Clinical trial NCT01986348
Conditions: Glioblastoma Glioma
Keywords: GBM Glioblastoma selinexor KPT-330 Karyopharm brain tumor brain cancer Glioma Astrocytoma Oligodendrogliomas Oligo-astrocytomas
Sponsor: Karyopharm Therapeutics Inc
Start date: 2014-03-03; Completion date: 2020-01-23
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, multicenter, Phase 2 study to evaluate the efficacy and safety of oral selinexor in participants with recurrent gliomas.

Detailed description:
This is an open-label, multicenter, Phase 2 study to evaluate the efficacy and safety of oral selinexor in participants with recurrent gliomas.

Initially, the study included 2 arms: an exploratory Surgical Arm (Arm A) with sequential enrollment for participants who require surgery and a medical arm (Arm B) for participants who are not eligible for surgery.

Enrollment in Arm B was stopped to explore alternative dosing in Protocol Versions ≥ 4.0 to potentially improve tolerability. Four arms (Arms C, D, E, and F) were added to the Medical Arm in Protocol Version 4.0. Arms E and F were eliminated in protocol version 6.0 and no participants were ever enrolled in these arms.

Participants in the primary population enrolled under Protocol Version ≥ 4.0 will be randomized to Arm C and Arm D (approximately 30 participants per arm) to explore alternative dosing to potentially improve tolerability.

After screening and registration/randomization in the study, participants enrolling in Arm A or randomized to Arm C will receive 60 mg selinexor orally twice weekly. Participants randomized to Arm D will receive 80 mg selinexor orally weekly.

Participants will be treated until progression of disease or the development of unacceptable toxicities. All participants will then undergo the End of Treatment (EOT) visit.

Arms: arm 1: Participants who required surgery received up to 3 doses of oral selinexor tablets 60 milligrams (mg) twice weekly (BIW) on Day 1, Day 3 and between 2 and 48 hours prior to surgery, subsequently underwent surgery for resection of their tumor and resumed selinexor tablets 60 mg BIW after recovery, during Week 1 to 4 of each 4-week cycle, until progression of disease (PD) or development of unacceptable toxicities. arm 2: Participants who were not eligible for surgery received selinexor tablets 50 mg per square meter (mg/m\^2) BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities. arm 3: Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities. arm 4: Participants who were not eligible for surgery received selinexor tablets 80 mg once weekly (QW) during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.
Interventions: intervention 1: Selinexor
Intervention descriptions: intervention 1: One cycle is 28 days (4 weeks).

Protocol documents:
Prot_000.pdf: 
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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
Confidential 
Page 4 of 137 
Version 6.0 
Investigator’s Agreement 
 
I have read the attached protocol entitled 
“A PHASE 2 STUDY EVALUATING THE EFFICACY AND SAFETY OF SELINEXOR 
(KPT-330) IN PATIENTS WITH RECURRENT GLIOMAS”  
and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation 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 Month yyyy) 
Investigator  
  
  
Investigator’s Institution 
  
  
 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 14 of 137 
Version 6.0 
GLOSSARY OF ABBREVIATIONS 
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 
BCNU 
Carmustine 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CCNU 
Lomustine 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CLL 
Chronic lymphocytic leukemia 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CYP450 
Cytochrome P450 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
FGFR 
Fibroblast growth factor receptor 
FLAIR 
Fluid-Attenuated Inversion Recovery 
GBM 
Glioblastoma  
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GSH 
Glutathione 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
High-density polyethylene 
HIV 
human immunodeficiency virus 
hr 
Hour 
HGG 
High-grade glioma 
IB 
Investigator’s Brochure 
IC50 
Inhibitory concentration, 50% (half maximal inhibitory concentration) 
ICH 
International Conference on Harmonisation 
IDH 
isocitrate dehydrogenase 
IEC 
Independent ethics committee 
IFN 
Interferon 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
K 
Karnofsky Performance Status 
LDH 
Lactate dehydrogenase 
LOCS III 
Lens Opacities Classification System III 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 17 of 137 
Version 6.0 
5.2.6 
End of Study ...................................................................................................... 46 
5.3 
Planned Treatment of the Patients after End of Treatment Phase ............................... 46 
5.4 
Removal of Patients from Treatment .......................................................................... 46 
5.5 
Study Discontinuation ................................................................................................. 46 
6 
Investigational Product .......................................................................................................... 47 
6.1 
Investigational medicinal product ............................................................................... 47 
6.2 
Preparation and Administration of Selinexor .............................................................. 47 
6.2.1 
Preparation and Administration of Selinexor .................................................... 47 
6.3 
Dose Modifications for Selinexor ............................................................................... 49 
6.3.1 
Selinexor Dose Reduction for Decreased Glomerular Filtration Rate .............. 55 
6.3.2 
Selinexor Dose Reduction in the Setting of Infection ....................................... 55 
6.3.3 
Dose Adjustments with Changes in BSA .......................................................... 56 
6.3.4 
Missed or Vomited Doses ................................................................................. 56 
6.4 
Concomitant Medication and Treatment ..................................................................... 56 
6.4.1 
Permitted Concomitant Medication .................................................................. 56 
6.4.2 
Restrictions and Prohibited Medications .......................................................... 57 
6.5 
Supportive Care Guidelines ........................................................................................ 58 
6.5.1 
Required 5-HT3 Antagonists ............................................................................ 58 
6.5.2 
Supportive Care Recommendations for Selinexor-Related Adverse Events .... 58 
6.5.3 
Liver Function Test Abnormalities ................................................................... 58 
7 
Assessment of Safety............................................................................................................. 59 
7.1 
Adverse Events and Laboratory Abnormalities Reporting ......................................... 59 
7.1.1 
Adverse Event ................................................................................................... 59 
7.1.2 
Adverse Drug Reaction ..................................................................................... 59 
7.1.3 
Serious Adverse Event ...................................................................................... 60 
7.1.4 
NOT to be reported as SAEs ............................................................................. 60 
7.1.5 
SUSAR/Unexpected Serious ADR ................................................................... 61 
7.2 
Reporting of SAEs ...................................................................................................... 61 
7.3 
Reporting of SUSARs/Expedited Reporting of Unexpected Serious ADRs .............. 62 
7.4 
Recording of Adverse Events ...................................................................................... 63 
7.5 
Laboratory Test Abnormalities ................................................................................... 63 
7.6 
Pregnancy .................................................................................................................... 64 
7.7 
Adverse Drug Reactions with Concomitant Medication ............................................. 64 
7.8 
Safety Surveillance ...................................................................................................... 64 
8 
Statistical Methods ................................................................................................................ 65 
8.1 
Trial Design and Hypotheses ...................................................................................... 65 
8.2 
Sample Size Calculation .............................................................................................. 65 
8.2.1 
Arm B (50 mg/m2 twice weekly) ...................................................................... 65 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 18 of 137 
Version 6.0 
8.2.2 
Flat Dosing Arms (Arm C and Arm D) ............................................................ 66 
8.3 
Evaluation Categories for Patients .............................................................................. 66 
8.3.1 
Modified Intent-to-Treat Population ................................................................. 66 
8.3.2 
Per Protocol Population ..................................................................................... 66 
8.3.3 
Surgical Patient Population ............................................................................... 67 
8.3.4 
Safety Population .............................................................................................. 67 
8.4 
Methods of Statistical Analysis ................................................................................... 67 
8.4.1 
General Statistical Considerations .................................................................... 67 
8.4.2 
Demographics and Baseline Characteristics ..................................................... 67 
8.4.3 
Efficacy Evaluation ........................................................................................... 68 
8.4.4 
Safety Evaluation .............................................................................................. 70 
8.5 
Interim and Final Analysis .......................................................................................... 71 
9 
Data Quality Assurance ......................................................................................................... 72 
10 Ethical Aspects ...................................................................................................................... 73 
10.1 
Good Clinical Practice ................................................................................................ 73 
10.2 
Patient Information and Informed Consent ................................................................. 73 
10.3 
Independent Ethics Committees and Regulatory Authorities ..................................... 73 
10.3.1 
Approval by Regulatory Authorities and Independent Ethics Committees ...... 73 
10.3.2 
Notification of the Study ................................................................................... 74 
10.3.3 
Obligation to Report and Document ................................................................. 74 
11 Conditions for Modifying the Protocol ................................................................................. 75 
12 Study Documentation, CRFs and Record-Keeping ............................................................... 76 
12.1 
Investigator’s Files/Retention of Documents .............................................................. 76 
12.2 
Source Documents and Background Data ................................................................... 76 
12.3 
Audits and Inspections ................................................................................................ 76 
12.4 
Case Report Forms ...................................................................................................... 77 
13 Monitoring of Study .............................................................................................................. 78 
14 Confidentiality of Trial Documents and Patient Records ..................................................... 79 
15 Study Report and Publication Policy..................................................................................... 80 
16 Appendices ............................................................................................................................ 81 
16.1 
Appendix 1 – Definitions According to ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 ............ 82 
16.2 
Appendix 2 – Karnofsky Performance Status ............................................................. 84 
16.3 
Appendix 3 – Cockroft-Gault Formula ....................................................................... 85 
16.4 
Appendix 4 – NCI-CTCAE version 4.03 .................................................................... 86 
16.5 
Appendix 5 Ophthalmic Examination ......................................................................... 87 
16.6 
Appendix 6 NCCN Clinical Practice Guidelines in Oncology: Antiemesis ............... 88 
16.7 
Appendix 7 NCCN Clinical Practice Guidelines in Oncology: Anorexia/Cachexia .. 90 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 19 of 137 
Version 6.0 
16.8 
Appendix 8  Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-acetylcysteine 
(NAC)-containing Products (Representative List) ...................................................... 91 
16.9 
Appendix 9  Summary of Changes and Rationales for Changes to Protocol KCP-330-
004 ............................................................................................................................... 92 
16.9.1 
Summary and Rationale for Changes to Version 5.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc ........................................................................... 92 
16.9.2 
Summary and Rationale for Changes to Version 4.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. .......................................................................... 95 
16.9.3 
Summary and Rationale for Changes to Version 3.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. ........................................................................ 100 
16.9.4 
Summary and Rationale for Changes to Version 2.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. ........................................................................ 109 
16.9.5 
Summary and Rationale for Changes to Version 1.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. ........................................................................ 115 
17 References ........................................................................................................................... 136 
 
List of Figures 
 
Figure 1: Rate of Tumor Growth (A) and Survival (B) of Mice over Time with XPO1 Inhibitors 
KPT-276 and KPT-330 (Selinexor) ...................................................................................... 26 
Figure 2: Overview of study design ............................................................................................. 32 
 
List of Tables 
 
Table 1: Schedule of Assessments During the Study ................................................................. 11 
Table 2: KPT-330 Concentration in Human Tumor Tissue and Plasma ..................................... 24 
Table 3: Pre-Surgery Dosing Table ............................................................................................. 31 
Table 4: Summary of the Proposed RANO Response Criteria ................................................... 39 
Table 5: Prespecified Dose/Schedule Modifications for Adverse Events Related to Study Drug 50 
Table 6: Supportive Care and Dose Adjustment Guidelines ....................................................... 50 
Table 7: Classification of Adverse Events by Causality .............................................................. 59 
 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 20 of 137 
Version 6.0 
1 BACKGROUND AND RATIONALE 
1.1 
Background 
1.1.1 Glioblastoma 
High-grade gliomas (HGG) are defined as World Health Organization (WHO) Grade 3 and 4 
tumors of glial origin. Grade 4 tumors are called glioblastoma (GBM). With approximately 70%, 
GBM is the most common type of malignant primary brain tumors. More than 14,000 cases are 
newly diagnosed in adults in the United States each year.1 
The prognosis of GBM is very poor. An extensive infiltration of the surrounding brain tissue limits 
the accessibility in surgical resection. Aggravating the blood-brain barrier is an obstacle for many 
chemotherapeutic agents. Only small and lipophilic molecules, e.g. nitrosoureas, are able to reach 
their target. Furthermore, GBM is frequently refractory to cytotoxic agents. Median overall 
survival (OS) from first diagnosis is about 13-18 months. 
First-line therapy 
For a long time, standard therapy comprised surgical resection followed by radiotherapy. In a 
randomized Phase 3 trial by the EORTC (European Organisation for Research and Treatment of 
Cancer) and the NCIC-CTG (National Cancer Institute of Canada – Clinical Trials Group), a 
significant benefit of concomitant radiotherapy and temozolomide plus six cycles of adjuvant 
chemotherapy over radiotherapy alone could be demonstrated for the first time. With the addition 
of the oral alkylating agent temozolomide, a median survival of 14.6 versus 12.1 months with 
radiotherapy alone was achieved. Patients had a two-year survival rate of 25.6% with radiotherapy 
plus temozolomide versus 10.4% with radiotherapy alone.2-4 
Recurrent disease 
Irrespective of the first-line therapy, patients with HGG have a high risk for relapse within 6 to 11 
months after the primary treatment.5 There is still no established standard treatment for recurrent 
HGG. Nitrosourea-based regimens are commonly used, e.g. carmustine (BCNU) or lomustine 
(CCNU) alone or combined with procarbazine and vincristine (PCV). 6-months progression-free 
survival (6mPFS) rates of approximately 20% were seen.6-9 
One other option is the treatment with temozolomide in a continuous dose-intense (50 mg/m²/d) 
regimen that could overcome resistance to standard therapy. In the RESCUE study, patients with 
GBM achieved a 6mPFS rate of 23.9% and the median overall survival (OS) was 9.3 months. 
Another Phase 2 study with 37 patients revealed a 6mPFS rate of 19% and a median OS of 
7 months. However, the benefit of continuous temozolomide was only true for GBM patients who 
had not experienced progression while on extended adjuvant treatment, i.e. beyond six cycles. Also, 
the success of this treatment strategy seems to be dependent on previous treatment with 
bevacizumab. One advantage of the regimen is its tolerability with a lower hematologic toxicity 
and nausea/vomiting compared to other chemotherapies such as nitrosoureas or other 
temozolomide schedules.6, 10, 11 
GBM was found to be one of the most vascularized human tumors with a high expression of 
vascular endothelial growth factor (VEGF). VEGF expression is associated with a poor prognosis. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 21 of 137 
Version 6.0 
Promising results were obtained with targeted therapies such as the monoclonal antibody 
bevacizumab that binds to VEGF inhibiting its activity, for which 6mPFS is 25% to 46%. 
Bevacizumab also showed a positive impact on quality of life.12-18 
As high activity of signal transduction pathways such as PI3K, AKT and mTOR (mammalian target 
of rapamycin) is associated with a poor prognosis, many inhibitors targeting various objectives in 
these pathways have reached Phase 1and 2 clinical trials. For example, the effect of the mTOR 
inhibitor added to bevacizumab after failure of a bevacizumab-containing second-line treatment 
was investigated, but did not show sufficient activity.19, 20 
Many other targets have recently been or are currently under investigation: Although amplification 
of epidermal growth factor receptor (EGFR) can be detected in approximately 40% of GBM, 
EGFR-inhibiting drugs such as erlotinib did not show sufficient activity in monotherapy.21 The 
EGFR antibody nimotuzumab is currently under investigation due to its lack of toxicity, although 
first data have proven only modest efficacy.22 
Similarly, nintedanib, a small, oral, triple angiokinase inhibitor targeting vascular endothelial 
growth factor receptor (VEGFR) 1-3, FGFR 1-3, and PDGFR-α/β, failed to show clinically relevant 
antitumor activity. In a Phase 2 study with 25 patients in second- or third-line therapy, best response 
was stable disease (SD) achieved by 12% of patients; one patient previously treated with 
bevacizumab had SD for more than 17 months. All other patients progressed within the first four 
28-day cycles. Median progression-free survival (PFS) was 1 month and median OS was 
6 months.23 
Vandetanib is a multitargeted tyrosine kinase inhibitor (TKI) of VEGF-2, EGFR, and the 
rearranged-during-transfection oncogene. In a Phase 2 trial with 64 patients with recurrent GBM 
and recurrent anaplastic glioma (AG), the 6mPFS was 6.5% in the GBM arm and 7.0% in the AG 
arm. Median OS was 6.3 months in the GBM arm and 7.6 months in the AG arm. Only 12.5% of 
GBM patients had radiographic response. Seizures were an unexpected toxicity of this therapy.24 
Another attempt was to investigate the activity of the TKIs imatinib combined with hydroxyurea. 
In a Phase 2 study with 231 patients, the combination therapy was, in fact, well tolerated, but its 
clinical antitumor activity was low with a 6mPFS of 10.6% and a median OS of 26 weeks.25 
With the lipophilic oral camptothecin analogue gimatecan, a similar 6mPFS rate of 12% was 
achieved in a Phase 2 study with 29 patients with recurrent GBM.26 Slightly better successes were 
achieved with the microtubule-destabilizing agent verubulin (MPC-6827) in combination with 
carboplatin, with a 6mPFS rate of 21% and a median PFS of 8 weeks. This combination was 
administered to 19 patients in one Phase 1 study.27 
Another approach currently under investigation is treatment with the antiangiogenic agent 
pazopanib in combination with the ErbB inhibitor lapatinib. Although the regimen has already 
shown limited antitumor activity in Phase 1/2 studies, pharmacokinetic (PK) data has revealed 
subtherapeutic doses of lapatinib, so this combination is still a candidate for further trials.28 
In summary, recurrent GBM still has poor outcome and treatment remains a challenge, as these 
data consistently show. Consequently, new treatment options for patients with recurrent GBM are 
desperately needed. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 22 of 137 
Version 6.0 
1.1.2 Selinexor 
Selinexor is a Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates 
Exportin 1 (XPO1), forcing the nuclear retention of key tumor suppressor proteins (TSPs). 
Transient retention of TSPs in the nucleus at high levels via XPO1 blockade activates their cell 
cycle checkpoint and genome surveying actions. This leads to the death of nearly all types of 
malignant cells, whereas normal cells undergo transient cell cycle arrest and recovery when the 
export block is released. The reactivation of multiple tumor suppressor pathways and inhibition of 
translation of key pro-survival proteins through inhibition of a non-redundant, single protein 
represents a novel approach to the treatment of neoplastic diseases including those with multiple 
genomic alterations and resistance mechanisms. More information about the mechanism of action, 
pharmacology, pre-clinical, and clinical studies with selinexor is available in the Selinexor/KPT-
330 Investigator’s Brochure (IB). 
Selinexor is being evaluated in multiple Phase 1 and 2 studies in patients with heavily pretreated 
relapsed and/or refractory hematological and solid tumor malignancies. More than 1,100 patients 
have received selinexor to date (as of 01 October 2015). Evidence of anti-cancer activity has been 
observed in a substantial number of patients and selinexor has been sufficiently well-tolerated to 
allow many of these patients to remain on therapy for prolonged periods, including several patients 
who have remained on treatment for over 12 months, with the longest treatment duration thus far 
of > 24 months. 
The main side effects of selinexor seen in heavily pretreated Phase 1 patients to date have been 
fatigue, nausea, anorexia, vomiting, and thrombocytopenia. These adverse events (AEs) are 
mainly Grades 1 and 2, and may be mitigated or eliminated with standard supportive care. Their 
prevalence and intensity typically decline after 4-8 weeks of treatment. Selinexor treatment is not 
associated with significant major organ toxicity. 
 
1.1.2.1 Preclinical Data 
A brief summary of preclinical data is provided below. More detailed information is available in 
the Selinexor/KPT-330 IB. 
In vitro experiments with continuous (72 hr) exposure to selinexor demonstrated potent pro 
apoptotic activity across a broad panel of tumor-derived cell lines and patient samples in culture, 
with the majority of 50% inhibitory concentration (IC50) values for cytotoxicity < 800 nM and 
most hematologic tumor lines having IC50 values of 20 – 400 nM for selinexor. In contrast, normal 
cells typically underwent (or remained in) cell cycle arrest but were resistant to apoptosis-
induction; cytotoxicity IC50 values were typically > 1 µM (based on results seen with MRC-5 
cells). Maximum selinexor serum levels of 1-2 µM are typically achieved in cancer patients 
following selinexor oral doses of 40-100 mg (~25-60 mg/m2). 
Selinexor, as well as other SINE compounds, have been administered in non-clinical efficacy 
studies to mice and dogs and in toxicology studies to rats and monkeys, with every-other-day oral 
dosing regimens (2-3 doses per week). Dosing regimens were designed based on pharmacodynamic 
observations that the biological effects of oral selinexor have durations > 48 hours. Efficacy was 
seen with these intermittent dosing regimens at doses of selinexor 5-20 mg/kg (15-60 mg/m2) in 
mouse models of myeloma, mantle cell lymphoma (MCL), T-cell acute lymphocytic leukemia 
(T-ALL) xenografts, and solid tumor models. Selinexor treatment resulted in significant survival 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 25 of 137 
Version 6.0 
effects of these changes on reproductive potential are unknown. Secondary developmental effects 
due to reduced maternal body weights were also noted during a study on rat embryo/fetal 
development. Please see the Selinexor/KPT-330 IB for additional information. As it is unknown if 
selinexor produces any reproductive toxicity in humans, all patients must agree to use effective 
contraception (see Section 6.4.1.1) during the study and for 3 months after the end of treatment. 
1.1.2.2.3 Efficacy 
Clinical Evidence of Anti-Cancer Activity 
Hematologic Malignancies: In the dose escalation phase of study KCP-330-001, tumor load 
reductions and disease stabilization have been noted across many tumor types, consistent with the 
broad anti-tumor mechanism and results observed in preclinical studies. Responses have been 
documented in patients with MM, mantle cell lymphoma and DLBCL, CLL, Richter’s Syndrome, 
and AML. Durability for 6-12 months has been observed. The safety and tolerability of selinexor 
in patients with relapsed peripheral T-cell lymphomas (PTCL and CTCL) are being evaluated in a 
separate arm. Optimal twice-weekly dosing (e.g., dosing on Days 1, 2 vs. 1, 3 vs. 1, 4) is being 
explored in additional arms. 
Solid Tumor Malignancies: In the dose escalation phase of study KCP-330-002, disease 
stabilization or responses for > 4 months has been observed in patients with colon cancer, cervical 
adeno- and squamous cancers, and endometrial stromal sarcoma. Tumor shrinkage has also been 
observed in patients with melanoma, head and neck cancers, Ewing sarcoma, and others. Dose 
expansion in patients with prostate, ovarian, squamous (head and neck, lung, and cervical), colon, 
and high-grade malignant gliomas is ongoing. Optimal twice-weekly dosing as described above is 
being explored in additional arms. 
1.1.3 XPO1 and Selinexor in High-Grade Gliomas (HGG) 
XPO1 is overexpressed in HGG, and the degree of over-expression correlates with tumor grade 
and survival. One substrate of XPO1 is p27, which functions as a tumor suppressor through cell 
cycle control29 and requires phosphorylation at its Ser10 site in order to interact with XPO1.30 In 
vitro studies have shown that in glioma, the expression of Ser10-phosphorylated p27 correlates 
directly with XPO1 expression; both are overexpressed in higher-grade lesions. The expression of 
total p27 correlates indirectly with XPO1 expression, and increase in total p27 protein levels is 
associated with lower-grade tumors. In contrast, low p27 levels are associated with a poor 
prognosis. These findings strengthen the rationale for studying the use of XPO1 inhibition in HGG 
and offer a point of entry into investigation of a disease-specific mechanism of action. 
The XPO1 inhibitors KPT-276 and KPT-330 (selinexor) were evaluated in a murine orthotopic 
patient-derived xenograft (PDX) model of GBM.35 Adult primary human glioma cells infected with 
a luciferase-expressing virus to allow serial imaging were injected into three groups of 10 mice 
each. When the bioluminescence level of the tumors reached 1,000 times its starting value, 
treatment of two of the groups with KPT-276 and KPT-330 (selinexor) began, with the third group 
acting as a control. 
As shown in Figure 1, over time the inhibitors had a significant effect on the rate of tumor growth 
(A) and survival (B). The main side effect in the mice was weight loss, but this could be overcome 
with dosing adjustments. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 26 of 137 
Version 6.0 
Figure 1: Rate of Tumor Growth (A) and Survival (B) of Mice over Time with XPO1 
Inhibitors KPT-276 and KPT-330 (Selinexor) 
 
Investigation of a mechanism of efficacy for XPO1 inhibition in HGG has shown an increase in 
apoptosis, but not cell cycle arrest, in vitro and in vivo. Preliminary results indicate that this effect 
may be mediated through sequestration of mRNA for Mcl1, an anti-apoptotic member of the Bcl2 
family, in the nucleus through inhibition of XPO1. This leads to failure of translation of Mcl1 and 
restoration of apoptosis; these inquiries are ongoing. Luxol Fast Blue/Cresyl Violet staining of 
sectioned mice brains of treated animals revealed no significant abnormalities in myelin health, 
and the treated mice had no significant neurologic side effects. 
1.2 
Study Rationale 
Patients with GBM have a high risk for recurrence shortly after first-line therapy. The overall 
survival times of patients with recurrent GBM are poor, approximately 10 months at the highest 
despite various new treatment approaches within recent years. Consequently, new treatment 
options are desperately needed. 
The cytotoxicity of selinexor against glioma (LN-229, U87MG, T-98G) cell lines was evaluated in 
MTT assays. IC50 values for selinexor ranged from 40 to 80 nM. Following this, seven patient-
derived HGG lines (four adult, three pediatric) were treated with selinexor in culture conditions 
where dose-responsive growth inhibition in all seven HGG lines (IC50 range 6-354 nM) was 
observed.35 Given these results, the ability of selinexor to inhibit in vivo growth of various glioma 
tumors was tested. In a xenograft model of glioma, U87MG cells were inoculated into severe 
combined immunodeficiency disease mice and selinexor was orally administered at 15 mg/kg three 
times weekly. Mean tumor weight and volume were significantly reduced with selinexor treatment 
(p<0.001). Selinexor has shown significant activity in multiple in-vitro glioma models. In a patient-
derived orthotopic model of HGG, BT145-wt-mCLP cells were injected intracranially into nude 
mice and tumor growth was measured by bioluminescence imaging and MRI at discrete time 
points.35 Selinexor at 20 and 25 mg/kg was administered via oral gavage three times a week 
(Monday, Wednesday, and Friday). All vehicle-treated mice were sacrificed by treatment day 79 
due to tumor progression and neurological symptoms. A significant prolongation in survival was 
observed in selinexor treatment groups (p < 0.0001). Tumor growth was markedly suppressed, 
based on bioluminescence imaging, and verified by MRI imaging. In addition, the number of 
TUNEL+ cells was significantly higher with selinexor treated tumors. These studies demonstrate 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 28 of 137 
Version 6.0 
 
 
  


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 37 of 137 
Version 6.0 
16.  Prior treatment with bevacizumab or other direct VEGF/ VEGFR inhibitors. For any 
question of the definition of a direct VEGF/VEGFR inhibitor, consult Sponsor.  
17. Arms C and D only: BSA <1.2 m2, to avoid a dose exceeding the maximum allowable 
dose of 70 mg/m2. 
18. Major surgery < 4 weeks prior to the start of study treatment 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 41 of 137 
Version 6.0 
intervention) must be recorded in the eCRF. When abnormal laboratory values or test results 
constitute an AE, they must be recorded on the eCRF Adverse Events page. 
Every effort must be made to follow the schedule outlined in the Schedule of Assessments. Safety 
laboratory assessments on the day of a study visit must be completed prior to study drug 
administration. 
5.2 
Study Procedures 
5.2.1 Screening Procedures  
All patients will be screened and screening procedures must be performed within 14 days prior to 
the start of study treatment unless otherwise indicated in the table below. These include the 
following:  
Procedure 
Notes 
Signed written informed consent 
Obtained prior to any study specific assessments are 
performed 
Confirmation of eligibility (Days -7 
to -1) 
Please refer to Section 4. 
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) 
(Days -7 to -1) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years.  
Physical examination and vital signs 
(Days - 7 to -1) 
• Body height and weight 
• BSA (to ensure no patient exceeds the maximum 
allowable dose of 70 mg/m2) 
• Blood pressure, pulse, temperature 
• Physical examination 
Karnofsky performance status 
(Days - 7 to -1) 
Please refer to Section 16.2; Appendix 2 
Standard clinical neurological 
examination  
A complete neurological exam will be performed 
(baseline exam).  
Ophthalmic exam 
A full ophthalmic exam will be conducted by an 
optometrist or ophthalmologist at screening. Additional 
ophthalmic assessments will be completed during the 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 45 of 137 
Version 6.0 
Procedure 
Notes 
Pregnancy test (if applicable) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years to exclude that a pregnancy 
occurred under treatment 
Physical examination and vital signs • Body weight 
• Blood pressure, pulse, temperature 
• Physical examination 
Karnofsky performance status  
Please refer to Section 16.2; Appendix 2 
Standard clinical neurological 
examination  
A complete neurological exam will be performed 
Cardiac evaluation  
12-lead ECG 
Hematology  
Hemoglobin, hematocrit, RBC count, WBC count, WBC 
differential, lymphocytes, monocytes, neutrophils, 
eosinophils, basophils, platelets. WBC differential may 
be automated or manual as per institutional standards. 
Reticulocytes may be done only when clinically 
indicated.  
Complete clinical chemistry  
Sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, calcium, phosphate, magnesium, 
ALT, AST, alkaline phosphatase, total bilirubin, total 
protein, albumin, amylase, lipase, creatinine kinase, 
urate, LDH.  
TSH 
TSH.  
AEs and concomitant medication 
Assessed on an ongoing basis until 30 days after the last 
dose of study medication (EOT visit). 
5.2.4 Follow-up Before Progression of Disease 
Patients who discontinue for reasons other than progression of disease (and withdrawal of consent 
for participation in the trial) should be encouraged to visit the clinic for clinical evaluation of their 
disease every 4 weeks (±7 days) and assessment by CT/MRI every 8 weeks (±7 days) until 
progression of disease is determined.  
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the Investigator should show "due diligence" by documenting in the source documents 
steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
5.2.5 Survival Follow-up 
After disease progression all patients will be evaluated for survival and further anticancer therapy 
every 3 months (±14 days). Patients who have not expired or progressed by the data analysis cutoff 
date for the 6mPFS rate will be censored at the date of their last disease assessment. Patients who 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 46 of 137 
Version 6.0 
have not expired by the data analysis cutoff date for OS will be censored at their last date known 
to be alive. 
5.2.6 End of Study 
End of study will be when the last patient in the study has died, has been off study treatment for 
12 months, has been lost to follow-up, or has withdrawn consent, whichever occurs first 
5.3 
Planned Treatment of the Patients after End of Treatment Phase 
After completion of the EOT visit, patients will generally be treated at the discretion of the 
Investigator according to standard medical routine. 
5.4 
Removal of Patients from Treatment 
Patients will be free to discontinue treatment or withdraw from the study at any time, for any reason, 
or they may be withdrawn/removed if necessary in order to protect their health (see reasons for 
withdrawal below). It is understood by all concerned that an excessive rate of withdrawals can 
render the study uninterpretable; therefore, unnecessary withdrawal of patients should be avoided. 
Patients will be removed from further treatment for the following reasons: 
• Disease progression 
• Adverse Event (unacceptable toxicity) 
• Non-compliance 
• 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 for any reason 
• Pregnancy 
• Termination of the study by the Sponsor 
If a patient has 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 an abnormal laboratory test result, the principal specific 
event or test will be recorded on the eCRF. 
5.5 
Study Discontinuation 
The whole study may be discontinued at the discretion of the Sponsor in the event of any of the 
following: 
•  Medical or ethical reasons affecting the continued performance of the study 
•  Difficulties in the recruitment of patients 
  


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 47 of 137 
Version 6.0 
6 INVESTIGATIONAL PRODUCT 
6.1 
Investigational medicinal product 
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 authorisation but used or assembled (formulated or packaged) in a way different from 
the authorised form, or when used for an unauthorised indication, or when used to gain further 
information about the authorised 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 
6.2.1 Preparation and Administration of Selinexor 
The Investigator or responsible site personnel must instruct the patient or caregiver to take the study 
drug as per protocol. 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 
eCRF. 
Tablets, including instructions for administration, are dispensed by study personnel on an 
outpatient basis. Patients will be provided with an adequate supply of study drug for self-
administration at home until at least their next scheduled study visit. 
6.2.1.1  Drug Name, Formulation and Storage 
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) that 
specifically blocks nuclear export by binding irreversibly to XPO1 protein.  
Molecular formula: C17H11F6N7O 
Molecular weight: 
443.31 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 51 of 137 
Version 6.0 
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose Modification 
Anorexia or Weight loss 
Grade 1 
• Rule out other causes of anorexia. 
• Assess dietary options (e.g., try a variety 
of other foods).  
• Add high-calorie supplements (e.g., 
Ensure®).  
• Consider addition of ≤ 4 mg 
dexamethasone or equivalent with each 
dose of selinexor +/- the day after 
selinexor. 
Maintain dose. 
Grade 2 
• Rule out other causes of anorexia. 
• Assess dietary options (e.g., try a variety 
of other foods).  
• Add high-calorie supplements (e.g., 
Ensure®).  
• Consider addition of ≤ 4 mg 
dexamethasone or equivalent with each 
dose of selinexor +/- the day after 
selinexor.  
• Consider megesterol acetate 80-400 mg 
daily (divided doses). 
• Consider anabolic steroids such as 
oxandrolone, or dronabinol (Marinol®) or 
other cannabinoid, mainly for patients 
who can’t tolerate steroids or at high risk 
to progress. 
• For additional supportive care see NCCN 
guidelinesb (Section 16.7; Appendix 7). 
Selinexor may be skipped intermittently 
(e.g., skip 1-2 doses) while supportive 
medications are instituted, usually for 
< 1 week.  
Grade 3  
See guidelines for Grade 2 anorexia. 
Interrupt dosing with selinexor. Restart 
selinexor at 1 dose level reduction (Table 
5) once anorexia resolves to Grade ≤ 2 and 
patient is clinically stable.  
Grade 4 (anorexia 
only) 
See guidelines for Grade 2 anorexia. 
• Stop dosing of selinexor.  
• Restart selinexor at 1 dose level 
reduction (Table 5) only if anorexia 
resolves to Grade ≤ 2, patient is 
clinically stable, and other contributing 
factors have been addressed.  


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 52 of 137 
Version 6.0 
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose Modification 
Nausea/- acute  (common) 
Grade 1 
• Ensure adequate caloric intake and assess 
volume status. 
• Consider alternate 5-HT3 antagonists 
and/or D2 antagonists as needed. 
Consider addition of NK1 antagonists. 
• Consider addition of ≤ 4 mg 
dexamethasone or equivalent with each 
dose of selinexor +/- the day after 
selinexor.  
 
Maintain dose. 
Grade 2 
(If intolerable 
Grade 2, follow 
guidelines for Grade 
3 below) 
• See guidelines for Grade 1 nausea 
• For additional options see NCCN 
guidelines for antiemesisc (Section 16.6; 
Appendix 6). 
Selinexor may be skipped intermittently 
(e.g., skip 1-2 doses) while supportive 
medications are instituted, usually for 
< 1 week. 
Grade 3 
• See guidelines for Grade 1 nausea 
• For additional options see NCCN 
guidelines for antiemesisc (Section 16.6; 
Appendix 6). 
• Interrupt selinexor dosing until resolved 
to Grade ≤ 2, For first occurrence of 
Grade 3, if adequate supportive care 
resulted in nausea improving to Grade 
≤ 1 within 3 days, restart selinexor at 
current dose. 
• Otherwise, restart selinexor at one dose 
level below (Table 5). 
• If nausea stabilizes for at least 4 weeks 
at Grade ≤ 1, then the original dose of 
selinexor may be resumed. 
Hyponatremia (common) 
Grade 1 (sodium 
levels <normal to 
130 nM) 
  
• Be certain sodium level is corrected for 
hyperglycemia (serum glucose 
> 150mmol/L). 
• Rule out other causes of low sodium 
(e.g., cardiac, hepatic, adrenal, renal and 
thyroid diseases, SIADH, Fanconi 
Syndrome, hyperglycemia, diuretic use). 
• Consider salt supplementation one to two 
times per day. 
Maintain dose. 
 
Grade 3 (sodium 
levels 126-129 nM) 
without symptoms  
• Be certain sodium level is corrected for 
hyperglycemia (serum glucose 
> 150mmol/L). 
• Consider immediate IV rehydration with 
appropriate saline solution. 
• Rule out other causes of low sodium 
(e.g., cardiac, hepatic, adrenal, renal and 
thyroid diseases, SIADH, Fanconi 
Syndrome, hyperglycemia, diuretic use). 
• Initiate salt supplementation two to three 
times per day. 
• Consider administration of appropriate 
saline solution and remeasure serum 
sodium levels. If (corrected) sodium is 
Grade ≤ 1, then patient may receive 
standard dosing. 
• If immediate sodium correction is not 
successful, skip one dose of selinexor, 
implement recommendations, and 
reassess sodium within 48 hours. 
Resume selinexor dosing at the same 
dose level when sodium is Grade ≤1 
(≥130 nM). 


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Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3 (120-
125 nM) or Grade 4 
or any Grade 3 with 
symptoms 
• Correct sodium as per institutional 
guidelines 
• Initiate salt supplementation two to three 
times per day. 
• Delay selinexor until resolved to 
Grade ≤ 1 (≥ 130 nM) then reduce 
selinexor dose by 1 level (Table 5). 
Sodium should be reassessed after one 
dose of selinexor is skipped (i.e., within 
48 hours) and corrective measures 
implemented. 
• For Grade 3 hyponatremia, if serum 
sodium stabilizes to Grade ≤ 1 for at 
least 4 weeks, then original dose of 
selinexor may be resumed. 
Diarrhea (common) 
Grade 1+2 
  
• Diet recommendation as per guidelines 
(Benson, 2004)d. 
• Institute standard anti-diarrheal therapy. 
• After the first occurrence of diarrhea, 
loperamide 2 mg should be considered 
prophylactically approximately 1-2 hrs 
before the administration of selinexor and 
repeated every 4 hrs for the first 12 hrs. 
For Grade 2 only, reduce selinexor one 
dose level (Table 5) until resolved to Grade 
≤ 1, then re-start at the current dose level. 
 
Grade 3  
• Institute intravenous fluids  
• Diet recommendation as per guidelines 
(Benson, 2004)d.  
• Institute standard anti-diarrheal therapy. 
• Once the symptoms resolve to Grade ≤ 1, 
loperamide 2 mg should be considered 
prophylactically approximately 1-2 hrs 
before the administration of selinexor and 
repeated every 4 hrs for the first 12 hrs. 
• Delay selinexor dosing until resolved to 
Grade ≤ 1, then reduce selinexor dose by 
one dose level (Table 5). 
• If diarrhea stabilizes for at least 4 weeks 
at Grade ≤ 1, then original dose of 
selinexor may be resumed. 
Grade 4 
• Rule out other causes of diarrhea, 
including infectious agents.  
• In case of opportunistic infection, 
withdraw all steroids (with tapering if 
medically appropriate) until culture is 
negative.  
• Follow institutional guidelines for Grade 
4 diarrhea. 
Delay selinexor dosing until resolved to 
Grade ≤ 1, then reduce selinexor dose by 
one dose level (Table 5). 
Thrombocytopenia 
Grade 1  
In cases of marked reduction in platelet 
numbers from baseline, consider 
implementing platelet growth factors (e.g. 
eltrombopag or romiplostim ± oprelvekin 
[IL 11]).). 
Maintain dose. 
Grade 2  
• Strongly consider implementing platelet 
growth factors (e.g. eltrombopag or 
romiplostim ± oprelvekin [IL 11]). 
• Monitor platelet counts weekly. 
If Grade 2 thrombocytopenia persists 
> 14 days, delay selinexor dosing until 
platelet count returns to Grade ≤, then re-
start at the current dose level. 


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Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3 
Thrombocytopenia 
without bleeding 
 
• Initiate platelet growth factors (e.g. 
eltrombopag or romiplostim ± oprelvekin 
[IL 11]).). 
• Monitor platelet counts at least weekly. 
• Consider holding anti-platelet agents. 
• Delay selinexor dosing until the 
patient’s platelet count returns to Grade 
≤ 2.  
• For Grade 2, restart selinexor at same 
dose level taken once weekly only until 
platelet counts resolve to Grade ≤ 1, 
then resume twice-weekly dosing at 
current dose. 
• Second occurrence: delay selinexor 
dosing until platelet counts return to 
Grade ≤ 2. For Grade 2, restart selinexor 
at same dose level taken once weekly 
only until platelet counts resolve to 
Grade ≤ , then resume twice-weekly 
dosing at one dose level below (Table 
5). 
• If platelet counts stabilize at Grade ≤ 1 
for at least 4 weeks, then original dose 
of selinexor may be resumed. 
Grade 4 
Thrombocytopenia 
without bleeding 
 
• Follow guidelines for Grade 3 
thrombocytopenia without bleeding. 
• Transfuse as per institutional guidelines. 
• Delay selinexor dosing until platelet 
counts return to Grade ≤ 2. For Grade 2, 
restart selinexor at same dose level 
taken once weekly only until platelet 
counts resolve to Grade ≤ 1, then resume 
twice-weekly dosing at one dose level 
(Table 5). 
• If platelet counts stabilize at Grade ≤1 
for at least 4 weeks, then original dose 
of selinexor may be resumed. 
≥ Grade 3 
Thrombocytopenia 
associated with 
bleeding 
• Transfuse as per institutional guidelines. 
• Follow guidelines for Grade 3 
thrombocytopenia without bleeding. 
Delay selinexor dosing until platelet counts 
return to Grade ≤ 1, and then resume 
selinexor dosing at one dose level below 
(Table 5).  
Neutropenia 
Grade 3 neutropenia 
without fever 
Implement growth factors per institutional 
guidelines. 
Delay dosing with selinexor until the 
patient’s ANC returns to Grade ≤ 2. 
Resume dosing with selinexor at current 
dose. 
Grade 4 neutropenia 
without fever 
Implement growth factors per institutional 
guidelines. 
• Delay dosing with selinexor until the 
patient’s ANC returns to Grade ≤ 2. 
Resume dosing with selinexor at current 
dose. 
• Second occurrence: delay dosing with 
selinexor until the patient’s ANC returns 
to Grade ≤ 2 then reduce selinexor dose 
by one dose level (Table 5).  


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Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3 or 4 
neutropenia with 
fever (febrile 
neutropenia) 
• Implement growth factors per 
institutional guidelines. 
• Implement broad anti-microbial coverage 
per institutional guidelines. 
• Please note that selinexor has not been 
associated to date with any opportunistic 
infections 
Delay dosing with selinexor until the 
patient’s ANC returns to Grade ≤1, fever 
has resolved and patient is stable, then 
reduce selinexor dose by one dose level 
(Table 5). 
Anemia 
Grade 1 or 2 
Initiate standard supportive care and follow 
institutional guidelines. 
 
Maintain dose. 
Grade 3 
Delay dosing with selinexor until resolved 
to Grade ≤ 2, then resume dosing with 
selinexor at current dose. 
Grade 3 
(symptomatic) or 
Grade 4 
Delay dosing with selinexor until resolved 
to Grade ≤ 2, then reduce selinexor dose by 
one dose level. 
Other clinically significant selinexor-related AEs* 
 
Grade 1 or 2 
Initiate standard supportive care and follow 
institutional guidelines. 
Maintain dose. 
Grade 3 
Delay dose until resolved to Grade ≤ 1, 
then reduce by one dose (Table 5). 
Grade 4 
Delay dose until resolved to Grade ≤ 1, 
then reduce by two dose levels (Table 5). 
All dose modifications should be based on the worst preceding toxicity. 
*Isolated values of Grade ≥ 3 alkaline phosphatase values will NOT require dose interruption. Determination of liver vs. bone etiology should 
be made, and evaluation of gamma-glutamyl transferase (GGT), 5'-nucleotidase (5’NT), or other liver enzymes should be performed. 
Note: for combinations of Grade 1 or 2 adverse events (e.g., nausea, fatigue, anorexia) that significantly impair the patient’s quality of life, 1-2 
doses of selinexor may be skipped and aggressive supportive care implemented. Selinexor may then be restarted at the original dose. 
aNational Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Fatigue. Available at 
http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf31  
bNational Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Palliative Care, version 
1.2014. Fort Washington, NY. April 2014. Available at: 
http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/facts.pdf32 
cNational Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Antiemesis, version 
2.2014. Fort Washington, NY. April 2014. Available at: http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. 33 
dBenson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Onc 2004; 
22:2918. 34 
If the patient tolerates a reduced dose for at least four weeks, patients may be dose escalated to the 
dose they received prior to the reduction after authorization from medical monitor and Principal 
Investigator. 
6.3.1 Selinexor Dose Reduction for Decreased Glomerular Filtration Rate 
Selinexor is not significantly eliminated by the kidney; therefore, no dose alteration of selinexor is 
required with renal dysfunction. If dialysis is implemented during selinexor treatment, then 
selinexor should always be given after dialysis. 
6.3.2 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. Dexamethasone should be adjusted per 
institutional guidelines, and adrenal suppression considered. After the infection has stabilized 
clinically or resolved, selinexor treatment may continue at the original dose. Missed doses will not 


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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. 
6.3.3 Dose Adjustments with Changes in BSA 
Patient BSA will be assessed to ensure that the 60 mg or 80 mg dose does not result in a dose 
>70 mg/m2. If a patient’s dose will exceed this limit, the Investigator should contact the medical 
monitor prior to administration to discuss appropriate dosing. 
6.3.4 Missed or Vomited Doses 
A maximum of two doses may be given per week; doses should not be administered less than 36 hrs 
apart. Every effort should be made to avoid missed doses. 
• Missed doses: Doses held due to AE will not be considered missed.  
• Vomited doses: If a dose is vomited within 1 hr of ingestion, it will be replaced. If vomiting 
occurs more than 1 hr after dosing, it will still be considered a complete dose. 
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 eCRF. Any diagnostic, therapeutic or surgical procedure 
performed during the study period should be recorded, including the dates, description of the 
procedure(s) and any clinical findings.  
6.4.1 Permitted Concomitant Medication 
Patients will receive concomitant medications to manage cancer symptoms, AEs, intercurrent 
illnesses, and supportive care agents, such as, pain medications, anti-emetics, short courses of low 
dose oral steroids, and anti-diarrheal agents are allowed 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 patients understand the need to use birth control while on this study. Female patients of 
child-bearing 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 child-bearing 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 


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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 RBC or platelet transfusions, if 
clinically indicated, per institutional guidelines. Patients who require repeated transfusion support 
should be discussed with the Primary Investigator, Sponsor, and medical monitor. 
Appropriate anti-coagulation is allowed during the study (e.g.: low molecular weight heparin, 
direct factor Xa inhibitors, etc.). 
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 or as recommended in Table 6 prior to entry and throughout the study. 
6.4.2 Restrictions and Prohibited Medications 
Concurrent therapies: Concurrent therapy with glucocorticoids as specified herein is allowed. 
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. 
Alcohol: Ethanol should be avoided on selinexor dosing days as it may compete for glutathione 
(GSH)-mediated metabolism. 
Diet: There are no dietary restrictions on this study. Patients should maintain adequate caloric 
and fluid intake. 
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 
on 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). 
Patients should not take 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 Section 16.8; Appendix 8 for a list of representative products. Patients 
must report all prescription and non-prescription medicines to their physicians during this study. 
Concurrent warfarin or other Coumadin-derived anticoagulants are prohibited. 


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6.5 
Supportive Care Guidelines 
6.5.1 Required 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 
daily thereafter, as needed. Alternative treatment may be provided if the patient does not tolerate 
5-HT3 antagonists. 
6.5.2 Supportive Care Recommendations for Selinexor-Related Adverse Events 
Supportive measures for optimal medical care shall be provided during participation in this study. 
Based on clinical observations in over 730 adult patients treated with selinexor as of 31 May 2015, 
the main side effects have been primarily related to anorexia with poor caloric and fluid intake, 
fatigue and nausea. Thrombocytopenia also occurs, although it is rarely associated with bleeding.  
In addition to required 5-HT3 prophylaxis, supportive care including additional anti-nausea/anti-
emetic therapy, acid suppression (proton-pump inhibitors [PPI] and/or H2-blockers) and other 
treatments may be administered as follows: 
• Glucocorticoids: ≤4 mg dexamethasone [or equivalent] on the day of, and the day after, 
each selinexor dose, with a maximum of 16 mg/week) may also be used as needed to 
improve appetite, reduce nausea or vomiting, and minimize fatigue. 
• Appetite stimulants: megesterol acetate at a dose of 80-400 mg daily.  
• Centrally acting agents: per National Comprehensive Cancer Network® [NCCN] Clinical 
Practice Guidelines® see, respectively, Section 16.6; Appendix 6 and Section 16.7; 
Appendix 7. 
• Neurokinin-1 receptor antagonist (NK1R antagonist): Aprepitant or equivalent should be 
considered and will be covered for selected patients who have severe nausea and vomiting 
Supportive care guidelines for managing AEs are provided in Table 6. 
6.5.2.1 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 in any patient with Grade 4 infection or clinical sepsis (in the absence of documented 
infection) until the condition is stabilized. Selinexor can then be re-started at the same dose. See 
also Table 6. 
6.5.3 Liver Function Test Abnormalities 
Since selinexor is metabolized by GSH conjugation, hepatic GSH depletion might occur. 
Therefore, in patients who develop liver function test abnormalities, supportive measures such as 
SAM 400 mg orally 1-4 times per day or other drugs that can replace GSH should be considered. 


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7 ASSESSMENT OF SAFETY 
The Selinexor/KPT-330 IB will be used as reference document for selinexor and will be provided 
to the Investigators. 
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 (GCP) as “any untoward medical occurrence in a patient or 
clinical investigation patient administered a pharmaceutical product and that does not necessarily 
have a causal relationship with this treatment” (ICH E6:1.2). 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom or disease temporally associated with the use of a medicinal 
product, whether or not it is considered related to the medicinal product. 
The Investigator will make a judgment regarding whether or not the AE was related to study drug, 
as outlined below in Table 7. 
Table 7: Classification of Adverse Events by Causality 
Not related 
The lack of a temporal relationship of the event to study treatment makes a causal 
relationship not reasonably possible, or other drugs, therapeutic interventions or 
underlying conditions 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 possible or probable will be 
considered treatment-related events. 
7.1.2 Adverse Drug Reaction 
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 adverse drug reaction (SADR) is an adverse drug reaction (ADR) that meets the 
definition of serious (provided below). 


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7.1.3 Serious Adverse Event 
A serious adverse event (SAE) is defined as an AE that 
• Is fatal 
• Is life threatening (places the patient 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 AE that does not meet 
one of the definitions of serious (e.g., visit to an emergency room, outpatient surgery, or requires 
urgent investigation) may be considered by the Investigator to meet the “other significant medical 
hazard” criterion for classification as an SAE. 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 patient 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. 
7.1.4 NOT to be reported as SAEs 
For this study, the following conditions or planned events are not classified as SAEs: 
• Progression, deterioration or other events secondary to 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 unrelated to the studied indication. 
• Hospital admission that is not associated with an AE (e.g. social hospitalization for 
purpose of respite care). 
• Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 


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• 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. 
7.1.5 SUSAR/Unexpected Serious ADR 
A SUSAR/Unexpected Serious ADR is defined as a suspected unexpected serious adverse reaction. 
An unexpected AE is any adverse drug event, the specificity or severity of which is not consistent 
with the current Selinexor/KPT-330 IB. Also, reports that provide significant information on the 
specificity or severity of a known, already documented AE constitute unexpected AEs. An event 
more specific or more severe than described in the IB would be considered “unexpected”. All 
suspected adverse reactions related to selinexor which occur in the trial and that are both 
unexpected and serious (SUSARs/Unexpected Serious ADR) are subject to expedited reporting. 
7.2 
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 (Section 16.4, Appendix 4) 
• 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 
• Information on any treatment procedures necessary for the SAE, concomitant 
medications, relevant lab tests and relevant medical history 


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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. 
7.3 
Reporting of SUSARs/Expedited Reporting of Unexpected Serious ADRs 
Sites within the EU: 
Karyopharm Therapeutics will ensure the notification of the appropriate ethics committees, 
competent authorities, and participating Investigators of all SUSARs events occurring at the sites 
in accordance with local legal requirements, statutes, and the European Clinical Trial Directive as 
follows: 
• Reporting of the SUSAR to the Competent Authorities and Ethics Committees within 
15 days (or within 7 days for fatal and life-threatening events). 
• Sending the event to all participating Investigators for information. 
 
In addition, all events that require a new assessment of the risk-benefit ratio will be reported to the 
Ethics Committee and the Competent Authority of each concerned Member State within 15 days. 
This includes: 
• Single reports of expected serious adverse reactions with unexpected outcome.  
• An increase in the rate of occurrence of expected serious adverse reactions which is 
judged to be clinically relevant. 
• Post-study SUSARs that occur after the patient has completed a clinical trial. 
• New events related to the conduct of the trial or the development of the investigational 
medicinal products and likely to affect the safety of the patients. 
Sites in the United States: 
Karyopharm Therapeutics will ensure Expedited reporting of unexpected Serious ADR to FDA in 
accordance with local legal requirements, statutes and ICH topic E2A  (Section 16.1, Appendix 1) 
as follows: 
• Reporting of the unexpected Serious ADR to FDA within 15 days (or within 7 days for 
fatal and life-threatening events) 
• Sending the event to all participating Investigators for information (with confirmation of 
receipt). 
Investigators must notify their Institutional Research Board (IRB) or Research Ethics Boards 
(REBs) in accordance with local regulations and file the report with their Investigator Site File. 
The Sponsor is responsible to ensure that the latest Selinexor/KPT-330 IB is used as the source 
document for determining the expectedness of an SAE.  


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7.4 
Recording of Adverse Events 
The Investigator is responsible for ensuring that all AEs observed by the Investigator or reported 
by patients are properly and no later than 7 days after patients visit recorded in the patient’s medical 
records and the eCRF.  
The following AE attributes must be assigned by the Investigator:  
• Severity grade according to the NCI-CTCAE criteria Version 4.03 (Section 16.4, 
Appendix 4) 
• Start date and stop date (or date of last assessment) 
• Outcome 
• Causality to study drug and chemotherapy (to be assessed as either related or unrelated) 
• Any action taken with study medication 
• Any treatment administered to the patient or procedure performed due to the adverse 
event  
AEs will be followed until they resolve to baseline or are considered stable. It will be left to the 
Investigator’s clinical judgment to determine whether an AE is related and of sufficient severity to 
require the patient’s removal from treatment or from the study. A patient may also voluntarily 
withdraw from treatment due to what he or she perceives as an intolerable AE. If either of these 
situations arises, the patient should be strongly encouraged to undergo an end-of-study assessment 
and be under medical supervision until symptoms cease or the condition becomes stable. 
Pre-existing diseases, when worsening during study therapy, have to be considered as AEs. They 
can lead to SAEs, if the meet the criteria described in Section 7.1.3. 
Intensity of AEs will be graded using the NCI-CTCAE, version 4.03 (Section 16.4, Appendix 4). 
If an AE occurs which is not described in the CTCAE version 4.03, the four-point scale below will 
be used. 
Mild: 
Discomfort noticed but no disruption of normal daily 
activity 
Moderate: 
Discomfort sufficient to reduce or affect daily activity 
Severe: 
Inability to work or perform normal daily activity 
Life-threatening: Represents an immediate threat to life 
7.5 
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 immediately (within 
24 hrs) 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 
AEs unless they are treatment-emergent and they satisfy one or more of the following conditions 
for clinical significance: 
1. Accompanied by clinical symptoms. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 64 of 137 
Version 6.0 
2. Leading to a change in study medication (e.g. dose modification, interruption or perma-
nent discontinuation). 
3. Requiring a change in concomitant therapy (e.g. addition of, interruption of, discontinua-
tion of, or any other change in a concomitant medication, therapy or treatment). 
Please note: Any laboratory result abnormality fulfilling the criteria for an SAE should be reported 
as such, in addition to being recorded as an AE in the eCRF. 
7.6 
Pregnancy 
Pregnancy per se is not considered an AE. A medical occurrence observed in the mother or 
fetus/newborn would be an AE. 
Female patients must be instructed to immediately inform the Investigator if they become pregnant 
during the study. If a patient becomes pregnant, 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 
should counsel the patient and 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 male patient participating in the study should also be 
reported to the Investigator.   The partner should be counselled and followed as described above.  
 
The investigator must report all pregnancies within 24 hours of knowledge to the Karyopharm 
Pharmacovigilance Department.  
7.7 
Adverse Drug Reactions with Concomitant Medication 
The Investigators must be aware that for all concomitant medications the regulations of post-
marketing reporting for suspected ADRs apply, i.e. reporting to the marketing authorization holder 
or the local regulatory bodies. 
7.8 
Safety Surveillance 
Regular safety teleconferences between the site Investigators and the Sponsor will be conducted. 
Any safety issues will be discussed and minutes recorded and distributed to all attendees.  


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Karyopharm Therapeutics Inc. 
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13 November 2015 
 
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• 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 to each on study evaluation will be summarized for 
each clinical laboratory parameter, including hematology and clinical chemistry. In the event of 
repeat values, the last non-missing value per study day/time will be used.  
Severity of select clinical lab measures will be determined using CTCAE v.4.03 criteria (e.g. those 
measures that have a corresponding CTCAE grade classification). Labs with CTCAE grades 
greater than or equal to 3 will be presented in a data listing. Shift tables that present changes from 
baseline to worst on-study values  
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. 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 Simon’s two-stage optimal design36, there will be a preliminary assessment of 
efficacy for Arms B, C, and D after the first 12 non-surgical patients enrolled in each arm have 
6-month data available to assess PFS. Note that this initial analysis may take place sooner than 
when the 12th patient has available data, should there be 2 or more PFS responders after fewer than 
12 patients. Should the trial be terminated at the first stage for Arms B, C, and D, 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 will take place after there are 30 patients evaluable for 
analysis of 6mPFS separately in Arm C and Arm D, as enrollment in Arm B was stopped to explore 
alternative dosing in Protocol Versions ≥ 4.0 (see details in Section 8.2). Additional data 
summarization may take place after all available survival data are collected, or after Sponsor 
decision, as appropriate.  


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13 November 2015 
 
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9 DATA QUALITY ASSURANCE 
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. 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. 
 


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13 November 2015 
 
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10 ETHICAL ASPECTS 
10.1 Good Clinical Practice 
The Investigator will ensure that the study is performed in accordance with the international 
standards of GCP and according to all local laws and regulations concerning clinical studies. 
10.2 Patient Information and Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from each patient, or 
their legally authorized representative, 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 the collection of data about his/her disease 
being recorded within the context of the clinical trial 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 personally signed and dated by the patient, or their legally authorized 
representative, must be kept on file by the Investigator(s) and documented in the eCRF 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 doctors 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 by Regulatory Authorities 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.  
Indemnity insurance will be arranged for the trial patients in accordance with the applicable local 
law.  


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13 November 2015 
 
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10.3.2 Notification of the Study 
The Sponsor is responsible for notifying the competent regional authority about the study and all 
Principal 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. 


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13 November 2015 
 
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11 CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made via amendment. The Sponsor is 
responsible for obtaining independent approval for substantial amendments from the applicable 
regulatory authority 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). 


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Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
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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 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 authorisation 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 
and 
laboratory 
reports, 
ECG, 
electroencephalogram, X-ray, etc.), signed informed consent forms 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 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. 
12.3 Audits and Inspections 
This study may be audited by the Sponsor, any person authorised by the Sponsor, or the competent 
health authority in order to determine the authenticity of the recorded data and compliance with the 
study protocol.  


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13 November 2015 
 
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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 
This study will use Electronic Data Capture (EDC). The designated Investigator site staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs have 
been built using fully validated secure web-enabled software that conforms to 21 CFR Part 11 
requirements. Investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies in the eCRFs and allow 
modification or verification of the entered data by the Investigator site staff. 
The Investigator is responsible for assuring that the data entered into eCRF is complete, accurate, 
and that entry and updates are performed in a timely manner. 
 


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Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
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13 MONITORING OF STUDY 
The monitor 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 GCP, 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. 


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13 November 2015 
 
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14 CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS 
The Investigator and the Sponsor (or designated person) must ensure that all data obtained in the 
course of a clinical study is treated with discretion in order to guarantee the rights of the patient’s 
privacy, according to the standards of the data protection law. eCRFs or other documents should 
be submitted to the Sponsor in pseudonymised 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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13 November 2015 
 
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15 STUDY REPORT AND PUBLICATION POLICY  
This study will be entered into a clinical trial protocol registry and clinical results database. The 
Sponsor is responsible for the timely reporting of study data.  
Study data may be analyzed and submitted to regulatory authorities in one or more interim clinical 
study reports (CSR) when ≥ 75% of patients have potentially completed ≥ 2 cycles of treatment or 
discontinued from the study. Any additional data for patients continuing to receive study treatment 
past the data cutoff, as allowed by the protocol, will be reported in a final CSR once all patients 
have discontinued from the study. The final, integrated CSR will be completed approximately one 
year after the end of the study (whether completed or prematurely terminated). The report has to 
be approved by the responsible specialist chosen by the Sponsor, the statistician, and the 
coordinating Investigator by provision of their signatures.  
The results from this study will be submitted for publication and made available through an on-
line clinical results database. The main publication will be a full publication of all data from all 
sites. Any publication of the results, either in part or in whole (abstracts in journals, oral 
presentations, etc.) by Investigators or their representatives will require a pre-submission review 
by the Sponsor and the coordinating Investigators. The two coordinating Investigators will have 
the opportunity to be the first and the last authors and corresponding authors for the main 
publication, unless they choose otherwise. The remaining positions will be based on recruitment, 
good data quality, and scientific input to the study. The final author list will be a joint agreement 
between the coordinating Investigators and the Sponsor. For all other publications, the order of the 
authors will be determined according to recruitment, data quality, and significant scientific input 
to the study, after consulting the coordinating Investigators. 
 


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13 November 2015 
 
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16 APPENDICES 
Appendix 1:  
Definitions According to ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, 
Topic E2 
Appendix 2: 
Karnofsky Performance Status 
Appendix 3:  
Cockroft-Gault Formula 
Appendix 4 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 
Appendix 5: 
Ophthalmic Examination 
Appendix 6: 
NCCN Clinical Practice Guidelines in Oncology: Antiemesis 
Appendix 7: 
NCCN Clinical Practice Guidelines in Oncology: Anorexia/Cachexia 
Appendix 8: 
Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-acetylcysteine 
(NAC)-containing Products (Representative List) 
Appendix 9: 
Summary of Changes and Rationale for Changes to Protocol KCP-330-004 


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Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
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16.1 Appendix 1 – Definitions According to ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 
An adverse event is any untoward medical occurrence in a patient or clinical investigation patient 
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 IMP related to any 
dose administered. 
An SAE 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 an emergency room 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 is one where the nature or severity is not consistent with the applicable 
product information. 
Causality is initially assessed by the Investigator. With respect to the obligation to report and 
document SAEs (i.e., to regulatory authorities, ethics committees, and other Investigators), 
causality can be one of two possibilities: 
 
• No (unrelated; equals not drug-related) 
• Yes (remotely, possibly, or probably drug-related) 
 
All adverse events not assessed as definitively “not drug-related” by the Investigator will be 
considered as ADRs. 


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13 November 2015 
 
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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 
an SAE. On the other hand, stroke which results in only a limited degree of disability may be 
considered a mild stroke, but would be an SAE. 
An SAE occurring during the study or which comes to the attention of the Investigator during the 
protocol-defined follow-up period, must be reported, whether considered treatment-related or not. 
In addition, SAEs 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 SAEs, at a minimum the following must be assessed and recorded on the adverse events page 
of the eCRF: intensity (severity), 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 inter-
national laws and regulations.  
For contact details and fax no. for SAE reporting, please refer to page 10. 


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Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
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16.2 Appendix 2 – Karnofsky Performance Status  
 
100% 
Normal, no complaints, no signs of disease 
90% 
Capable of normal activity, few symptoms or signs of disease 
80% 
Normal activity with some difficulty, some symptoms or signs 
70% 
Caring for self, not capable of normal activity or work 
60% 
Requiring some help, can take care of most personal requirements 
50% 
Requires help often, requires frequent medical care 
40% 
Disabled, requires special care and help 
30% 
Severely disabled, hospital admission indicated but no risk of death 
20% 
Very ill, urgently requiring admission, requires supportive measures or 
treatment 
10% 
Moribund, rapidly progressive fatal disease processes 
0% 
Death 
 Source: Karnofsky DA, Burchenal JH. The Clinical Evaluation of Chemotherapeutic Agents in Cancer. In:  
                MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ Press 1949:196 


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13 November 2015 
 
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16.3 Appendix 3 – Cockroft-Gault Formula 
 
Calculated CLCR (ml/min) =   
 
[(140 – patient’s age in years) x patient’s actual body weight in kilograms] * 
  
 
72 x patient’s serum creatinine (in mg/dL) 
 
*: x 0.85 for females 
 
 
Calculated CLCR (ml/min) =   
 
[(140 – patient’s age in years) x patient’s actual body weight in kilograms] x K* 
  
 
Patient’s serum creatinine (in µmol/L) 
 
K*: 1.23 for males, 1.05 for females 
 
 


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13 November 2015 
 
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16.4 Appendix 4 – NCI-CTCAE version 4.03 
 
Available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
 
 


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Confidential 
Page 87 of 137 
Version 6.0 
16.5 Appendix 5 
Ophthalmic Examination 
 
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 for newly enrolling patients or enrolled patients for 
whom no cataract/lens opacity have been detected to date, 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). However, 
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 
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. 
 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 88 of 137 
Version 6.0 
16.6 Appendix 6 
NCCN Clinical Practice Guidelines in Oncology: Antiemesis 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014.33 © 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. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 89 of 137 
Version 6.0 
 
 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014.33 © 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. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 90 of 137 
Version 6.0 
16.7 Appendix 7 
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.1.201432 © 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. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 91 of 137 
Version 6.0 
16.8 Appendix 8 
 Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-
acetylcysteine (NAC)-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 
(paracetamol) 
overdose 
acetylcysteine  
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 
 
 
 
 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 92 of 137 
Version 6.0 
16.9 Appendix 9 
 Summary of Changes and Rationales for Changes to 
Protocol KCP-330-004 
16.9.1 Summary and Rationale for Changes to Version 5.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc 
 
A Phase 2 Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in 
Patients with Recurrent Gliomas 
Clinical Trial Protocol No 
Sponsor Protocol No. KCP-330-004 
Development Phase: 
Phase 2 
Investigational Product: 
Selinexor 
Indication: 
Glioblastoma 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  02459  
USA 
From: Version 5.0 dated 01 July 2015 
To: Version 6.0 dated 13 November 2015 
 
 
 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 94 of 137 
Version 6.0 
Inclusion/Exclusion Criteria 
• Added an exclusion criterion requiring patients not to have undergone major surgery within 
four weeks prior to Cycle 1 Day 1. (Modified sections: Synopsis and Section 4.3) 
Background 
• Updated the number of patients (from 900 to > 1,100) exposed to selinexor in order to be 
consistent with the most recent version of the Investigatgor’s Brochure (as of 31 May 2015). 
(Modified section: Section 1.1.2.2). 
• Updated the number of patients (from 650 to 730) whose safety results have been analyzed 
to be consistent with the most recent version of the Investigatgor’s Brochure (as of 
31 May 2015). (Modified sections: Sections 1.1.2. and 6.5.2). 
• Updated the reported frequencies of the most common AEs to be consistent with the most 
recent version of the Investigatgor’s Brochure (as of 31 May 2015). (Modified section: 
Section 1.1.2.2). 
• Replaced “Figure 2: Overview of Study Design” to reflect the elimination of Arms E and 
F. (Modified section: Section 3.1.1)  
Classification of Adverse Events by Causality 
• Revised the definitions in the Classification of Adverse Events by Causality table for 
clarity. (Modified section: Table 7) 
Declaration of Helsinki 
• Deleted statement concerning the Declaration of Helsinki because it is not applicable to this 
study. However wording was retained that requires Investigators to comply with 
international standards for GCPs. (Modified section: Section 10.1) 
Study Reporting 
• Added text to explain that one or more interim CSRs may be submitted to regulatory 
authorities, in addition to the final CSR. (Modified section: Section 15) 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 95 of 137 
Version 6.0 
 
16.9.2 Summary and Rationale for Changes to Version 4.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. 
 
A Phase 2 Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in 
Patients with Recurrent Gliomas 
Clinical Trial Protocol No 
Sponsor Protocol No. KCP-330-004 
Development Phase: 
Phase 2 
Investigational Product: 
Selinexor 
Indication: 
Glioblastoma 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  02459  
USA 
 
 
From: Version 4.0 dated 23 March 2015 
To: Version 5.0 dated 01 July 2015 
 
 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 100 of 137 
Version 6.0 
16.9.3 Summary and Rationale for Changes to Version 3.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. 
 
A Phase 2 Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in 
Patients with Recurrent Glioblastoma or Other Brain Cancers after Failure of 
Radiation Therapy and Temozolomide 
Clinical Trial Protocol No 
Sponsor Protocol No. KCP-330-004 
Development Phase: 
Phase 2 
Investigational Product: 
Selinexor 
Indication: 
Glioblastoma 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  02459  
USA 
 
 
From: Version 3.0 dated July 16, 2014 
To: Version 4.0 dated March 23, 2015 
 
 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 107 of 137 
Version 6.0 
• Revised selinexor dose reduction in the setting of infection to recommend that 
dexamethasone should be adjusted per institutional guidelines and that adrenal suppression 
should be considered. (Modified section: Section 6.3.1) 
• Replaced prophylactic therapy (Section 6.2.1 in Version 3.0) with required and 
recommended supportive care guidelines (Section 6.5). Required supportive care includes 
administration of a 5-HT3 antagonist and recommended supportive care includes 
glucocorticoids, appetite stimulants, and centrally acting agents. These changes were made 
based on clinical experience in ongoing Phase 1 and Phase 2 clinical studies. 
Dexamethasone is no longer required supportive care but rather a supportive care option. 
Section 7.5 Supportive Care from Version 3.0 (now Section 6.5 Supportive Care 
Guidelines) was re-ordered for clarity, to reflect that much of the information in the text in 
Version 3.0 is now in Table 6. (Modified sections: Sections 1.1.2, 5.2.1, 5.2.2, 6.3, 6.3.1, 
and 6.5, Table 6) 
• Replaced “Liver enzyme increase” (Section 7.5.7 in Version 3.0) with “Liver Function Test 
Abnormalities” (Section 6.5.3) to update supportive measures to be taken in the event of 
GSH depletion. (New section: Section 6.5.3) 
• Replaced the use of olanzapine and mirtazapine (Sections 2.1.4, 6.2.1, 7.5.1, and 7.5.3 and 
Table 6 in Version 3.0) with references to the NCCN clinical practice guidelines in 
oncology for antiemesis and anorexia/cachexia based on feedback from the FDA. Added 
NCCN Guidelines for antiemesis as Appendix 7 and anorexia/cachexia as Appendix 8. 
(Modified sections: Section 6.5.2 and Table 6; New sections: Sections 16.7 and 16.8) 
• Clarified that the use of supportive care is in accordance with institutional guidelines or as 
recommended in the supportive care and dose adjustment guidelines (Table 6). (Modified 
section: Section 6.4.1.2) 
Concomitant Medications 
• Revised the text for prevention of pregnancy and related inclusion criteria with updated 
standard text for consistency across protocols (Modified sections: Synopsis [Inclusion 
criteria], Sections 4.2 and 6.4.1.1) 
• Deleted statement allowing warfarin. Concurrent warfarin or other Coumadin-derived 
anticoagulants are prohibited, as anticoagulants could increase the chance of bleeding in 
those patients with decreased platelets associated with selinexor. (Modified section: 
Section 6.4.2) 
• Concomitant medication guidelines were updated based on recent Phase 1 and Phase 2 
clinical trial results and Investigator input. (Modified section: Section 6.4.2) 
• Removed the acetaminophen (paracetamol) restriction as ongoing clinical safety 
evaluations on the use of selinexor in combination with acetaminophen (paracetamol) have 
not shown any significant clinical or laboratory abnormalities with doses of acetaminophen 
(paracetamol) up to 1 gram and selinexor up to 55 mg/m2 (approximately 80-100 mg). 
(Modified sections: Sections 6.4 and 6.4.2) 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 108 of 137 
Version 6.0 
• New guidance regarding GSH-, SAM-, or NAC-containing products was added, along with 
a new Appendix 9 listing representative products. These changes were based on FDA 
recommendations. (Modified sections: Sections 6.4.2 and 16.9) 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 109 of 137 
Version 6.0 
16.9.4 Summary and Rationale for Changes to Version 2.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. 
 
A Phase II, Two-Tier Study Evaluating the Efficacy and Safety of Selinexor (KPT-
330) in Patients with Recurrent Glioblastoma after Failure of Radiation Therapy 
and Temozolomide 
Clinical Trial Protocol No 
Sponsor Protocol No. KCP-330-004 
Development Phase: 
Phase 2 
Investigational Product: 
Selinexor 
Indication: 
Glioblastoma 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  02459  
USA 
 
 
From: Version 2.0 dated November 15, 2013 
To: Version 3.0 dated July 16, 2014 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 114 of 137 
Version 6.0 
Table A: Pre-Surgery Dosing Table 
Group 
No. Of 
patients 
1st 
dose 
2nd 
dose 
3rd dose 
Surgery 
1 
5 
Day 1 
Day 3 
2 hr prior to surgery 
(Day 8) 
Day 8 
2 
5 
Day 1 
Day 3 
12 hr prior to surgery 
(Day 7 or 8) 
Day 8 
3 
5 
Day 1 
Day 3 
24 hr prior to surgery 
(Day 8) 
Day 9 
4 
5 
Day 1 
Day 3 
48 hr prior to surgery 
(Day 8) 
Day 10 
• Updated the pre-specified dose/schedule modifications table for adverse events related to 
study drug from the dose of 50 mg/m2 twice weekly to once weekly (D1) in order to 
optimize specific anti-tumor activity and patient’s tolerability. (Modified sections: 7.3 
Table 3) 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 115 of 137 
Version 6.0 
16.9.5 Summary and Rationale for Changes to Version 1.0 Protocol KCP-330-004 
Karyopharm Therapeutics Inc. 
 
A Phase II, Two-Tier Study Evaluating the Efficacy and Safety of Selinexor 
(KPT-330) in Patients with Recurrent Glioblastoma after Failure of Radiation 
Therapy and Temozolomide 
Clinical Trial Protocol No 
Sponsor Protocol No. KCP-330-004 
Development Phase: 
Phase 2 
Investigational Product: 
Selinexor 
Indication: 
Glioblastoma 
Sponsor: 
Karyopharm Therapeutics Inc. 
Drug Discoverer: 
Karyopharm Therapeutics Inc. 
Sponsor Address: 
85 Wells Avenue 
Newton, MA  02459  
USA 
 
 
From: Version 1.0 dated September 17, 2013 
To: Version 2.0 dated November 15, 2013 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 117 of 137 
Version 6.0 
• Clarifying that Investigators are to report SAEs within 24 hours to the Sponsor, or 
designee, upon notification. 
Specific changes, by section, are displayed in the table in Boldface. [Note for changes not easily 
shown in a table, such as changes in the Schedule of Study Events, the original and revised table 
may be proved in separate pages as attachments that are referenced in the appropriate sections of 
the table.] 
Minor changes to correct typographical and other errors are not shown. A redline version of this 
document is available upon request. 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 123 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
•  Megesterol acetate 160-400 mg daily, 
0-3 days before the first dosing day of 
KPT-330  
OR 
• Dexamethasone 2-4 mg (or equivalent 
steroid) on days of dosing and the 
following day. Dexamethasone may be 
given prior to initiation of dosing or 
more frequently as needed 
AND 
•  Olanzapine 5.0 mg qhs or 2.5 mg bid, 
0-3 days before the first dosing day of 
KPT-330  
OR 
•  Mirtazapine 15 mg qd (qpm/phs), 0-3 
days before the first dosing day of KPT-
330  
If the patient is on steroids coming on 
the study, megesterol acetate should be 
added prophylactically to prevent 
anorexia. If an increased risk of adverse 
effects due to olanzapine is anticipated, 
olanzapine can be omitted. However, it is 
recommended that mirtazapine or other 
appetite stimulating serotonergic agent 
be used. Additional standard supportive 
care agents may be used as needed (prn). 
Supportive care may be tapered or 
discontinued in Cycle 2 or later in 
patients who tolerate Selinexor well in 
Cycle 1. 
 
treatment now required in this 
study.  
5.2.2 Screening 
Procedures 
(Ophthalmologic Exam) 
Full ophthalmologic exam: required at 
screening and of clinically indicated.  
Full ophthalmologic exam: required at 
screening and if clinically indicated 
during the treatment phase.  
Clarifies the investigator’s option 
to examine any patient as needed 
while the study is ongoing.  
Same Section 
(Prophylactic therapy)
 
 
[New Text] 
Initiated 0-3 days prior to first Selinexor 
dose (see section 5.2.1) 
 
Identifies the new requirement that 
all patients undergo Prophylactic 
therapy and its timing. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 124 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
 
6.2.1.1  Drug Name, 
Formulation and 
Storage 
[New Text] 
 
 
Tablets: Selinexor (KPT-330) for oral 
administration will be supplied in two (2) 
tablet strengths: 10 and 25 mg. Bottles of 
50 tablets per bottle will be supplied for 
each of the two strengths.  
 
Describes the tablets by strength 
dispensed. 
6.3 
Dose 
Modifications for 
Selinexor 
Re-escalation of the study drug is allowed as 
outlined in the sections that apply for the 
specific toxicity. If toxicity requires a treatment 
delay of more than 3 weeks the patient is taken 
off protocol treatment.  
 
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 
~12mg/m2 to ≥35mg/m2 orally twice weekly. 
At the present time, we cannot predict which 
patient's tumors will respond to lower doses, 
nor can tolerability be predicted. Therefore, in 
order to individualize and optimize therapeutic 
benefit with this oral SINE XPO1 antagonist, 
initiation of study therapy will be with a 
relatively high dose (35mg/m2 twice weekly by 
mouth) of Selinexor. Although this is a high 
dose, it is below the MTD of oral Selinexor, 
and we believe will maximize early disease 
control with good tolerability in the majority of 
patients. Flexible dose reductions and/or 
schedule modifications will be permitted. In 
patients with tolerability issues on Selinexor, it 
is recommended either: (1) reducing Selinexor 
dose by 30% or (2) reducing Selinexor dosing 
frequency to once weekly. In addition, if a 
patient is experiencing one or more Grade ≤2 
toxicities such as fatigue or anorexia, then 1-2 
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 3 
weeks the patient is taken off protocol 
treatment.  
At the present time, we cannot predict 
which patient's tumors will respond to 
lower doses, nor can tolerability be 
predicted. Therefore, in order to 
individualize and optimize therapeutic 
benefit with this oral SINE XPO1 
antagonist, initiation of study therapy will 
be with a relatively high dose (50mg/m2 
twice weekly by mouth) of Selinexor. 
Although this is a high dose, it is below the 
MTD of oral Selinexor, and we believe will 
maximize early disease control with good 
tolerability in the majority of patients. 
Therefore, in order to optimize specific 
anti-tumor activity and the patient’s 
tolerability, we will allow for dose and/or 
schedule modifications as described below 
(Table 5). Patients should also be treated 
aggressively with supportive care to 
reduce toxicities. 
 
 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 125 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
doses of Selinexor can be held, and then dosing 
resumed at the current dose. In this last 
iteration, dosing for e.g., 3 of every 4 weeks 
may be considered in some patients. In 
addition, given that 35mg/m2 is not the MTD of 
Selinexor (twice weekly 40mg/m2 and 50mg/m2 
are currently under investigation), we will 
allow patients with acceptable tolerability who, 
in the opinion of their treating oncologist, may 
benefit from a dose escalation in order to 
derive additional anti-tumor benefit, to 
increase their dose to 40mg/m2 or, as ongoing 
cohorts allow, to higher doses, twice weekly. In 
conclusion, the wide therapeutic range, lack of 
significant acute toxicity, reversibility of 
common adverse effects (anorexia, nausea, 
fatigue), and the oral dosing regimen of 
Selinexor allows for flexibility in treating 
patients with cancer, and as such, 
individualization of each patient's regimen is 
easily accomplished.  
6.3.1 Dose Adjustment 
Guidelines for Selinexor 
Related Toxicities 
(Table 4)  
[Formerly Table 3] 
[Significant New Text—See Table 4 
(Version 2)] 
This table has been heavily revised 
to reflect more specific dose 
adjustments, assessments, and 
timing of adjustments by adverse 
event class and AE Grade. Too 
extensive to present here. A line-
by-line tracked changes 
comparison of the table is 
available upon request. 
Same section, last 
paragraph 
If the patient tolerates a reduced dose for at 
least four weeks, patients dose may be  
escalated to the dose they received prior to the 
reduction after authorization from the medical 
monitor and Principal Investigator. 
[replaced by New Text] 
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 
This additional text was added in 
conjunction with the prophylactic 
therapy now required by this 
Amendment. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 126 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
supportive measures have been 
successful. 
6.3.2 Selinexor Dose 
Reduction in the Setting 
of Infection 
Patients with active uncontrolled infections 
should have Selinexor treatment withheld until 
the infection has clinically stabilized or 
resolved.  
After the infection has stabilized clinically, 
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 in 
consultation with the Medical Monitor, but the 
infection must be clinically resolved prior to 
restarting Selinexor. Prophylactic antibiotics 
are permitted concurrently with Selinexor 
treatment, but are not required.  
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 >170 patients treated as of 15 
October 2013.  
 
 
Clarifies details of reinitiation of 
study drug and describes the 
Sponsor’s current clinical 
experience with opportunistic 
infections.  
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. Patients 
should minimize the use of products containing 
acetaminophen, which can interfere with the 
metabolism of Selinexor. For combination 
painkillers containing acetaminophen it is 
recommended that single agent opiates or 
aspirin combinations (when clinically 
acceptable) be substituted. 
In vitro studies show that KPT-330 may 
have moderate CYP450 inhibition under 
some circumstances. Concomitant 
sensitive CYP3A4 substrates or CYP3A4 
substrates with a narrow therapeutic 
index should be used with caution as 
Selinexor could increase exposure to 
these substrates. It should be noted, 
however, that in >200 adult patients with 
advanced, relapsed/refractory 
hematologic cancers in ongoing Phase 1 
studies, no restrictions on concomitant 
medications with any CYP3A4 
substrates are required. In addition, 
there are no reports of drug-drug 
interactions in any of the >200 adult 
This text reflected the latest 
information available on CPY 
substrates and caution about using 
these agents in this study. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 127 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
[Replaced with new text] 
patients with cancers dosed with KPT-
330 as of 8 November 2013. 
6.4.2 Prohibited 
Medications  
Patients should minimize the use of products 
containing acetaminophen [new text]. For 
combination painkillers containing 
acetaminophen it is recommended that single 
agent opiates or aspirin combinations (when 
clinically acceptable) be substituted, 
particularly on the days of Selinexor dosing. 
[new text] 
Concurrent therapy with an approved or 
investigative anticancer therapeutic, other than 
glucocorticoids as specified herein, is not 
allowed.  
Inactivation of Selinexor by glutathione 
conjugation is a significant metabolic pathway 
in vitro and in vivo, including in humans. This 
process can be mediated in the absence of 
proteins, indicating that it is 
thermodynamically favorable.  
 
In vitro studies using human liver microsomes 
confirm in vivo findings that Selinexor 
undergoes minimal CYP450 metabolism. 
Therefore, administration of Selinexor with 
drugs which undergo substantial glutathione 
conjugation should be minimized or avoided. 
These drugs include acetaminophen 
(paracetamol) and ethyl alcohol. It should be 
noted that studies of Selinexor in combination 
with acetaminophen are to begin in late 2013 
and therefore that these recommendations are 
empirical.  
Patients should minimize the use of 
products containing acetaminophen on the 
days of Selinexor dosing. Acetaminophen 
should not be taken within 4 hours 
before or after Selinexor dosing. For 
combination painkillers containing 
acetaminophen it is recommended that 
single agent opiates or aspirin combinations 
(when clinically acceptable) be substituted, 
particularly on the days of Selinexor dosing 
within 4 hours before or after Selinexor 
dosing. 
 
Concomitant sensitive CYP3A4 
substrates or CYP3A4 substrates with a 
narrow therapeutic index should be used 
with caution as Selinexor could increase 
exposure to these substrates. It should be 
noted, however, that in >200 adult 
patients with advanced, 
relapsed/refractory hematologic cancers 
in ongoing Phase 1 studies, no 
restrictions on concomitant medications 
with any CYP3A4 substrates are 
required. In addition, there are no 
reports of drug-drug interactions in any 
of the >200 adult patients with cancers 
dosed with KPT-330 as of 8 November 
2013. 
Concurrent therapy with an approved or 
investigative anticancer therapeutic, 
other than glucocorticoids as specified 
herein, is not allowed.  
 
Inactivation of Selinexor by 
glucuoronidation is the most common 
This information is provided based 
on the most current clinical 
experience and to provide better 
guidance on dose timing if 
required.  


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 128 of 137 
Version 6.0 
Section 
Previous Wording 
New Wording 
Reason for Change 
metabolic pathway; glutathione 
conjugation is also significant metabolic 
pathway in vitro and in vivo, including 
in humans. 
 
In vitro studies using human liver 
microsomes confirm in vivo findings that 
Selinexor undergoes minimal CYP450 
metabolism. Therefore, administration of 
Selinexor with drugs which undergo 
substantial glutathione conjugation should 
be minimized or avoided. These drugs 
include acetaminophen (paracetamol) and 
ethyl alcohol.  
It should be noted that preliminary studies 
of Selinexor in combination with 
acetaminophen have shown no significant 
changes in adverse events relative to 
Selinexor alone, nor have there been any 
significant increases in liver function 
tests in these adult cancer patients pre-
dosed with 500-1000mg acetaminophen 
prior to dosing of Selinexor as of 8 
November 2013.  
6.5.2 Fatigue  
Patients with Selinexor associated fatigue 
should receive Selinexor no more than twice 
weekly unless the treating physician determines 
that the benefits outweigh the risks. If this does 
not reduce fatigue to an acceptable level, then 
a dose reduction of 30% should be instituted. 
Once-weekly dosing (at the higher dose) can 
also be considered in patients whose disease is 
highly responsive to Selinexor.[Text deleted] 
 
Patients with Selinexor associated fatigue 
should receive Selinexor no more than 
twice weekly unless the treating physician 
determines that the benefits outweigh the 
risks. If this does not reduce fatigue to an 
acceptable level, then a dose reduction of 
one level (see Table 3) should be 
instituted.  
This section was changed to be 
consistent with the dose reduction 
schedule outlined in Table 3 of this 
Amendment.  
6.5.5 Thrombocytopenia 
Physicians should consider the use of 
Intravenous immune globulin in patients with 
enlarged spleens and thrombocytopenia. 
Physicians should consider the use of 
Intravenous immune globulin in patients 
with enlarged spleens and 
thrombocytopenia. 
This section was changed to be 
consistent with the dose reduction 
in response to specific adverse 
events displayed in Table 4. These 


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Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 136 of 137 
Version 6.0 
17 REFERENCES 
1 
Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008;359:492-507. 
2 
Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus Concomitant and Adjuvant 
Temozolomide for Glioblastoma. N Engl J Med 2005;352:987-96. 
3 
Mirimanoff RO, Gorlia T, Mason W et al. Radiotherapy and Temozolomide for Newly Diagnosed 
Glioblastoma: Recursive Partitioning Analysis of the EORTC 26981/22981 – NCIC CE3 Phase III 
Randomized Trial. J Clin Oncol 2006;24:1563-2569. 
4 
Hart MG, Garside R, Rogers G, Stein K, Grant R. Temozolomide for high grade glioma. Cochrane 
Database Syst Rev 2013;4:CD007415. 
5 
Eftimov TN, Ivanov ID, Petkov AP, Nakov E. Management of recurrent high-grade gliomas. Cancer 
Therapy 2007;5:243-252. 
6 
Happold C, Roth P, Wick W, Steinbach JP, Linnebank M, Weller M, Eisele G. ACNU-based 
chemotherapy for recurrent glioma in the temozolomide era. J Neurooncol 2009;92(1):45-8. 
7 
Westphal M, Hilt DC, Bortey E, Delavault P et al. A phase 3 trial of local chemotherapy with 
biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. 
Neuro Oncology 2002;5:79-88. 
8 
Brandes AA, Tosoni A, Basso U, Reni M et al. Second-Line Chemotherapy With Irinotecan Plus 
Carmustine in Glioblastoma Recurrent or Progressive After First-Line Temozolomide Chemotherapy: 
A Phase II Study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). J Clin Oncol 
2004;22:4779-4786. 
9 
Kappelle AC, Postma TJ, Taphoorn MJB et al. PCV chemotherapy for recurrent glioblastoma 
multiforme. Neurology 2001;56:118-120. 
10 Perry JR, Bélanger K, Mason WP, Fulton D et al. Phase II trial of Continuous Dose-Intense 
Temozolomide in Recurrent Malignant Glioma: RESCUE Study. J Clin Oncol 2010;29:2051-2057. 
11 Omuro A, Chan TA, Abrey LE et al. Phase II trial of continuous low-dose temozolomide for patients 
with recurrent malignant glioma. Neuro Oncol 2013;15(2): 242-50. 
12 Gil-Gil MJ, Mesia C, Rey M, Bruna J. Bevacizumab for the Treatment of Glioblastoma. Clin Med 
Insights Oncol 2013;7:123-135. 
13 Bokstein F, Shpigel S, Blumenthal ST. Treatment with bevacizumab and irinotecan for recurrent high-
grade glial tumors. Cancer 2008;112:2267-2273. 
14 Vredenburgh JJ, Desjardins A, Herndon JE et al. Bevacizumab plus irinotecan in recurrent 
glioblastoma multiforme. J Clin Oncol 2007;25:4722-4729. 
15 Poulsen HS, Grunnet K, Sorensen M et al. Bevacizumab plus irinotecan in the treatment of patient 
with progressive recurrent malignant brain tumors. Acta Oncol 2009;48:52-58. 
16 Batchelor TT, Sorensen AG, di Tomaso E et al. AZD2171, a pan-VEGF receptor tyrosine kinase 
inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 
2007;11:83-95. 
17 Kesselheim JC, Norden AD, Wen PY, Joffe S. Discontinuing bevacizumab in patients with 
glioblastoma: an ethical analysis. Oncologist 2011;16(10):1435-9. 
18 Chinot OL. Bevacizumab-based therapy in relapsed glioblastoma: rationale and clinical experience to 
date. Expert Rev Anticancer Ther 2012;12(11):1413-27. 
19 Wen PY, Lee EQ, Reardon DA, Ligon KL, Alfred Yung WK. Current clinical development of PI3K 
pathway inhibitors in glioblastoma. Neuro Oncol 2012;14(7):819-29. 
20 Lassen U, Sorensen M, Gaziel TB et al. Phase II study of bevacizumab and temsirolimus combination 
therapy for recurrent glioblastoma multiforme. Anticancer Res 2013;33(4):1657-60. 
21 Van den Bent MJ, Brandes AA, Rampling R et al. Randomized Phase II Trial of Erlotinib Versus 
Temozolomide or Carmustine in Recurrent Glioblastoma: EORTC Brain Tumor Group Study 26034. 
J Clin Oncol 2009;27:1268-1274. 


Selinexor (KPT-330) 
Karyopharm Therapeutics Inc. 
Clinical Study Protocol: KCP-330-004 
13 November 2015 
 
Confidential 
Page 137 of 137 
Version 6.0 
22 Bode U, Massimino M, Bach F et al. Nimotuzumab treatment of malignant gliomas. Expert Opin Biol 
Ther 2012;12(12):1649-59. 
23 Muhic A, Poulsen HS, Sorensen M et al. Phase II open-label study of nintedanib in patients with 
recurrent glioblastoma multiforme. J Neurooncol 2013;111(2):205-12. 
24 Kreisl TN, McNeill KA, Sul J et al. A phase I/II trial of vandetanib for patients with recurrent 
malignant glioma. Neuro Oncol 2012;14(12):1519-26. 
25 Reardon DA, Dresemann G, Taillibert S et al. Multicentre phase II studies evaluating imatinib plus 
hydroxyurea in patients with progressive glioblastoma. Br J Cancer 2009;101(12):1995-2004. 
26 Hu J, Wen PY, Abrey LE et al. A phase II trial of oral gimatecan for recurrent glioblastoma. J 
Neurooncol 2013;111(3):347-53. 
27 Grossmann KF, Colman H, Akerley WA et al. Phase I trial of verubulin (MPC-6827) plus carboplatin 
in patients with relapsed glioblastoma multiforme. J Neurooncol 2012;110(2):257-64. 
28 Reardon DA, Groves MD, Wen PY et al. A phase I/II trial of pazopanib in combination with lapatinib 
in adult patients with relapsed malignant glioma. Clin Cancer Res 2013;19(4):900-8. 
29 Shen A, Wang Y, Zhao Y, Zou L, Sun L, Cheng C. Expression of CRM1 in human gliomas and its 
significance in p27 expression and clinical prognosis. Neurosurgery 2009;65(1): 153-9. 
30 Wang D, He F, Zhang L et al. The role of p27 (Kip1) phosphorylation at serine 10 in the migration of 
malignant glioma cells in vitro. Neoplasma 2011;58(1):65-73. 
31 National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®): Fatigue. Available at http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. 
32 National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®): Palliative Care, version 1.2014. Fort Washington, NY. April 2014. Available at: 
http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/fa
cts.pdf. 
33 National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®): Antiemesis, version 2.2014. Fort Washington, NY. April 2014. Available at: 
http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. 
34 Benson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer 
treatment-induced diarrhea. J Clin Onc 2004; 22:2918. 
35 Green AL, Ramkissoon SH, McCauley D, et al. Preclinical antitumor efficacy of selective exportin 1 
inhibitors in glioblastoma. Neuro-Oncology 2014;0:1–11, doi:10.1093/neuonc/nou303. 
36 Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials 
1989;10:1-10. 
37 Wen PY, Macdonald DR, Reardon DA et al., Updated Response Assessment Criteria for High-Grade 
Gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. J Clin Oncol 
2010:28(11);1963-72. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631110/. 

SAP_001.pdf: 
Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
1
STATISTICAL ANALYSIS PLAN 
 
KCP-330-004 (KING) 
 
A PHASE 2 STUDY EVALUATING THE EFFICACY AND SAFETY OF 
SELINEXOR (KPT-330) IN PATIENTS WITH RECURRENT GLIOMAS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This statistical analysis plan contains confidential information and is the proprietary property 
of Karyopharm Therapeutics, Inc. It cannot be copied or made available for review by an 
unauthorized person or firm without the prior written authorization of Karyopharm 
Therapeutics, Inc. 
 
 
 
 
 
Protocol Version: 
6.0 (13 November 2015) 
 
SAP Version: 
2.0 
 
Date: 
March 05, 2020 


Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
2 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
 
The undersigned has developed this statistical analysis plan (SAP): 
 
Name/Title 
Signature/Date 
 
 
 
The undersigned have reviewed this SAP and approve it in its entirety: 
 
Name/Title 
Signature/Date 
 
 
 
 
PPD
PPD


Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
3 
DOCUMENT HISTORY 
 
Version 
Date 
Author(s) 
Brief Summary of Changes 
2.0 
March 05, 2020 
SAP v2.0 differs from SAP v1.0 since SAP 
v1.0 was written based on Protocol v4.0. 
This version of SAP is based on Protocol 
v6.0 
1.0 
September 09, 2014 
 
SAP v1.0 was written based on Protocol 
v4.0 of August 12, 2014 
 
 
 
PPD
PPD


Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
4 
TABLE OF CONTENTS 
Section 
                   Page 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ...................................................... 10 
1.1 
STUDY DESIGN................................................................................................. 10 
1.2 
OBJECTIVES ...................................................................................................... 11 
1.2.1 
Primary Objective ................................................................................. 11 
1.2.2 
Secondary Objectives ........................................................................... 11 
1.2.3 
Exploratory Objectives ......................................................................... 11 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................ 11 
1.4 
INTERIM ANALYSIS ........................................................................................ 12 
1.5 
CHANGES IN THE STATISTICAL ANALYSIS PLAN .................................. 12 
2 
GENERAL STATISTICAL METHODS AND DATA HANDLING ....................... 13 
2.1 
GENERAL ANALYSIS METHODS .................................................................. 13 
2.2 
OBSERVATION PERIOD .................................................................................. 13 
2.3 
MISSING DATA HANDLING IN DATA PRESENTATION ........................... 13 
2.3.1 
Handling of Computation of Treatment Duration if Study 
End of Treatment Date is Missing ........................................................ 14 
2.3.2 
Handling of Missing/partial Dates for Adverse Events or 
Concomitant Medications ..................................................................... 14 
2.3.3 
Handling of Missing Assessment of Relationship of AEs to 
Study Treatment .................................................................................... 14 
2.4 
STUDY DAY CALCULATION ......................................................................... 14 
2.5 
BASELINE MEASUREMENT ........................................................................... 14 
2.6 
VISIT WINDOWS............................................................................................... 14 
2.7 
SUBGROUPS ...................................................................................................... 15 
2.8 
POOLING OF CENTERS FOR STATISTICAL ANALYSES .......................... 16 
2.9 
COMPUTING AND CODING STANDARDS................................................... 16 
3 
PATIENT INFORMATION ......................................................................................... 17 
3.1 
DISPOSITION OF PATIENTS AND ANALYSIS POPULATIONS ................ 17 
3.1.1 
Modified Intent-to-Treat (mITT) Population ........................................ 17 
3.1.2 
Per-protocol (PP) Population ................................................................ 17 
3.1.3 
 
3.1.4 
Safety Population .................................................................................. 18 
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Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
5
Section 
                   Page 
3.2 
DEMOGRAPHICS, MEDICAL HISTORY AND BASELINE 
CHARACTERISTICS ......................................................................................... 18 
3.2.1 
Demographic Data ................................................................................ 18 
3.2.2 
Prior Treatment: .................................................................................... 18 
3.2.3 
Medical History - Conditions and Procedures ...................................... 18 
3.2.4 
Disease History ..................................................................................... 18 
3.2.5 
Baseline Characteristics ........................................................................ 19 
3.3 
PRIOR AND CONCOMITANT MEDICATIONS AND 
PROCEDURES.................................................................................................... 19 
3.4 
EXTENT OF STUDY TREATMENT EXPOSURE AND 
COMPLIANCE.................................................................................................... 19 
3.4.1 
Extent of Study Treatment Exposure .................................................... 19 
3.4.2 
Compliance ........................................................................................... 20 
4 
EFFICACY ..................................................................................................................... 21 
4.1 
PRIMARY EFFICACY ENDPOINTS ................................................................ 21 
4.1.1 
Rate of 6-Month Progression-Free Survival (6mPFS) ......................... 21 
4.2 
SECONDARY EFFICACY ENDPOINTS ......................................................... 21 
4.2.1 
Objective Response Rate (ORR) .......................................................... 21 
4.2.2 
Overall Survival (OS) ........................................................................... 21 
4.2.3 
Progression-free Survival (PFS) ........................................................... 21 
4.3 
EXPLORATORY ANALYSIS ........................................................................... 23 
5 
SAFETY .......................................................................................................................... 24 
5.1 
ADVERSE EVENTS ........................................................................................... 24 
5.1.1 
Definitions ............................................................................................ 24 
5.1.2 
Analysis Methods ................................................................................. 24 
5.1.3 
Analysis of Treatment-Emergent Adverse Event (TEAE) ................... 25 
5.1.4 
Analysis of Serious Adverse Event (SAE) ........................................... 26 
5.2 
DEATH ................................................................................................................ 26 
5.3 
LABORATORY SAFETY VARIABLES ........................................................... 26 
5.4 
VITAL SIGNS AND PHYSICAL EXAMINATION VARIABLES .................. 26 
5.5 
NEUROLOGICAL EXAMINATIONS............................................................... 27 
5.6 
ELECTROCARDIOGRAM (ECG)..................................................................... 27 
5.7 
KARNOFSKY PERFORMANCE STATUS ...................................................... 27 


Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
6
Section 
                   Page 
6 
REFERENCES ............................................................................................................... 28 
 
 
 


Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
7
TABLES INCLUDED IN THE TEXT 
Table 4-1  
PFS outcome and censoring definition ............................................................................ 22 
 
 
  


Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation  
Definition 
6mPFS 
AE 
6-Month Progression-Free Survival 
Adverse Event 
AG 
ATC 
Anaplastic Gliomas 
Anatomical Therapeutic Class 
BMI 
BSA 
Body Mass Index 
Body Surface Area 
C1D1 
Cycle 1 Day 1 
CI 
Confidence Interval 
CTCAE 
CR 
Common Terminology Criteria for Adverse Events 
Complete Response 
DBP 
Diastolic Blood Pressure  
ECG 
eCRF 
Electrocardiogram 
Electronic Case Report Form 
EoT 
GBM 
mITT 
End-of-Treatment 
Glioblastoma 
Modified Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
 
 
PFS 
Progression-Free Survival 
 
PP 
 
Per-Protocol 
PR 
Partial Response 
PT 
Preferred Term 
RANO 
SAE 
Response Assessment in Neuro-Oncology Criteria 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
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Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
9
Abbreviation  
Definition 
SAS 
SBP 
SD 
Statistical Analysis System 
Systolic Blood Pressure 
Stable Disease 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TRAE 
treatment-emergent treatment-related adverse event 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
 
 
 
 
 
 


Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
10 
1 
OVERVIEW AND INVESTIGATIONAL PLAN 
1.1 
STUDY DESIGN 
KCP-330-004 (KING) is an open-label, multicenter, Phase 2 study to evaluate the efficacy and 
safety of oral selinexor in patients with recurrent gliomas. Patients were enrolled into either an 
 
Medical Arm (Arm B, Arm C and Arm D) for patients who are not eligible for surgery. 
Initially, the study included 2 arms:
 
medical arm (Arm B) for patients who are not 
eligible for surgery. The starting dose for Arms 
 B was 50 mg/m2 twice weekly, with one 
cycle defined as 28 days or 8 doses. 
 
 
 
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potentially improve tolerability. Two arms (Arms C and D) were added to the Medical Arm in 
Protocol Version 4.0. Patients in the primary population enrolled under Protocol Version 4.0 or 
above were randomized to Arm C and Arm D (approximately 30 patients per arm). 
 
 
Abbreviations: AG: anaplastic glioma, GBM: glioblastoma; PD: progressive disease 
* If the dose for a patient continuing in Arm 
 B is < 35 mg/m2, the Investigator should contact the medical monitor to 
determine the starting dose for flat dosing Refer to Table below for dose modifications: 
 
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Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
11 
 
Patients received treatment until occurrence of PD, death, consent withdrawal, loss to follow-up, 
or toxicity that could not be managed by standard care, whichever occurred first. Patients were 
also followed for survival status. End of study is defined as when the last patient in the study 
died, completed 12 months of study follow-up, was lost to follow-up, or withdrew consent, 
whichever occurred first. 
Enrollment in Arms C and D is based on Simon’s two-stage design. Formal statistical analyses 
for efficacy will pertain only to the medical arms in the primary population (Arms B, C, and D).  
 
1.2 
OBJECTIVES 
1.2.1 
Primary Objective 
x To determine the efficacy of selinexor in adults with recurrent GBM as determined by 
the 6-month progression-free survival (6mPFS) rate (Arms B, C and D). 
1.2.2 
Secondary Objectives 
Secondary objectives of the study (Arms B, C and D) are: 
x To determine the efficacy of selinexor in adults with recurrent GBM as determined by 
overall response rate (ORR) according to the Response Assessment in Neuro-Oncology 
(RANO) criteria. 
x To determine the efficacy of selinexor in adults with recurrent GBM as determined by 
median overall survival (OS). 
x To determine the efficacy of selinexor in adults with recurrent GBM as determined by 
median progression-free survival (PFS). 
x To evaluate safety and tolerability of selinexor. 
1.2.3 
Exploratory Objectives 
1.3 
DETERMINATION OF SAMPLE SIZE 
x Arm B (50 mg/m2 twice weekly) 
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Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
12 
 
x Flat Dosing Arms (Arm C and Arm D)  
 
1.4 
INTERIM ANALYSIS 
For all medical arms (Arms B, C, D), interim analyses were planned to be performed at the end 
of Stage 1 according to the Simon's two-stage design specified in Section 8.5 in the protocol. 
Interim analysis of Arm B did not show sufficient efficacy, therefore enrollment in Arm B was 
stopped to explore alternative dosing in Arm C and Arm D. Arm C was also stopped due to 
safety and tolerability reasons before its planned interim analysis. Arm D’s interim analysis 
showed sufficient efficacy evidence so that Arm D continued to enroll up to 30 patients.     
    
1.5 
CHANGES IN THE STATISTICAL ANALYSIS PLAN 
There are substantial changes between protocol version 3.0 and current protocol version 6.0. 
Thus, this new version of SAP is rewritten based on version 6.0 of study protocol, which is the 
latest version of study protocol.  
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Study KCP-330-004 (KING)                             
       
Karyopharm Therapeutics, Inc 
Statistical Analysis Plan 
 
Version 2.0
 
 
 
13 
2 
GENERAL STATISTICAL METHODS AND DATA HANDLING 
This statistical analysis plan (SAP) outlines the methods to be used in the analysis of clinical 
data to answer the study objectives. Populations for analysis, data handling rules, and statistical 
methods are provided. This SAP does not include endpoints and methods to be used in the 
analysis of 
, which will be included in a separate plan. 
 
2.1 
GENERAL ANALYSIS METHODS 
All summary statistics will be computed and displayed among the corresponding analysis 
population, and by each assessment time point whenever applicable. Tabulations will be 
produced for appropriate demographic, baseline, efficacy and safety endpoints. Summary 
statistics for continuous variables will in general include the number of patients (n), median, 
mean, standard deviation, minimum, and maximum. 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 
(CI), unless otherwise stated. For time-to-event variables, the Kaplan-Meier method will be used 
for descriptive summaries using 25th, 50th (median), and 75th percentiles with associated 2-sided 
95% CIs, as well as percentage of censored observations. 
 
2.2 
OBSERVATION PERIOD 
The observation period will be divided by the following:  
x The pre-treatment period is defined as the time from the signed informed consent date up 
to the time before the first dose of study treatment.   
x The treatment period is defined as the time from the first dose of study treatment up to 
the date of last study treatment + 30 days, or the day before initiation of a new anti-
neoplastic treatment, whichever comes first, inclusive.  
x The post-treatment period is defined as the time beyond the treatment period.  
 
2.3 
MISSING DATA HANDLING IN DATA PRESENTATION 
In general, missing baselines will not be imputed. The following approaches are default methods 
for missing data handling in summary tables. 
x Categorical data at baseline will be summarized using counts (n) and percentages (%). 
Denominator will be the total number of people in the corresponding treatment arm, 
based on the population specified for the summary, unless otherwise specified. Missing 
data may be presented as a separate category. 
x Continuous data will be summarized based on observed data only. 
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2.3.1 
Handling of Computation of Treatment Duration if Study End of Treatment 
Date is Missing 
For the calculation of treatment duration, the date of the last dose of study treatment is equal to 
the date of last study treatment dosing reported on the electronic case report form (eCRF) dosing 
page. If all the dosing dates are missing, then the duration is missing. 
2.3.2 
Handling of Missing/partial Dates for Adverse Events or Concomitant 
Medications 
In general, the imputation should be conservative such that onset dates should be imputed to be 
as early as possible and resolution dates will be imputed to be as late as possible. However, for 
categorization purpose, if the partial AE onset date information does not indicate whether the 
AE started prior to treatment or during the treatment period or after the treatment period, the AE 
will be classified as treatment-emergent. 
The data imputations are only for categorization purpose or calculation of AE duration, and will 
not be used in listings.  
Refer to the Karyopharm Biostatistics and Statistical Programming Rule Book v1.0 for details 
on imputation methods. 
2.3.3 
Handling of Missing Assessment of Relationship of AEs to Study Treatment 
If the assessment of the relationship to study treatment is missing, then the relationship to study 
treatment is considered as related. 
 
2.4 
STUDY DAY CALCULATION 
Study Day 1 is the date of first study treatment. The day before Day 1 is considered Day -1. 
There is no Day 0. Study day for a given assessment is defined as  
x the assessment date – the date of first study treatment + 1 if the assessment date is on or 
after Day 1, or  
x the assessment date – the date of first study treatment if the assessment date is before 
Day 1. 
 
2.5 
BASELINE MEASUREMENT 
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug for Medical Arms (Arms B, C and D), or 
 
.  
 
2.6 
VISIT WINDOWS 
For safety data that are summarized/plotted by time points, non-missing assessments from all 
scheduled and unscheduled visits will be mapped to an appropriate analysis visit using 
a windowing scheme.  
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Analysis visit windows are defined in the table below. If there are 2 or more assessments 
mapped to the same analysis visit for a patient, the assessment that is closest to the target visit 
day will be used for analysis. If there are 2 or more assessments mapped to the same analysis 
visit with the same distance from the target visit day, then select the latest one for the analysis.  
Visit Windows for Hematology (CBC), Limited Serum Chemistry and Vital Signs for 
Patients in Treatment  
 
Analysis Visit Name  
Target Visit Day  
Study Day Range in Window  
Baseline (C1)  
Day 1  
Prior to or on Day 1  
Day 8  
Day 8  
Day 2 to 11  
Day 15  
Day 15  
Day 12 to 18  
Day 22  
Day 22  
Day 19 to 25  
Day 29 (C2)  
Day 29  
Day 26 to 32  
Day 36  
Day 36  
Day 33 to 39  
Day 43  
Day 43  
Day 40 to 46  
Day 50  
Day 50  
Day 47 to 53  
Day 57 (C3)  
Day 57  
Day 54 to 64  
Day 71  
Day 71  
Day 65 to 78  
Day 85 (C4)  
Day 85  
Day 79 to 92  
Day 99  
Day 99  
Day 93 to 106  
Day 113 (C5)  
Day 113  
Day 107 to 120  
Day 127  
Day 127  
Day 121 to 134  
 Day 141 (C6)  
Day 141  
Day 135 to 155  
Day 169 (C7)  
Day 169  
Day 156 to 183  
…  
  
  
(every 28 days)  
 
 
NOTE: Day 1 is the start date of treatment period. The visit window for each Target Visit 
Date is listed in the 3rd column “Study Day Range in Window”. Analysis visit and visit 
window may change for certain parameters depending on the data availability.  
 
 
 
2.7 
SUBGROUPS 
Subgroup analyses on selected efficacy endpoints will be conducted by: 


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• Age groups 
• Baseline Karnofsky performance status scores 
• Number of lines of prior systematic therapy (1 vs. >1) 
 
2.8 
POOLING OF CENTERS FOR STATISTICAL ANALYSES 
Patient data from all study centers will be combined for analysis.  
 
2.9 
COMPUTING AND CODING STANDARDS 
Activities will be performed using the following tools: 
Table, listing, and figure production 
SAS Version 9.4 or higher 
Coding 
 
AEs 
MedDRA Version 22.0 or higher 
Medical Histories 
MedDRA Version 22.0 or higher 
Concomitant Procedures 
MedDRA Version 22.0 or higher 
Prior and Concomitant Medications 
WHO DDE B3 Version Sep2018 
Prior and Post Treatment Antineoplastic Therapies WHO DDE B3 Version Sep2018 
Grading 
 
AEs 
CTCAE Version 4.03 
Labs 
CTCAE Version 4.03 
 
 


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3 
PATIENT INFORMATION 
3.1 
DISPOSITION OF PATIENTS AND ANALYSIS POPULATIONS 
Patient disposition will be summarized in each of the following categories: 
x Patients who received at least one dose of study treatment (partial or complete) 
x End of treatment:  
o Patients still on treatment 
o Patients who discontinued treatment and primary reason for treatment 
discontinuation 
x Survival follow-up status 
o Patients in survival follow-up 
o Patients who are lost to survival follow-up 
x End of study:  
o Patients who complete or withdrew from study and primary reason for study 
discontinuation  
The number of patients in each analysis population will be presented.  
3.1.1 
Modified Intent-to-Treat (mITT) Population  
The modified intent-to-treat (mITT) population will consist of all enrolled patients in Arms B, C 
and D who have received at least one dose of study medication and have at least one post-
baseline efficacy follow-up assessment, unless the patient discontinued treatment prior to the 
first post-baseline assessment due to death, toxicity, or disease progression. This population will 
be used for primary analyses of efficacy.  
3.1.2 
Per-protocol (PP) Population 
The per-protocol population (PP) will consist of all Arms B, C and D patients who have been 
administered at least 2 months of study drug treatment, who are compliant with study 
assessments and have received at least 80% of their prescribed study medication, and who have 
no major protocol violations that would compromise the assessment of efficacy. Major 
violations will be determined independently of knowledge of response to therapy. This 
population will be used for supportive inferences concerning efficacy, however, if there are 
major differences between the results in this population and those obtained in the mITT 
population, this will be taken into consideration in the decision to continue to later phase 
studies, or in the design of further studies.  
3.1.3 
 
 
  
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3.1.4 
Safety Population 
The safety population will consist of all patients from Arms 
 B, C, and D who have received 
any amount of study medication. Patients in the safety population will be analyzed by each Arm. 
 
3.2 
DEMOGRAPHICS, MEDICAL HISTORY AND BASELINE 
CHARACTERISTICS 
Demographics, medical history and baseline characteristics will generally be summarized 
among mITT and safety populations, unless otherwise specified.  
3.2.1 
Demographic Data 
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 category. The categories for race will 
be those recorded in the database. For age at time of consent, the mean, median, minimum, 
maximum, and standard deviation will be provided for each group and the total sample. 
3.2.2 
Prior Treatment  
There are 3 types of prior treatments for GBM: radiation therapy, antineoplastic therapy and 
surgery.  Number and percentage of prior radiation therapy, prior antineoplastic therapy, and 
prior surgery will be summarized. 
3.2.3 
Medical History - Conditions and Procedures 
Medical history other than GBM will be summarized by system organ class (SOC) and 
preferred term (PT) using the number and percentage of patients who have at least one 
occurrence of a SOC and PT. The summary will be sorted by alphabetic order in SOC, and 
further by decreasing frequency of PT within each SOC.  
A separate summary will be provided for ongoing medical history conditions.  
3.2.4 
Disease History 
The following summary statistics will be summarized using descriptive statistics:  
x Number and percentage of initial diagnosis 
x Stage at initial diagnosis 
x Time since initial diagnosis to first recurrence/relapse 
x Time since initial diagnosis to most recent recurrence/relapse 
x Stage at most recent recurrence/relapse 
x Time since initial diagnosis to informed consent 
x Stage at study entry 
 
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• Time since most recent recurrent/relapse to informed consent  
3.2.5 
Baseline Characteristics  
Summary statistics will be presented separately in each treatment arm for the following 
variables: 
• Baseline height (cm), weight (kg), body surface area (m2), and BMI (kg/m2) 
• Baseline Karnofsky performance status 
• Baseline creatinine clearance (mL/min) (summarized as a continuous variable and as a 
categorical variable, with cutoff of < 30, 30 to < 60 and ≥ 60) 
 
3.3 
PRIOR AND CONCOMITANT MEDICATIONS AND 
PROCEDURES 
Prior medications are any treatments received by the patient prior to the first dose of study 
treatment. Prior medications can be discontinued before first dose of study treatment or can be 
ongoing during treatment period. Concomitant medications are any treatments received by the 
patient concomitantly with study treatment, from first dose of study treatment to last dose of 
study treatment + 30 days. Note that a medication can be classified as both a prior medication 
and a concomitant medication. All medications will be coded using the World Health 
Organization Drug Dictionary Enhanced (WHO DDE). 
Concomitant medication will generally be summarized among mITT and safety populations, 
unless otherwise specified. Concomitant medications will be summarized according to the 
WHO DDE by the ATC level 2 (therapeutic level), level 4 (generic level) and preferred name. A 
patient taking the same drug multiple times will only be counted once. 
Concomitant medications will be tabulated by arm and overall, where any medications that did 
not end prior to first dose will be included. If an end date is missing or the medication is 
ongoing, the medication will be included.  
The use of prior and concomitant medications and procedures may also be provided in a data 
listing. 
Please refer to Section 2.3 for details on data handling rules related to computation, dates, 
imputation for missing dates. 
 
3.4 
EXTENT OF STUDY TREATMENT EXPOSURE AND 
COMPLIANCE 
Extent of exposure and compliance will be summarized among the safety population. 
3.4.1 
Extent of Study Treatment Exposure 
The extent of exposure for the study treatment will be assessed using the following variables: 
• Duration of study treatment exposure (summarized as a continuous variable and as a 
categorical variable)  


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• Total dose received (summarized as a continuous variable)  
• Average dose received per week (summarized as a continuous variable)    
• Occurrence of dose reduction   
• Occurrence of dose interruption  
Duration of study treatment exposure is defined as the date of last study treatment - date of first 
study treatment + 1. 
Average dose received per week is defined as total dose received divided by duration of 
exposure, presented in mg/week. 
Duration of study drug exposure for each patient will be provided in a data listing and dosing 
information for each patient may also be provided in a data listing.  
3.4.2 
Compliance 
Study treatment compliance will be summarized descriptively as a quantitative variable, 
calculated as  
number of actual study treatment doses taken
number of  study treatment doses scheduled × 100 
A study treatment dose is considered scheduled if selinexor is scheduled. The number and 
percentage of patients with study treatment compliance ≥ 80% will be provided. Note that the 
number of scheduled study treatment doses does not include doses missed due to treatment 
interruption or other reasons not related to patient choice. Patients with study treatment 
compliance < 80% will be excluded from the PP population. 


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4 EFFICACY 
The efficacy analyses will be conducted by arms using the mITT population, unless otherwise 
specified. Efficacy analyses using the PP population will be considered as supportive.  
 
4.1 
PRIMARY EFFICACY ENDPOINTS 
4.1.1 
Rate of 6-Month Progression-Free Survival (6mPFS) 
The analysis of 6mPFS will be performed by calculating the estimated survival probability of 
KDYLQJ3)6PRQWKVEDVHGRQ.DSODQ-Meier method, where PFS will be calculated from the 
date of start of study treatment to the date of progression based on RANO criteria, or date of 
death should progression not have occurred. To accommodate potential changes in individual 
patient’s visit schedules, a window of ±14 days will be allowed around the 6-month visit for the 
primary analysis of rate of 6-month PFS. This window will be applied to the calculation of the 
estimate of 6mPFS; actual times of events (progression or death) will be used for the Kaplan-
Meier statistical summary of PFS.  
The primary analysis was planned to be performed when all patients have died, completed 6 
months of study treatment, have withdrawn, or have been lost to follow-up. A preliminary 
efficacy analysis was performed; however, the primary analysis is now planned for after 
database lock. A nominal two-sided 95% CI will also be calculated. The 6mPFS results will be 
presented for Arm B, C and D separately.  
A sensitivity analysis of the primary endpoint of 6mPFS will be performed to assess the 
potential influence of causality of deaths on study, where deaths due to causes that are clearly 
unrelated to the disease or study drug would not be considered as a PFS event and instead would 
be censored on the last response assessment before a censoring event.   
  
 
4.2 
SECONDARY EFFICACY ENDPOINTS 
4.2.1 
Objective Response Rate (ORR) 
ORR is defined as either complete response (CR) or partial response (PR) using the RANO 
criteria, calculated as a proportion and including a 95% exact CI. The ORR for each Arm will be 
presented separately.  
4.2.2 
Overall Survival (OS) 
OS will be calculated from the date of start of study treatment to the date of death. Patients who 
are still alive prior to the data cutoff for final efficacy analysis, or who dropout prior to study 
end, will be censored on the day they were last known to be alive. The analysis of OS will be 
based on the Kaplan-Meier method for estimation of summary statistics including 50th 
percentiles (median) and associated 95% CIs. 
4.2.3 
Progression-free Survival (PFS) 
PFS will be calculated from the date of start of study treatment to the date of progression based 
on RANO criteria, or date of death should progression not have occurred. The analysis of 
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median PFS will be similar to that of OS, using the Kaplan-Meier method; as noted above, 
actual event time will be used in this analysis. 
Duration is calculated as end date – treatment start date +1. For instance, if a PFS event occurs, 
then PFS time (in days) is defined as event date – date of treatment +1. If a censoring event 
occurs, then PFS time is defined as the censoring date – date of treatment +1. 
Please refer to Table 4-1 for details on PFS outcome status (PFS event vs. censored) and 
censoring definitions.  
Table.  4-1 
PFS outcome and censoring definition 
Situation 
Date of event or censoring 
Outcome 
No adequate post-baseline disease status 
assessment unless death occurs prior to 
first post-baseline assessment or 
withdrawal of informed consent 
Start of Study Treatment 
Censored 
Death before PD without a gap of 2 or 
more consecutively missed scheduled 
disease status assessments before death 
Date of Death 
PFS event 
PD without a gap of 2 or more 
consecutively missed scheduled disease 
status assessment before progression 
Date of PD 
PFS event 
 
 
No PD or death on or before  
a. database cut,  
b. withdrawal of informed consent, 
c. lost to follow-up,  
d. one day before start of new GBM 
treatment,  
whichever occurs first  
Date of last adequate disease 
assessment prior to the earliest 
occurrence of the events (a. – e.) 
listed in the left column 
Censored 
 
 
 
 
 
 
No PD or death before a gap of 2 or 
more consecutively missed scheduled 
disease status assessment  
Date of last adequate disease 
assessment prior to the gap 
Censored 
 


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4.3 
EXPLORATORY ANALYSIS 
 
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5 
SAFETY 
Safety analyses will be conducted using the Safety Population by arm.  
 
5.1 
ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence in a patient receiving a pharmaceutical 
product regardless of a causal relationship with this treatment. An AE can therefore be any 
unfavorable sign and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporarily associated with the use of a study treatment, whether related to the study 
treatment. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as any AE with onset beginning at the day of 
first administration of study drug, throughout the treatment period until 30 days after the last 
dose of study drug, or the day before the initiation of a new anti-neoplastic treatment, whichever 
occurs first, inclusive. Any event that was present at baseline but worsened in intensity or was 
subsequently considered drug-related by the Investigator through the end of the study will also 
be considered treatment-emergent. 
All AEs (including serious adverse events [SAEs]) will be coded to a Preferred Term (PT) and 
associated primary System Organ Class (SOC) using the MedDRA. 
The severity of all AEs will be graded according to the NCI CTCAE v4.03 Grading Scale. An 
AE with a CTCAE grade of 3 or higher is considered a severe AE. The severity of the AE is 
different from the seriousness of the AE.  
5.1.1 
Definitions 
• Treatment-emergent adverse event (TEAE) is any event that was not present prior to the 
initiation of study treatment or any event already present that worsens in either intensity 
or frequency following exposure to study treatment, from the first dose of study 
treatment to 30 days after the last dose of study treatment or the day before initiation of a 
new anti-neoplastic treatment, whichever occurs first, inclusive. Additionally, any AEs 
that occur 30 days after the last dose of study treatment will also be considered as TEAE, 
if assessed by the Investigator as related to any study treatment. 
• Serious adverse event (SAE) is any untoward medical occurrence that, at any dose, 
results in death; is life threatening (i.e., an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe); requires inpatient hospitalization or prolongation of 
existing hospitalization; results in persistent or significant disability/incapacity; or is a 
congenital anomaly/birth defect. 
• Treatment-emergent treatment-related adverse event (TRAE) is any TEAE that is 
considered by the Investigator to be related to any study treatment. 
5.1.2 
Analysis Methods  
Analyses of AEs will be performed only for TEAEs. 


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If an AE date/time of onset (occurrence or worsening) is incomplete, an imputation algorithm 
will be used to determine the AE as treatment-emergent. The algorithm for imputing date/time 
of onset will be conservative and will classify an AE as treatment-emergent unless there is 
definitive information to determine it is not treatment emergent. Details on classification of AEs 
with missing or partial onset dates are provided in Section 2.3.2. 
AE summaries will include number and percentage of patients who have experienced an TEAE. 
The denominator for computation of percentages is the number of patients in the corresponding 
treatment arm. Multiple occurrences of the same event in the same patient will be counted only 
once in the tables. Common AEs occurring in > 10% of the safety population will be presented 
by arm and overall. 
Unless otherwise specified, sorting order will follow the alphabetic order in SOC, and further by 
decreasing frequency of PTs within each SOC. When more than one PT has same number of 
events, the order of presentation will be alphabetical in PTs.  
5.1.3 
Analysis of Treatment-Emergent Adverse Event (TEAE) 
An TEAE overview summary table will be provided, which will include the number of patients 
with at least one 
• TEAEs  
• Serious TEAEs  
• TEAEs leading to dose modifications of study treatment 
• TEAEs leading to dose reduction of study treatment 
• TEAEs leading to dose interruption of study treatment 
• TEAEs leading to study treatment discontinuation 
• TEAEs leading to death  
• TRAE 
• Serious TRAEs  
• TRAEs leading to dose modifications of study treatment 
• TRAEs leading to dose reduction of study treatment 
• TRAEs leading to dose interruption of study treatment 
• TRAEs leading to study treatment discontinuation 
• TRAEs leading to death  
TEAEs will be summarized by primary SOC and PT and will include the following categories:  
• All TEAEs  
• All TEAEs, by maximum grade  
• Grade 3 or higher TEAEs  
• TEAEs leading to dose modifications of study treatment 


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• TEAEs leading to study treatment discontinuation 
5.1.4 
Analysis of Serious Adverse Event (SAE) 
Treatment-emergent SAEs will be summarized by primary SOC and PT and will include the 
following categories:  
• All treatment-emergent SAEs  
• Treatment-emergent SAEs leading to dose modifications of study treatment 
• Treatment-emergent SAEs leading to study treatment discontinuation 
All AEs and SAEs will be provided in a data listing.  
 
5.2 
DEATH  
The following summaries and listings on death events will be provided:  
• An overview of all death events and primary cause of death  
• TEAEs leading to death (death as an outcome on the AE report page as reported by the 
Investigator), by primary SOC and PT  
• TRAEs leading to death and are related to study treatment, by primary SOC and PT  
• Listing of all TEAEs leading to death 
• Listing of all death events  
 
5.3 
LABORATORY SAFETY VARIABLES 
Lab values in conventional units will be converted using the international system of units. 
Whenever applicable, severity of selected clinical laboratory measures will be determined based 
on the CTCAE v4.03 criteria. Laboratory values with CTCAE Grade ≥ 3 will be presented in a 
data listing and summary table. The worst toxicity grade in hematology and chemistry will be 
summarized by toxicity grade. Shift tables that present changes from baseline to the worst value 
and baseline to last value on-study will be presented.  
For key laboratory parameters, summary and box plots of actual value and change from baseline 
over time may be presented. 
 
5.4 
VITAL SIGNS AND PHYSICAL EXAMINATION VARIABLES 
Vital signs include height, weight, systolic and diastolic blood pressure (SBP and DBP), pulse 
rate, and body temperature. Body surface area (BSA) will be calculated by the Dubois (Dubois 
and Dubois, 1916) Method. 
Shift tables that present changes from baseline to worst on-study and last on-study for systolic 
blood pressure, diastolic blood pressure, pulse rate, and body temperature. Abnormal vital signs 
results will be summarized in the threshold/range analyses.  


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Abnormal physical examination findings will be provided in a data listing. All examination 
findings will be presented in a data listing.  
 
5.5 
NEUROLOGICAL EXAMINATIONS 
Neurological examination findings will be presented via shift tables, summarizing the changes 
from baseline to worst value for each parameter.  
All neurological examination findings will be presented in a data listing.  
 
5.6 
ELECTROCARDIOGRAM (ECG) 
Standard 12-lead ECG will be performed at screening (or predose on C1D1) and EoT visits. 
Changes from baseline for PR interval, QRS interval, QT interval and QT corrected using 
Fridericia's formula will be summarized using shift tables. For heart rate, changes from baseline 
will be presented. Abnormal ECG results will be summarized in the threshold/range analyses. 
ECG data for each patient will be provided in a data listing. 
 
5.7 
KARNOFSKY PERFORMANCE STATUS 
Karnofsky performance status at each time point will be summarized to indicate change in status 
score from baseline to each post-baseline assessment.  
Karnofsky performance status data for each patient will be provided in a data listing.  
 


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6 
REFERENCES 
Simon R. Optimal two-stage designs for phase II clinical trials[J]. Controlled clinical trials, 
1989, 10(1): 1-10.