Clinical trial NCT02025985
Conditions: Ovarian Carcinoma Endometrial Carcinoma Cervical Carcinoma
Keywords: Karyopharm KPT-330 Selinexor SIGN ovarian cancer endometrial cancer cervical cancer SINE™ HER2 negative
Sponsor: Karyopharm Therapeutics Inc
Start date: 2014-04-09; Completion date: 2017-03-29
Enrollment: 116 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary trial objective is to determine the efficacy of KPT-330 (selinexor) in participants with advanced or metastatic gynaecological cancers by disease control rate (complete response (CR) or partial response (PR) or stable disease (SD) for at least 12 weeks, assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Detailed description:
Two-stage Phase 2 study in 3 separate gynecological cancer cohorts, with an additional set of participants in the ovarian cohort randomized into 2 different treatment regimens. The study is divided between a Primary Treatment Phase and a Maintenance Phase with each phase supported by a separate database.

Part 1 - Three parallel cohorts of participants with ovarian (Cohort A), endometrial (Cohort B), or cervical (Cohort C) carcinoma were enrolled.

Part 2 - Based on the observed tolerability and efficacy profile in the ongoing ovarian cohort (Cohort A), 2 additional treatment schedules will be explored to optimize the dosing schedule in a participant population with ovarian carcinoma.

Arms: arm 1: Participants with ovarian carcinoma who were platinum refractory or platinum resistant and had received at least one line of chemotherapy for relapsed disease received a dose of 50 milligram per meter square (mg/m\^2) of selinexor oral tablets twice weekly (BIW) (doses at least 36 hours apart) with light meal and 120 milliliters (mL) of water in a 4-week treatment cycles. After 12 weeks of treatment, a dose of 60 mg/m\^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m\^2 once weekly (QW). This treatment continued until progression of disease (PD) or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. arm 2: Participants with endometrial carcinoma who had received at least one line of chemotherapy for relapsed or advanced (Stage IVb, IIIc) disease received a dose of 50 mg/m\^2 of selinexor oral tablets BIW (doses at least 36 hours apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 12 weeks of treatment, a dose of 60 mg/m\^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m\^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. arm 3: Participants with cervical carcinoma who had received at least one line of chemotherapy for relapsed or advanced (Stage IV) disease received a dose of 50 mg/m\^2 of selinexor oral tablets BIW (doses at least 36 hours apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 12 weeks of treatment, a dose of 60 mg/m\^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m\^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. arm 4: Participants with ovarian carcinoma who were platinum refractory or platinum resistant and had received at least one line of chemotherapy for relapsed disease received a dose of 35 mg/m\^2 of selinexor oral tablets BIW (doses at least 36 hours apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 6 weeks of treatment, a dose of 50 mg/m\^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m\^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. arm 5: Participants with ovarian carcinoma who were platinum refractory or platinum resistant and had received at least one line of chemotherapy for relapsed disease received a dose of 50 mg/m\^2 of selinexor oral tablets QW (doses at least 5 days apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 6 weeks of treatment, a dose of 60 mg/m\^2 of selinexor oral tablets QW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m\^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements.
Interventions: intervention 1: Selinexor
Intervention descriptions: intervention 1: Route of administration and dosage form: Oral tablet; Doses: 35 mg/m\^2 BIW, 35 mg/m\^2 QW, 50 mg/m\^2 BIW, 50 mg/m\^2 QW, 60 mg/m\^2 BIW, 60 mg/m\^2 QW.

Treatment cycles were 4 weeks each i.e., 28 day cycles.

Protocol documents:
Prot_000.pdf: 
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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 4 
 
Investigator’s Agreement 
 
I have read the attached protocol entitled: 
 
“A Phase II, Open-label Study of Efficacy and Safety of the Selective Inhibitor of Nuclear 
Export/SINE Compound KPT-330 (Selinexor) in Patients with Advanced Gynaecologic 
Malignancies” and agree to abide by all provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on Good 
Clinical Practice, all applicable national regulations as well as the requirements of the appropriate 
Institutional Review Board/Independent Ethics Committee and any other institutional requirements. 
 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the study sponsor. 
 
 
 
 
 
 
Signature  
  
Date (dd mmm yyyy)  
Investigator  
  
  
Investigator’s Institution 
  
  
 
 
 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 8 
8. Able to swallow and retain oral medication. 
9. Patients must give written informed consent according to the 
rules and regulations of the individual participating site. 
10. Negative serum pregnancy test in women of childbearing 
potential within 14 days of first dose of treatment, and patients of 
childbearing potential must agree to use effective contraception 
during treatment up to 3 months from last dose. Fertile male 
partners must be willing and able to use effective non-hormonal 
means of contraception (barrier method of contraception in 
conjunction with spermicidal jelly, or surgical sterilization) during 
and for at least 6 months post-study treatment. 
11. The patient must be recovered from any prior treatment/major 
operation. The treatment/major operation must be performed at 
least 4 weeks prior to start of study drug. Palliative radiotherapy 
is permitted until one week prior to the start of study drug. 
12. Only incurable patients with histologically or cytologically proven 
primary tumor and objective documentation of disease 
progression on prior treatment by computed tomography (CT)/ 
magnetic resonance imaging (MRI) may be enrolled. 
13. Ovarian, fallopian tube, or peritoneal carcinoma:  both platinum 
refractory* and platinum resistant** patients, who have received 
≥1 line of chemotherapy for relapsed disease (i.e., ≥ 2 lines of 
chemotherapy in total).  
* Platinum refractory is defined as progression during or 
within 4 weeks of last treatment with a platinum-containing 
therapy. 
** Platinum resistant is defined as relapse 4 weeks to 
< 6 months after a platinum-containing therapy.  
14. Endometrial carcinoma:  patients must have received ≥ 1 line of 
chemotherapy for relapsed or advanced (stage IV, IIIc) disease. 
15. Cervical carcinoma:  patients must have received ≥ 1 line of 
chemotherapy for relapsed or advanced (stage IVb) disease. 
16. Carcinosarcomas (Malignant Mixed Mullerian Tumor) are 
allowed, but all other non-epithelial cancers of the ovary, fallopian 
tube, endometrium, or cervix are excluded. 
17. Patients must have either measurable disease (Response 
Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]) or 
evaluable disease outside irradiated field on CT/MRI. For ovarian 
cancer:  Patients must have disease that is measurable 
according to RECIST or assessable according to the 
Gynecologic Cancer Intergroup (GCIG) CA-125 criteria. A rise in 
CA-125 or other tumor marker alone is not sufficient.  
Exclusion criteria  
Patients with any of the following will not be eligible for participation: 
1. Disease-Specific Exclusions: 
 
Evidence of complete or partial bowel obstruction.  
 
Need of Total Parenteral Nutrition. 
2. Patients who are pregnant or breast feeding. 
3. Radiation (except planned or on-going palliative radiation to bone 
outside of the region of measurable disease) ≤ 3 weeks prior to 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 9 
Cycle 1 Day 1. 
4. Chemotherapy, immunotherapy or any other systemic anti-
cancer therapy, (including investigational anti-cancer therapy) ≤ 
3 weeks prior to Cycle 1 Day 1. 
5. Diagnosis or recurrence of invasive cancer other than the present 
cancer within 3 years (except basal or squamous cell carcinoma 
of the skin that has been definitively treated). 
6. Unstable cardiovascular function: 
o 
Symptomatic ischemia, or  
o 
Uncontrolled 
clinically 
significant 
conduction 
abnormalities (e.g., ventricular tachycardia on anti-
arrhythmics are excluded and 1st degree AV block or 
asymptomatic LAFB/ RBBB will not be excluded), or  
o 
Congestive heart failure (CHF) of NYHA Class ≥ 3, or 
myocardial infarction (MI) within 3 months of Cycle 1 
Day 1. 
7. Uncontrolled active infection requiring parenteral antibiotics, 
antivirals, or antifungals within one week prior to the first dose. 
Active infection with concurrent treatment is acceptable only if the 
patient is clinically stable. 
8. Significantly diseased or obstructed gastrointestinal tract or 
uncontrolled vomiting or diarrhea. 
9. Concurrent therapy with approved or investigational anti-cancer 
therapeutics. 
10. Medical, psychological, or social conditions that may interfere 
with the patient's participation in the study or evaluation of the 
study results. 
11. Known brain metastases unless adequately treated (surgery or 
radiotherapy) with no evidence of progression and neurologically 
stable off anticonvulsants and glucocorticoids. 
12. All non-epithelial cancers of the ovary, fallopian tube, peritoneum, 
endometrium or cervix as well as neuro-endocrine tumors are 
excluded. 
Treatment scheme 
Primary Treatment Phase 
Treatment will continue until PD or unacceptable toxicity, death, 
withdrawal of consent by the patient, or non-compliance by the 
patient with protocol requirements. 
Each cycle is 28 days (4 weeks) long. In twice-weekly dose 
schedules (i.e., Part 1 and Part 2, Schedule 1), 8 doses of selinexor 
will be administered per cycle. In the once-weekly dose schedule 
(i.e., Part 2 Schedule 2), 4 doses of selinexor will be administered 
per cycle. Twice-weekly doses of selinexor must be administered at 
least 36 hours apart; once-weekly doses of selinexor must be 
administered at least 5 days apart. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 10 
Dose escalations and reductions/interruptions are permitted 
according to safety guidelines in this protocol or in consultation with 
a sponsor representative. 
Part 1:  Patients will receive oral selinexor 50 mg/m² twice weekly 
(e.g., Monday and Wednesday, Tuesday and Thursday, 
Wednesday and Friday or Thursday and Saturday) in each week of 
a 4-week cycle. 
If the patient has not experienced a major toxicity after 12 weeks of 
treatment, a selinexor dose escalation to 60 mg/m2 twice weekly will 
be allowed. 
Dose reductions (minimum dose: 35 mg/m2 once weekly) and 
interruptions are permitted. 
Part 2:   
Schedule 1  
Patients will receive oral selinexor 35 mg/m² twice weekly (e.g., 
Monday and Wednesday, Tuesday and Thursday, Wednesday and 
Friday or Thursday and Saturday) in each week of a 4-week cycle.  
If there has been no major toxicity after 6 weeks, a dose escalation 
to 50 mg/m2 twice weekly in each week of a 4-week cycle will be 
allowed. 
Schedule 2  
Patients will receive oral selinexor 50 mg/m² once weekly in each 
week of a 4-week cycle (e.g., Monday of each week).  
If the patient has not experienced a major toxicity after 6 weeks of 
treatment, a dose escalation to 60 mg/m2 once weekly will be 
allowed. 
Dose reductions (minimum doses - Schedules 1 and 2:  35 mg/m2 
once a week) and interruptions are permitted.  
Maintenance Phase 
See Section 18 (Appendix 16) for the schedule of assessments for 
the Maintenance Phase of the study to continue treatment with 
selinexor and/or survival follow-up under Version ≥3.2 of the 
protocol. 
Primary parameter 
The analysis of DCR will be performed for each study cohort by 
calculating the point estimate of the percentage of patients in that 
cohort who have CR, PR, or SD for at least 12 weeks, assessed 
according to RECIST 1.1. Duration of SD will be calculated from the 
date of start of study therapy until the date of PD, or last disease 
assessment should progression not have occurred; for patients 
without at least one post-baseline disease assessment, duration will 
be censored at time 0. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 11 
Secondary parameters 1. Response to therapy per RECIST 1.1: response for patients in 
each cohort will be determined by the objective response rate 
(ORR), defined as either CR or PR using RECIST 1.1 calculated 
as a proportion and including a two-sided 95% CI for that cohort. 
2. Response to therapy per GCIG response criteria (RECIST 1.1 
and CA-125): response for patients in the ovarian cohort will also 
be assessed for DCR and ORR, as described above, using the 
GCIG response criteria. 
3. Median Progression-free Survival (PFS):  PFS for patients in 
each cohort will be calculated from the date of start of study 
therapy to the date of PD based on RECIST 1.1, or date of death 
if PD does not occur. 
4. Overall Survival (OS): OS for patients in each cohort will be 
calculated from the date of start of study therapy to the date of 
death due to any cause. OS rate at 12 and 24 months will also 
be calculated.  
5. Safety and tolerability of selinexor will be evaluated descriptively 
for all study patients combined, according to NCI CTCAE, v.4.03. 
Safety endpoints include AEs, clinical laboratory data, vital signs, 
ECGs, and physical examinations, further described below. 
6. Quality of Life (QoL) will be evaluated for patients in each cohort, 
and for all study patients combined by EORTC QLQ-C30 after 6 
and 12 weeks of treatment and approximately every 8 weeks 
thereafter. 
Efficacy assessments 
During the Primary Treatment Phase, clinical and radiological 
examinations will be performed at baseline, after 6 and 12 weeks of 
treatment, and every 8 weeks thereafter. 
If a patient discontinues treatment due to any reason other than PD, 
death, or withdrawal of informed consent, the disease evaluations 
shall continue until PD. This includes patients who wish to 
discontinue treatment, but agree that further data are captured for 
the purpose of the study. OS data will be collected approximately 
every 3 months.  
Safety assessments 
All serious adverse events (SAEs) and adverse events (AEs) for the 
Primary Treatment Phase and Maintenance Phase occurring from 
the signing of the ICF and from the start of treatment (i.e., Cycle 1 
Day 1), respectively, and for up to 30 days after the last dose of 
study medication will be captured, documented, and reported, and 
graded according to CTCAE v.4.03. 
Safety blood samples include complete blood count, clinical 
chemistry, including liver function test, and coagulation. 
Statistical 
considerations 
Pre-planned subgroup analyses:  
Part 1 of the study will enroll three cohorts of ovarian (Cohort A), 
endometrial (Cohort B), and cervical (Cohort C) cancers which will 
be evaluated independently. Part 2 of the study will enroll additional 
ovarian patients to evaluate efficacy and safety of once-weekly 
versus twice-weekly dosing.  
Subtypes of each tumor (e.g., adenocarcinoma versus squamous 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 13 
TABLE 1:SCHEDULE OF ASSESSMENTS FOR THE PRIMARY TREATMENT PHASE. See Section 18 (Appendix 16) for the 
Schedule of Assessments for the Maintenance Phase for the patients who continue treatment with selinexor and/or survival 
follow-up under version ≥3.2 of the protocol. 
Assessment 
Baseline  
(Within 14 days 
prior to C1 D1) 
Day 1 of Each 
Cycle  
(-3 days) 
Day 15 of Each 
Cycle 
(± 3 days) 
After 6 Weeks of 
Treatment 
(± 7 days) 
After 12 Weeks 
of Treatment  
Every 8 weeks 
(± 7 days) Until 
PD 
End of 
Treatment 
(30 days ± 7 
days post-last 
dose) 
Survival 
Status 
(Every 3 
months) 
Informed consent1 
X 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history2 
X 
 
 
 
 
 
 
Pregnancy test (if 
applicable)3 
X 
 
 
 
 
 
 
Physical exam and 
ECOG4 
X 
X 
 
 
 
X 
 
Neurological exam5 
X 
 
 
 
 
 
 
Body height and 
weight6 
X 
X 
X 
 
 
X 
 
BSA 
X 
X 
 
 
 
 
 
Vital signs7 
X 
X 
 
 
 
X 
 
Ophthalmic exam8 
X 
 
 
 
 
 
 
12-lead ECG9 
X 
 
 
 
 
X 
 
Pulse oximetry10 
X 
 
 
 
 
X 
 
Hematology11 
X 
X 
X 
 
 
X 
 
GFR calculation12 (or 
measurement)  
X 
 
 
 
 
 
 
Clinical chemistry13 
X 
X 
X 
 
 
X 
 
Urinalysis14 
X 
 
 
 
 
X 
 
Coagulation test15 
X 
 
 
 
 
 
 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 16 
 
GLOSSARY OF ABBREVIATIONS 
-HCG 
Beta human chorionic gonadotropin 
ADR 
Adverse Drug reaction  
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-last 
Area under the concentration-time curve from time zero to last 
observed non-zero concentration 
AV block 
atrioventricular block 
BID 
Twice daily 
BP 
Blood pressure 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CA 
Competent Authority 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CLL 
Chronic lymphocytic leukemia 
Cmax 
maximum observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CRM1 
Chromosome region maintenance protein 1 
CRO 
Contract research organization 
CSR 
Clinical Study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CYP450 
Cytochrome P450 
D 
Day 
DCR 
Disease Control Rate 
DLBCL 
Diffuse large B-Cell Lymphoma 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-C30 
EOT 
End of treatment 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
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FIGO 
International Federation of Gynecology and Obstetrics 
FPI 
First patient in 
GCIG 
Gynecological Cancer Intergroup 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltransferase 
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
GRP 
Growth regulatory protein 
GSH 
Glutathione 
H 
Hour 
HPV 
Human papillomavirus 
HR 
Hazard ratio 
IC50 
50% inhibitory concentration 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalization ratio 
IRB 
Institutional review board 
ITT 
Intent to treat 
IV 
Intravenous 
LAFB 
Left anterior fascicular block 
LDH 
Lactate dehydrogenase 
LLN 
Lower Limit of Normal 
m² 
Square meter (body surface area) 
LMW 
Low molecular weight 
mg 
Milligram 
MCL 
Mantle Cell Lymphoma 
MI 
Myocardial infarction 
min 
Minute 
mL 
Milliliter 
MM 
Multiple myeloma 
MPA 
Medroxyprogesterone acetate 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute  
NES 
Nuclear export sequences 
NHL 
Non-Hodgkin lymphoma 
NK1R 
Neurokinin-1 receptor 
NPC 
Nuclear pore complex 
NYHA 
New York Heart Association 
ORR 
Overall response rate 


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OS 
Overall survival 
PBMC 
Peripheral  Blood Mononuclear cells 
PD 
Progressive disease, Progression of disease 
PDn 
Pharmacodynamic(s) 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PLT 
Platelets 
po 
By mouth 
PPS 
Per protocol set 
PR 
Partial response 
PRN 
as needed 
PT 
Prothrombin time 
qd 
every day 
qhs 
every night at bedtime 
qid 
Four times a day 
QoL 
Quality of life 
qpm 
every day after noon or every evening 
qRT-PCR 
Quantitative real time polymerase chain reaction 
RBBB 
Right bundle branch block 
RBC 
Red blood cell(s) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 Dose 
RR 
Response Rate 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 
SAM 
S-Adenosyl methionine 
SD 
Stable disease 
SINE 
Selective inhibitor of nuclear export 
SMC 
Safety Monitoring Committee 
SUSAR 
Suspected unexpected serious adverse reaction 
SUV 
Standardized uptake value 
T1/2 
Half-life 
TGI 
Tumor growth inhibition 
Tmax 
Time of first observation of Cmax 
TSP 
Tumor suppressor protein 
ULN 
Upper limit of normal 
WBC 
White blood cell(s) 
WHO 
World Health Organization 
XPO1 
Exportin 1 


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TABLE OF CONTENTS 
1 BACKGROUND AND RATIONALE ................................................................................ 24 
1.1 
Background ................................................................................................. 24 
1.1.1 Gynaecological Malignancies............................................................ 24 
1.1.2 Selinexor ........................................................................................... 27 
1.1.2.1 Mechanism of Action ............................................................ 27 
1.1.2.2 Clinical Experience ............................................................... 28 
1.2 
Rationale ..................................................................................................... 29 
1.2.1 XPO1 and Selinexor in Gynaecological cancer................................. 29 
1.3 
Study Rationale ........................................................................................... 30 
1.4 
Rationale for the Maintenance Phase (Continued Access to Treatment following 
termination of Primary Treatment Phase) .................................................... 30 
2 OBJECTIVES OF THE STUDY ..................................................................................... 31 
2.1 
Primary Treatment Phase ............................................................................ 31 
2.1.1 Objective ........................................................................................... 31 
2.1.2 Secondary Objectives ....................................................................... 31 
2.1.3 Exploratory Objectives ...................................................................... 31 
2.2 
Maintenance Phase ..................................................................................... 31 
3 INVESTIGATIONAL PLAN ........................................................................................... 32 
3.1 
Overview of Study Design and Dosing Regimen ......................................... 32 
3.1.1 Definition of Treatment Cycle and Duration ...................................... 32 
3.2 
Registration of Patients ................................................................................ 33 
3.2.1 Treatment Phase .............................................................................. 33 
3.2.2 End of Treatment Visit ...................................................................... 34 
3.2.3 Follow-Up Phase ............................................................................... 34 
3.3 
Study Duration ............................................................................................. 34 
4 SELECTION OF THE STUDY POPULATION ...................................................... 35 
4.1 
Target Population ........................................................................................ 35 
4.2 
Eligibility Criteria .......................................................................................... 35 
4.2.1 Inclusion criteria ................................................................................ 35 
4.2.2 Exclusion criteria ............................................................................... 36 
5 SCHEDULE OF ASSESSMENT AND PROCEDURES ........................................................ 38 
5.1 
Primary Treatment Phase Study Assessments ........................................... 38 
5.1.1 Tumor Assessments ......................................................................... 38 
5.1.2 Exploratory Assessments ................................................................. 39 
5.1.2.1 Pharmacokinetics ................................................................. 39 
5.1.2.2 Pharmacodynamics .............................................................. 39 
5.1.3 Safety Assessments ......................................................................... 40 
5.1.4 Laboratory Assessments .................................................................. 40 
5.2 
Maintenance Phase (Continued Access to Treatment and Survival Follow-up 
following Termination of the Primary Treatment Phase) .............................. 41 
5.3 
Primary Treatment Phase Study Procedures .............................................. 41 
5.3.1 Baseline ............................................................................................ 41 
5.3.2 Treatment Phase .............................................................................. 42 
5.3.3 End of Treatment .............................................................................. 43 


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5.3.4 Follow-Up .......................................................................................... 43 
5.3.5 End of Study ..................................................................................... 44 
5.4 
Planned Treatment of the Patient after End of Treatment Phase ................ 44 
5.5 
Removal of Patients from Treatment ........................................................... 44 
5.6 
Study Discontinuation .................................................................................. 45 
5.7 
Maintenance Phase (Continued Access to Treatment following Termination of 
the Primary Treatment Phase) ..................................................................... 45 
6 INVESTIGATIONAL PRODUCT .................................................................................... 46 
6.1 
Investigational medicinal product (IMP) ....................................................... 46 
6.2 
Preparation and Administration of Selinexor ................................................ 46 
6.2.1 Drug Name, Formulation and Storage .............................................. 46 
6.2.2 Administration of Study Drug ............................................................ 47 
6.2.3 Compliance ....................................................................................... 48 
6.3 
Dose Modifications for Selinexor ................................................................. 48 
6.3.1 Intrapatient Dose Escalation: ............................................................ 50 
6.3.2 Dose Adjustment Guidelines for Selinexor-Related Toxicities .......... 51 
6.3.3 Selinexor Dose Reduction in the Setting of Infection ........................ 58 
6.3.4 Dose Adjustments with Changes in BSA .......................................... 58 
6.3.5 Missed or Vomited Doses ................................................................. 58 
6.3.6 Dose Adjustments with impressive tumor response .......................... 58 
6.4 
Concomitant Medication and Treatment ...................................................... 59 
6.4.1 Permitted Concomitant Medication ................................................... 59 
6.4.1.1 Prevention of Pregnancy ...................................................... 59 
6.4.1.2 Use of Blood Products ......................................................... 59 
6.4.1.3 Glucocorticoid therapy ......................................................... 60 
6.4.2 Restricted and Prohibited Medications .............................................. 60 
6.4.2.1 Concurrent Therapies .......................................................... 60 
6.4.2.2 Alcohol (ethanol) .................................................................. 60 
6.4.2.3 Acetaminophen (paracetamol) containing medications ........ 60 
6.4.2.4 Miscellaneous ...................................................................... 60 
6.5 
Supportive Care Guidelines ......................................................................... 61 
6.5.1 Required Supportive Care Medication .............................................. 61 
6.5.2 Supportive Care Recommendations for Selinexor-Related Adverse 
Events 61 
6.5.3 Liver Enzyme Increase ..................................................................... 61 
7 ADVERSE EVENT ASSESSMENT ................................................................................. 62 
7.1 
Adverse Events and Laboratory Abnormalities Reporting ........................... 62 
7.1.1 Adverse Event ................................................................................... 62 
7.1.2 Adverse Drug Reaction ..................................................................... 63 
7.1.3 Laboratory Test Abnormalities .......................................................... 63 
7.1.4 Serious Adverse Event ..................................................................... 63 
7.1.5 Events NOT to be reported as SAEs ................................................ 64 
7.1.6 Suspected Unexpected Serious Adverse Reaction (SUSAR) ........... 65 
7.2 
Reporting of SAEs ....................................................................................... 65 
7.2.1 Primary Treatment Phase ................................................................. 65 
7.2.2 Maintenance Phase .......................................................................... 66 
7.3 
AE and SAE Follow-up ................................................................................ 66 
7.4 
Pregnancy ................................................................................................... 66 


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8 STATISTICAL METHODS ........................................................................................... 67 
8.1 
Trial Design and Hypotheses ....................................................................... 67 
8.2 
Sample Size Calculation .............................................................................. 67 
8.3 
Evaluation Categories for Patients .............................................................. 68 
8.3.1 Modified Intent-to-Treat Population ................................................... 68 
8.3.2 Per Protocol Population .................................................................... 68 
8.3.3 Safety Population .............................................................................. 68 
8.4 
Methods of Statistical Analysis .................................................................... 69 
8.4.1 General Statistical Considerations .................................................... 69 
8.4.2 Demographics and Baseline Characteristics .................................... 69 
8.4.3 Efficacy Evaluation ............................................................................ 69 
8.4.4 Safety Evaluation .............................................................................. 71 
8.4.4.1 Adverse Events .................................................................... 71 
8.4.4.2 Laboratory Data ................................................................... 71 
8.4.4.3 Vital Signs and Physical Examinations ................................ 72 
8.4.4.4 Concomitant Medications ..................................................... 72 
8.5 
Interim and Final Analysis ............................................................................ 72 
9 DATA QUALITY ASSURANCE ..................................................................................... 73 
10 ETHICAL ASPECTS .................................................................................................. 74 
10.1 Good Clinical Practice ................................................................................. 74 
10.2 Patient Information and Informed Consent .................................................. 74 
10.3 Independent Ethics Committees and Regulatory Authorities ....................... 74 
10.3.1 Approval of the Study by the Regulatory Authority and Independent 
Ethics Committees ............................................................................ 74 
10.3.2 Notification of the Study .................................................................... 75 
10.3.3 Obligation to Report and Document .................................................. 75 
11 CONDITIONS FOR MODIFYING THE PROTOCOL ........................................................... 76 
12 STUDY DOCUMENTATION, CRFS AND RECORD-KEEPING ........................................... 77 
12.1 Investigator’s Files / Retention of Documents .............................................. 77 
12.2 Source Documents and Background Data ................................................... 77 
12.3 Audits and Inspections ................................................................................. 78 
12.4 Case Report Forms ..................................................................................... 78 
13 MONITORING THE STUDY ......................................................................................... 79 
14 SAFETY MONITORING COMMITTEE ........................................................................... 80 
15 CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS .............................. 81 
16 STUDY REPORT AND PUBLICATION POLICY ............................................................... 82 
17 REFERENCES ......................................................................................................... 83 
18 PROTOCOL VERSION ≥3.2: MAINTENANCE PHASE ................................................... 110 
1. INVESTIGATIONAL PLAN FOR THE MAINTENANCE PHASE ........................................... 110 
1.1. Maintenance Phase Design ....................................................................... 110 
1.1.1. Transition from Primary Treatment Phase to Maintenance Phase .. 110 
1.1.2. Study Treatment ............................................................................. 110 
1.1.2.1. Selinexor Tablets ............................................................... 110 
1.1.2.2. Selinexor Dosing ................................................................ 111 
1.1.2.3. Concurrent Treatments ...................................................... 111 
1.1.3. Study Visits ..................................................................................... 111 
1.1.4. Study Assessments ........................................................................ 111 
1.1.5. End of Treatment (EOT) and End of Study ..................................... 112 


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2. STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 115 
2.1. Objectives .................................................................................................. 115 
2.1.1. Primary Objective ............................................................................ 115 
2.1.2. Secondary Objectives ..................................................................... 115 
2.2. Endpoints ................................................................................................... 115 
3. SELINEXOR SUPPORTIVE CARE AND DOSE MODIFICATIONS ...................................... 115 
3.1. Supportive Care ......................................................................................... 115 
3.1.1. Infection .......................................................................................... 115 
3.2. Selinexor Dose Modifications for Toxicity .................................................. 116 
3.2.1. Reporting of SAEs .......................................................................... 116 
 
LIST OF TABLES 
Table 1: Schedule of Assessments for the Primary Treatment Phase. See Section 18 
(Appendix 16) for the Schedule of Assessments for the Maintenance Phase 
for the patients who continue treatment with selinexor and/or survival follow-
up under version ≥3.2 of the protocol. ....................................................... 13 
Table 2: Pre-specified Dose/Schedule Modifications for AEs Related to Study Drug in 
Part 1 ......................................................................................................... 50 
Table 3: Pre-specified Dose/Schedule Modifications for AEs Related to Study Drug in 
Part 2 ......................................................................................................... 50 
Table 4: Criteria for Dose Adjustments for Selinexor-related Toxicities ................... 51 
Table 5: Classification of Adverse Events by Causality ........................................... 62 
Table 6: Summary of Efficacy Data from Recent Trials for Ovarian Cancer ............ 90 
Table 7: Summary of Efficacy Data from Recent Trials for Cervical Cancer ........... 93 
Table 8: Summary of Efficacy Data from Recent Trials for Endometrial Cancer ..... 94 
Table 9: Evaluation of Best Overall Response in Patients Without Initial Measurable 
Disease and Who Are Evaluable by CA-125 ........................................... 107 
Table 10: Best Overall Response in Patients with Measureable Disease and Who Are 
Also Evaluable by CA-125 ....................................................................... 108 
Table 11: Schedule of Assessments ....................................................................... 113 
 
 
LIST OF APPENDICES 
Appendix 1: 
Summary of Efficacy Data from Recent Trials for Ovarian Cancer ... 90 
Appendix 2: 
Summary of Efficacy Data from Recent Trials for Cervical Cancer ... 93 
Appendix 3: 
Summary of Efficacy Data from Recent Trials for Endometrial Cancer94 
Appendix 4: 
Adverse Event Categories for Determining Relationship to Test Drug96 
Appendix 5: 
Definitions According to ICH Topic E2A Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting ............ 97 
Appendix 6: 
ECOG Performance Status Scale ..................................................... 98 
Appendix 7: 
Cockroft-Gault Formula ..................................................................... 99 
Appendix 8: 
NCI-CTCAE Version 4.03 ............................................................... 100 
Appendix 9: 
Ophthalmic Exam ............................................................................ 101 
Appendix 10: 
NCCN Clinical Practice Guidelines in Oncology:  Antiemesis ......... 102 
Appendix 11: 
NCCN Clinical Practice Guidelines in Oncology:  Anorexia/Cachexia105 
Appendix 12: 
Evaluation of Response According to CA-125 ................................ 106 


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Appendix 13: 
Evaluation of Best Overall Response in Patients Without Initial 
Measurable Disease and Who Are Evaluable by CA-125 ....................... 107 
Appendix 14: 
Best Overall Response in Patients with Measureable Disease and Who 
Are Also Evaluable by CA-125 ................................................................ 108 
Appendix 15: 
Glutathione (GSH), N-Acetylcysteine (NAC), or S-Adenosylmethionine 
(SAM)-Containing Products (Representative List)Glutathione (GSH) .... 109 
Appendix 16 Maintenance Phase ............................................................................ 110 
Appendix 17: 
Summary and Rationale for Changes to Protocol KCP 330-005..... 118 
 


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1 
BACKGROUND AND RATIONALE 
1.1 Background 
1.1.1 Gynaecological Malignancies 
Gynaecological malignancies include all cancer types of the woman’s reproductive 
organs. The main types are cervical, ovarian, uterine, vaginal, and vulvar cancer. 
Ovarian Cancer 
Ovarian cancer continues to be a leading cause of cancer-related deaths in women and 
is the leading cause of deaths attributed to gynaecological malignancies. 
Ovarian cancer was the eighth most common cancer in women in 2008 worldwide with 
roughly 235,000 new diagnoses. Approximately 140,000 women died from ovarian cancer 
making it the seventh leading cause of cancer death in the world.1 Approximately 90% of 
primary malignant ovarian tumors are epithelial carcinomas.2 
The disease is classified into three grades depending on their percentage of solid growth 
on glandular and papillary component by the FIGO (International Federation of 
Gynecology and Obstetrics) system, whereas early disease is defined as FIGO stage I-
IIa, and advanced disease includes FIGO stage IIb-IIIc. In stage IV, distant metastases 
are present.2  
Primary cytoreductive surgery is the method of choice for the initial treatment of patients 
with advanced ovarian carcinoma. In a meta-analysis of 81 studies involving 6,885 
patients, Bristow et al showed that patients with ≤ 25% maximal cytoreduction had a 
median overall survival of 22.7 months, whereas patients with ≥ 75% maximal 
cytoreduction achieved an increase in overall survival of 50%, to 33.9 months.3 Even if 
optimal tumor debulking is not feasible, an interval debulking surgery performed after a 
short course of induction chemotherapy of 2-3 cycles may lengthen survival for the 
individual patient.4  
Because ovarian cancer is usually asymptomatic in its early stages, the disease often has 
spread outside of the pelvic region at the time of diagnosis and requires debulking surgery 
followed by systemic chemotherapy. First-line chemotherapy involves platinum-based 
treatments, 
including 
the 
widely 
adopted 
regimens 
of 
cisplatin/paclitaxel, 
carboplatin/paclitaxel, and single-agent carboplatin. Although these regimens yield 
relatively satisfactory tumor response rates, the vast majority of patients experience 
disease recurrence and receive additional treatments. For such patients, a number of anti-
tumor agents with distinct mechanisms of action (topotecan, gemcitabine, pegylated 
liposomal doxorubicin, docetaxel, etoposide) have been utilized, in addition to retreatment 
with platinum, with the goal of re-establishing remission or disease control, minimizing 
disease-related symptoms, improving quality of life, and extending patient survival.  
Patients with progression during treatment with platinum are called “platinum-refractory”, 
whereas patients who develop recurrence < 6 months after completion of first-line 
platinum chemotherapy have what is known as “platinum-resistant” disease.5 While 
patients with “platinum-sensitive” disease, i.e. > 6 months without recurrence, may 
respond again to a platinum-based chemotherapy, patients with platinum-refractory or 
resistant ovarian carcinoma have a poor prognosis. Most trials suggest that median life 


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expectancy is < 12 months in these resistant/ refractory cases. In these situations, single 
agent treatment is usually recommended outside of the research setting, and the toxicity 
from the chemotherapy regimen should be a major consideration in choosing additional 
therapy. 
It is difficult to justify the use of secondary cytoreductive surgery in women with platinum-
resistant disease due to the significant morbidity of the surgery and the fact that platinum 
resistance is associated with a poor overall prognosis regardless of surgical intervention.6 
Initial platinum-based chemotherapy will produce a response rate of approximately 70% 
in patients with epithelial ovarian cancer. The response rates to second-line therapy vary 
considerably based on the length of time from the completion of therapy to the time the 
recurrence is diagnosed.5 However, when ovarian cancer recurs within 6 months of 
completing chemotherapy, the overall response to additional therapy is very poor. In this 
setting, the most active agents have shown an overall response rate (ORR) of about 10% 
to 30%, with a progression-free survival (PFS) of < 7 months and an OS of approximately 
< 16 months. See Table 6 (Appendix 1).7-33 
Cervical Cancer  
Cervical cancer is the second most common cancer affecting women worldwide, and it 
remains a major health problem in developing countries because of high oncogenic 
human papilloma virus (HPV) infection rates, the absence of screening programs and the 
lack of access to affordable vaccination programs.34 The main cause is HPV infection. 
Although the HPV vaccine is expected to reduce its incidence over the next decades, for 
the present, cervical carcinoma is still a major public health concern.35  
In economically developed countries, most women are diagnosed at early stages 
(associated with frequent Pap smears and/or HPV testing) of their disease and can be 
cured by surgery. However, the risk of recurrent disease is 10–20% for International 
Federation of Obstetrics and Gynecology (FIGO) stages I–IIa and 50–70% in locally 
advanced cases (stages IIb–IVa).39 
Early cervical cancer (FIGO stage IA1 to IIA1) is treated with conization, hysterectomy or 
radical trachelectomy, depending on the stage.36 For patients with locally advanced 
cervical cancer, concurrent platinum-based chemoradiation is the current treatment of 
choice. One meta-analysis with data from 18 randomized trials revealed a 5-year survival 
benefit of 8% for overall disease-free survival, 9% for locoregional disease-free survival, 
and 7% for metastases-free survival. If cisplatin is not tolerated, carboplatin or non-
platinum chemoradiation schedules are options.37 Adjuvant chemotherapy after 
chemoradiation with cisplatin-gemcitabine has demonstrated benefits, but is not yet 
recommended as standard treatment.35-38 
Patients with distant metastases and/or with disease recurrence not amenable to loco-
regional control have a poor prognosis.39 In this setting, systemic chemotherapy is a 
palliative treatment aimed at prolonging survival and improving quality of life (QOL). The 
combination of cisplatin and paclitaxel is considered the standard of care, as it showed a 
higher response rate (RR) and longer progression-free survival (PFS) than single-agent 
cisplatin, although there were no significant differences in QOL.40,41 No other cisplatin 
doublet has shown superiority in overall survival (OS) when compared with cisplatin–


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paclitaxel.42 Responses to platinum-based chemotherapy are short-lived and effective 
second-line options are lacking.43 
The treatment of patients with metastatic or recurrent cervical carcinoma is palliative. 
cisplatin-based regimens are preferred, e.g., cisplatin plus paclitaxel or topotecan, but the 
response is poor especially in patients who have previously undergone chemotherapy.44 
In several clinical trials with women in advanced stage (IVB), which means recurrent or 
persistent cervical cancer, response rates of 3% to approximately 35% have been 
achieved. The median overall survival times ranged from 3.5 to 9.4 months and the 
median progression-free survival times lay between 3.5 months to 7.1 months. See Table 
7 (Appendix 2).45-51 
Endometrial Cancer 
In 2008, endometrial cancer (uterine cancer) was the 6th leading malignancy in women 
worldwide, approximately 288,000 new cases were diagnosed.1 In 2013, endometrial 
cancer was the most common gynaecological malignancy in the United States and other 
developed countries.52  
The standard surgical therapy is total hysterectomy with or without lymphadenectomy, 
depending on the stage of the disease. In stage III-IV, maximal surgical cytoreduction is 
recommended for patients with a good performance status.53 For patients with localized 
endometrial cancer, an optimal adjuvant treatment has not yet established. Options are 
radiotherapy, platinum-based chemotherapy or a combined radiochemotherapy.53-55 
Endometrial cancer generally carries a favorable prognosis, mainly because the majority 
of women present with bleeding early on in the disease course. As a result, the disease 
is caught early and for most women the disease is curable by surgery; 5-year survival 
rates of 80% to 90% are generally reported.56,57 However, for women with advanced stage 
disease or high-risk histologies, the prognosis is poor, with 5-year survival rates of 57% 
for regional disease (stage III) and 19% for distant spread (stage IV).1 
The overall rate of recurrence for endometrial cancer is about 15%, with more than half 
occurring within 2 years of primary treatment. Recurrence rates for patients with early 
stage disease range from 2% to 15%, whereas it is up to 50% in women with advanced 
stage disease or in patients with aggressive histologies (grade 3 or non-
endometrioid).58,59,60  
In the setting of recurrent disease, certain clinico-pathologic factors are associated with a 
good prognosis, including a longer disease-free interval, low-grade and endometrioid 
histology, and isolated recurrence at the vaginal cuff. The disease in women with non-
endometrioid histologies (uterine serous carcinoma and clear cell) behaves more 
aggressively and carries a significantly worse prognosis in regard to response to 
chemotherapy and overall survival.  
Although non-endometrioid histologies, such as uterine serous cancer and clear cell, 
constitute < 10% of all cases of endometrial cancer, they account for a disproportionately 
high number of cancer-related deaths and cases of recurrence.61-66 The poor prognosis 
associated with serous tumors, in particular, may be due to their advanced disease at the 
time of diagnosis.64 


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In addition to isolated vaginal recurrences, patients may present with disease isolated to 
the pelvis, which is considered a loco-regional recurrence. For these patients, treatment 
is similar to the management of metastatic disease. 
Survival rates for women whose disease recurs outside of the pelvis are dramatically lower 
than those for women with a local, vaginal relapse. In fact, they are comparable to those 
of women with distant disease.67 
For women with metastatic disease, the predominant modality of treatment is systemic 
therapy with either endocrine therapy or chemotherapy. However, the prognosis for these 
patients is poor. Cytotoxic chemotherapy has activity in endometrial cancer with response 
rates ranging from 7 to 25%. See Table 8 (Appendix 3)68-83. 
There is no single optimal treatment regimen. Rather, one must consider the patient’s 
performance status and prior treatment history.  
1.1.2 Selinexor 
1.1.2.1 Mechanism of Action 
Exportin-1 (XPO1, also called chromosomal region maintenance protein 1 [CRM1]) is a 
nuclear export protein that transports tumor suppressor proteins (TSPs) out of the 
nucleus, leading to their inactivation. XPO1 is overexpressed 2-4 fold in all cancers 
studied to date and overexpression is frequently correlated with poor prognosis and/or 
reduced survival, suggesting that XPO1 could have a direct role in the etiology of the 
malignant phenotype.  
Selinexor (KPT-330) is a first-in-class Selective Inhibitor of XPO1-mediated Nuclear 
Export (SINE) compound that binds and inactivates XPO1. XPO1 inhibitors, including 
selinexor, have been shown to block the nuclear export of key TSPs (e.g., p53, IkB, FOXO 
and p21) into the cytoplasm, leading to their accumulation in the nucleus, as nuclear 
import proceeds unimpeded. Moreover, nuclear retention appears to prevent proteasome-
mediated degradation (which is typically cytoplasmic) of these TSPs. Forced nuclear 
retention of TSPs leads to activation of their tumor suppressing functions and can 
counteract a multitude of oncogenic (and inflammatory) pathways that perpetuate the 
neoplastic phenotype. Forcing nuclear retention of proteins such as survivin84 and 
p21CIP185 that can be anti-apoptotic when present in the cytoplasm can prevent their anti-
apoptotic functions and, for p21, expose its antitumor activities. 
In addition, XPO1 inhibition prevents the eIF4e-mediated messenger ribonucleic acid 
(mRNA) nuclear export of proteins with short half-lives, leading to down regulation of 
multiple oncogenic proteins including FLT3, c-KIT, cyclin D1, and c-MYC, further providing 
anticancer activity. 
Inhibition of XPO1 activity by selinexor also reduces deoxyribonucleic acid (DNA) damage 
repair, enhancing the effect of DNA damaging agents (e.g., X-rays and alkylating agents) 
on cancer cells and promoting apoptosis86,87. 
More information about the mechanism of action, pharmacology, nonclinical, and ongoing 
clinical studies for selinexor are available in the Selinexor/KPT-330 Investigator’s 
Brochure (IB). 


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1.1.2.2 Clinical Experience 
1.1.2.2.1 Overview 
Selinexor is currently in clinical development and has not been approved by any regulatory 
authority for commercial use. 
Phase 1 and 2 studies with oral selinexor are being conducted in patients with advanced 
hematological malignancies and solid tumors (multiple indications for each). As of 01 June 
2016, more than 1500 patients have received selinexor in Karyopharm Therapeutics Inc. 
(Karyopharm)-sponsored clinical studies, most with single-agent selinexor. (Additional 
patients have been treated in investigator-sponsored studies.) Based on preliminary, 
interim, unaudited safety for 1175 patients from Karyopharm-sponsored studies as of 31 
May 2016, selinexor has been relatively well tolerated, with the most frequently reported 
treatment-emergent adverse events (TEAEs) being low-grade nausea, fatigue, anorexia, 
vomiting, and thrombocytopenia that were generally manageable with standard supportive 
care88. (Additional information is provided in the Selinexor/KPT-330 IB.) Selinexor 
treatment is not associated with significant major organ toxicity. Moreover, clinically-
relevant cumulative toxicities have not been observed during long-term treatment, with 
more than 15 patients remaining on selinexor therapy for > 1 year, with the longest for > 
2 years. 
1.1.2.2.2 Potential Risks of Selinexor 
Since selinexor is still being evaluated in ongoing clinical studies, the full safety profile for 
selinexor is not defined. A summary of safety results reported as of 31 May 2015 is 
provided in the Selinexor/KPT-330 IB.  
In ongoing clinical studies, the most common AEs suspected to be related to selinexor 
(incidences in parentheses) have been low-grade nausea (55%), fatigue (54%), anorexia 
(43%), vomiting (35%), and mild/moderate thrombocytopenia (30%). Most of these effects 
can be managed effectively with dose modification and/or supportive care initiated prior 
to first dosing.  
In a previous study, one patient who had been, heavily pre-treated for recurrent pancreatic 
cancer, developed acute cerebellar syndrome following 3 doses of selinexor at 85 mg/m2 
body surface area (BSA) twice weekly. The patient experienced abnormal speech, loss of 
coordination, and was unable to walk. Since the date of the initial reported event, this 
patient is recovering, with both speech and mobility recovered to near baseline over ~6 
weeks. No other patients have reported similar symptoms to date.  
Low-grade blurred vision was reported in 12% of patients treated with selinexor. In 
patients without pre-existing cataracts, blurred vision was not associated with objective 
findings of lens opacity (or other abnormalities) on expert ophthalmic examination. The 
cases have generally been self-limiting without progression, even when selinexor dosing 
was continued.  
Overall, increased rates of infection associated with selinexor have not been reported, 
however greater incidences of sepsis were seen with selinexor versus physician’s choice 
in patients with relapsed/refractory acute myeloid leukemia (AML) who were > 60 years 
of age and receiving higher doses of selinexor (most patients were receiving 100 mg) in 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 32 
3 
INVESTIGATIONAL PLAN 
3.1 Overview of Study Design and Dosing Regimen 
This trial has been designed as a multi-center, open-label, Simon two-stage, Phase 2 
study with 3 parallel gynaecological cancer cohorts, with an additional set of patients in 
the ovarian cohort randomized into two different dosing regimens. This study will include 
a Primary Treatment Phase and a Maintenance Phase. 
Primary Treatment Phase 
Patients are informed, screened and enrolled in the study after PD on prior chemotherapy 
documented by CT/ MRI. Selinexor treatment should be started within two weeks after 
enrollment.  
The cohorts to be enrolled in Parts 1 and 2 are: 
 Part 1 – Three parallel cohorts of patients with ovarian (Cohort A), endometrial 
(Cohort B), or cervical (Cohort C) carcinoma will be enrolled.  
 Part 2 - Based on the observed tolerability and efficacy profile in the ongoing 
ovarian cohort (Cohort A), two additional treatment schedules will be explored to 
optimize the dosing schedule in patients with ovarian carcinoma.  
Clinical and radiological examinations for disease status as well as QoL assessments will 
be performed at baseline, after 6 and 12 weeks of treatment, and approximately every 8 
weeks thereafter.  
Treatment will continue until PD or unacceptable toxicity, death, withdrawal of consent by 
the patient, or patient discontinuation due to non-compliance with protocol requirements. 
Safety assessments will be performed at the baseline visit and during each cycle through 
the EoT visit.  
If a patient discontinues treatment due to any reason other than PD, death, or withdrawal 
of informed consent, the disease evaluations shall continue until PD. This includes 
patients who wish to discontinue treatment, but agree to have further data captured for 
the purpose of the study. 
After treatment discontinuation, a call will be made to the patient (or the patient’s family) 
approximately every 3 months to inquire about the patient’s survival status. 
Maintenance Phase (Continued Access to Treatment and Survival Follow-up 
Following Termination of the Primary Treatment Phase) 
See Section 18 (Appendix 16) for a description of the investigational plan (including the 
schedule of assessments) for the Maintenance Phase of the study (protocol version ≥3.2). 
3.1.1 Definition of Treatment Cycle and Duration 
Each cycle is 28 days (4 weeks) long. In twice-weekly dose schedules (i.e., Part 1 and 
Part 2, Schedule 1), 8 doses of selinexor will be administered per cycle. In the once-
weekly dose schedule (i.e., Part 2 Schedule 2), 4 doses of selinexor will be administered 
per cycle. Twice-weekly doses of selinexor must be administered at least 36 hours apart; 
once weekly doses of selinexor must be administered at least 5 days apart. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 33 
Dose escalations and reductions/interruptions are permitted according to safety 
guidelines in this protocol or in consultation with a sponsor representative (see 
Section 6.3). 
Dose schedules in Parts 1 and 2 are as follows: 
 Part 1:  Patients will receive oral selinexor 50 mg/m² twice weekly (e.g., Monday 
and Wednesday, Tuesday and Thursday, Wednesday and Friday or Thursday and 
Saturday) in each week of a 4-week cycle.  
 
 Part 2:  
o Schedule 1 – Patients will receive oral selinexor 35 mg/m² twice weekly 
(e.g., Monday and Wednesday, Tuesday and Thursday, Wednesday and 
Friday or Thursday and Saturday) in each week of a 4-week cycle. 
o Schedule 2 – Patients will receive oral selinexor 50 mg/m² once weekly in 
each week of a 4-week cycle (e.g., Monday of each week).  
3.2 Registration of Patients  
Patients to be enrolled are as follows: 
 Part 1:  As described in Section 8.2, approximately 21 evaluable patients will be 
enrolled in each cohort (Cohorts A, B, and C). 
 Part 2:  Approximately 32 additional patients (16 per schedule) with ovarian cancer 
will be enrolled in Cohort A. Each patient enrolled into this part of the study will be 
randomized into two treatment groups (Schedule 1 and Schedule 2) using 
centralized randomization via an interactive web-response system (IWRS). 
Randomization will be performed within the ovarian cohort and will not be specific 
to the study site. 
Study drug administration may be delayed for toxicity as described in Section 6.3. 
Patient eligibility will be confirmed by GSO once all screening procedures are completed. 
There will be no exceptions. Any questions should be addressed to GSO prior to 
registration. The eligibility check form/ Patient Registration Form will be sent from the site 
to GSO either by fax or email for evaluation. Upon confirmation of eligibility, GSO will 
assign a patient number and return the signed eligibility check form/ Patient Registration 
Form via fax or email to the site. The Patient Registration Form will confirm the treatment 
arm in which the patient will participate. 
GSO  
Fax:  0049-40-44 19 54 78  
UMS Fax:  0049- 32 12 14 88 842 
Email:  sign@gso-hamburg.com 
3.2.1 Treatment Phase  
Treatment will be continued until PD is demonstrated by CT/MRI, unacceptable toxicities 
occur in individual patients, death, consent is withdrawn, or discontinuation due to non-
compliance by the patient. Details of the study schedule are illustrated in the Table 1. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 34 
3.2.2 End of Treatment Visit  
Patients that discontinue from treatment will undergo an EoT visit, regardless of the 
reason of discontinuation, 30 days (± 7 days) after the last dose of study medication. 
3.2.3 Follow-Up Phase  
Investigators should continue to collect survival data for patients after PD unless the 
patient withdraws consent to participate in the study.  
After treatment discontinuation, a call will be made to the patient (or the patient’s family) 
approximately every 3 months to inquire about the patient’s survival status. If the patient 
has died, the patient’s date of death will be collected, together with the reason for death, 
if possible. 
3.3 Study Duration 
Patients will be followed as outlined in Section 3.2 until the End of Study (EoS). End of 
study will be defined as 30 days after the last patient has PD, an unacceptable toxicity, 
withdrawn consent or died. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 35 
4 
SELECTION OF THE STUDY POPULATION 
4.1 Target Population 
Three cohorts of patients will be enrolled in parallel: 
 Cohort A: patients with ovarian, fallopian tube, or peritoneal carcinoma who are 
platinum refractory or platinum resistant and have received at least one line of 
chemotherapy for relapsed disease will be enrolled. (Part 1 and Part 2) 
 Cohort B: patients with endometrial carcinoma who have received at least one line 
of chemotherapy for relapsed or advanced (stage IVb, IIIc) disease will be enrolled. 
(Part 1) 
 Cohort C: patients with cervical carcinoma who have received at least one line of 
chemotherapy for relapsed or advanced (stage IV) disease will be enrolled. (Part 
1) 
Progression of disease (PD) on prior treatment must be documented by CT/MRI. Baseline 
tumor assessment must have taken place within 4 weeks prior to start of treatment. Under 
no circumstances are patients, who were previously enrolled in this study, permitted to re-
enroll. 
4.2 Eligibility Criteria 
4.2.1 Inclusion criteria  
To be eligible for enrollment, patients must fulfill the following  criteria:  
1. Female patients aged ≥18 years 
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 
3. Adequate hematologic function defined as:  
 platelets ≥ 125 x 109/L  
 hemoglobin ≥ 5.59 mmol/L or 9 g/dL 
 ANC ≥ 1.5 x 109/L 
 WBC ≥ 3.0 x 109/L 
 Up to 5% deviation is tolerated. Transfusions and growth factors are allowed. 
4. Adequate liver function defined as adequate hepatic function within 14 days prior to 
Cycle 1 Day 1: total bilirubin < 2 times the upper limit of normal (ULN) (except patients 
with Gilbert’s syndrome, who must have a total bilirubin of < 3 times ULN), aspartate 
aminotransferase (AST) < 2.0 times ULN, and alanine aminotransferase (ALT) < 2.0 
times ULN. In the case of known (radiologically and/or biopsy- documented) liver 
metastasis, AST < 5.0 times ULN and ALT < 5.0 times ULN is acceptable. Up to 10% 
deviation is acceptable. 
5. Renal function defined as a calculated or measured glomerular filtration rate 
≥ 30 mL/min. 
6. The patient has recovered to Grade ≤ 1 by the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.03 (NCI-CTCAE v4.03) from the 
effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other 
targeted therapies, with the exception of alopecia. The exceptions for such effects are 
allowed lab values of ≤ Grade 2 specified elsewhere in these inclusion criteria. 
7. Life expectancy of at least 12 weeks. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 36 
8. Able to swallow and retain oral medication. 
9. Patients must give informed consent according to the rules and regulations of the 
individual participating sites. 
10. Negative serum pregnancy test in women of childbearing potential within 14 days of 
first dose of treatment, and patients of childbearing potential must agree to use 
effective contraception during treatment up to 3 months from last dose. Fertile male 
partners must be willing and able to use effective non-hormonal means of 
contraception (barrier method of contraception in conjunction with spermicidal jelly, or 
surgical sterilization) during and for at least 6 months post-study treatment. 
11. The patient must be recovered from any prior treatment/major operation. The 
treatment/major operation must be performed at least 4 weeks prior to start of study 
drug. Palliative radiotherapy is permitted until one week prior to the start of study drug. 
12. Only incurable patients with histologically or cytologically proven primary tumor and 
objective documentation of disease progression on prior treatment by CT/MRI may be 
enrolled. 
13. Ovarian, fallopian tube, or peritoneal carcinoma:  both platinum refractory* and 
platinum resistant** patients, who have received ≥1 line of chemotherapy for 
relapsed disease (i.e., ≥ 2 lines of chemotherapy in total).  
* Platinum refractory is defined as progression during or within 4 weeks of last 
treatment with a platinum-containing therapy. 
** Platinum resistant is defined as relapse 4 weeks to < 6 months after a 
platinum-containing therapy. 
14. Endometrial carcinoma:  patients must have received ≥ 1 line of chemotherapy for 
relapsed or advanced (stage IV, IIIc) disease. 
15. Cervical carcinoma:  patients must have received ≥ 1 line of chemotherapy for relapsed 
or advanced (stage IVb) disease. 
16. Carcinosarcomas (Malignant Mixed Mullerian Tumor) are allowed, but all other non-
epithelial cancers of the ovary, fallopian tube, endometrium, or cervix are excluded. 
17. Patients must have either measurable disease per RECIST 1.1 or evaluable disease 
outside irradiated field on CT/MRI. For ovarian cancer:  Patients must have disease 
that is measurable according to RECIST or assessable according to the GCIG CA-125 
criterion. A rise in CA-125 or other tumor marker alone is not sufficient. 
4.2.2 Exclusion criteria  
Patients who meet any of the following  exclusion criteria will not be eligible for the study: 
Patients with any of the following will not be eligible for participation: 
1. Disease-Specific Exclusions: 
 
Evidence of complete or partial bowel obstruction.  
 
Need of Total Parenteral Nutrition. 
2. Patients who are pregnant or breast feeding. 
3. Radiation (except planned or on-going palliative radiation to bone outside of the region 
of measurable disease) ≤ 3 weeks prior to Cycle 1 Day 1. 
4. Chemotherapy, endocrine therapy, immunotherapy or any other systemic anti-cancer 
therapy (including investigational anti-cancer therapy) ≤ 3 weeks prior to Cycle 1 
Day 1. 
5. Diagnosis or recurrence of invasive cancer other than the present cancer within 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 37 
3 years (except basal or squamous cell carcinoma of the skin that has been definitively 
treated). 
6. Unstable cardiovascular function: 
o Symptomatic ischemia, or  
o Uncontrolled clinically significant conduction abnormalities (e.g. ventricular 
tachycardia on anti-arrhythmics are excluded and 1st degree AV block or 
asymptomatic LAFB/ RBBB will not be excluded), or  
o Congestive heart failure (CHF) of NYHA Class ≥ 3, or myocardial infarction (MI) 
within 3 months of Cycle 1 Day 1. 
7. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals 
within one week prior to the first dose. Active infection with concurrent treatment is 
acceptable only if the patient is clinically stable. 
8. Significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or 
diarrhea. 
9. Concurrent therapy with approved or investigational anti-cancer therapeutics. 
10. Medical, psychological, or social conditions that may interfere with the patient's 
participation in the study or evaluation of the study results. 
11. Known brain metastases unless adequately treated (surgery or radiotherapy) with no 
evidence of progression and neurologically stable off anticonvulsants and 
glucocorticoids. 
12. All non-epithelial cancers of the ovary, fallopian tube, peritoneum, endometrium or 
cervix as well as neuro-endocrine tumors are excluded. 
 
 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 38 
5 
SCHEDULE OF ASSESSMENT AND PROCEDURES 
5.1 Primary Treatment Phase Study Assessments 
5.1.1 Tumor Assessments 
Objective response will be evaluated based on RECIST v. 1.1 using CT or MRI101. For 
patients with multiple measurable lesions, up to 5 lesions in total and 2 lesions per organ 
should be identified.  
The imaging modality (i.e., either CT or MRI) used for measurement of lesions will be left 
to the discretion of the Investigator, however, for each patient the same technique must 
be used throughout the study, assessed whenever possible by the same person. 
The CT/MRI scan of the abdomen must include the pelvis. A PET-CT is allowed for all 
patients, but ultrasound and x-ray of thorax for patients with is not sufficient for protocol 
requirements. If optional PET-CT scan is employed at baseline and first evaluation, 
standardized uptake value (SUV) should be reported for each of the target lesions 
determined in the assessment according to RECIST v.1.1 and for any new lesions. 
All lesions identified at screening must be assessed at each scheduled tumor 
measurement. Patients with measurable lesions will be eligible for inclusion. Measurable 
lesions must have at least one diameter of 10 mm by CT scan (CT slice thickness no 
greater than 5 mm. When CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness). Where there are several 
lesions, assessment is based on the sum of the longest diameters of the individual target 
lesions. Lymph nodes with a short axis of > 15 mm are considered measurable and 
assessable as target lesions. The short axis measurement should be included in the sum 
of lesions in calculation of tumor response. Nodes that shrink to < 10 mm short axis are 
considered normal. All other pathological nodes (those with short axis > 10 mm but < 15 
mm) should be considered as non-target lesions.  
A CT/MRI scan must be performed if there is clinical suspicion of relapse in order to 
document PD; in cases where there is suspicion of PD before the next scheduled 
assessment, an unscheduled tumor assessment should be performed. 
If a detected increase in tumor size is below the resolution limit of the CT/MRI scanner, it 
is acceptable to continue with treatment until a second assessment at a later time point 
unequivocally confirms PD. Partial response (PR) requires confirmation with a follow-up 
scan at least 4 weeks apart.  
The following are defined as non-target lesions: bone lesions, leptomeningeal disease, 
pleural/ pericardial effusion, ascites, inflammatory breast disease, lymphangitis, cystic 
lesions and lesions not measurable by CT/MRI. All non-target lesions are described over 
time and need not be measured. 
The tumor assessment for inclusion must be recorded and measured within 28 days prior 
to treatment start.  
A first evaluation of disease status by imaging will be done after 6 weeks of treatment. 
The second tumor assessment will be performed after 12 weeks. Thereafter, tumor 
assessments will be performed every 8 weeks during treatment, independent of cycle 
delays.  


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 41 
 Urinalysis: urine bilirubin, glucose, hemoglobin, ketones, pH, and protein.  
 Coagulation test: prothrombin time (PT), international normalization ratio (INR), and 
activated partial thromboplastin time (aPTT). 
 CA-125 (Ovarian cancer patients only) 
5.2 Maintenance Phase (Continued Access to Treatment and Survival Follow-up 
following Termination of the Primary Treatment Phase) 
See Section 18 (Appendix 16) for a description of the investigational plan (including the 
schedule of assessments) for the Maintenance Phase of the study (protocol version ≥3.2). 
5.3 Primary Treatment Phase Study Procedures  
5.3.1 Baseline  
All patients will be screened and baseline procedures performed within 14 days prior to 
the start of treatment on Cycle 1 Day 1, unless specified otherwise below:  
Procedure 
Notes 
Signed written informed consent 
Obtained prior to any study-specific assessments 
Demographics and medical history 
 
Age, gender, ethnic background 
 
Details on tumor diagnosis 
 
Details on prior cancer therapy, including start and 
stop dates, disease progression during or after 
therapy, as well as discontinuation due to toxicities 
 
Previous and concurrent relevant diseases 
 
Current symptoms and/or residual toxicities from 
prior therapies 
Pregnancy test (if applicable) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years. In case the sampling date 
for the serum pregnancy test exceeds 7 days before 
treatment start, a urine test is required for 
confirmation. 
Physical examination and vital 
signs  
 
Body height and weight 
 
BSA 
 
Blood pressure, pulse, temperature 
 
Pulse oximetry 
 
Physical examination 
ECOG performance status  
Please refer to Appendix 6 
Standard clinical neurological 
examination  
A neurological exam will be performed to assess motor, 
sensory and balance functions. 
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). Please 
note:  patients enrolled under a prior version of the 
protocol who had detectable cataracts graded 
according to the LOCS III will continue to have their 
cataracts graded according to LOCS III and will not 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 44 
5.3.5 End of Study 
The primary statistical analysis will be performed after all patients have discontinued 
treatment with study medication.  
5.4 Planned Treatment of the Patient after End of Treatment Phase 
After receiving their final dose of study drug, patients will generally be treated at the 
discretion of the Investigator according to medical routine.  
5.5 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 who are withdrawn from the study will 
not be replaced. 
Patients will be removed from further treatment for the following reasons: 
 Disease progression (PD) 
 Adverse event (unacceptable toxicity) 
 Non-compliance 
 Need of treatment with medications not allowed by the study protocol 
 Patient no longer consents to participate in the study 
 Intercurrent illness that interferes with study assessments 
 Incidence or severity of AEs in this study indicates a potential health hazard to the 
patient 
 Investigator discretion 
 Pregnancy 
 Termination of the study by the Sponsor 
If there is a medical reason for withdrawal of treatment, the patient will remain under the 
supervision of the Investigator until AEs (if relevant) have resolved or declined to baseline 
values. 
If a patient fails to attend scheduled assessments or withdraws consent to participate in 
the study, every effort will be made to determine the reasons and circumstances as 
completely and accurately as possible.  
When a patient discontinues study treatment, the EoT visit should be performed, if 
possible. The eCRF section entitled “End of Treatment” must be completed in all cases. 
If the reason for removal of a patient from the study is an AE or abnormal laboratory test 
result, the principal specific event or test will be recorded on the eCRF. 
If a patient is discontinued from study treatment, the patient should still be followed for PD 
and survival. If a patient withdraws consent for further participation in the study, follow-up 
assessments will be discontinued. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 45 
5.6 Study Discontinuation 
The study may be discontinued at the sole discretion of the Sponsor for any reason, 
including medical or ethical reasons affecting the continued performance of the study, or 
difficulties in the recruitment of patients. Medical reasons may include, but are not limited 
to, such features as deemed by the Safety Monitoring Committee (SMC) to constitute an 
unacceptable risk to the patients in the study, such as lack of efficacy or SAEs, such as 
Grade 4 anorexia and fatigue unresponsive to medical treatment.  
The sponsor (Karyopharm), in conjunction with appropriate regulatory authorities, will 
determine if the trial should be modified or terminated. If this occurs, the sponsor will notify 
IRBs and Investigators. 
5.7 Maintenance Phase (Continued Access to Treatment following Termination 
of the Primary Treatment Phase) 
See Section 18 (Appendix 16) for a description of the investigational plan (including the 
schedule of assessments) for the Maintenance Phase of the study (protocol version ≥3.2). 
 
 


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6 
INVESTIGATIONAL PRODUCT 
6.1 Investigational medicinal product (IMP) 
An investigational medicinal product (IMP) is a pharmaceutical form of an active 
substance or placebo being tested or used as a reference in a clinical trial, including 
products already with a marketing authorization but used or assembled (formulated or 
packaged) in a way different from the authorized form, or when used for an unauthorized 
indication, or when used to gain further information about the authorized form. 
The IMP in this study is selinexor (KPT-330). 
The Investigator or other appropriate individual, who is designated by the local principal 
Investigator, should maintain records of the inventory at the site, the use for each patient 
and delivery, storage and destruction. Investigators should maintain records that 
adequately document that patients were provided the doses specified in the protocol and 
reconcile all investigational product(s) received from the sponsor. 
6.2 Preparation and Administration of Selinexor 
The Investigator or responsible site personnel must instruct the patient or caregiver to 
take the study drug as described in this protocol. Study drug will be dispensed to the 
patient by authorized site personnel only. All dosages prescribed to the patient and all 
dose changes during the study must be recorded on the Dosage Administration Record 
eCRF. 
Selinexor tablets, with instructions for administration, will be 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. 
6.2.1 Drug Name, Formulation and Storage 
Recommended INN:   
Selinexor 
Company´s Drug ID:  
KPT-330 
Chemical name: 
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-
(pyrazin-2-yl)acrylohydrazide 
Classification: 
Cell biological modifier: Apoptosis-inducing agent 
Mechanism of action: 
Selinexor is a Selective Inhibitor of Nuclear Export/SINE 
compound that specifically blocks nuclear export by reversible 
covalent binding to XPO1 protein.  
Molecular formula: 
C17H11F6N7O 
Molecular weight: 
443.31 
Approx. solubility:  
< 0.03 mg/mL in water (pH 2-8) 
 
> 10 mg/mL in dimethylsulfoxide 
 
< 2 mg/mL in 40% v/v PEG-400/ H2O 
 
< 2 mg/mL in 15% v/v EtOH/ H2O 


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Tablets: 
Selinexor (KPT-330) for oral administration will be supplied in up to three (3) tablet 
strengths: 10 mg, 20 mg, and 25 mg. Bulk bottles of 50 tablets per bottle will be supplied 
to the pharmacies for both the 10 mg and 25 mg strength tablets. The 20 mg tablets will 
be provided in blister packs when available. 
Labeling: 
Each bottle or blister pack of selinexor tablets will be labeled in accordance with current 
ICH guidelines and specific national requirements. 
Storage: 
10 mg and 25 mg Tablets 
Selinexor tablets will be supplied in white high-density polyethylene (HDPE) bottles with 
induction seals and desiccant. They will be stored at ambient temperatures between 5–
30 °C in a locked and secured area with restricted access to study staff. Do not freeze. 
20 mg Tablets 
Selinexor tablet blister packs can be stored at room temperature or refrigerated, at or 
below 86 ˚F or 30 ˚C, but not frozen. Room temperature storage is recommended. The 
study site will be required to maintain documentation of the temperature and/or 
temperature excisions where the study medication is stored. 
6.2.2 Administration of Study Drug 
The dose of selinexor to be administered will be determined, by patient, on a mg/m² basis, 
based on the patient’s actual calculated body surface area (BSA) at baseline. Patients 
with a BSA > 2.5 m² will receive a dose based upon a 2.5 m² BSA. 
Primary Treatment Phase 
Dose Schedules in Parts 1 and 2: 
 Part 1:  Selinexor tablets will be dosed at 50 mg/m2 orally twice weekly (e.g., 
Monday and Wednesday, Tuesday and Thursday, Wednesday and Friday or 
Thursday and Saturday) in each week of a 4-week cycle. 
 Part 2:  
 Schedule 1 – Selinexor tablets will be dosed orally at 35 mg/m² twice weekly 
(e.g., Monday and Wednesday, Tuesday and Thursday, Wednesday and Friday 
or Thursday and Saturday) in each week of a 4-week cycle. 
 Schedule 2 - selinexor will be dosed orally at 50 mg/m² once weekly (e.g., 
Monday of each week) in each week of a 4-week cycle. 
Once- and Twice-weekly Dose Schedules: 
 Twice-weekly dose schedules (Part 1 and Part 2 Schedule 1): Eight (8) doses of 
selinexor will be administered, ≥ 36 hours apart, during each 28-day (4-week) cycle. 
 Once-weekly dose schedules (Part 2 Schedule 2): Four (4) doses of selinexor will 
be administered, ≥ 5 days apart, in each 28-day (4-week) cycle.  


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Selinexor should be taken with a light meal (to optimize tolerability) together with 120 mL 
(4 ounces) of water. 
Maintenance Phase: See Section 18 (Appendix 16) for study treatment during the 
Maintenance Phase of the study (Version ≥ 3.2). 
6.2.3 Compliance 
The Investigator should ensure that the investigational product is used only in accordance 
with the protocol. All doses given are to be documented in the eCRF, including exact dose, 
number of tablets, time and date administered. The principal Investigator or the designee 
will account for the number of tablets dispensed against those stored at the site. Any 
deviations and missed doses will be recorded in the eCRF and drug accountability logs 
for verification with the reasons for missed doses. The Investigator/ designee will try to 
ensure complete compliance with the dosing schedule by providing timely instructions to 
the patients. It will be requested from patients to document intake of selinexor in a patient 
diary. 
The investigational product should be stored as specified by the sponsor and in 
accordance with applicable regulatory requirements. 
6.3 Dose Modifications for Selinexor 
See Section 18 (Appendix 16) for supportive care and dose modification 
recommendations during the Maintenance Phase of the study (Version ≥3.2). 
Toxicity will be graded according to NCI CTCAE, v.4.03; the therapy modifications 
described below are applied according to this severity grading. 
If more than one different type of toxicity occurs concurrently, the most severe grade will 
determine the modification. 
Re-escalation of the study drug is only allowed as outlined in the sections that apply for 
the specific toxicity. If toxicity requires a treatment delay of more than 4 weeks the patient 
is taken off protocol treatment.  
Each dose modification or treatment delay has to be documented in the eCR, including 
the respective reason. 
Based on observations from the ongoing Phase 1 studies in patients with advanced 
hematological and solid tumors, selinexor (KPT-330) shows a wide therapeutic range, 
with documented anti-cancer activity from ~ 12 mg/m2 to ≥ 50 mg/m2 orally twice weekly. 
At the time of Part 1 it could not be predicted which patient's tumors would respond to 
lower doses, nor could tolerability be predicted. Therefore, in order to individualize and 
optimize therapeutic benefit with selinexor, initiation of study therapy occurred at a dose 
just below the MTD (50 mg/m2 twice weekly by mouth). To optimize specific anti-tumor 
activity and the patient’s tolerability, dose and/or schedule modifications were allowed. 
Based on preliminary findings from this study and other studies, the dosing in Part 2 was 
modified as follows:  Part 2 Schedule 1 to 35 mg/m² twice weekly, Part 2 Schedule 1 to 
50 mg/m2 once weekly. Dose modifications are allowed as described in Table 2 and 
Table 3. 
Patients should also be treated aggressively with supportive care to reduce toxicities. 


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Patients will continue to receive selinexor until they need to have their dose reduced 
below the 35 mg/m2 once weekly (reduced) dose in Part 1 and Part 2 (Schedules 1 and 
2), at which time treatment will be discontinued. 
 


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Table 2: 
Pre-specified Dose/Schedule Modifications for AEs Related to Study 
Drug in Part 1 
Dose Level 
Dose of Selinexor 
Dose level 0 
50 mg/m2 twice weekly (D1, D3) 
Dose level -1 
35 mg/m2 twice weekly (D1, D3) 
Dose level -2 
50 mg/m2 once weekly (D1) 
Dose level -3 
35 mg/m2 once weekly (D1) 
Dose level -4 
Discontinue dosinga 
a 
Patient discontinues treatment, but continues to be assessed. 
Table 3: 
Pre-specified Dose/Schedule Modifications for AEs Related to Study 
Drug in Part 2 
Dose Level 
Schedule 1 
Schedule 2 
Dose level 0 (Starting dose) 
35 mg/m2 twice weekly  
50 mg/m2 once weekly  
Dose level -1 
50 mg/m2 once weekly  
35 mg/m2 once weekly  
Dose level -2 
35 mg/m2 once weekly  
Discontinue dosinga 
Dose level -3 
Discontinue dosinga 
Not applicable 
a 
Patient discontinues treatment, but continues to be assessed. 
6.3.1 Intrapatient Dose Escalation: 
Intrapatient dose escalation can be considered after 12 weeks for patients in Part 1 and 
after 6 weeks for patients in Part 2 if the patient has not experienced a major toxicity; this 
requires approval of the Sponsor. Intrapatient dose escalations will be permitted as 
follows: 
Part 1:  Dose increase to 60 mg/m2 twice weekly in each week of a 4-week cycle. 
Part 2 Schedule 1:  Dose increase to 50 mg/m2 twice weekly in each week of a 4-week 
cycle (8 doses total). 
Part 2 Schedule 2:  Dose increase to 60 mg/m2 once weekly in each week of a 4-week 
cycle (4 doses total). 


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6.3.2 Dose Adjustment Guidelines for Selinexor-Related Toxicities 
Table 4: 
Criteria for Dose Adjustments for Selinexor-related Toxicities 
Toxicity and Intensity 
Dose Modification 
Part 1:  50 mg/m2 twice weekly 
Part 2, Schedule 1:  35 mg/m2 twice 
weekly – Ovarian only 
Part 2, Schedule 2:  50 mg/m2 once 
weekly – Ovarian only 
Fatigue (common) 
Grade 1 
Ensure adequate caloric intake and 
assess volume status. Adjust other 
medications. Rule out other causes of 
fatigue such as electrolyte imbalance, 
hyperglycemia. 
Ensure adequate caloric intake and 
assess volume status. Adjust other 
medications. Rule out other causes of 
fatigue such as electrolyte imbalance, 
hyperglycemia. 
Ensure adequate caloric intake and 
assess volume status. Adjust other 
medications. Rule out other causes of 
fatigue such as electrolyte imbalance, 
hyperglycemia. 
Grade 2 
1. As in grade 1 
2. Consider patient diary to evaluate 
fluid and food intake.  
3. Add medroxyprogesterone acetate 
(MPA) (ovarian and cervical only) or 
4 mg dexamethasone (or equivalent) 
on day after selinexor dosing. 
4. In case of dehydration add IV fluids 
on the dosing day.  
5. If fatigue does not resolve to grade 1 
or baseline, reduce one dose level 
of selinexor 
6. For additional support see NCCN 
guidelinesa. 
1. As in grade 1 
2. Consider patient diary to evaluate 
fluid and food intake.  
3. Add MPA or 4 mg dexamethasone 
(or equivalent) on day after 
selinexor dosing. 
4. In case of dehydration add IV fluids 
on the dosing day.  
5. If fatigue does not resolve to grade 
1 or baseline, reduce one dose level 
of selinexor  
6. For additional support see NCCN 
guidelinesa. 
1. As in grade 1 
2. Consider patient diary to evaluate 
fluid and food intake.  
3. Add MPA or 4 mg dexamethasone 
(or equivalent) 3 days post dosing of 
selinexor. 
4. In case of dehydration add IV fluids 
on the dosing day.  
5. If fatigue does not resolve to grade 
1 or baseline, reduce one dose level 
of selinexor  
6. For additional support see NCCN 
guidelinesa. 
Grade 3 mm3  
As in grade 2; if symptoms not resolved 
within 7 days, interrupt selinexor dosing 
until symptoms return to grade 1 or 
baseline and restart treatment with one 
dose reduction of selinexor 
As in grade 2; if symptoms not resolved 
within 7 days, interrupt selinexor dosing 
until symptoms return to grade 1 or 
baseline and restart treatment with one 
dose reduction of selinexor  
As in grade 2; if symptoms not resolved 
within 7 days, interrupt selinexor dosing 
until symptoms return to grade 1 or 
baseline and restart treatment with one 
dose reduction of selinexor  


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Toxicity and Intensity 
Dose Modification 
Part 1:  50 mg/m2 twice weekly 
Part 2, Schedule 1:  35 mg/m2 twice 
weekly – Ovarian only 
Part 2, Schedule 2:  50 mg/m2 once 
weekly – Ovarian only 
Anorexia/Weight Loss (common) 
Grade 1 
Ensure adequate caloric intake and 
assess volume status. Adjust other 
medications. Rule out other causes of 
anorexia/weight loss such as electrolyte 
imbalance, hyperglycemia 
Ensure adequate caloric intake and 
assess volume status. Adjust other 
medications. Rule out other causes of 
anorexia/weight loss such as electrolyte 
imbalance, hyperglycemia 
Ensure adequate caloric intake and 
assess volume status. Adjust other 
medications. Rule out other causes of 
anorexia/weight loss such as electrolyte 
imbalance, hyperglycemia 
Grade 2 
1. As grade 1 
2. Consider patient diary to evaluate 
fluid and food intake.  
3. Add MPA (ovarian and cervical only) 
or 4 mg dexamethasone (or 
equivalent) on day after selinexor 
dosing. 
4. In case of dehydration add IV fluids 
on the dosing day.  
5. If anorexia dose not resolve to 
Grade 1 or baseline, reduce one 
dose level of selinexor 
6. For additional supportive care see 
NCCN guidelinesb 
1. As grade 1 
2. Consider patient diary to evaluate 
fluid and food intake.  
3. Add MPA or 4 mg dexamethasone 
(or equivalent) on day after 
selinexor dosing. 
4. In case of dehydration add IV fluids 
on the dosing day.  
5. If anorexia dose not resolve to 
Grade 1 or baseline, reduce one 
dose level of selinexor  
6. For additional supportive care see 
NCCN guidelinesb 
1. As grade 1 
2. Consider patient diary to evaluate 
fluid and food intake.  
3. Add MPA or 4 mg dexamethasone 
(or equivalent) 3 days post dosing of 
selinexor. 
4. In case of dehydration add IV fluids 
on the dosing day.  
5. If anorexia dose not resolve to 
Grade 1 or baseline, reduce one 
dose level of selinexor  
6. For additional supportive care see 
NCCN guidelinesb 
Grade ≥ 3 (Grade 4 for 
anorexia only) 
1. As in grade 2  
2. Add MPA (ovarian and cervical only) 
or megestrol acetate 
3. If symptoms not resolved within 7 
days, interrupt selinexor dosing until 
resolved to grade 1 or baseline and 
restart treatment with one dose 
reduction of selinexor 
1. As in grade 2  
2. Add MPA or megestrol acetate 
3. If symptoms not resolved within 7 
days, interrupt selinexor dosing until 
resolved to grade 1 or baseline and 
restart treatment with one dose 
reduction of selinexor 
1. As in grade 2  
2. Add MPA or megestrol acetate 
3. If symptoms not resolved within 7 
days, interrupt selinexor dosing until 
resolved to grade 1 or baseline and 
restart treatment with one dose 
reduction of selinexor 
Nausea/Emesis (common) 
Grade 1 
5-HT3 antagonists, D2 antagonists as 
needed. Consider adding 4 mg 
dexamethasone (or equivalent) on day 
after selinexor dosing. 
5-HT3 antagonists, D2 antagonists as 
needed. Consider adding 4 mg 
dexamethasone (or equivalent) on day 
after selinexor dosing. 
5-HT3 antagonists, D2 antagonists as 
needed. 
Consider 
adding 
4 
mg 
dexamethasone (or equivalent) on day 
after selinexor dosing. 
 
 


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Grade 2 
Implement one or more combinations of 
anti-nausea medications. Next dose add 
neurokinin-1 receptor (NK1R) antagonist 
(e.g., aprepitant) prophylactic. If nausea 
does not resolve to Grade ≤ 1 or 
baseline, reduce one dose level of 
selinexor. Consider NK1R antagonist as 
prophylaxis next cycle. For additional 
options see NCCN guidelines for 
antiemesis.c 
Implement one or more combinations of 
anti-nausea medications. Next dose add 
NK1R 
antagonist 
(e.g., 
aprepitant) 
prophylactic. If nausea does not resolve 
to Grade ≤ 1 or baseline, reduce one 
dose level of selinexor. Consider NK1R 
antagonist as prophylaxis next cycle. For 
additional options see NCCN guidelines 
for antiemesis.c 
Implement one or more combinations of 
anti-nausea medications. Next dose add 
NK1R 
antagonist 
(e.g., 
aprepitant) 
prophylactic. If nausea does not resolve 
to Grade ≤ 1 or baseline, reduce one 
dose level of selinexor. Consider NK1R 
antagonist as prophylaxis next cycle. For 
additional options see NCCN guidelines 
for antiemesis.c 
Grade ≥ 3 (Grade 4 for 
emesis only) 
As in grade 2; if symptoms persist hold 
dose until nausea and vomiting resolve to 
grade 1 or baseline. Restart dose of 
selinexor, one dose below. Start NK1R 
antagonist as prophylaxis next cycle. 
As in grade 2; if symptoms persist hold 
dose until nausea and vomiting resolve 
to grade 1 or baseline. Restart dose of 
selinexor, one dose below. Start NK1R 
antagonist as prophylaxis next cycle. 
As in grade 2; if symptoms persist hold 
dose until nausea and vomiting resolved 
to grade 1 or baseline. Restart dose of 
selinexor, one dose below. Start NK1R 
antagonist as prophylaxis next cycle. 
Hematologic 
Neutropenia  
Grade ≤ 3  
1. Maintain dose level 
2. The use of growth factors during 
selinexor treatment is permitted and 
in patients with poor marrow 
function, encouraged. If ANC drops 
to < 1000/mm3, growth factors are 
encouraged to reduce dose 
interruptions. 
1. Maintain dose level 
2. The use of growth factors during 
selinexor treatment is permitted and 
in patients with poor marrow 
function, encouraged. If ANC drops 
to < 1000/mm3, growth factors are 
encouraged to reduce dose 
interruptions. 
1. Maintain dose level 
2. The use of growth factors during 
selinexor treatment is permitted and 
in patients with poor marrow 
function, encouraged. If ANC drops 
to < 1000/mm3, growth factors are 
encouraged to reduce dose 
interruptions. 
Grade 4 (ANC < 500/mm3) 1. Delay study treatment until ANC 
returns to  > 800/mm3, then: 
2. If increased to > 800/mm3 by ≤ 7 
days after suspending selinexor, 
maintain dose level 
3. If increased to > 800/mm3  by > 7 
days after suspending selinexor, 
then reduce one dose level. 
4. The use of growth factors during 
selinexor treatment is encouraged. 
1. Delay study treatment until ANC 
returns to  > 800/mm3, then: 
2. If increased to > 800/mm3  by ≤ 7 
days after suspending selinexor, 
maintain dose level 
3. If increased to > 800/mm3 by > 7 
days after suspending selinexor, 
then reduce one dose level. 
4. The use of growth factors during 
selinexor treatment is encouraged. 
1. Delay study treatment until ANC 
returns to  > 800/mm3, then: 
2. If increased to > 800/mm3 by ≤ 7 
days after suspending selinexor, 
maintain dose level 
3. If increased to > 800/mm3 by > 7 
days after suspending selinexor, 
then reduce one dose level 
4. The use of growth factors during 
selinexor treatment is encouraged. 


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Febrile neutropenia, or 
fever of unknown origin 
without clinically or 
microbiologically 
documented infection 
(ANC < 1.0 x 109/L, fever 
≥ 38.5°C)  
1. Delay study treatment until patient 
has stabilized, then reduce selinexor 
one dose level. 
2. Selinexor may be re-initiated at the 
reduced dose when patient’s 
condition has stabilized following 
initiation of antibiotic therapy. 
3. Selinexor dose may be re-escalated 
after ≥ 1 cycle at the reduced dose 
provided ANC is adequate. 
1. Delay study treatment until patient 
has stabilized, then reduce 
selinexor one dose level. 
2. Selinexor may be re-initiated at the 
reduced dose when patient’s 
condition has stabilized following 
initiation of antibiotic therapy. 
3. Selinexor dose may be re-escalated 
after ≥ 1 cycle at the reduced dose 
provided ANC is adequate. 
1. Delay study treatment until patient 
has stabilized, then reduce 
selinexor one dose level. 
2. Selinexor may be re-initiated at the 
reduced dose when patient’s 
condition has stabilized following 
initiation of antibiotic therapy. 
3. Selinexor dose may be re-escalated 
after ≥ 1 cycle at the reduced dose 
provided ANC is adequate. 
Thrombocytopenia (Platelets) 
 
Grade ≤ 2  
Maintain dose level 
Maintain dose level 
Maintain dose level 
Grade ≥ 3 without 
bleeding 
First 
occurrence: 
Delay 
selinexor 
treatment until resolved to ≤ grade 1 or 
baseline (max 4 weeks), and restart at 
50 mg/m2 once a week.  Thrombocyte 
growth 
factors 
(e.g., 
romiplostim, 
eltrombopag, 
oprelvekin) 
are 
recommended. 
Second occurrence: Delay selinexor 
treatment until resolved to ≤ grade 1 or 
baseline (max 4 weeks), and restart 
35 mg/m2 once a week. Start treatment 
with thrombocyte growth factors. 
Third occurrence: stop treatment 
First 
occurrence: 
Delay 
selinexor 
treatment until resolved to ≤ grade 1 or 
baseline (max 4 weeks), and restart at 
50 mg/m2 once a week. Thrombocyte 
growth 
factors 
(e.g., 
romiplostim, 
eltrombopag, 
oprelvekin) 
are 
recommended. 
Second occurrence: Delay selinexor 
treatment until resolved to ≤ grade 1 or 
baseline (max 4 weeks), and restart at 
35 mg/m2 once a week. Start treatment 
with thrombocyte growth factors. 
Third occurrence: stop treatment 
First 
occurrence: 
Delay 
selinexor 
treatment until resolved to ≤ grade 1 or 
baseline (max 4 weeks), and restart at 
35 mg/m2 once a week Thrombocyte 
growth 
factors 
(e.g., 
romiplostim, 
eltrombopag, 
oprelvekin) 
are 
recommended. 
Second occurrence: Delay selinexor 
treatment until resolved to ≤ grade 1 or 
baseline (max 4 weeks), and restart at 
35 mg/m2 once a week. Start treatment 
with thrombocyte growth factors. 
Third occurrence: stop treatment 


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≥ Grade 3 
Thrombocytopenia 
associated with purpura or 
bleeding 
1. Delay selinexor treatment until 
resolved to ≤ grade 1 or baseline 
(max 4 weeks), and restart at 35 
mg/m2 once a week. 
2. Transfuse platelets per institutional 
guidelines. If medically indicated, 
discontinue any anti-platelet agents. 
Implement platelet growth factors 
and/or transfusions. Platelet growth 
factors may require 2-4 weeks to 
take effect, and should be 
maintained until platelets are 
consistently > 100,000/mm3. 
1. Delay selinexor treatment until 
resolved to ≤ grade 1 or baseline 
(max 4 weeks), and restart at 
35 mg/m2 once a week. Transfuse 
platelets per institutional guidelines. 
If medically indicated, discontinue 
any anti-platelet agents. Implement 
platelet growth factors and/or 
transfusions. Platelet growth factors 
may require 2-4 weeks to take 
effect, and should be maintained 
until platelets are consistently 
> 100,000/mm3. 
2. When purpura or bruising resolves, 
restart selinexor at level -1.  
1. Delay selinexor treatment until 
resolved to ≤ grade 1 or baseline 
(max 4 weeks), and restart at 
35 mg/m2 once a week Transfuse 
platelets per institutional guidelines. 
If medically indicated, discontinue 
any anti-platelet agents. Implement 
platelet growth factors and/or 
transfusions. Platelet growth factors 
may require 2-4 weeks to take 
effect, and should be maintained 
until platelets are consistently 
> 100,000/mm3. 
2. When purpura or bruising resolves, 
restart selinexor at level -1. 
Platelet Stimulators 
The use of platelet stimulators is 
encouraged in patients with a history of 
thrombocytopenia 
or 
compromised 
marrow function, or in patients in whom 
selinexor is having demonstrable disease 
control. IL-11 (oprelvekin), eltrombopag, 
or romiplastin should be considered. 
The use of platelet stimulators is 
encouraged in patients with a history of 
thrombocytopenia or compromised 
marrow function, or in patients in whom 
selinexor is having demonstrable 
disease control. IL-11 (oprelvekin), 
eltrombopag, or romiplastin should be 
considered.  
The use of platelet stimulators is 
encouraged in patients with a history of 
thrombocytopenia or compromised 
marrow function, or in patients in whom 
selinexor is having demonstrable 
disease control. IL-11 (oprelvekin), 
eltrombopag, or romiplastin should be 
considered. 
Hyponatremia (common) 
Grade 1 (Lower Limit of 
Normal to 130 nM) 
 
Maintain dose level, assure adequate 
fluid, electrolyte and caloric intake, 
adjust other medications, consider salt 
supplementation, rule out other causes. 
Maintain dose level, assure adequate 
fluid, electrolyte and caloric intake, 
adjust other medications, consider salt 
supplementation, rule out other causes. 
Maintain dose level, assure adequate 
fluid, electrolyte and caloric intake, 
adjust other medications, consider salt 
supplementation, rule out other causes. 
Grade ≥ 3 (120-130 nM) 
Discontinue selinexor until resolved to 
grade ≤ 1, then reduce dose by 1 level. 
Check renal function, serum, and urinary 
electrolytes, and rule out other causes. 
Discontinue selinexor until resolved to 
grade ≤ 1, then reduce dose by 1 level. 
Check renal function, serum, and 
urinary electrolytes, and rule out other 
causes. 
Discontinue selinexor until resolved to 
grade ≤ 1, then reduce dose by 1 level. 
Check renal function, serum, and 
urinary electrolytes, and rule out other 
causes. 
AST or ALT (rare) 
Grade 1 (> ULN - 2.5 x 
ULN) 
Maintain dose level 
Maintain dose level 
Maintain dose level 


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Grade 2 (> 2.5 - 5.0 x 
ULN) 
Delay selinexor until resolved to grade ≤ 
1 or baseline, then maintain dose level. 
Consider addition of S-
adenosylmethionine (SAM) 400 mg qd-
bid. 
Delay selinexor until resolved to grade ≤ 
1 or baseline, then maintain dose level. 
Consider addition of S-
adenosylmethionine (SAM) 400 mg qd-
bid. 
Delay selinexor until resolved to grade ≤ 
1 or baseline, then maintain dose level. 
Consider addition of S-
adenosylmethionine (SAM) 400 mg qd-
bid. 
Grade 3 (> 5.0 - 20.0 x 
ULN) 
1. Delay selinexor until resolved to 
≤ grade 2 or baseline, then reduce 
by 1 dose level (Table 2 & Table 3) 
2. Consider addition of S-
adenosylmethionine (SAM) 400 mg 
qd-qid. 
3. If no further AST or ALT elevations 
occur during one cycle (4 weeks) at 
the reduced dose level, then dose 
may be continued at the reduced 
dose. 
4. Discontinuation of selinexor is 
required if concurrent elevations of 
direct bilirubin > 2.0 X upper limit of 
normal (ULN) and ALT or AST > 3.0 
X ULN are observed. 
5. In order to characterize hepatic 
toxicity more precisely, fractionation 
of bilirubin and alkaline 
phosphatases will be required for 
elevated values > 2.0 X ULN and ≥ 
CTCAE grade 2, respectively. 
1. Delay selinexor until resolved to 
≤ grade 2 or baseline, then reduce 
by 1 dose level (Table 2 & Table 3) 
2. Consider addition of S-
adenosylmethionine (SAM) 400 mg 
qd-qid. 
3. If no further AST or ALT elevations 
occur during one cycle (4 weeks) at 
the reduced dose level, then dose 
may be continued at the reduced 
dose. 
4. Discontinuation of selinexor is 
required if concurrent elevations of 
direct bilirubin > 2.0 X upper limit of 
normal (ULN) and ALT or AST > 3.0 
X ULN are observed. 
5. In order to characterize hepatic 
toxicity more precisely, fractionation 
of bilirubin and alkaline 
phosphatases will be required for 
elevated values > 2.0 X ULN and ≥ 
CTCAE grade 2, respectively. 
1. Delay selinexor until resolved to 
≤ grade 2 or baseline, then reduce 
by 1 dose level (Table 2 & Table 3) 
2. Consider addition of S-
adenosylmethionine (SAM) 400 mg 
qd-qid. 
3. If no further AST or ALT elevations 
occur during one cycle (4 weeks) at 
the reduced dose level, then dose 
may be continued at the reduced 
dose. 
4. Discontinuation of selinexor is 
required if concurrent elevations of 
direct bilirubin > 2.0 X upper limit of 
normal (ULN) and ALT or AST > 3.0 
X ULN are observed. 
In order to characterize hepatic 
toxicity more precisely, fractionation 
of bilirubin and alkaline 
phosphatases will be required for 
elevated values > 2.0 X ULN and ≥ 
CTCAE grade 2, respectively. 
Grade 4 (> 20.0 x ULN) 
Delay selinexor until resolved to ≤ grade 
2, then reduce by 2 dose levels. 
Delay selinexor until resolved to ≤ grade 
2, then reduce by 2 dose levels. 
N/A 
 
Diarrhea (common) 
Grade 1 (despite maximal 
anti-diarrheal medication) 
At the first sign of abdominal cramping, 
loose stools, or onset of diarrhea, it is 
recommended that the patient be treated 
according to institutional standard of 
care. Maintain dose level of selinexor. 
At the first sign of abdominal cramping, 
loose stools, or onset of diarrhea, it is 
recommended that the patient be 
treated according to institutional 
standard of care. Maintain dose level of 
selinexor. 
At the first sign of abdominal cramping, 
loose stools, or onset of diarrhea, it is 
recommended that the patient be treated 
according to institutional standard of 
care. Maintain dose level of selinexor. 


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Grade 2 (despite maximal 
anti-diarrheal medication) 
 
First occurrence: reduce selinexor to 
once weekly until resolved to ≤ grade 1, 
then re-start twice weekly at the current 
dose level.  
Second occurrence: reduce selinexor 
dose by one dose level and dose once 
weekly until resolved to ≤ grade 1, then 
re-start twice weekly at reduced dose 
level 
First occurrence: reduce to selinexor 
to once weekly until resolved to ≤ grade 
1, then re-start twice weekly at the 
current dose level.  
Second occurrence: reduce selinexor 
dose by one dose level and dose once 
weekly until resolved to ≤ grade 1, then 
re-start twice weekly at reduced dose 
level 
First occurrence:  reduce selinexor to 
35 mg/m2 until resolved to ≤ grade 1 or 
baseline, then re-start at the Dose level 
0.  
Second occurrence: reduce one dose 
level 
Grade 3/4 (despite 
maximal anti-diarrheal 
medication) 
Delay selinexor until resolved to ≤ grade 
2 or baseline, then follow guidelines 
above. 
Delay selinexor until resolved to ≤ grade 
2 or baseline, then follow guidelines 
above. 
Delay selinexor until resolved to ≤ grade 
2 or baseline then reduce one dose level. 
Other selinexor-related adverse events 
Grade 1 or 2 
Maintain dose level and initiate standard 
supportive care. 
Maintain dose level and initiate standard 
supportive care. 
Maintain dose level and initiate standard 
supportive care. 
Grade 3 
Delay dose until resolved to ≤ grade 1 or 
baseline, then reduce by one dose level. 
Delay dose until resolved to ≤ grade 1 
or baseline, then reduce by one dose 
level. 
Delay dose until resolved to ≤ grade 1 or 
baseline, then reduce to Dose level -1. 
Grade 4 
Discontinue selinexor and rule out other 
causes. If other causes of grade 4 
adverse event are uncovered, selinexor 
may be re-started at a reduced dose level 
Discontinue selinexor and rule out other 
causes. If other causes of grade 4 
adverse event are uncovered, selinexor 
may reduce in 2 dose level 
Discontinue selinexor and rule out other 
causes. If other causes of grade 4 
adverse event are uncovered, selinexor 
may be re-started at a reduced dose 
level. 
All dose modifications should be based on the worst preceding toxicity. 
Isolated values of ≥ grade 3 alkaline phosphatase values will NOT require dose interruption. Determination of liver vs bone etiology should be made, and evaluation of gamma-glutamyl 
transferase (GGT), 5'-nucleotidase (5’NT), or other liver enzymes should be performed. 
≥ Grade 3 anemia judged to be a hemolytic process secondary to study drug will require interruption of study treatment until resolved to ≤ grade 1. Selinexor may then be re-instituted at 1 level 
below original dose (Table 2 and Table 3. 
≥ Grade 3 lymphopenia considered clinically significant will require dose interruption until resolved to ≤ grade 2, then reduce by 1 dose level. 
Patients are allowed dose reductions to a minimum dose of 35 mg/m2 once weekly for Part 1 and Part 2 (Schedules 1 and 2) as described in Table 2 and Table 3, respectively.  
If a patient requires a dose interruption of > 28 days, then the patient must be discontinued from the study. Patients who discontinue the study for a study-related adverse event or abnormal 
laboratory value must be followed at least once a week for 28 days and subsequently at 28-day intervals until resolution or stabilization of the event, whichever comes first. 
Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) or otherwise specified values. 
aNational Comprehensive Cancer Network®.  NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®):  Fatigue. Available at 
http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. 
bNational Comprehensive Cancer Network®.  NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®):  Palliative Care, version 2.2015. Fort Washington, NY.  May 2015.  
Available at: http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/facts.pdf. Attached as Appendix 11. 
cNational Comprehensive Cancer Network®.  NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®):  Antiemesis, version 1.2015. Fort Washington, NY.  April 2015.  Available 
at: http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf.  Attached as Appendix 10. 


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For patients whose dose has been reduced due to neutropenia, anorexia or fatigue, dose 
re-escalation is permitted if the institution of supportive care measures has reduced these 
toxicities to Grade ≤ 1 or to baseline for at least 2 weeks. Dose re-escalation is only 
permitted for these adverse events when supportive measures have been successful. 
6.3.3 Selinexor Dose Reduction in the Setting of Infection 
Patients with active uncontrolled infections should have selinexor treatment withheld until 
the infection has resolved or 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. Prophylactic 
antibiotics are permitted concurrently with selinexor treatment, but are not required. 
Opportunistic infections related to selinexor therapy have not been reported in 730 
patients evaluable for safety as of 31 May 2015. 
6.3.4 Dose Adjustments with Changes in BSA 
Dose adjustments do not need to be made for weight gains/losses of ≤ 20%. For patients 
dosed on a mg/m2 basis, patients with a Body Surface Area (BSA) of greater than 2.5 m² 
will receive a doses of selinexor based on a BSA of 2.5 m². For patients receiving selinexor 
doses of 60 mg or 80 mg, BSA will be calculated to ensure that the 60 mg or 80 mg dose 
does not result in a dose > 70 mg/m.2 If a patient’s dose will exceed this limit, the 
Investigator should contact the Medical Monitor prior to administration to discuss 
appropriate dosing. 
6.3.5 Missed or Vomited Doses 
For once weekly dosing, a maximum of one dose may be given per week; for twice weekly 
dosing, a maximum of two doses may be given per week. Doses should not be 
administered less than 5 days apart for once weekly dosing and less than 36 hours apart 
for once weekly dosing. Every effort should be made to avoid missed doses. 
Missed doses 
Doses held due to AE(s) will not be considered missed. 
Vomited doses 
If a dose is vomited within one hour of ingestion, it will be replaced. If vomiting occurs 
more than 1 hour after dosing, it will still be considered a complete dose. 
6.3.6 Dose Adjustments with impressive tumor response 
If the shrinkage of the tumor is ≥ 50% compared to the baseline tumor assessment, the 
dose of selinexor may be reduced to once-weekly dosing. 


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6.4 Concomitant Medication and Treatment 
Concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements. Patients may continue their baseline medication(s). 
All concomitant medication(s) must be reported in the case report form (CRF). 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.  
6.4.1 Permitted Concomitant Medication 
Patients will receive concomitant medications to treat symptoms, adverse events and 
intercurrent illnesses that are medically necessary as standard care. Medications to treat 
concomitant diseases like diabetes, hypertension, etc. are allowed. 
6.4.1.1 Prevention of Pregnancy 
Patients should not become pregnant or father a child while on this study because the 
drugs 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. A woman of childbearing potential is defined as a premenopausal female 
capable of becoming pregnant. This includes women on oral, injectable or mechanical 
contraception; women who are single and women whose male sexual partners have been 
vasectomized or whose male sexual partners have received or are utilizing mechanical 
contraceptive devices. Female patients of childbearing potential must have a negative 
serum pregnancy test at screening and agree to use reliable methods of contraception for 
three months after their last dose of medication. Such methods include intrauterine 
devices, hormonal contraceptives [contraceptive pills, implants, transdermal patches, 
hormonal vaginal devices or injections with prolonged release], abstinence or sterilization 
of the partner. Male patients must use a reliable method of contraception (abstinence or 
contraception with one of the above-described methods for your partner) if sexually active 
with a female of childbearing potential. Total (true) abstinence (when this is in line with the 
preferred and usual lifestyle of the patient), is an acceptable method of contraception. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post- ovulation methods) 
and withdrawal are not acceptable methods of contraception. For both male and female 
patients, effective methods of contraception must be used throughout the study and for 
three months following the last dose. 
6.4.1.2 Use of Blood Products 
During the administration of selinexor, patients may receive red blood cell (RBC) or 
platelet transfusions, if clinically indicated, per institutional guidelines. Patients who 
require repeated transfusion support should be discussed with the Investigator, Sponsor 
and Medical Monitor. 
Appropriate anti-coagulation is allowed during the study (e.g., LMW heparin, direct factor 
Xa inhibitors). Warfarin is allowed during the study provided that patients are monitored 
for INR twice a week during the first two cycles of therapy, then weekly to biweekly 
thereafter.  


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Patients may receive supportive care with erythropoietin, darbepoetin, G-CSF or GM-
CSF, pegylated growth factors, and platelet stimulatory factors, in accordance with clinical 
practice or institutional guidelines prior to entry and throughout the study. 
6.4.1.3 Glucocorticoid therapy 
Ongoing glucocorticoids (e.g., ≤ 10 mg oral prednisone [or equivalent]) per day are 
permitted at baseline and during the study for non-malignant conditions (i.e., asthma) as 
needed. 
As part of supportive care (e.g., for nausea or anorexia), oral dexamethasone, up to 
40 mg/week, may be given to patients, in consultation with the Medical Monitor. 
Dexamethasone (4-12 mg) or prednisone (10-20 mg) on days of (± 1 day after) selinexor 
dosing (± 1 day after) may improve appetite, reduce nausea or vomiting, and minimize 
fatigue. 
6.4.2 Restricted and Prohibited Medications 
6.4.2.1 Concurrent Therapies 
Concurrent therapy with any other approved or investigative anticancer therapeutic is not 
allowed. Other investigational agents should not be used during the study. Use of any 
immunosuppressive agents during the study must be confirmed by the Medical Monitor. 
Note that the use of denosumab is not allowed. 
6.4.2.2 Alcohol (ethanol) 
Ethanol should be avoided on selinexor dosing days as it may compete for glutathione 
(GSH)-mediated metabolism. 
6.4.2.3 Acetaminophen (paracetamol) containing medications 
There are no longer any restrictions on the use of acetaminophen (paracetamol) or 
acetaminophen (paracetamol) -containing products in combination with selinexor, 
EXCEPT on days of selinexor dosing, when acetaminophen (paracetamol) must not 
exceed a total daily dose of 1 gram. Although acetaminophen (paracetamol) use in 
combination with selinexor was restricted in previous selinexor studies based on 
theoretical interactions with GSH, ongoing clinical safety evaluations on the use of these 
drugs together have not shown any significant clinical or laboratory abnormalities with 
doses of acetaminophen (paracetamol) of up to 1 gram and selinexor up to 55 mg/m2 
(approximately 80-100 mg). 
6.4.2.4 Miscellaneous 
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. See Appendix 15 for a list of 
representative products. Patients must report all prescription and non-prescription 
medicines to their physicians during this study. 


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6.5 Supportive Care Guidelines 
6.5.1 Required Supportive Care Medication 
5-HT3 Antagonists 
In order to minimize nausea, unless contraindicated, all patients must receive 5-HT3 
antagonists (ondansetron 8 mg or equivalent) starting before the first dose of selinexor 
and continued 2-3 times a day, as needed. Alternative anti-emetic therapy may be used 
for patients who cannot tolerate 5-HT3 antagonists. 
6.5.2 Supportive Care Recommendations for Selinexor-Related Adverse Events 
Supportive measures for optimal medical care should be provided during participation in 
this clinical trial. Based on clinical observations in over 560 adult patients treated with 
selinexor with evaluable safety data as of 01 February 2015, the main side effects are 
primarily related to anorexia with poor caloric and fluid intake, fatigue, and nausea. 
Thrombocytopenia also occurs, although it is rarely associated with bleeding. 
Besides the required 5-HT3 (Section 6.5.1), supportive care including anti-nausea / anti-
emetic therapy, acid suppression (proton pump inhibitors and/or H2-blockers) and other 
treatments may be administered as described below: 
1. Glucocorticoids:  dexamethasone (4-12 mg) or equivalent glucocorticoid (e.g., 
prednisone 10-20 mg) on days of, and 1 day after, selinexor dosing may improve 
appetite, reduce nausea or vomiting, and minimize fatigue. A maximum of 40 mg 
dexamethasone or equivalent may be given per week. 
2. Appetite stimulants:  megesterol acetate at a dose of 80-400 mg daily. 
3. Centrally acting agents:  per National Comprehensive Cancer Network® (NCCN) 
Clinical Practice Guidelines® for antiemesis98 and anorexia/cachexia (palliative care)99 
see Appendix 10 (antiemesis) and Appendix 11 (anorexia), respectively. 
4. NK1R antagonist:  aprepitant or equivalent should be considered and will be covered 
for selected patients who have severe nausea and vomiting. 
6.5.3 Liver Enzyme Increase 
Liver toxicities in rodents and monkeys were not observed in the GLP toxicology studies. 
To date, significant liver toxicity has not been reported in patients treated with selinexor. 
Patients should minimize their use of alcohol as this drug may deplete hepatic glutathione 
which could alter selinexor metabolism. Glutathione- (GSH-) replacing agents such as N-
acetylcysteine or S-adenosylmethionine may be considered if selinexor induced liver 
dysfunction is suspected. 


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7 
ADVERSE EVENT ASSESSMENT 
The Selinexor IB is a reference source for selinexor and will be provided to the 
Investigators in the Investigator’s File. 
7.1 Adverse Events and Laboratory Abnormalities Reporting 
7.1.1 Adverse Event 
An adverse event (AE) is defined in the International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice as “any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment” (ICH E6: 1.2). 
An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not it is considered related to the medicinal 
product. 
Pregnancy per se is not considered an AE. A medical occurrence observed in the mother 
or fetus/newborn would be an AE. 
All AEs will be collected from the start of treatment, i.e., Cycle 1 Day 1, until 30 days (± 7 
days) after the last dose of study medication. 
Table 5: 
Classification of Adverse Events by Causality 
Class 
Description 
Not related 
The lack of a temporal relationship of the event to study treatment makes a 
causal relationship not reasonably possible, or by any other drugs, 
therapeutic interventions or underlying conditions that provide a sufficient 
explanation. 
Possibly 
related 
The temporal relationship of the event to study treatment makes a causal 
relationship reasonably possible, and the event is more likely explained by 
exposure to the study treatment than by any other drugs, therapeutic 
interventions or underlying conditions. 
Related 
The temporal relationship of the event to 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. 
 
For the purpose of safety analyses, all AEs that are classified as related or possibly related 
will be considered treatment-related events. 
The Investigator is responsible for ensuring that all adverse events observed by the 
Investigator or reported by patients are properly recorded in the patients’ medical records 
and the electronic case report form.  
The Investigator must assign the following attributes:  


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 Severity grade according to the NCI CTCAE criteria Version 4.03 
 Start date and stop date (or date of last assessment) 
 Outcome 
 Causality to study drug and chemotherapy (to be assessed as either related or not 
related) 
 Any action taken with the study drug 
Pre-existing diseases, when worsening during study therapy, have to be considered as 
adverse events. They can lead to serious adverse events, if they meet the criteria 
described in Section 7.1.4. 
7.1.2 Adverse Drug Reaction 
Adverse drug reactions (ADRs) include all untoward and unintended responses to a 
medicinal product related to any dose administered. 
The phrase “responses to a medicinal product” means that a causal relationship between 
the medicinal product and the AE is at least a reasonable possibility, i.e. the relationship 
cannot be ruled out. 
A serious ADR (SADR) is an ADR that meets the definition of serious (provided below). 
7.1.3 Laboratory Test Abnormalities 
Laboratory test results will be recorded on the laboratory results pages of the eCRF. In 
the event of unexplained abnormal laboratory test values, the tests should be repeated 
and followed up until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found.  
Laboratory test value abnormalities as such should not be reported on the AE page of the 
eCRF as adverse events unless they are treatment-emergent and they satisfy one or more 
of the following conditions for clinical significance: 
1. Accompanied by clinical symptoms 
2. Leading to a change in study medication (e.g., dose modification, interruption or 
permanent discontinuation) 
3. Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 
Please note:  Any laboratory result abnormality fulfilling the criteria for a serious adverse 
event (SAE) should be reported as such, in addition to being recorded as an adverse 
event in the eCRF. 
7.1.4 Serious Adverse Event 
SAEs will be collected from the time of Informed Consent through 30 days (± 7 days) after 
the last dose of study medication. 


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A serious adverse event (SAE) is defined as an adverse event that meets one or more of 
the following: 
 is fatal 
 is life threatening (places the subject at immediate risk of death) 
 requires in-patient hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 other important medical events 
A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a healthcare facility. Any 
adverse event that does not meet one of the definitions of serious (e.g. visit to A&E, 
outpatient surgery, or requires urgent investigation) may be considered by the Investigator 
to meet the “other significant medical hazard” criterion for classification as a serious 
adverse event. Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias. 
Important medical events are defined as those occurrences that may not be immediately 
life threatening or result in death, hospitalization, or disability, but may jeopardize the 
subject or require medical or surgical intervention to prevent one of the other outcomes 
listed above. Medical judgment should be exercised in deciding whether such an AE 
should be considered serious. 
In addition, all cases of cerebellar toxicities of Grade 3 or higher must be captured as an 
SAE and reported to the regulatory authorities, IRBs, ECs, and Investigators in an 
expedited Safety Report within 7 days of awareness of the event. 
7.1.5 Events NOT to be reported as SAEs 
For this study, the following are not classified as SAEs: 
 Progression or deterioration of the malignancy under study (including new metastatic 
lesions) or death due to progression. 
 Hospitalization for the performance of protocol-required procedures or administration 
of study treatment. However, hospitalization or a prolonged hospitalization for a 
complication of therapy administration will be reported as an SAE. 
 Hospitalization or procedures planned prior to study start. A pre-planned procedure 
must be documented in the source documents. However, hospitalization or prolonged 
hospitalization for a complication remains to be reported as an SAE. 
 An elective hospitalization for a pre-existing condition not related to the studied 
indication. 
 Hospital admission that is not associated with an adverse event (e.g., social 
hospitalization for purpose of respite care). 


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 Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
 The administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication of 
such transfusions remains to be reported as an SAE. 
 Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above. 
7.1.6 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Per the definitions provided above, SUSARs are adverse events that have been 
determined by the investigator to be serious, suspected of being caused by selinexor 
(related or possibly related) and are unexpected according to the most current version of 
the investigator’s brochure for selinexor. 
7.2 Reporting of SAEs  
7.2.1 Primary Treatment Phase 
Any clinical adverse event or abnormal laboratory test value that is serious occurring 
during the course of the study from the date of signing the informed consent, irrespective 
of the treatment received by the patient, must be reported to GSO within 24 hours 
following knowledge of the SAE.  
The following detailed information must be recorded for each serious adverse event in the 
SAE report form: 
 The severity grade as assessed by the investigator according to the definitions in 
NCI-CTCAE Version 4.03 
 The date of becoming serious and the date of becoming known (if different) 
 The reason for seriousness 
 The outcome of the SAE at the time of the report 
 Information on administration of the study drug and chemotherapy and any action 
taken 
 Information on any procedures necessary to treat the SAE, concomitant 
medications, relevant lab tests and relevant medical history 
The completed SAE form must be sent to: 
GSO 
Fax:  0049-40-44 19 54 78 
EMail:  signsae@gso-hamburg.com 
Karyopharm Therapeutics will ensure the notification of the appropriate ethics 
committees, competent authorities and participating investigators of all SUSAR events 
occurring at the sites in accordance with local legal requirements, statutes and the 
European Clinical Trial Directive. 


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7.2.2 Maintenance Phase 
See Section 18 (Appendix 16) for reporting of SAEs during the Maintenance Phase of 
the study (Version ≥3.2). 
7.3 AE and SAE Follow-up 
All AEs will be followed in accordance with good medical practice until they are resolved, 
stabilized or judged no longer clinically significant or, if a chronic condition, until fully 
characterized. Any AEs that are considered drug-related (possibly related or related) must 
be followed until resolution or until stabilization. 
7.4 Pregnancy 
Female patients must be instructed to immediately inform the Investigator if they become 
pregnant during the study. The study treatment must immediately be stopped and the 
patient must be withdrawn from the study. Pregnancies occurring up to 3 months after the 
completion of the last treatment cycle must also be reported to the Investigator. The 
Investigator must report all pregnancies within 24 hours of knowledge to GSO. GSO will 
forward all pregnancy reports to the sponsor within 24 hours. The Investigator should 
counsel the patient; discuss the risks of continuing the pregnancy and the possible effects 
on the fetus. The patient should be monitored until the conclusion of the pregnancy. 
Pregnancy occurring in the partner of a patient participating in the study should also be 
reported to the Investigator, the sponsor and the CRO. The partner should be counseled 
and followed as described above. 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 69 
8.4 Methods of Statistical Analysis 
8.4.1 General Statistical Considerations 
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety 
parameters. For categorical variables, summary tabulations of the number and 
percentage of patients within each category (with a category for missing data) of the 
parameter will be presented, as well as two-sided 95% confidence intervals, unless 
otherwise stated. For continuous variables, the number of patients, mean, median, 
standard deviation, minimum, and maximum values will be presented. Time-to-event data 
will be summarized using Kaplan-Meier methodology using 25th, 50th (median), and 75th 
percentiles with associated 2-sided 95% confidence intervals, as well as percentage of 
censored observations. 
No imputation of missing efficacy data is planned. For time to event analyses, patients 
who have no efficacy evaluations for disease recurrence will be considered censored at 
time 0. 
For AEs, missing dates will not be imputed, however, if partial dates are available, they 
will be used to assess if the AE occurred during the treatment period. Missing severities 
of AEs will not be imputed and will be considered missing in any tabulations of AE severity. 
If an AE is missing a response to the question regarding relationship to treatment, the 
event will be considered to be related.  
8.4.2 Demographics and Baseline Characteristics 
The demographic characteristics to be summarized will include gender, race, ethnicity 
(Hispanic origin), and age at time of consent. For gender, race, and Hispanic origin, the 
summary statistics will be the number and percentage of patients within each group or the 
total sample. The categories for race will be those recorded in the database. For age at 
time of consent, the mean, median, minimum, maximum, and standard deviation will be 
provided for each group and the total sample.  
Baseline characteristics include:  ECOG performance status; duration from initial 
diagnosis; response to previous therapy (Y/N). 
8.4.3 Efficacy Evaluation 
Primary analysis disease control rate. 
The analysis of disease control rate will be performed for each study cohort by calculating 
the point estimate of the percentage of patients in that cohort who have CR, PR, or SD 
for at least 12 weeks, assessed according to RECIST 1.1. 
Duration of SD will be calculated as follows: 
- 
For patients with documented disease progression, duration will be calculated from 
the date of start of study therapy until the date of disease progression. 
- 
For patients without documented disease progression, duration will be calculated 
from the date of start of study therapy until the date of last disease assessment. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 70 
- 
For patients without at least one post baseline disease assessment, duration will 
be censored at time 0. 
To be consistent with a Simon’s two-stage optimal design, a lower one-sided 90% CI will 
be presented for the DCR in each study cohort; additionally, for descriptive purposes a 
two-sided 95% CI will also be calculated for each cohort, using exact methods. The DCR 
for each cohort will be presented for the first stage of the study and for both stages 
combined, consistent with the Simon’s two-stage optimal design. 
The analysis of differences in DCR for the randomized part of the study (Part 2) will be 
performed using Fisher’s Exact test, accompanied by confidence intervals. 
The analysis of duration of disease control will be based on the Kaplan-Meier method for 
estimation of summary statistics, and will include the 25th, 50th (median), and 75th 
percentiles and associated 95% CIs. 
Secondary Analyses: 
1. Response to therapy per RECIST 1.1:  response for patients in each cohort will be 
determined by ORR, defined as either CR or PR using RECIST 1.1, calculated as 
a proportion and including a two-sided 95% CI for that cohort. Duration of response 
(DOR) will also be calculated; from the date of first documented occurrence of 
response (CR or PR) until the date of documented progression, or last disease 
assessment, should progression not have occurred. The analysis of DOR will be 
based on the Kaplan-Meier method for estimation of summary statistics, and 
include the 25th, 50th (median), and 75th percentiles and associated 95% CIs. 
2. Response to therapy per GCIG response criteria (RECIST 1.1 and CA-125): 
response for patients in the ovarian cohort will also be assessed for DCR and ORR, 
as described above, using the GCIG response criteria. Only patients with sufficient 
data to be assessed based on this criteria (i.e., has a baseline CA-125 assessment) 
will be included. Number and frequency of patients in the ovarian cancer cohort 
who can be assessed using the GCIG response criteria will be presented. 
3. Median Progression-free Survival:  PFS for patients in each cohort will be 
calculated from the date of start of study therapy to the date of progression based 
on RECIST 1.1 , or date of death should progression not have occurred. Patients 
who drop out prior to study end or do not have documented PD will be censored at 
the day of last documented disease assessment. The analysis of PFS for patients 
in each cohort will be based on the Kaplan-Meier method for estimation of summary 
statistics, and include the 25th, 50th (median), and 75th percentiles and associated 
95% CIs. PFS will also be presented with progression defined per GCIG response 
criteria (RECIST 1.1 and CA-125) for patients in the ovarian cohort with sufficient 
data to be assessed based on this criteria (i.e., has a baseline CA-125 
assessment). 
4. Overall Survival:  OS for patients in each cohort will be calculated from the date of 
start of study therapy to the date of death due to any cause. OS rate at 12 and 24 
months will also be calculated. Patients who drop out prior to study end will be 
censored at the day they were last known to be alive. The analysis of OS for 
patients in each cohort will be based on the Kaplan-Meier method for estimation of 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 71 
summary statistics, and include the 25th, 50th (median), and 75th percentiles and 
associated 95% CIs. 
5. Quality of Life (QoL): will be evaluated for patients in each cohort, and for all study 
patients combined by EORTC QLQ-C30 after 6 and 12 weeks of treatment and 
approximately every 8 weeks thereafter. 
8.4.4 Safety Evaluation 
Safety and tolerability of selinexor will be evaluated descriptively for all study patients 
combined, according to NCI CTCAE, v. 4.03. Safety endpoints include AEs, clinical 
laboratory data, vital signs, ECGs, and physical examinations, further described below. 
8.4.4.1 Adverse Events 
Adverse Events (AEs) will be coded using the MedDRA dictionary and displayed for all 
study patients combined, in tables and listings using System Organ Class (SOC) and 
Preferred Term.  
Analyses of AEs will be performed for those events that are considered treatment 
emergent, where treatment-emergent is defined as any AE with onset or worsening of a 
pre-existing condition on or after the first administration of study medication through 30 
days following last dose or any event considered drug-related by the Investigator through 
the end of the study. AEs with partial dates will be assessed using the available date 
information to determine if treatment-emergent; AEs with completely missing dates will be 
assumed to be treatment-emergent.  
AEs will be summarized by patient incidence rates, therefore, in any tabulation, a patient 
contributes only once to the count for a given AE preferred term.  
The number and percentage of patients with any treatment-emergent AE will be 
summarized for each dosing regimen and for all study patients combined. The number 
and percentage of patients with treatment-emergent AEs assessed by the Investigator as 
at least possibly related to treatment will also be tabulated. The number and percentage 
of patients with any grade ≥ 3 treatment-emergent AE will be tabulated in the same 
manner. In the event a patient experiences repeated episodes of the same AE, then the 
event with the highest severity and/or strongest causal relationship to study treatment will 
be used for purposes of tabulations.  
Serious AEs will also be tabulated.  
No formal hypothesis-testing analysis of AE incidence rates will be performed.  
All AEs (treatment emergent and post-treatment) will be listed in patient data listings.  
By-patient listings will be provided for the following:  patient deaths; serious AEs; and AEs 
leading to withdrawal.  
8.4.4.2 Laboratory Data  
The actual value and change from baseline for each on study evaluation will be 
summarized for each clinical laboratory parameter, including hematology and clinical 
chemistry, for all study patients combined. In the event of repeat values, the last non-


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 72 
missing value per study day/time will be used.  
Severity of select clinical lab measures will be determined using CTCAE criteria (e.g., 
those measures that have a corresponding CTCAE grade classification). Labs with 
CTCAE grades ≥ 3 will be presented in a data listing. Shift tables that present changes 
from baseline to worst on-study values relative to CTCAE classification ranges will be 
produced.  
8.4.4.3 Vital Signs and Physical Examinations  
The actual value and change from baseline to each on study evaluation will be 
summarized for vital signs for all study patients combined. By-patient listings of vital sign 
measurements will be presented in data listings.  
Physical examination results at screening will be summarized; all other abnormal physical 
examination data were to be recorded on the AE eCRF. All examination findings will be 
presented in a data listing.  
8.4.4.4 Concomitant Medications  
The use of concomitant medications will be included in by-patient data listings. 
8.5 Interim and Final Analysis 
In accordance with the Simon’s two-stage optimal design of Part 1, there will be a 
preliminary assessment of efficacy for each cohort after the first 8 patients enrolled in that 
cohort have 6-month data available to assess DCR, as defined in Section 8.4.3. Note that 
this initial analysis for a cohort may take place sooner than when the 8th patient has 
available data, should there be 3 or more disease control achievers after fewer than 8 
patients are enrolled. Should the trial be terminated at the first stage, all efficacy and safety 
analyses as noted above will be performed. Patient enrollment into the trial will continue 
while the first stage analysis is being conducted. 
The final analysis of the primary endpoint DCR for each cohort will take place after the 
target number of patients evaluable for DCR has been reached. Additional data 
summarization may take place after all available survival data are collected, or after 
Sponsor decision, as appropriate. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 73 
9 
DATA QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Standard Operational Procedures of GSO. Accurate and reliable data collection will be 
assured by verification and cross-check of the eCRFs against the Investigator’s records 
by the study monitor (source document verification), and the maintenance of a drug–
dispensing log by the Investigator. Data for this study will be recorded via eCRF. Data 
from the Maintenance Phase will be collected in a separate database to allow locking of 
the Primary Treatment Phase database after initiation of the Maintenance Phase. It will 
be transcribed by the site from the source documents onto the eCRF. Data are reviewed 
and checked for omissions, apparent errors, and values requiring further clarifications 
using computerized and manual procedures. Data queries requiring clarification are 
communicated to the site for resolution. Only authorized personnel will make corrections 
to the clinical database and an audit trail will document all corrections. 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 74 
10 ETHICAL ASPECTS 
10.1 Good Clinical Practice 
This clinical study was designed, implemented and shall be 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. 
10.2 Patient Information and Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from each 
patient participating in this study, after an adequate explanation of the aims, importance, 
anticipated benefits, potential hazards and consequences of the study according to 
applicable local laws. Written informed consent must be obtained before any study-
specific procedures are performed. It must be also explained to the patient that they are 
completely free to refuse to enter the study or to withdraw from it at any time, for any 
reason, without incurring any penalty or withholding of treatment on the part of the 
Investigator.  
With the declaration of consent, the patient agrees to data about his/ her disease being 
recorded within the context of the clinical study and that it may be transferred to the 
Sponsor in pseudonymized form. 
The patient also agrees to allow the monitor/auditor/health authorities to verify the patient 
data collected against the patient’s original medical records for the purpose of source data 
verification.  
The informed consent form (ICF) personally signed and dated by the patient must be kept 
on file by the Investigator and documented in the CRF and the patient’s medical records. 
The Investigator must confirm with the sponsor that he/ she has obtained written informed 
consent. 
If new safety information results in significant changes to the risk/ benefit assessment, the 
consent form should be reviewed and updated if necessary. All patients (including those 
already being treated) should be informed of the new information and must give their 
written informed consent to continue in the study. 
If family physicians are to be informed of their patients’ participation in the clinical study, 
this should be mentioned in the consent form. 
10.3 Independent Ethics Committees and Regulatory Authorities 
10.3.1 Approval of the Study by the Regulatory Authority and Independent Ethics 
Committees 
It is the responsibility of the Sponsor to obtain and maintain independent approval from 
the applicable regulatory authority and a positive opinion from the competent ethics 
committees to conduct the study in accordance with local legal requirements and statutes.  


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 75 
Indemnity insurance will be arranged for the trial patients in accordance with the applicable 
local laws.  
10.3.2 Notification of the Study 
The Sponsor is responsible for notifying the competent regional authority about the study 
and all Investigators at the participating investigational sites, if applicable by local law. 
10.3.3 Obligation to Report and Document 
The Sponsor and the Investigator are responsible for complying with the requirements for 
reporting and documentation in accordance with local legal requirements and statutes. 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 76 
11 CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to on-going studies must be made via amendment. The Sponsor is 
responsible for obtaining independent approval for substantial amendments from 
applicable regulatory authorities and a positive opinion from the competent ethics 
committees in accordance with local legal requirements, statutes, and the European 
Clinical Trial Directive. Approval must be obtained before any changes can be 
implemented, except for changes necessary in order to eliminate an immediate hazard to 
trial patients or when the changes are non-substantial and involve only logistical or 
administrative aspects of the trial (e.g., change of telephone numbers). 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 77 
12 STUDY DOCUMENTATION, CRFS AND RECORD-KEEPING 
12.1 Investigator’s Files / Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into two separate categories:  Investigator’s study file and 
subject/ patient data. 
The Investigator’s study file will contain all essential documents such as the protocol/ 
amendments, case report and query forms, patient information and informed consent 
form, ethics committee and regulatory authority approval, notification of the federal 
regulatory authority and competent regional authorities (if applicable), drug records, staff 
curriculum 
vitae 
and 
authorization 
forms, 
and 
other 
appropriate 
documents/correspondence, etc. 
Patient data includes patient hospital/ clinic records (e.g., medical reports, surgery reports 
appointment book, medical records, pathology, laboratory reports, and ECG), signed ICFs 
and patient screening and eligibility screening forms.  
The Investigator must keep these two categories of documents on file for as long as legally 
required by local and national regulations, or local IRB/ethics board policies whichever is 
longer, after completion or discontinuation of the study. The documents must be archived 
in a secure place and treated as confidential material.  
Should the Investigator wish to assign the study records to another party or move them to 
another location, the sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and the Sponsor to store these in sealed containers outside of the site so that 
they can be returned sealed to the Investigator in the event of a regulatory audit. Where 
source documents are required for the continued care of the patient, appropriate copies 
should be made for storing outside of the site. 
All documents must be archived in a secure place and treated as confidential material. 
12.2 Source Documents and Background Data 
The Investigator shall supply the Sponsor on request with any required background data 
from the study documentation or clinic records. This is particularly important when case 
report forms are illegible or when errors in data transcription are suspected. In the event 
of special problems and/or governmental queries or requests for audit inspections, it is 
also necessary to have access to the complete study records, provided that patient 
confidentiality is protected. According to the standards of the data protection law, all data 
obtained in the course of a clinical study must be treated with discretion in order to 
guarantee the rights of the patient’s privacy. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 78 
12.3 Audits and Inspections 
This study may be audited by the Sponsor, any person authorized by the sponsor, or the 
competent health authority in order to determine the authenticity of the recorded data and 
compliance with the study protocol.  
The Investigator must be aware that source documents for this trial should be made 
available 
to 
appropriately 
qualified 
personnel 
working 
on 
behalf 
of 
the 
sponsor/monitor/auditor/health authority inspectors after appropriate notification for the 
purposes of source data verification and proper review of the study progress. The 
verification of the eCRF data must be done via direct inspection of the source documents. 
The Investigator agrees to comply with the Sponsor and regulatory authority requirements 
regarding the auditing of the study. 
All materials used in clinical studies are subjected to quality control. 
12.4 Case Report Forms 
For each patient enrolled, an electronic case report form (eCRF) must be completed and 
signed by the Investigator or an authorized delegate from the study team. This also applies 
to records for those patients who fail to complete the study. If a patient withdraws from the 
study, the reason must be noted in the eCRF. If a patient is withdrawn from the study 
because of a treatment-limiting AE, thorough efforts should be made to document the 
outcome clearly. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 79 
13 MONITORING THE STUDY 
The clinical monitor or clinical research associate is responsible for familiarizing the 
Investigator(s) and the entire center staff involved in the study with all study procedures, 
including the administration of the study drug. 
The monitor will visit the clinical study center before the first patient has been enrolled 
(initiation visit). During the study, the monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs (source data 
verification), the adherence to the protocol to Good Clinical Practice, the progress of 
enrollment, and to ensure that study drug is being stored, dispensed, and accounted for 
according to specifications.  
Key study personnel must be available to assist the monitor during these visits. The 
Investigator (or his/her deputy) agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 80 
14 SAFETY MONITORING COMMITTEE 
A Safety Monitoring Committee (SMC) will provide additional oversight on the safety of 
the investigational product, selinexor (KPT-330), as used in this study. The SMC is 
responsible for reviewing accumulated safety data from the study.  
The SMC will have access to all data necessary to formulate their opinion on the safety 
of the study. This includes efficacy data at the scheduled meetings as this is relevant to 
assessing the acceptability of the AE profile observed. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 81 
15 CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS 
The Investigator and the Sponsor (or designated person) will ensure that all data obtained 
in the course of this study is treated with discretion in order to guarantee the rights of the 
patients’ privacy, according to the standards of the data protection law. CRFs or other 
documents should be submitted to the sponsor in pseudonymized form. The Investigator 
should keep a patient identification log showing codes and names. The Investigator 
should maintain documents not intended for submission to the sponsor, e.g. patients’ 
written consent forms, in the strictest confidence. 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
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Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
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Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
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Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
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Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
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Block the Expression of DNA Damage Repair Proteins and Sensitize Cancer Cells to DNA 
Damage Inducing Therapeutic Agents. 26th EORTC-NCI-AACR Symposium on Molecular 
Targets and Cancer Therapeutics, 2014.  
87. Ferreiro-Neira I, Torres NE, Liesenfeld LF, et al. XPO1 Inhibition Enhances Radiation 
Response in Preclinical Models of Rectal Cancer. Clin Cancer Res 2016 Apr;22(7):1663-73. 
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90. Wang Y, Wang Y, Xiang J et al. Knockdown of CRM1 inhibits the nuclear export of p27Kip1 
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Appendix 1: Summary of Efficacy Data from Recent Trials for Ovarian Cancer 
Table 6: 
Summary of Efficacy Data from Recent Trials for Ovarian Cancer 
Source 
Prior 
treatment 
Number of 
patients 
enrolled 
(evaluable) 
Drug 
Dose 
ORR 
(CR / 
PR) 
SD 
PFS 
(months) 
OS 
(months) 
Mirza et al. 
(2010) 7 
average > 
2 
79 (-) 
PLD (with 
Gemcitabine) 
average 5 cycles 
PLD 25mg/m²  
Gemcitabine: 
800mg/m² 
5% CR 
28% 
PR 
56% 
6,4 
12,5 
Markman et 
al. (2006) 8 
average 1 
48 (-) 
Paclitaxel 
(weekly) 
(80 mg/m²/week) 21% (-) 
(-) 
4,9 
13,1 
Miller et al. 
(2009) 9 
average 1 
51 (-) 
Pemetrexed 
900 mg/m² every 
21 days 
(median, 
4 cycles) 
21% (1 
CR, 9 
PR) 
35% 
2,9 
11,4 
Coleman et 
al. (2011) 10 
average 1 
51 (47) 
Nab-paclitaxel 
100 mg/m² days 
1,8,15 on a 28-
day schedule, 
median 4 cycles 
23% (1 
CR, 10 
PR) 
36% 
4,5 
17,4 
Schilder et 
al. (2005) 11 
average 
1-2 
30 (27) 
Gefitinib 
500 mg daily, 
1 cycle =28 
days;median 
2 cycles 
4% (-) 
(-) 
2,2 
12,2 
Schilder et 
al. (2008) 12 
average 
1-2 
56 (56) 
Imatinib 
400 mg twice 
daily 
2% (1 
CR, 0 
PR) 
13% 
2,0 
16,0 
Matei et al. 
(2011) 13 
average 
1-2 
73 (71) 
Sorafenib 
400 mg orally 
twice per day, 
1 cycle = 4 
weeks, median 2 
3% (0 
CR, 2 
PR) 
34% 
2,1 
16,3 
Modesitt et 
al. (2008) 14 
average 
1-2 
27 (-) 
Vorinostat 
400 mg daily 
4% (0 
CR, 1 
PR) 
(-) 
3,4 
(-) 
Behbakht et 
al. (2011) 15 
average 
1-2 
60 (54) 
Temsirolimus 
25 mg weekly iv, 
1 cycle 
=4 weeks, 
median 2,5 
9% (0 
CR, 5 
PR) 
41% 
3,2 
11,6 
Usha et al 
(2011) 16 
average 
1-2 
27 (-) 
Enzastaurin 
loading dose of 
375 mg TID on 
day 1 
followed by 
continuous 
treatment with 
500 mg daily, 1 
cycle =28 days, 
median 2 cycles 
7% (-) 
22% 
1,9 
15,1 
Rocereto et 
al. (2010) 17 
average 
1-2 
24 (22) 
Mifepristone 
200 mg  daily, 1 
cycle =28 days 
5% (0 
CR, 1 
PR) 
(-) 
(-) 
(-) 
Sabbatini et 
al. (2008) 18 
average 
1-2 
78 (-) 
Paclitaxel 
poliglumex 
175 mg/m² every 
21 days 
16% (0 
CR, 8 
PR) 
41% 
2,8 
15,4 
Kavanagh et 
al. (2008) 19 
average 
1-2 
27 (26) 
Karenitecin 
(Cositecan) 
1.0 mg/m² daily 
for 5 days every 
21 days 
12% (1 
CR, 2 
PR) 
(-) 
4,5 
15,0 


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Source 
Prior 
treatment 
Number of 
patients 
enrolled 
(evaluable) 
Drug 
Dose 
ORR 
(CR / 
PR) 
SD 
PFS 
(months) 
OS 
(months) 
Monk et al. 
(2011) 20 
average < 
3 
71 (71) 
Docetaxel + 
trabectedin 
average 6 cycles 
Docetaxel 
60mg/m² 
Trabectedin 1,1 
mg/m² 
30% (-) 
(-) 
4,5 
16,9 
Mutch et al. 
(2007) 21 
1st line 
with 
platinum-
based CT 
99 (-) 
PLD 
50 mg/m² 
8% (2 
CR, 6 
PR) 
39% 
3,1 
13,5 
96 (-) 
Gemcitabine 
1000 mg/m² 
6% (1 
CR, 5 
PR) 
55% 
3,6 
12,7 
Ferrandina 
et al. (2008) 
22 
average 1 
(platinum, 
paclitaxel) 
76 (-) 
PLD 
40 mg/m² 
16% (3 
CR, 8 
PR) 
43% 
16 wk 
56 wk 
77 (-) 
Gemcitabine 
1000 mg/m² 
29% (3 
CR, 15 
PR) 
43% 
20 wk 
51 wk 
Vergote et 
al. (2009) 23 
average 2 
229 (-) 
PLD or 
Topotecan 
PLD 50mg/m² 
Topo 1,5 mg/m² 
11% (-) 
(-) 
19 wk 
59 wk 
232 (-) 
Canfosfamide 
1000 mg/m² 
4% (-) 
(-) 
10 wk 
37 wk 
Monk et al. 
(2010) 24 
average 1 
335 (-) 
PLD 
50 mg/m² 
19% (4 
CR, 59 
PR) 
(-) 
5,8 
(-) 
337 (-) 
PLD + 
Trabectedin 
PLD 30mg/m² 
Trabectedin 1,1 
mg/m² 
28% (2 
CR, 91 
PR) 
(-) 
7,3 
(-) 
Naumann et 
al. (2010) 25 
average < 
2 
31 (-) 
PLD 
50 mg/m² 
15% 
(-) 
12 wk 
(-) 
60 (-) 
PLD + EC145 
EC145: 2,5 mg  
PLD 50 mg/m² 
17% (-) 
(-) 
24 wk 
(-) 
Colombo et 
al. (2012) 26 
average < 
3 
417 (-) 
PLD 
50 mg /m² 
8% (0 
CR, 33 
PR) 
48% 
3,7 
12,7 
412 (-) 
Patupilone 
10 mg/m² 
16% (0 
CR, 64 
PR) 
44% 
3,7 
13,2 
Nishimura et 
al. (2007) 27 
(-) 
19 (13) 
Irinotecan + 
Doxorubicin 
every 4 weeks 
Irinotecan: 
50mg/m² 
Doxorubicin: 
40mg/m² 
31% (-) 
(-) 
(-) 
(-) 
Cannistra et 
al. (2007) 28 
average 3 
44 (-) 
Bevacizumab 
15 mg/kg 
intravenously 
every 3 weeks 
16% (0 
CR, 16 
PR) 
(-) 
4,4 
10,7 
Ray-
Coquard et 
al. (2009) 29 
average 
1-2 
50 
Gemcitabine + 
Oxaliplatin 
median 6 cycles 
Oxa: 100 mg/m² 
Ge 1000 mg/m² 
31% (-) 31% 
4,6 
11,4 
Gupta et al. 
(2009) 30 
average 2 
27 (24) 
Topotecan + 
Docetaxel 
6 cycles 
Topotecan: 3,5 
mg/m² 
Docetaxel: 30 
mg/m² 
25% 
(8% 
CR, 
17% 
PR) 
13% 
8,5 
18,5 
Itani et al. 
(2009) 31 
average > 
2 
34 (32) 
Gemcitabine + 
Docetaxel 
average > 4 
cycles 
DL1 
DOC 70 mg/m² 
GEM 800 mg/m² 
22% (1 
CR, 6 
PR) 
19% 
4,8 
13,0 


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Source 
Prior 
treatment 
Number of 
patients 
enrolled 
(evaluable) 
Drug 
Dose 
ORR 
(CR / 
PR) 
SD 
PFS 
(months) 
OS 
(months) 
DL2 
DOC 70 mg/m² 
GEM 1000 
mg/m² 
Vergote et 
al. (2010) 32 
average 3 
71 (-) 
Irinotecan 
(NKTR-102) 
NKTR-102: 145 
mg/m² 
27% (-) 
(-) 
(-) 
(-) 
Pujade-
Lauraine et 
al (2012) 
AURELIA 33 
average 2 
361 (-) 
Chemotherapy 
+ 
Bevacizumab 
every 2 weeks 
until PD 
10 mg/kg 
31% (-) 
(-) 
6,7 
not stated 
(-)=not assessed 


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Appendix 2: Summary of Efficacy Data from Recent Trials for Cervical Cancer 
Table 7: 
Summary of Efficacy Data from Recent Trials for Cervical Cancer 
Source 
Prior 
treatment 
Number of 
patients 
enrolled 
(evaluable) 
Drug 
Dose 
ORR 
(CR / 
PR) 
SD 
PFS 
(months) 
OS 
(months) 
Fracasso et al 
(2003) 45 
average 1  
28 (22) 
Oxaliplatin 
Cisplatin 130 
mg/m² 
8% (1 
CR, 1 
PR) 
38% 
(-) 
(-) 
Goncalves et al 
(2008) 46 
average 1  
30 (28) 
Gefitinib 
Gefitinib 500 
mg daily 
0% (0 
CR, 0 
PR) 
20% 
37 days 
3,5 
Long et al 
(2005) 47 
average 1  
146 
Cisplatin 
(CPT) 
average 3 
cycles cisplatin 
50 mg/m² 
13% (4 
CR, 14 
PR) 
50% 
2,9 
6,5 
147 
Topotecan + 
Cisplatin (CT) 
average 4 
cycles 
Topotecan 
0,75 mg/m² + 
Cisplatin  50 
mg/m² 
27% 
(14 CR, 
22 PR) 
45% 
4,6 
9,4 
Rose et al 
(2006) 48 
average 1  
27 (26) 
PLD  
average 2 
cycle PLD 40 
mg/m² 
11% (0 
CR, 3 
PR) 
(-) 
(-) 
(-) 
Tinker et al 
(2013) 49 
average 1  
38 (33) 
Temsirolimus 
Temsirolimus 
25mg 
3% (0 
CR, 1 
PR) 
58% 
3,5 
(-) 
Wright et al 
(2006) 50 
(-) 
6 (-) 
Bevacizumab 
(-) 
34% (1 
CR, 1 
PR) 
33% 
4,3 
(-) 
Zighelboim et al 
(2013) 51 
average 1  
27 (26) 
Cisplatin + 
Topotecan + 
Bevacizumab 
average 3 
cycles cisplatin 
50 mg/m², 
topotecan 0,75 
mg/m² and 
bevacizumab 
15 mg/kg 
35% (1 
CR, 8 
PR) 
39% 
7,1 
13,2 
(-)=not assessed 
 
 


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Appendix 3: Summary of Efficacy Data from Recent Trials for Endometrial Cancer 
Table 8: 
Summary of Efficacy Data from Recent Trials for Endometrial Cancer 
Source 
Prior 
treatment 
Number of 
patients 
enrolled 
(evaluable) 
Drug 
Dose 
ORR 
(CR / 
PR) 
SD 
PFS 
(months) 
OS 
(months) 
Alvarez et al 
(2013) 68 
average 1 
or 2 
53 (49) 
Bevacizumab 
+ 
Temsirolimus 
Bevacizumab 
10 mg/kg + 
Temsirolimus 
25 mg weekly 
25% (1 
CR, 11 
PR) 
(-) 
5,6 
16,9 
Aghajanian 
et al (2011) 
69 
average 1 
or 2 
56 (52) 
Bevacizumab 
average 5 
cycles 
Bevacizumab 
15 mg/kg every 
3 weeks 
14% (1 
CR, 6 
PR) 
50% 
4,2 
10,5 
Coleman et 
al (2012) 70 
average 2 
49 (45) 
Aflibercept 
Aflibercept 4 
mg/kg 
7% (0 
CR, 3 
PR) 
(-) 
2,9 
14,6 
Colombo et 
al (2013) 71 
average 
of more 
than 2 
45 
Ridaforolimus  
Ridaforolimus  
12mg 
11 % (0 
CR, 5 
PR) 
18% 
(-) 
(-) 
Dizon et al 
(2009) 72 
average 1 
52 (50) 
Ixabepilone 
average 4 
cycles 
Ixabepilone 
40mg/m² 
12% (1 
CR, 5 
PR) 
60% 
2,9 
8,7 
Garcia et al 
(2008) 73 
average 1 
27 (26) 
Docetaxel 
Docetaxel 36 
mg/m² 
8% (0 
CR, 2 
PR) 
31% 
(-) 
(-) 
McMeekin et 
al (2007) 74 
average 1 
27 (24) 
Thalidomide 
 Thalidomide 
200 mg daily 
13% (0 
CR, 3 
PR) 
8% 
1,7 
6,3 
Oza et al 
(2011) 75 
average 1 
27 (25) 
Temsirolimus 
average 3 
cycles  
Temsirolimus 
25 mg 
4% (0 
CR, 1 
PR) 
48% 
3,3 
(-) 
Ray-Coquard 
(2013) 76 
average 1 
44 
Everolimus 
Everolimus 10 
mg 
5% (O 
CR, 2 
PR) 
29% 
2,8 
8,1 
Slomovitz et 
al (2010) 77 
average 1 
or 2 
35 (28) 
Everolimus 
Everolimus 10 
mg 
0% (0 
CR, 0 
PR) 
43% 
4,5 
(-) 
Homesley et 
al (2005) 78 
(-) 
56 (52) 
Liposomal 
doxorubicin 
at least one to 
max of 20 
cycles 
Liposomal 
doxorubicin 
40mg/m² 
12% (2 
CR, 4 
PR) 
60% 
(-) 
(-) 
Lincoln et al 
(2003) 79 
average 1 
or 2 
48 (44) 
Paclitaxel 
average of 2 
cycles 
Paclitaxel 
200mg/m² or 
175 mg/m² for 
patients with 
prior pelvic 
27% (3 
CR, 9 
PR) 
(-) 
4,2 
10,3 


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Source 
Prior 
treatment 
Number of 
patients 
enrolled 
(evaluable) 
Drug 
Dose 
ORR 
(CR / 
PR) 
SD 
PFS 
(months) 
OS 
(months) 
radiation 
therapy 
Moore et al 
(1999) 80 
average 
of 1 
27 (25) 
Dactinomycin 
Dactinomycin 2 
mg/m² 
12% (1 
CR, 2 
PR) 
(-) 
(-) 
(-) 
Muggia et al 
(2002) 81 
average 
of 1 
46 (42) 
Liposomal 
doxorubicin 
average of 2,5 
courses 
PLD 50 mg/m² 
every 4 weeks 
10% (0 
CR, 4 
PR) 
(-) 
(-) 
8,2 
Miller et al 
(2002)82 
average 
of 1 
29 (22) 
Topotecan 
2 to 11 courses 
Topotecan 0,5 
to 1,5 mg/m² 
every 3 weeks 
9% (1 
CR, 1 
PR) 
55% 
(-) 
(-) 
Fracasso et 
al (2006)83 
average 
of 1 
54 (50) 
Oxaliplatin 
Oxaliplatin 130 
mg/m² every 21 
days 
14% (3 
CR, 4 
PR) 
29% 
(-) 
(-) 
(-)=not assessed  
 
 


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Appendix 4: Adverse Event Categories for Determining Relationship to Test Drug 
(a) Related (must satisfy one of the following) 
This category applies to those adverse events that are considered to be related to the test 
drug. An adverse event may be considered related if: 
1. It follows a reasonable temporal sequence from administration of the drug 
2. It cannot be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors or other modes of therapy administered to the 
subject 
3. It disappears or decreases on cessation or reduction in dose. (There are important 
exceptions when an adverse event does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists:  e.g. (1) bone marrow depression, (2) tardive 
dyskinesias.) 
4. It follows a known pattern of response to the suspected drug 
5. It reappears upon rechallenge 
(b) Not related 
This category is applicable to those adverse events which are judged to be clearly and 
incontrovertibly due only to extraneous causes (disease, environment, etc.) and do not meet 
the criteria for drug relationship listed under related. 
 


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Appendix 5: Definitions According to ICH Topic E2A Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject who has been administered a pharmaceutical product, and which does not 
necessarily have to have a causal relationship with this treatment. 
Adverse reactions are defined as all untoward and unintended responses to an 
investigational medicinal product related to any dose administered. The phrase 
"responses to a medicinal products" means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out. 
A serious adverse event or serious adverse reaction is any experience that suggests a 
significant hazard, contraindication, side effect or precaution. It is any adverse event that 
at any dose fulfills at least one of the following criteria: 
 is fatal (results in death) (NOTE:  Death is an outcome, not an event) 
 is life-threatening (NOTE:  The term “life-threatening” refers to an event in which the 
patient was at immediate risk of death at the time of the event; it does not refer to an 
event which could hypothetically have caused a death had it been more severe) 
 required in-patient hospitalisation or prolongation of existing hospitalisation 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is medically significant or requires intervention to prevent one or other of the outcomes 
listed above 
Medical and scientific judgement should be exercised in deciding whether expedited 
reporting to the sponsor is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalisation 
but may jeopardise the patient or may require intervention to prevent one of the outcomes 
listed in the definitions above. These situations should also usually be considered serious. 
Examples of such events are intensive treatment in A&E or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation, or 
development of drug dependency or drug abuse. 
An unexpected adverse event, the nature or severity of which is not consistent with the 
applicable product information (e.g., Investigator's Brochure for an unapproved 
investigational medicinal product) 
Causality is initially assessed by the Investigator. With respect to the obligation to report 
and document (regulatory authorities, ethics committees and other Investigators) serious 
adverse events, causality can be one of two possibilities: 
 No (not related; equals not drug-related) 
 Yes (remotely, possibly or probably drug-related) 


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All adverse events not assessed as definitively “not drug-related” by the Investigator will 
be considered as adverse drug reactions. 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction 
whose nature or severity is not consistent with the applicable product information. 
It is important that the severity of an adverse event is not confused with the seriousness 
of the event. For example, vomiting which persists for many hours may be severe, but is 
not necessarily a serious adverse event. On the other hand, stroke which results in only 
a limited degree of disability may be considered a mild stroke, but would be a serious 
adverse event. 
A serious adverse event occurring during the study or which comes to the attention of the 
Investigator within three weeks of stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, must be reported, whether considered treatment-related 
or not. In addition, serious adverse events occurring after this time should be reported if 
considered related to test “drug”. 
Such preliminary reports will be followed by detailed descriptions later that will include 
copies of hospital case reports, autopsy reports and other documents. 
For serious adverse events, the following must be assessed and recorded on the adverse 
events page of the case report form:  intensity, relationship to test substance, action taken, 
and outcome to date. 
The obligation to document and report must be adhered to according to the national and 
international laws and regulations.  
For contact details and fax no. for SAE and pregnancy reporting, please refer to page 14. 
Appendix 6: ECOG Performance Status Scale 
GRADE SCALE 
0 
Fully active, able to carry out all pre-disease performance without 
restriction  
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work 
2 
Ambulatory and capable of all self-care, but unable to carry out work 
activities. Up and about more than 50% of waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to 
bed or chair. 
5 
Dead  
  


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Appendix 7: Cockroft-Gault Formula 
 
Calculated CLCR (ml/min) =  
[(140 – subject’s age in years) x subject’s actual body weight in kilograms] * 
 
 
 
 
 
 
 
72 x subject’s serum creatinine (in mg/dL) 
*: x 0.85 for females 
 
 
 
 
Calculated CLCR (ml/min) =  
[(140 – subject’s age in years) x subject’s actual body weight in kilograms] x K* 
 
 
 
 
 
 
 
subject’s serum creatinine (in µmol/L) 
K*: 1.05 for females 
 
 
 
 


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Appendix 8: NCI-CTCAE Version 4.03 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
 


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Appendix 9: 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). 
Please note:  patients enrolled under a prior version of the protocol who had detectable 
cataracts graded according to the LOCS III will continue to have their cataracts graded 
according to LOCS III and will not switch to the new Grade 1-4 cataract scale. For new 
patients or patient for whom no cataracts have been detected to date, if cataracts are 
detected they will be graded according to the Grade 1-4 scale. 
 
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 
opacity 
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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Appendix 10: 
NCCN Clinical Practice Guidelines in Oncology:  Antiemesis 
 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.201498. © 2014 National Comprehensive Cancer Network, Inc. 
All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most 
recent and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other 
NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.201498. © 2014 National Comprehensive Cancer Network, Inc. 
All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most 
recent and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other 
NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 
 


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Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.201498. © 2014 National Comprehensive Cancer Network, Inc. 
All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most 
recent and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other 
NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 
 
 


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Appendix 11: 
NCCN Clinical Practice Guidelines in Oncology:  Anorexia/Cachexia 
 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Palliative Care V.1.201499. ©2014 National Comprehensive Cancer Network, 
Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the 
most recent and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other 
NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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Appendix 12: 
Evaluation of Response According to CA-125 
(Modified from Rustin, Vergote, Eisenhauer et al) 
 
A CA-125 response is defined as at least a 50% reduction in CA-125 levels from a 
pretreatment sample. The response must be confirmed and maintained for at least 28 
days. Patients can be evaluated according to CA-125 only if they have a pretreatment 
sample that is at least twice the upper limit of the reference range and within 2 weeks 
before starting the treatment. 
To calculate CA-125 responses accurately, the following rules apply: 
 Intervening samples and the 28-day confirmatory sample must be less than or 
equal to (within an assay variability of 10%) the previous sample. 
 Variations within the reference range of CA-125 levels will not interfere with the 
response definition. 
 For each patient, the same assay method must be used, and the assay must be 
tested in a quality control scheme. 
 Patients are not evaluable by CA-125 if they have received mouse antibodies 
(unless the assay used has been shown not to be influenced by human anti-
mouse antibody) or if there has been medical and/or surgical interference with 
their peritoneum or pleura during the previous 28 days (e.g., paracentesis). If 
assessing therapy that includes 2 treatment modalities for relapse (e.g., surgery 
and chemotherapy), any CA-125 response results from both treatment 
modalities. CA-125 cannot distinguish between the effects of the 2 treatments 
The date when the CA-125 level is first reduced by 50% is the date of the CA-125 
response. To calculate response, an intent-to-treat analysis should be used that 
includes all patients with an initial CA-125 level of at least twice the upper limit of the 
reference range as eligible and evaluable. In addition, as a separate analysis, those 
patients who have a CA-125 response and whose CA-125 level falls to within the 
reference range can be classified as CA-125 complete responders. 
In Table 9 (Appendix 13) and Table 10 (Appendix 14) where CA-125 is stated as 
normalized or normal, means within the reference range. Patients who have a fall of 
CA-125 to within the reference range but whose initial CA-125 was less than twice the 
upper limit of the reference range have not had a CA-125 response and cannot 
therefore be classified as a CA-125 complete responder. 
 
 


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Appendix 13: 
Evaluation of Best Overall Response in Patients Without Initial 
Measurable Disease and Who Are Evaluable by CA-125 
Table 9: 
Evaluation of Best Overall Response in Patients Without Initial 
Measurable Disease and Who Are Evaluable by CA-125 
CA-125 
Nontarget 
Lesionsa 
New 
Lesions 
Overall 
Serological 
Response 
Best Response for this 
Category also Requires 
Response and 
Normalized 
CR 
No 
CR 
Confirmed and maintained 
for at least 28 days 
Response 
Non-PD 
No 
PR 
 
Normalized but no 
response 
Non-CR/Non-
PD 
No 
SD 
 
Non-PR/non-PD 
Non-PD 
No 
SD 
 
PD 
Any 
Yes or No 
PD 
 
Any 
PDb 
Yes or No 
PD 
 
Any 
Any 
Yes 
PD 
 
a 
Nontarget lesions include ascites and peritoneal thickening, which are not measureable according to RECIST. 
b 
Unequivocal progression in nontarget lesions maybe accepted as disease progression. 
CR-complete response; PD-progressive disease; PR-partial response; SD-stable disease 
 
 
 


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Appendix 14: 
Best Overall Response in Patients with Measureable Disease 
and Who Are Also Evaluable by CA-125 
Table 10: 
Best Overall Response in Patients with Measureable Disease and Who 
Are Also Evaluable by CA-125 
Target 
Lesiona 
Nontargetb 
New Lesion 
CA-125 
Overall Best 
Response 
Comments 
CR 
CR 
No 
Normal  
CR 
Best RECIST 
1.1 response 
for CR and PR 
also requires it 
to be 
confirmed and 
maintained for 
at least 28 
days if 
response is 
primary 
endpoint 
CR 
Non-CR Non-
PD 
No 
Not PD 
PR 
CR 
CR 
No 
PR but not 
normal 
PR 
CR 
NE 
No 
PR 
PR 
PR 
Non-PD or 
NAE 
No 
Not PD 
PR 
NAE 
Non-PD 
No 
PR 
PR 
PD or New  
>28 days from 
CA-125 PRd 
-- 
PR 
PR 
SDc 
Non-PD 
No 
PR 
PR 
SDc 
Non-PD or 
NAE 
No 
Not PR and 
not PD 
SD 
PD or New 
≤28 days from 
CA-125 PRd 
-- 
PR 
PD 
PD 
Any 
Yes or No 
Any 
PD 
Any 
PD 
Yes or No 
Any 
PD 
Any 
Any 
Yes 
Any 
PD 
Any 
Any 
Yes or No 
PD 
PD 
a 
Target lesions include up to 5 measurable lesions (2 per organ) as defined by RECIST 1.1. 
b 
Nontarget lesions include ascites and peritoneal thickening which are not measureable according to RECIST 1.1. 
c 
The protocol should specify the minimum time interval between 2 measurements for classification as stable 
disease. 
d 
Patients who have CA-125 response that occurs more than 28 days from PD according to RECIST 1.1 are 
considered a PR, according to best response, but PD if the RECIST 1.1 PD is within 28 days of CA-125 response. 
CR-complete response; PD-progressive disease; PR-partial response; SD-stable disease; NE-not evaluable; NAE-
not all evaluated 
 
 


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Appendix 15: Glutathione 
(GSH), N-Acetylcysteine 
(NAC), or S-
Adenosylmethionine (SAM)-
Containing Products 
(Representative 
List)Glutathione (GSH) 
N-acetylcysteine (NAC) 
S-adenosylmethionine (SAM) 
Product Name 
Ingredient 
Product Name 
Ingredient 
Product Name 
Ingredient 
Glutathione 
glutathione 
Antidote for 
acetaminophen 
overdose 
acetylecysteine  
SAM-e Complete 
S-adenosyl-
methionine 
L-Glutathione 
L-glutathione 
Cerefolin NAC: 
medical food for 
age-related 
memory loss 
L-methylfolate 
vitamin B12 
N-acetyl 
cysteine 
SAMe 
S-adenosyl-L-
methionine 
Glutathione 
reduced 
glutathione 
NAC 
N-acetyl 
cysteine 
Double Strength 
SAMe 400 
S-adenosyl-
methionine 
Reduced 
glutathione with 
alpha lipoic acid 
Setria L-
glutathione 
N-A-C Sustain 
N-acetyl L-
cysteine 
 
 
Glutathione, 
Cysteine & C 
glutathione 
L-cysteine 
vitamin C 
Best NAC 
Detox 
Regulators 
N-acetyl 
cysteine 
 
 
(Mega-) 
Liposomal 
Glutathione 
glutathione 
 
  
 
 
Lypospheric 
GSH 
glutathione 
 
 
 
 
Ivory Caps Skin 
Enhancement 
Formula 
glutathione 
 
 
 
 
 
 
 
 
 
 
 


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18 PROTOCOL VERSION ≥3.2: MAINTENANCE PHASE 
Appendix 16 Maintenance Phase  
1. 
INVESTIGATIONAL PLAN FOR THE MAINTENANCE PHASE 
1.1. 
Maintenance Phase Design  
As of Version 3.2 of the protocol, Karyopharm will terminate the Primary Treatment Phase 
of the study and the remaining patients on study will transfer to the Maintenance Phase 
of the study to continue treatment with selinexor and/or survival follow-up. These patients 
will be followed primarily for safety. The patients will be allowed to receive treatment until 
disease progression, Investigator or patient decision to discontinue study treatment, 
pregnancy, unacceptable AEs or toxicity that cannot be managed by supportive care, 
withdrawal of consent, death, or termination of the study. Data from the Maintenance 
Phase will be collected in a separate database to allow locking of the Primary Treatment 
Phase database after initiation of the Maintenance Phase. 
1.1.1. 
Transition from Primary Treatment Phase to Maintenance Phase 
Patients will complete their current cycle in the Primary Treatment Phase and then 
transition to the Maintenance Phase of the study (Maintenance Phase Cycle 1 Day 1).  
1.1.2. 
Study Treatment 
The treatment under investigation in the Maintenance Phase of the study (i.e., the 
“investigational medicinal product” [IMP]) is selinexor 20 mg tablets for oral 
administration.  Patients will continue on the same dose of selinexor (as they were 
receiving prior to this amendment) and dosing may be modified as needed according to 
the guidelines in this protocol. For more details on selinexor dosing see Section 1.1.2.2. 
1.1.2.1. 
Selinexor Tablets 
Selinexor 20 mg tablets will be provided as coated, immediate-release tablets for oral 
administration in blister packs. Patients will be given a supply of tablets for non-clinic 
dosing days. Additional information about selinexor is available in the Selinexor IB. 
1.1.2.1.1. Labeling 
All labels will include conditions for storage, lot number, and other pertinent information 
such as Sponsor and caution statement. Selinexor should not be used after the expiration 
date. 
1.1.2.1.2. Dispensing Directions 
Dispensing instructions for selinexor will be provided in the Pharmacy Manual. 
1.1.2.1.3. Storage 
Selinexor tablets should be stored at or below 86°F (30°C) in a secured area with access 
restricted to the site staff pharmacist or designee(s) at room or refrigerated temperature. 


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Room temperature storage is preferred. The tablets must not be stored at freezer 
temperatures or frozen. Refer to the Pharmacy Manual for detailed information on 
selinexor storage, stability, and administration. 
1.1.2.1.4. Accountability 
The Investigator or designee must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Study treatment accountability 
will be noted by the clinical research associate during site visits and at the completion of 
the study. Patients will be asked to return all unused study treatment and packaging on a 
regular basis, at the time of study treatment discontinuation or at the end of the study 
(See Section 1.1.5 for definition of end of study). 
1.1.2.2. 
Selinexor Dosing 
Patients will receive the same selinexor dose and schedule during the Maintenance 
Phase as they received during the Primary Treatment Phase. Selinexor doses will be 
administered in 20 mg dose increments (e.g., 20 mg, 40 mg, 60 mg, etc.), consistent with 
the dose that the patient received in the Primary Treatment Phase of the study. However, 
if the patient was previously receiving a dose that was in between these 20 mg doses 
(e.g., 30 mg), the Investigator should consult with the Medical Monitor to determine the 
appropriate dose for that patient in the extension study. In no instance will the dose of 
selinexor exceed 70 mg/m2. 
1.1.2.3. 
Concurrent Treatments 
Concurrent treatments, if any, that the patient received in the Primary Treatment Phase 
of the study, may be continued, at the discretion of the Investigator, but they will not be 
provided by Karyopharm. No new, additional treatments for the patient’s malignancy 
(except for supportive care) may be added without the consent of the Medical Monitor.  
The patient should receive concomitant treatment, as needed per standard of care and 
institutional standards. In addition, the patient will receive concomitant medications to 
treat symptoms, AEs, and intercurrent illnesses that are medically necessary as part of 
standard care. See Section 6.4.2 for prohibited medications. 
1.1.3. 
Study Visits 
During the Maintenance Phase of the study, assessments will take place at once-monthly 
visits for Cycles 1-7, then, provided that the patient is clinically stable, at every-other 
month visits thereafter for Cycles > 7. Each cycle will last 28 days.  
1.1.4. 
Study Assessments 
Safety will be assessed by adverse events (AEs) graded according to National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v. 4.03 (as 
was done in antecedent studies). Disease assessment (response to treatment), where 
appropriate, to monitor disease status and response to therapy are not required per 
protocol, but it is requested that if possible the Investigator provide any disease status 
and response to treatment information obtained from disease assessments performed as 
part of institutional standard of care. Treatment will continue until disease progression, 


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Investigator or patient decision to discontinue study treatment, pregnancy, or 
unacceptable AEs or toxicity that cannot be managed by supportive care, withdrawal of 
consent, death, or termination of the study. See Table 11 for a full schedule of 
assessments.  
1.1.5. 
End of Treatment (EOT) and End of Study  
The EOT Visit will occur ≤ 14 days after the patient receives their last dose of study 
treatment. A Safety Follow-up Call/Visit will be performed 30 days (+7 days) after last 
dose of study treatment. Follow-up ends when the patient has either completed that 30-
day follow-up, withdrawn consent, been withdrawn by the Investigator, died, or been lost 
to follow-up. The end of study (EOS) will occur upon completion of the 30-day follow-up 
period for the last patient treated, or when Karyopharm has decided to end the study. 


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Table 11: 
Schedule of Assessments 
 
 
Maintenance Phase 
Activity/Assessment1 
Cycle 1 
Cycles 2-7 
Visits 
Cycles >7 
(Every Other 
Cycle) Visits 
End-of-Treatment 
(EoT) Visit 
Safety 
Follow-up 
Call/Visit5 
Day 1 
Day 1 
(± 3 Days) 
Day 1 
(± 3 Days) 
≤ 14 Days Post 
Last Dose 
30 Days 
(+ 7 Days) 
Post Last Dose 
Clinical Assessments 
 
 
 
 
 
Weight and BSA 
X 
X 
X 
X 
 
Vital signs (BP, pulse, 
temperature)  
X 
X 
X 
X 
 
Complete physical 
exam 
X 
 
 
 
 
Symptom-directed 
physical exam 
 
X 
X 
 
 
Ophthalmic 
examination 
As clinically indicated 
 
Laboratory Assessments 
 
 
 
 
 
Urinalysis 
X 
X 
X 
X 
 
CBC with differential 
X 
X 
X 
X 
 
Complete serum 
chemistry 
X 
X 
X 
X 
 
Serum amylase and 
lipase levels2 
X 
X 
X 
X 
 


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Maintenance Phase 
Activity/Assessment1 
Cycle 1 
Cycles 2-7 
Visits 
Cycles >7 
(Every Other 
Cycle) Visits 
End-of-Treatment 
(EoT) Visit 
Safety 
Follow-up 
Call/Visit5 
Day 1 
Day 1 
(± 3 Days) 
Day 1 
(± 3 Days) 
≤ 14 Days Post 
Last Dose 
30 Days 
(+ 7 Days) 
Post Last Dose 
Coagulation tests 
X 
X 
 
X 
 
Serum hCG pregnancy 
test3 
As clinically indicated 
 
Administration of 
selinexor in clinic4 
X 
X 
X 
 
 
AE/SAE reporting 
THROUGHOUT 
 
Concomitant medication 
use 
THROUGHOUT 
 
Telephone contact 
 
 
 
 
X 
Antineoplastic therapy 
after EoT  
 
 
 
X 
X 
Abbreviations: AE: adverse event; BSA = body surface area; CBC = complete blood count; hCG = serum human chorionic 
gonadotropin; SAE = serious adverse event. 
1 If study treatment is administered on a visit day, assessments for that visit should be performed before study treatment is administered. Disease 
assessments to monitor disease status and response to therapy are not required per protocol, but it is requested that if possible the Investigator 
provide any disease status and response to treatment information obtained from disease assessments performed as part of institutional standard 
of care. 
2 If not included in the complete serum chemistry panel, amylase and lipase levels must be performed at the same time points as the complete 
serum chemistry. 
3  Applicable for women of childbearing potential only. 
4  Dosing on days of clinic visits will occur in the clinic; dosing on subsequent days within a cycle will be done at home. 
5 At the 30-day safety follow-up the patient should be contacted (by phone or visit) to assess survival status, disease status, overall medical condition, 
and collect information on any antineoplastic therapies used after discontinuation of study treatment.  


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
To provide continued access to selinexor (KPT-330) for the patients remaining on 
treatment at the time of the termination of the Primary Treatment Phase. 
2.1.2. 
Secondary Objectives 
To collect additional long-term safety, tolerability, and disease response (as collected 
through standard of care) data for selinexor. 
2.2. 
Endpoints 
Safety and tolerability of study treatment will be evaluated by means of AE reports, 
physical examination results (including vital signs), clinical laboratory results, and 
ophthalmic examination results where appropriate. 
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
[CTCAE], v. 4.03 will be used for grading the severity of AEs. For all AEs and SAEs, 
Investigators will provide their assessment of causality as either related or not related. 
Efficacy data will be collected per standard of care. 
3. 
SELINEXOR SUPPORTIVE CARE AND DOSE MODIFICATIONS 
3.1. 
Supportive Care 
Supportive measures for optimal medical care should be provided to patients as needed. 
Based on clinical observations in 730 adult patients analyzed for safety as of 31 May 2015, 
the most frequently reported side effects seen with selinexor are primarily related to 
anorexia with poor caloric and fluid intake leading to weight loss, fatigue, and nausea. 
Thrombocytopenia also occurs, although it is rarely associated with bleeding. 
In order to minimize nausea, unless contraindicated, the patient will receive 5 HT3 
antagonists (ondansetron 8 mg or equivalent) twice daily (bid) – three times a day(tid) as 
needed (prn). 
Supportive care including additional anti-nausea/anti-emetic therapy, acid suppression 
(proton-pump inhibitors and/or H2-blockers) and other treatments should be administered 
per Investigator judgement and institutional guidelines. 
3.1.1. 
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 the patient develops Grade 4 infection or clinical sepsis 


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(in the absence of documented infection) until the condition is stabilized. Selinexor can 
then be re-started at the same dose. 
3.2. 
Selinexor Dose Modifications for Toxicity 
Based on observations from the ongoing Phase 1 studies in patients with advanced 
hematological and solid tumors (KCP-330-001 to -003), selinexor shows a reasonably 
wide therapeutic range with activities from ~15 mg to ≥100 mg (~10 mg/m2 to ≥ 60 mg/m2). 
Therefore, in order to optimize specific antitumor activity and tolerability by the patient, 
dose reductions and/or schedule modifications will be allowed after discussion with the 
Medical Monitor. Patients should also be treated aggressively with supportive care, as 
needed, to reduce toxicities. 
In general, if a patient experiences an AE that the Investigator believes is associated with 
selinexor, appropriate supportive care should be implemented per institutional standards. 
If the AE does not resolve, the Investigator should discuss the possibility of holding, 
discontinuing, or lowering the dose of selinexor with the Medical Monitor. If selinexor 
dosing is held, it may be re-introduced upon recovery to Grade ≤ 1 or Baseline at one 
dose level lower, at the discretion of the Investigator, after consulting the Medical Monitor. 
3.2.1. 
Reporting of SAEs 
Any clinical AE or abnormal laboratory test value that is serious occurring during the 
course of the study from the date of signing the informed consent, irrespective of the 
treatment received by the patient, must be reported to the Sponsor within 24 hrs 
(expedited notification). For each patient, all SAEs must be reported up to 30 days after 
the last dose of investigational product. SAEs occurring more than 30 days after a patient 
is discontinued from the study treatment may be reported at the discretion of the 
Investigator. 
The completed SAE form must be sent to: 
Pharmacovigilance Department 
Karyopharm Therapeutics Inc. 
Email: pharmacovigilance@karyopharm.com 
Fax: +1-617-334-7617 (US) 
+49-89-9218-5650 (Germany) 
 
The Sponsor will medically review all SAEs. 
The following detailed information must be recorded for each SAE in the SAE report form: 
 A description of the AE  
 The severity grade as assessed by the Investigator according to the definitions in 
NCI-CTCAE Version 4.03 (Appendix 8) 
 The date of becoming serious and the date of becoming known (if different) 
 The reason for seriousness 
 The outcome of the SAE at the time of the report 
 Information on administration of the study drug and any action taken 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 117 
 Information on any treatment procedures necessary for the SAE, concomitant 
medications, relevant lab tests and relevant medical history 
If in any one patient the same SAE occurs on several occasions, then the SAE in question 
must be documented and assessed anew each time. 
The Investigator is required to submit SAE Follow-up reports until the SAE has resolved 
or stabilized and all queries have been answered. 
 
 
 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 118 
Appendix 17: 
Summary and Rationale for Changes to Protocol KCP 330-005 
Summary and Rationale for Changes to Version 3.1 Protocol 
KCP-330-005 
Karyopharm Therapeutics Inc. 
 
A Phase II, Open-label Study of Efficacy and Safety of the Selective Inhibitor of Nuclear 
Export/SINE Compound KPT-330 (Selinexor) in Patients with Advanced Gynaecologic 
Malignancies 
 
 
Clinical Trial Protocol 
No:  
Sponsor Protocol No. KCP-330-005 
 
Development Phase: 
Phase II 
Investigational Product: 
Selinexor (KPT-330) 
Indication: 
Gynaecologic malignancies 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  
USA 02459 
 
 
 
From: Version 3.1 dated January 08, 2016 
To: Version 3.2 dated August 04, 2016 
 
 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 119 
The clinical study protocol KCP-330-005, A Phase II, Open-label Study of Efficacy and Safety of 
the Selective Inhibitor of Nuclear Export/SINE Compound KPT-330 (Selinexor) in Patients with 
Advanced Gynaecologic Malignancies has been amended by the Sponsor to incorporate 
changes suggested internally, improve clarity by eliminating inconsistencies among sections, 
and correcting errors from previous versions. 
The revised protocol Version 3.2 dated 04 August 2016 will be submitted by the Principal 
Investigator or designee to all applicable Institutional Review Boards (IRBs), Independent Ethics 
Committees (IECs), or Research Ethics Boards (REBs), and by Karyopharm Therapeutics Inc. to 
all applicable Regulatory Authorities.  
Descriptions of the key changes that have been made in protocol KCP-330-005 Version 3.2, 
from the previous Version 3.1, including the rationales for these changes, are provided below. 
 
Administrative 
 
Updated the version number and date of protocol from Version 3.1 dated 08 January 2016 
to Version 3.2 dated 04 August 2016 (Modified sections:  Global) 
Background 
 
Updated introduction text (Modified sections:  Section 1.1) 
References 
 
Updated to reflect the revised introduction text (Modified sections:  Section 17) 
 
Rationale, Objectives, Investigational Plan (including study treatment), Supportive Care 
and Dose Modifications 
 
Due to the termination of the Primary Treatment Phase of the study, a maintenance 
schedule has been added to allow the existing patients on the study to continue treatment 
with selinexor and/or survival follow-up. The revised Maintenance Phase includes study 
treatment, schedule of assessments, supportive care, dose modification and data 
collection for separate Maintenance Phase database. (Modified sections [added 
sections]: Synopsis, Table 1, Section 1.4, Section 2.1, Section 2.2, Section 3.1, Section 
5.1, Section 5.2, Section 5.3, Section 5.7, Section 6.2.1, Section 6.2.2, Section 6.3, Section 
7.2.1, Section 7.2.2, Section 9, Section 17, and Section 18 [Appendix 16])  


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 120 
 
Appendix 18: 
Summary and Rationale for Changes to Protocol KCP 330-005 
Summary and Rationale for Changes to Version 3.0 Protocol 
KCP-330-005 
Karyopharm Therapeutics Inc. 
 
A Phase II, Open-label Study of Efficacy and Safety of the Selective Inhibitor of Nuclear 
Export/SINE™ Compound KPT-330 (Selinexor) in Patients with Advanced Gynaecologic 
Malignancies 
 
 
Clinical Trial Protocol 
No:  
Sponsor Protocol No. KCP-330-005 
 
Development Phase: 
Phase II 
Investigational Product: 
Selinexor (KPT-330) 
Indication: 
Gynaecologic malignancies 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  
USA 02459 
 
 
 
From: Version 3.0 dated November 12, 2014 
To: Version 3.1 dated January 08, 2016 
 
 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 121 
The clinical study protocol KCP-330-005, A Phase II, Open-label Study of Efficacy and Safety of 
the Selective Inhibitor of Nuclear Export/SINE™ Compound KPT-330 (Selinexor) in Patients with 
Advanced Gynaecologic Malignancies has been amended by the Sponsor to incorporate 
changes suggested internally, improve clarity by eliminating inconsistencies among sections, 
and correcting errors from previous versions. 
The revised protocol Version 3.1 dated 08 January 2016 will be submitted by GSO to all 
applicable Institutional Review Boards (IRBs), Independent Ethics Committees (IECs), or 
Research Ethics Boards (REBs), and by Karyopharm Therapeutics Inc. to all applicable 
Regulatory Authorities.  
Descriptions of the key changes that have been made in protocol KCP-330-005 Version 3.1, 
from the previous Version 3.0, including the rationales for these changes, are provided below. 
Administrative 
 
Internal changes were made to improve clarity and to eliminate inconsistencies among 
sections, and to correct previously existing errors. (Modified sections:  Global) 
 
Updated the version number and date of protocol from Version 3.0 dated 12 November 
2014 to Version 3.1 dated 08 January 2016. (Modified sections:  Global) 
 
Minor corrections were made to grammar and punctuation throughout. (Modified 
sections:  Global) 
Background 
 
Replaced Figure 1 with an updated (similar) figure of the mechanism of action of 
selinexor, which appears in the most recent Selinexor Investigator’s Brochure (Modified 
section: 1.1.2) 
 
Deleted Figure 2: KPT-SINE Compounds (XPO1 Inhibitors) Induce Distinct Outcomes in 
Normal and Malignant Cells because it was unnecessary  (Modified section: 1.1.2) 
 
In the Pre-clinical Safety sub-section, moved the brief description of histotoxicology 
studies performed in rats and monkeys from Section 1.1.4: Clinical Summary to Section 
1.1.3 (Pre-clinical). 
 
Revised selinexor clinical summary and replaced outdated and unnecessary information 
with more recent information (Modified section: Section 1.1.5) 
 
Updated patient exposure to selinexor to 730 patients, which is consistent with Selinexor 
Investigator’s Brochure, v.5, dated 12 August 2015. (Modified section: 1.1.4) 
 
Updated (favorable) results, seen in an interim analysis performed on 29 April 2015 
(Modified section: 1.2) 
Study Design 
 
Clarified the definitions of platinum refractory and platinum resistant in the inclusion 
criteria. (Modified sections:  Synopsis – inclusion criteria; Section 4.2.1) 
 
Clarified that dose escalation can occur if there is tolerability and no sign of progression 
after 12 weeks of treatment for patients in Parts 1 and 2. (Modified sections:  Synopsis 
– treatment scheme; Section 3.1, Section 6.3.1) 
 
Revised wording related to the number of subjects to specify that 21 and 32 evaluable 
patients are needed in Parts 1 and Part 2, respectively. (Modified sections:  Synopsis 
[planned sample size, sample size calculation], Section 3.2, Section 8.2) 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 122 
 
Removed supportive care text for the following events as guidance for these events is 
now provided in the dose adjustment/supportive care table in Section 6.3.2:  Anorexia, 
fatigue, emesis, acute emesis, diarrhea, and thrombocytopenia. (Modified sections:  
former sections – Section 6.5)  
 
Consolidated and reformatted guidance for restricted and prohibited medications into one 
section. (Modified section:  Section 6.4.2) 
 
Clarified that the overall survival objective will include overall survival rates at 12 and 24 
months. (Modified sections:  Synopsis, Section 2.3, Section 8.4.3) 
 
Clarified reasons for which the study can be discontinued (Modified section:  Section 
5.5) 
 
Clarified primary and secondary parameters, including details of the efficacy evaluation). 
(Modified sections: Synopsis – primary and secondary parameters, Section 8.4.3) 
 
Added total abstinence as a method of prevention of pregnancy. (Modified section:  
Section 6.4.1.1) 
 
Modified the definitions of the ITT population. (Modified section:  Section 8.3.1) 
 
Added a provision to perform a primary analysis for submission in a CSR when patients 
are still on treatment, and subsequently perform a final analysis (to be reported in a final 
CSR) after all patients have completed treatment. (Modified section: 16) 
 
A table of GSH-, NAC-, and SAM-containing products was added as an appendix based 
on FDA feedback on a different protocol. (Modified sections:  Section 17, Appendix 14) 
Study Assessments 
 
Clarified the timing of collection of AEs and SAEs. (Modified sections: Schedule of 
Assessments, Section 7.1.1, Section 7.1.3) 
 
Revised the window for assessments to be completed following 6 weeks of treatment for 
gynaecological cancers from ±5 days to ±7 days. (Modified sections: Schedule of 
assessments) 
 
Added a baseline assessment for CA-125 to comply with CGIG CA-125 response criteria 
requirements (Modified sections: Schedule of assessments, Section 5.2.1) 
Selinexor Dosing 
 
The use of 20 mg tablets was added for increased tolerability based on the results of the 
ongoing Phase 1 studies. (Modified section:  Section 6.2.1.) 
 
Clarified that doses of selinexor must be at least 36 hours apart for twice weekly dosing 
and at least 5 days apart for once weekly dosing. (Modified sections: Synopsis – 
treatment scheme, Section 3.1, Section 3.1.1, Section 6.2.1.2, Section 6.3.5) 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 123 
Summary and Rationale for Changes to Version 2.0 Protocol 
KCP-330-005 
Karyopharm Therapeutics Inc. 
 
A Phase II, Open-label Study of Efficacy and Safety of the Selective Inhibitor of Nuclear 
Export/SINE™ Compound KPT-330 (Selinexor) in Patients with Advanced Gynaecologic 
Malignancies 
 
 
Clinical Trial Protocol 
No:  
Sponsor Protocol No. KCP-330-005 
 
Development Phase: 
Phase II 
Investigational Product: 
Selinexor (KPT-330) 
Indication: 
Gynaecologic malignancies 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  
USA 02459 
 
 
 
From: Version 2.0 dated September 09, 2014 
To: Version 3.0 dated November 12, 2014 
 
 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 124 
The clinical study protocol KCP-330-005, A Phase 2, Open-label Study of Efficacy and Safety of 
the Selective Inhibitor of Nuclear Export/SINE™ Compound KPT-330 (Selinexor) in Patients with 
Advanced Gynaecologic Malignancies has been amended by the Sponsor to incorporate 
changes suggested internally and to provide clarity to eliminate inconsistencies between 
sections, and to correct prior errors. 
The revised protocol Version 3.0 dated 12 November 2014 will be submitted by GSO to all 
applicable Institutional Review Boards (IRBs), Independent Ethics Committees (IECs), or 
Research Ethics Boards (REBs), and by Karyopharm Therapeutics Inc. to all applicable 
Regulatory Authorities.  
Description of the key changes that have been made to protocol KCP-330-005 Version 3.0 from 
the previous Version 2.0, including rationale for the changes, are listed below. 
Administrative 
 
Internal changes suggested by the sponsor to provide clarity and to eliminate 
inconsistencies between sections, and to correct prior errors (Modified sections:  
Global) 
 
Updated the version number and date of protocol from Version 2.0 dated 09 September 
2014 to Version 3.0 dated 12 November 2014 (Modified sections:  Global) 
 
Minor corrections to grammar throughout (Modified sections:  Global) 
Inclusion/Exclusion Criteria 
 
Revised inclusion criterion # 5 to specify that patients with ovarian cancer must have 
disease that is measureable according to RECIST or assessable according to the GCIG 
CA-125 criteria. (Modified sections: Synopsis [inclusion criteria] and Section 4.2) 
 
Revised exclusion criterion # 11 to clarify that receipt of an investigational drug within 3 
weeks prior to Cycle 1 Day 1 is prohibited; however, participation in an anti-cancer study 
within 3 weeks prior to receiving study drug is acceptable. (Modified sections: Synopsis 
[Exclusion criteria], Section 4.3) 
Study Design 
 
Revised the dosing schedule for Part 2, Schedule 1 from 35 mg/m2 twice weekly during 
Weeks 1-3 of a 4-week cycle for a total of 6 doses per cycle to 35 mg/m2 twice weekly 
during Weeks 1-4 of a 4-week cycle for a total of 8 doses per cycle to enable comparison 
of 4-week dosing between Part 2 Schedules 1 and 2. In Part 1, the dose is 50 mg/m2 
twice weekly for a total weekly dose of 100 mg/m2. Two additional doses are being 
evaluated in Part 2 of the study:  in Schedule 1 the dose is 35 mg/m2 twice weekly for a 
total weekly dose of 70 mg/m2 and 280 mg/m2 per cycle; in Schedule 2 the dose is 50 
mg/m2 once weekly for a total weekly dose of 50 mg/m2 and 200 mg/m2 per cycle. The 
dosing schedule for Part 2, Schedule 1 was revised from 35 mg/m2 twice weekly during 
Weeks 1-3 of a 4-week cycle to 35 mg/m2 twice weekly during Weeks 1-4 of a 4-week 
cycle. This change was made so that all Part 2 patients would receive doses in each 
week of their 4-week cycle, enabling a more direct comparison of the Part 2 results 
obtained with 35 mg/m2 twice weekly versus 50 mg/m2 once weekly dosing. (Modified 
sections:  Synopsis [Study design, treatment scheme], Section 3.1, Section 3.1.1, 
Section 6.2.1.2, Section 6.3.1, Section 8.2). 
 
Added CA-125 response definition (Modified sections:  Synopsis [inclusion criteria], 
Section 4.2, Appendix 13) 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 125 
Safety and Tolerability 
 
Removed the acetaminophen restriction as ongoing clinical safety evaluations on the use 
of selinexor in combination with acetaminophen have not shown any significant clinical or 
laboratory abnormalities with doses of acetaminophen up to 1 gram and selinexor up to 
55 mg/m2 (approximately 80-100 mg). (Modified sections:  Section 6.4, Section 6.4.2, 
Section 6.5.8) 
 
Revised the prophylactic and supportive care:  During Part 1 of the study, gynaecological 
patients primarily suffered from anorexia secondary to nausea and vomiting; treatment of 
these symptoms with neurokinin-1 receptor antagonist is highly effective. Mirtazapine 
and olanzapine will be retained only as a second line of treatment. Additionally, treatment 
with dexamethasone (or equivalent) was changed from required prophylactic treatment to 
recommended supportive care because some patients enrolled in the study may be 
intolerant of glucocorticoids. (Modified sections:  Section 1.1.4, Section 5.2.1, Section 
6.3.2 [Table 4], Section 6.5.1) 
 
Revised the dose modification table to include revised dose modification guidance for 
thrombocytopenia and nausea/emesis, and specified that guidance used for Grade 3 
toxicities should also be used for toxicities that are Grade ≥ 3. The table was also revised 
to include specific guidance for Part 1 and Part 2 (Schedules 1 and 2). For 
thrombocytopenia, this change was made as in preclinical and ongoing Phase 1 studies 
thrombocytopenia has been observed to be time dependent rather than dose dependent. 
Therefore, reducing the frequency of dosing with KPT-330 instead of reducing the dose 
of KPT-330 can decrease the recovery time from thrombocytopenia. For nausea/emesis, 
these changes were made as during Part 1 of the study, gynaecological patients 
primarily suffered from anorexia secondary to nausea and vomiting; treatment of these 
symptoms with neurokinin-1 receptor antagonist is highly effective. Mirtazapine and 
olanzapine should be considered a second line of treatment (Modified sections:  
Section 6.3.2 [Table 4]) 
 
Revised the pre-specified dose/schedule modifications for adverse events (AEs) related 
to study drug for Part 2, Schedules 1 and 2. For both schedules, it is specified that upon 
the discontinuation of dosing, patients will continue to be assessed. These changes were 
made to improve tolerance to treatment with selinexor in the context of various AEs. 
(Modified sections:  Synopsis [Treatment scheme], Section 6.3 [Table 3], Section 6.3.2 
[Table 4]). The following changes were made: 
o Schedule 1 
 
Dose level -1 was changed from 25 mg/m2 twice weekly to 50 mg/m2 once 
weekly. 
 
Dose level -2 was changed from discontinue dosing to 35 mg/m2 once 
weekly. 
 
Dose level -3 (discontinue dosing) was added. 
o Schedule 2 
 
Dose level -1 was changed from 40 mg/m2 once weekly to 35 mg/m2 once 
weekly. 
 
Dose level -2 (discontinue dosing) was added. 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc.  
Clinical Study Protocol:  KCP-330-005 (SIGN) 
 
Version 3.2, 04 August 2016 
Confidential 
Page 127 
Summary and Rationale for Changes to Version 1.0 Protocol 
KCP-330-005 
Karyopharm Therapeutics Inc. 
 
A Phase II, Open-label Study of Efficacy and Safety of the Selective Inhibitor of Nuclear Export 
(SINE) KPT-330 (Selinexor) in Patients with Advanced Gynaecologic Malignancies 
 
 
Clinical Trial Protocol 
No:  
Sponsor Protocol No. KCP-330-005 
 
Development Phase: 
Phase II 
Investigational Product: 
Selinexor (KPT-330) 
Indication: 
Gynaecologic malignancies 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  
USA 02459 
 
 
 
From: Version 1.0 dated November 11, 2013 
To: Version 2.0 dated September 09, 2014 
 
 
 


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