Phase I/II Randomized Clinical Trial of Selinexor Plus Gemcitabine in Selected Advanced Soft-tissue Sarcomas
Phase: PHASE2
Conditions: Sarcoma,Soft Tissue
Sponsor: Asociación Europea y Latinoamericana SELNET para la Investigación en Sarcomas

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
Version 5.0 
Page 1 of 98 
Confidential 
Clinical Study Protocol 
SELNET-7-1 (SeliSarc) 
 
Phase I/II randomized clinical trial of selinexor plus 
gemcitabine in selected advanced soft-tissue sarcomas  
 
Study Number: 
SELNET-7-1 
Study Phase: 
Phase I/II 
Product Name(s): 
Selinexor (KPT-330), gemcitabine 
EudraCT Number: 2019-000652-33 
IST Identifier: 
IST-319 
Indication: 
Advanced soft-tissue sarcomas  
Sponsor: 
Asociación Europea y Latinoamericana Selnet para la 
Investigación en Sarcomas 
Calle de la Sierra de Pajarejo, 5, 5A 
28023, Madrid, Spain 
Sponsor-
Investigator: 
Dr. Javier Martín Broto –  
Hospital Universitario Fundación Jiménez Díaz (Madrid) 
Collaborators: 
• Grupo Español de Investigación en Sarcomas (GEIS) 
• Sarcoma as a model to improve diagnosis and clinical 
care of rare tumors through a European and Latin 
American multidisciplinary network (SELNET) 
Selinexor 
Supplier/Drug 
Supplier and 
Funding Source: 
Karyopharm Therapeutics, Inc.  
85 Wells Avenue 
Newton, MA 02459 USA 
Tel. + (617) 658-0600 
Additional 
Funding Sources: 
 
None 
Protocol Version 
and Date: 
Version 5.0 of 17 February 2023 
CONDUCT 
In accordance with the ethical principles that originate from the Declaration of Helsinki and 
that are consistent with International Council for Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP) and regulatory requirements as applicable. 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
Version 5.0 
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 INVESTIGATORS' AGREEMENT 
I have read and understand the contents of this clinical protocol for Study No. 
SELNET-7-1 version 5.0 and dated 17 February 2023 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 Practices, 
ICH E6, and applicable EMA regulatory requirements. 
 
Sponsor-Investigator’s 
Signature: 
 
Investigator’s Name: 
JAVIER MARTÍN BROTO 
Institution: 
Hospital Universitario Fundación Jiménez 
Díaz 
Date: 
 
 
 
Investigator’s Signature: 
 
Investigator’s Name: 
 
Institution: 
 
Date: 
 
 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................... 3 
LIST OF IN-TEXT TABLES ................................................................................................... 8 
LIST OF IN-TEXT FIGURES .................................................................................................. 8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................... 9 
1 
PROTOCOL SYNOPSIS................................................................................................ 12 
2 
STUDY SCHEMATICS AND SCHEDULE OF ASSESSMENTS AND DOSING ..... 22 
3 
INTRODUCTION AND RATIONALE ......................................................................... 33 
3.1 
Rationale for the Use of Selinexor in Sarcomas ................................................... 33 
3.2 
Gemcitabine in the Treatment of Soft-Tissue Sarcoma ........................................ 34 
3.3 
Study and Dose Rationale ..................................................................................... 37 
3.3.1 
Dose Schedule Rationale ............................................................................ 37 
3.3.1.1 
Selinexor Dosing ............................................................................... 37 
3.3.1.2 
Gemcitabine Combination: Dose Levels .......................................... 38 
4 
STUDY OBJECTIVES ................................................................................................... 39 
5 
STUDY DESIGN ............................................................................................................ 42 
5.1 
Overall Study Design ............................................................................................ 42 
5.1.1 
Phase I Part ................................................................................................. 42 
5.1.2 
Phase II Part ................................................................................................ 43 
5.2 
Total sample size of the phase II part ................................................................... 43 
6 
STUDY POPULATION ................................................................................................. 44 
6.1 
Study Population ................................................................................................... 44 
6.2 
Inclusion Criteria .................................................................................................. 44 
6.3 
Exclusion Criteria ................................................................................................. 45 
7 
STUDY TREATMENTS AND TREATMENT ASSIGNMENT .................................. 46 
7.1 
Treatments Administered ...................................................................................... 46 
7.1.1 
Selinexor ..................................................................................................... 46 
7.1.2 
Gemcitabine ................................................................................................ 46 
7.2 
Study Treatment Labeling and Storage ................................................................. 46 
7.2.1 
Labeling ...................................................................................................... 46 
7.2.2 
Storage ........................................................................................................ 46 
7.3 
Study Treatment Dosing and Administration ....................................................... 47 
7.3.1 
Dispensing Directions ................................................................................. 47 
7.3.2 
Dosing Information ..................................................................................... 47 
7.3.2.1 
Selinexor ........................................................................................... 47 
7.4 
Method of Assigning Patients to Treatment Groups ............................................. 47 
7.5 
Dose Schedules for Evaluation ............................................................................. 47 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
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IST Identifier: IST-319 
 
 
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7.5.1 
Selinexor + Gemcitabine (Phase II) ............................................................ 47 
7.6 
Study Phases and Determination of RP2D ........................................................... 47 
7.6.1 
Phase 1: Dose Escalation Phase .................................................................. 47 
7.6.1.1 
Treatments to be Escalated ............................................................... 48 
7.6.1.2 
Dose Escalation Procedures .............................................................. 48 
7.6.1.3 
Dose-Limiting Toxicity .................................................................... 49 
7.6.2 
Determination of RP2D .............................................................................. 49 
7.6.3 
Phase 2: Dose Expansion Phase .................................................................. 50 
7.7 
Missed or Vomited Doses ..................................................................................... 50 
7.7.1 
Missed Doses of Study Treatments ............................................................. 50 
7.7.2 
Vomited Doses of Selinexor ....................................................................... 50 
7.8 
Dose Modifications and Delays ............................................................................ 50 
7.8.1 
Selinexor Dose Reduction Guidelines ........................................................ 52 
7.8.1.1 
Selinexor Dose Adjustment in the Setting of Infection .................... 55 
7.8.1.2 
Conditions Not Requiring Selinexor Dose Modification .................. 55 
7.8.2 
Dose Increases ............................................................................................ 55 
7.8.3 
Gemcitabine Dose Modifications ............................................................... 56 
7.9 
Duration of Treatment and Follow-up .................................................................. 56 
7.10 
Study Treatment Accountability ........................................................................... 56 
7.11 
Treatment Compliance .......................................................................................... 57 
7.12 
Supportive Care, Contraception Requirements, Concomitant Medications, and 
Restrictions ........................................................................................................... 57 
7.12.1 
Required 5-HT3 Antagonists/Anti-emetics ................................................ 57 
7.12.2 
Recommended Supportive Care for All Patients ........................................ 57 
7.12.2.1 
Infection ............................................................................................ 57 
7.12.2.2 
Overdose ........................................................................................... 58 
7.12.3 
Contraception Requirements ....................................................................... 58 
7.12.4 
Concomitant Medication and Treatment .................................................... 59 
7.12.5 
Permitted Concomitant Medication ............................................................ 59 
7.12.6 
Use of Blood Products ................................................................................ 59 
7.12.7 
Radiation Treatment .................................................................................... 59 
7.12.8 
Prohibited Medications ............................................................................... 59 
7.12.9 
Restrictions for Study Treatment ................................................................ 60 
7.12.9.1 
Restrictions for Selinexor ................................................................. 60 
7.12.9.2 
Restrictions for Gemcitabine ............................................................ 60 
8 
STUDY ASSESSMENTS .............................................................................................. 61 
8.1 
Informed Consent .................................................................................................. 61 
8.2 
Demographic and Baseline Characteristics Assessments ..................................... 61 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
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8.2.1 
Demographics ............................................................................................. 61 
8.2.2 
Medical History .......................................................................................... 61 
8.3 
Efficacy Assessments ............................................................................................ 61 
8.3.1 
Tumor Assessment ...................................................................................... 61 
8.4 
Safety Assessments ............................................................................................... 62 
8.4.1 
Adverse Events ........................................................................................... 62 
8.4.2 
Concomitant Medications ........................................................................... 62 
8.4.3 
Clinical Safety Assessments ....................................................................... 62 
8.4.3.1 
Weight, Height, and BSA ................................................................. 62 
8.4.3.2 
Physical Examination, Vital Signs, and ECOG Performance 
Status ................................................................................................. 62 
8.4.4 
Electrocardiography and Echocardiography ............................................... 63 
8.4.5 
Laboratory Safety Assessments .................................................................. 63 
8.4.5.1 
Clinical Laboratory Tests .................................................................. 63 
8.4.5.2 
Pregnancy Testing ............................................................................. 64 
8.5 
Other Assessments ................................................................................................ 64 
8.5.1 
Nutritional Consultation .............................................................................. 64 
8.5.2 
Durability of Response and Survival Follow-up Visit(s) ........................... 64 
9 
SAFETY DEFINITIONS, RECORDING, AND REPORTING .................................... 65 
9.1 
Adverse Events ..................................................................................................... 65 
9.1.1 
Definitions ................................................................................................... 65 
9.1.2 
Recording of Adverse Events ..................................................................... 65 
9.1.2.1 
Laboratory Test Abnormalities ......................................................... 65 
9.1.2.2 
Tumor Lysis Syndrome ..................................................................... 66 
9.1.3 
Adverse Event Severity ............................................................................... 67 
9.1.4 
Adverse Event Causality ............................................................................. 67 
9.2 
Serious Adverse Events ........................................................................................ 68 
9.2.1 
Events that Do Not Meet the Definition of a Serious Adverse Event ........ 68 
9.2.2 
Recording of Serious Adverse Events ........................................................ 68 
9.2.3 
Reporting of Serious Adverse Events ......................................................... 68 
9.2.4 
Suspected Unexpected Serious Adverse Reactions .................................... 69 
9.2.5 
Adverse Event Reporting ............................................................................ 69 
9.3 
Procedures for Handling Special Situations ......................................................... 70 
9.3.1 
Pregnancy and Breastfeeding ...................................................................... 70 
9.3.2 
Overdose, Abuse, Misuse, Medication Errors, and Occupational 
Exposure ..................................................................................................... 70 
9.3.2.1 
Overdose ........................................................................................... 71 
9.3.2.2 
Abuse, Misuse, or Medication Error ................................................. 71 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
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9.3.2.3 
Occupational Exposure ..................................................................... 71 
10 DISCONTINUATION CRITERIA ................................................................................ 72 
10.1 
Early Termination of the Study ............................................................................. 72 
10.2 
Discontinuation of Study Treatment and/or Withdrawal of Patients from the 
Study ..................................................................................................................... 72 
11 STUDY VISITS .............................................................................................................. 73 
11.1 
Description of Study Days .................................................................................... 73 
11.1.1 
Screening ..................................................................................................... 73 
11.1.2 
Cycle 1 ........................................................................................................ 74 
11.1.2.1 
Study Procedures (Days 1-21) .......................................................... 74 
11.1.2.2 
Study Treatment Dosing ................................................................... 74 
11.1.3 
Cycle 2 ........................................................................................................ 75 
11.1.3.1 
Study Procedures .............................................................................. 75 
11.1.3.2 
Study Treatment Dosing ................................................................... 75 
11.1.4 
Cycle ≥3 ...................................................................................................... 76 
11.1.4.1 
Study Procedures .............................................................................. 76 
11.1.4.2 
Study Treatment Dosing ................................................................... 76 
11.1.5 
End-of-Treatment Visit (within 30 Days after Last Dose) ......................... 76 
11.1.6 
Survival Follow-Up .................................................................................... 77 
12 TRANSLATIONAL STUDY ......................................................................................... 78 
13 PLANNED STATISTICAL METHODS ....................................................................... 82 
13.1 
General Considerations ......................................................................................... 82 
13.2 
Determination of Sample Size .............................................................................. 82 
13.3 
Analysis Populations ............................................................................................. 83 
13.3.1 
Intent-to-Treat Population ........................................................................... 83 
13.3.2 
Per Protocol Population .............................................................................. 83 
13.3.3 
Safety Population ........................................................................................ 83 
13.4 
Demographics and Baseline Characteristics ......................................................... 84 
13.5 
Efficacy Analysis .................................................................................................. 84 
13.6 
Safety Analysis ..................................................................................................... 85 
13.6.1 
Adverse Events ........................................................................................... 85 
13.6.2 
Laboratory Data .......................................................................................... 85 
13.6.3 
Vital Signs and Physical Examinations ...................................................... 86 
14 ADMINISTRATIVE MATTERS ................................................................................... 87 
14.1 
Regulatory and Ethical Compliance ..................................................................... 87 
14.2 
Ethics Committees ................................................................................................ 87 
14.3 
Regulatory Authority Approval ............................................................................ 87 
14.4 
Protocol Adherence ............................................................................................... 87 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
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14.5 
Amendments to the Protocol ................................................................................. 87 
14.6 
Informed Consent .................................................................................................. 88 
14.7 
Patient Confidentiality and Disclosure ................................................................. 88 
14.8 
Collection, Auditing Study Documentation, and Data Storage ............................ 88 
14.8.1 
Study Documentation, Record Keeping and Retention of Documents ....... 88 
14.8.2 
Auditing Procedure ..................................................................................... 89 
14.9 
Termination of the Study ...................................................................................... 89 
15 DATA MANAGEMENT ................................................................................................ 90 
15.1 
Electronic case report form (eCRF) ...................................................................... 90 
15.2 
Record keeping ..................................................................................................... 91 
16 REFERENCE LIST ........................................................................................................ 92 
APPENDIX 1 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS CRITERIA ...................................................................................................... 97 
APPENDIX 2 
NAUSEA MANAGEMENT RECOMMENDATIONS ............................. 98 
 
 
 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
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LIST OF IN-TEXT TABLES 
Table 1: Schedule of Study Activities and Assessments (PHASE I) ............................................. 22 
Table 2: Schedule of Study Activities and Assessments (PHASE II) ............................................ 26 
Table 3: Dosing Schedule (Phase I Part and Phase II with Selinexor plus Gemcitabine) ............. 30 
Table 4: Objectives and Endpoints ................................................................................................ 39 
Table 5: Dose Escalation Rules for Defining MTD ........................................................................ 49 
Table 6: Hematology and Biochemistry Day 1 Criteria (see also Table 7) .................................... 50 
Table 7: General Guidelines for Dose Modification Due to Hematologic Toxicity ......................... 51 
Table 8: Dosage Reduction Guidelines for Gemcitabine Due to Hepatic Toxicities in Day +8 ..... 52 
Table 9: Pre-specified Dose Modifications for AEs Related to Study Treatment .......................... 53 
Table 10: Supportive Care and Selinexor Dose Adjustment Guidelines for AEs Related to 
Selinexor 
53 
Table 11: Dose Reduction Levels for Gemcitabine ....................................................................... 56 
Table 12: Clinical Laboratory Tests ............................................................................................... 63 
Table 13: Study Procedures for Cycle 1 ........................................................................................ 74 
Table 14: Study Procedures for Cycle 2 ........................................................................................ 75 
Table 15: Study Procedures for Cycles ≥3 .................................................................................... 76 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Phase I Design ................................................................................................................ 31 
Figure 2: Phase I Dose Levels ....................................................................................................... 32 
 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
Version 5.0 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase (SGPT) 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (SGOT) 
AV 
arterioventricular 
BIW 
twice weekly 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CI 
confidence Interval 
cm 
centimeter 
CR 
complete remission 
CRM1 
chromosomal region maintenance protein 1 
CSR 
clinical study report 
CST 
Company-Sponsored Trial 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
EAP 
Expanded Access Program 
EC 
ethics committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
EU 
European Union 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GGT 
gamma-glutamyl transferase 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GRP 
growth regulatory protein 
GSH 
glutathione 
Hb 
hemoglobin 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
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Abbreviation 
Definition 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
hr 
hour 
HTLV 
human T-cell lymphotropic virus 
IC50 
inhibitory concentration, 50% (half maximal inhibitory concentration) 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
eIF4E 
mRNA cap-binding protein eukaryotic translation factor 4E 
IL 
interleukin  
INR 
international normalization ratio 
IR 
intermediate risk 
IRB 
Institutional Review Board 
ISS 
International Staging System 
IST 
Investigator-Sponsored Trial 
ITT 
intent-to-treat 
IV 
intravenous 
IWG 
International Working Group 
kg 
kilogram 
LDH 
lactic dehydrogenase 
m2 
square meters 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MI 
myocardial infarction 
min 
minute 
miRNA 
microRNA 
mL 
milliliter 
mITT 
modified Intent-to-Treat 
MM 
multiple myeloma 
mmHg 
millimeters of mercury 
MTD 
maximum tolerated dose 
MR 
minor response 
mRNA 
messenger ribonucleic acid 
MUGA 
multiple gated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NES 
nuclear export sequences 
NHL 
non-Hodgkin’s lymphoma 
NK1R 
neurokinin 1 receptor 
NPC 
nuclear pore complex 
ORR 
overall response rate (sCR + CR + VGPR + PR) 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
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Abbreviation 
Definition 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PDn 
pharmacodynamics 
PE 
physical examination 
PFS 
progression free survival 
PI 
proteasome inhibitor  
PK 
pharmacokinetic 
PP 
per protocol 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
QW 
once weekly 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
RR 
Relapsed/Refractory 
RT 
Richter’s transformation 
SAE 
serious adverse event 
SAM 
S-adenosylmethionine 
SC 
subcutaneous 
sCR 
stringent complete response 
SD  
stable disease 
SINE 
selective inhibitor of nuclear export 
SOC  
standard of care; system organ class 
SOP 
standard operating procedure 
STD 
standard deviation 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum serum concentration 
TRAE 
treatment-related adverse event 
TSP 
tumor suppressor protein 
TTP 
time to progression 
ULN 
upper limit of normal 
US 
United States 
VGPR 
very good partial response 
WBC 
XPO1 
white blood cell 
Exportin 1 
 
 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
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1 
PROTOCOL SYNOPSIS 
Sponsor-Investigator/Institution: 
Asociación Europea y 
Latinoamericana Selnet para la 
Investigación en Sarcomas 
 
Investigational Product 
(s): 
Selinexor (KPT-330), 
gemcitabine  
Developmental Phase: 
Phase I/II 
Title of Study: Phase I/II randomized clinical trial of selinexor plus gemcitabine in selected 
advanced soft-tissue sarcomas  
Protocol Number: SELNET-7-1 (SeliSarc) 
Protocol version: 5.0 of 17 February 2023 
EudraCT number: 2019-000652-33 
IST Identifier: IST-319 
Indication: Advanced soft-tissue sarcoma  
 
Rationale for the use of selinexor in sarcomas 
Exportin-1 (XPO-1, also known as CRM1) is the main mediator of nuclear export in many cell 
types and it mediates leucine-rich nuclear export signal (NES)-dependent protein transport. 
Inhibition of XPO1-mediated nuclear export blocks the ‘’escape’’ of multiple tumour suppressor 
proteins, turning off oncogenic signals and enhancing tumour suppression. Besides, XPO-1 
overexpression has been associated with therapy resistance, reduced apoptosis and poor survival 
in solid tumours(1). In line with this observation, XPO-1 was described to be overexpressed in 
osteosarcoma(2), where it is associated with reduced progression-free survival (PFS) and overall 
survival (OS)(3). XPO-1 is the main target of the small molecule inhibitor selinexor(4).  
Selinexor (KPT-330) is a first-in-class, highly specific, slowly reversible and orally bioavailable 
small-molecule inhibitor of XPO-1 that is approved in the USA for the treatment of patients with 
RRMM and DLBCL. This molecule was tested in a phase I clinical trial, in patients with advanced 
metastatic solid tumours, showing evident clinical benefit, as well as an acceptable safety profile. 
In this trial, among the 157 patients evaluated for efficacy, 1 patient had a complete response 
(CR), 6 patients had partial responses (PR) and 67 patients had stable disease (SD), with 27 
patients reaching the stabilization at least for 4 months. In the translational study associated with 
this trial selinexor reduced cell proliferation and increased apoptosis, due to the nuclear 
accumulation of tumour suppressor proteins, such as p53 and FOXO3(5). Likewise, selinexor was 
tested in patients with advanced sarcomas, including STS and bone sarcoma, showing 21 patients 
SD, alongside with decreased tumour load (ranging from 5 – 23%) in 7 of them. The median PFS 
of selinexor was 4.2 months and 3.7 months, for patients with progressive liposarcoma or 
leiomyosarcoma, respectively. Selinexor pharmacokinetics was similar to previously published 
data and it was observed a better absorption in the fed state compared to fasting. Selinexor 
bioavailability was not affected by fat content. Biopsies taken pre- and post-treatment with 
selinexor (n=6) showed target inhibition of XPO-1, nuclear accumulation of p53, apoptosis by 
increased cleaved caspase, remarkable reduction in Ki-67 and cell content, and increased stroma. 
Furthermore, oral selinexor administered twice a week was well tolerated with manageable 
toxicities(6). Based on this data, a randomized, multicentre, double-blind, placebo-controlled 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
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Sponsor-Investigator/Institution: 
Asociación Europea y 
Latinoamericana Selnet para la 
Investigación en Sarcomas 
 
Investigational Product 
(s): 
Selinexor (KPT-330), 
gemcitabine  
Developmental Phase: 
Phase I/II 
phase II/III clinical trial, with oral selinexor, in patients with advanced unresectable dedifferentiated 
liposarcoma (DDLPS) (SEAL -NCT02606461) was performed.  
Phase II-III data has been reported with the PFS being significantly longer with selinexor versus 
placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 
months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; 
medians 5.8 v 3.2 months)(7). 
Furthermore, pre-clinical studies confirmed that selinexor targets the nuclear exportation of 
several tumour suppressor proteins, including APC, p21, p27, p53, Rb, FOXO proteins and 
FAS(4,8), sustaining the observations withdrawn from the clinical trials-associated translational 
studies. Selinexor avoids also survivin exportation to the cytoplasm, blocking its anti-apoptotic 
function(9). In general, the inhibition of nuclear exportation of all these proteins leads to reduced 
cell proliferation and increased apoptosis, in numerous types of solid tumours, including 
sarcoma(10). In sarcomas, selinexor proved to have a potent in vitro and in vivo activity, mostly 
by inducing G1 cell cycle arrest. Remarkably, in liposarcoma cell lines with MDM2 and CDK4 
amplification, selinexor induced cell cycle arrest and apoptosis, independently of TP53 expression 
or mutation. Nonetheless, p53 and p21 protein expression increased, suggesting a post-
transcriptional regulatory effect(10). Of note, selinexor synergizes with Gemcitabine, in pancreatic 
cancer, enhancing apoptosis and inhibiting tumour growth.  
Gemcitabine in the treatment of soft-tissue sarcoma 
Gemcitabine is a deoxycytidine analogue used in the treatment of a large spectrum of tumours, 
including STS(11). This drug accumulates intracellularly, mainly through the nucleoside 
transporter hENT1, and undergoes a series of phosphorylations in order to become active. Then, 
Gemcitabine-tri-phosphorylated acts as a competitive substrate of deoxycytidine triphosphate, 
being incorporated, irreversibly and undetectably into DNA during replication. This incorporation 
inhibits DNA elongation, causing a solid G1 cell cycle arrest and increasing cell death by 
apoptosis(12). Besides, Gemcitabine seems to enhance the activity of Fas/ Fas ligand pathway, 
inducing cell death and tumour regression, by an independent pathway(13). The form of 
gemcitabine with two phosphates attached (dFdCDP) also has activity; it inhibits the 
enzyme ribonucleotide reductase, which is needed to create new nucleotides. The lack of 
nucleotides drives the cell to uptake more of the components it needs to make nucleotides from 
outside the cell, which increases uptake of gemcitabine as well. 
Nowadays, and in the metastatic setting of STS, gemcitabine is administrated as a single agent 
or in combination with docetaxel, showing special activity in leiomyosarcoma.. Additionally, several 
clinical studies with gemcitabine in combination with other cytotoxic drugs, including 
dacarbazine(14) and paclitaxel(15), showed synergistic activity and proved the usefulness of 
gemcitabine in STS treatment. Nevertheless, gemcitabine was reported to be rapidly inactivated 
by cytidine deaminase (CDA) and numerous tumours developed resistance against this drug due 
to the loss of its transporters, lack of gemcitabine phosphorylation or by triggering gemcitabine-
dependent angiogenesis. All these mechanisms of chemoresistance may justify the limited 
therapeutic effect of gemcitabine and therefore, new strategies are urgently required in order to 
improve intracellular gemcitabine and to potentiate its activity in STS. A quite stimulating and 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
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Confidential 
Sponsor-Investigator/Institution: 
Asociación Europea y 
Latinoamericana Selnet para la 
Investigación en Sarcomas 
 
Investigational Product 
(s): 
Selinexor (KPT-330), 
gemcitabine  
Developmental Phase: 
Phase I/II 
promising strategy is the combination of gemcitabine with selinexor, since this combination was 
shown to be synergistic in pancreatic cancer.  
Rationale for the combination gemcitabine plus selinexor  
A relevant finding derived from preclinical experiments is that Selinexor reduces mRNA and 
protein expression of DNA damage repair (DDR) gene products. In relation with that, selinexor 
has shown to be synergistic with DNA damage drugs. Moreover, eIF4e, an essential nuclear 
export of various proto-oncogenes as c-Myc, is thought to be involved since c-Myc regulates the 
transcription of other DNA damage repair genes. This biological effect of selinexor would prevent 
different repair signalling allowing rationale for combination with DNA damage agents as 
gemcitabine(16). In vitro experiments in sarcoma and other tumor cells have shown synergistic 
action with the combination of single (docetaxel, or gemcitabine) and double (cisplatin) strand 
breaks agents along with selinexor. These combinations showed increased cell death by cleaved 
caspase-3 and reduction of DNA damaged repair gene products. In vivo experiments, the 
combination of single strand break agent as docetaxel plus selinexor lowered DNA damage repair 
proteins expression while cisplatin or docetaxel did not produce DDR proteins reduction. Selinexor 
showed reduction in a wide range of DDR gene products as Rad51, CHEK1, MLH1, MSH2, 
MSH6, PMS2 and PARP1 and this effect was observed in several tumor types.  
Importantly, the sequence turned out to be relevant and cytotoxicity was higher if DNA damage 
agent was first administered and then selinexor. Authors stated this could be related to the cycle 
arrest induced by selinexor, this would eventually prevent cells to enter in phase S which means 
less chemosensitivity.  
Preclinical experiments in vitro and in vivo in pancreatic tumor models have shown synergistic 
action with the combination of gemcitabine and selinexor. In addition to the previous mentioned 
mechanism involving the DDR genes inhibition, authors found that nuclear retention of p27, the 
proapoptotic bax protein and the anti-apoptotic surviving, could explain the synergy seen between 
gemcitabine and selinexor(17).  
Gemcitabine alone produces limited cytotoxicity which is in accordance with lack of apoptotic cell 
death seen in preclinical experiments with this drug in some cell lines. However, gemcitabine 
induces a significant increase of γH2AX immunoreactivity demonstrating DNA damage. Thus it is 
strategic to combine it with other drugs, as selinexor, that could increase apoptotic signalling 
through the blockade of DNA repair genes(16).  
Nevertheless, gemcitabine can induce a p53 dependent apoptosis which is in relation to 
accumulation of pro-apoptotic proteins as bax. Selinexor could stabilize bax through the nuclear 
accumulation of nucleophosmin(18). This is another possible synergistic point with selinexor, 
through the retention of p53 in the nuclei(19).  
Finally, FAS pathway can represent another potential synergistic mechanism since gemcitabine 
sensitizes FAS activation(13) and selinexor contributes as well to FAS activation(20). FAS could 
be a relevant prognostic factor in osteosarcoma(21) and in soft tissue sarcomas(22).  
Taking together the previous information, we hypothesize that selinexor will have a synergistic 
effect with gemcitabine in sarcoma patients. The phase I trial will permit the selection of the best 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
Version 5.0 
Page 15 of 98 
Confidential 
Sponsor-Investigator/Institution: 
Asociación Europea y 
Latinoamericana Selnet para la 
Investigación en Sarcomas 
 
Investigational Product 
(s): 
Selinexor (KPT-330), 
gemcitabine  
Developmental Phase: 
Phase I/II 
dose level for the phase II. The determination of predictive biomarkers to this combination will 
benefit the selection of future patients and will provide with the mechanism underlying the activity 
of selinexor plus gemcitabine. 
Gemcitabine administration in sarcomas has been diverse. Mainly used in combination with doses 
ranging from 675 to 1800 mg/m2 and infusion rates ranging from 30 minutes and 10 mg/m2/min. 
This latter being the most frequently recommended. The GEIS scheme administered 1800 mg/m2 
of gemcitabine (10 mg/m2/min) along with 500 mg/m2 of dacarbazine every 2 weeks in advanced 
and progressing STS. Grade 3-4 neutropenia, anemia and thrombocytopenia was observed in 
48%, 4% and 6 % respectively(15). In osteosarcoma patients progressing to standard treatments 
gemcitabine was administered at 800 mg/m2/d on days 1 and 8 of cycle, (10 mg/m2/min) along 
with rapamycin 5 mg (on a daily dose). With this scheme, the grade 3-4 neutropenia, anemia and 
thrombocytopenia were seen in 37%, 23% and 20% respectively.28 The original combination of 
gemcitabine 900 mg/m2/d on days 1 and 8 of cycle (10 mg/m2/min) plus docetaxel 75 mg/m2 on 
day 8 in advanced STS reported G3-4 neutropenia, anemia and thrombocytopenia was observed 
in 16%, 7% and 40% respectively(23). Finally, in the British randomized phase III trial, gemcitabine 
was administered at 675 mg/m2/d on days 1 and 8 of cycle (90 min of infusion rate) along with 
docetaxel 75 mg/m2 on day 8 of each cycle. The hematological grade 3-4 toxicity reported was 
neutropenia 20%, anemia 6% and thrombocytopenia 0%). Then the total dose per cycle is related 
with the extent of grade 3-4 hematological toxicity(24).  
We estimate that the starting dose of 1000 mg/m2 for gemcitabine is appropriate and we have 
considered two different infusion-rates for this dose in order to be more cautious in the dose-levels 
design for the phase I part. As thrombocytopenia could be the most frequent hematological toxicity 
for selinexor we estimate that the first level will be safe, but still, a -1 dose-level was considered.  
 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
PHASE I 
Primary 
• 
To determine the maximum 
tolerated dose (MTD) or the 
recommended dose for phase II of 
selinexor plus gemcitabine.  
 
• 
Based on Dose Limiting Toxicities (DLTs) 
observed during first cycle (day 1-21). 
 
Secondary 
 
• 
To evaluate the safety profile 
according to CTCAE 5.0.  
 
• 
Safety profile of the experimental treatment, 
through assessment of adverse event type, 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
Version 5.0 
Page 16 of 98 
Confidential 
Sponsor-Investigator/Institution: 
Asociación Europea y 
Latinoamericana Selnet para la 
Investigación en Sarcomas 
 
Investigational Product 
(s): 
Selinexor (KPT-330), 
gemcitabine  
Developmental Phase: 
Phase I/II 
 
 
 
• 
To determine the overall response 
rate (ORR). 
 
 
 
• 
To evaluate efficacy according to 
Choi response. 
 
 
• 
To evaluate the patients’s quality of 
life (QoL). 
 
incidence, severity, time of appearance, related 
causes, as well as physical explorations and 
laboratory tests. Toxicity will be graded and 
tabulated by using CTCAE 5.0 
• 
Overall Response Rate (ORR): ORR is defined 
as the number of subjects with a Best Overall 
Response (BOR) of Complete Response (CR) 
or Partial Response (PR) divided by the 
number of response evaluable subjects 
(according to RECIST 1.1 criteria). 
• 
Efficacy measured through tumor response 
according to Choi criteria. The evaluation 
criteria will be based on the identification of 
target lesions in baseline and their follow-up 
until tumor progression.  
• 
Quality of life will be measured with EORTC 
QLQ-C30. 
 
 
PHASE II 
Primary 
• 
To evaluate the efficacy of the 
selinexor plus gemcitabine 
combination as measured by the 
progression-free survival rate 
(PFSR) at 6 months in patients with 
selected advanced soft-tissue 
sarcomas. 
• 
Progression-free survival rate (PFSR): Efficacy 
measured by the PFSR at 6 months according 
to RECIST 1.1. PFSR at 6 months is defined as 
the percentage of patients who did not 
experience progression or death due to any 
cause since the first dose of experimental 
treatment until month 6 after treatment 
initiation.  
 
Secondary  
• 
To evaluate overall survival (OS).  
 
 
 
• 
Overall survival (OS): OS is defined as the time 
between the date of first dose and the date of 
death due to any cause. OS will be censored 
on the last date a subject was known to be 
alive. 
 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
Version 5.0 
Page 17 of 98 
Confidential 
Sponsor-Investigator/Institution: 
Asociación Europea y 
Latinoamericana Selnet para la 
Investigación en Sarcomas 
 
Investigational Product 
(s): 
Selinexor (KPT-330), 
gemcitabine  
Developmental Phase: 
Phase I/II 
• 
To determine the overall response 
rate (ORR). 
 
 
 
• 
To evaluate efficacy according to 
Choi response. 
 
 
• 
To evaluate the safety profile 
according to CTCAE 5.0.  
 
 
 
• 
To evaluate the outcome of post 
protocol treatments. 
 
 
 
• 
To evaluate the patients’s quality of 
life (QoL) 
 
• 
Overall Response Rate (ORR): ORR is defined 
as the number of subjects with a Best Overall 
Response (BOR) of Complete Response (CR) 
or Partial Response (PR) divided by the 
number of response evaluable subjects 
(according to RECIST 1.1 criteria). 
• 
Efficacy measured through tumor response 
according to Choi criteria. The evaluation 
criteria will be based on the identification of 
target lesions in baseline and their follow-up 
until tumor progression.  
• 
Safety profile of the experimental treatment, 
through assessment of adverse event type, 
incidence, severity, time of appearance, related 
causes, as well as physical explorations and 
laboratory tests. Toxicity will be graded and 
tabulated by using CTCAE 5.0.  
• 
Clinical outcomes of post protocol treatments 
assessed by observation of such treatments in 
follow-up stage. 
Clinical outcomes of post protocol treatments 
assessed by observation of such treatments in 
follow-up stage. 
• 
Quality of life will be measured with EORTC 
QLQ-C30. 
 
Exploratory: translational study (Phase I and II) 
• 
To determine potential predictive 
biomarkers to the combination of 
selinexor plus gemcitabine in 
sarcomas in tumor blocks and 
peripheral blood samples. 
 
• 
To understand the mechanisms and 
the cell signaling pathways related 
with response or resistance to the 
combination in FFPE tumor 
samples. 
 
• 
Potential biomarkers will be determined using 
gene expression analysis with HTG technology, 
protein expression with immunohistochemistry 
and analysis of plasmatic factors (ProcartaPlex 
Immunoassay). 
• 
Correlation of the different identified biomarkers 
with outcome will be analyzed.  
 
 
 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
Version 5.0 
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Confidential 
Sponsor-Investigator/Institution: 
Asociación Europea y 
Latinoamericana Selnet para la 
Investigación en Sarcomas 
 
Investigational Product 
(s): 
Selinexor (KPT-330), 
gemcitabine  
Developmental Phase: 
Phase I/II 
• 
To validate the translational study 
results in pre-clinical models of 
sarcoma. 
• 
In vitro studies will be done with different STS 
cell lines.  
Overall Study Design: 
Phase I-II, non-randomized, single-arm, open-label, multicenter, international clinical trial. 
Patients with advanced soft-tissue sarcoma (leiomyosarcoma or malignant peripheral nerve 
sheath tumor) will receive selinexor in combination with gemcitabine. 
In the Phase I part safety and toxicity of the combination will be assessed using a 3+3 design. 
The recommended dose for the Phase II will be determined.  
 
In the Phase II part there will be 2 different cohorts: 
 
Cohort 1: Leiomyosarcoma (LMS) 
Cohort 2: Malignant peripheral nerve sheath tumor (MPNST) 
 
Number of Patients (planned): Phase I part 4-18; Phase II: 82 patients (88 including non-
evaluable) 
Study Population: 
Patients with selected advanced (metastatic or locally advanced unresectable) soft-tissue 
sarcoma (leiomyosarcoma or malignant peripheral nerve sheath tumor).  
Inclusion Criteria (Phase II): 
Patients must meet all of the following inclusion criteria to be eligible for this study:  
 
1. 
Patients must provide written informed consent prior to performance of any study-specific 
procedures and must be willing to comply with treatment and follow-up. Informed consent 
must be obtained prior to start of the screening process. Procedures conducted as part of 
the patient’s routine clinical management (e.g. imaging tests), obtained prior to signature of 
informed consent may be used for screening or baseline purposes as long as these 
procedures are conducted as specified in the protocol.   
2. 
Age: 18-80 years. 
3. 
Histologic diagnosis of soft tissue sarcoma (leiomyosarcoma or malignant peripheral nerve 
sheath tumor) confirmed by central pathology review prior to enrollment with an archive 
tumor sample. A fresh paraffin embedded tumor tissue block must be provided for all 
subjects for biomarker analysis before and (when feasible) after treatment with 
investigational products. 
4. 
Metastatic/advanced disease in progression in the last 6 months. 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
Version 5.0 
Page 19 of 98 
Confidential 
Sponsor-Investigator/Institution: 
Asociación Europea y 
Latinoamericana Selnet para la 
Investigación en Sarcomas 
 
Investigational Product 
(s): 
Selinexor (KPT-330), 
gemcitabine  
Developmental Phase: 
Phase I/II 
5.   Patients have previously received at least one previous line of systemic therapy. 
6. 
Measurable disease according to RECIST 1.1 criteria. 
7. 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 
8. 
Adequate hepatic, renal, cardiac, and hematologic function. 
9. 
Laboratory tests as follows: 
• Absolute neutrophil count ≥ 1,500/mm³ 
• Platelet count ≥ 100,000/mm³ 
• Bilirubin ≤ 1.5 mg/dL 
• AST and ALT ≤ 2.5 times upper limit of normal 
• Creatinine ≤ 1.5 mg/dL 
10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan. 
11. Females of childbearing potential must have a negative serum or urine pregnancy test 
within 72 hours prior to enrollment and agree to use birth control measures during study 
treatment and for 3 months after its completion. Patients must not be pregnant or nursing at 
study entry. Women/men of reproductive potential must have agreed to use an effective 
contraceptive method. 
Exclusion Criteria (Phase II): 
Patients meeting any of the following exclusion criteria are not eligible for this study: 
1. Three or more systemic treatment lines (including both chemotherapy and targeted therapy) 
for advanced disease (localized unresectable or metastatic). 
2. Patients who have received any other anti-cancer therapy or investigational product in the 
last 21 days prior to enrollment. 
3. Prior malignancy that required treatment or has shown evidence of recurrence (except for 
non-melanoma skin cancer, adequately treated cervical carcinoma in situ, superficial bladder 
carcinoma) during the 5 years prior to randomization. Cancer treated with curative intent for 
>5 years previously and without evidence of recurrence will be allowed. 
4. Prior selinexor or another XPO1 inhibitor treatment. 
5. Administration of a previous gemcitabine-containing treatment. 
6. Any concurrent medical condition or disease (e.g. uncontrolled active hypertension, 
uncontrolled active diabetes, active systemic infection, etc.) that is likely to interfere with 
study procedures. 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
Version 5.0 
Page 20 of 98 
Confidential 
Sponsor-Investigator/Institution: 
Asociación Europea y 
Latinoamericana Selnet para la 
Investigación en Sarcomas 
 
Investigational Product 
(s): 
Selinexor (KPT-330), 
gemcitabine  
Developmental Phase: 
Phase I/II 
7. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 
week prior to Cycle 1 Day 1 (C1D1). Patients on prophylactic antibiotics or with a controlled 
infection within 1 week prior to C1D1 are acceptable.  
8. Pregnant or breastfeeding females. 
9. Body surface area (BSA) <1.4 m2 at baseline, calculated by the Du Bois(25) or Mosteller(26) 
method. 
10. Life expectancy of less than 3 months. 
11. Major surgery within 4 weeks prior to C1D1. 
12. Any active gastrointestinal dysfunction interfering with the patient’s ability to swallow tablets, 
or dysfunction that could interfere with absorption of study treatment. 
13. Inability or unwillingness to take supportive medications such as anti-nausea and 
anti-anorexia agents as recommended by the NCCN CPGO for antiemesis and 
anorexia/cachexia (palliative care). 
14. Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion of 
the Investigator, could interfere with treatment, compliance, or the ability to give informed 
consent.  
15.  Presence of brain or central nervous system metastases, unless they are controlled 
(patients with treated and stable metastasis are eligible). 
 
Study Treatment/Treatment Groups, Dose, and Mode of Administration:  
Selinexor  
Pharmaceutical form: Tablet (20 mg tablets) 
Route of administration: Oral use. 
 
Gemcitabine 
 
Pharmaceutical form: Concentrate for solution for infusion  
Route of administration: Intravenous use. 
 
Predefined dose levels (Phase I part) 
Dose level 
Selinexor weekly (given on days 1, 
8 and 15 of each cycle) 
Gemcitabine weekly (given on days 
1, 8 of each cycle) 
-1 
60 mg 
800 mg/m2 (30 min) 
1 
60 mg 
1000 mg/m2 (30 min) 
2 
60 mg 
1000 mg/m2 (10 mg/m2/min) 
3 
60 mg 
1200 mg/m2 (10 mg/m2/min) 
4 
80 mg 
1200 mg/m2 (10 mg/m2/min) 
 

SELNET-7-1 (SeliSarc)                                                                                                                                     Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33 
 
V5.0 of 17 February 2023 
IST Identifier: IST-319 
 
 
Version 5.0 
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Confidential 
Sponsor-Investigator/Institution: 
Asociación Europea y 
Latinoamericana Selnet para la 
Investigación en Sarcomas 
 
Investigational Product 
(s): 
Selinexor (KPT-330), 
gemcitabine  
Developmental Phase: 
Phase I/II 
 
Phase II:  
For gemcitabine + selinexor: 
• 
Selinexor will be given at 60 mg once per week orally days 1, 8 and 15 every 21 days 
• 
Gemcitabine will be given at the dose 1200 mg/m2 (10 mg/m2/min) days 1 and 8 every 21 
days 
Cycles of 21 days. 
Treatment cycles are unlimited and given until progression, unacceptable toxicity, or investigator’s 
or patient’s decision.
 
Duration of Treatment and Follow-up:  
Phase I: 
• 
Administrative start-up: 6 months 
• 
First subject first visit (FSFV): November 2020 
• 
Total recruitment period duration: 20 months 
• 
Follow-up period (last patient in): 12 months 
Phase II: 
• 
First subject first visit (FSFV): April 2023 
• 
Total recruitment period duration: 30 months 
• 
Follow-up period (last patient in): 6 months 
• 
Estimated end of study date: May 2026   
Statistical Methods: 
Phase I: 3+3 design 
Phase II:  Sample size for LMS and MPNST cohorts were calculated using Simon two-stage 
optimal designs (Section 13.2).   
 

SELNET-7-1 (SeliSarc)  
Selinexor (KPT-330) / gemcitabine 
EudraCT: 2019-000652-33  
IST Identifier: IST-319 
 
 
 
Version 5.0 
Page 22 of 98 
Confidential 
2 
STUDY SCHEMATICS AND SCHEDULE OF ASSESSMENTS AND DOSING  
Table 1: Schedule of Study Activities and Assessments (PHASE I) 
 
Activity/Assessment  
Screening
a 
Cycle 1 
Cycle 2 
Cycles ≥3 
End-of-
Treatment  
(EoT) Visit 
Durability 
of 
Response 
and 
Survival  
Follow-up 
(Every 2-3 
months)b 
Day -28 to 
Day -1 
Day 1  
Day 8 
Day 15 
Day 1  
Day 8 
Day 15 
Day 1 
Day 8 
Day 15 
≤30 Days 
Post-Last 
Dose 
-3 days ± 1 day 
± 1 day 
± 2 days ± 2 days ± 2 days ± 2 days ± 2 days  
 
± 14 days 
   ICFc 
X 
 
 
 
 
 
 
 
 
 
 
 
   Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient History 
 
 
 
 
 
 
 
 
 
 
 
 
   Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
   Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Central diagnostic confirmation in 
archived tumord 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
   Height  
X 
 
 
 
 
 
 
 
 
 
 
 
   Weight 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
   Body Surface Area (BSA)e 
X 
 
 
 
 
 
 
 
 
 
 
 
   Vital signsf 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
   ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
   Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
   12-lead ECGg 
X 
 
 
 
Perform if clinically indicated 
X 
 
   Echocardiogram or    
   MUGA 
X 
 
 
 
X 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
   CBC with differentialh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
   Complete serum chemistryh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
   Coagulation test 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 

SELNET-7-1 (SeliSarc)  
Selinexor (KPT-330) / gemcitabine 
EudraCT: 2019-000652-33  
IST Identifier: IST-319 
 
 
 
Version 5.0 
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Confidential 
Activity/Assessment  
Screening
a 
Cycle 1 
Cycle 2 
Cycles ≥3 
End-of-
Treatment  
(EoT) Visit 
Durability 
of 
Response 
and 
Survival  
Follow-up 
(Every 2-3 
months)b 
Day -28 to 
Day -1 
Day 1  
Day 8 
Day 15 
Day 1  
Day 8 
Day 15 
Day 1 
Day 8 
Day 15 
≤30 Days 
Post-Last 
Dose 
-3 days ± 1 day 
± 1 day 
± 2 days ± 2 days ± 2 days ± 2 days ± 2 days  
 
± 14 days 
   Urinalysis 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
   Pregnancy test (if   
   applicable)i 
X 
 
 
 
X 
 
 
X (even # 
cycles 
only) 
 
 
X 
 
DLT period assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Study samplesj 
 
 
 
 
 
 
 
 
 
 
 
 
   Tumor sample for diagnosis 
confirmation 
X 
 
 
 
 
 
 
 
 
 
 
 
   Tumor for translational research 
X 
 
 
 
 
 
 
 
 
 
X 
 
   Blood for translational research 
X 
At each radiological assessment (every 6 weeks during the first 6 months of treatment, every 
8 weeks after the first 6 months of treatment) 
X 
 
Disease Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
   Scans (e.g. CT/MRI)for   
   response assessmentsk 
X 
Every 6 weeks during the first 6 months of treatment, every 8 weeks after the first 6 months of 
treatment 
X 
X 
   Administration of selinexor 
 
Days 1, 8, 15 every cycle 
 
 
   Administration of gemcitabine 
 
Days 1 and 8 every cycle 
 
 
   Adverse events recordingl 
X 
Throughout 
 
   SAE reporting 
 
   Concomitant medication recording 
X 
Throughout 
 
   Nutritional consultationm 
X 
Perform if clinically indicated 
 
 
   Telephone contact 
 
 
 
 
 
 
 
 
 
 
 
X 
   Collection of information regarding 
antineoplastic therapy used after 
EoT 
 
 
 
 
 
 
 
 
 
 
 
X 

SELNET-7-1 (SeliSarc)  
Selinexor (KPT-330) / gemcitabine 
EudraCT: 2019-000652-33  
IST Identifier: IST-319 
 
 
 
Version 5.0 
Page 24 of 98 
Confidential 
Activity/Assessment  
Screening
a 
Cycle 1 
Cycle 2 
Cycles ≥3 
End-of-
Treatment  
(EoT) Visit 
Durability 
of 
Response 
and 
Survival  
Follow-up 
(Every 2-3 
months)b 
Day -28 to 
Day -1 
Day 1  
Day 8 
Day 15 
Day 1  
Day 8 
Day 15 
Day 1 
Day 8 
Day 15 
≤30 Days 
Post-Last 
Dose 
-3 days ± 1 day 
± 1 day 
± 2 days ± 2 days ± 2 days ± 2 days ± 2 days  
 
± 14 days 
   Quality of Life assessmentn 
 
X 
 
 
X 
 
 
Every 3 
cycles 
(day 1) 
 
 
X 
 
 
 
AE: adverse event; BSA: body surface area; CBC: complete blood count; C1D1: Cycle 1 Day 1; D: day; ECG: electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; EoT: end of treatment; hCG: human chorionic gonadotropin; ICF: informed consent form; MUGA: multiple gated acquisition; PE: physical 
examination; SAE: serious adverse event 
a) 
Procedures that are performed as part of standard of care should not be repeated if they are within the Screening window and are done prior to signing the 
ICF. 
b) 
After discontinuation of selinexor if feasible and clinically indicated, evaluations should be performed every 2 months (8 weeks) for patients who have not 
progressed and every 3 months in progressed patients to assess durability of response. If sarcoma evaluations cannot be performed, at a minimum, a 
telephone call will be made to the patient (or the patient’s family) to assess the survival status, status of the patient’s sarcoma, and overall medical condition of 
the patient and collect information on any antineoplastic therapies used after discontinuation of study treatment (see Section 8.5.2). 
c) 
ICF must be signed before any study-specific procedures are performed. 
d) 
Central pathological confirmation: one archived formalin-fixed paraffin-embedded (FFPE) tumor block sample will be sent for central pathological confirmation 
before treatment initiation.   
e) 
BSA should be calculated during Screening and as needed during the study. 
f) 
 Blood pressure and pulse rate should be measured after the patient has been in a supine or sitting position for 5 minutes and assessed on the same arm 
throughout the study. Vital signs do not need to be repeated if they are performed as part of the physical examination. 
g) 
Patients must rest for at least 5 minutes prior to the ECG recording.  
h) 
CBC with differential and complete serum chemistry will be performed on days 1, 8, and 15 on Cycle 1 and 2 and on days 1 and 8 in the rest of 
cycles.*=Limited serum chemistry: WBC differential may be automated or manual as per institutional standards. Reticulocytes may be done only when 
clinically indicated. Urea (mg/dL) = Blood urea nitrogen (mg/dL) × 2.14. Microscopy will only be performed if clinically indicated. 
i) 
For females of childbearing potential; negative serum hCG or urine pregnancy test must be obtained within 3 days before the first dose of study treatment. 
Pregnancy testing (serum hCG or urine) is also required for females of childbearing potential prior to dosing on Day 1 of even Cycles ≥2 while on treatment (a 
negative pregnancy test must be documented prior to administration of study drug) and at the EoT Visit (serum hCG or urine). Pregnancy testing may also be 
performed as clinically indicated during the study. 

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j) 
Translational samples: Tumor: One recent (not archived) (FFPE) tumor block sample mandatorily collected at baseline (minimum 6 tru-cuts); Blood: 2 10mL 
EDTA tubes of peripheral blood within 72 hours prior to starting treatment (baseline), two 10mL EDTA within ±72 h of each radiological assessment (TC scan, 
MRI) and two 10mL EDTA tubes of peripheral blood at the end of treatment (within 72 hours after progressive disease is documented). Another two 10mL EDTA 
tubes of peripheral blood when tumor response is observed. Plasma will be separated by a Ficoll-Paque protocol. Mononuclear cells will be also collected for 
further analysis. 
k) 
CT scans or MRI will be performed every 6 weeks (±7 days).  CT Scans will be performed every 8 weeks (±7 days) after 6 months of treatment. During Follow 
up CT scan or MRI will be done every 8 weeks (±7 days) if patient did not progress to assess durability of response. Screening CT Scan/MRI have to be done 
within 28 days prior treatment initiation.  
l) 
All AEs that begin or worsen after the patient has provided informed consent will be recorded. SAEs must be reported to GEIS within 24 hours of first awareness.  
m) Patients must be given nutritional consultation to discuss any food recommendations and strategies for managing potential nausea and appetite changes 
experienced with selinexor. This may be completed within the screening period for the study and prior to administration of study treatment on C1D1. The 
nutritional consultation can be done by a study nurse and can be done on a phone call. 
n) 
Quality of Life will be assessed with EORTC QLQ-C30. It will be performed on C1D1, C2D1 and then every 3 cycles and in EoT visit. 
 
 
 

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Table 2: Schedule of Study Activities and Assessments (PHASE II) 
 
Activity/Assessment  
Screeninga
Cycle 1 
Cycle 2 
Cycles ≥3 
End-of-
Treatment  
(EoT) Visit 
Durability of 
Response and 
Survival  
Follow-up 
(Every 2-3 
months)b 
Day -28 
to Day -1 
Day 1  
Day 8 
 
Day 15 
Day 1  
Day 8 
Day 15 
Day 1 
Day 8 
Day 15 
≤30 Days 
Post-Last 
Dose 
-3 
days 
± 1 day 
± 2 
days 
± 2 days ± 2 days 
± 2 
days 
± 2 days ± 2 days 
 
 
± 14 days 
   ICFc 
X 
 
 
 
 
 
 
 
 
 
 
 
   Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient History 
 
 
 
 
 
 
 
 
 
 
 
 
   Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
   Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
   Height  
X 
 
 
 
 
 
 
 
 
 
 
 
   Weight 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
   Body Surface Area (BSA)d 
X 
 
 
 
 
 
 
 
 
 
 
 
   Vital signse 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
   ECOG 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
   Physical examination 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
   12-lead ECGf 
X 
Perform if clinically indicated 
X 
 
   Echocardiogram or MUGA 
X 
X 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
   CBC with differentialg 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
   Complete serum chemistryg 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
 

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Activity/Assessment  
Screeninga
Cycle 1 
Cycle 2 
Cycles ≥3 
End-of-
Treatment  
(EoT) Visit 
Durability of 
Response and 
Survival  
Follow-up 
(Every 2-3 
months)b 
Day -28 
to Day -1 
Day 1  
Day 8 
 
Day 15 
Day 1  
Day 8 
Day 15 
Day 1 
Day 8 
Day 15 
≤30 Days 
Post-Last 
Dose 
-3 
days 
± 1 day 
± 2 
days 
± 2 days ± 2 days 
± 2 
days 
± 2 days ± 2 days 
 
 
± 14 days 
     Coagulation test 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
     Urinalysis 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
     Pregnancy test (if   
     applicable)h 
X 
 
 
 
X 
 
 
X 
(even # 
cycles 
only) 
 
 
X 
 
Study samplesi 
 
 
 
 
 
 
 
 
 
 
 
 
   Tumor sample for  diagnosis    
confirmation 
X 
 
 
 
 
 
 
 
 
 
 
 
   Tumor for translational research 
X 
 
 
 
 
 
 
 
 
 
X 
 
   Blood for translational research 
X 
At each radiological assessment (every 6 weeks during the first 6 months of treatment, 
every 8 weeks after the first 6 months of treatment) 
X 
 
Disease Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
   Scans (eg, CT/MRI)for response 
assessmentsj 
X 
Every 6 weeks during the first 6 months of treatment, every 8 weeks after the first 6 
months of treatment 
X 
 
   Administration of selinexor (only 
on cohorts randomized to 
selinexor) 
 
Days 1, 8, and 15 every cycle 
 
 

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Activity/Assessment  
Screeninga
Cycle 1 
Cycle 2 
Cycles ≥3 
End-of-
Treatment  
(EoT) Visit 
Durability of 
Response and 
Survival  
Follow-up 
(Every 2-3 
months)b 
Day -28 
to Day -1 
Day 1  
Day 8 
 
Day 15 
Day 1  
Day 8 
Day 15 
Day 1 
Day 8 
Day 15 
≤30 Days 
Post-Last 
Dose 
-3 
days 
± 1 day 
± 2 
days 
± 2 days ± 2 days 
± 2 
days 
± 2 days ± 2 days 
 
 
± 14 days 
Administration of Gemcitabine 
 
Days 1 and 8 every cycle 
 
 
   Adverse events recordingk 
X 
Throughout 
 
   SAE reporting 
 
   Concomitant medication 
recording 
X 
Throughout 
 
   Nutritional consultationl 
X 
Perform if clinically indicated 
 
 
   Telephone contact 
 
 
 
 
 
 
 
 
 
 
 
X 
   Collection of information 
regarding antineoplastic therapy 
used after EoT 
 
 
 
 
 
 
 
 
 
 
 
X 
   Quality of Life assessmentm 
 
X 
 
 
X 
 
 
Every 3 
cycles 
 
 
X 
 
 
 
AE: adverse event; BSA: body surface area; CBC: complete blood count; C1D1: Cycle 1 Day 1; D: day; ECG: electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; EoT: end of treatment; hCG: human chorionic gonadotropin; ICF: informed consent form; MUGA: multiple gated acquisition; PE: physical 
examination; SAE: serious adverse event 
a) 
Procedures that are performed as part of standard of care should not be repeated if they are within the Screening window and are done prior to signing the 
ICF. 
b) 
After discontinuation of selinexor if feasible and clinically indicated, evaluations should be performed every 2 months (8 weeks) for patients who have not 
progressed and every 3 months in progressed patients to assess durability of response. If sarcoma evaluations cannot be performed, at a minimum, a 

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telephone call will be made to the patient (or the patient’s family) to assess the survival status, status of the patient’s sarcoma, and overall medical condition of 
the patient and collect information on any antineoplastic therapies used after discontinuation of study treatment (see Section 8.5.2). 
c) 
ICF must be signed before any study-specific procedures are performed. 
d) 
BSA should be calculated during Screening and as needed during the study  
e) 
Blood pressure and pulse rate should be measured after the patient has been in a supine or sitting position for 5 minutes and assessed on the same arm 
throughout the study. Vital signs do not need to be repeated if they are performed as part of the physical examination. 
f) 
Patients must rest for at least 5 minutes prior to the ECG recording. 
g) 
CBC with differential and complete serum chemistry will be performed on days 1 and 8, on Cycle 1 and 2 and on day 1 in the cycles ≥3. *=Limited serum 
chemistry: WBC differential may be automated or manual as per institutional standards. Reticulocytes may be done only when clinically indicated. Urea 
(mg/dL) = Blood urea nitrogen (mg/dL) × 2.14. Microscopy will only be performed if clinically indicated. 
h) 
For females of childbearing potential; negative serum hCG or urine pregnancy test must be obtained within 3 days before the first dose of study treatment. 
Pregnancy testing (serum hCG or urine) is also required for females of childbearing potential prior to dosing on Day 1 of even Cycles ≥2 while on treatment (a 
negative pregnancy test must be documented prior to administration of study drug) and at the EoT Visit (serum hCG or urine). Pregnancy testing may also be 
performed as clinically indicated during the study. 
i) 
Central pathological confirmation: one archived formalin-fixed paraffin-embedded (FFPE) tumor block sample will be sent for central pathological confirmation 
before treatment initiation.  Translational samples: Translational samples: Tumor: One recent (not archived) formalin-fixed paraffin-embedded (FFPE) tumor 
block sample mandatorily collected at baseline (minimum 6 tru-cuts); Blood: 2 10mL EDTA tubes of peripheral blood within 72 hours prior to starting treatment 
(baseline), two 10mL EDTA within ±72h of each radiological assessment (TC scan, MRI) and two 10mL EDTA tubes of peripheral blood at the end of treatment 
(within 72 hours after progressive disease is documented). Another two 10mL EDTA tubes of peripheral blood when tumor response is observed. Plasma will 
be separated by a Ficoll-Paque protocol. Mononuclear cells will be also collected for further analysis. 
j) 
CT scans or MRI will be performed every 6 weeks (±7 days) . CT Scans will be performed every 8 weeks (±7 days) after 6 months of treatment. During Follow 
up CT scan or MRI will be done every 8 weeks (±7 days)  if patient did not progressed to assess durability of response. Screening CT Scan/MRI have to be 
done within 28 days prior treatment initiation.   
k) 
All AEs that begin or worsen after the patient has provided informed consent will be recorded. SAEs must be reported to GEIS within 24 hours of first awareness.  
l) 
Patients must be given nutritional consultation to discuss any food recommendations and strategies for managing potential nausea and appetite changes 
experienced with selinexor. This may be completed within the screening period for the study and prior to administration of study treatment on C1D1. The 
nutritional consultation can be done by a study nurse and can be done on a phone call. 
m) Quality of Life will be assessed with EORTC QLQ-C30. It will be performed on C1D1, C2D1 and then every 3 cycles and in EoT visit. 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 3: Dosing Schedule (Phase I Part and Phase II with Selinexor plus Gemcitabine) 
 
Treatment 
Week 1 
Week 2 
Week 3 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 D11 D12 D13 D14 D15 D16 D17 D18 D19 D20 D21 
Selinexor 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Gemcitabine 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
D: Study Day; X: dosing day. 
 
 
 
 
 

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Figure 1: Phase I Design  
 
 
 
 
 
CYCLE 1
CYCLE 2 and beyond
D1                  D8                      D15                                   D1                    D8                   
D15
G
selinexor
gemcitabine
biopsy
Blood
(Translational)
(*) Every assessment, 
response and progression
G
G
G
G
S
S
S
S
S
S
S
*
PHASE I DESIGN

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Figure 2: Phase I Dose Levels 
 
 

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3 
INTRODUCTION AND RATIONALE 
 
3.1 
Rationale for the Use of Selinexor in Sarcomas 
Exportin-1 (XPO-1, also known as CRM1) is the main mediator of nuclear export in many cell 
types and it mediates leucine-rich nuclear export signal (NES)-dependent protein transport. 
Inhibition of XPO1-mediated nuclear export blocks the ‘’escape’’ of multiple tumour 
suppressor proteins, turning off oncogenic signals and enhancing tumour suppression. 
Besides, XPO-1 overexpression has been associated with therapy resistance, reduced 
apoptosis and poor survival in solid tumours(1). In line with this observation, XPO-1 was 
described to be overexpressed in osteosarcoma(2), where it is associated with reduced 
progression-free survival (PFS) and overall survival (OS)(3). XPO-1 is the main target of the 
small molecule inhibitor selinexor(4).  
Selinexor (KPT-330) is a first-in-class, highly specific, slowly reversible and orally bioavailable 
small-molecule inhibitor of XPO-1. This molecule was tested in a phase I clinical trial, in 
patients with advanced metastatic solid tumours, showing evident clinical benefit, as well as 
an acceptable safety profile. In this trial, among the 157 patients evaluated for efficacy, 1 
patient had a complete response (CR), 6 patients had partial responses (PR) and 67 patients 
had stable disease (SD), with 27 patients reaching the stabilization at least for 4 months. In 
the translational study associated with this trial selinexor reduced cell proliferation and 
increased apoptosis, due to the nuclear accumulation of tumour suppressor proteins, such as 
p53 and FOXO3(5). Likewise, selinexor was tested in patients with advanced sarcomas, 
including STS and bone sarcoma, showing 21 patients SD, alongside with decreased tumour 
load (ranging from 5 – 23%) in 7 of them. The median PFS of selinexor was 4.2 months and 
3.7 months, for patients with progressive liposarcoma or leiomyosarcoma, respectively. 
Selinexor pharmacokinetics was similar to previously published data and it was observed a 
better absorption in the fed state compared to fasting. Selinexor bioavailability was not 
affected by fat content. Biopsies taken pre- and post-treatment with selinexor (n=6) showed 
target inhibition of XPO-1, nuclear accumulation of p53, apoptosis by increased cleaved 
caspase, remarkable reduction in Ki-67 and cell content, and increased stroma. Furthermore, 
oral selinexor administered twice a week was well tolerated with manageable toxicities(6). 
Based on this data, a randomized, multicentre, double-blind, placebo-controlled phase II/III 
clinical trial, with oral selinexor, in patients with advanced unresectable dedifferentiated 
liposarcoma (DDLPS) (SEAL - NCT02606461) is currently ongoing. Phase II data has been 
presented recently and the median PFS on selinexor arm, by RECIST 1.1, was 5.6 months, 
compared with 1.8 in the placebo arm, supporting the continuation of the phase III part(27).  
Furthermore, pre-clinical studies confirmed that selinexor targets the nuclear exportation of 
several tumour suppressor proteins, including APC, p21, p27, p53, Rb, FOXO proteins and 
FAS(4,8), sustaining the observations withdrawn from the clinical trials-associated 
translational studies. Selinexor avoids also survivin exportation to the cytoplasm, blocking its 
anti-apoptotic function(9). In general, the inhibition of nuclear exportation of all these proteins 
leads to reduced cell proliferation and increased apoptosis, in numerous types of solid 
tumours, including sarcoma(10). In sarcomas, selinexor proved to have a potent in vitro and 
in vivo activity, mostly by inducing G1 cell cycle arrest. Remarkably, in liposarcoma cell lines 
with MDM2 and CDK4 amplification, selinexor induced cell cycle arrest and apoptosis, 
independently of TP53 expression or mutation. Nonetheless, p53 and p21 protein expression 
increased, suggesting a post-transcriptional regulatory effect(10).  

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3.2 Gemcitabine in the Treatment of Soft-Tissue Sarcoma 
Gemcitabine is a deoxycytidine analogue used in the treatment of a large spectrum of 
tumours, including STS(11). This drug accumulates intracellularly, mainly through the 
nucleoside transporter hENT1, and undergoes a series of phosphorylations in order to 
become active. Then, Gemcitabine-tri-phosphorylated acts as a competitive substrate of 
deoxycytidine triphosphate, being incorporated, irreversibly and undetectably into DNA during 
replication. This incorporation inhibits DNA elongation, causing a solid G1 cell cycle arrest and 
increasing cell death by apoptosis(12). Besides, Gemcitabine seems to enhance the activity 
of Fas/ Fas ligand pathway, inducing cell death and tumour regression, by an independent 
pathway(13). The form of gemcitabine with two phosphates attached (dFdCDP) also has 
activity; it inhibits the enzyme ribonucleotide reductase, which is needed to create new 
nucleotides. The lack of nucleotides drives the cell to uptake more of the components it needs 
to make nucleotides from outside the cell, which increases uptake of gemcitabine as well. 
Nowadays, and in the metastatic setting of STS, gemcitabine is administrated as a single 
agent or in combination with docetaxel, showing special activity in leiomyosarcoma(28,29). 
Additionally, several clinical studies with gemcitabine in combination with other cytotoxic 
drugs, including dacarbazine(14) and paclitaxel(15), showed synergistic activity and proved 
the usefulness of gemcitabine in STS treatment. Nevertheless, gemcitabine was reported to 
be rapidly inactivated by cytidine deaminase (CDA) and numerous tumours developed 
resistance against this drug due to the loss of its transporters, lack of gemcitabine 
phosphorylation or by triggering gemcitabine-dependent angiogenesis(11,30–32). All these 
mechanisms of chemoresistance may justify the limited therapeutic effect of gemcitabine and 
therefore, new strategies are urgently required in order to improve intracellular gemcitabine 
and to potentiate its activity in STS. A quite stimulating and promising strategy is the 
combination of gemcitabine with selinexor, since this combination was shown to be synergistic 
in pancreatic cancer.  
Rationale for the Combination Gemcitabine Plus Selinexor  
A relevant finding derived from preclinical experiments is that selinexor reduces mRNA and 
protein expression of DNA damage repair (DDR) gene products. In relation with that, selinexor 
has shown to be synergistic with DNA damage drugs. Moreover, eIF4e, an essential nuclear 
export of various proto-oncogenes as c-Myc, is thought to be involved since c-Myc regulates 
the transcription of other DNA damage repair genes. This biological effect of selinexor would 
prevent different repair signalling allowing rationale for combination with DNA damage agents 
as gemcitabine(16). In vitro experiments in sarcoma and other tumor cells have shown 
synergistic action with the combination of single (docetaxel, or gemcitabine) and double 
(cisplatin) strand breaks agents along with selinexor. These combinations showed increased 
cell death by cleaved caspase-3 and reduction of DNA damaged repair gene products. In vivo 
experiments, the combination of single strand break agent as docetaxel plus selinexor 
lowered DNA damage repair proteins expression while cisplatin or docetaxel did not produce 
DDR proteins reduction. Selinexor showed reduction in a wide range of DDR gene products 
as Rad51, CHEK1, MLH1, MSH2, MSH6, PMS2 and PARP1 and this effect was observed in 
several tumor types.  
Importantly, the sequence turned out to be relevant and cytotoxicity was higher if DNA 
damage agent was first administered and then selinexor. Authors stated this could be related 

SELNET-7-1 (SeliSarc)    
    Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33                                                                                                                                                   V5.0 of 17 February 2023 
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to the cycle arrest induced by selinexor, this would eventually prevent cells to enter in phase 
S which means less chemosensitivity.  
Preclinical experiments in vitro and in vivo in pancreatic tumor models have shown synergistic 
action with the combination of gemcitabine and selinexor. In addition to the previous 
mentioned mechanism involving the DDR genes inhibition, authors found that nuclear 
retention of p27, the proapoptotic bax protein and the anti-apoptotic surviving, could explain 
the synergy seen between gemcitabine and selinexor(17).  
Gemcitabine alone produces limited cytotoxicity which is in accordance with lack of apoptotic 
cell death seen in preclinical experiments with this drug in some cell lines. However, 
gemcitabine induces a significant increase of γH2AX immunoreactivity demonstrating DNA 
damage. Thus it is strategic to combine it with other drugs, as selinexor, that could increase 
apoptotic signalling through the blockade of DNA repair genes(16).  
Nevertheless, gemcitabine can induce a p53 dependent apoptosis which is in relation to 
accumulation of pro-apoptotic proteins as bax. Selinexor could stabilize bax through the 
nuclear accumulation of nucleophosmin(18). This is another possible synergistic point with 
selinexor, through the retention of p53 in the nuclei(19).  
Finally, FAS pathway can represent another potential synergistic mechanism since 
gemcitabine sensitizes FAS activation(13) and selinexor contributes as well to FAS 
activation(20). FAS could be a relevant prognostic factor in osteosarcoma(21) and in soft 
tissue sarcomas(22).  
Taking together the previous information, we hypothesize that selinexor will have a synergistic 
effect with gemcitabine in sarcoma patients. The phase I trial will permit the selection of the 
best dose level for the phase II. The determination of predictive biomarkers to this combination 
will benefit the selection of future patients and will provide with the mechanism underlying the 
activity of selinexor plus gemcitabine. 
Gemcitabine administration in sarcomas has been diverse. Mainly used in combination with 
doses ranging from 675 to 1800 mg/m2 and infusion rates ranging from 30 minutes and 10 
mg/m2/min. This latter being the most frequently recommended. The GEIS scheme 
administered 1800 mg/m2 of gemcitabine (10 mg/m2/min) along with 500 mg/m2 of 
dacarbazine every 2 weeks in advanced and progressing STS. Grade 3-4 neutropenia, 
anemia and thrombocytopenia was observed in 48%, 4% and 6 % respectively(15). In 
osteosarcoma patients progressing to standard treatments gemcitabine was administered at 
800 mg/m2/d on days 1 and 8 of cycle, (10 mg/m2/min) along with rapamycin 5 mg (on a daily 
dose). With this scheme, the grade 3-4 neutropenia, anemia and thrombocytopenia were seen 
in 37%, 23% and 20% respectively(33). The original combination of gemcitabine 900 mg/m2/d 
on days 1 and 8 of cycle (10 mg/m2/min) plus docetaxel 75 mg/m2 on day 8 in advanced STS 
reported G3-4 neutropenia, anemia and thrombocytopenia was observed in 16%, 7% and 
40% respectively(23). Finally, in the British randomized phase III trial, gemcitabine was 
administered at 675 mg/m2/d on days 1 and 8 of cycle (90 min of infusion rate) along with 
docetaxel 75 mg/m2 on day 8 of each cycle. The hematological grade 3-4 toxicity reported 
was neutropenia 20%, anemia 6% and thrombocytopenia 0%). Then the total dose per cycle 
is related with the extent of grade 3-4 hematological toxicity(24).  
 
 
 

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Absence of signal of activity detected in osteosarcoma 
In vitro studies of synergy were performed in osteosarcoma cell lines, for the combination of 
selinexor with gemcitabine. Our results indicated the absence of synergy between the two 
drugs, in the three lines of osteosarcoma that have been tested: MG63, SAOS2 and U2OS. 
Through cell viability assays, using the MTS reagent, antagonism for the combination has 
been observed in these lines at concentrations in the IC50 range. Specifically, the combination 
indices are 1.67 for MG63, 1.54 for SAOS2, and 1.23 for U2OS. Furthermore, in apoptosis 
assays using Annexin V-FITC/PI kits, the percentage of apoptotic cells is not significantly 
higher or lower between the monotherapies and the combination for MG63 and U2OS. 
Osteosarcoma patients enrolled in the phase I part of SELISARC progressed quickly and, in 
contrast with other sarcoma subtypes treated, no signal of activity was detected.  
 
Selinexor in malignant peripheral nerve sheath tumor (MPNST) 
MPNST is a malignant neoplasm derived from peripheral nerve sheath with typically 
aggressive behavior. In up to 50% of MPNST cases there is a NF1 context and in 10% may 
emerge in previous irradiated places, the remaining 40% are sporadic MPNST. Plexiform 
neurofibroma is the characteristic precursor of MPNST in the NF1 syndrome. It has been also 
reported malignant transformation from epithelioid schwannoma, but this is clearly less 
frequent.  
Pathological features are the presence of alternating areas of hypocellular and hypercellular 
(marbling appearance), with perivascular accentuation. Heterologous differentiation can be 
present in up to 10-15% of cases. Like dedifferentiated liposarcoma, rhabdomyoblastic 
features correlated with worse outcome(34). Uniform spindle cells with hyperchromatic thin 
nuclei is usually seen but epithelioid morphology can be present. Immunostaining can reveal 
positivity to SOX10 and s100 which is usually patchy while myogenin or desmin can be seen 
in rhabdomyoblastic elements. Loss of nuclear H3K27me3 in high grade sporadic and 
radiation associated MPNST is characteristic(35). Loss of INI1 can be seen in the subset of 
epithelioid MPNST(36). 
Even when MPNST constitutes one of the 5 most frequent sarcoma subtypes of limbs and 
trunk wall, it represents an unmet need since the overall survival is still poor. Globally, the 5-
year overall survival is around 40% considering all the MPNST cases and, in recent times, no 
significant difference has been detected between MPNST associated to NF1 or sporadic(37). 
Despite few relevant advances in the therapeutic field in the last decades, relevant advances 
in tumor biology and preclinical analysis have been reported.  
NF1 loss is seen not only in MPNST linked to NF1 syndrome, but also in the majority of 
sporadic MPNST, suggesting that the loss of this tumor suppressor gene is a cornerstone in 
all MPNST. Genetic alteration of CDKN2A and TP53 are also detected in sporadic and 
radiation-related MPNST(38,39). 
Somatic mutations in SUZ12 and EED that encodes components of the polycomb repressive 
complex 2 (PRC2) were communicated in sporadic and NF1-related MPNST(39,40). PRC2 
acts as histone methyltransferase and marks chromatin for silencing. SUZ12 encodes a 
chromatin modifying protein and its loss stimulate growth in NF1 deficient gliobastoma cell. 
Moreover, SUZ12 ablation induces loss of trimethylation at lysine 27 of histone 3 (H3K27 me3) 
and an increase of H3K27me3 acetylation which entails bromodomain protein 
recruitment(41). Frequent co-alterations between SUZ12 and NF1 are seen in MPNST. 

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    Selinexor (KPT-330) plus gemcitabine 
EudraCT: 2019-000652-33                                                                                                                                                   V5.0 of 17 February 2023 
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SUZ12 maps near NF1 in 17q11.2 and is commonly affected in microdeletions at the NF1 
locus. Then the loss of NF1 function is an early driver event in MPNST pathogenesis. 
Additional genetic hits are loss of tumor suppressor genes as CDKN2A, TP53, RB1 or genes 
encoding PRC2 components as SUZ12 or EED. Then, selinexor might have an important role 
in the treatment of this disease preventing the efflux to cytoplasm of proteins encoded by 
some of these tumor suppressor genes.  
Interestingly, a recent collected experience of 9 advanced MPNST patients treated with 
selinexor-based therapy reported 3 partial responses, 4 stabilizations and 2 progressions. Of 
3 partial responses, 2 were treated with selinexor in monotherapy and 1 with the combination. 
Duration of response ranged from 3 to 8+ months. A patient with stable disease had a 
progression free survival of 13.5 months. The mean duration of disease control was 4.5 
months(42). Probably tumor suppressor proteins relevant in MPNST are retained in the nuclei 
preventing the proliferative action in this aggressive sarcoma subtype.  
Furthermore, gemcitabine is also an active drug in the context of MPNST, and this could 
indicate a potential synergistic effect in the context of this aggressive sarcoma(43). 
 
3.3 
Study and Dose Rationale 
3.3.1 
Dose Schedule Rationale 
3.3.1.1 Selinexor Dosing 
Based on the pharmacology, pharmacokinetics, pharmacodynamics (PDn), tolerability, and 
efficacy observed in clinical studies, the previously recommended dose for the use of single-
agent selinexor in most cancer indications is 60 mg twice weekly (BIW), administered on Days 
1 and 3 of each week, continuously. In patients with heavily pretreated MM, the combination 
of 80 mg selinexor plus 20 mg dexamethasone BIW was identified as the RP2D (Karyopharm 
internal report: Selinexor Exposure-Response White Paper, 06 April 2017) and this dose has 
been shown to be active in penta-refractory MM.  As data has matured from two studies in 
relapsed / refractory myeloma (KCP-330-017 STOMP; NCT02343042 and XPORT-MM-028; 
NCT04414475), the dosing schedule for selinexor has evolved. As of 01 September 2022, a 
total of 95 patients received the selinexor + pomalidomide + dexamethasone (SPd) regimen. 
Dosing schedules ranged from 60 mg to 80 mg selinexor twice weekly (BIW) or 40 to 100 mg 
selinexor QW. Dexamethasone was dosed at 40 mg weekly, and pomalidomide was dosed 2 
to 4 mg once daily (QD) on Days 1 through 21, administered in 28-day cycles (44). Among 
patients with pomalidomide-naïve or non-refractory MM in STOMP (n=44), overall response 
rate (ORR) was 57% and median progression-free survival (mPFS) was 12.2 months. Two 
expansion cohorts dosed with selinexor either at 40 mg QW (SPd-40) or 60 mg QW (SPd-60) 
in combination with pomalidomide 4 mg once daily (QD) on Days 1 through 21 and 
dexamethasone 40 mg QW were enrolled. Preliminary data available at the inception of this 
study suggested that the SPd-60 regimen conferred higher response rates and deeper 
responses compared to SPd-40. However, Grade 1/2 AEs and dose modifications were more 
frequent in the SPd-60 cohort compared to SPd-40 (45). With more data maturity, mPFS 
equalized between SPd40 and SPd 60. With sufficient follow-up data in patients treated with 
SPd-60 and SPd-40 in the STOMP and XPORT-MM-028 studies accumulated to identify SPd-
40 as the optimal dose regimen of SPd based on benefit/risk assessment.   
Based on the above data and latest risk/benefit analysis, the starting dose of selinexor will be 
60 mg weekly, as listed in table 3.3.1.2. 
 

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3.3.1.2 Gemcitabine Combination: Dose Levels 
The following dose levels have been determined to be tested in Phase I: 
Dose level 
Selinexor weekly (given on days 
1, 8 and 15 of each cycle) 
Gemcitabine weekly (given on 
days 1, 8 of each cycle) 
-1 
60 mg 
800 mg/m2 (30 min) 
1 
60 mg 
1000 mg/m2 (30 min) 
2 
60 mg 
1000 mg/m2 (10 mg/m2/min) 
3 
60 mg 
1200 mg/m2 (10 mg/m2/min) 
4 
80 mg 
1200 mg/m2 (10 mg/m2/min) 
 
After having completed the Phase I part, the recommended dose for Phase II is: 
Selinexor will be given at 60 mg once per week orally days 1, 8 and 15 every 21 days. 
Gemcitabine will be given at the dose 1200 mg/m2 (10 mg/m2/min) days 1 and 8 every 21 
days. 
 

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4 
STUDY OBJECTIVES 
Table 4: Objectives and Endpoints 
Objectives 
Endpoints 
PHASE I 
Primary 
• 
To determine the maximum tolerated 
dose (MTD) or the recommended dose 
for phase II of selinexor plus 
gemcitabine.  
 
 
• 
Based on Dose Limiting Toxicities (DLTs) 
observed during first cycle (day 1-21). 
Secondary 
 
• 
To evaluate the safety profile 
according to CTCAE 5.0.  
 
 
 
 
 
 
• 
To determine the overall response rate 
(ORR). 
 
 
 
 
 
 
• 
To evaluate efficacy according to Choi 
response. 
 
 
 
 
 
 
• 
To evaluate the patients’s quality of life 
(QoL). 
 
 
 
 
• 
Safety profile of the experimental treatment, 
through assessment of adverse event type, 
incidence, severity, time of appearance, related 
causes, as well as physical explorations and 
laboratory tests. Toxicity will be graded and 
tabulated by using CTCAE 5.0. 
 
• 
Overall Response Rate (ORR): ORR is defined as 
the number of subjects with a Best Overall 
Response (BOR) of Complete Response (CR) or 
Partial Response (PR) divided by the number of 
response evaluable subjects (according to RECIST 
1.1 criteria). 
 
• 
Efficacy measured through tumor response 
according to Choi criteria. The evaluation criteria 
will be based on the identification of target lesions 
in baseline and their follow-up until tumor 
progression.  
 
 
• 
Quality of life will be measured with EORTC QLQ-
C30. 
 
 
 
 

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PHASE II 
Primary 
• 
To evaluate the efficacy of the 
selinexor plus gemcitabine 
combination as measured by the 
progression-free survival rate (PFSR) 
at 6 months in patients with selected 
advanced soft-tissue sarcomas. 
• 
Progression-free survival rate (PFSR): Efficacy 
measured by the PFSR at 6 months according to 
RECIST 1.1. PFSR at 6 months is defined as the 
percentage of patients who did not experience 
progression or death due to any cause since the 
first dose of experimental treatment until month 6 
after treatment initiation.  
 
Secondary  
• 
To evaluate overall survival (OS).  
 
 
 
• 
To determine the overall response rate 
(ORR). 
 
 
 
 
• 
To evaluate efficacy according to Choi 
response. 
 
 
 
• 
To evaluate the safety profile 
according to CTCAE 5.0.  
 
 
 
 
• 
To evaluate the outcome of post 
protocol treatments. 
 
 
 
 
• 
To evaluate the patients’ quality of life 
(QoL). 
 
• 
Overall survival (OS): OS is defined as the time 
between the date of first dose and the date of 
death due to any cause. OS will be censored on 
the last date a subject was known to be alive. 
• 
Overall Response Rate (ORR): ORR is defined as 
the number of subjects with a Best Overall 
Response (BOR) of Complete Response (CR) or 
Partial Response (PR) divided by the number of 
response evaluable subjects (according to RECIST 
1.1 criteria). 
• 
Efficacy measured through tumor response 
according to Choi criteria. The evaluation criteria 
will be based on the identification of target lesions 
in baseline and their follow-up until tumor 
progression.  
• 
Safety profile of the experimental treatment, 
through assessment of adverse event type, 
incidence, severity, time of appearance, related 
causes, as well as physical explorations and 
laboratory tests. Toxicity will be graded and 
tabulated by using CTCAE 5.0.  
• 
Clinical outcomes of post protocol treatments 
assessed by observation of such treatments in 
follow-up stage. 
Clinical outcomes of post protocol treatments 
assessed by observation of such treatments in 
follow-up stage.  
• 
Quality of life will be measured with EORTC QLQ-
C30. 
 
 
Exploratory: Translational study (Phase I and II) 

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• 
To determinate potential predictive 
biomarkers to the combination of 
selinexor plus gemcitabine in 
sarcomas in tumor blocks and 
peripheral blood samples. 
 
• 
To understand the mechanisms and 
the cell signaling pathways related 
with response or resistance to the 
combination in FFPE tumor samples. 
 
• 
To validate the translational study 
results in pre-clinical models of 
sarcoma. 
• 
Potential biomarkers will be determined using gene 
expression analysis with HTG technology, protein 
expression with immunohistochemistry and 
analysis of plasmatic factors (ProcartaPlex 
Immunoassay). 
 
• 
Correlation of the different identified biomarkers 
with outcome will be analyzed.  
 
 
 
• 
In vitro studies will be done with different STS cell 
lines.  
 
 
 

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5 
STUDY DESIGN 
This is a phase I-II, non-randomized, single-arm, open-label, multicenter, international clinical 
trial. 
Patients with selected advanced soft-tissue sarcoma (leiomyosarcoma or malignant 
peripheral nerve sheath tumor) will receive selinexor in combination with gemcitabine. 
 
In the Phase I part safety and toxicity of the combination will be assessed using a 3+3 design. 
The recommended dose for the Phase II will be determined.  
 
In the Phase II part there will be 2 different cohorts: 
 
Cohort 1: Leiomyosarcoma (LMS) 
Cohort 2: Malignant peripheral nerve sheath tumor (MPNST) 
Dose escalation levels (Phase I):  
 
Dose level 
Selinexor weekly (given on days 
1, 8 and 15 of each cycle) 
Gemcitabine weekly (given on 
days 1, 8 of each cycle) 
-1 
60 mg 
800 mg/m2 (30 min) 
1 
60 mg 
1000 mg/m2 (30 min) 
2 
60 mg 
1000 mg/m2 (10 mg/m2/min) 
3 
60 mg 
1200 mg/m2 (10 mg/m2/min) 
4 
80 mg 
1200 mg/m2 (10 mg/m2/min) 
 
After having completed the Phase I part, the recommended dose for Phase II is: 
Selinexor will be given at 60 mg once per week orally days 1, 8 and 15 every 21 days. 
Gemcitabine will be given at the dose 1200 mg/m2 (10 mg/m2/min) days 1 and 8 every 21 
days. 
5.1 
Overall Study Design 
5.1.1 
Phase I Part   
The dose escalation rules proceed as follows: escalating in cohorts of 3-6 patients per dose 
level. Three patients are treated at a given dose level. If at least 2 patients are observed to 
have dose-limiting toxicity (DLT), the prior dose level is defined as the maximum tolerable 
dosage (MTD) (unless only 3 patients have been treated at that level, in which case it is the 
tentative MTD). If 0 of the 3 patients are observed to have DLT, the dose level is escalated 
one step for the next cohort of 3 patients, and the process continues as above. If exactly 1 of 
the 3 patients treated show DLT, 3 additional patients are treated at the current dose level. If 
none of these additional 3 patients show DLT, the dose level is escalated for the next cohort 
of 3 patients, and the process continues as above; otherwise, the prior dose level is defined 
as the MTD. 
Dose-limiting toxicity (DLT) is usually defined as cycle 1 grade 3 or above toxicity, excepting 
grade 3 neutropenia unaccompanied by either fever or infection. More specifically, for this 

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clinical trial, DLT will be applied only to either of the following toxicities occurring during the 
first treatment cycle (days 1-21): 
Hematological toxicity: 
- 
Febrile neutropenia with documented Grade ≥3 infection or sepsis 
- 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by hemorrhage 
>G1 bleeding 
- 
Grade 4 neutropenia lasting 7 days or longer 
- 
 
Non-hematological toxicities: 
Any grade 3-4 events, excluding: 
- 
Nausea/vomiting/diarrhea unless uncontrolled by maximal antiemetic/ anti-diarrheal 
therapy  
- 
Grade 3 fatigue persisting <14 days 
- 
Grade 3 increased serum creatinine or electrolyte abnormalities deemed not clinically 
significant and which required no treatment 
- 
Grade 3 transaminitis will not be considered Dose Limiting Toxicity unless this would 
entail a delay in the treatment administration. 
 
5.1.2 
Phase II Part   
Sample size calculations for LMS and MPNST cohorts are described in Section 13.2. 
(46)(47)(48)(49)(46)(50)(51) 
5.2 
Total sample size of the phase II part 
2 cohorts: 
(1) LMS: 38 evaluable patients (41 including non-evaluable) 
(2) MPNST: 44 patients (47 including non-evaluable) 
Total: 82 patients (88 including non-evaluable) 

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STUDY POPULATION 
6.1 
Study Population 
Patients with advanced (metastatic or locally advanced unresectable) soft-tissue sarcoma 
(leiomyosarcoma or malignant peripheral nerve sheath tumor).  
6.2 
Inclusion Criteria  
Patients must meet all of the following inclusion criteria to be eligible for this study (Phase II):  
 
1. Patients must provide written informed consent prior to performance of any study-specific 
procedures and must be willing to comply with treatment and follow-up. Informed consent 
must be obtained prior to start of the screening process. Procedures conducted as part 
of the patient’s routine clinical management (e.g.  imaging tests), obtained prior to 
signature of informed consent may be used for screening or baseline purposes as long 
as these procedures are conducted as specified in the protocol.   
2. 
Age: 18-80 years. 
3. 
Histologic diagnosis of soft tissue sarcoma (leiomyosarcoma or malignant peripheral 
nerve sheath tumor) confirmed by central pathology review prior to enrolment with an 
archive tumor sample. A fresh paraffin embedded tumor tissue block must be provided 
for all subjects for biomarker analysis before and (when feasible) after treatment with 
investigational products. 
4. 
Metastatic/advanced disease in progression in the last 6 months. 
5. 
Patients have previously received at least one previous line of systemic therapy. 
6. 
Measurable disease according to RECIST 1.1 criteria. 
7. 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 
8. 
Adequate hepatic, renal, cardiac, and hematologic function. 
9. 
Laboratory tests as follows: 
• Absolute neutrophil count ≥ 1,500/mm³ 
• Platelet count ≥ 100,000/mm³ 
• Bilirubin ≤ 1.5 mg/dL 
• AST and ALT ≤ 2.5 times upper limit of normal 
• Creatinine ≤ 1.5 mg/dL 
10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan. 
11. Females of childbearing potential must have a negative serum or urine pregnancy test 
within 72 hours prior to enrollment and agree to use birth control measures during study 
treatment and for 3 months after its completion. Patients must not be pregnant or nursing 
at study entry. Women/men of reproductive potential must have agreed to use an 
effective contraceptive method. 

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6.3 
Exclusion Criteria  
Patients meeting any of the following exclusion criteria are not eligible for this study (Phase 
II): 
1. Three or more systemic treatment lines (including both chemotherapy and targeted 
therapy) for advanced disease (localized unresectable or metastatic). 
2. Patients who have received any other anti-cancer therapy or investigational product in the 
last 21 days prior to enrollment. 
3. Prior malignancy that required treatment or has shown evidence of recurrence (except for 
non-melanoma skin cancer, adequately treated cervical carcinoma in situ, superficial 
bladder carcinoma) during the 5 years prior to randomization. Cancer treated with curative 
intent for >5 years previously and without evidence of recurrence will be allowed. 
4. Prior selinexor or another XPO1 inhibitor treatment. 
5. Administration of a previous gemcitabine-containing treatment. 
6. Any concurrent medical condition or disease (e.g. uncontrolled active hypertension, 
uncontrolled active diabetes, active systemic infection, etc.) that is likely to interfere with 
study procedures. 
7. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals 
within 1 week prior to Cycle 1 Day 1 (C1D1). Patients on prophylactic antibiotics or with a 
controlled infection within 1 week prior to C1D1 are acceptable.  
8. Pregnant or breastfeeding females. 
9. Body surface area (BSA) <1.4 m2 at baseline, calculated by the Du Bois(25) or 
Mosteller(26) method. 
10. Life expectancy of less than 3 months. 
11. Major surgery within 4 weeks prior to C1D1. 
12. Any active gastrointestinal dysfunction interfering with the patient’s ability to swallow 
tablets, or dysfunction that could interfere with absorption of study treatment. 
13. Inability or unwillingness to take supportive medications such as anti-nausea and 
anti-anorexia agents as recommended by the NCCN CPGO for antiemesis and 
anorexia/cachexia (palliative care). 
14. Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion 
of the Investigator, could interfere with treatment, compliance, or the ability to give 
informed consent.  
15. Presence of brain or central nervous system metastases, unless they are controlled 
(patients with treated and stable metastasis are eligible) 

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7 
STUDY TREATMENTS AND TREATMENT ASSIGNMENT 
7.1 
Treatments Administered 
Selinexor 
 
Pharmaceutical form: Tablet (20 mg tablets). 
Route of administration: Oral use. 
 
Gemcitabine 
 
Pharmaceutical form: Concentrate for solution for infusion. 
Route of administration: Intravenous use. 
 
 
Selinexor has to be taken before gemcitabine infusion. 
7.1.1 
Selinexor 
Selinexor will be provided as tablets for oral administration in blister packs (see IST Pharmacy 
Manual for more information). Selinexor tablets will contain 20 mg of the active pharmaceutical 
ingredient (API).  
Study treatments must be dispensed only by a pharmacist or appropriately qualified staff. 
Study treatments are to be dispensed only to patients enrolled in this study. 
7.1.2 
Gemcitabine  
Gemcitabine is a commercially available product and should be stored, reconstituted and 
discarded per manufacturer’s instructions.  
Gemcitabine will be administered at different dose levels during Phase I:  
Dose level -1: Gemcitabine 800 mg/m2 (30 min) D1 and D8 every three weeks 
Dose level 1: Gemcitabine 1000 mg/m2 (30 min) D1 and D8 every three weeks 
Dose level 2: Gemcitabine 1000 mg/m2 (10 mg/m2/min) D1 and D8 every three weeks. 
Dose level 3: Gemcitabine 1200 mg/m2 (10 mg/m2/min) D1 and D8 every three weeks 
Dose level 4: Gemcitabine 1200 mg/m2 (10 mg/m2/min) D1 and D8 every three weeks 
7.2 
Study Treatment Labeling and Storage 
7.2.1 
Labeling 
All labels will include conditions for storage, lot number, and other information required by the 
European medicine Agency (EMA), International Council for Harmonization (ICH), and/or 
Annex 13, and all local regulations for investigational medications. 
7.2.2 
Storage 
Refer to the IST Pharmacy Manual for selinexor storage.  
Gemcitabine should be stored as described in the prescribing information. 

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7.3 
Study Treatment Dosing and Administration 
7.3.1 
Dispensing Directions 
Dispensing instructions for selinexor will be provided in the IST Pharmacy Manual. 
For doses of oral selinexor to be taken on nonclinical days, patients will be provided with an 
adequate supply of selinexor for self-administration at home until at least their next scheduled 
study visit. Patients will be provided with a take home diary to complete on home dosing days; 
the patient diary will be reviewed at each clinic visit. 
 
7.3.2 
Dosing Information 
7.3.2.1 Selinexor 
Refer to the IST Pharmacy Manual for details of selinexor formulation, preparation, and 
administration. 
Selinexor tablets should be taken orally with at least 120 mL (half a glass) of water at 
approximately the same time each day. It can be taken with or without food. Selinexor tablets 
should be swallowed whole (not crushed) to prevent an increased risk of dermatologic toxicity 
if the powder comes in contact with skin. 
For doses of selinexor that are to be taken on nonclinical days, the patient will be provided 
with selinexor by the site pharmacy and selinexor may be self-administered by the patient on 
an outpatient basis. 
7.4 
Method of Assigning Patients to Treatment Groups 
For phase I part no randomization will performed. All subjects will be treated with the two 
drugs (selinexor, gemcitabine). 
For phase II part, patients will be assigned to either LMS cohort or MPNST cohort depending 
on their confirmed diagnosis. 
7.5 
Dose Schedules for Evaluation 
7.5.1 
Selinexor + Gemcitabine (Phase II) 
• 
Selinexor will be given at 60 mg once per week orally days 1, 8 and 15 every 21 days. 
• 
Gemcitabine will be given at the dose 1200 mg/m2 (10 mg/m2/min) days 1 and 8 every 
21 days. 
7.6 
Study Phases and Determination of RP2D 
7.6.1 
Phase 1: Dose Escalation Phase 
The dose schedule for evaluation during the Dose Escalation Phase I is presented in Figure 
2. 

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7.6.1.1 Treatments to be Escalated 
The dose of gemcitabine and selinexor will be escalated using a standard 3 + 3 approach as 
follows: 
Dose level 
Selinexor weekly (given on days 
1, 8 and 15 of each cycle) 
Gemcitabine weekly (given on 
days 1, 8 of each cycle) 
-1 
60 mg 
800 mg/m2 (30 min) 
1 
60 mg 
1000 mg/m2 (30 min) 
2 
60 mg 
1000 mg/m2 (10 mg/m2/min) 
3 
60 mg 
1200 mg/m2 (10 mg/m2/min) 
4 
80 mg 
1200 mg/m2 (10 mg/m2/min) 
 
The procedure for dose escalation to establish the MTD of the combination is provided in the 
following sections.  
 
7.6.1.2 Dose Escalation Procedures 
A standard 3 + 3 dose escalation schedule will be used for all escalations. Initially, 3 patients 
will be entered in each cohort at the scheduled starting dose level for that cohort. If a drug-
related DLT (see 7.6.1.3) is not seen during the first cycle, the dose will be escalated for 
another group of 3 patients.  
If 1 of 3 patients experiences a drug-related DLT, then 3 additional patients will receive that 
dose. If 1 of 6 patients experiences a drug-related DLT, the next scheduled dose level will be 
enrolled. If, at a given dose level, ≥2 patients experience a drug-related DLT, the MTD will 
have been exceeded, additional enrollment within that cohort will cease, and dose escalation 
will stop.  
Subsequently, if a dose level proves intolerable (≥2 patients experience a DLT), enrollment 
will proceed at one dose-level lower. These rules are summarized in the table below. 
 
 
 

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Table 5: Dose Escalation Rules for Defining MTD  
Number of Patients with Drug-Related DLT 
at a Given Dose Level 
Dose Escalation Step 
0 of 3 
Proceed to next dose level 
1 of 3 
Treat 3 more patients at the same dose level 
≥2 of 3 
Dose escalation stops; MTD is next lower dose 
level 
1 of 6 
Proceed to next dose level 
≥2 of 6 
Dose escalation stops; MTD is next lower dose 
level 
≤1 of 6 at the highest dose level 
MTD 
 
All patients will be considered evaluable for DLT unless they cannot complete the first cycle 
of therapy due to withdrawal of consent or disease progression. A patient who is not DLT-
evaluable will be replaced.  
 
7.6.1.3 Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) is usually defined as cycle 1 grade 3 or above toxicity, excepting 
grade 3 neutropenia unaccompanied by either fever or infection. More specifically, for this 
clinical trial, DLT will be applied only to either of the following toxicities occurring during the 
first treatment cycle: 
Hematological toxicity: 
- 
Febrile neutropenia with documented Grade ≥3 infection or sepsis 
- 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by hemorrhage 
> G1 bleeding 
- 
Grade 4 neutropenia lasting 7 days or longer 
- 
 
Non-hematological toxicities: 
Any grade 3-4 events, excluding: 
- 
Nausea/vomiting/diarrhea unless uncontrolled by maximal antiemetic/ anti-diarrheal 
therapy.  
- 
Grade 3 fatigue persisting <14 days. 
- 
Grade 3 increased serum creatinine or electrolyte abnormalities deemed not clinically 
significant and which required no treatment)  
- 
Grade 3 transaminitis will not be considered Dose Limiting Toxicity unless this would 
entail a delay in the treatment administration. 
 
7.6.2 
Determination of RP2D 
The sponsor will collect and analyse the treatment and toxicity data from cycle 1 from every 
group of patients in the same dose level from the eCRF. The results will be evaluated by an 
Independent Data Monitoring Committee. This committee will give recommendations to 
escalate dose during phase I trial and to select the RP2D.  
All sites, reviewers and Karyopharm will be informed of every decision taken. 

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7.6.3 
Phase 2: Dose Expansion Phase 
The dose for the phase II trial will be selected in the phase I.  
Phase II is developed in one stage and therefore treatment and toxicity analysis will be 
performed when the specified number of patients has been completed in each cohort.  
7.7 
Missed or Vomited Doses 
7.7.1 
Missed Doses of Study Treatments 
Missed doses should be managed as follows:  
• 
If a dose was missed, If a dose was missed, and the patient realize in the first 48 hours, 
the patient will take the dose of this week. If the dose is delayed more than 48 hours, the 
dose of this week will be skipped (e.g. if the patient missed the dose of Monday, he will 
take this week Tuesday or Wednesday, no latter) 
• 
If a dose must be skipped (e.g. due to recommendation of treating physician), the next 
dose will be taken as per schedule. Doses should not be administered less than 36 hours 
apart and all missed and delayed doses should be documented. 
If a patient missed a full 1- or 2-week period of dosing for non-study treatment-related events 
(e.g. a required medical procedure or an unanticipated personal emergency), the days missed 
won't be replaced. For example, if patient missed Cycle 2 Day 8 to Cycle 2 Day 15, then the 
patient will start the next dosing on Cycle 3 Day 1 following the break. Similarly, if a patient 
misses Cycle 3 Day 1 to Cycle 3 Day 15, then the patient will start the next dosing on Cycle 4 
Day 1.  
 
7.7.2 
Vomited Doses of Selinexor 
If a dose of selinexor is vomited within 1 hour of ingestion, it will be replaced. If vomiting occurs 
more than 1 hour after dosing, it will be considered a complete dose. 
7.8 
Dose Modifications and Delays 
To begin each cycle (Day 1), the following criteria must be fulfilled:  
 
Table 6: Hematology and Biochemistry Day 1 Criteria (see also Table 7) 
 
 
VALUE 
Neutrophil count 
≥1.5 × 10
3 cells/μL (≥1500 cells/μL; ≥1.5 × 109/L) 
Platelets  
≥75 × 10 cells/μL  
Haemoglobin  
≥8.0 g/dL. Note: cycle can be started if a transfusion is indicated   
AST and ALT  
≤3.0 x ULN, or ≤5 x ULN if the transaminase elevation is due to 
liver metastases 
 
Any treatment-related non-hematologic toxicity that is NCI-CTCAE, v5.0 Grade <3 or 
equivalent severity to baseline, unless toxicity consists of laboratory abnormalities (for 

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example, potassium, magnesium, or phosphate) that are managed per institutional standard 
or is judged as clinically not significant by investigator (e.g. alopecia).  
All dose modifications will be captured in the medical files and registered in the Case Report 
Form. 
Delays: 
If dose delays of gemcitabine are indicated due to toxicity, selinexor can be maintained if the 
toxicity is not related with selinexor at investigator’s discretion.  
Treatment may be delayed for up to 21 days to allow a patient sufficient time for recovery from 
study drug-related toxicity.  
 
Table 7: General Guidelines for Dose Modification Due to Hematologic Toxicity 
Treatment 
day 
Neutrophil 
count 
Platelet 
Gemcitabine 
dose (mg/m2) 
Selinexor 
Day 1 
>1000 / 
<1500/ml 
>50000 / 
<75.000 
Delay 
Maintain at 
investigator 
discretion 
Day 1 
<500 
< 50000 
Delay 
Delay 
Day 8 
>1000 
>100000 
Administer full 
dose 
Maintain 
Day 8 
500-1000 
>50000, < 
100000 
Administer 80% 
total dose 
Maintain at 
investigator 
discretion 
Day 8 
< 500 
Any 
Omit/delay dose 
Delay until 
G2 or less 
Day 8 
Any 
<50000 
Omit/delay dose 
Delay until 
G2 or less 
Day 15 
>1000 
>100000 
 
Maintain 
Day 15 
500-1000 
>50000, < 
100000 
 
Maintain at 
investigator 
discretion 
Day 15 
< 500 
Any 
 
Delay until 
G2 or less 
Day 15 
Any 
<50000 
 
Delay until 
G2 or less 

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In the case of toxicity, the day 8 administration of gemcitabine can be delayed to day 15 trying 
to preserve the dose intensity. If this strategy entails additional delays, then for the next cycle 
if the same toxicity is found , then the advice will be to omit the gemcitabine dose rather than 
additional delay.  
Table 8: Dosage Reduction Guidelines for Gemcitabine Due to Hepatic Toxicities in Day +8 
Investigation 
Level 
Gemcitabine dose 
(mg/m2) 
Selinexor 
Bilirubin 
<1.5 ULN  
Administer 
Maintain if < G3 
AST /ALT 
Grade ≥3 
elevation 
Delay (Max 21 days) 
until recovery to 
Grade ≤1 or pre-
therapy baseline. 
After recovery, 
reduce 1 dose level 
(see 7.8.4) for all 
subsequent cycles.  
If recovery to Grade 
≤1 does not occur, 
discontinue 
gemcitabine.  
A second dose 
reduction is allowed if 
Grade ≥3 elevations 
recur. 
Maintain if < G3 
 
7.8.1 
Selinexor Dose Reduction Guidelines 
Dose reductions and/or schedule modifications are allowed in order to optimize the antitumor 
activity and tolerability of selinexor. For some AEs, dose interruption and/or reduction is 
recommended. See Table 9 for pre-specified dose modifications for AEs related to study 
treatment and see Table 10 for dose reduction and interruption recommendations. 
While drug-related major organ toxicities are not prominent, thrombocytopenia and a number 
of constitutional side effects can limit dosing with selinexor. Therefore, patients should also 
be treated with supportive care to reduce toxicities (see Section 7.12.2). In addition, it should 
be noted that the constitutional side effects often attenuate over the first 4 to 6 weeks of 
dosing. Finally, some patients with rapid tumor responses experience significant fatigue, 
nausea, malaise and/or asthenia after 1 or more doses of selinexor. This effect has not been 
associated with typical markers of TLS, but if suspected, assessment of tumor response is 
strongly recommended in order to better inform treatment recommendations. 
The CTCAE v 5.0 is used for grading the severity of AEs; the therapy modifications described 
in Table 10 are applied according to this severity grading. Toxicity will be documented as 
described in Section 9.1.3. If more than 1 type of toxicity occurs concurrently, the most severe 
grade will determine the modification. 

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Each dose modification or treatment delay, as well as the reason, must be documented (Table 
9 and Table 10).  
Table 10 summarizes the starting dose (Dose Level 0) and preferred dose modifications for 
AEs listed in Table 10. General supportive care guidelines are provided in Section 7.12.1 and 
Section 7.12.2. 
 
Table 9: Pre-specified Dose Modifications for AEs Related to Study Treatment 
Selinexor Dose 
Modification1 
Selinexor Dose Schedule 
Dose level 0 (starting 
dose) 
That derived from phase I 
 1st  reduction 
Reduce by 20 mg. 
2nd reduction 
 An additional 20 mg will be permitted  
 
1For some AEs, dose interruption rather than reduction is recommended. See Table 
10: Supportive Care and Selinexor Dose Adjustment Guidelines for AEs Related to 
Selinexor 
Table 10: Supportive Care and Selinexor Dose Adjustment Guidelines for AEs Related to 
Selinexor 
Adverse Event 
Occurrence 
Action 
Hematologic Adverse Events 
Thrombocytopenia 
Platelet count 25 × 109/L 
to <75 × 109/L 
Any 
• 
Mantain selinexor. Consider reduction by 
1 dose level at investigator discretion. 
• 
Consider additional supportive care and 
discuss with Sponsor’s Medical Monitor  
Platelet count 25 × 109/L 
to <75 × 109/L with 
concurrent bleeding 
Any 
• 
Interrupt selinexor 
• 
Restart selinexor at 1 dose level lower 
after bleeding has resolved  
• 
Consider additional supportive care and 
discuss with Sponsor’s Medical Monitor 
Platelet count 
<25 × 109/L 
Any 
• 
Interrupt selinexor 
• 
Monitor until platelet count returns to at 
least 50 × 109/L 
• 
Restart selinexor at 1 dose level lower  
• 
Consider additional supportive care and 
discuss with Sponsor-Investigator’s 
Medical Monitor 
Neutropenia 
ANC 0.5 to 1.0 × 109/L 
without fever 
Any 
• 
Initiate growth factor support 

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Adverse Event 
Occurrence 
Action 
ANC <0.5 × 109/L OR 
febrile neutropenia 
Any 
• 
Interrupt selinexor 
• 
Monitor until ANC returns to ≥1.0 × 109/L 
• 
Restart selinexor at 1 dose level lower  
• 
Initiate growth factor support 
Anemia 
Hb <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 until Hb returns to ≥8.0 g/dL 
• 
Restart selinexor at 1 dose level lower 
• 
Administer blood transfusions and/or 
other treatments per clinical guidelines 
Nonhematologic Adverse Events 
Hyponatremia 
Sodium ≤130 mmol/L  
First 
• 
Interrupt selinexor and provide 
appropriate supportive care 
• 
Monitor until sodium returns to 
>130 mmol/L 
• 
Restart selinexor at same dose 
 
Second 
• 
Interrupt selinexor and provide 
appropriate supportive care 
• 
Monitor until sodium returns to 
>130 mmol/L 
• 
Restart selinexor at 1 dose lower  
Fatigue 
Grade 2 lasting >7 days 
OR Grade 3 
Any 
• 
Interrupt selinexor and provide 
appropriate supportive care 
• 
Add methylphenidate 
• 
Monitor until fatigue resolves to Grade 1 
or baseline 
• 
Restart selinexor at 1 dose level lower  
Nausea and Vomiting (See Appendix 2) 
Grade 1 or 2 nausea OR 
Grade 1 or 2 vomiting 
Any 
• 
Maintain selinexor and initiate additional 
anti-nausea medications 
Grade 3 nausea OR 
Grade ≥3 vomiting 
Any 
• 
Interrupt selinexor 
• 
Monitor until nausea or vomiting has 
resolved to ≤Grade 2 or baseline. 
• 
Initiate additional anti-nausea medications 
• 
Restart selinexor at 1 dose level lower  
Diarrhea 
Grade 2 
First 
• 
Maintain selinexor and institute supportive 
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Adverse Event 
Occurrence 
Action 
 
Second and 
subsequent 
• 
Reduce selinexor by 1 dose level Institute 
supportive care 
Grade ≥3 
Any 
• 
Interrupt selinexor and institute supportive 
care 
• 
Monitor until diarrhea resolves to 
Grade ≤2 
• 
Restart selinexor at 1 dose level lower  
Weight Loss and Anorexia 
Weight loss of 10% to 
<20% OR anorexia 
associated with 
significant weight loss or 
malnutrition 
Any 
• 
Interrupt selinexor and institute supportive 
care 
• 
Monitor until weight returns to >90% of 
baseline weight 
• 
Restart selinexor at 1 dose level lower  
Other Nonhematologic Adverse Events 
Grade 3 or 4 
Any 
• 
Interrupt selinexor and institute supportive 
care 
• 
Monitor until resolved to ≤Grade 2 
• 
Restart selinexor at 1 dose level lower  
 ANC=absolute neutrophil count; Hb=hemoglobin. 
 
 
7.8.1.1 Selinexor Dose Adjustment in the Setting of Infection 
Patients with active uncontrolled or suspected infections should have treatment withheld until 
the infection has clinically resolved and/or the patient is clinically stable. When ready to 
resume dosing, treatment may continue at the original dose. Patients may continue antibiotics 
for prolonged periods while re-initiating their treatment at the discretion of the Investigator.  
 
7.8.1.2 Conditions Not Requiring Selinexor Dose Modification 
The following conditions are exceptions to the dose-modification guidelines. Selinexor does 
not need to be interrupted or reduced in the following cases: 
• 
Alopecia of any grade 
• 
Electrolyte or serum analyte (e.g. urate) abnormalities that are reversible with standard 
interventions 
• 
Isolated values of Grade ≥3 alkaline phosphatase. Determination of liver versus bone 
etiology should be made, and evaluation of gamma-glutamyl transferase, 5' 
nucleotidase, or other liver enzymes should be performed. 
 
7.8.2 
Dose Increases 
In select cases (e.g. for patients showing SD or PR and tolerating treatment particularly well), 
the selinexor dose may be increased after discussions between the Sponsor-Investigator and 
Karyopharm. However, in no case may the dose for any patient exceed 70 mg/m2. Prior to 
any potential dose increase, the BSA for the patient will be calculated. In no case should the 

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dose of selinexor be increased to >100 mg twice weekly. Patients will be followed as long as 
possible until disease progression or death. 
 
7.8.3 
Gemcitabine Dose Modifications 
As a general rule, for clinically significant Grade 3-4 toxicities, treatment with gemcitabine has 
to be delayed one week until recovery < Grade 2, and then restart at the same dose level.  
If the toxicity recurs, delay again until recovery < Grade 2 and then restart at the next dose 
level. 
Reductions only have to be done in the drug that is related with this toxicity. 
 
Table 11: Dose Reduction Levels for Gemcitabine  
Gemcitabine Level 
Gemcitabine Dose Schedule 
Starting dose 
 That derived from Phase I 
1st reduction 
Modify the administration rate from 10 mg/m2/min to 30 
min instead of dose reduction. 
2nd reduction 
 To reduce gemcitabine dose by 200 mg/m2 per dose 
3rd reduction 
 To reduce additional 200 mg/m2 per dose 
 4th reduction 
 To reduce additional 200 mg/m2 per dose being the 
minimum dose of 600 mg/m2 in 30 min administration.  
 
 
7.9 
Duration of Treatment and Follow-up 
Treatment will be maintained until disease progression, death, unacceptable toxicity, patient’s 
consent withdrawal or investigator decision. In the case of permanent discontinuation of one 
of the drugs due to toxicity, the patient may continue treatment with the other drugs, at the 
discretion of the investigator.  
7.10 Study Treatment Accountability 
Selinexor will be provided by the drug supplier, Karyopharm. Sites must request study 
treatment by submitting an order form to GEIS for the study treatment to be shipped to the 
site pharmacy. The Investigator or delegated pharmacy staff will verify and acknowledge 
receipt of all study treatment shipments by signing and returning all required forms.  
Study treatment accountability and destruction records will be maintained by the Sponsor-
Investigator.  
Selinexor should not be used for any purpose outside the scope of this protocol, nor may 
selinexor be transferred or licensed to any party not participating in the clinical study. Data for 
selinexor are confidential and proprietary and shall be maintained as such by the 
Investigators. 

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The Investigator, or a responsible party designated by the Investigator, must maintain a 
careful record of the inventory and disposition of unused material.  
All drug supplies provided by the drug supplier must be kept in an appropriate, limited access, 
secure place until used or returned to the drug supplier for destruction. Drug supplies will be 
counted and reconciled at the site before being returned. 
7.11 Treatment Compliance 
The Investigator or other study staff will either directly administer or supervise study treatment 
given in the clinic and instruct the patient on study treatment self-administration, as 
appropriate.  
Patients will be asked to bring their study treatment containers with them at each visit and 
compliance with protocol-defined study treatment intake at home will be checked by tablet 
count.  
Compliance to oral study treatment taken at home will be assessed by the Investigator and/or 
study personnel at each visit and recorded in source documents after discussion with the 
patient and after performing study treatment accountability. 
The Investigator/research staff will account for the number of tablets dispensed against those 
returned by the patient. Any deviations and missed doses will be recorded in the site’s internal 
database and drug accountability logs along with the reasons for subsequent verification. 
7.12 Supportive 
Care, 
Contraception 
Requirements, 
Concomitant 
Medications, and Restrictions 
7.12.1 
Required 5-HT3 Antagonists/Anti-emetics 
In order to minimize nausea, all patients should receive 5-hydroxytryptamine (5-HT3) 
antagonists (e.g. ondansetron 8 mg or equivalent) unless contraindicated, starting on C1D1 
before the first dose of selinexor and continued q 8 hours for days 1-3. . In addition for the first 
month olanzepine 2.5 mg po qm is also required. Olanzepine may be discontinued after the 
first month. Alternative treatment may be provided if the patient does not tolerate 5-HT3 
antagonists (see Appendix 2). 
 
7.12.2 
Recommended Supportive Care for All Patients 
Supportive measures for optimal medical care should be provided to all patients during 
participation in this study. In addition to the required prophylactic therapy with 5-HT3 
antagonists (Section 7.12.1) supportive care per institutional guidelines and/or the National 
Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (CPGO) 
(NCCN CPGO) should be used as clinically indicated at the discretion of the Investigator.  
Supportive care guidelines for managing AEs are provided in Table 10: Supportive Care and 
Selinexor Dose Adjustment Guidelines for AEs Related to Selinexor. 
 
7.12.2.1 Infection 
No prophylactic antimicrobial agent is recommended for most patients initiating therapy with 
selinexor. Patients with a history of recurrent infections or those at high risk for specific 

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infections may continue their prophylactic antimicrobial regimens without modification when 
initiating selinexor therapy. 
In patients who develop fever or other signs of systemic infection, an appropriate antimicrobial 
should be initiated immediately. Selinexor should be suspended in any patient with a Grade 4 
infection or sepsis (even in the absence of documented infection) until the patient’s clinical 
condition is stabilized. Selinexor can then be restarted at the previous dose once the patient’s 
clinical status has stabilized, even in the setting of continued IV (and/or oral) antimicrobial 
agents. Selinexor is not known to have any drug interactions with standard antimicrobials. 
Please also see Table 10: Supportive Care and Selinexor Dose Adjustment Guidelines for AEs 
Related to Selinexor. 
7.12.2.2 Overdose 
As selinexor is metabolized by glutathione (GSH) conjugation, it is possible, but not 
demonstrated, that hepatic GSH depletion might occur in case of extreme overdose. 
Therefore, in patients who develop liver function test abnormalities, supportive measures such 
as SAM or other drugs that can replace GSH might be considered as part of the overall 
management plan. 
 
7.12.3 
Contraception Requirements 
Patients should not become pregnant or father a child while on this study because the study 
treatments in this study can affect an unborn baby. Women should not breastfeed a baby 
while on this study. It is important that patients understand the need to use birth control while 
on this study.  
Female patients of childbearing potential and fertile male patients must agree to 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 3 months after the end of 
treatment. 
Highly effective methods include: 
• 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable 
• 
intrauterine device 
• 
intrauterine hormone-releasing system 
• 
bilateral tubal occlusion 
• 
vasectomized partner 
• 
sexual abstinence 
Please see Section 9.3.1 for additional safety information related to pregnancy. 
 

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7.12.4 
Concomitant Medication and Treatment 
Concomitant medications include any prescription or over-the-counter preparation, including 
vitamins, dietary supplements, over-the-counter medications, and oral herbal preparations 
taken during the study. Patients may continue their baseline medication(s). 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. 
 
7.12.5 
Permitted Concomitant Medication  
Patients will receive concomitant medications to treat symptoms, AEs, and intercurrent 
illnesses that are medically necessary as part of standard care. Medications to treat 
concomitant diseases like diabetes, hypertension, etc., are allowed. 
 
7.12.6 
Use of Blood Products 
During treatment, patients may receive red blood cell (RBC) or platelet transfusions, if 
clinically indicated, per institutional guidelines. Patients who require repeated transfusion 
support should be discussed with the Sponsor-Investigator. 
Appropriate anti-coagulation is allowed during the study (e.g. low molecular weight heparin, 
direct factor Xa inhibitors, etc.). Warfarin is allowed during the study provided patients are 
monitored for INR twice a week during the first 2 cycles of therapy, then weekly to biweekly 
thereafter. 
Patients may receive supportive care with erythropoietin, darbepoetin, granulocyte-colony 
stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF), 
PEGylated growth factors, and platelet stimulatory factors, in accordance with clinical practice 
or institutional guidelines prior to entry and throughout the study.  
In this study, prophylactic granulocyte-colony stimulating factor (G-CSF) will not be 
recommended unless a previous G4 neutropenia had occurred.  
 
7.12.7 
Radiation Treatment 
If clinically indicated, palliative radiation therapy to non-target lesions is permitted but study 
treatment should be held for ≥1 day before the start of palliative radiation therapy and ≥1 day 
following each dose of palliative radiation therapy. Study treatment shall not be discontinued 
solely due to palliative radiation. 
 
7.12.8 
Prohibited 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-Investigator. Refer to the fact sheet for gemcitabine for the 
most current information on prohibited concurrent medications. 
 

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7.12.9 
Restrictions for Study Treatment 
7.12.9.1 Restrictions for Selinexor 
Medications: There are no restrictions on the use of acetaminophen or acetaminophen-
containing products in combination with selinexor, EXCEPT on days of 
selinexor dosing, when acetaminophen use must not exceed a total daily dose 
of 1 g. 
Patients 
should not take GSH-, S-adenosylmethionine (SAM)-, or 
N-acetylcysteine-containing products during their participation in this study as 
these products may enhance the metabolism of selinexor. These agents are 
permitted if the patient has elevated liver function tests, but all natural products 
or supplements containing these agents should be avoided. 
Diet: 
There are no dietary restrictions on this study. Patients on selinexor should 
maintain adequate caloric and fluid intake. 
 
7.12.9.2 Restrictions for Gemcitabine  
Refer to the full prescribing information for gemcitabine for the most current information for 
restrictions. 

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8 
STUDY ASSESSMENTS 
The next study assessments will be performed along the screening process, treatment period 
and follow up. 
Each time point for the next assessment could be found in Tables 1 and 2 Schedule of 
Assessments.  
Procedures that are performed as part of standard of care should not be repeated if they are 
within the Screening window and are done prior to signing the ICF. 
8.1 
Informed Consent 
Assessments may not be performed until the patient provides written informed consent (see 
Section 14.6.) 
Patients that are pre-selected for participation in the study must sign an Informed Consent 
Form (IC) prior to performing any study procedures. Once patient signs the Informed Consent 
all specific study procedures can be performed.  
The ICs are accompanied by a Patient Information Sheet (PIS) that explains the study and 
translational study procedures. Nevertheless, the Principal Investigator at the site or the 
delegated person should ensure that the patient has completely understood the study and no 
other clarification is needed before signing the consent.  
8.2 
Demographic and Baseline Characteristics Assessments 
8.2.1 
Demographics 
Patient demographics (including date of birth, sex, race, ethnicity, and date of Informed 
Consent signature) will be collected. 
 
8.2.2 
Medical History 
A complete medical history will be obtained from each patient. Medical history will include 
baseline symptoms as well as a detailed history of prior cancer and their therapies (i.e. 
chemotherapy, hormonal therapy, immunotherapy, biotherapy, radiotherapy, and surgery), 
including start and end dates, best response, PD during or after therapy, as well as 
discontinuations due to intolerability or toxicity. Smoking history will be recorded. Evaluate the 
risk of TLS based on a clinical evaluation of comorbidity (such as presence of renal impairment 
or cardiac insufficiency). 
Data from standard-of-care procedures will be part of the patient's medical history and may 
be used for study purposes. 
8.3 
Efficacy Assessments 
8.3.1 
Tumor Assessment 
Tumor assessment will be performed by evaluation of CT scan and MRI images according to 
RECIST 1.1 and Choi criteria.  
Screening imaging techniques (CT scan/MRI) have to be done within 28 days prior to study 
treatment initiation. 

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Tumor assessments will be done every 6 weeks (±7 days) during the first 6 months of 
treatment. Tumor assessments will be performed every 8 weeks (±7 days) after 6 months of 
treatment. 
A central radiology reviewer will check measures to establish the best response and 
progression. Images will be sent by sites in DICOM format and coded with patient ID.  
8.4 
Safety Assessments 
8.4.1 
Adverse Events 
Information regarding AEs and SAEs will be collected according to CTC 5.0. See Section 9. 
 
8.4.2 
Concomitant Medications 
Concomitant medications will be documented for each patient at each scheduled visit. A 
detailed history of medications will be documented. At each study visit, patients will be asked 
whether they have taken any medication other than the study treatment (from screening 
through the end of the study). All concomitant medications including dietary supplements, 
over-the-counter medications, and oral herbal preparations, as well as changes in medication, 
should be recorded.  
Necessary supportive care such as appetite stimulants, anti-emetics, and anti-diarrheal, etc., 
is allowed (see Section 7.12.1, Section 7.12.2, and Table 10: Supportive Care and Selinexor 
Dose Adjustment Guidelines for AEs Related to Selinexor. 
 
8.4.3 
Clinical Safety Assessments 
8.4.3.1 Weight, Height, and BSA 
Height (without shoes) in centimeters and weight (indoor clothing without shoes) in kilograms 
will be measured. BSA will be calculated by the Du Bois(25) or Mosteller(26) method to 
determine the volume of gemcitabine to be administered. 
 
8.4.3.2 Physical Examination, Vital Signs, and ECOG Performance Status  
Complete physical examinations should include general appearance, skin, neck, eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and neurological 
examinations.  
Symptom-directed physical examinations should include body systems as appropriate. These 
examinations will be performed according to the standards at each institution. 
Information about the physical examinations must be present in the source documentation at 
the study site. Clinically relevant findings made after the start of study dosing, which meet the 
definition of an AE, must be recorded. 
Vital signs include systolic and diastolic blood pressure, pulse measurements, and body 
temperature. Vital signs should be assessed pre-dose on the scheduled visit day, if possible. 
Blood pressure and pulse rate should be measured after the patient has been in a supine or 
sitting position for 5 minutes and assessed on the same arm throughout the study.  
The ECOG performance status assessments39 will be performed during the study to assess 
how the disease affects the daily living abilities of the patients (<Appendix 1>). 

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8.4.4 
Electrocardiography and Echocardiography 
A standard 12-lead ECG will be performed. Patients must rest for at least 5 minutes prior to 
the ECG recording. The date and time the ECG was performed and the following parameters 
will be recorded: heart rate, PR interval, QT interval, QRS interval, and QT corrected using 
Fridericia's formula.40 The Investigator will interpret the ECG using 1 of the following 
categories: normal, abnormal but not clinically significant, or abnormal and clinically 
significant. 
An echocardiogram or multiple gated acquisition (MUGA) scan to assess cardiac function and 
risk of cardiac dysfunction, including cardiomyopathy, will be performed. The same procedure 
(either MUGA or echocardiogram) that was performed at screening/baseline should be 
performed throughout the study. Preferably the same cardiologist/radiologist should read and 
report the outcome to minimize variability in results. Copies of all transthoracic 
echocardiograms and/or MUGA scans performed on patients who have a ≥20% decrease in 
left ventricular ejection fraction (LVEF) from baseline and whose cardiac ejection fraction is 
below the institution’s lower limit of the normal range (LLN) will be required by the Sponsor-
Investigator for review. 
 
8.4.5 
Laboratory Safety Assessments 
8.4.5.1 Clinical Laboratory Tests 
The next table presents the clinical laboratory tests that will be performed during the study. 
 
Table 12: Clinical Laboratory Tests 
 
Complete Blood Count with Differential (Blood sample: whole blood + EDTA) 
Hemoglobin 
Hematocrit 
Mean corpuscular 
volume 
Mean corpuscular 
hemoglobin 
Mean corpuscular 
hemoglobin 
concentration 
WBC count 
WBC differentiala 
Lymphocytes 
Neutrophils 
Platelets 
Complete Serum Chemistry (Blood sample:  serum) 
Sodium* 
Potassium* 
Chloride* 
Uric acid 
Urea or BUN*, b 
Creatinine* 
Glucose* 
Calcium 
Phosporus 
Magnesium 
ALT* 
AST* 
Alkaline 
Phosphatase* 
Total bilirubin* 
LDH* 
Total protein 
Albumin 
 
 
 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; EDTA: 
ethylenediaminetetraacetic acid; LDH: lactate dehydrogenase; RBC: red blood cell; ULN: upper limit 
of normal; WBC: white blood cell. 
*=Limited serum chemistry 
 
a. WBC differential may be automated or manual as per institutional standards. 
Reticulocytes may be done only when clinically indicated. 
b. Urea (mg/dL) = Blood urea nitrogen (mg/dL) × 2.14. 
c. Microscopy will only be performed if clinically indicated. 
 

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All laboratory safety assessments will be performed and analyzed at each site by a certified 
local laboratory. The Investigator or designee will review the laboratory results and assess the 
clinical significance of all abnormal values. Appropriate action will be taken for any clinically 
significant abnormal values. Values will be documented on the laboratory report until 
stabilized, or the laboratory value returns to a clinically acceptable range (regardless of 
relationship to study treatment) or baseline. 
Any laboratory value that remains abnormal at End of Treatment (EoT) Visit and that is 
considered clinically meaningful will be followed according to accepted medical standards for 
up to 30 days or until resolution of the abnormality or return to baseline. Toxicity will be graded 
using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v 5.0.  
A copy of the laboratory certification and normal ranges for each parameter measured must 
be provided to the Sponsor.  
 
8.4.5.2 Pregnancy Testing 
For females of childbearing potential, a negative urine or serum human chorionic 
gonadotropin (hCG) pregnancy test must be obtained within 3 days before the first dose of 
study treatment. A serum hCG or urine pregnancy test is also required for these patients at 
the EoT Visit. 
Pregnancy testing (serum hCG or urine) is also required for females of childbearing potential 
prior to dosing on Day 1 of pair Cycles (2, 4, 6, 8…) while on treatment. A negative pregnancy 
test must be documented prior to administration of study drug. 
Pregnancy testing may also be performed as clinically indicated during the study. 
 
8.5 
Other Assessments 
8.5.1 
Nutritional Consultation 
Patients must be given nutritional consultation to discuss any food recommendations and 
strategies for managing potential nausea and appetite changes experienced with selinexor. 
This consultation may be given by a study nurse and can be done by phone. 
 
8.5.2 
Durability of Response and Survival Follow-up Visit(s) 
After discontinuation of selinexor/gemcitabine if feasible and clinically indicated, the following 
assessments should be performed at Durability of Response and Survival Follow-up Visits for 
patients who have not progressed to assess durability of response: clinical visit (when 
feasible), CT scan every 8 weeks. If these assessments cannot be performed, at a minimum, 
a telephone call will be made to the patient (or the patient’s family) to assess the survival 
status, status of the patient’s sarcoma, and overall medical condition of the patient and collect 
information on any antineoplastic therapies used after discontinuation of study treatment. 
 

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9 
SAFETY DEFINITIONS, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definitions 
• 
Adverse event (AE): Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of study treatment, whether or not considered 
related to the study treatment. 
• 
Treatment-emergent adverse event (TEAE): Any event that was not present prior to the 
initiation of study treatment or any event already present that worsens in either intensity 
or frequency following exposure to study treatment. 
• 
Serious adverse event (SAE): Any untoward medical occurrence that, at any dose, results 
in death; is life threatening (i.e. an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe); requires inpatient hospitalization or prolongation of existing 
hospitalization; results in persistent or significant disability/incapacity; or is a congenital 
anomaly/birth defect; or defined by the Investigator as medically important. (See Section 
9.2.3 for additional information about SAE reporting.)  
 
9.1.2 
Recording of Adverse Events 
All AEs that begin or worsen after the patient has provided informed consent should be 
recorded by the Investigator, regardless of relationship to study drugs. AE registration in the 
eCRF should be continued for at least 30 days following the last dose of study treatment (i.e. 
through 30 days following last dose or until resolution or through the end of the study for 
events considered related to study treatment by the Investigator). 
AEs (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 visit. AEs may also be recorded when they are 
volunteered by the patient, or through physical examination, laboratory tests, or other clinical 
assessments. 
An AE should be followed and an assessment should be made at each visit (or more 
frequently, if necessary) 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. 
 
9.1.2.1 Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (i.e. are considered to be 
clinically significant, induce clinical signs or symptoms, require concomitant therapy, or require 

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changes in study treatment), should be recorded as an AE. 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 an adequate 
explanation of the abnormality is identified. When an abnormal laboratory or test result 
corresponds to a sign/symptom of an already reported AE, it is not necessary to separately 
record the laboratory/test result as an additional event. 
A laboratory abnormality that does not meet the definition of an AE should not be recorded as 
an AE. A Grade 3 or 4 event (considered to be severe per the current version of NCI CTCAE) 
does not automatically indicate a SAE unless it meets the definition of serious as defined in 
Section 9.1.1 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. 
9.1.2.2 Tumor Lysis Syndrome  
As of 31 March 2021, TEAEs of TLS were reported in a total of 10 patients; overall, 8 SAEs 
and 3 non-serious AEs were reported in these patients (one patient had two events). Of the 8 
SAEs, 2 were reported from CST, 2 from IST and 4 from EAP. Three non-serious events of 
TLS were reported in 3 patients from CST. One patient from CST was reported to have 
experienced 2 TEAEs (1 SAE and 1 non-serious event) of TLS. Going forward all events of 
TLS will be upgraded to serious by the company irrespective of the reporter’s seriousness. 
The reported TEAEs of TLS occurred in patients with heavily pretreated haematologic 
malignancies (7 patients with MM, 2 patients with ALL, and 1 patient with AML). The event 
intensity was reported as Grade 3 in 6 events, Grade 4 in 3 events, and was reported as 
severe in 2 events. The outcomes were reported as recovered in 6 events and not recovered 
for 3 events; and were not reported in 2 events. Of the ten patients with reported TLS, the 
majority (6) received a combination treatment with selinexor and other agents, specifically: 
dexamethasone (2), dexamethasone and pomalidomide (2), bortezomib (1) and bortezomib 
and dexamethasone (1) (administration dates for bortezomib and dexamethasone were not 
reported). TLS is listed in the Warnings and Precautions sections of bortezomib and 
pomalidomide labels. Four patients received selinexor treatment only.   
The following actions were taken with selinexor in these events: dose not changed (4), 
temporarily interrupted (3), action taken was not applicable (selinexor was withdrawn prior to 
the onset of the event (2), and treatment was withdrawn (2).  
No fatal outcomes due to TLS have been reported in any studies with selinexor, or in the 
ongoing selinexor EAP. Of the 10 patients, deaths were reported in 4; all deaths were reported 
to be from causes other than TLS, specifically due to the following Grade 5 events: respiratory 
failuire secondary to advanced MM (1); Sepsis (1); Respiratory failure, chemotherapy (non-
selinexor) induced cardiomyopathy and ALL (1), Plasma cell myeloma (Disease progression) 
(1).   
Early recognition of signs and symptoms in patients at risk for TLS, including identification of 
abnormal clinical and laboratory values, is key and Investigators must ensure that patients 
being treated with selinexor maintain adequate caloric and fluid intake. Close monitoring and 
management of patients with hematological malignancies, including MM, for potential signs 
and symptoms of TLS are most relevant. 

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See Table 10: Supportive Care and Selinexor Dose Adjustment Guidelines for AEs Related to 
Selinexor for selinexor dose modification guidance. 
 
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, v. 5.0 (the NCI CTCAE files can be accessed online at the following URL: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
If there is not a specific NCI CTCAE grading scale for an AE, the severity will be characterized 
as mild, moderate, severe, or life-threatening according to the following definitions: 
• 
Grade 1: Asymptomatic or Mild symptoms, clinical or diagnostic observations 
only, intervention is not indicated. 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living(eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, 
bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden). 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care.  
• 
Grade 4: Life-threatening consequences; urgent intervention indicated.  
• 
Grade 5: Fatal. 
Note: Grade 4 AE should be only considered as life threatening if its occurrence places the 
patient at immediate risk of death. It does not include any AE or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death. 
 
9.1.4 
Adverse Event Causality 
The Investigator will make a judgment regarding the relationship of the AE to study treatment, 
as defined below. 
• 
Not related: These events will lack a 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 relationship, and the event is more likely 

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explained by exposure to the study treatment than by any other 
drugs, therapeutic interventions, or underlying conditions. 
9.2 
Serious Adverse Events 
See Section 9.1.1 for the definition of an SAE. Please note that SAEs that occur at any time 
between the signing of the ICF up to the first dose of study treatment must be reported (in 
addition to SAEs that occur after the first dose of study treatment). 
Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention to 
prevent 1 of the outcomes listed in this definition. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in in-patient hospitalization, or the development 
of drug dependency or drug abuse. 
 
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 (i.e. 
an overnight stay to facilitate 24-hour urine collection) 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 in inpatient to 
the hospital (e.g. undesirable effects of any administered treatment) and must be documented 
as an SAE. 
Progression of the malignancy/disease (including fatal outcomes) should NOT be reported as 
an SAE during the study or within the safety reporting period (see Section 9.2.3). Sudden or 
unexplained death should 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 SAE Report Form provided by GEIS in addition 
to being recorded in the eCRF. The original SAE Report Form must be retained in the 
Investigator’s site file. 
All applicable sections of the 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 SAE Report Form in English. 
 
9.2.3 
Reporting of Serious Adverse Events 
Every SAE, regardless of the causal relationship to the study drugs, occurring after the patient 
has signed informed consent until at least 30 days after the patient has stopped the study 
drugs must be reported to GEIS within 24 hours of learning of its occurrence. The 

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investigational site personnel must use the SAE Report Form provided by GEIS for reporting 
any SAE. 
Upon completion, the SAE Report Form must be immediately emailed or faxed to: 
Study CRO: Sofpromed Investigación Clínica, SLU 
ensayos@sofpromed.com 
Fax: +34 971 570 222 
Any SAE observed after the 30-day follow-up period should only be reported to GEIS if the 
Investigator suspects that the SAE has causal relationship to the study drugs. 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 and 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. 
Investigators are responsible as applicable for notifying their appropriate Health Authorities, 
Institutional Review Board or Local and Central Ethics Committees (EC) of all SAEs in 
accordance with local regulations.  
Karyopharm will report applicable SAEs to other applicable regulatory authorities and 
Investigators utilizing selinexor, as may be required. 
 
9.2.4 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected 
(per the current version of the IB) and judged by the Investigator or Karyopharm to be related 
to the selinexor administered. All SUSARs will be collected and reported to the competent 
authorities and relevant ethics committees in accordance with the EMA’s “Safety Reporting 
Requirements for Investigational New Drugs and Bioanalytical/Bioequivalence Studies” or as 
per national regulatory requirements in participating countries. 
 
9.2.5 
Adverse Event Reporting 
The Sponsor will report all AEs (including all non-serious AEs) to Karyopharm 
Pharmacovigilance twice per year in the form of line-listings in an excel spreadsheet.  
Karyopharm, the drug supplier, will supply the cut-off dates of each requested line listing. The 
line listings will contain the following information: study ID, unique subject ID, adverse event 
term, serious event (yes or no), onset date (complete or partial), end date (complete or partial), 
action taken with selinexor, causality to selinexor, event ongoing (yes or no), outcome of AE, 
severity CTCAE Grade (1-5), subject dosed with selinexor (yes or no), date of first dose of 
selinexor, preferred term, system organ class (optional). 
 

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9.3 
Procedures for Handling Special Situations 
9.3.1 
Pregnancy and Breastfeeding 
Note: Pregnancy per se is not considered to be an AE; however, it is discussed here because 
of the importance of reporting pregnancies that occur during studies and because a medical 
occurrence observed in the mother or fetus/newborn would be classified as an AE. 
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 3 months after 
the end of treatment. 
A list of highly effective methods of contraception is provided in Section 7.12.3. 
A pregnancy test will be performed on each premenopausal female patient of childbearing 
potential prior to the first dose of study drug, on Day 1 of Cycles ≥2 while on treatment, and 
again at treatment discontinuation during the End-of-Treatment visit. A negative pregnancy 
test must be documented prior to administration of study drug. 
If a patient is confirmed pregnant during the study, study drug administration must be 
discontinued immediately. The Investigator must immediately notify the Sponsor of this event 
and record the Pregnancy on the Pregnancy Form. The initial information regarding a 
pregnancy must be forwarded to GEIS by email or fax within 24 hours of first knowledge of its 
occurrence. A pregnancy report form is provided by GEIS. 
The pregnancy should be followed up to determine the outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.  
All pregnancies occurring within 3 months after the patient’s last dose of study drug must be 
reported to GEIS, regardless of whether the patient received the 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 GEIS 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 a selinexor-containing regimen.  
 
9.3.2 
Overdose, Abuse, Misuse, Medication Errors, and Occupational Exposure 
All incidences of overdose, abuse, misuse, medication errors, and occupational exposure are 
required to be reported to GEIS on a SAE report form regardless of whether or not there is an 
associated AE or SAE. 
 

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9.3.2.1 Overdose 
An overdose is a deliberate or accidental administration of study drugs to a study patient, at 
a dose greater than that which was assigned to that patient per the study protocol. If an 
overdose occurs, GEIS 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 recorded. Information regarding the 
overdose is to be recorded on a SAE report form and sent to GEIS 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 GEIS within 24 hours of awareness. If there 
is no AE or SAE, the report must be submitted within 24 hours of awareness. 
As selinexor is metabolized by GSH conjugation, it is possible, but not demonstrated, that 
hepatic GSH depletion might occur in case of extreme overdose. Therefore, in overdose 
cases, if patients develop liver function test abnormalities, supportive measures such as SAM 
or other drugs that can replace GSH might be considered as part of the overall management 
plan. 
 
9.3.2.2 Abuse, Misuse, or Medication Error 
Abuse is the persistent or sporadic, intentional excessive use of selinexor 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. 
All occurrences of abuse, misuse, or medication error with the study drug are to be recorded 
on a SAE report form and sent to GEIS 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 GEIS within 24 
hours of awareness. If there is no AE or SAE, the report must be submitted within 24 hours of 
awareness. 
 
9.3.2.3 Occupational Exposure 
Occupational exposure is the exposure to a study treatment as a result of one’s professional 
or non-professional occupation.  
All occurrences of occupational exposure with the selinexor are to be recorded on a SAE 
report form and sent to GEIS 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 GEIS within 24 hours of awareness. If there is no AE or SAE, 
the report must be submitted within 24 hours of awareness. 
 

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10 DISCONTINUATION CRITERIA 
10.1 Early Termination of the Study 
The study may be terminated at the 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.  
The Sponsor, in conjunction with appropriate regulatory authorities, would then decide if the 
study should be modified or terminated. 
 
10.2 Discontinuation of Study Treatment and/or Withdrawal of Patients from 
the Study 
The Investigator may remove a patient from study treatment for any of the following reasons: 
• 
Unacceptable AEs or toxicity that cannot be managed by supportive care (this 
must be linked in the study database to the AE or toxicity event to support 
discontinuation). 
• 
Any medically appropriate reason or significant protocol violation, in the opinion 
of the Investigator 
The Investigator must remove a patient from study treatment for any of the following reasons: 
• 
Disease progression  
• 
Patient elects to discontinue study treatment 
• 
Pregnancy 
Patients may discontinue study treatment for any reason. Patients who choose to discontinue 
study treatment should be encouraged to continue in the study so that follow-up information 
on PD and survival status may be obtained. 
Patients may elect to withdraw consent and decline further participation in the study at any 
time. Patients who withdraw consent must be withdrawn from the study. 
The reason for the patient’s discontinuation of study treatment must be clearly documented in 
the site source data and include supporting data (i.e. discontinuation for PD must be 
accompanied by data points in the database to support PD; additionally, if the reason for 
discontinuation is physician decision, ample justification must be provided and linked to PD 
values, AEs, etc.). 
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. 
All patients will be followed until disease progression, they withdraw consent, are withdrawn 
from the study by the Investigator, have died, or have been lost to follow up. 

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11 STUDY VISITS 
11.1 
Description of Study Days 
11.1.1 
Screening  
Screening will include the study procedures described below and will be performed within 28 
days prior to the start of therapy (i.e. Day -28 to Day -1), as summarized in Study Schematics 
and Schedule of Assessments and Dosing  
Table 1: Schedule of Study Activities and Assessments (PHASE I) 
The Investigator should not repeat procedures that are performed as part of standard of care 
(SOC), if they are within the screening window and are done prior to signing the ICF. Data 
from SOC procedures will be part of the patient's medical history and may be used for study 
purposes.  
Screening may be divided into two (or more) clinic visits at the discretion of the Investigator. 
The procedures to be performed during screening are listed below assuming such a division, 
however the decision is up to the Investigator, as long as all procedures are performed and 
Randomization occurs on Day -3 to Day -1 (i.e. prior to the first day of study administration). 
 
DAY -28 TO DAY -1 ( FOR PHASE 1 AND PHASE 2) 
• 
Sign written informed consent (note age on day consent signed) 
• 
Demographics (date of birth, gender) 
• 
Medical history 
• 
Height 
• 
Weight 
• 
Body Surface Area 
• 
Vital signs (BP, pulse, and temperature) 
• 
ECOG 
• 
Physical examination 
• 
12-lead ECG 
• 
Echocardiogram or MUGA 
• 
CBC with differential 
• 
Complete serum chemistry 
• 
Coagulation test 
• 
Urinalysis 
• 
Pregnancy test 
• 
Tumor sample for diagnosis confirmation 

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• 
Tumor for translational research 
• 
Blood for translational research 
• 
Scans (e.g. CT/MRI) 
• 
Adverse events recording  
• 
SAE reporting 
• 
Concomitant medication recording 
• 
Nutritional consultation 
 
11.1.2 
Cycle 1  
 
11.1.2.1 Study Procedures (Days 1-21) 
These procedures will be followed for all cohorts: 
Table 13: Study Procedures for Cycle 1 
 
Procedure 
Phase 1 (Days) 
Phase 2 (Days) 
Weight 
1, 8, and 15 
1 and 8 
Vital signs (BP, pulse, and 
temperature) 
1, 8, and 15 
1 and 8 
ECOG 
1, 8, and 15 
1 and 8 
Physical examination 
1, 8, and 15 
1 and 8 
CBC with differential 
 
1, 8, and 15 
1 and 8 
Complete serum chemistry 
1, 8, and 15 
1 and 8 
Coagulation test 
1 
1 
Urinalysis 
1 
1 
Adverse events recording 
Throughout the cycle 
Throughout the cycle 
SAE reporting 
Throughout the cycle 
Throughout the cycle 
Concomitant medication 
recording 
Throughout the cycle 
Throughout the cycle 
Nutritional consultation 
Perform if clinically indicated Perform if clinically indicated 
Quality of Life assessment 
1 
1 
 
 
11.1.2.2 Study Treatment Dosing 
• 
Selinexor administration (Days 1, 8, and 15) 
• 
Gemcitabine administration (Days 1 and 8) 

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11.1.3 
Cycle 2  
The procedures will be followed for all cohorts: 
 
11.1.3.1 Study Procedures 
Table 14: Study Procedures for Cycle 2 
 
Procedure 
Phase 1 (Days) 
Phase 2 (Days) 
Weight 
1 
1 
Vital signs (BP, pulse, and 
temperature) 
1 
1 
ECOG 
1, 8, and 15 
1 and 8 
Physical examination 
1, 8, and 15 
1 and 8 
12-lead ECG 
Perform if clinically indicated Perform if clinically indicated 
Echocardiogram or MUGA 
Perform if clinically indicated Perform if clinically indicated 
CBC with differential 
 
1, 8, and 15 
1 and 8 
Complete serum chemistry 
1, 8, and 15 
1 and 8 
Coagulation test 
1 
1 
Urinalysis 
1 
1 
Pregnancy test 
1 
1 
Adverse events recording 
Throughout the cycle 
Throughout the cycle 
SAE reporting 
Throughout the cycle 
Throughout the cycle 
Concomitant medication 
recording 
Throughout the cycle 
Throughout the cycle 
Nutritional consultation 
Perform if clinically indicated Perform if clinically indicated 
Quality of Life assessment 
1 
1 
 
 
11.1.3.2 Study Treatment Dosing 
• 
Selinexor administration (Days 1, 8, and 15) 
• 
Gemcitabine administration (Days 1 and 8) 
 

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11.1.4 
Cycle ≥3 
11.1.4.1 Study Procedures 
Table 15: Study Procedures for Cycles ≥3  
Procedure 
Phase 1 (Days) 
Phase 2 (Days) 
Weight 
1 
1 
Vital signs (BP, pulse, and 
temperature) 
1 
1 
ECOG 
1 
1 
Physical examination 
1 
1 
12-lead ECG 
Perform if clinically indicated Perform if clinically indicated 
Echocardiogram or MUGA 
Perform if clinically indicated Perform if clinically indicated 
CBC with differential 
 
1 and 8 
1 
Complete serum chemistry 
1 and 8 
1  
Coagulation test 
1 
1 
Urinalysis 
1 
1 
Pregnancy test 
1 (even cycles only) 
1 (even cycles only) 
Adverse events recording 
Throughout the cycle 
Throughout the cycle 
SAE reporting 
Throughout the cycle 
Throughout the cycle 
Concomitant medication 
recording 
Throughout the cycle 
Throughout the cycle 
Nutritional consultation 
Perform if clinically indicated Perform if clinically indicated 
Quality of Life assessment 
1 (every 3 cycles) 
1 (every 3 cycles) 
 
 
11.1.4.2 Study Treatment Dosing 
• 
Selinexor administration (Days 1, 8, and 15) 
• 
Gemcitabine administration (Days 1 and 8) 
 
11.1.5 
End-of-Treatment Visit (within 30 Days after Last Dose) 
Study procedures will be performed within 30 days (+ 7 days) after the last dose of study 
treatment for all patients, including early termination patients, as summarized below. 
• 
Weight 
• 
Vital signs (BP, pulse, and temperature) 
• 
ECOG 
• 
Physical examination 

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• 
12-lead ECG 
• 
Echocardiogram or MUGA 
• 
CBC with differential 
• 
Complete serum chemistry  
• 
Coagulation test  
• 
Pregnancy test 
• 
Blood for translational research 
• 
Tumor sample for translational research (optional) 
• 
Adverse events recording 
• 
SAE reporting 
• 
Concomitant medication recording 
• 
Scans (if visit is not due to progression) 
• 
Quality of Life assessment 
 
11.1.6 
 Survival Follow-Up 
After treatment discontinuation, a telephone call will be made to the patient (or the patient’s 
family) every 3 months to inquire about the patient’s status, general health, and information 
on any antineoplastic therapies utilized since discontinuation of study treatment. 
If the patient has not progressed but ended treatment a scan (CT/MRI) will be performed every 
8 weeks (±7days). 
If the patient has progressed, a scan (CT/MRI) will be performed at least every 3 months.  
  

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12 TRANSLATIONAL STUDY 
 
12.1 Biological samples 
1. One formalin-fixed paraffin-embedded (FFPE) tumor block sample mandatorily collected at 
baseline (primary/ metastatic tumor, from surgery/biopsy). Tumor blocks should be collected 
within the 28 days prior to starting the treatment, except for patients that have a tumor sample 
in the last 3 months and have not been exposed to any line of treatment, within this time.  
NOTE 1: Mandatory biopsies for the translational study must follow the following guideline: 
minimum of 6 Tru-Cut cylinders (14g-16g needle) divided into two tubes, which in turn will be 
included in separate paraffin blocks.  
NOTE 2: Tumor samples will be centralized at central lab, in IBiS (Seville). Biological samples 
will be shipped directly from each local site to the central laboratory, via courier, within the first 
week after enrollment.  
2. One formalin-fixed paraffin-embedded (FFPE) tumor block sample optional collected at the 
End of Treatment. 
3. Two 10mL VACUETTE® TUBE K3E K3EDTA tubes of peripheral blood within 72 hours 
prior to starting treatment (baseline), two 10mL VACUETTE® TUBE K3E K3EDTA within ±72h 
of  each radiological assessment (TC scan, MRI, or PET scan) and two 10mL VACUETTE® 
TUBE K3E K3EDTA tubes of peripheral blood at the end of treatment (within 72 hours after 
progressive disease is documented). Plasma will be separated by a Ficoll-Paque protocol. 
Mononuclear cells will be also collected for further analysis. 
NOTE 3: Blood samples will be collected and immediately shipped to central lab. Peripheral 
blood samples need to be processed within the first 24 hours after being collected. 
NOTE 4: Peripheral blood samples cannot be collected at Fridays and the day before a 
holiday.  
NOTE 5: Central laboratory needs to be informed every time that a blood sample is shipped, 
in order to book the cytometer. This point is mandatory and it should occur at the same time 
that the courier is requested.  
 
12.1.1 Objectives 
• 
To determinate potential predictive biomarkers to the combination of selinexor plus 
gemcitabine in sarcomas in tumor blocks and peripheral blood samples. 
• 
To understand the mechanisms and the cell signaling pathways related with response 
or resistance to the combination in FFPE tumor samples. 
• 
To validate the translational study results in pre-clinical models of sarcoma. 
 
12.1.2 Methodology 
A) HTG Molecular Oncology Biomarker Panel Assay: 
Gene expression, in pre-treatment tumor samples, will be evaluated with HTG EdgeSeq 
Oncology Biomarker Panel (OBP) (HTG Molecular; Tucson, AZ, USA). Briefly, samples will 

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be prepared from FFPE (1.5μm section in a slide), through a chemical lysis without nucleic 
acids extraction. Then, a protection probe will bind specifically to the target RNA, which will 
be later eliminated by heat and base treatment. Subsequently, precise sequencing adaptors 
will be added to the library and this library will be amplified. Afterwards, the library will be 
quantified and normalized to a pool library and sequenced by Next-Generation Sequencing 
(NGS) with a HiSeq 2500 System. The data will be analyzed using the HTG EdgeSeq software 
and the results represented in terms of copy number alteration (CNA). Tumor samples will 
have more than 70% of tumor area and minimum of 13 mm2 of area. Gene expression levels 
will be correlated with clinical data, to determine potential prognostic and/ or predictive 
biomarkers. Moreover, cell signaling pathways that may be predictive to treatment will be also 
determined, using gene expression profile. Cell signaling pathways results will be validated in 
in vitro studies. In bioinformatics analysis, particular interest will be putted in DDR-related 
genes/ cell signaling pathways, as predictive biomarkers of selinexor combination.  
B) Gene expression validation of HTG Oncology Biomarker Panel assay results: 
The results of gene expression, obtained with OBP panel, will be validated by qRT-PCR, using 
RNA extracted from FFPE samples. Of FFPE samples, three 20μm-thick sections will be 
obtained for total RNA extraction using the Recover All Total Nucleic Acid Isolation® kit 
(Ambion; Austin, USA), following the manufacturer’s instructions. RNA concentration will be 
measured at 260 and 280nm using the Nanodrop® 1000 spectrophotometer (Thermo 
Scientific; Waltham, MA, USA). Next, the reverse transcription will be performed from 40ng of 
total RNA using the High Capacity cDNA Reverse Transcription Kit® (Applied Biosystems; 
Foster City, CA, USA) and following manufacturer’s protocol. The changes on target genes 
expression will be determined in triplicate, by qRT-PCR, in 10μl reactions, containing: 2μl of 
the synthesized cDNA, 5μl of TaqMan Fast Universal PCR Master Mix (Applied Biosystems) 
and 1μl of the corresponding expression assay (Applied Biosystems). All PCR reactions will 
be carried out on a 7500 Fast Real Time PCR system (Applied Biosystems). The expression 
of these genes will be normalized to β2-microglobulin mRNA levels (Hs99999907_m1, 
Applied Biosystems). When necessary a different housekeeping gene will be used. 
C) Protein expression analysis in FFPE samples: 
The genomic alterations determined in FFPE samples will be also validated at protein level 
by immunohistochemistry (IHC), using complete sections of tumor blocks. The blocks will be 
revised by a pathologist expert in sarcomas and a hematoxylin-eosin staining will be 
performed on each block to check for the existence of the tumor. 3μm sections will be used 
for IHC. Immunodetection will be performed with the DAKO EnVision Visualization Method 
(DAKO), with diaminobenzidine chromogen as substrate. The sections will be counterstained 
with hematoxylin. 
Peer Review: To improve the reliability of the IHC analysis, the results will be read by two 
pathologists, experts in sarcomas. 
D) Protein expression analysis in plasma: 
The protein levels of soluble factors (i.e. angiogenic factors, chemokines, cytokines and 
others), that proven to be potential predictive biomarkers in OBP assay, will be evaluated and 
validated, through a ProcartaPlex Immunoassay (ThermoFisher Scientific), using plasma 
samples collected at different time points during the treatment. Plasma will be isolated from 
peripheral blood, following a Ficoll-Paque protocol. The protein levels will be accessed by 
ELISA or ProcartaPlex Immunoassay following the manufacturer’s instructions. The soluble 
factors levels will be correlated with clinical data, to determine potential prognostic and/ or 
predictive biomarkers, as well as to determine the alterations induced by treatment in these 
proteins.  

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E) Peripheral blood mononuclear cells counting: 
Variations on peripheral blood mononuclear cells in response to treatment will be assessed 
by flow cytometry. Regulatory T-cells (Tregs) will be sorted as CD3, CD4, CD25, CD127 cells. 
Cytotoxic T-cells will be sorted as CD3, CD8 cells and helper T-cells (Th Cells) as CD3, CD4, 
CXCR3/ CCR4 cells. Mature B-cells will be sorted as IgM, CD19 cells and activated B cells 
as CD19, CD25, CD30 cells. Monocytes subsets will be sorted as CD14, CD16, CD64 cells, 
macrophages subsets as CD11b, CD68, CD86, CD163, CD206 cells, dendritic cells subsets 
as CD1c, CD83, CD141, CD209, MHC II cells and natural killers as CD3(-), CD16, CD56. Cell 
count number and ratios between cell populations will be correlated with clinical data.  
F) Statistical Plan: 
For variables with binomial distributions and categorical variables, frequency and percentages 
will be calculated. A Chi-square test and Fisher´s exact test will be used to compare 
categorical variables. For time-to-event variables (i.e. PFS or OS) Kaplan-Meier estimations 
will be used and to compare groups the Log-Rank test. To analyze the reduction of risk Cox 
Regression will be applied. The translational data will be correlated with clinical results. 
12.2 Pre-clinical study 
Cell lines: 
a) Human leiomyosarcoma cell line SK-UT-1 
b) Human primary leiomyosarcoma cell line AA 
c) Human primary leiomyosarcoma cell line CP0024 
d) Human primary leiomyosarcoma cell line ICP055 
e) Human primary leiomyosarcoma cell line IEC005 
f) Human primary UPS cell line IEC016 
g) Human osteosarcoma cell line U2OS 
h) Human osteosarcoma cell line SAOS-2 
i) Human osteosarcoma cell line HOS 
j) Human osteosarcoma cell line MG-63 
12.2.1 Methods 
Determination of IC50 proliferation indexes 
Working cell lines will be seeded in 96-well plates and treated separately with increasing 
concentrations of selinexor (1x10-13 to 1x10-7), Gemcitabine (1x10-13 to 1x10-7) for 72 hours 
in order to analyze cell proliferation. Cell proliferation will be evaluated by MTT assay and the 
concentrations that inhibit 50% of cell growth (IC50) will be determined using nonlinear 
regression in Prism 5.0 (GraphPad Software). 
In vitro studies of cell death 
The induction of late apoptosis will be evaluated after exposing the cell lines to selinexor 
and/or Gemcitabine. Cells will be seeded in 6-well plates and treated with concentrations in 
IC50 range. After the respective treatment (72 hours later), cells will be further staining with 
Propidium Iodide and Annexin-V. The percentage of cells undergoing apoptosis will be 
determined in a BD FACSCANTO II flow cytometer. Moreover, protein will be extracted in 

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order to evaluate the presence of cleaved Caspase-3 and cleaved PARP-1, by SDS-PAGE/ 
Western blotting. 
In vitro validation of the transcriptional activity in response to treatment  
The transcriptional profile determined in the translational study (OBP panel) will be validated 
in the cell line panel. Cells will be treated, for 72 hours, with selinexor and Gemcitabine l in 
monotherapy or in combinations, using concentrations in the IC50 range. For qRT-PCR, total 
RNA will be isolated by the TRIzol® (Invitrogen Corp., Carlsbad, CA) -chloroform method, 
from all cell lines, according to the manufacturer’s protocol. One microgram of total RNA will 
be submitted to reverse transcription using the High Capacity cDNA Reverse Transcription Kit 
(Applied Biosystems™ - Thermo Fischer Scientific., Carlsbad, CA), in the presence of 
MultiScribe™ Reverse Transcriptase and a random primer scheme for initiating cDNA 
synthesis. The cDNA obtained will be amplified and quantified by real-time quantitative PCR, 
using the GoTaq® qPCR Master Mix Kit (Promega, Madison, WI). The relative expression of 
target genes will be normalized to β2 microglobulin (β2M) and the expression in each sample, 
compared to the control (RNA pool: Universal Human Reference RNA; Agilent Technologies, 
Santa Clara, CA, USA). Individual quantification of gene expression will be performed using 
the comparative CT method (CT) and the relative expression will be calculated as 2–ΔCT.  
The results obtained in the translational study using the OBP panel of HTG Molecular will be 
also validated at protein levels by SDS-PAGE/ WB and immunofluorescence (IF).  
In vitro validation of Multicarta Plex results 
Potential predictive biomarkers and changes in protein expression of soluble factors, 
determined through a ProcartaPlex Immunoassay (ThermoFisher Scientific), in the 
translational study will be validated by ELISA assay. For this purpose, it will be used cell 
medium collected from cell culture supernatants, before treatment and after 72 hours 
treatment. ELISA will be performed following manufacturer’s instructions.  
In vivo experiments 
Experiments in in vivo models of sarcoma are not scheduled; however, if any result or 
mechanisms needs be evaluated or validated in PDX models of sarcoma, the protocol will be 
amended and the corresponding ethics committee submitted for approval.  
 
 

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13 PLANNED STATISTICAL METHODS 
13.1 General Considerations 
All the sample size calculations have used Type II error of 80% and one sided, type I error of 
5%.  
GEIS will have the responsibility of the statistical analysis. The software package used for 
statistical analysis will be SPSS Statistics (version 20).  
For variables with binomial distributions, frequencies and percentages will be calculated with 
their corresponding 95% CIs.  
To compare categorical variables, Fisher’s exact or χ2 tests will be used where applicable.  
Time-to-event variables (overall survival and progression-free survival) will be measured from 
the date of therapy onset and will be estimated according to Kaplan-Meier survival analysis.  
Comparisons between the variables of interest will be done with the log-rank test. 
Multivariate analyses with the variables that appear to be significant in the univariate analyses 
will be done according to the Cox proportional hazard regression model.  
The validity of proportional hazard assumption will verified by adding a time- dependent 
variable to each model to confirm that the hazard ratio for each covariate do not increase or 
decrease over time.  
All p values reported will be two-sided, and significance is defined as a p value lower than 
0.05.  
13.2 Determination of Sample Size 
Sample Size Estimation for Leiomyosarcoma (Single-Arm Cohort) 
Sample size is obtained for the primary endpoint of 6-month progression-free survival rate, 
and estimated accrual 24 months. A 6-m PFSR of 20% will be considered not promising 
whereas of 45% will be considered promising in this population. With a type I error α of 0.05 
and a power of 0.90, 38 patients were estimated in this cohort. With Simon’s two-stage 
Optimal design(46), at least 5 cases over the 16 first patients (stage 1) should have ≥ 6-m 
PFS. Then additional 22 patients would be accrued up to 38 patients. If at least 12 patients 
had a 6-m PFS or longer, further investigation of the drug is warranted.  
Bibliographic support 
In comparative studies with advanced leiomyosarcoma, in PALETTE trial comparing 
pazopanib vs placebo, the median of PFS reported with approved drugs was around 4.5 
months with a calculated 6-month PFSR of 37%(47). Similarly, in phase III trial comparing 
trabectedin vs dacarbazine, the median of PFS for the trabectedin was 4.2 months, 
significantly better than 1.5 months for dacarbazine. The calculated 6-month PFSR for the 
active drug was 37% while it was 14% for dacarbazine. The only phase III conducted in 
advanced soft tissue sarcoma with gemcitabine combination was addressed in first line 
obtaining 46.4% of 6-month PFSR, in second or further line this should be less than 40%.3 
Interestingly, a recent case-series focusing on advanced leiomyosarcoma reported in 
leiomyosarcoma with molecular-aberrant related therapies a median PFS of 5.8 months 

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whereas in leiomyosarcoma without aberration-related therapies the median PFS was 1.9 
months with a calculated 6-month PFSR of 12%(48).  
More recently, a new benchmark recommended by EORTC for advanced/metastatic 
leiomyosarcoma has been shared. For second or further lines, the updated threshold for 
activity in leiomyosarcoma is a 6-month PFS rate of >30%(49). Thus, the statistical 
assumptions are based on this data. 
 
Sample Size Estimation for Malignant Peripheral Nerve Sheath Tumor (Single-Arm 
Cohort) 
Sample size is obtained for the primary endpoint of 6-month progression-free survival rate, 
and estimated accrual 24 months. A 6-m PFSR of 15% will be considered not promising 
whereas of 35% will be considered promising in this population. With a type I error α of 0.05 
and a power of 0.90, 44 patients were estimated in this cohort. With Simon’s two-stage 
Optimal design(46), at least 4 cases over the 19 first patients (stage 1) should have ≥ 6-m 
PFS. Then additional 25 patients would be accrued up to 44 patients. If at least 11 patients 
had a 6-m PFS or longer, further investigation of the drug is warranted.  
Bibliographic support 
MPNST is classically considered more resistant to chemotherapy than other common 
subtypes of soft tissue sarcoma, and there is no threshold released by EORTC nor by other 
cooperative groups for the systemic treatment activity of MPNST. The classic benchmark 
would fit with the expectation of PFS at 6 months(50). One compilation of advanced MPNST 
treated with systemic therapies, reported a median PFS of 3.3 months for second lines 
showing 
a 
dismal 
prognosis 
in 
MPNST 
progressing 
after 
anthracycline-based 
chemotherapy(51).  
13.3 Analysis Populations 
13.3.1 
Intent-to-Treat Population 
The intent-to treat population is formed by all the patients providing informed consent and with 
a centrally confirmed diagnosis of leiomyosarcoma, UPS, MPNST or ASPS.   
Progression-free survival rate at 6 months (the primary objective), overall survival and 
progression-free survival will be measured with the intention-to-treat population. 
 
13.3.2 
Per Protocol Population 
The per-protocol population is defined as the subset of the intention-to-treat population with 
measurable disease at study entry per RECIST. Patients in this population also received at 
least 21 days (one cycle) of treatment and had at least one radiological assessment. 
Otherwise the patient was not considered assessable (the exception will be early progression 
or death, for which patients will be included).  
 
13.3.3 
Safety Population 
Safety population is defined as all the patients receiving at least one dose of any of the study 
drugs.   

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13.4 Demographics and Baseline Characteristics 
The following demographic data will be collected: 
- 
Date of birth 
- 
Gender 
- 
Date of initial diagnosis 
- 
Stage at diagnosis (localized/locally advanced/metastatic) 
- 
Size at diagnosis (mm) 
- 
Site of primary tumor 
- 
Previous surgery (Yes/No) 
- 
Date of metastatic disease 
- 
Relevant medical history 
 
In baseline the following data will be collected:  
- 
ECOG  
- 
Concomitant medication 
- 
Stage at study initiation (locally advanced/metastatic) 
- 
Site of metastasis 
- 
Number of previous lines of systemic therapy for advanced disease 
- 
Date of progression for study inclusion 
13.5 Efficacy Analysis 
• 
Progression-free survival rate (PFSR): Efficacy measured by the PFSR at 6 months 
according to RECIST 1.1. PFSR at 6 months is defined as the percentage of patients who 
did not experience progression or death due to any cause since the first dose of 
experimental treatment until month 6 after treatment initiation.  
• 
Overall survival (OS): OS is defined as the time between the date of first dose and the 
date of death due to any cause. OS will be censored on the last date a subject was known 
to be alive. 
• 
Overall Response Rate (ORR): ORR is defined as the number of subjects with a Best 
Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) divided 
by the number of response evaluable subjects (according to RECIST 1.1 criteria). 
• 
Efficacy measured through tumor response according to Choi criteria. The evaluation 
criteria will be based on the identification of target lesions in baseline and their follow-up 
until tumor progression.  
• 
Clinical outcomes of post protocol treatments assessed by observation of such treatments 
in follow-up stage. 

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13.6 Safety Analysis 
13.6.1 
Adverse Events 
 
The safety profile of the experimental treatment will be analyzed through assessment of 
adverse event type, incidence, severity, time of appearance, related causes, as well as 
physical explorations and laboratory tests. Toxicity will be graded and tabulated by using 
CTCAE 5.0. 
Adverse Events (AEs) will be coded using the MedDRA dictionary and displayed in tables and 
listings using System/Organ/Class (SOC) and Preferred Term.  
Analyses of AEs will be performed for those events that are considered to be treatment 
emergent AEs (TEAEs), defined as any AE with onset or worsening of a pre-existing condition 
on or after the first administration of study treatment through 30 days following last dose or 
any event considered drug-related by the investigator through the end of the study. AEs with 
partial dates will be assessed using the available date information to determine if treatment-
emergent; AEs with completely missing dates will be assumed to be treatment-emergent.  
AEs will be summarized by patient incidence rates. In all tabulations, a patient may contribute 
only once to the count for a given AE preferred term.  
The number and percentage of patients with TEAEs will be summarized, as well as the 
number and percentage of patients with TEAEs assessed by the Investigator as at least 
possibly related to treatment. The number and percentage of patients with any Grade ≥ 3 
TEAE will be tabulated in the same manner. In the event a patient experiences repeated 
episodes of the same TEAE, the event with the highest severity and/or strongest causal 
relationship to study treatment will be used for purposes of tabulations.  
Serious AEs (SAEs) will also be tabulated.  
No formal hypothesis-testing analysis of AE incidence rates will be performed.  
All AEs (treatment emergent and post-treatment) will be listed in patient data listings.  
Separate by-patient listings will be provided for the following: patient deaths, SAEs, and AEs 
leading to withdrawal.  
 
13.6.2 
Laboratory Data  
The actual value and change from baseline for each on study evaluation will be summarized 
for each clinical laboratory parameter, including hematology and clinical chemistry, by arm, 
and for all study patients combined. In the event of repeat values, the last non-missing value 
per study day/time will be used.  
Severity of select clinical lab measures will be determined using CTCAE criteria (i.e. 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 values relative to CTCAE classification ranges will be produced.  
 

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13.6.3 
Vital Signs and Physical Examinations  
The actual value and change from baseline to each on-study evaluation will be summarized 
for vital signs for all study patients combined. By-patient listings of vital sign measurements 
will be presented in data listings.  
Physical examination results at screening will be summarized; all other abnormal physical 
examination data will be recorded. All examination findings will be presented in a data listing.  

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14 ADMINISTRATIVE MATTERS 
14.1 
Regulatory and Ethical Compliance  
This clinical study was designed and will be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice (GCP). Applicable local 
regulations, including European Regulation (EU) No 536/2014 on clinical trials on medicinal 
products for human use, repealing Directive 2001/20/EC, and the ethical principles outlined 
in the Declaration of Helsinki will be followed. 
14.2 Ethics Committees 
The protocol, the proposed ICF, and any amendment must be reviewed and approved by a 
properly constituted ethics committee (e.g. IRB/IEC/REB) before proceeding to use these 
documents. 
This study will be performed according to the Ethic Principles originated in The Declaration of 
Helsinki adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and  
amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975; 35th WMA 
General Assembly, Venice, Italy, October 1983; 41st WMA General Assembly, Hong Kong, 
China, September 1989; 48th WMA General Assembly, Somerset West, Republic of South 
Africa, October 1996, and the 52nd WMA General Assembly, Edinburgh, Scotland, October 
2000, clarification note of paragraph 29, added by WMA, Washington 2002, Clarification note 
of paragraph 30, added by WMA General Assembly, Tokyo 2004, 59th General Assembly, 
Seoul, Korea, October 2008 (Annex XII), 64th General Assembly, Fortaleza, Brazil, (October 
2013) and the Good Clinical Practice issued by the work group of Efficacy of Medicinal 
Substances of the European Community (1990) (CPMP/ICH/135/95) and all legal 
requirements and laws of each country participating in the Clinical Trial. 
14.3 Regulatory Authority Approval 
Before implementing this study, the protocol must be approved by relevant, competent 
regulatory authorities. 
14.4 Protocol Adherence  
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 the instructions and procedures 
found in this protocol and to give access to all relevant data and records to the drug supplier, 
Quality Assurance representatives, designated agents of the Sponsor-Investigator, ethics 
committees, and regulatory authorities as required. Investigators attest they will apply due 
diligence to avoid protocol deviations. All significant protocol deviations will be recorded and 
reported in the clinical study report (CSR). A significant protocol deviation is defined as any 
change to the execution of the protocol that affects the scientific integrity or design of the 
study, or the rights, safety or welfare of study patients. 
14.5 Amendments to the Protocol  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be provided by the Sponsor-Investigator, reviewed/approved by the drug supplier, and 

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approved by Health Authorities where required, and the ethics committee (e.g. IRB). Only 
amendments that are required for patient safety may be implemented prior to ethics committee 
(e.g. IRB) approval. Notwithstanding the need for approval of formal protocol amendments, 
the Investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, the Sponsor-Investigator should be notified of this action and the ethics committee 
(e.g. IRB) at the study site should be informed according to local regulations but not later than 
10 working days. 
14.6 Informed Consent 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law, ethics committee [e.g. IRB], or regulation), ethics committee (e.g. IRB)-
approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures. Note 
age on date consent is signed. Procedures that are part of the clinical routine evaluations 
during the initial diagnostic work-up of the patient may be performed before the ICF is signed 
and dated (i.e. procedures that are not specific to the conduct of the study). 
Informed consent must also be obtained for patients before conducting any study-specific 
procedures for treatment. 
The process of obtaining informed consent should be documented in the patient source 
documents. A copy of the ICF must be given to the patient or to the person signing the form 
on behalf of the patient. The Investigator or designee must record the date when the study 
ICF was signed in the medical records of the patient. The name and role of the witness, if 
required, should also be documented. 
The Sponsor-Investigator will provide to the drug supplier, in a separate document, a 
proposed ICF that is appropriate for this study and complies with the ICH GCP guideline and 
regulatory requirements.  
14.7 Patient Confidentiality and Disclosure 
The Investigator must ensure anonymity of all patients; patients must not be identified by 
names in any documents submitted to the drug supplier or its designee. Signed ICFs and 
patient enrollment logs must be kept strictly confidential. 
14.8 Collection, Auditing Study Documentation, and Data Storage 
14.8.1 
Study Documentation, Record Keeping and Retention of Documents 
Each participating site will maintain appropriate medical and research records for this study, 
in compliance with Section 4.9 of ICH E6 GCP, and according to the regulatory and 
institutional requirements.  
Source data include all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study.  
Data collection is the responsibility of the clinical study staff at the site under the supervision 
of the site Investigator. The study database is the primary data collection instrument for the 
study. The Investigator is responsible for the accuracy, completeness, and timeliness of the 

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data reported in the database and all other required reports. Data reported in the database, 
which are derived from source documents, should be consistent with the source documents 
or the discrepancies should be explained. All data requested on the source documents must 
be recorded. Any missing data must be explained. If electronic records are used, an audit trail 
will be maintained by the system, in compliance with 21 CFR Part 11. 
The Investigator/institution should maintain study documents as specified in 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 
15 years from the completion of the clinical study unless the 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. 
 
14.8.2 
Auditing Procedure 
Institution could be audited by GEIS and health authorities.  
GEIS will give notice with 3 weeks in advance to the site the auditing date and the planned 
agenda.  
14.9 Termination of the Study 
It is agreed that, for reasonable cause, either the Sponsor-Investigator or drug provider, may 
terminate the Investigator’s participation in this study after submission of a written notice. The 
drug provider may terminate the study at any time upon immediate notice for any reason 
including the drug provider’s belief that discontinuation of the study is necessary for patient 
safety. 
 
 

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15 DATA MANAGEMENT 
15.1 Electronic case report form (eCRF) 
In this protocol the term electronic case report form (e-CRF) refers to a web-based electronic 
data record in which the patient data will be collected.  
An e-CRF is required to be completed by each participating site for each recruited patient. 
Only duly authorized and trained staff of each center will be granted access to enter and 
modify data in the e-CRF. Staff in charge of e-CRF usage will be given a unique user name 
and password. 
The completed original electronic CRF files are the sole property of the Sponsor and should 
not be made available in any form to third parties, except for authorized representatives of the 
Sponsor or regulatory authorities, without written permission from the Sponsor. 
The investigators have the ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the e-CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic, attributable, complete, consistent, 
legible, timely, enduring and available when requested. The e-CRF must be signed 
electronically by the investigator or by an authorized staff member to attest that the data 
contained in the e-CRF is true. Any changes to entries made in the e-CRF will be tracked by 
an audit trail system that will identify the old and new values of the data fields, the person who 
made the change and the reason of modification (if necessary), thus not obscuring the original 
entry. 
The data will be recorded in the e-CRF GCP-compliantly at the study center. The e-CRF 
application is designed to be entirely server-based. All stages in the processing, with the 
exception of the actual data entry and display, are performed centrally on a web/database 
server. All the data will be stored in the central server. The server will be securely housed at 
a professional hosting provider hired by the study CRO in Spain, guaranteeing effective 
security and backup mechanisms.  
For data entry and print-outs, the e-CRF system is based fully on a web interface. Entry forms 
and reports are displayed on the client computer as HTML pages via any Web browser 
(Firefox 57+ and Chrome 75+). No additional software is necessary to operate the e-CRF on 
the investigator’s client computer (no plugin installations or software/hardware adaptations 
needed). The e-CRF is operating system independent (Win/Mac). 
The data will be checked for correctness by validity and consistency checks. Implausible or 
missing data can be corrected or supplemented following discussion with the investigator. All 
corrections will be tracked and stored by the audit trail system. 
Other than the investigator, only expressly authorized persons trained for the study may 
complete the e-CRF. Access control will be implemented by an auditable registry of user 
logins and logouts. Automatic session logouts will be implemented after predefined periods of 
inactivity for security reasons. The e-CRF will not show patient personal identification data 
(each subject will be identified by a unique trial number only). 
A comprehensive Data Management Plan will be developed by the study CRO specifying e-
CRF/Database design and data-related procedures and policies. 

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15.2 Record keeping 
To permit evaluations, audits and/or inspections from regulatory authorities or the Sponsor, 
investigators agree to keep records, including the identity of all participating patients (e.g. 
enough information to link records), all original signed informed consent documents, safety 
reporting forms, source documents and appropriate documentation of relevant 
correspondence (e.g. letters, meeting minutes, telephone call reports). The records should be 
kept by the investigator according to International Conference on Harmonisation (ICH) and 
local regulations. In case an investigator becomes unable for any reason to continue the 
retention of study records for the required period, the Sponsor should be prospectively 
notified. The study records must be transferred to a designee acceptable to the Sponsor. 
Investigators must receive the Sponsor’s written permission before disposing of any records. 
 
 
 
 
 

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Appendix 1 
Eastern Cooperative Oncology Group Performance 
Status Criteria 
ECOG Performance Status Scale39 
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 2 
Nausea management recommendations 
Primary prophylaxis 
 
• 
Ondansetron 8mg (or another inhibitor, according to standard of care): Its 
administration is recommended 30-60 minutes before each selinexor dose. Then, it is 
recommended to take it every 8 hours during the following 2-3 days (extend or shorten 
the interval according to patient’s tolerance). 
• 
Olanzapine 2.5 mg: Its administration is recommended once per day (preferably at 
night). It is permitted to take it the day before selinexor administration. Maintain daily 
or intermittent dose according to patient’s tolerance. If nausea are under control only 
with ondansetron, olanzapine can be interrupted. 
 
Optional 
• 
Metoclopramide: 10 mg every 6-8 hours can be added. 
• 
Dexamethasone: It can be added on day 1 and 8 with gemcitabine administration 
according to standard of care. It is not mandatory and to limit administration days is 
recommended.