to recommendation of Investigator), the next dose will be 
taken as per the schedule. Doses should not be administered <72 hours apart and all missed and 
delayed doses should be documented. 
If a dose is vomited within one hour of ingestion and all intact selinexor tablets are seen, it will 
be replaced. If vomiting occurs more than one hour after dosing, it will still be considered a 
complete dose. 
 
 


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7. 
DISCONTINUATION OF STUDY TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Patient Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at his/her own request, for any reason, or may 
be withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons.  
The Investigator must determine the primary reason for a patient’s discontinuation of study 
treatment/withdrawal from the study and record this information on the eCRF. 
The Investigator may remove a patient from study treatment for any of the following reasons: 
• PD as defined by RECIST v 1.1 (Appendix 1) 
• Clinical progression as determined by the Investigator in consultation with the Sponsor’s 
Medical Monitor 
• Unacceptable AEs or toxicity that cannot be managed by supportive care 
• Any other medically appropriate reason or significant protocol violation, in the opinion of 
the Investigator 
• Patient withdraws consent to continue study treatment. For information regarding from 
which part of the study the patient withdraws consent should be documented and 
recorded in the eCRF (i.e., if a patient only withdraws consent only to study treatment but 
agrees to complete the safety and survival follow-up per protocol, or a patient withdraws 
consent to all study procedures). 
• Pregnancy 
Patients who discontinue study treatment for any reason (e.g., AE, PD, personal or Investigator 
decision) should be encouraged to continue in the study, so follow-up information on PD and 
survival status may be collected. If the patient is receiving clinical benefit despite PD and it is in 
the best interest of the patient, per the physician, the patient may remain on therapy. 
 Patients may withdraw consent and decline further participation in the study at any time. 
Patients who withdraw consent must be withdrawn from the study. Withdrawal of consent will 
be documented and recorded in the eCRF. 
7.2. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and explain to the patient the importance of maintaining the assigned visit 
schedule and ascertain whether the patient wishes to and/or should continue in the study.  


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• Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 documented telephone 
calls or local equivalent methods). These contact attempts should be documented in the 
patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to be lost to 
follow-up, and this will be documented in the patient medical record.  
• Any patient who does not withdraw from the study but who stops attending study visits 
and does not respond to 3 documented contact attempts will be considered lost to follow-
up. 
7.3. 
Early Termination of the Study 
The study may be terminated at the sole discretion of the Sponsor 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, the Sponsor will notify IECs, IRBs, Investigators, and 
regulatory authorities. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA. 
• Immediate safety concerns should be discussed with the Sponsor’s Medical Monitor 
immediately upon occurrence or awareness to determine if the patient should continue or 
discontinue study treatment. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the patient’s routine clinical management (e.g., blood 
count) that were obtained prior to signing of the informed consent form (ICF) may be 
utilized for screening purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA. 
8.1. 
Informed Consent 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/research ethics board (REB)-approved informed consent 
(Section 11.3). Informed consent must be obtained before conducting any study-specific 
procedures (i.e., all procedures described in the protocol, unless performed as part of the 
patient’s routine clinical management as mentioned above). The process of obtaining informed 
consent should be documented in the patient source documents. 
8.2. 
Baseline Assessments 
8.2.1. 
Demographics 
Patient demographics (including gender, race, ethnicity, and age at the time of consent) will be 
collected, as allowed by local regulations. 
8.2.2. 
Medical History 
The medical history will include medical conditions or symptoms experienced during the 
previous 30 days as well as those ongoing at the time of Screening, any medical conditions that 
require medication, including the start date of all current medical history/conditions by at least 
the month/year. A complete ophthalmic history and smoking history will be obtained and 
documented.  
A detailed history of prior anti-cancer procedures/therapies for the disease under study (e.g., 
chemotherapy, hormonal therapy, immunotherapy, biotherapy, radiotherapy, or surgery), 
including start and end dates, best response, PD during or after therapy, as well as 
discontinuations due to intolerability or toxicity. A detailed history of disease-specific diagnostic 
and prognostic testing and test results (such as phenotypic and cancer molecular profiling, 
including but not limited to RAS mutations, EGFR mutations, ALK fusion protein, PD-L1 


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e x pressi o n le vel, d M M R a n d micr osatellite sta bilit y stat us ) will als o  be c ollecte d. Data fr o m 
sta n dar d- of-care pr oce d ures will be part of t he patie nt's me dical hist or y a n d ma y be use d f or 
st u d y p ur p oses. 
 
F or t he p ur p os e of pre vi o us li nes of s yste mic t hera p y d oc u me ntati o n please use t he f oll o wi n g 
defi niti o ns:  
Defi niti ve c he m ora di ot hera p y f oll o we d b y a dj u va nt t hera p y w o ul d be c o u nte d as o ne li ne of 
s yste mic t hera p y. 
A dj u va nt t he rap y, ne oa dj u va nt t hera p y, or mai nte na nce t hera p y al o ne will n ot be c o u nte d as o ne 
li ne of s yste mic t hera p y. Adj u va nt/ ne oa dj u va nt c he m ot hera p y s h o ul d be d oc u me nte d e ve n if n ot 
c o nsi dere d a li ne of t hera p y. 
8. 3.  
Effic ac y Assess m ents  
8. 3. 1.  
Res p o nse Criteri a  
C T or M RI  
C T or M RI sca ns will be perf or me d at t he ti me p oi nts s pecifie d i n t he S o A. C o m p ute d 
t o m o gra p h y ( C T) sca ns wit h c o ntrast are preferre d. T he met h o d use d at Scree ni n g f or a gi ve n 
patie nt s h o ul d be use d c o nsiste ntl y t hr o u g h o ut t he st u d y f or t hat patie nt. T he s a me met h o d of 
assess me nt ( C T or M RI of c hest, a b d o me n a n d pel vis [ ot her re gi o ns as cli nicall y i n dicate d f or 
t he assess me nt of disease]) s h o ul d be use d t hr o u g h o ut t he st u d y f or eac h tar get lesi o n. C T or 
M RI of t he c hest, a b d o me n, a n d pel vis perf or me d m ore t ha n 3 0 da ys pri or t o C 1 D 1 ma y be 
all o we d t o be use d f or t he baseli ne sca n f oll o wi n g disc ussi o n wit h t he S p o ns or’s Me dical 
M o nit or. T u m or assess me nts will be perf or me d as s pecifie d i n t he S o A.  
Baseli ne t u m or assess me nt will be perf or me d d uri n g Scree ni n g. As  part of t he me dical hist or y 
d oc u me ntati o n, e ver y eff ort s h o ul d be ma de t o o btai n t he latest hist oric sca ns a vaila ble 
( prefera bl y C T), a n d t o use t he m t o perf or m lesi o n i de ntificati o n, c haracterizati o n a n d 
meas ure me nt. T his hist oric i nf or mati o n will be re p orte d i n t he electr o nic data ca pt ure ( E D C ) 
disease assess me nt ta ble as t he pre -baseli ne ti me p oi nt.  
Res p o nse assess me nt will be deter mi ne d per R E CI S T 1. 1 f or all ar ms (A p pe n di x 1 ) at t he ti me 
p oi nts s pecifie d b y t he i n vesti ga t or.  
8. 3. 2.  
C arci n oe m br y o nic A nti ge n  
Carci n oe m br y o nic a nti ge n ( C E A)  is a n o nc ofetal pr otei n t hat is o vere x presse d b y a p pr o xi matel y 
8 5 % c ol orectal ca ncers a n d detecta ble i n ser u m  (Ma yer  1 9 7 8). A S C O & N C C N cli nical practice 
g ui deli nes rec o m me n d serial m o nit ori n g of t he C E A le vel w hile patie nts are o n acti ve treat me nt 
(C hi orea n 2 0 2 0 ). Re d ucti o ns a n d ele vati o ns  i n C E A le vels ma y hel p i de ntif y res p o nse a n d 
resista nce t o treat me nt bef ore i ma gi n g, are pr o g n ostic a n d c orrelate wit h o utc o mes .  
I ncreasi n g C E A le vels are ass ociate d wit h p o or o utc o mes (Herrera  1 9 7 7) w hile decreasi n g le vels 
are ass ociate d wit h better s ur vi val ( S ha ni  1 9 7 8).  
C CI
C CI


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Bl o o d sa m ples will be c ollecte d fr o m all patie nts partici pati n g i n t his st u d y f or m o nit ori n g C E A 
le vels, as i n dicate d i n t he S o A. 
C CI


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8. 5.  
S afet y Assess me nts  
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A . 
8. 5. 1.  
P h ysic al E x a mi n ati o ns   
T he p h ysical e xa mi nati o n 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.  
P h ysical e xa mi nati o n  will be perf or me d o n t he sc he d ule d da ys as i n dicate d i n t he S o A. P h ysical 
e xa mi nati o ns s h o ul d i ncl u de ge neral a p peara nce, der mat ol o gical, hea d, e yes, ears, n ose, t hr oat, 
res pirat or y, car di o vasc ular, a b d o mi nal, l y m p h n o des, m usc ul os keletal, a n d ne ur ol o gical 
e xa mi nati o ns. F ull p h ysical e xa mi nati o n will be  perf or me d pri or t o recei vi n g first d ose of st u d y 
dr u g a n d at E O T Visit. All ot her p h ysical e xa mi nati o ns d uri n g t he st u d y s h o ul d be li mite d a n d 
s y m pt o m-dir ecte d e xa mi nati o ns.  
Hei g ht ( wit h o ut s h oes) i n ce nti meters 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 d uri n g t he p h ysical e xa mi nati o ns.  
I nf or mati o n a b o ut t he p h ysical e xa mi nati o n m ust be prese nt i n t he s o urce d oc u me ntati o n at t he 
st u d y site. T he res ult of t he p h ysical e xa mi nati o n pri or t o t he start of Da y1 d osi n g m ust be 
i ncl u de d i n t he Rele va nt Me dical Hist or y/ C urre nt Me dical C o n diti o ns e C R F. Cli nicall y rele va nt 
fi n di n gs ma de after t he start of st u d y treat me nt, w hic h meet t he defi niti o n of a n A E, m ust be 
rec or de d a n d e ntere d i nt o t he A E e C R F. 
8. 5. 2.  
Vit al Si g ns  
Vital si g ns will  i ncl u de: 
C CI




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Blood chemistry will be analyzed at each study center by a certified laboratory. The Investigator 
or designee will review the laboratory report after receipt of the results and assess the clinical 
significance of all abnormal values. Results must be reviewed prior to dosing and appropriate 
action taken for any clinically significant abnormal values.  
The Investigator or designee will review the laboratory report after receipt of the results and 
assess and document the clinical significance of all abnormal values. Results must be reviewed 
prior to dosing and appropriate action taken for any clinically significant abnormal values.  
At any time during the study, abnormal laboratory values that are clinically significant 
(e.g., require dose modification and/or interruption of study treatment, manifest clinical 
symptoms or signs or require therapeutic intervention), whether specifically requested in the 
protocol or not, must be documented in the eCRF.  
If any abnormal laboratory value or test result constitutes an AE, then these must be recorded on 
the AE eCRF. Values will be documented in the eCRF until stabilized, or the laboratory value 
returns to a clinically acceptable range (regardless of relationship to study treatment) or baseline. 
Any laboratory value that remains abnormal at the EOT visit that is considered clinically 
significant will be followed according to accepted medical standards for up to 30 days or until 
resolution of the abnormality or return to baseline levels. For lab parameters included in the 
CTCAE, toxicity will be assessed using the NCI CTCAE, v5.0. 
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. 
8.5.6. 
Adverse Events and Serious Adverse Events 
Detailed information related to the collection and reporting of AEs and SAEs is in Section 9. 
All AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to study treatment or study procedures, or that caused 
the patient to discontinue study drug (Section 9.1). 
8.5.6.1. 
Pregnancy Testing 
Pregnancy testing will be performed only for female patients of childbearing potential as 
indicated in the SoA. A negative serum hCG pregnancy test must be obtained at Screening (≤ 3 
days before selinexor administration). A urine hCG test is allowed if serum hCG test is not 
available. Pregnancy testing may be performed if clinically indicated during the study. 


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8.6. 
Other Assessments 
8.6.1. 
Collection of Information on Antineoplastic Therapy 
Information on any antineoplastic therapies planned to be used or used after discontinuation of 
study treatment will be collected. 
8.6.2. 
Telephone Contacts 
A telephone call will be performed at C1D3, Safety Follow-up and at the Survival Follow-up. 
The purpose of this telephone call with the patient is to evaluate supportive care medications, 
concomitant medications, and adverse events, and to adjust supportive care as appropriate. After 
discontinuation of study treatment, follow-up phone calls will be performed 30 days and every 3 
months until 12 months, start of new therapy, withdrawal of consent to assess the survival status, 
and collect information on any antineoplastic therapies used after discontinuation of study 
treatment. 
8.7. 
Post-treatment Assessments 
See the SoA for more information on the tests to be performed at each of the following timepoints. 


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9. 
ADVERSE EVENTS 
9.1. 
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. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. (See Section 9.2.3 for additional information about SAE 
reporting.)   
• Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse 
event or suspected adverse reaction is considered "life-threatening" if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of death. 
It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death.  
• Suspected adverse reaction: Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.  
• Unexpected adverse event or unexpected suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered "unexpected" if it is not listed in the Investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an 
Investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the Investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 


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(by virtue of greater specificity) if the Investigator brochure listed only cerebral vascular 
accidents. "Unexpected," as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the Investigator brochure as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not but are not 
specifically mentioned as occurring with the particular drug under investigation. 
See Section 9.2.3 for additional information about SAE reporting. 
9.1.1. 
Recording of Adverse Events 
AE will be reported and recorded in the eCRF from the time of the first dose of study treatment 
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 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. 
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.   
9.1.2. 
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 eCRF. 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 baseline levels (as measured during the screening visit) or are deemed no longer 
clinically significant. 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. 


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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 (considered to be severe per NCI CTCAE, v5.0) does not 
automatically indicate an SAE unless it meets the definition of serious as defined in Section 9.1 
and/or as per the opinion of the Investigator. 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 
eCRF. 
9.1.3. 
Adverse Event Severity 
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. 
The severity of the AE will be graded by the Investigator according to the NCI CTCAE Grading 
Scale, v5.0 (the NCI CTCAE files can be accessed online at the following URL: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html).  
Events that are not specifically defined in CTCAE v5.0 should be assessed according to the 
guidance provided on page 2 of the CTCAE v5.0 document 
9.1.4. 
Adverse Event Causality 
The Investigator will make a judgment regarding the relationship of the AE to study treatment (for 
each study drug), as defined below. 
• Not related: These events will lack a strong temporal relationship of the event to the 
study treatment, making a causal relationship not reasonably possible. Exposure to other 
drugs, therapeutic interventions, or underlying conditions may provide a sufficient 
explanation for the event. 
• Related: There is a temporal relationship of the event to the study treatment making a 
definitive or reasonably possible relationship, and the event is more likely explained by 
exposure to the study treatment than by any other drugs, therapeutic interventions, or 
underlying conditions. 
9.2. 
Serious Adverse Events 
See Section 9.1 for the definition of an SAE.  
Please note that SAEs that occur at any time between the signing of the Informed Consent Form 
up to the first dose of study treatment must be reported (in addition to SAEs that occur after the 
first dose of study treatment). 
9.2.1. 
Events that Do Not Meet the Definition of a Serious Adverse Event 
Elective hospitalizations to administer, or to simplify study treatment or study procedures (e.g., 
an overnight stay for social reasons) or other medical procedures, are not considered SAEs. A 
‘serious’ hospitalization is defined as 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 as an inpatient to the hospital (e.g., 


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undesirable effects of any administered treatment) and in which case it must be documented as 
an SAE.  
Progression of the malignancy/disease (including fatal outcomes), events that are clearly 
consistent with the expected pattern of progression of the underlying disease, should NOT be 
reported as an SAE throughout the study (Section 9.2.3). Any sudden and unexplained death 
must be reported as an SAE. If there is any uncertainty about a finding being due solely to 
progression of malignancy/disease, the finding should be reported as an AE or SAE, as 
appropriate.  
9.2.2. 
Recording of Serious Adverse Events 
It is the responsibility of the Investigator to record and document all SAEs occurring from the 
time when the ICF is signed until at least 30 days after the patient has stopped study treatment. 
All SAEs must be reported on the designated Sponsor’s SAE Report Form in addition to being 
recorded in the eCRF. The original SAE Report Form, completed query forms and follow-up 
reports, must be retained in the Investigator’s site file. 
All applicable sections of the SAE Report 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 form in English. 
See ICH E2A (Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting) for key data elements that are required for expedited reporting. 
9.2.3. 
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. The investigational site 
personnel must use the SAE Report Form (paper or electronic) provided by Karyopharm for 
reporting any SAE to the Karyopharm Pharmacovigilance Department. The immediate report 
should be made by the investigator within a very short period of time and under no 
circumstances should this exceed 24 hours following knowledge of the SAE. After the 30-day 
follow-up period SAEs should only be reported to Karyopharm if the Investigator suspects that 
the SAE has a causal relationship to the study treatment. 
To complete the electronic SAE Report Form, a Log Line must first be completed in the Adverse 
Events eCRF. The SAE will then be linked to an electronic SAE Report Form. It is then 
necessary to complete a Log Line in the corresponding SAE Report Form eCRF within 24 hours 
of learning of the SAE’s occurrence. It is not necessary to submit a paper SAE Report Form if 
the SAE was originally declared using the electronic SAE Report Form. 
If the SAE is to be reported via a paper SAE Report Form, upon completion, the SAE Report 
Form must be immediately emailed or faxed to: 
Pharmacovigilance Department 
Karyopharm Therapeutics Inc. 
Email: pharmacovigilance@karyopharm.com 


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Fax: 
+1-617-334-7617 (USA) 
+49-89-9218-5650 (Germany) 
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. An 
assessment should be made at each study 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 of the event 
9.2.4. 
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. All 
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. 
If required by local regulations, the Investigator is responsible for notifying his/her IRB or local 
ethics committee of all SAEs 
9.3. 
Procedures for Handling Special Situations 
9.3.1. 
Pregnancy and Breastfeeding 
Note: Pregnancy is not considered to be an AE; however, it is important to follow-up and report 
pregnancies that occur during studies. A medical untoward occurrence observed in the mother or 
fetus/newborn would be classified as an AE. 
Female patients of childbearing potential and fertile male patients will be informed as to the 
potential risk of conception while participating in this study and will be advised that they must 
use highly effective contraception listed below (i.e., results in a low failure rate when used 
consistently and correctly) during the dosing period and for a period of at least 4  months after 
the end of treatment. 
Highly effective methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 


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− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized patient or female patient’s partner 
• Sexual abstinence 
A pregnancy test will be performed on each premenopausal female patient of childbearing 
potential prior to the first dose of study drug, at Screening, and again at treatment discontinuation 
during the EOT. A negative serum hCG pregnancy test must be documented within 3 days prior 
to first study dose on C1D1.  
If a patient is confirmed pregnant during the study, study drug administration must be 
discontinued immediately. The Investigator must immediately notify the Sponsor’s Medical 
Monitor of the event and record the pregnancy on the Pregnancy Form (provided by 
Karyopharm). The initial information regarding a pregnancy must be forwarded to Karyopharm’s 
Pharmacovigilance by email or fax within 24 hours of first knowledge of its occurrence.  
The pregnancy should be followed up to determine the outcome, including any spontaneous or 
voluntary termination, details of the birth, and any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.  
All pregnancies occurring within 4 months after the patient’s last dose of study drug must be 
reported to Karyopharm, regardless of whether the patient received selinexor or other study 
drugs, withdraws from the study, or the study is completed. 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, or birth defect) and reported within 24 hours in accordance with the 
procedure for reporting SAEs (described in Section 9.2.3) 
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 selinexor-containing regimen. Consent to report 
information regarding these pregnancy outcomes should be obtained from the female partner. 
It is not known whether selinexor passes into the breast milk. Mothers should not breastfeed 
while being treated with selinexor-containing regimen.  


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9.3.2. 
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 regardless of whether or not there is 
an associated AE or SAE. Reporting should be completed via the electronic SAE Report Form 
when technically possible. To complete the electronic SAE Report Form, a Log Line must first 
be completed in the Medication Error eCRF. The incident will then be linked to an electronic 
SAE Report Form. If electronic reporting is not possible, reporting should be completed via a 
paper SAE Report Form emailed to pharmacovigilance@karyopharm.com. 
9.3.2.1. 
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 then Sponsor 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. Information regarding the overdose 
is to be recorded on an SAE Report Form and sent to Karyopharm Pharmacovigilance 
Department at pharmacovigilance@karyopharm.com, 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. 
9.3.2.2. 
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 
following: prescribing, order communication, nomenclature, compounding, dispensing, 
distribution, administration, education, monitoring, and use. 
Misuse is situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorized product information. 
All occurrences of abuse, misuse, or medication error with any study treatment are to be 
recorded on an SAE Report Form and sent 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 at pharmacovigilance@karyopharm.com, 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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9.3.2.3. 
Occupational Exposure 
Occupational exposure is the exposure to a study treatment as a result of one’s professional or 
nonprofessional occupation. For this protocol, please follow the instructions for preparation and 
administration of selinexor. 
All occurrences of occupational exposure with any study treatment are to be recorded on an SAE 
Report Form and sent 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 within 24 hours of 
awareness. 


Cli nical St u d y Pr ot oc ol : X P O R T-C R C -0 4 1  
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1 0.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
A statistical a nal ysis pla n ( S A P) will be fi nalize d pri or t o data base l oc k. A n y c ha n ges fr o m t he 
statistical a nal yses descri be d i n t his d oc u me nt will be descri be d i n t he S A P, a n d a n y de viati o n 
fr o m t he fi nal S A P will be descri be d i n t he fi nal re p ort. 
1 0. 1.  
Ge ner al C o nsi der ati o ns  
S u m mar y ta b ulati o ns w ill be pr o vi de d f or dis p ositi o n, de m o gra p hic, baseli ne c haracteristics, 
efficac y, a n d safet y data as n ote d i n t he f oll o wi n g secti o ns. All data c ollecte d o n t he e C R F will 
be pr o vi de d i n b y- patie nt data listi n gs.  
F or cate g orical varia bles, s u m mar y ta b ulati o n s of t he n u m ber a n d perce nta ge of patie nts wit hi n 
eac h cate g or y ( wit h a cate g or y f or missi n g data) of t he para meter will be prese nte d.  
F or c o nti n u o us varia bles, t he n u m ber of patie nts, mea n, me dia n, sta n dar d de viati o n, mi ni m u m, 
a n d ma xi m u m  val ues will be prese nte d. Ti me- t o-e ve nt data will be s u m marize d wit h Ka pla n-
Meier met h o d usi n g 5 0
t h ( me dia n) perce ntiles wit h ass ociate d 2-si de d 9 5 % CIs as well as 
perce nta ge of ce ns ore d o bser vati o ns if a p plica ble.  
1 0. 1. 1.  
Pr oce d ures f or H a n dli n g Missi n g D at a  
I n ge neral, t here will be n o s u bstit uti o ns ma de t o acc o m m o date missi n g data p oi nts. 
F or ti me t o e ve nt a nal yses, patie nts w h o ha ve n o efficac y e val uati o ns will be c o nsi dere d as 
ce ns ore d at date of first treat me nt.  
F or A Es, missi n g dates will be i m p ute d per t he r ules o utli ne d i n t he S A P. Eac h A E will be 
gra de d f or se verit y acc or di n g t o N CI C T C A E. Missi n g se verities of A Es will n ot be i m p ute d a n d 
will be c o nsi dere d missi n g i n a n y ta b ulati o ns of A E se verit y. If a n A E is missi n g a res p o nse t o 
t he q uesti o n re gar di n g relati o ns hi p t o treat me nt, t he e ve nt will be c o nsi dere d t o be relate d. 
1 0. 2.  
St atistic al H y p ot heses  
Details of statistical h y p ot heses will be pr o vi de d i n t he S A P.  
1 0. 3.  
S a m ple Size Deter mi n ati o n  
C CI


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Gi ve n a b o ve ass u m pti o ns, t he t otal sa m ple size is a p pr o xi matel y 7 8 patie nts wit h 2 6 i n eac h ar m. 
1 0. 4.  
P o p ul ati o ns f or A n al yses  
1 0. 4. 1.  
I nte nt t o Tre at P o p ul ati o n   
I nte nt-t o-Treat P o p ulati o n (I T T): All patie nts ra n d o mize d t o st u d y treat me nt. Patie nts will be 
a nal yze d i n t he treat me nt ar m t o w hic h t he y will be ra n d o mize d. 
1 0. 4. 2.  
S afet y P o p ul ati o n 
All patie nts w h o ha ve bee n assi g ne d t o st u d y treat me nt a n d w h o ha ve recei ve d ≥1 d ose of st u d y 
dr u g. Patie nts will be a nal yze d acc or di n g t o t he st u d y treat me nt recei ve d. 
1 0. 5.  
St atistic al A n al yses  
S u m mar y ta b ulati o ns will be pr o vi de d f or dis p ositi o n, de m o gra p hic, baseli ne, efficac y, a n d safet y 
data as n ote d i n t he f oll o wi n g secti o ns.  
1 0. 5. 1.  
Effic ac y  A n al yses 
All efficac y a nal yses will be perf or me d o n t he I T T P o p ulati o n. T he a nal ysis of ti me-t o-e ve nt 
e n d p oi nts ( P F S, O S) will be base d o n Ka pla n- Meier met h o d f or esti mati o n of s u m mar y statistics 
a n d will i ncl u de t he me dia n e ve nt ti mes a n d ass ociate d 9 5 % CIs, as well as t he n u m ber a n d 
perce nta ge of ce ns ore d patie nts. I n a d diti o n, C o x pr o p orti o nal hazar ds re gressi o n m o dels will be 
use d t o esti mate a H R f or t he ris k of pr o gressi o n i n t he seli ne x or o nl y or seli ne x or a n d 
pe m br oliz u ma b ar m vers us t he S O C c o ntr ol ar m, a n d t he seli ne x or a n d pe m br oliz u ma b ar m 
vers us seli ne x or o nl y ar m c o m paris o ns. 
Det ails will be s pecifie d i n t he S A P.  
1 0. 5. 2.  
S afet y A n al yses 
All safet y a nal yses will be perf or me d o n t he Safet y P o p ulati o n, u nless ot her wise s pecifie d a n d 
will be prese nte d b y act ual treat me nt ar m. 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 seli ne x or will be e val uate d b y mea ns of dr u g -relate d A E re p orts, 
p h ysical e xa mi nati o ns, a n d la b orat or y safet y e val uati o ns. T he gra di n g of t he se verit y of t he A Es 
will be d o ne acc or di n g t o C T C A E, v 5. 0. I n vesti gat ors will pr o vi de t heir asse ss me nt as eit her t he 
A E is relate d or n ot relate d t o st u d y dr u g.  
Treat me nt -e mer ge nt A Es, S A Es, A Es of at least Gra de 3 i n se verit y, relate d A Es, a n d A Es 
lea di n g t o wit h dra wal of treat me nt will be s u m marize d b y Ar m a n d i n t he o verall S afet y 
P o p ulati o n. Tre at me nt-e mer ge nt A Es will be t h ose t hat start or w orse n o n or after t he first da y of 
st u d y treat me nt, t hr o u g h 3 0 da ys after last d ose ( or t he da y bef ore i nitiati o n of a ne w a nti-
ne o plastic treat me nt, w hic he ver occ urs first). Relate d A Es will be t h ose wit h a n I n vesti gat or 
deter mi nati o n of relate d t o st u d y dr u g.  
La b orat or y data will be a nal yze d b y s u m mar y statistics o ver ti me, as well as b y s hift ta bles base d 
o n se verit y. 
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Continual monitoring of safety data will be performed by the independent Data Safety 
Monitoring Board (DSMB). Adverse events and concomitant medications will be coded 
according to Medical Dictionary for Regulatory Activities (MedDRA) and World Health 
Organization (WHO) Drug, respectively. 
10.5.2.1. Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and displayed in tables and listings using MedDRA system organ class and preferred term. 
In those instances where the AE only has a partial date recorded, the AE will be assessed using 
the available date information to determine if it is treatment emergent. For AEs in which the date 
is completely missing, the AE will be assumed to be treatment emergent. No formal hypothesis-
testing of AE incidence rates will be performed. 
Adverse events will be summarized by patient incidence rates; therefore, in any tabulation, a 
patient contributes only once to the count for a given AE (by PT). The number and percentage of 
patients with any TEAE will be summarized for each arm, classified by SOC and PT. The 
number and percentage of patients with TEAEs assessed by the Investigator as related to 
treatment will also be tabulated. The number and percentage of patients with any Grade ≥3 
TEAE will be tabulated in the same manner.  
In the event a patient experience repeat episodes of the same AE, then the event with the highest 
severity and/or strongest causal relationship to treatment will be used for purposes of tabulations. 
SAEs will be summarized in the same manner as TEAEs. 
All AEs (treatment emergent and post-treatment) will be listed in by-patient data listings, 
classified by arm, patient, and day on study. In addition, separate by patient listings will be 
provided for the following: patient deaths; serious AEs; and AEs leading to withdrawal. 
10.5.2.2. Laboratory Data 
Clinical laboratory values will be expressed using SI units. 
For each arm, the actual value and change from baseline (Day 1, prior to the first administration 
of study drug) to each on study evaluation will be summarized for each clinical laboratory 
parameter, including hematology, and clinical chemistry. In the event of repeat values, the last 
non-missing value per study day/time will be used. In the event that Day 1 data are unavailable 
for a given patient/parameter, the screening value will substitute as the baseline value. 
Severity of select clinical lab measures will be determined using CTCAE criteria (e.g., those 
measures that have a corresponding CTCAE grade classification). Labs with CTCAE Grades ≥3 
will be presented in a data listing. 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. 
10.5.2.3. Vital Signs and Physical Examinations 
The actual value and change from baseline (Day 1, prior to the first administration of study 
treatment) to each on study evaluation will be summarized for vital signs. 
By-patient listings of vital sign measurements will be presented in data listings. 


Cli nical St u d y Pr ot oc ol : X P O R T-C R C -0 4 1  
Seli ne x or  
Versi o n 2. 0  
 
2 6  Ma y  2 0 2 1  
 
C o nfi de ntial  
 
Pa ge 7 0  of 8 7  
 
A b n or mal p h ysical e xa mi nati o n res ults at scre e ni n g, a n d a b n or mal p h ysical e xa mi nati o n res ults 
( A Es) d uri n g t he st u d y, will be s u m marize d. All p h ysical e xa mi nati o n fi n di n gs will be prese nte d 
i n b y-patie nt data listi n gs.  
1 0. 5. 2. 4.  C o nc o mit a nt Me dic ati o ns  
T he use of c o nc o mita nt me dicati o ns will be i ncl u de d i n b y- patie nt data listi n gs.  
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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Ethical and Administrative Obligations 
11.1.1. 
Regulatory and Ethical Considerations 
This clinical study was designed and shall be implemented and reported in accordance with the 
International Council for Harmonisation (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC 
and US Code of Federal Regulations (CFR) Title 21), and with the ethical principles that 
originate from the Declaration of Helsinki. 
The protocol and the proposed ICF(s) must be reviewed and approved by a properly constituted 
IRB/IEC before study start. Prior to study start, the Investigator is required to sign a protocol 
signature page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access to 
all relevant data and records to Karyopharm monitors, auditors, designated agents of 
Karyopharm, IRBs/IECs, and regulatory authorities as required. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
11.1.2. 
Responsibilities of the Investigator and Good Clinical Practice 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC and per local regulatory requirements 
• Notifying the IRB/IEC of SUSARs or other significant safety findings as required per local 
regulatory requirements 
• Providing oversight of the conduct of the study at the site and adherence to requirements of 
ICH guidelines, the IRB/IEC, 21 CFR and European regulation 536/2014 for clinical studies 
(as applicable), and all other applicable local regulatory requirements 
11.2. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information to allow the Sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate Regulatory Authorities. Investigators are responsible for 
providing information on financial interests at the beginning of the study, at the time of study 
closure, and for 1 year after completion of the study. 


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Versi o n 2. 0  
 
2 6  Ma y  2 0 2 1  
 
C o nfi de ntial  
 
Pa ge 7 2  of 8 7  
 
1 1. 3.  
I nf or me d C o nse nt Pr ocess 
Eli gi ble patie nts ma y o nl y be i ncl u de d i n t he st u d y after pr o vi di n g writte n ( wit nesse d, w here 
re q uire d b y la w or re g ulati o n) i nf or me d c o nse nt t hat has bee n a p pr o ve d b y a n I R B/I E C/ researc h 
et hics b oar d ( R E B)  ass ociate d wit h t he st u d y site.  
T he i nf or me d c o nse nt m ust be o btai ne d pri or t o t he i nitiati o n of a n y st u d y- s pecific meas ures. 
T he pr ocess of o btai ni n g i nf or me d c o nse nt s h o ul d be d oc u me nte d i n t he patie nt s o urce 
d o c u me nts. T he date w he n t he i nf or me d c o nse nt was o btai ne d a n d t he f or m si g ne d, will be 
ca pt ure d i n t he patie nt’s C R Fs.  
T he S p o ns or will pr o vi de t o I n vesti gat ors  pr o p ose d I C F(s) t hat are c o nsi dere d a p pr o priate f or 
t his st u d y a n d c o m pl y wit h t he I C H G C P g ui deli nes a n d l ocal re g ulat or y re q uire me nts. A n y 
c ha n ges t o t he I C F(s) s u g geste d b y t he I n vesti gat or m ust be a gree d t o b y t he S p o ns or bef ore 
s u b missi o n t o t he I R B/I E C, a n d a c o p y of t he a p pr o ve d versi o n(s) m ust be pr o vi de d t o t he 
S p o ns or after I R B/I E C a p pr o val.  
Fe males of c hil d beari n g p ote ntial a n d male patie nt s wit h c hil d beari n g p ote ntial part ners will be 
i nf or me d t hat ta ki n g t he st u d y dr u g ma y i n v ol ve u n k n o w n ris ks t o t he fet us if pre g na nc y were t o 
occ ur d uri n g t he st u d y a n d a gree t hat i n or der t o partici pate i n t he st u d y t he y m ust a d here t o t he 
c o ntrace pti o n re q uire me nt as per i ncl usi o n criteria . If t here is a n y q uesti o n t hat t he patie nt will 
n ot relia bl y c o m pl y, t he y s h o ul d n ot be e ntere d i n t he st u d y. 
•  T he In vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he patie nt  or 
his/ her le gall y a ut h orize d re prese ntati ve a n d a ns wer all  q uesti o ns re gar di n g t he st u d y. 
•  Patie nt s m ust b e i nf or me d t hat t heir partici pati o n is v ol u ntar y. Patie nt s will be re q uire d t o si g n 
a state me nt of i nf or m e d c o nse nt t hat meets t he re q uire me nts of 2 1 C F R 5 0, l ocal re g ulati o ns, 
I C H  g ui deli nes,  Healt h  I ns ura nce  P orta bilit y  a n d  Acc o u nta bilit y  Act  re q uire me nts,  w here 
a p plica ble, a n d t he I R B/I E C or st u d y ce nter. 
•  T he pr ocess a n d date of o btai ni n g t he patie nt’s i nf or me d c o nse nt m ust be d oc u me nte d i n t he 
patie nt’ s s o urce d oc u me nts. T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o 
si g n t he I C F. 
•  Patie nt s m ust be re-c o nse nte d t o t he m ost c urre nt versi o n of t he I C F d uri n g t heir partici pati o n 
i n  t he st u d y,  as  l o n g  as  t he  c ha n ges  ma de  i ncl u de  safet y  i nf or mati o n or  ot her  i nf or mati o n 
rele va nt t o t he patie nt a n d/ or ma y affect t he patie nt’s c o nse nt t o c o nti n ue partici pati n g i n t he 
st u d y. 
•  A  c o p y  of  t he  I C F  m ust  be  pr o vi de d  t o  t he patie nt  or  t he patie nt ’s  legall y  a ut h orize d 
re prese ntative, a n d t he ori gi nall y si g ne d d oc u me nt m ust be file d at t he site. 
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Versi o n 2. 0  
 
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C o nfi de ntial  
 
Pa ge 7 3  of 8 7  
 
Patie nts will be t ol d t hat t he y are free t o ref use t o partici pate a n d ma y wit h dra w t heir c o nse nt at 
a n y ti me a n d f or a n y reas o n d uri n g t he st ora ge peri o d. If re q uire d b y l ocal re g ulati o ns, i n 
a d diti o n t o t he pri mar y I C F, t here will be a se parate f or m f or fe male part ners of partici pati n g 
male patie nts w h o are se x uall y acti ve a n d acce pt ris ks.  
1 1. 4.  
D at a C ollecti o n a n d M a n a ge me nt  
1 1. 4. 1.  
D at a C o nfi de nti alit y  
T he I n vesti gat or m ust e ns ure a n o n y mit y of t he patie nts. Eac h p atie nt will be assi g ne d a u ni q ue 
i de ntifier. Ori gi nall y s i g ne d I C Fs a n d patie nt e nr oll me nt l o gs m ust be ke pt strictl y c o nfi de ntial t o 
e na ble patie nt i de ntificati o n at t he site.  
A n y patie nt rec or ds or datasets t hat are tra nsferre d t o t he S p o ns or will c o ntai n t he i de ntifier o nl y; 
patie nt na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he patie nt i de ntifia ble will n ot be 
tra nsferre d. 
I nf or mati o n a b o ut st u d y patie nts will be ke pt c o nfi de ntial a n d ma na ge d u n der t he a p plica ble 
la ws a n d re g ulati o ns. T h ose re g ulati o ns, w here a p plica ble, re q uire a si g ne d patie nt a ut h orizati o n 
i nf or mi n g t he patie nt of t he f oll o wi n g: 
•  W hat pr otecte d healt h i nf or mati o n ( P HI) will be c ollecte d fr o m patie nts i n t his st u d y  
•  W h o will ha ve access t o t hat i nf or mati o n a n d w h y  
•  W h o will use or discl ose t hat i nf or mati o n  
•  T he ri g hts of a researc h patie nt t o re v o ke t heir a ut h orizati o n f or use of t heir P HI.  
I n t he e ve nt t hat a patie nt re v o kes a ut h orizati o n t o c ollect or use P HI, t he I n vesti gat or, b y 
re g ulati o n, retai ns t he a bilit y t o use all i nf or mati o n c ollecte d pri or t o t he re v ocati o n of patie nt 
a ut h orizati o n. F or patie nts t hat ha ve re v o ke d a ut h orizati o n t o c o llect or use P HI, atte m pts s h o ul d 
be ma de t o o btai n per missi o n t o c ollect f oll o w -u p safet y i nf or mati o n ( e. g., has t he patie nt 
e x perie nce d a n y ne w or w orse ne d A Es) at t he e n d of t heir sc he d ule d st u d y peri o d. 
T he data c ollecti o n s yste m f or t his st u d y uses b u ilt-i n sec urit y feat ures t o e ncr y pt all data f or 
tra ns missi o n i n b ot h directi o ns, pre ve nti n g u na ut h orize d access t o c o nfi de ntial patie nt 
i nf or mati o n. Access t o t he s yste m will be c o ntr olle d b y a se q ue nce of i n di vi d uall y assi g ne d user 
i de ntificati o n c o des an d pass w or ds, ma de a vaila ble o nl y t o a ut h orize d pers o n nel w h o ha ve 
c o m plete d prere q uisite trai ni n g.  
1 1. 4. 2.  
D at a C ollecti o n  
Data c ollecti o n is t he res p o nsi bilit y of t he cli nical st u d y staff at t he site, u n der t he s u per visi o n of 
t he site I n vesti gat or. T he st u d y e C R F is t he pri mar y data c ollecti o n i nstr u me nt f or t he st u d y. T he 
I n vesti gat or s h o ul d e ns ure t he acc urac y, c o m plete ness, le gi bilit y, a n d ti meli ness of t he data 
re p orte d i n t he e C R Fs a n d all ot her re q uire d re p orts. Data re p orte d o n t he e C R F t hat are deri ve d 
fr o m s o urce d oc u me nts s h o ul d be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies 
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should be explained. All data requested on the eCRF must be recorded. Any missing data must 
be explained. An audit trail will be maintained by the eCRF system.  
11.4.3. 
Site Monitoring 
Before study initiation, Karyopharm personnel (or designated contract research organization 
[CRO]) will review the protocol with the Investigators and their staff (e.g., at a site initiation 
visit). During the study, the monitor will visit the site regularly to check the completeness of 
patient records, accuracy of entries on the CRFs, adherence to the protocol and to Good Clinical 
Practice (GCP), progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the monitor during these visits. 
The Investigator must maintain source documents for each patient in the study, consisting of case 
and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information recorded on CRFs must be traceable to source documents in the patient's file. The 
Investigator must also keep the original signed ICF (a signed copy is given to the patient). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Karyopharm monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the CRFs 
are performed according to the study-specific monitoring plan. 
11.4.4. 
 Data Captures 
This study will utilize electronic data capture (EDC), the designated clinical site staff will enter 
the data required by the protocol into the eCRF. The eCRFs will be constructed using fully 
validated secure web-enabled software that conforms to 21 CFR Part 11 requirements. Clinical 
site staff will not be given access to the EDC system until they have been trained. Automatic 
validation programs check for data discrepancies in the eCRFs and allow modification or 
verification of the entered data by the Investigator site staff. 
The Investigator is responsible for assuring that the data entered into the eCRF is complete and 
accurate, and that entry and updates are performed in a timely manner. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical (ATC) 
classification system. Medical history/current medical conditions and AEs will be coded using 
the MedDRA terminology. 
11.4.5. 
Database Management and Quality Control 
Karyopharm personnel (or designated CRO) will review the eCRF data entered by 
investigational staff for completeness and accuracy. Electronic data queries stating the nature of 


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the problem and requesting clarification will be created for discrepancies and missing values and 
sent to the investigational site via the EDC system. Designated Investigator site staff are required 
to respond promptly to queries and to make any necessary changes to the data. 
At the conclusion of the study, after discrepancies and missing values have been completed and 
the data have been verified to be complete and accurate, the database will be declared locked.  
For EDC studies, after database lock, the Investigator will receive a CD-ROM or paper copies of 
the patient data for archiving at the investigational site. 
11.5. 
Structure of Committees 
11.5.1. 
Data Safety Monitoring Board 
An independent DSMB will be established and will review the safety of study treatment and any 
SAEs that occur during the study. Details on how the DSMB will review safety and response 
data are provided in the DSMB Charter. 
The DSMB will be composed of at least 2 oncologists (at least one of whom specializes in CRC) 
and a statistician. Following their initial meeting, the DSMB will meet approximately every 6 
months to review clinical data and provide recommendations to the Sponsor on whether the 
study should continue. The DSMB may also meet more frequently, if needed.  
11.6. 
Dissemination of Clinical Study Data 
Results from the study (including demographics, baseline characteristics, primary and secondary 
endpoints) will be posted in a publicly accessible database (such as ClinicalTrials.gov or 
EudraCT) in accordance with applicable laws, regulations, and/or guidelines.  
In addition, upon study completion and finalization of the clinical study report, the results of this 
study may be submitted for publication in a peer-reviewed journal or presented at a 
scientific/biomedical conference. 
11.7. 
Source Documents 
Each participating site will maintain appropriate medical and research records for this study (i.e., 
source documents), in compliance with Section 4.9 of the ICH E6 GCP, local regulatory and 
institutional requirements, for the protection of confidentiality of patients.  
As part of participating in a Karyopharm-sponsored study, each site will permit authorized 
representatives of Karyopharm and regulatory agencies to examine (and when required by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits and 
evaluation of the study safety and progress. 
Source data are all information as initially recorded, including original records of clinical 
findings, observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study. Examples of these original documents and data records include, but are 
not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, patients’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 


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instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and patient files and 
records kept at the pharmacy, at the laboratories, and medico-technical departments involved in 
the clinical study. 
The Investigator/institution should maintain the study documents as specified in ICH GCP- 
Essential Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The Investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the clinical study unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time because 
of applicable laws, regulations and/or guidelines. 
11.8. 
Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion and database lock. A study site will be considered closed when all required 
documents and study supplies have been collected, the Trial Master File has been audited and 
considered complete for the study site, the database is locked or all site eCRFs are signed/locked 
and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further study intervention development 
11.9. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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12. 
REFERENCES 
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through an international consortium. Cancer Discov. 7, 818–831 (2017). 
2. Abdul Razak AR, Mau-Soerensen M, Gabrail NY, Gerecitano JF, Shields AF, Unger TJ, et 
al. First-in-class, first-in-human phase I study of selinexor, a selective inhibitor of nuclear 
export, in patients with advanced Solid Tumors. J Clin Oncol. 2016;34(34):4142–50. 
3. Aladhraei, M., Kassem Al-Thobhani A, Poungvarin N, Suwannalert P. Association of XPO1 
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2 6  Ma y  2 0 2 1  
 
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13. 
APPENDICES 
APPENDIX 1. 
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 <10 mm. 
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 PD. 
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. 
 
 




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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. 
Ultrasound 
When the primary endpoint of the study is objective response evaluation, ultrasound should not be 
used to measure tumor lesions that are clinically not easily accessible. It is a possible alternative 
to clinical measurements for superficial palpable nodes, subcutaneous lesions and thyroid nodules. 
Ultrasound 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 tumor types such as germ cell tumors, where known residual benign tumors can 
remain). The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor 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 PD. 
 
 


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APPENDIX 2. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS CRITERIA 
Source: Oken 1982. 
 
 
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. 


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APPENDIX 3. STRONG AND MODERATE CYP3A INHIBITORS AND 
INDUCERS 
Type 
Example Medications 
Strong CYP3A inducers 
Apalutamide, avasimibe, carbamazepine, enzalutamide, ivosidenib, 
lumacaftor, mitotane, phenobarbital, phenytoin, rifampin, rifapentine, St 
John's Wort extract 
Moderate CYP3A inducers 
Asunaprevir, beclabuvir, bosentan, cenobamate, dabrafenib, daclatasvir, 
efavirenz, elagolix, etravirine, lersivirine lesinurad, lopinavir, lorlatinib, 
modafinil, nafcillin, rifabutin, ritonavir, semagacestat, talviraline, telotristat 
ethyl, thioridazine, tipranavir 
Strong CYP3A inhibitors  
Aquinavir, boceprevir, ceritinib, cobicistat, conivaptan, clarithromycin, 
danoprevir/ritonavir, elvitegravir/ritonavir, grapefruit juice DS, idelalisib, 
indinavir, indinavior/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, mifepristone, nefazodone, nelfinavir,  posaconazole, ribociclib, 
ritonavir, saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir 
(GS-9350), troleandomycin, VIEKIRA pak, voriconazole 
Moderate CYP3A inhibitors  
amprenavir, aprepitant, atazanavir, atazanavir/-ritonavir, casopitant, 
cimetidine, ciprofloxacin, crizotinib, cyclosporine, darunavir, darunavir 
/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, faldaprevir, 
fedratinib, fluconazole, grapefruit juice, imatinib, isavuconazole, 
istradefylline, lefamulin, letermovir, Magnolia vine (Schisandra 
sphenanthera), netupitant, nilotinib, ravuconazole, tofisopam, verapamil, 
voxelotor 
Note: Based on Metabolism and Transport Drug Interaction Database (https://www.druginteractioninfo.org/), and is 
not an exhaustive list.  
For an updated FDA list, see the following link: https://www fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers#cypEnzymes.  
 
 
 
 
 
 
 
  

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K ary o p h ar m T her a pe utics, I nc.  
St atistic al A n alysis Pl a n  
 
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S T A TI S TI C A L A N A L Y SI S  P L A N  
 
Pr ot oc ol X P O R T -C R C -0 4 1  
 
A P h ase 2 O pe n -L a bel M ultice nter St u d y t o E v al u ate t he S afet y a n d Effic ac y 
of Seli ne x or wit h or wit h o ut Pe m br oliz u m a b vers us St a n d ar d of C are i n 
Pre vi o usl y tre ate d Met ast atic C ol orect al C a ncer wit h R A S m ut ati o ns  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T his statistical a nal ysis pla n c o ntai ns c o nfi de ntial i nf or mati o n a n d is t he pr o prietar y pr o pert y 
of Kar y o p h ar m T hera pe utics, I n c. It ma y n ot be c o pie d or ma de a v aila ble f or re vie w b y a n 
u na ut h orize d pers o n or fir m wit h o ut t he pri or writte n a ut h orizati o n of Kar y o p har m 
T hera p e utics, I nc.  
 
 
 
 
Pr ot oc ol V ersi o n:  
2 .0  
 
T y pe of A n al ysis Pl a n:  
Fi n al A n al ysis  
 
S A P V ersi o n:  
1 .0  
 
D ate:  
2 3 M ar 2 0 2 3  
 
A ut h or:  
 P h D 
P P D


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S T A TI S TI C A L A N A L Y SI S P L A N SI G N A T U R E P A G E  
See last pa ge f or si g nat ures.  
P P D


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D O C U M E N T HI S T O R Y  
 
Versi o n  
D ate  
A ut h or(s)  
Brief S u m m a r y of C h a n ges  
1 .0  
2 3 Mar 2 0 2 3  
 P h D. 
Ori gi nal b ase d o n  P V 2 . 0 
 
P P D


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TABLE OF CONTENTS 
Section 
Page 
1. 
OVERVIEW AND INVESTIGATIONAL PLAN ........................................................ 9 
1.1. 
OVERALL DESIGN ............................................................................................. 9 
1.2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................ 10 
1.3. 
DETERMINATION OF SAMPLE SIZE ............................................................ 12 
1.4. 
STUDY PLAN ..................................................................................................... 12 
1.5. 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE 
PROTOCOL ........................................................................................................ 12 
1.6. 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL 
ANALYSIS PLAN .............................................................................................. 12 
2. 
GENERAL STATISTICAL METHODS AND DATA HANDLING ....................... 13 
2.1. 
GENERAL ANALYSIS METHODS .................................................................. 13 
2.2. 
MISSING DATA HANDLING ........................................................................... 13 
2.2.1. 
Handling of Computation of Treatment Duration if 
Study Treatment End of Treatment Date is Missing....................... 13 
2.2.2. 
Handling of Missing/Partial Dates for Adverse Events or 
Concomitant Medications .................................................................. 13 
2.2.3. 
Handling of Missing or Partial Birth Date for 
Calculation of Age ............................................................................... 14 
2.2.4. 
Handling of Missing Assessment of Relationship of AEs 
to Study Treatment ............................................................................. 14 
2.2.5. 
Handling of Missing Severity of AEs ................................................ 14 
2.3. 
STUDY TREATMENT DOSING DATE ........................................................... 14 
2.4. 
OBSERVATION PERIOD .................................................................................. 14 
2.5. 
STUDY DAY CALCULATION ......................................................................... 14 
2.6. 
BASELINE MEASUREMENT ........................................................................... 15 
2.7. 
SUBGROUPS ...................................................................................................... 15 
2.8. 
POOLING OF CENTERS FOR STATISTICAL ANALYSES .......................... 15 
2.9. 
COMPUTING AND CODING STANDARDS................................................... 15 
3. 
PATIENT INFORMATION ......................................................................................... 16 
3.1. 
DISPOSITION OF PATIENTS AND ANALYSIS POPULATIONS ................ 16 
3.1.1. 
Intent-to-Treat (ITT) Population ...................................................... 16 
3.1.2. 
Safety Population ................................................................................ 16 


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Section 
Page 
3.2. 
DEMOGRAPHICS, MEDICAL HISTORY, AND BASELINE 
CHARACTERISTICS ......................................................................................... 16 
3.2.1. 
Demographic Data .............................................................................. 16 
3.2.2. 
Baseline Characteristics ..................................................................... 16 
3.2.3. 
Prior Antineoplastic Therapy ............................................................ 17 
3.2.4. 
Medical/surgical History .................................................................... 17 
3.2.5. 
Disease History .................................................................................... 17 
3.3. 
CONCOMITANT MEDICATIONS AND PROCEDURES ............................... 17 
3.4. 
EXTENT OF STUDY TREATMENT EXPOSURE AND 
COMPLIANCE.................................................................................................... 18 
3.4.1. 
Treatment Compliance ....................................................................... 18 
4. 
EFFICACY ..................................................................................................................... 19 
4.1. 
EFFICACY ENDPOINTS ................................................................................... 19 
4.1.1. 
Overall Response Rate (ORR) ........................................................... 19 
4.1.2. 
Disease control rate (DCR) ................................................................ 19 
4.1.3. 
Progression-free Survival (PFS) ........................................................ 19 
4.1.4. 
Duration of Response (DOR) ............................................................. 19 
4.1.5. 
Overall Survival (OS) ......................................................................... 19 
4.2. 
STATISTICAL METHODS FOR EFFICACY ENDPOINTS............................ 20 
5. 
SAFETY .......................................................................................................................... 21 
5.1. 
ADVERSE EVENTS ........................................................................................... 21 
5.1.1. 
Definitions of Treatment-Emergent Adverse Events 
(TEAEs), Serious Adverse Events (SAEs), and 
Treatment-Emergent Treatment-Related Adverse 
Events (TRAEs)................................................................................... 21 
5.1.1.1. Treatment-Emergent Adverse Event (TEAE)................... 21 
5.1.1.2. Serious Adverse Event (SAE) ............................................. 21 
5.1.1.3. Treatment-emergent Treatment-Related 
Adverse Events (TRAEs) ..................................................... 22 
5.1.2. 
Analysis Methods ................................................................................ 22 
5.1.3. 
Analysis of TEAE ................................................................................ 23 
5.1.4. 
Analysis of SAE ................................................................................... 23 
5.2. 
DEATH ................................................................................................................ 24 
6. 
REFERENCES ............................................................................................................... 25 


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Section 
Page 
LIST OF TABLES 
Table 1-1 
Study Objectives and Endpoints ...................................................................................... 10 
Table 2-1 
Coding Standards ............................................................................................................ 15 
Table 4-1 
PFS or DOR (responders only) outcome and censoring definition ................................. 20 
 
LIST OF FIGURES 
Figure 1 
Study Schema .................................................................................................................... 9 
 
 
 
 


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LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
A b bre vi ati o n  
Defi niti o n  
A E  
a d verse  e ve nt 
BI D  
t wice dail y  
B O R  
best  o verall  res p o nse 
C  
c ycle 
CI  
c o nfi de nce  i nter val 
C R  
c o m plete res p o nse 
C R C  
c ol orectal  ca ncer 
C T C A E  
C o m m o n  T er mi n ol o g y  Criteria  f or A d verse  E ve nts  
D  
da y  
D C R  
disease  c o ntr ol  rate 
d M M R  
deficie nt  mis matc h  re pair 
D O R  
d urati o n  of  res p o nse 
E C O G  
Easter n  C o o perati ve  O nc ol o g y  Gr o u p  
e C R F 
electr o nic  case  re p ort f or m 
E O T  
e n d of  treat me nt 
H R  
hazar d  rati o 
I T T 
i nte nt t o treat 
I V 
i ntra ve n o us(l y) 
Me d D R A  
Me dical  Dicti o nar y  f or Re g ulat or y  Acti vities  
M SI -H  
micr osatellite i nsta bilit y -hi g h  
N CI  
Nati o nal  Ca ncer  I nstit ute 
O R R  
o bj ecti ve  res p o nse rate 
P D  
pr o gressi ve disease  
P F S  
pr o gressi o n -free s ur vi val 
P O  
orall y  
P R  
partial  res p o nse 
Q W  
o nce  wee kl y  
R A S  
rat sarc o ma 
R E CI S T  
Res p o nse  E val uati o n  Criteria  i n S oli d  T u m ors  
C CI
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A b bre vi ati o n  
Defi niti o n  
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n  
SI  
I nter nati o nal S yste m  of  U nits  
S O A  
sc he d ule of  assess me nts 
S O C  
sta n dar d of  care 
S O C  
s yste m or ga n class 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T R A E  
treat me nt-e mer ge nt treat me nt-relate d a d verse e ve nt  
W H O D D E  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y E n ha nce d  
 
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1.  
O V E R VI E W A N D I N V E S TI G A TI O N A L P L A N  
1. 1.  
O V E R A L L  D E SI G N  
T his is a p hase 2, o pe n -la bel, m ultice nter st u d y t hat will e val uate t he efficac y a n d 
safet y of seli ne x or a n d p e m br oliz u ma b  i n patie nts  wit h  a d va nce d  or  m etastatic  C R C.   
T he  st u d y sc he m a is de pi cte d i n Err or! Refere nce s o urce n ot f o u n d. . 
Fi g ure 1  
St u d y Sc he m a  
 
S O C  =  Sta n dar d  of  care,  P D  =  pr o gressi ve  dise ase;  M SI -H  =  micr osat ellite  i nsta bilit y 
hi g h;  d M M R  = d eficie nt mis matc h re pair; Q W = o nce wee kl y; BI D =t wice dail y; 
C R C =c ol orectal ca ncer  
A p pr o xi matel y  7 8  patie nts  wit h  a d va nce d  or  metastatic  C R C  will  be  e nr olle d,  a n d 
ra n d o mize d t o Ar m A, B or C base d o n t he f oll o wi n g stratificati o n fact or:  
All  eli gi ble patie nts  i n Ar m  A  will  be  treate d wit h  seli ne x or 8 0  m g  Q W  orall y  as a 
m o n ot hera p y o n Da y 1 of eac h wee k of a 4 2 -d a y c ycle. Ar m B patie nts will be 
treate d wit h seline x or at t he sa me d ose as Ar m A i n c o m bi nati o n wit h 
pe m br oliz u ma b 4 0 0 m g I V o nce e v er y 6 wee ks. Ar m C patie nts will be a d mi nistere d 
t he sta n dar d of care treat me nt trifl uri di ne a n d ti piracil 3 5 m g/ m2/ d ose orall y BI D  
( ma x 8 0 m g / d ose) o n Da ys 1 t hr o u g h  5 a n d Da ys 8 t hr o u g h 1 2  of eac h 2 8 -da y c ycle. 
Trifl uri di ne a n d ti piracil s h o ul d be ta ke n wit h f o o d.  
Pri mar y effic ac y will be assesse d b y  P F S, as assesse d b y t h e i n vesti gat or per 
R E CI S T 1. 1  f or seli ne x or pl us pe m br oliz u ma b a n d f or SO C assesse d fr o m 
ra n d o mizati o n u ntil disease pr o gressi o n or d eat h fr o m a n y ca use, w hic he ver occ urs 
first. O bjecti ve res p o nse rate ( O R R) defi ne d as t h e pr o p orti o n  of  patie nts  w h o  ac hie ve  
c o m plete res p o nse ( C R) or  partial  res p o nse ( P R), per  R E CI S T  1. 1  as d ef i n e d b y  t he 
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1. 3.  
D E T E R MI N A TI O N O F S A M P L E SI Z E  
Gi ve n  a b o ve ass u m pti o ns,  t he t otal sa mple  siz e is a p pr o xi matel y 7 8  patie nts  wit h  2 6  i n eac h ar m. 
1. 4.  
S T U D Y P L A N  
F or eac h patie nt t hat si g ns t he i nf or me d c o nse nt, t he st u d y c o nsists of:  
•  Scree ni n g/ baseli ne visit: occ urs wit hi n 2 1  da ys pri or t o recei vi n g t he 1 st d os e of st u d y 
treat me nt 
•  Treat me nt peri o d: T here is n o ma xi m u m treat me nt d urati o n.  Treat me nt c ycles of ar m A 
a n d B last 4 2  da ys a n d ar m C last 2 8 da ys.  P atie nts ma y c o nti n ue t o recei ve st u d y dr u gs 
u ntil t he patie nt has c o nfir me d P D, wit h dra ws c o nse nt, is l ost t o f oll o w -u p, e x peri e nces 
i nt olera ble t o xicit y w hi c h precl u des f urt her treat me nt, or treat me nt is disc o nti n ue d at t he 
discreti o n of t he patie nt, I n v esti gat or, or Kar y o p h ar m. Patie nts w h o ha ve o bjecti ve 
disease pr o gressi o n b ut ha ve e vi de nce of o verall cli nical be nefit ma y, at t he re q uest of 
t he treati n g p h ysicia n, c o nti n ue treat me nt wit h st u d y dr u gs after dis c ussi o n wit h t he 
Me dical M o nit or.  
•  F oll o w -u p peri o d: d ura bilit y of res p o ns e a n d s ur vi val p h o ne call will be ma de t o patie nt 
e ver y 3 m o nt hs u p t o o ne year  after last d ose of st u d y treat me nt . 
1. 5.  
M O DI FI C A TI O N S T O T H E S T A TI S TI C A L S E C TI O N O F T H E 
P R O T O C O L  
T he c urre nt S A P is base d o n Pr ot oc ol Versi o n 2 . 0 date d 2 6  Ma y  2 0 2 1 . 
1. 6.  
S T A TI S TI C A L M O DI FI C A TI O N S M A D E I N T H E 
S T A TI S TI C A L A N A L Y SI S P L A N  
N o ne.  
C CI
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2.  
G E N E R A L S T A TI S TI C A L M E T H O D S  A N D D A T A H A N D LI N G  
T his statistical a nal ysis pla n ( S A P) o utli ne s t he met h o ds t o be use d i n t he a nal ysis of cli nical  
data i n or der t o a ns wer t h e pri mar y a n d s ec o n dar y st u d y o bjecti ves. P o p ulati o ns f or a nal ysis, 
data ha n dli n g r ules, a n d statistical met h o ds are pr o vi de d. 
 
 
2. 1.  
G E N E R A L A N A L Y SI S M E T H O D S  
All s u m mar y statistics will be c o m p ute d a n d dis pla ye d a m o n g t he c orres p o n di n g a n al ysis 
p o p ulati o n, a n d b y eac h s c he d ule d ass ess me nt ti me p oi nt w he ne ver a p plica ble. S u m mar y 
statistics f or c o nti n u o us varia bles will mi ni mall y i ncl u de n, me dia n,  mea n, sta n dar d de via ti o n, 
mi ni m u m, a n d ma xi m u m. F or cate g orical varia bl es, fre q ue n cies a n d p erce nta ges will be 
prese nte d wit h t he d e n o mi nat ors f or t he perce nta ges d eter mi ne d b ase d o n t he a nal ysis 
p o p ulati o n use d, u nless ot her wise s pecifie d. F or ti me -t o-e ve nt v aria bles, t h e Ka pla n -M eier 
met h o d will be use d f or descri pti ve s u m maries. Gra p hical dis pla ys will be pr o vi de d as 
a p pr o priate.  
2. 2.  
MI S SI N G D A T A H A N D LI N G  
I n ge neral, missi n g baseli nes will n ot be i m p ute d. T he f oll o wi n g a p pr oac hes are defa ult met h o ds 
f or missi n g data h a n dli n g in s u m mar y ta bles.  
•  Cate g orical data at baseli ne will be s u m marize d usi n g c o u nts ( n) a n d perce nta ges ( %). 
De n o mi nat or will be t he t otal n u m ber of pe o ple i n a c orres p o n di n g treat me nt ar m, base d 
o n t he p o p ulati o n s pecifi e d f or t he s u m mar y, u nl ess ot her wise s pe cifi e d.   Missi n g data 
ma y b e pres e nte d as a s e parate cate g or y.  
•  C o nti n u o us data: s u m maries will be base d o n o bs er ve d dat a o nl y.  
2. 2. 1.  
H a n dli n g of C o m p ut ati o n of T re at me nt D ur ati o n if St u d y Tre at me nt  E n d of 
T re at me nt D ate is M issi n g 
F or t he calc ulati o n of tr eat me n t d urati o n, t he date of t he last d ose of st u d y treat me nt is e q ual t o 
t he date of last st u d y treat me nt d osi n g re p ort e d o n st u d y treat me nt d osi n g f or m. If all t he d osi n g 
dates are missi n g, t he n t h e d urati o n is missi n g.  
T he last d ose i nta ke  s h o ul d be clearl y i de ntifie d o n t he e C R F d osi n g p a ge a n d s h o ul d n ot be 
a p pr o xi mate d b y t he last ret ur ne d p ac ka ge date.  
2. 2. 2.  
H a n dli n g of M issi n g/P arti al D ates f or A d vers e E ve nts or C o nc o mit a nt 
M e dic ati o ns  
I n ge neral, t he i m p utati o n s h o ul d be c o nser vati ve s uc h that o nset dates s h o ul d be i m p ute d t o be 
as earl y as p ossi ble a n d res ol uti o n dates will be i m p ute d t o be as late as p ossi ble.  I m p ute 
res ol uti o n date first a n d t he n i m p ute o nset date usi n g i m p ute d res ol uti o n date. H o we ver, f or 
cate g orizati o n p ur p ose, if t he  partial A E o nset dat e i nf or mati o n d oes n ot i n dicate w het h er t he 
A E starte d pri or t o treat me nt or after t h e treat me nt -e mer ge nt a d verse e ve nt ( T E A E) peri o d, t he 
A E will be classifie d as treat me nt -e mer ge nt.   
T hese data i m p utati o ns are f or cate g orizati o n p ur p ose or cal c ulati o n of A E d urati o n,  a n d will 
n ot be use d i n listi n gs.  
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Refer to the Karyopharm Biostatistics and Statistical Programming Rule Book 2.0 for details on 
imputation methods. 
2.2.3. 
Handling of Missing or Partial Birth Date for Calculation of Age 
Refer to the Karyopharm Biostatistics and Statistical Programming Rule Book 2.0 for details on 
imputation methods. 
2.2.4. 
Handling of Missing Assessment of Relationship of AEs to Study Treatment 
If the assessment of the relationship to study treatment is missing, then the relationship to study 
treatment in the frequency tables is considered as related. 
2.2.5. 
Handling of Missing Severity of AEs 
If the severity is missing for one of the treatment-emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences, a “missing” category will be added in the summary table. 
2.3. 
STUDY TREATMENT DOSING DATE 
Study treatment dosing date is the date on which a patient actually received study treatment 
(partial or complete), as recorded on the study drug exposure eCRF. 
The date of first study treatment is defined as the earliest date of non-zero dose of study 
treatment.   
The date of last study treatment is defined as the latest date of non-zero dose of study treatment.   
2.4. 
OBSERVATION PERIOD 
The observation period will be divided by the following: 
• The pre-treatment period is defined as the time from the signed informed consent date up 
to the time before the start date of study treatment.   
• The treatment period is defined as the time from the start date of study treatment up to 
the last day of study treatment+30 days inclusive, or the day before initiation of a new 
anti-neoplastic treatment, whichever occurs first. 
• The post-treatment period is defined as the time beyond the treatment period. 
2.5. 
STUDY DAY CALCULATION 
Study Day 1 is the date of first study treatment. The day before Day 1 is considered Day -1; 
there is no Day 0. 
A patient is considered as treated in a cycle if the patient received any non-zero dose of study 
treatment in that cycle. 
Study day for a given assessment is defined as  
• the assessment date – the date of first study treatment + 1 if the assessment date is on or 
after Day 1, or  
• the assessment date – the date of first study treatment if the assessment date is before 
Day 1. 


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2.6. 
BASELINE MEASUREMENT 
For treatment period, the baseline value is defined as the latest value prior to the first dose of 
study treatment.  
In the case an assessment performed on the same date as the first dose, but it is impossible to 
determine the evaluation time relative to the time of taking the first dose, the evaluation time 
will be assumed to be following the protocol-defined schedule. 
2.7. 
SUBGROUPS 
No subgroup analysis is planned due to the small sample size. 
2.8. 
POOLING OF CENTERS FOR STATISTICAL ANALYSES 
All participating centers in the study will be pooled together for analysis. 
2.9. 
COMPUTING AND CODING STANDARDS 
Activities will be performed using the following tools: 
Table 2-1 
Coding Standards 
Table, listing, and figure production 
SAS Version 9.4 or higher 
Coding 
 
 AEs 
MedDRA Version 24.1 or higher 
 Medical Histories 
MedDRA Version 24.1 or higher 
 Prior and Concomitant Medications 
WHODrug-Global-B3/202109 
Grading 
 
 AEs 
CTCAE Version 5.0 or higher 
 


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3. 
PATIENT INFORMATION 
3.1. 
DISPOSITION OF PATIENTS AND ANALYSIS POPULATIONS 
Patient disposition will be summarized in each of the following categories: 
• Patients who were randomized 
• Patients who were randomized and received at least one dose of the study treatment 
(partial or complete) 
• End of treatment: 
o Patients who discontinued treatment and primary reason for discontinuation 
• Survival follow-up status 
o Patients in survival follow-up 
o Patients who died during survival follow-up 
• End of study 
o Patients who discontinued from study and primary reason for study 
discontinuation 
3.1.1. 
Intent-to-Treat (ITT) Population 
Intent-to-Treat Population (ITT): All patients randomized to study treatment. Patients 
will be analyzed in the treatment arm to which they were randomized. 
3.1.2. 
Safety Population 
All patients who have been assigned to study treatment and who have received ≥1 dose of 
study drug. Patients will be analyzed according to the study treatment received. 
3.2. 
DEMOGRAPHICS, MEDICAL HISTORY, AND BASELINE 
CHARACTERISTICS 
In general, the baseline value is defined as latest value prior to the first dose of study treatment. 
Demographics, medical history and baseline characteristics will generally be summarized 
among ITT and safety populations, unless otherwise specified. P-values on demographic, 
medical history and baseline characteristic data will not be calculated. 
3.2.1. 
Demographic Data 
Demographic variables include sex, race, ethnicity, and age at study entry. 
3.2.2. 
Baseline Characteristics 
Summary statistics including the number and percentage of patients will be presented for the 
following variables: 
• Baseline height (cm)/ weight (kg)/ body surface area (m2)/ BMI (kg/m2) 
• Baseline ECOG performance status 


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3.2.3. 
Prior Antineoplastic Therapy 
Prior antineoplastic therapy will be summarized with the following variables: 
• Number of prior regimens of antineoplastic therapy 
• Best response to prior regimens of antineoplastic therapy 
• Days since discontinuation of most recent prior antineoplastic therapy the start of study 
treatment, which will be calculated as the date of first study treatment – stop date of 
most recent antineoplastic therapy+1 
• Days since most recent disease progression to the start of study treatment 
The detailed history of prior systemic therapy including start and end dates of the medication, 
best response, progression during or after therapy, as well as discontinuations due to, toxicity 
and/or intolerability may also be provided in a data listing. 
3.2.4. 
Medical/surgical History 
Medical history will be summarized in the ITT population by system organ class (SOC) and 
preferred term (PT) using the number and percentage of patients who have at least one 
occurrence of a SOC and PT. The summary will be sorted by alphabetic order in SOC, and 
further by decreasing frequency of PT within each SOC. When more than one PT has the same 
frequency, the order of presentation will be alphabetical in PTs. 
3.2.5. 
Disease History 
Summary statistics including the number and percentage of patients will be presented for the 
disease history at initial diagnosis and/or screening 
3.3. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
Concomitant medication consists of any prescription or over-the-counter preparation, including 
vitamins, dietary supplements, over-the-counter medications, and oral herbal preparations taken 
during the study, as well as changes in medication. Patients may continue their baseline 
medication(s).  Concomitant medications include any medications used to treat symptoms, 
concomitant diseases such as diabetes, hypertension, etc., AEs and intercurrent illnesses that are 
medically necessary as part of standard care. All concomitant medication(s) must be reported on 
the eCRF. Any diagnostic, therapeutic, or surgical procedure performed during the study period 
should be recorded, including the dates, description of the procedure(s), and any clinical 
findings, if applicable. Concomitant medication will generally be summarized among ITT and 
safety populations, unless otherwise specified. 
All medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHO DDE, WHODrug-Global-B3/202109). 
Prior medications are any treatments received by the patient prior to the first dose of study 
treatment. Prior medications can be discontinued before first dose of study treatment or can be 
ongoing during treatment period. 
Concomitant medications are any treatments received by the patient concomitantly with study 
treatment, from first dose of study treatment to last dose of study treatment + 30 days. 


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Concomitant medications will be summarized according to the WHO DDE by the ATC level 2 
(therapeutic level), level 4 (generic level) and standard name. A patient taking the same drug 
multiple times will only be counted once. 
Note that a medication can be classified as both a prior medication and a concomitant 
medication.  
The use of prior and concomitant medications and procedures may also be provided in a data 
listing. 
3.4. 
EXTENT OF STUDY TREATMENT EXPOSURE AND 
COMPLIANCE 
Study treatment is considered taken when patient actually received any study drug, partial or 
complete. Extent of exposure and compliance will generally be summarized among ITT and 
safety populations, unless otherwise specified.   
The extent of exposure for the study treatment will be assessed using the following variable: 
• Duration of study treatment exposure 
The following will be presented separately for selinexor, pembrolizumab, trifluridine, and 
tipiracil: 
• Duration of exposure 
• Total dose received  
• Average dose received per week  
• Number and percentage of patients with dose reduction   
• Number and percentage of patients with dose interruption  
• Number and percentage of patients with missed dose 
Duration of exposure is defined as the date of last dose - date of first dose + 1. 
3.4.1. 
Treatment Compliance 
Study treatment compliance will be summarized descriptively as a quantitative variable, 
calculated as 
number of study treatment doses taken
number of  study treatment doses prescribed × 100%. 
Note that the number of scheduled study treatment doses does not include doses missed due to 
treatment interruption or other reasons not related to patient choice.  
Treatment compliance will also be presented separately for selinexor as 
number of actual doses taken
number of doses scheduled × 100. 
Similarly, the number of scheduled doses does not include doses missed due to treatment 
interruption or other reasons not related to patient choice.  


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4. 
EFFICACY 
Response assessment will be determined per RECIST 1.1 for all arms at the time points 
specified by the investigator.  All efficacy analyses will be performed on the ITT 
Population. 
4.1. 
EFFICACY ENDPOINTS 
4.1.1. 
Overall Response Rate (ORR) 
ORR is defined as the proportion of patients who have a response of partial response (PR) or 
complete response (CR) as assessed by RECIST 1.1 before disease progression or initiating a 
new antineoplastic treatment.  ORR can be computed based on best overall response (BOR) of 
each patient.  BOR is only censored by disease progression, new antineoplastic treatment event, 
database cut. 
For descriptive purposes, a two-sided exact 95% CI of ORR will also be presented. The number 
and percentage of patients in the following response categories will also be presented, along 
with exact 95% CIs: CR, PR, SD, and NE. 
4.1.2. 
Disease control rate (DCR) 
DCR is defined as the proportion of patients who have best response of PR or better, or at least 
12 continuous weeks of SD before disease progression or initiating a new antineoplastic 
treatment.  For descriptive purposes, a two-sided exact 95% CI will also be presented. 
4.1.3. 
Progression-free Survival (PFS) 
PFS is defined as the time from the randomization date until the date of first PD determined by 
PI per RECIST 1.1, or death due to any cause, whichever occurs first. The outcome and 
censoring definitions are provided in Table 4-1. The number and percentage of censored 
patients will be reported.  The 25th, 50th (median), and 75th percentiles for PFS and associated 
95% CIs will be estimated based on the KM method. 
4.1.4. 
Duration of Response (DOR) 
DOR is defined for patients with PR or CR as the duration from the date of first PR or better to 
the date of first PD or death due to any cause, whichever occurs first. Details on the outcome 
and censoring definitions used for DOR are provided in Table 4-1. 
The number and percentage of censored patients will be reported. The 25th, 50th (median), and 
75th percentiles for DOR and associated 95% CIs will be estimated based on the KM method. 
4.1.5. 
Overall Survival (OS) 
OS is defined as time since the randomization date until death due to any cause. If death event 
did not occur during the follow-up period, the patient is censored at the date of discontinuation 
from the study, or date of last participating visit (e.g., a telephone contact with patient status 
being alive) on or before database cut-off date, whichever occurs first.  
 
 


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Table 4-1 
PFS or DOR (responders only) outcome and censoring definition 
Situation 
Date of event or censoring 
Outcome 
No adequate post-baseline disease status 
assessment unless death occurs prior to 
first post-baseline assessment 
Date of first study treatment 
Censored 
Death due to any reason before PD 
Date of death 
Event 
PD 
Date of PD 
Event 
No PD or death due to any reason on or 
before  
a. database cut,  
b. withdrawal of informed consent, 
c. lost to follow-up,  
d. start of new antineoplastic 
treatment,  
whichever occurs first  
Date of last adequate disease 
assessment on or prior to the 
earliest occurrence of the events 
(a. – d.) listed in the left column 
Censored 
No PD or death due to any reason 
Date of last adequate disease 
assessment prior to the gap 
Censored 
4.2. 
STATISTICAL METHODS FOR EFFICACY ENDPOINTS 
Binary endpoints of ORR and DCR will be calculated by point estimate with a 95% confidence 
interval (CI) using the exact method. 
The analysis of time-to-event endpoints (PFS, OS, DOR) will be based on Kaplan-Meier method 
for estimation of summary statistics and will include the median event times and associated 95% 
CIs, as well as the number and percentage of censored patients. In addition, Cox proportional 
hazards regression models will be used to estimate a HR for the risk of progression in the 
selinexor only or selinexor and pembrolizumab arm versus the SOC control arm, and the 
selinexor and pembrolizumab arm versus selinexor only arm comparisons. 


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5. 
SAFETY 
Safety analyses will use safety population evaluated by means of AE reports.  The analyses of 
the safety variables will be essentially descriptive, and no statistical testing is planned. 
5.1. 
ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence in a patient receiving a pharmaceutical 
product regardless of a causal relationship with this treatment. An AE can therefore be any 
unfavorable sign and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporarily associated with the use of a study treatment, whether or not related to the 
study treatment. 
All AEs (including serious adverse events [SAEs]) will be coded to a preferred term (PT) and 
associated primary system organ class (SOC) using the MedDRA. 
The severity of all AEs will be graded according to the NCI CTCAE Grading Scale, Version 
5.0. An AE with a CTCAE grade of 3 or higher is considered a severe AE. The severity of the 
AE is different from the seriousness of the AE. For AEs not covered by CTCAE, the severity 
will be characterized as “mild,” “moderate,” “severe”, “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. 
5.1.1. 
Definitions of Treatment-Emergent Adverse Events (TEAEs), Serious Adverse 
Events (SAEs), and Treatment-Emergent Treatment-Related Adverse Events 
(TRAEs) 
5.1.1.1. 
Treatment-Emergent Adverse Event (TEAE) 
Treatment-emergent adverse events (TEAE) of study treatment are defined as any event that 
was not present prior to the initiation of any study treatment (selinexor and/or other drugs) or 
any event already present that worsens in either intensity or frequency following exposure to 
study treatment, from the first dose of study treatment to 30 days after the last dose of study 
treatment inclusive, or the day before the start of a new antineoplastic treatment, whichever 
occurs first. Additionally, any AEs that occurred 30 days after the last dose of study treatment or 
after the start of a new antineoplastic treatment will also be considered as TEAE, if assessed by 
the Investigator as related to any drug of the study treatment. 
5.1.1.2. 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence, at any dose, that: 
• Results in death 


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• 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 
• Results in a congenital anomaly/birth defect 
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 one of 
the outcomes listed in this definition. SAE needs to be clearly documented on the AE form. 
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). 
5.1.1.3. 
Treatment-emergent Treatment-Related Adverse Events (TRAEs) 
A TRAE is any TEAE that is related to any study treatment. 
5.1.2. 
Analysis Methods 
The primary focus of AE reporting will be on TEAEs.  
If an AE date/time of onset (occurrence or worsening) is incomplete, an imputation algorithm 
will be used to determine the AE as treatment-emergent. The algorithm for imputing date/time 
of onset will be conservative and will classify an AE as treatment-emergent unless there is 
definitive information to determine it is not treatment emergent. Details on classification of AEs 
with missing or partial onset dates are provided in Section 2.2.2. 
AE summaries will include number (n) and percentage (%) of patients who have experienced an 
AE. The denominator for computation of percentages is the number of patients in the 
corresponding treatment arm. Multiple occurrences of the same event in the same patient will be 
counted only once in the tables. 
Unless otherwise specified, sorting order will follow the alphabetic order in SOC, and further by 
decreasing frequency of PTs within each SOC. When more than one PT has same number of 
events, the order of presentation will be alphabetical in PTs.  
The summary of AEs by causality will generally include the following categories of causality. 
• Related to selinexor or pembrolizumab or trifluridine or tipiracil 
• Related to selinexor only  
• Related to pembrolizumab only  
• Related to trifluridine only 
• Related to tipiracil only 
• Not related to selinexor or pembrolizumab or trifluridine or tipiracil  


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5.1.3. 
Analysis of TEAE 
An TEAE overview summary table will be provided, which will include the number of patients 
with at least one of the adverse events:  
• TEAEs  
• Grade 3/4 TEAEs  
• Serious TEAEs  
• TEAEs leading to dose modifications of study treatment 
• TEAEs leading to dose reduction of study treatment 
• TEAEs leading to dose interruption of study treatment 
• TEAEs leading to study treatment discontinuation 
• TEAEs leading to death  
• TRAE 
• Serious TRAEs  
• TRAEs leading to dose modifications of study treatment 
• TRAEs leading to dose reduction of study treatment 
• TRAEs leading to dose interruption of study treatment 
• TRAEs leading to study treatment discontinuation 
• TRAEs leading to death  
TEAEs will be summarized by primary SOC and PT and will include the following categories:  
• All TEAEs  
• All TEAEs, by causality 
• All TEAEs, by maximum grade  
• TEAEs leading to dose modifications of study treatment 
• TEAEs leading to study treatment discontinuation 
5.1.4. 
Analysis of SAE 
Treatment-emergent SAEs will be summarized by primary SOC and PT and will include the 
following categories:  
• All treatment-emergent SAEs  
• All treatment-emergent SAEs, by causality 
• Treatment-emergent SAEs leading to dose modifications of study treatment 
• Treatment-emergent SAEs leading to study treatment discontinuation 


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5.2. 
DEATH 
The following summaries on death events will be provided:  
• An overview of all death events and primary cause of death  
• TEAEs leading to death by primary SOC and PT  
• Listing of all death events  
 


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6. 
REFERENCES 
1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargen, D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009; 45:228-47. 
2. Karyopharm Biostatistics and Statistical Programming Rule Book, Karyopharm 
Therapeutics Inc., version 2.0 


D oc u me nt A p pr o vals
A p pr o ve d Date: 2 3 Mar 2 0 2 3
A p pr o val Tas k
Ver dict:  A p pr o ve
I a p pr o ve t his d oc u me nt
2 2- Mar- 2 0 2 3 2 1: 4 1: 5 2 G M T + 0 0 0 0
A p pr o val Tas k
Ver dict:  A p pr o ve
I a p pr o ve t his d oc u me nt
2 2- Mar- 2 0 2 3 2 3: 1 0: 5 8 G M T + 0 0 0 0
A p pr o val Tas k
Ver dict:  A p pr o ve
I a p pr o ve t his d oc u me nt
2 3- Mar- 2 0 2 3 1 2: 5 9: 0 7 G M T + 0 0 0 0
P P D
P P D
P P D