Clinical trial NCT03193437
Conditions: Thymoma Advanced Thymic Epithelial Tumor
Keywords: Thymus Selinexor KPT-330
Sponsor: Georgetown University
Start date: 2018-04-03; Completion date: 2022-01-31
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety, tolerability and effectiveness of selinexor in patients with advanced thymic epithelial tumor progressing after primary chemotherapy. This is a multicenter, open label phase II trial that uses a Simons two stage design. The study population is adults with histologically confirmed, advanced, inoperable TETs who are progressing after treatment with at least one platinum containing chemotherapy regimen.

This study is comprised of 2 similar phase II trials, one running in US (25 patients) and one running in EU (25 patients):

There are two study arms:

Arm A: Thymoma

* Stage 1: 15 patients
* Stage 2: 10 patients

Arm B: Thymic carcinoma

* Stage 1: 15 patients
* Stage 2: 10 patients

Detailed description:

Arms: arm 1: Open Label Selinexor 40 mg
Interventions: intervention 1: Open Label Selinexor
Intervention descriptions: intervention 1: Selinexor 40 mg oral tablets will be administered twice weekly, either on Monday/Wednesday, Tuesday/Thursday, Wednesday/Friday, Thursday/Saturday, or Friday/Sunday in a 3-weeks-on and 1-week-off schedule.

Protocol documents:
Prot_SAP_000.pdf: 
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PROTOCOL NUMBER: 2016-0622 
PROTOCOL TITLE: A phase 2, open-label, investigator sponsored study of selinexor (KPT-330) in patients 
with advanced thymic epithelial tumor (TET) progressing after primary chemotherapy (SELECT) 
Sponsor-Investigator: 
Chul Kim, MD  
 
 
Georgetown Lombardi Comprehensive Cancer Center 
 
 
3800 Reservoir Rd. NW 
 
 
LCCC 2nd Level Podium B 
 
 
Washington, DC 20007 
 
 
Phone: (202) 444-1285 
 
 
 
 
 
Email: chul.kim@gunet.georgetown.edu 
 
Sub-Investigator(s): 
Stephen Liu, MD 
 
 
Georgetown Lombardi Comprehensive Cancer Center 
 
 
3800 Reservoir Rd. NW 
 
 
LCCC 2nd Level Podium D 
 
 
Washington, DC 20007 
 
 
Phone: (202) 444-3958 
  
 
 
Email: Stephen.V.Liu@gunet.georgetown.edu 
 
 
 
Deepa Subramaniam, MD 
 
 
Georgetown Lombardi Comprehensive Cancer Center 
 
 
3800 Reservoir Rd. NW 
 
 
LCCC 2nd Level Podium B 
 
 
Washington, DC 20007 
 
 
Phone (202) 444-2144 
 
 
Email: DSS26@gunet.georgetown.edu 
 
 
 
Martin E. Gutierrez, MD 
 
 
Director, Drug Discovery/Phase I Unit 
 
 
John Theurer Cancer Center/Hackensack University Medical Center 
 
 
92 Second St.  
 
 
Hackensack, NJ 07601 
 
 
Phone (551) 996-5499 
 
 
Email: MartinGutierrez@hackensackumc.org 
 
 
 
 
Biostatistician: 
Ming Tan, PhD 
 
 
Georgetown University Medical Center 
 
 
4000 Reservoir Rd. NW 
 
 
Building D-180 
 
 
Phone: (202) 687-2511 
 
 
Email: Ming.Tan@georgetown.edu 
 
Study Drug:  
Selinexor (KPT-330) 
IND Number:  
132625 
IND Holder Name: 
Chul Kim, MD 
 
Drug Supplier/Partial Funding Source:                  Karyopharm Therapeutics, Inc. 
 
 
 
 


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Current version: Final version 3.0, 5/11/2020 
Initial version:  
Version 1.0 4/16/2016 
Amended: 
 
Version 2.0 10/17/2017 
 
 
Version 2.1 7/22/2018 
 
 
Version 2.2 10/04/2018 
 
 
Version 3.0 5/11/2020 
 
Sponsor: Lombardi Comprehensive Cancer Center at Georgetown University Clinical Research 
Management Office 
3900 Reservoir Rd. NW 
Pre-Clinical Sciences Building Suite LR-3  
 
Participating Sites: 
Lombardi Comprehensive Cancer Center - Georgetown University Medical Center 
John Theurer Cancer Center – Hackensack University Medical Center 
 
European Investigators: 
Gedske Daugaard, Dept of Oncology, Rigshospitalet, Copenhagen, Denmark 
Nicolas Girard, Service of Pulmonology, Les Hospital Civils de Lyon, Lyon, France 
Benjamin Besse, Institute Gustav Roussy, Villejuif cedex, France 
 
 


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SYNOPSIS 
Protocol no. 
3.0 
Protocol version (Date) 
May 11, 2020 
Title 
Selinexor in patients with advanced thymoma 
Detailed title 
A phase II study of selinexor (KPT-330) in patients with advanced thymic 
epithelial tumour (TET) progressing after primary chemotherapy. 
European Principal 
investigator 
Gedske Daugaard, Department of Oncology, Rigshospitalet, 
Copenhagen, Denmark 
Sponsor-Investigator 
Chul Kim, MD, Georgetown Lombardi Comprehensive Cancer Center, 
Washington, DC 
Sponsor 
Lombardi Comprehensive Cancer Center at Georgetown University  
Study design 
International, multicenter, open label phase II, Simons two stage 
design. 
Anticipated start date 
2018.01.01 
Duration of study 
24 month accrual and 6 months follow-up 
Total number of sites 
2 in the US 
Study population 
Adults with histologically confirmed, advanced, inoperable TETs who 
are progressing after treatment with at least one platinum containing 
chemotherapy regimen. 
Objectives 
 
Primary objective 
 
 
To determine the efficacy of selinexor in adults with TETs 
determined by overall response rate (RECIST 1.1) in patients with 
advanced thymomas progressing after primary chemotherapy 
Secondary objectives 
 
To determine the efficacy of Selinexor in adults with thymoma 
determined by overall response rate according to modified ITMIG 
response criteria 
 
To determine six months PFS of patients with thymoma treated 
with selinexor 
 
To determine overall survival of patients with thymoma treated 
with selinexor 
 
To evaluate exploratory biomarkers for prediction of response to 
selinexor in patients with thymoma 
 
To determine progression free survival in patients with advanced, 
inoperable thymoma treated with selinexor 
 
To evaluate safety and tolerability of Selinexor 
Planned sample size 
This study is comprised of 2 similar phase II trials, one running in US (25 
patients) and one running in EU (25 patients):  
 
Arm A: Thymoma 
 
Stage 1: 15 patients 
 
Stage 2: 10 patients (across all EU and US sites) 
 
Arm B: Thymic carcinoma (closed due to interim analysis) 
 
Stage 1: 15 patients 
 
Stage 2: 10 patients 
 
Inclusion criteria 
 
Histologically confirmed advanced TET (thymoma) 
 
Progression after Primary Chemotherapy 


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 
No more than two previous lines (Neoadjuvant or 
chemoradiotherapy will count as one line if disease progression has 
occurred within 6 months) 
 
Inoperable per local Investigator (Masaoka Stage III or IV) 
 
Progression after treatment with least one platinum containing 
chemotherapy regimen  
 
Measurable disease (RECIST 1.1) 
 
Age ≥18 years 
 
ECOG PS <2 
 
Patients must have recovered from the toxic effects of prior 
therapy at the time of initiation of the study drug unless toxicity is 
stable. 
 
A 4 weeks or five half lives interval from any investigational agents 
or cytotoxic chemotherapy to start of study is required (whichever 
is shorter) 
 
Signed informed consent 
 
Adequate bone marrow function and organ function: 
- 
Hematopoietic function: total white blood cell count (WBC) 
≥ 3000/mm³, absolute neutrophil count (ANC) ≥ 1500/mm³, 
platelet count ≥ 100,000/mm²; Hemoglobin > 9.0 gm/dL 
- 
Hepatic function: bilirubin < 1.5 times the upper limit of 
normal (ULN), ALT < 2.5 times ULN or ALT < 5.0 times ULN 
in the presence of liver metastases 
- 
Creatinine clearance  > 30 ml/min according to Cockcroft-
Gault 
 
Patients of childbearing potential must agree to use adequate birth 
control during and for 7 months after participation in this study 
Exclusion criteria 
 
No significant medical illness that in the investigator’s opinion 
cannot be adequately controlled with appropriate therapy or would 
compromise the patient’s ability to tolerate this therapy, including 
- 
Unstable cardiovascular function 
- 
Known active hepatitis A, B, or C infection; or known to be 
positive for HCV RNA or HBsAg (HBV surface antigen) 
- 
Markedly decreased visual acuity 
- 
Active infection requiring intravenous antibiotics 
 
Pregnancy or breast-feeding 
 
Symptomatic brain metastasis requiring corticosteroids 
 
Uncontrolled autoimmune disorders. Patients with autoimmune 
disorders under control on medication may be included. Patients 
with pure red cell aplasia may be included if haemoglobin levels are 
relatively stable on transfusions or medication 
 
Significantly diseased or obstructed gastrointestinal tract, 
malabsorption, uncontrolled vomiting or diarrhea or inability to 
swallow oral medications 
 
No dehydration of NCI-CTCAE grade ≥ 1 
 
Serious psychiatric or medical conditions that could interfere with 
treatment. 


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 
No history of organ allograft 
 
No concurrent therapy with approved or investigational anticancer 
therapeutics 
Treatment schema 
Patients will receive oral Selinexor 40 mg twice weekly (Monday/ 
Wednesday, Tuesday/ Thursday, or Wednesday/Friday). One cycle is 28 
days. Patients will be dosed 3 weeks on and one week off in 4 week-
cycles (6 doses/cycle). Treatment will continue until disease progression 
or the development of unacceptable toxicities or until deemed without 
benefit to the patient. 
Primary parameter 
 
Overall response rate according to RECIST 1.1 
Secondary parameters 
 
Overall response rate according to modified ITMIG response criteria  
 
Six months PFS 
 
Overall survival 
 
Common Terminology Criteria for Adverse Events (CTCAEs) version 
4.03 
Exploratory parameters 
 
Exploratory biomarkers in archived tissue samples (TBD) 
Study procedures 
 
CT scans after every 2 cycles of Selinexor 
 
Physical examination every 2 weeks for the first 2 cycles, then every 
4 weeks 
Randomisation procedure 
N/A 
Sample size calculation 
Simon's minimax design will be used. The following assumptions are 
used in each of the two arms:  
 
A response rate of 10 % is considered clinically irrelevant 
 
A response rate of 30 % is considered promising and clinically 
relevant 
 
Type one error rate: 0.05 
 
Power: 0.80 
In stage 1, 15 evaluable patients are to be included. If response 
according to RECIST 1.1 and/or ITMIG criteria is observed in 2/15 
patients in stage 1, accrual of 10 evaluable patients will continue in 
stage 2. If responses are observed in 5 out of 25 patients, the 
alternative hypothesis is accepted and Selinexor is considered active 
and appropriate for further evaluation. This is not an intention to treat 
(ITT) study and included patients who are not evaluable for response 
will be replaced. 
Planned interim analysis 
An interim analysis is planned after stage 1. Decision to go to stage 2 
will be made by a consortium with representatives from both EU study 
and US study and Karyopharm. In case 2 patients out of 15 patients 
derive clear clinical benefit according to a unanimous agreement 
among members of the consortium, a decision can be made to proceed 
to stage 2. Clear clinical benefit is defined as: non-progressive disease 
with improvement in tumor related symptoms and treatment is well 
tolerated. 


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FLOW CHART: SCHEDULE OF ASSESSMENTS DURING THE STUDY 
 
Screening 
Cycle  
1- 2 
Cycle ≥3 
EOT 
Visit 
EOS 
Visit 
 
< 28 days 
prior to 
start of 
therapy 
< 7 days 
prior to 
start of 
therapy 
Day 1 & 
15 
± 3 days 
Day 1  
± 3 days 
Off 
treat-
ment 
 
30 days 
± 7 days 
Visit window [days] 
Informed consent1 
x 
 
 
 
 
 
Inclusion and exclusion criteria 
 
x 
 
 
 
 
Demographics 
x 
 
 
 
 
 
Medical History2 
x 
 
 
 
 
 
Pregnancy test (if applicable)3 
 
x 
 
 
x 
 
Body height and weight4 
 
x 
x 
x 
x 
x 
Vital signs5 
 
x 
x 
x 
x 
x 
Physical examination and ECOG6 
X 
 
x 
x 
x 
x 
12-lead ECG 
x 
 
 
 
 
 
Hematology (CBC)7, 8 
 
x 
x 
x 
x 
x 
Complete Serum chemistry7,9 
 
x 
x 
 
x 
x 
Limited Serum chemistry10 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Assessment of disease status12 
x 
 
 
x 
x 
 
Selinexor Dispensing  
 
 
x16 
x 
 
 
Adverse events 
x 
x 
x 
x 
x 
x 
Concomitant Medication 
x 
x 
x 
x 
x 
x 
Obtain Archive Tumour biopsy 
tissue13 
 
x 
 
 
 
 
Ophthalmic exam14 
X 
 
 
 
 
 
Nutritional consultation15 
x 
 
 
 
 
 
Notes 
1 Prior to the first study-specific measures 
2 Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including start and stop dates, 
disease progression during or after therapy, as well as discontinuations due to intolerability or any other serious illness. 
3 Applicable for women of childbearing potential. Serum -HCG test within 7 days before the first dose of study drug. To be 
repeated by urine test, if date of first result exceeds the 7-day window 
4 Body height will be measured at screening only 
5 Vital signs: blood pressure, pulse and temperature 
6 Full physical examination for baseline and end of study visit. Physical examinations during the study should be symptom directed. 
7 Laboratory assessments do not need to be repeated on Day 1 if they were completed within the previous 7 days. 
8 Hematology: hemoglobin, hematocrit, mean corpuscular volume, white blood cell (WBC) count, WBC differential, neutrophils,  
platelets.  WBC differential may be automated or manual as per institutional standards. Reticulocytes may be done only when 
clinically indicated. Hematology will be repeated twice a week in case of severe (grade 3-4) neutropenia or thrombocytopenia. 
9 Complete Serum Chemistry for baseline, cycles 1&2 and end of study/treatment visit include Sodium, Potassium, Creatinine, 
Glucose, Calcium ion, Magnesium, ALT, AST, Alkaline Phosphatase, Total Bilirubin, LDH,  Albumin, TSH.   
10 Limited Chemistry including: Sodium, Potassium, Creatinine, Glucose, ALT, AST, Alkaline Phosphatase, Total Bilirubin   
12 Disease status will be measured once every two cycles with CT scan of chest and abdomen.  
13 Tumour tissue will be obtained pre-dose provided that the patient has available archival biopsy tissue.  
14 Full ophthalmic examination is required at Screening, and, if clinically indicated, during the study. Prior to dilation, best corrected 
visual acuity, slit lamp examination including tonometry, following dilation; fundoscopy and slit lamp to document lens clarity – if a 
cataract/lens opacity is seen during the examination, the cataract/lens opacity will be graded according to a Grade 1-4 system. 
15 Nurse/research nurse can provide this in person or via phone call. 
16 Dispensing only occurs at Day 1 of Cycle 1 and 2. 


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1 
Background and Rationale 
1.1 Background 
1.1.1 
Thymic Epithelial Malignancies 
Thymomas and thymic carcinomas (TC) are rare epithelial tumours of the thymus. Based on cancer registry 
data, the overall incidence of thymoma in the US is 0.13 per 100,000 person-years. Thymoma is exceedingly 
uncommon in children and young adults, rises in incidence in middle age, and peaks in the seventh decade 
of life.  
Although most thymomas have organo- typic features (i.e., resemble the normal thymus), TC are 
morphologically indistinguishable from carcinomas in other organs. Apart from their different morphology, 
TC and thymomas differ also in functional terms (TC, in contrast to thymomas, have lost the capacity to 
promote the maturation of intratumourous lymphocytes), have different genetic features, a different 
immunoprofile (most TC overexpress c-KIT, whereas thymomas usually do not), and different clinical 
features (TC, in contrast to thymomas, are usually not associated with myasthenia gravis or other 
autoimmune phenomena). Thus, although all the data suggest that the biology of thymomas and TC is 
different, in clinical practice, their therapeutic management up to now is similar [1]. However, thymic 
carcinoma are more often diagnosed at a later stage, are less often radically resectable and respond less 
well to standard chemotherapy. Overall survival of TC is inferior even in advanced stages. 
Histology 
Based on available current knowledge about the biology of these tumours, the World Health Organization 
(WHO) classification of thymic epithelial tumours separates thymomas from thymic carcinomas [1]. 
Thymomas are defined as neoplasms arising from or exhibiting differentiation toward thymic epithelial 
cells, usually with a variable component of non-neoplastic lymphocytes. All types of thymomas have the 
potential of metastasising and are hence malignant [2]. 
From a morphologic point of view, there are two major types of thymoma: in type A, the neoplastic 
epithelial cells have a spindle- or oval-shaped nucleus with a uniform bland cytology. In type B, the tumour 
cells have a predominantly round or polygonal appearance. Type B thymomas are further subdivided 
depending on the degree of atypia and the size of the lymphocyte component into B1 (richest in 
lymphocytes), B2, and B3 (richest in epithelial cells). Thymomas combining type A with type B features are 
designated AB [2, 3]. 


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Apart from their different morphology, type A, AB, and B thymomas also show differences with respect to 
molecular genetics, expression of immunohistochemical markers, such as MHC class II or AIRE 
(autoimmune regulator)[2-4], a different capacity to promote maturation of intratumoural lymphocytes, 
and different association with clinical autoimmune syndromes, such as myasthenia gravis (MG). Together 
with gene expression data, these findings have led to the unifying hypothesis that the different histologic 
thymoma subtypes may reflect different maturational stages of a thymic epithelial progenitor cell. 
In most published series, the predominant histologic subtypes are B2 and AB thymomas (each 20–35% of all 
cases), whereas type B1 and type A thymomas are more rare types (5–10% in most studies). For clinical 
purposes, thymomas can be stratified into two different risk groups: type A, AB and B1 thymomas in most 
retrospective studies pursued an indolent course with 5- and 10-year overall survival rates between 80 and 
100%. By contrast, type B2 and B3 thymomas are potentially aggressive tumours with a potential for distant 
metastases (approximately 15% of cases), usually to lung, liver, bone, and soft tissues. More frequently (up 
to 25% of cases in some series), these tumours show pleural dissemination. Lymph node metastases are 
rare. 
Thymic carcinomas by definition are malignant epithelial tumours with overt cytologic atypia, almost 
invariably invasiveness and lack the “organotypic” (thymus-like) features of thymomas. They are further 
subclassified into squamous cell, basaloid, lymphoepithelioma-like, neuroendocrine, and many other types. 
Squamous cell carcinoma is the most frequent subtype with a higher incidence in Asia than in western 
countries. The typical autoimmune phenomena seen in thymoma (e.g. MG, pure red cell aplasia) are usually 
not found in thymic carcinoma, although other paraneoplastic syndromes such as polymyositis can occur. In 
contrast to thymomas, thymic carcinomas may show metastasis to regional lymph nodes (mediastinal, 
cervical, and axillary). They frequently express CD117 (c-KIT), a helpful immunohistochemical feature, to 
differentiate thymic carcinomas from mediastinal metastases of carcinomas located elsewhere. 
Staging 
Thymomas are staged according to the Masaoka-Koga classification system according to involvement of 
adjacent structures and spread. Tumour extent is defined as follows [4]: 
 
Stage I: completely encapsulated 
 
Stage II: invasion by the second layer surrounding the tumour 
 
Stage III: direct invasion beyond the second layer 
 
Stage IV: Discontinuous progression 


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Invasion into the pleural cavity is preceded by breaching of anatomic barriers in the following sequence: 
capsule, mediastinal pleura, visceral pleura, and finally lung. On the other hand, when the tumour invades 
the mediastinum, it invades through the capsule, mediastinal adipose tissue, pericardium or great vessels, 
and finally heart. Accordingly, the second layer surrounding the tumour is either the mediastinal pleura or 
mediastinal adipose tissue. Stage IV disease is divided into two categories IVa and IVb. Stage IVa consists of 
serosal dissemination, i.e., involvement of the pleura and pericardium. Stage IVb consists of metastasis via 
lymphogenous and hematogenous routes. Accordingly, stage IVb includes cases with lymph node 
metastasis at any station. 
Patients with a high Masaoka-Koga stage have a worse prognosis [4]. A new WHO staging stystem is 
anticipated in 2016 [5]. 
Treatment 
Although the treatment of malignant thymomas and thymic carcinomas in daily clinical practice is similar, 
the available data suggest that their biology is different and that in fact they may also require different 
therapeutic approaches. Advanced thymomas and TC that cannot be completely resected require 
neoadjuvant or adjuvant systemic treatment, often in combination with radiotherapy. Cisplatin-based 
regimens, such as the PAC scheme (cisplatin, adriamycin, and cyclophosphamide) are most often used with 
response rates as first line therapy of 50%-80% [6-8]. Relapses or progressive disease can be expected to 
occur in 10 to 30% of all patients. In 20 to 30% of these patients, objective remissions can be achieved by 
cisplatin-based regimens after relapse-free intervals. Approximately 50% of patients with an advanced 
malignant thymoma or thymic carcinoma will be candidates for a—so far undefined— second-line 
treatment [1]. 
Initial studies of targeted treatment in thymoma have demonstrated disappointing results [9]. In thymic 
carcinoma, the multikinase inhibitor sunitinib achieved a response rate of 25% in a recently reported phase 
II trial [10]. Other targeted agents investigated in patents with TETs include EGFR targeted agents, HDAC 
inhibitor, antiangiogenic agents, IGFR targeted therapies and studies investigating PD-1/PD-L1 targeted 
agents are under development. 
1.1.2 
Nuclear Export 
Over 10 major tumour suppressor pathways have evolved in order to prevent the development and 
progression of neoplasia. The majority of the tumour suppressor (TSP) and growth regulatory proteins (GRP) 
mediating these pathways act in the cell nucleus downstream of signaling pathways. Accumulating data 
suggest that in order to maintain their malignant behaviour, neoplastic cells must inactivate most or all of 


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the known TSP and GRP pathways. Active nuclear export of TSP/GRP is one very efficient and rapid means of 
overcoming the normal cell cycle and genomic instability checkpoints mediated by these proteins.  
The majority of proteins > 40 kD and many RNAs require specific transporters in order to enter and exit the 
nucleus through the nuclear pore complex (NPC), and these transporters are known as importins or 
exportins, depending on their specific activity. There are seven known nuclear export proteins, exportins 1-
7. Exportin 1 (XPO1), also called chromosome region maintenance protein 1 (CRM1), is the major nuclear 
export protein in the cell and has found to be overexpressed in many types of cancer.  
XPO1 is the sole exportin responsible for the transport of most of the TSP and GRP out of the nucleus into 
the cell. 
 
Figure 1: XPO1 nuclear export cycle 
The regulation of TSP and GRP is normally tightly regulated by the cell in response to environmental signals. 
In order for cells to divide efficiently, ordered activation and inactivation of cell cycle control proteins is 
required. One of the most efficient means of altering a protein’s functions is simply to change the protein’s 
location. Because TSP and GRP mediate the majority of their control functions in the nucleus, the nuclear 
export of these molecules is an efficient means of inactivating them. Emerging data suggest that tumour cells 
take advantage of this by increasing XPO1 levels.  
XPO1 can be inhibited by the Selective Inhibitor of Nuclear Export (SINE) selinexor (see Section 1.1.3). 
Thereby, the nuclear retention of key TSP/GRP is forced and multiple TSPs/GRPs are enhanced, as shown in 
Table 1.  
 
 


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Table 1: XPO1 inhibition enhances multiple TSPs/GRPs 
Oncogenic Pathway 
TSP/GRP Enhanced by 
XPO1 inhibition 
Oncogenic Pathway 
TSP/GRP Enhanced by 
XPO1 inhibition 
AKT↑, PI3K↑, PTEN↓  
FOXO, p27 
CDK2-CyclinE-E2F1 
pRb, p27, p21CIP1 
deletion p53, MDM2↑ 
p21CIP1, p53, p14ARF 
NPM1 Mutation 
p53, p14ARF 
HER2, EGF-R 
FOXO, pRB 
c-Myc ↑ 
PP2A, p21CIP1 
p16INK4A↓ or p14ARF↓ 
pRB, p53 
Bcr-Abl 
PP2A, Abl 
mTOR↑ 
p53, p27, FOXO 
Bcl2 ↑, Bcl-xL ↑ 
p53, p16INK4A 
Wnt / ß-Catenin ↑ 
APC, HMGBP1 
Notch ↑ 
FOXO 
deletion pRb 
p27 
NF-êB ↑ 
I-қB 
  
For each of the major growth and tumour stimulating pathways found across the various cancers, XPO1 
appears to stimulate at least one counteracting pathway. This may explain the broad activity of XPO1 
inhibitors in vitro and in animal models. Similar data are now emerging in the ongoing clinical trials of 
Selinexor (KPT-330) in both solid tumours and hematologic malignancies. By activating a genome survey, 
TSP/GRP can “distinguish” between cancerous and normal cells, inducing apoptosis in the former, and 
maintain cell cycle arrest in the latter (until the XPO1 export block is released, see Figure 2): 
 
Figure 2: KPT-SINE (XPO1 inhibitors) induce distinct outcomes in normal and malignant cells 
 


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1.1.3 
Selinexor:  Mechanism of Action  
A brief summary of key aspects of the preclinical evaluation of selinexor is presented below.  Further 
detailed information is provided in the Investigator’s Brochure.  
Selinexor is an oral, first in class, potent, slowly reversible, covalent Selective Inhibitor of Nuclear Export 
(SINE™) that specifically blocks the karyopherin protein Exportin 1 (XPO1/Exportin 1), also called 
chromosome region maintenance 1 (CRM1).   
XPO1 is overexpressed 2-4 fold in all cancers studied to date.  XPO1 is an exclusive nuclear transporter for 
shuttling the major Tumour Suppressor Proteins (TSPs) and other growth regulators out of the nucleus.  
Since TSPs require nuclear localization to mediate their deoxyribonucleic acid (DNA) damage 
assessment/tumour suppressing functions, nuclear export leads to their functional inactivation.  In 
addition, many TSPs are degraded by the proteasome when they are transported to the cytoplasm.   
Blockade of XPO1 leads to marked accumulation of TSPs in the nucleus of all cells, leading to cell cycle 
arrest at the G1±G2 checkpoints.  Cells with damaged genomes – i.e., cancer cells – undergo apoptosis, 
whereas undamaged normal cells remain in cell cycle arrest until the XPO1 block is released.  Consistent 
with its activation of multiple TSPs, selinexor has shown broad anti-cancer activity in nonclinical murine 
xenograft, orthotopic, primagraft, and leukemograft models, largely independent of the resistance profile 
of the cancer cell line being investigated.   
A related SINE™ compound, KPT-335 (INN “verdinexor”), has shown potent oral single agent activity in dogs 
with spontaneous newly diagnosed or chemotherapy refractory Non-Hodgkin’s lymphomas (NHL, primarily 
diffuse large B-cell lymphoma (DLBCL) and some T-cell lymphomas) with a response rate of 31% at doses of 
25-30 mg/m2 (1.25-1.5 mg/kg) orally 2-3 times per week.  
Nonclinical studies indicated that the major side effects (dose limiting toxicities, DLTs) of SINE™ across all 
species are reduced appetite with anorexia-induced weight loss partially consistent with satiety induction.  
High calorie foods, appetite stimulants and glucocorticoids can mitigate weight loss in animals taking SINE™ 
XPO1 antagonists. 
In vitro experiments with continuous (~72 hour) exposure to selinexor demonstrated potent pro-apoptotic 
activity across a broad panel of tumour-derived cell lines and patient samples in culture including resistant 
cancers due to multiple factors, with the majority of 50% inhibitory concentration (IC50) values for 
cytotoxicity <800 nM and most hematologic tumour lines having IC50 values of 20 – 400 nM for selinexor.  
Moreover, selinexor demonstrated cytotoxicity in multiple myeloma (MM) and chronic lymphocytic 
leukemia (CLL) cells in the absence or presence of bone marrow stroma cells (BMSC).  In contrast, normal 


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cells typically underwent (or remained in) cell cycle arrest but were resistant to apoptosis-induction; 
cytotoxicity IC50 values were typically >5 µM. 
As noted above, selinexor had little effect on normal (nonmalignant) lymphocytes or other nontransformed 
cells, which correlated with the low incidence in animals of the typical side effects seen with most anti-
cancer therapies such as significant myelosuppression, alopecia, mucositis and other gastrointestinal (GI) 
dysfunction. 
1.1.4 
Selinexor:  Clinical Summary  
1.1.4.1 Clinical Pharmacokinetics and Pharmacodynamics 
Selinexor is orally bioavailable and exhibits dose-proportional exposure with moderate- to –high inter-
patient variability across a wide dose range of doses in patients with advanced hematologic malignancies or 
solid tumors. The elimination (terminal) half-life (t½) of selinexor is approximately 6 to 8 hours.  
Clinical pharmacodynamics (PDn) of selinexor have been studied in patients with advanced neoplasms, 
showing that XPO1 inhibition by selinexor leads XPO1 mRNA induction and nuclear retention of TSPs. 
Selinexor-induced nuclear localization of TSPs, including p53, p27, FOXO-1, and FOXO-3A, was evident in-
patient biopsies. Reduction in the proliferation marker Ki67, with increases in apoptotic markers, was also 
observed. 
1.1.4.2 Clinical Efficacy and Safety 
Results from ongoing clinical studies have shown that selinexor induces durable antitumor responses across 
a broad range of relapsed/refractory (R/R) hematologic and solid tumor cancers, which is consistent with its 
proposed mechanism of action. In general, these effects appear to be independent of tumor type or prior 
treatment(s). 
In Part 2 of the STORM study (KCP-330-012), a total of 123 patients with RRMM were treated with selinexor 
80 mg in combination with dexamethasone 20 mg. The ORR of the 122 patients in the efficacy population 
was 26.2%, which included 2 sCRs (both assessed as MRD negative), 6 VGPRs, and 24 PRs assessed by the 
IRC using IMWG criteria. The median time to first response was 4 weeks (range: 1 to 10 weeks). The median 
OS was 8.6 months overall, with patients who had ≥PR or ≥MR having a median OS of 15.6 months (both 
groups), compared with 1.7 months for patients with PD or NE). 
In the SADAL study (KCP-330-009), as of the cutoff date for the IB of 31 March 2019, the overall ORR was 
28.3%, with 13 CRs and 23 PRs, and the ORR was 33.9% and 20.6% for patients with the GCB or non-GCB 


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subtypes, respectively. The median DOR was 9.2 months. The median OS for all patients was 9.0 months, 
but median OS was not reached in responding (≥PR) patients. 
As of 31 March 2019, 3111 patients with hematologic or solid-tumor malignancies had received at least 1 
dose of selinexor; in addition, 115 patients received at least 1 dose of selinexor or blinded study treatment 
(ie, selinexor or placebo) to a total of 3226 patients. These 3226 patients include 2076 patients from 
Company-sponsored trials (CSTs; 1961 who received selinexor and 115 who received blinded study 
treatment), 1016 patients from ISTs who received selinexor, and 130 patients from the selinexor expanded 
access program (EAP) who received selinexor; and 4 patients who received selinexor through clinical trials 
sponsored by Ono Pharmaceutical Co., Ltd. Safety data from all CSTs, ISTs and the EAP are reviewed at least 
monthly by the Sponsor. 
Serious adverse events (SAEs) from all patients (CSTs, ISTs and the EAP) are collected in the Sponsor global 
safety database; cumulative summaries of SAEs through 31 March 2019 for all patients have been reviewed 
and quantified in Appendix 12 of the IB v 9. Summaries of clinical safety data including SAEs and adverse 
events (AEs) are provided in Section 5.4 in IB v 9. The most commonly reported treatment-emergent 
adverse events (TEAEs) in CSTs were nausea (65.1%), fatigue (57.9%), thrombocytopenia (52.1%), anorexia 
(includes MedDRA “decreased appetite”; 51.0%), anemia (42.3%), vomiting (38.2%), and diarrhea (36.0%), 
that were generally low-grade and reversible (Section 5.4.2 and Table 39 in IB v 9). TEAEs of 
thrombocytopenia and anemia, which can be higher grade, were reported primarily in patients with 
hematologic malignancies. In addition to safety results, efficacy (response and duration of disease control) 
results from ongoing clinical studies are included by cancer type in this IB update. An overview of ongoing 
CSTs (as of 31 March 2019, except where noted) is provided in Appendix 1 of IB v 9. Additional ISTs are 
ongoing and efficacy results from these studies are not discussed in this IB. Based on these preliminary 
efficacy and safety data, the Sponsor plans to continue the development of selinexor to treat a wide variety 
of malignancies, including diseases that are not currently mentioned in this IB. 
1.1.5 
Dosing rationale 
An analysis of Phase 1 patient data showed that patients receiving doses ≤60 mg stayed on study longer 
than patients receiving doses ≥65 mg (120 days vs 90 days).  In addition, a higher percentage of patients 
receiving 60 mg stayed on study ≥4 months as compared to patients receiving doses ≥65 mg (27% vs 19%).  
The 60 mg dose was associated with maximal responses (CR, PR, SD).  These data supported 60 mg as the 
RP2D when the current study originally was designed. However, tolerability seems poorer than expected 
among the first 16 patients included in total in the EU and US studies. Either dose reductions or 
discontinuation of treatment due to toxicity have been necessary in ten out of 16 patients and 


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consequently most patients have been treated at 40 mg twice weekly for three weeks in a four week 
schedule. In general, toxicities resulting in dose reductions were typically nausea, vomiting, loss of appetite 
and fatigue followed by grade 4 thrombocytopenia (n=1) and severe pneumonia. Based on these data, the 
starting dose going forward will be 40 mg twice weekly.   
Recent analysis of the existing PK data from Phase 1 trials KCP-330-001 and KCP-330-002 supports the use 
of fixed rather than BSA-based dosing.   The 5th and 95th percentile for BSA values encountered to date in 
Phase 1 trials KCP-330-001 and KCP-330-002 are 1.5 and 2.3 m2, respectively (N=331). PK values (Cmax and 
AUC(0-∞)) for a given flat (fixed) dose of selinexor were similar across this typical BSA range, indicating 
that exposure is not strongly correlated with BSA. 
 
Currently the dosing schedule for selinexor in phase II trials is twice weekly (Day 1 and 3) during each week.   
This schedule is supported by pharmacodynamics studies showing selinexor binding to its XPO1 target 
persisted for at least 48 hours.   A dosing regimen of 10 doses per Cycle (3 doses during weeks 1 and 3, 2 
doses during weeks 2 and 4) was evaluated in Phase 1 studies and found to be less tolerated than the twice 
weekly (8 doses per Cycle) regimen, supporting the use of the twice weekly dosing regimen as the 
preferred regimen (Chen C et al, ASH 2015). 


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1.1.6 
XPO1 and Selinexor in Thymic Epithelial Tumours 
XPO1/CRM1 is overexpressed in many tumour cells including pancreas, prostate and gastric cancers, 
glioma, osteosarcoma, myeloma, AML and lymphoma. Expression of XPO1/CRM1 in TETs are not well 
characterised. However, both RB and P16INK4 have been implicated in TETs [11]. Selinexor enhances the 
nuclear presence of these proteins, where phosphorylated RB lead to G1→S block. 
Furthermore, TETs seems to be largely dependent on alterations in the BCL-2 family (BCL-1 and BCL-xl), and 
FOXC1. Copy number variations in the BCL-2 family and FOXC1 seems to be frequent and correlated with 
poor prognosis [12-14]. 
1.2 Study Rationale 
So far, four patients with advanced TETs have been treated with selinexor in phase I trials. Metabolic 
response was noted in a patient with squamous thymic carcinoma previously treated with two lines of 
chemotherapy and radiotherapy. Structural tumour shrinkage and metabolic responses were seen in two 
patients. A patient with recurrent type B2 thymoma achieved a 15 % reduction in tumour measurements 
that was sustained for 20 months. A partial response of 44 % was achieved in a patient with type B1 
thymoma who had progressed after multiple surgery, radiotherapy and two lines of chemotherapy. The 
fourth patient remains on study for 10 months with stable disease. 
Available data suggest that TETs may be dependent on the activity of only few oncogenic pathways 
including BCL-2 family and inactivation of few tumour suppressors including FOXC1 and RB. TETs are usually 
described as tumours with few genetic alterations and therefore little redundancy. This makes them 
theoretically very susceptible to activation of tumour suppressors and more unlikely to develop resistance. 
Selinexor has shown retention of tumour suppressors to the nucleus, which are capable of reverting the 
malignant phenotype of cells harbouring these alterations, making selinexor a possible active drug in these 
tumours. Furthermore, studies in cell lines have shown activity of selinexor in TETs (unpublished data). 
2 
Study Objectives 
2.1 Primary Objectives 
The aim of the study is to determine the efficacy of selinexor in adults with TETs determined by overall 
response rate (RECIST 1.1) in two parallel cohorts of patients with advanced thymomas progressing after 
primary chemotherapy. 
2.2 Secondary Objectives 
Secondary objectives of the study are 


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 
To determine the efficacy of Selinexor in adults with TETs determined by overall response rate 
according to modified ITMIG response criteria. 
 
To determine the overall response rate of selinexor in patients with advanced thymomas. 
 
To determine six months PFS of patients with TET treated with selinexor. 
 
To determine overall survival of patients with TET treated with selinexor. 
 
To evaluate exploratory biomarkers for prediction of response to selinexor in patients with TET. 
 
To determine progression free survival in patients with advanced, inoperable TETs treated with 
selinexor 
 
To evaluate safety and tolerability of Selinexor. 
3 
Investigational Plan 
3.1 Study Design and Dosing Regimen 
3.1.1 
Definition of Treatment Cycle 
One cycle is defined as 28 days. Selinexor 40 mg oral tablets will be administered twice weekly, either on 
Monday/Wednesday, Tuesday/Thursday, Wednesday/Friday, Thursday/Saturday, or Friday/Sunday in a 3-
weeks-on and 1-week-off schedule. Patients will receive a supply of selinexor tablets for at-home dosing.  
Study drug administration may be delayed for toxicity according to protocol Section 6.3.  
3.1.2 
Treatment Duration 
Patients will discontinue treatment with selinexor if one of the following events should occur  
 
Progression of disease demonstrated by CT scan according to RECIST 1.1 
 
Clinical progression in the opinion of the investigator 
 
Unacceptable toxicities 
 
Patient’s request to discontinue  
 
The investigator considers it in the patient’s best interest to discontinue treatment.  
Details of the study schedule are illustrated in the study flow chart. 
3.1.3 
End of Treatment Visit 
Patients who discontinue treatment will be encouraged to undergo an end-of-treatment visit unless they 
have withdrawn consent to participate in the trial. 


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3.1.4 
Follow-Up Phase 
Patients who discontinued for reasons other than progression of disease (and withdrawal of consent for 
participation in the trial) should be encouraged to attend an End-of-Study visit 30 days after 
discontinuation of treatment and to visit the clinic for clinical evaluation of their disease every 4 weeks and 
assessment by CT scan every 12 weeks until disease progression. If the patient is in follow-up and/or 
treated post-study, the clinical evaluation can be done by the treating physician and the patient need not to 
visit the site. After disease progression all patients will be evaluated for survival and further therapy by 
reviewing their medical charts regularly.  
4 
Study population 
4.1 Target Population 
Adults with histologically confirmed, advanced, inoperable TETs who are progressing after primary 
chemotherapy. 
4.2 Inclusion Criteria 
Please refer to the synopsis. 
4.3 Exclusion Criteria  
Please refer to the synopsis. 
5 
Schedule of Assessments and Procedures 
Please refer to the Schedule of Assessments at the end of the synopsis for an overview. 
Data will be collected via the completion of a Case Report Form (CRF) for each enrolled patient. The 
investigator should confirm eligibility of the patient according to the inclusion and exclusion criteria of the 
study. Written Informed Consent must be obtained before any study specific assessment is performed. A 
study specific assessment is defined as a procedure that is not part of the routine assessments performed 
for diagnostic purposes or standard care. Screening assessments should occur within 28 days of the first 
administration of study drug. Patients who do not meet the eligibility criteria will not be enrolled in the 
study. Patients should receive their first dose of study treatment as soon as possible after registration, but 
not later than 7 days after registration. 


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5.1 Study Assessments 
5.1.1 
Tumour Assessment 
The disease status will be measured by CT scans and response will be assessed according to RECIST 1.1. 
Only patients with measurable disease will be enrolled. Furthermore, disease status will be evaluated 
according to ITMIG response criteria. 
The baseline CT scan must be recorded and measured within 28 days prior to treatment start. A CT scan 
performed as part of standard of care can be used as the baseline CT scan provided study treatment will 
start within the 28-day window. 
Patients are evaluated for surgery as per institutional standards. 
5.1.2 
Translational and pharmacodynamics (PDn) analyses 
Tumour Biopsies 
Archived Tumour tissue may be obtained from before the first dose. Tissue may be tested for levels of 
expression and cellular localization (nuclear/ cytoplasm) of biomarkers of response including XPO1; 
representative XPO1 cargos such as: P53, SURVIVIN, FOXO1; markers of direct-tumour response such as the 
proliferation marker Ki-67 and the apoptotic marker Cl. Casp3 and potential predictive biomarkers by 
immunohistochemistry.  
Tumour tissue obtained before treatment should be available as paraffin embedded-formalin fixed sample. 
Tumour samples may be stained by OHC for XPO-1 antibody and protein expression will be quantified. XPO-
1 expression will be correlated with response to treatment. 
Samples  collected may be sequenced using NEXTGEN technology on our recently acquired Miseq 
sequencer (Georgetown University). Patients who have no available tissue will be eligible for the trial. A 
custom-designed cancer-associated gene panel which includes all the identified recurrent mutations in 
thymic carcinomas, published cancer driver genes and COSMIC cancer gene census 
(http://cancer.sanger.ac.uk/cosmic/census) will be used for targeted sequencing [15-17]. Comparative 
sequencing analysis of the tumour/blood pairs will allow us to identify specific somatic mutations and the 
number of somatic mutations in a given tumour. In addition, samples may be sequenced for the 
identification of mutations in DNA damage repair genes such: ATM, ATR, BRCA1, BRCA2, CHEK1, CHEK2, 
FAM175A, GEN1, MRE11A, MSH2, MSH6, NBN, PALB2, PMS2, RAD51, ERCC1, MLH1. The data will be 
employed to evaluate the correlation between the type/number of mutations and patients’ response to 
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All biopsy-related studies will be performed at Georgetown Lombardi Comprehensive Cancer Center. 
5.1.3 
Safety and Tolerability Assessments 
Safety will be monitored by assessing physical examinations including vital signs and weight, performance 
status, concomitant medication use, and laboratory parameters. Information regarding AEs will be 
collected and each AE will be graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE v 4.03) beginning at day of first administration of study drug, throughout 
the treatment period and to the extent possible until 30 days after last dose of study drug. 
5.1.4 
Laboratory Assessments 
The standard clinical laboratory analysis is to be performed by the study site’s local laboratories according 
to the Schedule of Assessments. More frequent examinations may be performed at the investigator’s 
discretion if medically indicated; results should be recorded on the eCRFs. At any time during the study, 
abnormal laboratory parameters that are clinically relevant (e.g. interruption or delay of study treatment or 
require therapeutic intervention) must be recorded in the CRF. When abnormal laboratory values or test 
results constitute an adverse event, they must be recorded on the CRF Adverse Events page. Every effort 
must be made to follow the schedule outlined in the Schedule of Assessments.  
5.2 Study Procedures 
5.2.1 
Screening Procedures 
All patients will be screened and screening procedures must be performed within 28 days prior to the start 
of study treatment unless otherwise stated in FLOW CHART: SCHEDULE OF ASSESSMENTS DURING THE 
STUDY. 
Please refer to FLOW CHART: SCHEDULE OF ASSESSMENTS DURING THE STUDY in the end of the synopsis 
for details on screening procedures. 
5.2.2 
Treatment Phase 
Please refer to FLOW CHART: SCHEDULE OF ASSESSMENTS DURING THE STUDY in the end of the synopsis. 
5.2.3 
End of Treatment and End of Study 
Patients who discontinue therapy for any reason other than withdrawal of consent will be encouraged to 
have an End of Treatment (EOT) and End of Study (EOS) visit at the day they are withdrawn from study and 
30 day after EOT, respectively. At the EOT and EOS visits, the patients will undergo safety assessments 
according to the FLOW CHART: SCHEDULE OF ASSESSMENTS DURING THE STUDY in the end of the synopsis. 


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5.2.4 
Follow-up before progression of disease 
For patients who discontinued for reasons other than progression of should be encouraged to visit the 
clinic for clinical evaluation and CT evaluation every three months for the first year, then every 6 months 
until progression of disease is determined. 
5.2.5 
Survival Follow-up 
After disease progression all patients will be evaluated for survival and document subsequent anticancer 
therapy by reviewing their medical charts every 3 months. Patients who have not expired by the data 
analysis cut-off date will be censored at their last date known to be alive. 
5.2.6 
Completion of Study 
The study will be completed when the last patient has died or all patients have completed EOT and have 
been followed for at least 6 months after their last dose of study drug, or have been lost to follow-up, or 
withdrew consent, whichever occurs first. 
5.3 Planned Treatment of the Patients after End of Treatment Phase 
After completion of the End of Treatment visit, patients will be treated at the discretion of the investigator 
according to standard medical routine. 
5.4 Removal of Patients from Treatment 
Patients will be free to discontinue treatment or withdraw from the study at any time, for any reason, or 
they may be withdrawn/removed if necessary in order to protect their health (see reasons for withdrawal 
below). It is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawal of patients should be avoided. 
Patients will be removed from further treatment for the following reasons: 
 
Disease progression 
 
Non-compliance 
 
Patient no longer consents to participate in the study 
 
Illness that interferes with study assessments 
 
The patient undergoes radical surgery 
 
Incidence or severity of AEs in this study indicates a potential health hazard to the patient 
 
Investigator discretion for any reason 
 
Pregnancy 
 
Termination of the study by the sponsor 


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If a patient has failed to attend scheduled assessments in the study, the investigator must determine the 
reasons and circumstances as completely and accurately as possible. 
In case of premature discontinuation of the study treatment, the safety evaluation for the EOT should be 
performed, if possible. The CRF section entitled “End of Treatment” must be completed in all cases. Should 
a patient decide to withdraw, every effort will be made to complete and report the observations as 
thoroughly as possible. A complete final evaluation at the time of the patient’s withdrawal should be made, 
with an explanation of why the patient is withdrawing from the study. If the reason for removal of a patient 
from the study is an adverse event or an abnormal laboratory test result, the principal specific event or test 
will be recorded on the CRF. 
5.5 Study Discontinuation 
The study may be discontinued at the discretion of the sponsor in the event of any of the following: 
 
Medical or ethical reasons affecting the continued performance of the study 
 
Difficulties in the recruitment of patients 
6 
Investigational medicinal product (IMP) 
The IMP in this study is selinexor. 
6.1 Preparation and Administration of Selinexor 
6.1.1 
Preparation and Administration of Selinexor 
The investigator or responsible site personnel must instruct the patient or caregiver to take the study drug 
as per protocol.  
Tablets, including instructions for administration, are dispensed by study personnel on an outpatient basis. 
Patients will be provided with an adequate supply of study drug for self-administration at home until at 
least their next scheduled study visit. 
6.1.1.1 Drug Name, Formulation and Storage 
Drug name: Selinexor (KPT-330)  
Formulation: Tablets. Selinexor will be supplied and administered as coated, immediate-release oral tablets 
in a strength of 20 mg tablets in wallet-sized blister packs.  
Storage: Do not store above 30°C. Do not freeze. Store in a locked and secured area with access restricted 
to the site staff pharmacist or designee(s). Selinexor tablets are currently in on-going stability studies. The 


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expiry will be based on concurrent stability studies and extended during the course of the study as further 
stability data becomes available. 
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic 
agent in a self-contained and protective environment. 
Availability 
Selinexor is an investigational agent and will be supplied free-of-charge from Karyopharm Therapeutics, Inc. 
Preparation 
No special preparation required. 
NOTE: Tablets of selinexor should not be crushed because of increased risk of dermatologic toxicity if 
powder comes in contact with skin. 
Administration 
Selinexor will be provided as tablets to be administered by mouth. Selinexor is to be taken within 30 
minutes of solid food consumption together with at least 120 mL (4 ounces) of fluids (water, milk, etc.). 
Ordering 
Drug order forms with all the needed contact information will be provided at the start of the trial, along 
with recommended initial and resupply stock orders. Orders submitted via e-mail will be filled within 7-10 
business days of receipt.  
Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent (investigational or free of charge) using the NCI Drug 
Accountability Record or another comparable drug accountability form. (see the Cancer Therapy Evaluation 
Program [CTEP] website at http://ctep.cancer.gov/ protocolDevelopment for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the drug accountability form). 
Destruction and Return 


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At the end of the study, unused supplies of selinexor should be destroyed and documented according to 
institutional policies.  Copies of drug accountability records must be sent to Karyopharm Therapeutics, Inc. 
upon request and at the end of the trial. 
6.1.1.2 Route of Administration 
Selinexor tablets will be taken orally twice weekly, either on Monday and Wednesday or on Tuesday and 
Thursday or Wednesday and Friday in a 4-weeks cycle with dosing in weeks 1-3. Selinexor is to be taken 
with a solid food consumption together with a glass of water. Each dose will consist of flat dose 40 mg 
selinexor for oral administration. 
6.1.1.3 Compliance 
The investigator should ensure that the investigational product is used only in accordance with the 
protocol. The investigator/ designee will try to ensure complete compliance with the dosing schedule by 
providing timely instructions to the patients. The investigational product should be stored as specified by 
the sponsor and in accordance with applicable regulatory requirements. 
6.2 Supportive Care and Dose Reduction Guidelines 
6.2.1 
Clinical Supportive Care Recommendations 
Supportive measures for optimal medical care should be provided during participation in this clinical trial.  
Based on clinical observations in over 2500 adult patients treated with selinexor as of 31 Mar 2018, the 
main side effects are primarily related to anorexia with poor caloric and fluid intake, weight loss, fatigue, 
and nausea.  Thrombocytopenia also occurs, although it is rarely associated with bleeding.   
Besides 5-HT3 antagonists, supportive care including anti-nausea / anti-emetic therapy, per institutional 
guidelines and/or National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology 
(NCCN CPGO) should be utilized as clinically indicated at the discretion of the treating physician.  
Required 5-HT3 Antagonists  
Prophylactic therapy with 5-HT3 antagonists is required  for all patients initiating selinexor treatment on 
day of selinexor q 8 hours  and for 2 days post selinexor (see Nausea and Vomiting guidance in Section 6.1.2 
for additional details). In addition all patient should receive a second anti-emetic of olazepine 5 mg daily 
qhs.  
Particular attention should be paid to anorexia with poor caloric and fluid intake which can lead to weight 
loss, dehydration and fatigue. Supportive care per institutional guidelines and/or National Comprehensive 


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Cancer Network® Clinical Practice Guidelines in Oncology (NCCN) should be utilized as clinically indicated at 
the discretion of the treating physician.  
Supportive care recommendations based on the cumulative clinical experience with selinexor to date are 
presented in the following sections. Dose reduction guidance, including specific supportive care 
recommendations by AE grade, to address selinexor-related adverse events is provided in Table 3.  
Gastrointestinal and Constitutional Effects 
Nausea and Vomiting 
Nausea and vomiting are very common, occurring in the majority of patients who do not receive supportive 
care. All patients are required to receive prophylactic anti-emetics. Note: Patients are required to receive 
ondansetron 8 mg (or similar 5-HT3 antagonist) before their first dose of selinexor and continued 2 or 3 
times daily.  Additionally, olanzapine are required to be  given prior to the first dose of selinexor and 
continued qhs per NCCN Guidelines. Neurokinin-1 receptor antagonists (e.g., aprepitant) should also be 
considered in the event of uncontrolled emesis with standard treatments. Patients with severe nausea and 
vomiting early in their course may be experiencing significant anti-tumor response, and early response 
assessment should be considered. 
Anorexia (Decreased Appetite) 
In patients with problematic food/liquid/caloric intake secondary to anorexia, a patient log of food and 
drink should be considered and monitored by site staff. Maintaining adequate fluid intake is also of 
paramount importance, particularly in older patients whose thirst reflex may be attenuated. Fresh juices, 
simple carbohydrates, as well as ginger-containing foods and beverages can improve appetite; ginger 
containing foods may also improve dysgeusia. 
Patients should also receive dietary counselling and monitor both their caloric and fluid intake carefully. 
Dysguesia may contribute to the anorexia, and dietary adjustments can be helpful. It is strongly 
recommended that patients receive ongoing weight assessment and nutritional consultation. 
Administration of high caloric beverages (e.g., Boost®, Ensure®) and appetite stimulating agent(s) should be 
considered in patients who develop early signs of anorexia despite the required prophylactic therapy.  
A combination of appetite stimulating agents and anti-emetics is usually effective in managing selinexor 
associated anorexia that does not respond to the above interventions.  Appetite stimulating medications 
can be tapered in many patients in Cycle 1, but prevention of anorexia is much more effective than 
treatment once problems begin. Additional information on the management of anorexia is provided in the 
NCCN Guidelines.  


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Diarrhea 
Diarrhea associated with selinexor is typically low grade and usually responds to treatment with standard 
anti-diarrheal agents (e.g., loperamide) and/or dose modification. Careful assessment of the patient’s 
volume status is essential.  Fluid replacement is important to prevent dehydration, fatigue and electrolyte 
abnormalities (e.g., hyponatremia). 
Fatigue 
Prevention of anorexia, vomiting, and dehydration may reduce fatigue. Hemoglobin levels must be 
optimized as anemia appears to contribute substantially to fatigue, particularly in patients with heavily 
pretreated hematologic malignancies. Please see the NCCN Guidelines for more information. In patients 
with adequate anti-tumor control on selinexor, once-weekly dosing is often associated with improvement 
in fatigue and other side effects.  
Renal 
Maintenance of adequate volume status is essential to prevent creatinine increases and other renal effects 
observed in patients treated with selinexor.  Patients with acute increases in creatinine (usually 
accompanied by disproportionately higher elevations of BUN) should be evaluated for volume status and 
fluid intake as well as electrolyte levels.  Fluid repletion usually leads to resolution of creatinine increases in 
patients with dehydration associated with selinexor. 
Hematologic Effects 
Thrombocytopenia 
Selinexor may induce reductions in platelet counts, with minimal effects on numbers of megakaryocytes.  
The effects of selinexor on platelet generation are related to a slowing of maturation of megakaryocytes 
and a reduction in their average ploidy. There is no known effect on platelet function, and bleeding 
associated with low platelets has been uncommon. 
Interruption or dose reduction of selinexor therapy, when appropriate, may lead to return of platelet 
counts in 1-3 weeks.  See Table 3 for specific guidance for managing Grades 1-4 thrombocytopenia.   
Neutropenia 
Standard granulocyte growth factors are highly effective for the treatment of neutropenia seen during 
treatment with selinexor and should be used early in patients whose neutrophil counts decline during 


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treatment.  Patients should be instructed to report any symptoms or signs of infection such as fever, pain, 
sweating, and redness to their physician immediately. 
Anemia 
Selinexor-induced anemia may contibute to dizziness, confusion, syncope and/or fatigue, particularly in 
elderly patients and patients who are at greater risk of cognitive sequellae. Per NCCN Guidelines, treatment 
with RBC transfusions and/or growth factors, per institutional guidelines, should be considered for patients 
with symptomatic anemia.  
Other Adverse Events Observed during Studies 
Vision Blurred and Cataracts  
Patients reporting blurry vision or other visual changes should be evaluated by an ophthalmologist.  Nearly 
all cases of treatment emergent visual changes have not been associated with objective findings.  Changes 
in lens prescriptions and/or wetting drops may improve vision.  Blurred vision associated with selinexor use 
is typically self-limited, and dosing can usually be maintained at the same level and frequency. 
Patients who are at risk of cataract formation, or have cataracts present at baseline, should be monitored 
for changes in lens opacity. If changes in lens opacity are observed, the patient should be evaluated by an 
ophthalmologist. In selinexor clinical studies, several patients have undergone cataract surgery with 
minimal to no interruption of selinexor dosing and without complications. 
Hyponatremia 
Investigators should rule out the possibility of pseudo-hyponatremia due to elevated glucose (or 
monoclonal protein) levels. Abnormal serum sodium levels should be corrected. Adequate fluid and caloric 
intake, including electrolyte-rich beverages instead of plain water, has led to reversal of hyponatremia. 
Diuretic use should be addressed and possibly stopped, and salt supplements should be considered. If 
hyponatremia persists, cardiac, hepatic, adrenal, renal and thyroid disorders, along with the Syndrome of 
Inappropriate Antidiuretic Hormone Secretion (SIADH), and Fanconi syndrome should be ruled out.  
Infection 
Appropriate broad-spectrum intravenous antibiotics and antifungal agents should be started immediately 
in patients who develop fever or other signs of systemic infection. Selinexor should be suspended in any 
patient with Grade 4 infection or sepsis (even in the absence of documented infection) until the patient’s 
clinical condition is stabilized. Selinexor can then be re-started at the same dose once the patient’s clinical 
status has stabilized, even in the setting of continued intravenous antibacterial or other anti-microbial 


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agents (see section 6.1.3). Selinexor is not known to have any drug interactions with standard 
antimicrobials. 
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 2 for 
pre-specified dose modifications for AEs related to study treatment and see table 3 for dose reduction and 
interruption recommendations.  Please note, however, that investigators should refer to specific dose 
reduction and interruption guidance within each protocol for the most up-to-date recommendations for each 
study. 
While drug-related major organ toxicities are not prominent, there are a number of constitutional side effects 
(and thrombocytopenia) that can limit dosing with selinexor. Therefore, patients should also be treated with 
supportive care to reduce toxicities. 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 tumor lysis syndrome, but if suspected, assessment of tumor 
response is strongly recommended in order to better inform treatment recommendations. 
The CTCAE v 4.03 is used for grading the severity of AEs; the therapy modifications described in Table 3 below 
are applied according to this severity grading. Toxicity will be documented as described in Section 7. If more 
than 1 type of toxicity occurs concurrently, the most severe grade will determine the modification. 
Each dose modification or treatment delay, as well as the reason, must be documented.  
Tumour lysis syndrome 
As of 31 March 2019, selinexor treatment-emergent TLS has been reported in a total of 8 patients including 
6 SAEs. Four were from selinexor CSTs, 2 from IST, and 2 from EAP. 
These 8 cases of tumor lysis syndrome occurred in patients with heavily pretreated malignancies (including 
5 patients with MM, 2 patients with ALL, and 1 patient with AML). The intensity was reported as Grade 3 in 
5 cases and as Grade 4 in 3 cases. The outcome was reported as recovered in 4 patients and not recovered 
in 2 patients; and was not reported in 2 patients. Total selinexor dosage prior to the event onset ranged 
from 20 mg to 320 mg (median 160 mg) and event onset latency ranged from 3 to 8 days (median 4 days). 
Out of 4 cases of TLS reported in 4 CSTs, 2 patients (Studies KCP 330-001 and KCP-330-008) received 
selinexor only, 1 patient (Study KCP-330-012) received selinexor plus dexamethasone, and 1 patient (Study 


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KCP-330-017) received selinexor, dexamethasone, and pomalidomide. In the selinexor EAP, 1 patient 
received selinexor plus dexamethasone and the other patient received selinexor plus bortezomib and 
dexamethasone (administration dates for bortezomib and dexamethasone were not reported). 
Two patients from ISTs were reported receiving only selinexor. Treatment with selinexor was stopped prior 
to the event in 2 cases, withdrawn in 1 case, temporarily interrupted in 3 cases, and dose not changed in 2 
cases. 
Of the 8 cases summarized above, there were 3 cases with fatal events reported. The cause of death in 
each of these cases was reported as: 
• Grade 5 Respiratory failure secondary to advanced MM 
• Grade 5 Sepsis 
• Grade 5 Respiratory failure, chemotherapy (non-selinexor) induced cardiomyopathy, and ALL 
 No fatal outcomes due to TLS have been reported in any studies with selinexor, or in the ongoing 
selinexor EAP. 
As a causal relationship between selinexor treatment and the onset of TLS cannot be completed excluded, 
it was determined that TLS should be considered as an important potential risk for selinexor. 
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. 
 
 
 
Table 2. Pre-specified Dose/Schedule Modifications for Adverse Events Related to Study Drug  


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Dose Level 
Dose of Selinexor 
Dose level 0 (starting dose) 
40 mg twice weekly, 3 weeks on/1 week off  
Dose level -1 
20 mg day 1 plus 40 mg day 2, 3 weeks on/1 week off 
Dose level -2 
40 mg once weekly , 3 weeks on/1 week off 
Dose level -3 
20 mg once weekly, 3 weeks on/1 week off 
Dose level -4 
Discontinue Dosing 
 
6.2.2 
Dose Adjustment Guidelines for Selinexor Related Toxicities 
All selinexor related non-hematological toxicities except those mentioned in the table below should be 
handled as follows: 
Interrupt selinexor dosing in case of grade > 3 non-hematological toxicity and resume dosing when resolved 
to grade 1 or less. Reduce selinexor dose by one dose level. 
Table 3. Suggested Supportive Care and Dose Adjustment Guidelines for AEs Related to Selinexor 
(according to IB v 9) 
Adverse Event 
Occurrence 
Action 
Hematologic Adverse Events 
Thrombocytopenia 
Platelet count 25 × 109/L to 
<75 × 109/L 
Any 
 
Reduce selinexor by 1 dose level (see Table 2) 
 
Consider additional supportive care and 
discuss with Sponsor-Investigator 
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 (see Table 2) 
 
Consider additional supportive care and 
discuss with Sponsor-Investigator 
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 (see 
Table 2) 
 
Consider additional supportive care and 
discuss with Sponsor-Investigator 
Neutropenia 


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ANC 0.5 to 1.0 × 109/L 
without fever 
Any 
 
Initiate growth factor support 
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 (see 
Table 2) 
 
Initiate growth factor support 
Anemia 
Hb <8.0 g/dL 
Any 
 
Administer blood transfusions and/or other 
treatments per clinical guidelines 
 
Adverse Event 
Occurrence 
Action 
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 (see 
Table 2) 
 
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 (see Table 2) 
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 (see 
Table 2) 
Nausea and Vomiting 


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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 (see 
Table 2) 
Adverse Event 
Occurrence 
Action 
Diarrhea 
Grade 2 
First 
 Maintain selinexor and institute supportive care 
Second and 
subsequent 
 Reduce selinexor by 1 dose level (see Table 2) 
 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 (see 
Table 2) 
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 (see 
Table 2) 
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 (see 
Table 2) 
 


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Conditions Not Requiring  Selinexor Dose Reduction 
The following conditions are exceptions to the dose-modification guidelines. Selinexor does not need to be 
held for alopecia of any grade, or forelectrolyte or serum analyte (e.g., urate) abnormalities that are 
reversible with standard interventions 
Selinexor Dose Adjustment in the Setting of Infection 
In patients who develop fever or other signs of systemic infection, appropriate antimicrobial should be 
initiated immediately. Selinexor should be withheld in any patient with active uncontrolled infection, any 
Grade 4 infection or sepsis (even in the absence of documented infection) until the patient is clinically 
stable. After the infection has stabilized clinically or resolved, Selinexor treatment may continue at the 
original dose. Missed doses will not be replaced. Patients may continue on antibiotics for prolonged periods 
while re-initiating their Selinexor regimen at the discretion of the investigator. Selinexor is not known to 
have any drug interactions with standard antimicrobials. 
Prophylactic antibiotics are permitted concurrently with Selinexor treatment, but are not recommended for 
most patients. Patients with a history of recurrent infections or those at high risk for specific infections may 
continue their prophylactic antimicrobial regimens without modification when initiating selinexor therapy. 
In a randomised study in old patients with acute myeloid leukemia (AML), sepsis occurred more frequently 
in patients receiving Selinexor compared with patients receiving physician’s choice of therapy. 
6.2.3 
Dose reduction for decreased glomerular filtration rate (GFR) 
Selinexor is not significantly eliminated by the kidney, therefore, no dose alteration of selinexor is required 
in patients with renal dysfunction. 
However, creatinine increase and other renal effects have been observed in patients treated with selinexor. 
For their prevention, maintenance of adequate volume status is essential. Acute increases in creatinine are 
usually accompanied by disproportionately higher elevations of BUN. Therefore, all patients with renal 
dysfunction should be evaluated for volume status and fluid intake as well as electrolyte levels. Fluid 
repletion usually leads to resolution of creatinine increases in patients with dehydration associated with 
selinexor. 
6.2.4 
Missed or vomited doses 
Missed Doses 
Missed doses should be managed as follows:  
If a dose was missed, the schedule of that week should be altered to accommodate two doses in that week 
with at least 36 hours between two consecutive doses.  


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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 one- or two-week period of dosing for non-study treatment-related events (e.g., a 
required medical procedure or an unanticipated personal emergency), the days missed will be replaced. For 
example, if patient missed Cycle 2 Day 7 to Cycle 2 Day 14, then the patient will start the next dosing on Cycle 
2 Day 7 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 3 Day 1. In this fashion, laboratory and radiographic assessments remain 
appropriate for timing of the administration of anti-cancer therapy. 
Vomited Doses 
If a dose is vomited within 1 hour of ingestion, it will be replaced. If vomiting occurs more than 1 hour after 
dosing, it will be considered a complete dose. 
6.2.5 
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. 
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. 
Restrictions and Prohibited Medications 
Concurrent 
Therapies: 
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.   
Alcohol: 
Ethanol should be avoided on selinexor dosing days as it may compete for glutathione 
(GSH)-mediated metabolism. 


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Diet: 
There are no dietary restrictions on this study.  Patients on selinexor should maintain 
adequate caloric and fluid intake. 
Medications: 
 
Patients should not take glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-
acetylcysteine (NAC)-containing products during their participation in this study as these 
products may enhance the metabolism of selinexor. However, they are permitted if the 
patient has elevated liver function tests     
Given the theoretical potential for GSH depletion, the total dose of acetaminophen should 
be ≤1 gram per day on days of selinexor dosing. 
6.2.6 
Use of Blood Products 
During treatment, patients may receive red blood cell (RBC) or platelet transfusions, if clinically indicated, 
per institutional guidelines.  
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 two cycles of therapy, then weekly to biweekly thereafter. 
Patients may receive supportive care with erythropoietin, darbepoetin, granulocyte-colony stimulating factor 
or granulocyte macrophage-colony stimulating factor, pegylated growth factors, and platelet stimulatory 
factors, in accordance with clinical practice or institutional guidelines prior to entry and throughout the study.  
6.2.7 
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 must agree to use two methods of contraception (one highly effective and one 
effective) and have a negative serum pregnancy test at Screening, and male patients must use an effective 
barrier method of contraception if sexually active with a female of childbearing potential.  
Highly effective methods include:  
Hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and 
implants)  
Intrauterine device or intrauterine system 
Vasectomy or tubal ligation 


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Effective methods include:  
Barrier methods of contraception (e.g., male condom, female condom, cervical cap, diaphragm, 
contraceptive sponge) 
Notes: 
o No barrier method by itself achieves a highly effective standard of contraception 
o The proper use of diaphragm or cervical cap includes use of spermicide and is considered one 
barrier method. 
o The cervical cap and contraceptive sponge are less effective in parous women. 
o The use of spermicide alone is not considered a suitable barrier method for contraception. 
o When used consistently and correctly, “double barrier” methods of contraception (e.g., male 
condom with diaphragm, male condom with cervical cap) can be used as an effective 
alternative to the highly effective contraception methods described above. 
o Male and female condoms should not be used together as they can tear or become damaged. 
Alternatively, the following fulfill the contraception requirements: 
A sexual partner who is surgically sterilized or post-menopausal. 
Total (true) abstinence (when this is in line with the preferred and usual lifestyle of the patient), is 
an acceptable method of contraception. NOTE: Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
The method of acceptable contraception must be explained to both male and female potential patients.  In 
order to be eligible for the study, patients must agree to use the methods of birth control described above 
throughout the study and for 3 months following the last dose of study treatment at the time of consent 
for the study. 
Please see Section 7.12.1 for additional safety information related to pregnancy.  
6.2.8 
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. Treatment with selinexor shall not be discontinued solely due to palliative 
radiation.  


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7 
Assessment of Safety 
7.1 Adverse Events 
7.1.1 
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.  
7.1.2 
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 treatment. AE monitoring 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 AEs occur during the study. 
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 until its resolution or until it is judged to be permanent, and assessment should 
be made at each visit (or more frequently, if necessary) of any changes in severity of the event, the 
suspected relationship to the study treatment, the interventions required to treat the event, and the 
outcome. 
7.2 LABORATORY TEST ABNORMALITIES 


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Laboratory abnormalities that constitute an AE in their own right (i.e., are considered to be clinically 
significant, induce clinical signs or symptoms, require concomitant therapy, or require changes in study 
treatment), should be recorded as an AE. Whenever possible, a diagnosis rather than a symptom should be 
recorded (e.g., anemia instead of low hemoglobin). Laboratory abnormalities that meet the criteria for an 
AE should be followed until they have returned to normal or an adequate explanation of the abnormality is 
identified. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported AE, it is not necessary to separately record the laboratory/test result as an additional event. 
A laboratory abnormality that does not meet the definition of an AE should not be recorded as an AE. A 
laboratory abnormality that results in a dose being held or modified would, by definition, be an AE. A Grade 
3 or 4 event (severity per the current version of NCI CTCAE) does not automatically indicate an SAE unless it 
meets the definition of serious as defined in Section 1.1.1 and/or as per the Investigator’s discretion.  
7.3 ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 
AESIs for selinexor include cataracts and acute cerebellar syndrome. All cases of cerebellar toxicity, Grade 3 
or higher must be reported (see Section 7.8). 
7.4 Adverse Event Severity Assessments 
The severity* of the AE should be graded by the Investigator according to the NCI CTCAE Grading Scale, 
utilizing NCI CTCAE (version 4.03: June 14, 2010).  NCI CTCAE files can be accessed online at the following 
URL: http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
If NCI CTCAE grading does not exist for an AE, the severity should be characterized as ‘mild,’ ‘moderate,’ 
‘severe,’ ‘life-threatening’, or ‘fatal’ (corresponding to Grades 1 to 5) according to the following definitions: 
 
Mild events are usually transient and do not interfere with the patient’s daily activities. 
 
Moderate events introduce a low level of inconvenience or concern to the patient and may 
interfere with daily activities. 
 
Severe events interrupt the patient’s usual daily activities. 
 
Life-threatening  
 
Fatal event. 


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*Severity is not the same as Seriousness:  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.  Grades do not define seriousness. 
7.5 Adverse Event Causality 
The Investigator will make a judgment regarding the relationship of the AE to study treatment, as outlined 
in Table 7. 
7.6 Table 7: Classification of Adverse Events by Causality 
Not related: The lack of a temporal relationship of the event to the study treatment makes a causal 
relationship not reasonably possible, or other drugs, therapeutic interventions, or underlying conditions 
provide a sufficient explanation. 
Related: The temporal relationship of the event to the study treatment makes a definitive relationship, and 
the event is more likely explained by exposure to the study treatment than by any other drugs, therapeutic 
interventions, or underlying conditions. 
7.7 Adverse Event Reporting 
The Investigator will report all AEs (including all non-serious AEs) to Karyopharm Pharmacovigilance every 6 
months in the form of line-listings.  The line listings will include the following information: subject number, 
study drug information (start/stop date, dosage, and frequency), adverse event (onset/stop date, event 
intensity, event outcome and action taken), seriousness (serious with applicable criteria, or non-serious), 
and the Investigator’s causality assessment.  Karyopharm Therapeutics will provide the preferred template. 
7.8 Serious Adverse Events 
An AE is considered an SAE if at least one of the following conditions applies:  
 
Death was an outcome of an adverse event;  
 
Life threatening AE (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; 


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 
Emergency room visits that do not result in admission to the hospital should be evaluated for one of 
the other serious outcomes (e.g., life-threatening; required intervention to prevent permanent 
impairment or damage; other serious medically important event);  
 
Results in persistent or significant disability/incapacity;  
 
Is a congenital anomaly/birth defect;  
 
A new cancer diagnosed during the study (histopathologically different from the cancer under study; 
and  
 
Any important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent 1 of the outcomes 
listed in this definition. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in in-
patient hospitalization, or the development of drug dependency or drug abuse. 
Hospitalizations for elective surgery or other medical procedures that are not due to an AE are not 
considered SAEs. A hospitalization meeting the regulatory definition for ‘serious’ is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility. An emergency room visit is 
not considered a hospitalization unless it results in an official admission to the hospital. 
Progression of the malignancy (including fatal outcomes) should not be reported as an SAE during the study 
or within the safety reporting period (see Section 6.9.2.2). Sudden and unexplained death should be 
reported as an SAE. If there is any uncertainty about a finding being due solely to progression of 
malignancy, the finding should be reported as an AE or SAE, as appropriate.  
7.9 Recording of Serious Adverse Events 
Per the Good Clinical Practices, it is recommended that Investigator has the responsibility to record and 
document all SAEs occurring from the signing of the Informed Consent Form until at least 30 days after the 
patient has stopped study treatment. 
 


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7.10 Reporting of Serious Adverse Events 
Every SAE, regardless of the causal relationship to the Karyopharm medications, occurring after the patient 
has signed informed consent until 30 days after the patient has stopped study treatment must be reported 
to the Karyopharm Pharmacovigilance within 24 hours of awareness. Karyopharm Therapeutics, Inc. will 
provide the required SAE Report Form.. For reporting any SAE to Karyopharm Pharmacovigilance 
Department, a completed and signed (by the Investigator) SAE Report Form will be submitted to 
Karyopharm Pharmacovigilance: 
Completed and signed SAE report forms must be emailed to: 
Pharmacovigilance Department 
Karyopharm Therapeutics Inc. 
Email: pharmacovigilance@karyopharm.com 
Any SAE observed after the 30-day follow-up period should only be reported to Karyopharm if the 
Investigator suspects that the SAE has causal relationship to study treatment.  
An SAE should be followed until its resolution or until it is judged to be permanent, and assessment should 
be made at each visit (or more frequently, if necessary) of any changes in severity of the event, the 
suspected relationship to the study treatment, the interventions required to treat the event, and the 
outcome.  New information, recurrences, complications, or progression of the initial SAE must be reported 
as follow-up to the initial report within 24 hours of the Investigator receiving the follow-up information. 
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 Therapeutics will report applicable SAEs to other applicable Regulatory Agencies and 
Investigators utilizing the Karyopharm product, as may be required. 
7.11 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 study treatment 
administered.  


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SUSARs will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with the FDA’s ‘Safety Reporting Requirements for Investigational New Drugs and 
Bioanalytical/Bioequivalence Studies’ or as per national regulatory requirements in participating countries. 
7.12 Procedures for Handling Special Situations 
7.12.1 Pregnancy 
Note: Pregnancy per se is not considered to be an AE; however, it is discussed here because of the 
importance of reporting pregnancies that occur during studies and because a medical occurrence observed 
in the mother or fetus/newborn would be classified as an AE. 
To ensure patient safety, a pregnancy occurring while the patient is on study treatment must be reported 
to Karyopharm Pharmacovigilance by email or fax within 24 hours of first knowledge of its occurrence. A 
pregnancy report form is provided by Karyopharm Therapeutics Inc.  
The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
A pregnancy in a female partner of a male patient must be reported to Karyopharm Pharmacovigilance 
within 24 hours of learning of its occurrence.  
Pregnancies must be reported to Karyopharm Pharmacovigilance, regardless of whether the patient 
withdraws from the study or the study is completed, for 3 months after the patient receives his/her last 
dose of study treatment. Patients should be instructed to inform the investigator regarding any 
pregnancies.  
Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., maternal serious 
complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, 
birth defect) and reported within 24 hours in accordance with the procedure for reporting SAEs. 
7.12.2 Abuse, Misuse, Medication Errors, Overdose, and Occupational Exposure 
All incidences of abuse, misuse, medication errors, overdose, and occupational exposure are required to be 
reported to Karyopharm pharmacovigilance on an SAE report form emailed to 
pharmacovigilance@karyopharm.com, regardless of whether or not there is an associated AE or SAE.   
 


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7.13 OVERDOSE 
An overdose is a deliberate or accidental administration of any Karyopharm treatment to a study patient, at 
a dose greater than that which was assigned to that patient per the study protocol. If an overdose occurs, 
Karyopharm Pharmacovigilance 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. Overdose is to be reported on an SAE report form to 
Karyopharm pharmacovigilance regardless of whether or not an AE or SAE has occurred due to the 
overdose. If the overdose is associated with an SAE, the SAE report form must be submitted to Karyopharm 
pharmacovigilance within 24 hours of awareness.  If there is no AE or SAE, the report must be submitted as 
soon as possible. 
7.14 ABUSE, MISUSE, OR MEDICATION ERROR 
Abuse is the persistent or sporadic, intentional excessive use of the study drug which is accompanied by 
harmful physical or psychological effects.  
A medication error is any preventable incident that may cause or lead to inappropriate medication use or 
patient harm while the medication 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 prescribing; order communication; and 
nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use.’ 
All occurrences of abuse, misuse or medication error with Karyopharm drug are to be reported on an SAE 
report form to Karyopharm pharmacovigilance regardless of whether or not an AE or SAE has occurred due 
to the abuse, misuse or medication error.  If the abuse, misuse or medication error is associated with an 
SAE, the SAE report form must be submitted to Karyopharm pharmacovigilance within 24 hours of 
awareness.  If there is no AE or SAE, the report must be submitted as soon as possible. 
7.15 OCCUPATIONAL EXPOSURE 
Occupational exposure is the exposure to a study drug as a result of one’s professional or non-professional 
occupation.   


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All occurrences of occupational exposure with Karyopharm drug are to be reported on an SAE report form 
to Karyopharm pharmacovigilance regardless of whether or not an AE or SAE has occurred due to the 
occupational exposure.  If the occupational exposure is associated with an SAE, the SAE report form must 
be submitted to Karyopharm pharmacovigilance within 24 hours of awareness.  If there is no AE or SAE, the 
report must be submitted as soon as possible. 
8 
Statistical Considerations 
8.1 Trial Design 
This is a non-randomised, open label two armed phase II trial. Arm A includes patients with thymoma and 
arm B include patients with thymic carcinoma. 
The primary objective of the trial is to determine the effect of selinexor in patients with inoperable 
thymoma and in patients with thymic carcinomas, previously treated with with at least one platinum 
containing chemotherapy regimen as determined by overall response rate according to RECIST 1.1.  
The study is composed of two similar phase II trials conducted in the US and Europe. The final analysis will 
be performed on data pooled from both trials.  The calculation of the total sample size is based on the 
pooling of data from both trials.   
 The following assumptions are the basis for the sample size: 
 
Simon's minimax design will be used 
 
A response rate of 10 % is considered clinical irrelevant. 
 
A response rate of 30 % is considered undesirable to overlook. 
 
Type one error rate: 0.05 
 
Power: 0.80 
 
Stage 1: 15 evaluable patients in each arm 
 
Stage 2: 10 evaluable patients in each arm 
 
For each arm: If response is observed in 2/15 patients in stage 1, accrual will continue in stage 2. 
 
For each arm: If response in 5 out of 25 patients, the alternative hypothesis is accepted and the 
drug is considered active and appropriate for further evaluation.   
Included patients who are not evaluable for response will be replaced. 
All patients receiving at least one dose of selinexor will be included in the final analysis of primary and 
secondary endpoints. However this is not an intention to treat (ITT) study. 


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8.1.1 
Interim analysis 
Patient inclusion is reported to the sponsor and shared between US and EU sponsor. EU sponsor has the 
responsibility to monitor the inclusion rate and in collaboration with the US sponsor announce when 
inclusion should be halted for interim analysis. After inclusion of 15 evaluable patients in each arm 
(comprising both US and EU trial), an interim analysis will be performed. A decision to continue in stage 2 
will be based on pooled data of stage 1 in both the US and European trial. Each study arm may be closed 
separately after stage 1, if it does not reach the pre-specified responses. Decision to go to stage 2 will be 
made by a consortium consisting of US sponsor, EU sponsor, one investigator from each site in US and EU, 
and 1-2 Karyopharm representatives. In case 2 patients out of 15 patients derive clear clinical benefit 
according to a unanimous agreement among members of the consortium, a decision can be made to 
proceed to stage 2. Clear clinical benefit is defined as: non-progressive disease with improvement in tumor 
related symptoms and treatment is well tolerated. 
The results of the interim analysis showed three responses out of fifteen patients in the thymoma cohort (3 
according to ITMIC and 2 according RECSIST). Therefore, the thymoma cohort will be continued and 
additional 10 patients will be included across all EU and US sites. 
No response was observed in the thymic carcinoma group. This cohort will be closed. 
8.2 Statistical plan 
8.2.1 
Study populations 
Thymoma 
This population consists of all patients with thymoma who have received at least one dose of study drug on 
trial. 
Thymic carcinoma 
This population consists of all patients with thymic carcinoma who have received at least one dose of study 
drug on trial. This arm was closed as no response was observed within the fifteen patients. 
Safety population 
This population consists of all patients who have received at least one dose of study drug on trial. 
8.2.2 
Demographics and baseline characteristics 
Demographics and baseline characteristics will be summarized separately for each cohort and will include 
at a minimum age, gender, diagnosis, performance status, and number of prior lines of therapy.  


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8.2.3 
Analysis of primary endpoint 
Analysis of ORR according to RECIST 1.1 will be reported with 95% CI. Each arm will be analysed separately. 
8.2.4 
Analysis of secondary endpoints 
Analysis of time to event endpoints will be done using the Kaplan-Meier method. Median time and 95% CI 
will be reported. 
8.2.5 
Analysis of exploratory endpoints 
Data from biomarker analysis will be treated as continuous or discrete variables as appropriate and 
correlated to response, time to event endpoints and safety endpoints using univariate and multivariate 
analysis. Biomarker data will be transformed prior to analysis as appropriate. 
 
 


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9 
Administrative Matters 
9.1 Data Safety Monitoring Plan 
The Georgetown Lombardi Comprehensive Cancer Center will be responsible for the data and safety 
monitoring of this multi-site trial.  As this study is an investigator initiated study Phase II study utilizing a 
non-FDA approved drug for which the PI holds the IND it is considered a high risk study which requires real-
time monitoring by the PI and study team and quarterly reviews by the LCCC Data and Safety Monitoring 
Committee (DSMC). 
The Principal Investigator and the Co-Investigators will review the data including safety monitoring at their 
weekly institution based disease group meetings and on monthly disease group teleconferences.   
All Severe Adverse Events (SAEs) are required to be reported to the IRB.  Based on SAEs, the IRB retains the 
authority to suspend further accrual pending more detailed reporting and/or modifications to further 
reduce risk and maximize the safety of participating patients. 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and Safety 
Monitoring Committee every 4 months from the time the first patient is enrolled on the study. Results of 
the DSMC meetings will be forwarded to the IRB with recommendations regarding need for study closure.  
DSMC recommendations should be based not only on results for the trial being monitored as well as on 
data available to the DSMC from other studies.  It is the responsibility of the PI to ensure that the DSMC is 
kept apprised of non-confidential results from related studies that become available.  It is the responsibility 
of the DSMC to determine the extent to which this information is relevant to its decisions related to the 
specific trial being monitored. 
A written copy of the DSMC recommendations will be given to the trial PI, Karyopharm Therapeutics, Inc. 
(drug supplier) and the IRB.  If the DSMC recommends a study change for patient safety or efficacy reasons 
the trial PI must act to implement the change as expeditiously as possible.  In the unlikely event that the 
trial PI does not concur with the DSMC recommendations, then the LCCC Deputy Director must be informed 
of the reason for the disagreement.  The trial PI, DSMC Chair, and the LCCC Deputy Director will be 
responsible for reaching a mutually acceptable decision about the study and providing details of that 
decision to the IRB.  Confidentiality must be preserved during these discussions.  However, in some cases, 
relevant data may be shared with other selected trial investigators and staff to seek advice to assist in 
reaching a mutually acceptable decision. 


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If a recommendation is made to change a trial for reasons other than patient safety or efficacy the DSMC 
will provide an adequate rationale for its decision. If the DSMC recommends that the trial be closed for any 
reason, the recommendation will be reviewed by the LCCC Deputy Director.  Authority to close a trial for 
safety reasons lies with the IRB, with the above described input from DSMC and the LCCC Deputy Director.   
9.2 Collaboration with Other Institutions (in the US and EU) 
This study (US) will be conducted in collaboration with Hackensack University Medical Center. Dr. Chul Kim 
is the US Principal Investigator for the study and will oversee the study including the data gathering, safety 
and reporting. Dr. Martin E. Gutierrez will be the main study contact at Hackensack University Medical 
Center. Patients will be recruited at all institutions for the study. 
Monthly conference calls will be conducted between all institutions to follow up on the progress of the 
trial. Dr. Kim will be responsible for coordination of the trial between all institutions. Study coordinators 
will notify Dr. Kim upon the accrual of any patients in any institution. 
Monthly teleconferences will also be conducted between the centers in the US and those in Europe. An 
update of each center will be provided in writing and detailed in terms of US and EU participation. Accrual, 
safety and activity will be discussed in detail during these teleconferences. 
9.2.1 
Personnel 
At each site, personnel dedicated to this protocol will be: 
            - A study PI 
            - A research coordinator 
            - A data manager 
In addition, at Lombardi-Georgetown, there will be a dedicated “multi-institutional” research coordinator 
who will play the primary role in coordinating the trial between Lombardi-Georgetown and additional 
sites.  This coordinator will be the main point of contact for Dr. Kim and the other site PIs for any study 
related concerns, and to screen each patient being considered for enrollment (Including “remote” 
screening for the patients being screened at other sites).  This coordinator will also be the point of contact 
for the data managers for data entry questions.  Finally, this coordinator will play a major role in regulatory 
coordination of the study, specifically by: 1) Reviewing and confirming all study-related adverse events; 2) 
Submitting all SAE reports to the Georgetown IRB (The research coordinators at the other sites will prepare 
SAE reports for patients treated at their respective sites, but the “multi-institutional” coordinator will 
submit the final report); 3) Gathering and preparing primary source data for review/audit. 


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9.2.2 
Patient Enrollment 
Enrollment at the sites will be competitive. If a patient is being screened for enrollment, the local research 
coordinator must send an email within 24 - 48 hours containing the subject number, to the PI, and to the 
multi-institutional coordinator. If a patient is successfully screened, the local research coordinator must 
send all supporting documentation to the multi-institutional research coordinator.  Patients should not 
start therapy until both PI and the multi-institutional coordinator have reviewed the patient’s records and 
confirmed that the patient is indeed eligible for enrollment. 
9.2.3 
Conference Calls 
A monthly conference call will be held between Lombardi-Georgetown and the other sites to review 
patient enrollment, toxicity, and response assessment.  
9.3 Data Management 
Patient data will be entered into the on-line accessible Oracle Clinical database. This database is housed at 
Georgetown, but is accessible anywhere there is internet access. All research coordinators and data 
managers will attend an on-line training session to learn how to accurately enter any data into the Oracle 
database. All screening data should be entered prior to starting therapy, and all ongoing patient data 
should be entered within one week of each patient visit. The LCCC QA Manager will be reviewing all online 
data on a regular basis to ensure compliance. 
9.4 Regulatory and Ethical Compliance 
This clinical study was designed, shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including 
European Directive 2001/20/EC and US Code of Federal Regulations Title 21), Division 5 of the Health 
Canada Food and Drug Regulations - Drugs For Clinical Trials Involving Human Subjects, and with the ethical 
principles laid down in the Declaration of Helsinki. 
9.5 Institutional Review Boards/Ethics Committees 
The protocol and the proposed informed consent form must be reviewed and approved by a properly 
constituted Institutional Review Board (IRB) before study start. Prior to study start, the Investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this protocol and to 


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give access to all relevant data and records to the Sponsor, Quality Assurance representatives, designated 
agents of the Sponsor, IRBs/IECs/REBs and regulatory authorities as required. 
9.6 Regulatory Authority Approval 
Before implementing this study, the protocol must be approved by the FDA. 
9.7 Protocol Adherence  
Investigators attest they will apply due diligence to avoid protocol deviations. All significant protocol 
deviations will be recorded and reported in the final clinical study report (CSR). 
9.8 Amendments to the Protocol  
Any change or addition to the protocol can only be made in a written protocol amendment, and approved 
by the FDA where required, and the IRB. Only amendments that are required for patient safety may be 
implemented prior to 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 
PI should be notified of this action and the IRB at the study site should be informed according to local 
regulations but not later than 10 working days. 
9.9 Informed Consent 
Eligible patients may only be included in the study after providing written (witnessed, where required by 
law or regulation), IRB-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (i.e., all procedures 
described in this protocol). The process of obtaining informed consent should be documented in the 
patient source documents. The date when a patient’s informed consent was actually obtained will be 
recorded in their CRFs. 
 Additionally, consent will be requested to obtain/retain a blood sample for future analysis as warranted by 
our rapidly-advancing understanding in this field. Each patient’s ICF will reflect that samples collected may 
be used for pharmacogenomic investigations. 
 
 


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9.10 Patient Confidentiality and Disclosure 
The Investigator must ensure anonymity of all patients; patients must not be identified by names in any 
documents submitted to Sponsor or its designee. Signed ICFs and patient enrollment logs must be kept 
strictly confidential to enable patient identification at the site. 
9.11 Collection, Auditing Study Documentation, and Data Storage 
9.11.1 Study Documentation, Record Keeping and Retention of Documents 
The Georgetown Lombardi Clinical Research Management Office will maintain appropriate medical and 
research records for this trial, in compliance with Section 4.9 of ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of patients.  Authorized representatives of the Sponsor 
and regulatory agencies will be permitted to examine (and when required by applicable law, to copy) 
clinical records for the purposes of quality assurance reviews, audits and evaluation of the study safety and 
progress. 
Source data include all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the PI. The 
study CRF is the primary data collection instrument for the study. The investigator should ensure the 
accuracy, completeness, and timeliness of the data reported in the CRFs and all other required reports. 
Data reported on the CRFs, which are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. For electronic CRFs, an audit trail will be maintained by the 
system.  
The Investigator/Institution should maintain trial 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. 


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Essential documents (written and electronic) should be retained for a period of not less than fifteen (15) 
years from the completion of the Clinical Trial. 
9.11.2 Auditing Procedure 
The drug supplier or the regulatory authority may conduct an audit or an inspection (during the study or 
after its completion) to evaluate compliance with the protocol and the principles of GCP. 
The Sponsor-Investigator agrees that representatives of the drug supplier and Regulatory Authorities will 
have direct access, both during and after the course of this study, to audit and review all study-relevant 
medical records.  
In the event that a major compliance or regulatory issues arises, the drug supplier may conduct an audit 
without prior notice. 
9.12 Disclosure of Information 
All information provided to the Investigator by the Sponsor, or its designee, will be kept strictly 
confidential. No disclosure shall be made except in accordance with a right of publication granted to the 
Investigator in the Clinical Trial Agreement. 
No information about this study or its progress will be provided to anyone not involved in the study other 
than to the Sponsor, or its authorized representatives, or in confidence to the IRB, or similar committee, 
except if required by law. 
9.13 Discontinuation of the Study 
It is agreed that, for reasonable cause, the Sponsor or drug supplier, may terminate the Investigator’s 
participation in this study after submission of a written notice. The Sponsor may terminate the study at any 
time upon immediate notice for any reason including the Sponsor’s belief that discontinuation of the study 
is necessary for patient safety. 
9.14 Study Report and Publication Policy 
The PI assures that the key design elements of this protocol will be posted in a publicly accessible database 
such as www.clinicaltrials.gov. In addition, upon study completion the results of this study will be either 
submitted for publication and/or posted in a publicly accessible database of clinical study results. 
 


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10 
Appendices 
Appendix A: KPTI SAE form 
Appendix B: Ophthalmic Exam 
Appendix C: 6 m AE LL spreadsheet template


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References: 
1. 
Strobel P, Hohenberger P, Marx A. Thymoma and thymic carcinoma: molecular pathology and 
targeted therapy. J Thorac Oncol 2010; 5: S286-290. 
2. 
Marx A, Ströbel P, Badve SS et al. ITMIG Consensus Statement on the Use of the WHO Histological 
Classification of Thymoma and Thymic Carcinoma: Refined Definitions, Histological Criteria, and 
Reporting. Journal of Thoracic Oncology 2014; 9: 596-611. 
3. 
den Bakker MA, Roden AC, Marx A, Marino M. Histologic Classification of Thymoma: A Practical 
Guide for Routine Cases. Journal of Thoracic Oncology 2014; 9: S125-S130. 
4. 
Masaoka A. Staging system of thymoma. J Thorac Oncol 2010; 5: S304-312. 
5. 
Detterbeck FC, Stratton K, Giroux D et al. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: 
Proposal for an Evidence-Based Stage Classification System for the Forthcoming (8th) Edition of the 
TNM Classification of Malignant Tumors. Journal of Thoracic Oncology 2014; 9: S65-S72. 
6. 
Kim ES, Putnam JB, Komaki R et al. Phase II study of a multidisciplinary approach with induction 
chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy 
for unresectable malignant thymomas: final report. Lung Cancer 2004; 44: 369-379. 
7. 
Loehrer PJ, Sr., Chen M, Kim K et al. Cisplatin, doxorubicin, and cyclophosphamide plus thoracic 
radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 1997; 15: 
3093-3099. 
8. 
Wei ML, Kang D, Gu L et al. Chemotherapy for thymic carcinoma and advanced thymoma in adults. 
Cochrane Database Syst Rev 2013; 8: CD008588. 
9. 
Kelly RJ, Petrini I, Rajan A et al. Thymic malignancies: from clinical management to targeted 
therapies. J Clin Oncol 2011; 29: 4820-4827. 
10. 
Thomas A, Rajan A, Berman A et al. Sunitinib in patients with chemotherapy-refractory thymoma and 
thymic carcinoma: an open-label phase 2 trial. Lancet Oncol 2015; 16: 177-186. 
11. 
Hirabayashi H, Fujii Y, Sakaguchi M et al. p16INK4, pRB, p53 and cyclin D1 expression and 
hypermethylation of CDKN2 gene in thymoma and thymic carcinoma. Int J Cancer 1997; 73: 639-644. 
12. 
Engel P, Francis D, Graem N. Expression of bcl-2 in fetal thymus, thymomas and thymic carcinomas. 
Association with p53 expression and review of the literature. APMIS 1998; 106: 449-455. 
13. 
Petrini I, Meltzer PS, Zucali PA et al. Copy number aberrations of BCL2 and CDKN2A/B identified by 
array-CGH in thymic epithelial tumors. Cell Death Dis 2012; 3: e351. 
14. 
Petrini I, Wang Y, Zucali PA et al. Copy number aberrations of genes regulating normal thymus 
development in thymic epithelial tumors. Clin Cancer Res 2013; 19: 1960-1971. 
15. 
Petrini I, Meltzer PS, Kim IK et al. A specific missense mutation in GTF2I occurs at high frequency in 
thymic epithelial tumors. Nat Genet 2014; 46: 844-849. 
16. 
Vogelstein B, Papadopoulos N, Velculescu VE et al. Cancer genome landscapes. Science 2013; 339: 
1546-1558. 
17. 
Wang Y, Thomas A, Lau C et al. Mutations of epigenetic regulatory genes are common in thymic 
carcinomas. Sci Rep 2014; 4: 7336. 


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Appendix A: KPTI SAE form 
Serious Adverse Event Report Form 
Protocol Number: 
Investigator:  
 
 Initial Report 
Follow up Report Number: 
Patient Information 
Patient ID# / initials 
  ID#         
 
Initials: 
Weight (kg): 
Height (cm): 
Date of birth 
 
Male  
 
Female  
 
 Adverse Event 
 ADVERSE EVENT TERM (verbatim):      
 ONSET DATE:  
 CTCAE/SEVERITY* 
 OUTCOME TO DATE OF THIS REPORT 
 
  Grade 1/ mild 
 
  Death 
 
  Grade 2/ moderate 
 
  Not recovered/Not resolved 
 
  Grade 3/ severe 
 
  Recovered with Sequelae 
On date: 
 
Time: 
 
  Grade 4 
 
  Recovered/Resolved 
On date: 
 
Time: 
 
  Grade 5 
  Other:  
SERIOUS CRITERIA 
  Death 
Date of Death:  
  Life threatening 
Hospitalization: 
  Hospitalization/Prolonged hospitalization 
      Admission Date:  
  Persistent / significant disability / incapacity 
      Discharge Date:  
  Congenital anomaly / birth defect 
  Important medical event  
 
RELATIONSHIP TO STUDY MEDICATION 
OTHER POSSIBLE CAUSES FOR THE OCCURRENCE OF 
EVENT 
  Related 
  Underlying disease 
  Possibly related 
  Pre-existing condition:   
  Not related 
  Other:   


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Serious Adverse Event Report Form – Page 2 
Protocol Number: 
Site ID/Patient ID:               /  
Study Medication 
MEDICATION NAME: 
THERAPY DATES (dd/mmm/yyyy) 
MEDICATION DOSAGE and FREQUENCY  
Date first dose: 
First dose:  
mg / 
Date dose changed:                   
Dose reduced to:  
mg / 
Date last dose prior to event: 
 
Last dose administered: 
 
mg 
 
ACTION TAKEN WITH STUDY MEDICATION 
Did event abate after stopping/reducing medication? 
  Dose unchanged 
  Yes 
  Dose reduced 
  No  
 
  NA 
  Medication withdrawn 
  
  Medication temporarily withdrawn 
Did event reappear after re-administration?  
  Date of withdrawal: 
   Yes 
  Date of re-initiation: 
   No 
 
  NA 
Baseline Condition(s) 
Condition 
Diagnosis date 
 
 
 
 
Past Medical History 
Medical condition 
From date 
To date (dd/mm/yyyy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Serious Adverse Event Report Form – Page 3 
Protocol Number: 
Site ID/Patient ID:               / 
Relevant Concomitant Medication 
MEDICATION NAME AND INDICATION 
DATES AND DOSE/FREQUENCY OF ADMINISTRATION 
1 
Name: 
From: 
To: 
 
Indication: 
Dose/frequency: 
mg/  
2 
Name: 
From:  
To: 
 
Indication: 
Dose/frequency: 
mg/  
3 
Name: 
From: 
To: 
 
Indication: 
Dose/frequency: 
mg/  
4 
Name: 
From: 
To: 
 
Indication: 
Dose/frequency: 
mg/  
5 
Name: 
From: 
To: 
 
Indication:  
Dose/frequency: 
mg/  
Other Relevant Medical Conditions 
 
Additional Details of SAE (include medication/other measures administered to the patient to treat the event, etc.) 
 
Reporter Contact Details 
Report completed by:  
Telephone: 
Email: 
INVESTIGATOR’S SIGNATURE 
DATE OF THIS REPORT: 
 
 


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Appendix B: Ophthalmic Exam 
An ophthalmic examination by an optometrist or ophthalmologist is required at screening and if 
clinically indicated during the study (e.g., monitoring of pre-existing cataracts, visual disturbances). 
The examination is to include the following:  
Prior to dilation:   
 
best corrected visual acuity  
 
slit lamp examination 
 
tonometry 
Following dilation:  
 
fundoscopy 
 
slit lamp examination to document lens clarity  
If a cataract/lens opacity is seen during the examination, the cataract/lens opacity will be graded 
according to a Grade 1-4 system (modified from Optometric Clinical Practice Guideline:  Care of the 
Adult Patient with Cataracts: available on the American Optometric Association website:  
www.aoa.org).   
 
 
 


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Original protocol: 
 
Current version: Final version 3.0, 5/11/2020 
Grading of Cataracts* 
Cataract Type 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nuclear 
Yellowing and 
sclerosis of the lens 
nucleus 
Mild 
Moderate 
Pronounced 
Severe 
Cortical 
Measured as 
aggregate percentage 
of the intrapupillary 
space occupied by the 
opacity 
Obscures 
10% of 
intrapupillary 
space 
Obscures 
10% -50% 
of intra-
pupillary 
space 
Obscures 
50% -90% 
of intra-
pupillary 
space 
Obscures 
>90% of 
intrapupillary 
space 
Posterior subcapsular 
Measured as the 
aggregate percentage 
of the posterior 
capsular area 
occupied by the 
opacitiy 
Obscures 
10% of the 
area of the 
posterior 
capsule 
Obscures 
30% of the 
area of the 
posterior 
capsule 
Obscures 
50% of the 
area of the 
posterior 
capsule 
Obscures 
>50% of the 
area of the 
posterior 
capsule 
*Designation of cataract severity that falls between grade levels can be made by addition of a + 
sign (e.g., 1+, 2+). Grading of cataracts is usually done when pupil is dilated. 


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Selinexor in TETs 
 
 
Original protocol: 
 
Current version: Final version 3.0, 5/11/2020 
Appendix C:  6 m AE LL spreadsheet template 
 
Study ID
Unique 
Subject ID
Adverse Event Term 
Serious Event? 
(Yes/No)
Onset Date
(complete or partial)
End Data 
(complete or partial)
Action Taken with 
Study Treatment 
Causality to 
Study Treatment 
Ongoing
(Yes/No)
Outcome of 
Adverse Event
Severity CTCAE 
Grade (1-5)
Date of First 
Dose
Preferred Term
System Organ 
Class
Notes:
1. For AE term (Columns C), it would be perferred to report the verbatim name of the event instead of a derived code. 
2. For AE onset date and end date (column E and F), please provide a partial date to the best of your knowledge if the exact date is unknown.
3. If the AE was still ongoing at the time of data cut, please mark the "Ongoing" column (column I) as "Yes" and leave the end date (column F) blank.
4. Preferred Term and System Organ Class (Column M and N) are optional. Please report them if available as well as the MedDRA version.