Clinical trial NCT02088541
Conditions: Acute Myeloid Leukemia (AML)
Keywords: Relapsed/Refractory Acute Myeloid Leukemia Acute Myeloid Leukemia AML Karyopharm Selinexor KPT-330
Sponsor: Karyopharm Therapeutics Inc
Start date: 2014-03-01; Completion date: 2018-01-08
Enrollment: 317 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, multicenter, open-label, phase 2 study of the SINE compound, selinexor given orally versus specified investigator choices (one of three potential salvage therapies). Participants age ≥ 60 years with relapsed or refractory AML of any type except for AML M3, after one prior therapy only, who have never undergone and who are not currently eligible for stem cell transplantation and are currently deemed unfit for intensive chemotherapy.

Detailed description:
This is a randomized, multicenter, open-label phase 2 study of the SINE compound, selinexor given orally versus restricted investigator choice (i.e., one of three potential salvage therapies).

Participants who have never been transplant eligible, are currently deemed unfit for intensive chemotherapy, ≥ 60 years old, who have AML (except Acute Promyelocytic Leukemia: APL, AML M3) after one prior treatment of either hypomethylating agent or a regimen including Ara-C, and are meeting the inclusion and exclusion criteria will be randomized to receive either oral selinexor or physician's choice (one of three potential treatments: best supportive care (BSC) alone, or BSC + hypomethylating agent, or BSC + low dose Ara-C until disease progression, death or intolerance has occurred.

Arms: arm 1: Participants under protocol versions (PV) less than (\<) 5.0 (those who had one prior line of acute myeloid leukemia (AML) therapy), receive oral selinexor tablets at a dose of approximately 55 mg/m\^2 (milligrams per square meter) (60 to 120 mg based on body surface area \[BSA\]) twice weekly, on Day 1 and 3 of each week of 4-week cycle (28 days per cycle). arm 2: Participants under PV \< 5.0 (those who had one prior line of AML therapy), receive oral selinexor tablets at a fixed dose of 60 mg (equivalent to 35 mg/m\^2), based on BSA, twice weekly, on Day 1 and 3 of each week of 4-week cycle (28 days per cycle). arm 3: Participants under PV \>= 5 (PV 5: those who had at least one prior line of AML therapy, PV 5.1: who had at least two prior line of AML therapy), receive oral selinexor tablets at a dose of 60 mg (equivalent to 35 mg/m\^2) twice weekly, on Day 1 and 3 of each week of 4-week cycle (28 days per cycle). arm 4: Participants under PV \< 5.0 (those who had one prior line of AML therapy) received Best Supportive Care (BSC) which included blood product transfusions, antimicrobials, growth factors as needed, and hydroxyurea. arm 5: Participants under PV \>= 5 (PV 5: those who had at least one prior line of AML therapy, PV 5.1: who had at least two prior line of AML therapy), received BSC along with subcutaneous injection of arabinoside cytosine (Ara-C), 20 mg, twice daily, for 10 days, repeated at 28 to 42 day intervals.
Interventions: intervention 1: Selinexor intervention 2: Hydroxyurea intervention 3: Ara-C
Intervention descriptions: intervention 1: Selinexor oral tablet. intervention 2: None intervention 3: Ara-C Subcutaneous Injection.

Protocol documents:
Prot_000.pdf: 
Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol: KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
KCP-330-008 
A RANDOMIZED, OPEN LABEL, PHASE 2 STUDY OF THE SELECTIVE 
INHIBITOR OF NUCLEAR EXPORT (SINE) SELINEXOR (KPT-330) 
VERSUS SPECIFIED PHYSICIAN’S CHOICE IN PATIENTS ≥ 60 YEARS 
OLD WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA 
(AML) WHO ARE INELIGIBLE FOR INTENSIVE CHEMOTHERAPY 
AND/OR TRANSPLANTATION 
SOPRA Study:  Selinexor (KPT-330) in Older Patients with Relapsed AML 
Drug Development  
Phase: 
Phase 2 
Investigational  
Product: 
Selinexor (KPT-330) 
Indication: 
Acute Myeloid Leukemia 
EudraCT Number: 
2014-000920-26 
Sponsor: 
Karyopharm Therapeutics, Inc. 
85 Wells Avenue 
Newton, MA 02459 USA 
Protocol Date  
and Version: 
 
 
 
 
21 January 2014, Version 1.0 
03 July 2014, Version 2.0 (Amendment 1) 
30 September 2014, Version 2.1 
           (United Kingdom-specific Amendment 2) 
25 November 2014, Version 3.0 (Amendment 3) 
24 April 2015, Version 4.0 (Amendment 4) 
09 July 2015, Version 4.1 
           (Germany-specific Amendment 4.1) 
04 August 2015, Version 5.0 (Amendment 5) 
Conduct:  In accordance with the ethical principles that originate from the Declaration of 
Helsinki and that are consistent with International Conference on Harmonisation (ICH) 
guidelines on Good Clinical Practice (GCP) and regulatory requirements as applicable.  
CONFIDENTIAL INFORMATION 
This document is the sole property of Karyopharm Therapeutics, Inc. (Karyopharm).  
This document and any and all information contained herein has to be considered and 
treated as strictly confidential. This document shall be used only for the purpose of the 
disclosure herein provided. No disclosure or publication shall be made without the 
prior written consent of Karyopharm. 


PPI
PPI
PPI
PPI
PPI
PPI
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Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol: KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 3 
PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of this clinical protocol Version 5.0 for Study No. 
KCP-330-008 dated 04 August 2015 and will adhere to the study requirements as presented, 
including all statements regarding confidentiality. In addition, I will conduct the Study in 
accordance with current Good Clinical Practices, ICH E6 and applicable FDA regulatory 
requirements: 
Name of Principal Investigator: 
Principal Investigator’s Signature: 
 
Principal Investigator’s Name: 
 
Institution: 
 
Date: 
 
 
 
 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol: KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 4 
PROTOCOL SYNOPSIS 
Sponsor: 
Karyopharm Therapeutics, Inc. 
Investigational Product: 
Selinexor (KPT-330) 
Developmental 
Phase: 
Phase 2 
Title of Study:  SOPRA (Selinexor in Older Patients with Relapsed AML): A 
Randomized, Open Label, Phase 2 Study of the Selective Inhibitor of Nuclear Export (SINE) 
Selinexor (KPT-330) versus Specified Physician’s Choice in Patients ≥ 60 Years Old with 
Relapsed/Refractory Acute Myeloid Leukemia (AML) Who are Ineligible for Intensive 
Chemotherapy and/or Transplantation 
Protocol Number:  KCP-330-008 
Indication:  Acute Myeloid Leukemia (AML) 
Objectives: 
Primary Objective: 
To determine overall survival (OS) of selinexor as compared to physician’s choice (PC) in 
patients ≥ 60 years old with relapsed/refractory AML that requires treatment and are ineligible 
for intensive chemotherapy and/or transplantation. 
Secondary Objectives: 
• To determine the proportion of patients whose OS is at least 3 months (OS3.0) 
• To determine the complete remission rate (CRR), including complete remission with 
full hematologic recovery (CR), and median disease free survival (DFS) for patients 
who achieve CR 
• To determine the modified CRR (mCRR), including CR or complete remission with 
incomplete hematologic recovery (CRi) (including complete remission with 
incomplete platelet recovery [CRp]), and median DFS for patients who achieve CR or 
CRi (including CRp) 
• To determine the overall response rate (ORR) and duration of overall response 
(DOR), including CR, CRi, morphologic leukemia-free state (MLFS), and partial 
remission (PR) 
• To determine the disease control rate (DCR) defined as ORR + stable disease for 
≥ 4 weeks (SD), and duration of DCR 
• To assess the safety and tolerability of selinexor (KPT-330), as compared to 
physician's choice (PC) 
• Quality of life and patient reported outcomes (FACT-Leukemia, EQ-5D-5L) (QoL) 
Methodology: 
This is a randomized, multicenter, open-label, Phase 2 study of the Selective Inhibitor of 
Nuclear Export (SINE) compound selinexor given orally versus specified investigator choices 
(one of three potential salvage therapies). 
Approximately 300 patients will be randomized into the selinexor or PC treatment arms in a 
2:1 allocation, with a 2:1 allocation performed within each of the 2 x 2 x 2 stratification levels. 
Two separate cohorts will be randomized. Under Protocol Versions < 5.0, approximately 
110 patients were randomized to selinexor at a fixed dose of ~55 mg/m2 versus PC as of 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol: KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 5 
Sponsor: 
Karyopharm Therapeutics, Inc. 
Investigational Product: 
Selinexor (KPT-330) 
Developmental 
Phase: 
Phase 2 
04 August 2015; enrollment will continue until Protocol Version 5.0 is approved. 
Approximately 171 additional patients will be randomized under Protocol Versions ≥ 5.0, to 
either 60 mg of selinexor (flat dose) or PC, again in a 2:1 randomization allocation within 
strata. Patients will be stratified for randomization using three criteria:  (1) duration of their 
first CR on prior therapy, > 6 months versus ≤ 6 months or never achieved CR; (2) number of 
prior therapies, 1 versus >1; (3) peripheral leukemic blast counts ≥ 10,000/μL versus 
< 10,000/μL. 
Diagnosis and Main Criteria for Inclusion: 
Patients age ≥ 60 years with relapsed/refractory AML (defined using WHO criteria) of any 
type except for acute promyelocytic leukemia (APL; AML M3), who have poor prognosis 
(intermediate or adverse risk) cytogenetics, with relapsed or refractory AML, after at least one 
prior AML therapy (must have included an adequate trial of a hypomethylating agent with at 
least 2 cycles), who have never undergone, and who are not currently eligible for stem 
cell transplantation, and are currently deemed unfit for intensive chemotherapy. 
Main Criteria for Exclusion: 
Patients with AML M3, known central nervous system (CNS) leukemia, who are in blast 
transformation of chronic myeloid leukemia (CML), or whose AML is classified as favorable 
according to the European LeukemiaNet (ELN) disease risk assessment will be excluded from 
this study. 
Test Product, Dose and Mode of Administration:   
Selinexor (KPT-330) will be given initially at an oral fixed dose of 60 mg (equivalent to 
~35 mg/m2) twice weekly (e.g., Monday and Wednesday or Tuesday and Thursday or 
Wednesday and Friday). Patients who were randomized to selinexor (~55 mg/m2) under 
protocol versions < 5.0 will be switched to the 60 mg fixed dose. The dose has been reduced 
in response to a possible increase in sepsis related serious adverse events for selinexor 
~55 mg/m2 (8 sepsis events) versus PC (2 sepsis events) (a ratio of 4:1 and not the expected 
2:1) that was detected during an annual review of clinical safety data (29 July 2015). 
Reference Therapy, Dose and Mode of Administration:  One of the following three best 
supportive care (BSC) regimens will be selected by the treating physician / investigator 
(physician's choice [PC]):  (1) BSC including blood product transfusions, antimicrobials, 
growth factors as needed, and hydroxyurea; or (2) BSC + low dose AraC, 20 mg bid by 
subcutaneous (sc) injection daily on Days 1-10/14 (20/28 doses) to be repeated at 28 to 42 day 
intervals; or (3) BSC + hypomethylating agent:  azacitidine 75 mg/m2 by sc injection daily on 
Days 1-7 or 1-5 and 8-9 (7 doses) to be repeated at ≥28 day intervals, or decitabine (20 mg/m2 
IV over 1 hour daily on days 1-5 or days 1-10 to be repeated at ≥ 28 day intervals). 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol: KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 6 
Sponsor: 
Karyopharm Therapeutics, Inc. 
Investigational Product: 
Selinexor (KPT-330) 
Developmental 
Phase: 
Phase 2 
Supportive Care and Concomitant Medications:   
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 twice daily (bid) – three times a day (tid) as needed (prn). In addition, aggressive 
use of other supportive care including anti-nausea/anti-emetic therapy, appetite stimulants, 
acid suppression (proton pump inhibitors and/or H2-blockers) and other treatments is strongly 
recommended 
Patients may continue their baseline medication(s). Patients will receive concomitant 
medications to treat symptoms, AEs, and intercurrent illnesses that are medically necessary as 
standard care. Medications to treat concomitant diseases like diabetes, hypertension, etc., are 
allowed. Patients may receive red blood cell (RBC) or platelet transfusions, if clinically 
indicated, per institutional guidelines. Glucocorticoids ≤ 10 mg oral prednisone (or equivalent) 
per day are permitted at baseline and during the study for non-malignant conditions (i.e., 
asthma, irritable bowel disease [IBD], etc.) as needed but patients should preferably have been 
on a stable dose for at least two weeks before study entry. Acetaminophen on days of selinexor 
dosing will not exceed a total daily dose of 1 gram. 
Concurrent therapy with glucocorticoids and hydroxyurea as specified herein is allowed in 
both arms. Hydroxyurea may be used at any time during the study, typically in patients with 
WBC ≥ 30,000/μL or per institutional guidelines. Prior to the initiation of hydroxyurea please 
consider the contraindications in the Summary of Product Characteristics (SPC), including 
leukocytopenia (< 2.5 x 109 leukocytes/L), thrombocytopenia (< 100 x 109 platelets/L) or 
severe anemia. 
Concurrent therapy with any other approved or investigative anticancer therapeutic is not 
allowed in either arm. Use of any immunosuppressive agents during the study must be 
confirmed by the Medical Monitor. Other investigational agents should not be used during the 
study.  
Study Duration:   
The treatment period for an individual patient is expected to be up to 6 months, but there is no 
maximum treatment duration. Treatment may continue until: 
• Disease progression defined as an increase in blast counts and absence of 
hematologic recovery (one or more lineages) 
• Unacceptable AEs 
• Patients decides to withdraw from the study 
• Significant patient non-compliance with protocol 
 
Patients will be followed for survival until the last patient has been followed for 6 months from 
the end of treatment, disease progression, another withdrawal criterion is met, or until death, 
whichever comes first. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol: KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 7 
Criteria for Evaluation: 
Safety: 
The safety and tolerability of selinexor and PC will be evaluated by means of AE reports, 
physical examinations, and laboratory safety evaluations. The Common Terminology Criteria 
for Adverse Events (CTCAE) V4.03 will be used for grading of AEs. Investigators will provide 
their assessment of causality for all AEs as 1) unrelated, 2) possibly related, or 3) related. 
Efficacy: 
Overall survival (OS) is the primary efficacy variable for the study, where OS is measured 
from date of randomization to study drug (selinexor or PC) until date of death from any cause. 
The analysis of OS will be performed on the intent-to-treat (ITT) population as the primary 
analysis, and on the per-protocol (PP) population as a supportive analysis. 
Secondary efficacy variables will include the following, assessed in hierarchical fashion in the 
order presented, according to the definitions presented above (Secondary Objectives): 
• OS3.0 
• CRR and DFS for CRR 
• mCRR and DFS for mCRR 
• ORR and DOR 
• DCR and duration of DCR 
• Quality of Life (QoL) 
 
Disease response assessment will be made according to the International Working Group 
(IWG) criteria (Cheson 2003). Response assessments (CRR, mCRR, ORR, DCR) will be 
assessed for treatment arm differences in rates of response, followed by assessment of 
differences in duration of response. 
Criteria for Treatment Discontinuation: 
At the discretion of the investigator, the investigator may remove a patient from study 
treatment for the following reasons: 
• Disease progression defined as an increase in blast counts and absence of hematologic 
recovery (one or more lineages) 
• Unacceptable AEs or failure to tolerate the study treatment 
• Patient decides to discontinue study therapy 
• Significant deviation from entry criteria (e.g., non-relapsed or non-refractory AML) 
• Misuse of study medication (e.g., deliberate overdosing by patient)  
• Missed / unscheduled / off-schedule / incomplete / incorrect assessments that result in 
patients being put at risk 
• Any other medically appropriate reason or significant protocol violation in the opinion 
of the investigator. 
 
Patients may decide to discontinue study treatment for any reason. Patients who elect not to 
initiate study treatment or to discontinue study treatment should be encouraged to continue in 
the study so that follow-up information on disease progression and survival status may be 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol: KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 8 
Sponsor: 
Karyopharm Therapeutics, Inc. 
Investigational Product: 
Selinexor (KPT-330) 
Developmental 
Phase: 
Phase 2 
obtained. However, patients may elect to withdraw consent and decline further participation 
in the trial. 
Statistical Methods:   
Patients enrolled under Protocol Versions < 5.0 will not be included in the efficacy analyses 
due to changes to the selinexor dose and the inclusion criteria. Therefore, sample size 
justification refers to patients enrolled under Protocol Versions ≥ 5.0. The sample size is 
designed to have 80% power to detect an improvement in the median OS with selinexor of 
~5.2 months, versus investigator choice of ~3.0 months, using a one-sided alpha of 0.025, with 
a 2:1 allocation of treatment to selinexor:PC, and allowing for two interim analyses. A total of 
123 events (deaths) are required for the primary analysis. The follow up period for survival is 
up to 6 months after the end of treatment for the last enrolled patient for the primary analysis, 
and an ~20% drop out rate is assumed. 
Two interim efficacy analyses will be conducted. The first interim analysis will take place after 
31 (25%) OS events have occurred, and will be conducted to assess futility only (non-binding). 
Futility would be concluded if the p-value from the log-rank test is ≥ 0.8084. The second 
interim analysis will take place after 62 (50%) deaths, and will allow for a conclusion of 
significant efficacy at an α-level < 0.0015, and stopping for futility (non-binding) at an α-level 
≥ 0.2879. The final hypothesis test will be performed after 123 OS events are observed with a 
one-sided significance level of 0.0245. Type I error adjustments will be made using the 
O’Brien-Fleming approach. 
The intent-to-treat population (ITT) will consist of all patients who are randomized to study 
therapy under Protocol Versions ≥ 5.0. This population will be used for primary analyses of 
efficacy. An additional, per-protocol population will consist of all patients randomized under 
Protocol Versions ≥ 5.0 who receive at least one dose of study medication, have post-baseline 
efficacy follow-up information and are otherwise compliant with all critical protocol 
requirements, as determined by blinded review of protocol violations prior to study 
completion. 
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety 
parameters. For categorical variables, summary tabulations of the number and percentage of 
patients within each category (with a category for missing data) of the parameter will be 
presented, as well as two-sided 95% confidence intervals, unless otherwise stated. For 
continuous variables, the number of patients, mean, median, standard deviation (SD), 
minimum, and maximum values will be presented. Time-to-event data will be summarized 
using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% confidence intervals, as well as percentage of censored observations. 
The stratified log-rank test will be used to test the null hypothesis that the OS distributions are 
the same for both treatment groups versus the alternative hypothesis that the duration of OS 
for the selinexor + BSC treatment arm is longer than the group treated with PC. Stratification 
factors in this analysis are those that were used for randomization. The hazard ratio for 
treatment group will be estimated from a stratified Cox proportional hazards model (stratified 


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Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 10 
Table 1: 
Schedule of Assessments and Study Activities 
 
Screening 
Cycle 1 
(28 days 
per cycle) 
Cycles 1-3 
Cycles 2-5 
Cycle ≥ 6 
(28 days per 
cycle) 
Final Visit 
30 Day 
Safety 
Follow-up27 
Survival 
Follow-
up28 
Cycles 2-5 
(28 days per 
cycle) 
Cycle 2 only 
(28 days per 
cycle) 
 
Within 
14 days 
prior to 
start of 
therapy 
Within 
7 days 
prior to 
start of 
therapy 
Day 1 of 
each week 
Day 4 
of each 
week25  
Days 1 & 
Day 15 
Days 8 & 
Day 22 
Day 1 
< 30 days 
after last 
dose 
Visit window [days] 
 
 
± 1 day 
+ 1 day 
± 2 days 
± 2 days 
± 2 days 
± 7 days 
± 7 days 
 
Study Visit Number 
Visit 1 
Visit 2 
Visits 3, 
5, 6, 7 
Visit 4 
(C1D4) 
/Weekly 
Phone Call 
Visits 8, 10, 
12-17 
Visits 9 & 11 
Visits 18+ 
In Clinic 
Clinic or 
Phone 
Phone 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
 
 
 
Randomization3 
 
 
X3 
 
 
 
 
 
 
 
Body height and weight4 
 
X 
X 
 
X 
 
X 
X 
 
 
BSA5 
 
X 
X 
 
X 
 
X 
 
 
 
Vital signs6 
 
X 
X 
 
X 
X 
X 
X 
 
 
Physical examination and ECOG7 
 
X 
X 
 
X 
 
X 
X 
 
 
Baseline Symptoms 
X 
X 
 
 
 
 
 
 
 
 
Disease risk assessment (Visit 1 or 2) 
X 
 
 
 
 
 
 
 
 
Ophthalmic exam8 
X 
 
 
 
 
 
 
X 
 
 
Oxygen saturation9 
 
X 
X 
 
X 
 
X 
X 
 
 
12-lead ECG10 
X 
 
X 
 
X 
 
X 
X 
 
 
Urine analysis11 
 
X 
X 
 
X 
 
X 
X 
 
 
Hematology (CBC with 
differential)12 
 
X 
X 
 
X 
X26 
X 
X 
 
 
Complete Serum chemistry13 
 
X 
X 
 
 
X26 
 
X 
 
 
Limited Serum chemistry14 
 
 
 
 
X 
 
X 
 
 
 
Coagulation test (PT, PTT or TT) 15 
 
X 
X 
 
X 
 
X 
 
 
 


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Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 12 
 
Screening 
Cycle 1 
(28 days 
per cycle) 
Cycles 1-3 
Cycles 2-5 
Cycle ≥ 6 
(28 days per 
cycle) 
Final Visit 
30 Day 
Safety 
Follow-up27 
Survival 
Follow-
up28 
Cycles 2-5 
(28 days per 
cycle) 
Cycle 2 only 
(28 days per 
cycle) 
 
Within 
14 days 
prior to 
start of 
therapy 
Within 
7 days 
prior to 
start of 
therapy 
Day 1 of 
each week 
Day 4 
of each 
week25  
Days 1 & 
Day 15 
Days 8 & 
Day 22 
Day 1 
< 30 days 
after last 
dose 
Visit window [days] 
 
 
± 1 day 
+ 1 day 
± 2 days 
± 2 days 
± 2 days 
± 7 days 
± 7 days 
 
Study Visit Number 
Visit 1 
Visit 2 
Visits 3, 
5, 6, 7 
Visit 4 
(C1D4) 
/Weekly 
Phone Call 
Visits 8, 10, 
12-17 
Visits 9 & 11 
Visits 18+ 
In Clinic 
Clinic or 
Phone 
Phone 
Collect information regarding 
antineoplastic therapy after end of 
selinexor or PC treatment 
 
 
 
 
 
 
 
X 
X 
X 
BSA = Body Surface Area; ECOG = Eastern Cooperative Oncology Group; PT = Prothrombin Time; PTT = Partial Thromboplastin Time; FACT-Leu = Functional Assessment of 
Cancer Therapy - Leukemia; QoL = Quality of Life. 
 
1 Prior to the first study-specific measures 
2 Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including start and stop dates, disease progression during or after therapy, as 
well as discontinuations due to intolerability or any other serious illness. 
3Randomization must occur ≤ 3 calendar days of Cycle 1 Day 1. 
4 Body height will be measured at screening only 
5 Body Surface Area (BSA) calculated by Dubois (Dubois and Dubois, 1916) or Mosteller (Mosteller 1987) method 
6 Vital signs:  blood pressure, pulse and temperature 
7 Full physical examination for baseline and end of study visit. Physical examinations during the study should be symptom-directed. 
8 Full ophthalmic examination will be conducted on all patients by an optometrist or ophthalmologist at screening, as clinically indicated during the study and at the Final Visit. 
The full ophthalmic assessment includes:  
• 
prior to dilation:  best corrected visual acuity and slit lamp examination including tonometry  
• 
following dilation:  fundoscopy and a slit lamp exam to document lens clarity. If a cataract is seen during the examination for newly enrolling patients or enrolled 
patients for whom no cataracts have been detected to date, the cataract will be graded using a Grade 1-4 scale (Appendix 3). 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. 
9 Pulse oximetry is performed for patients at rest breathing room air. 
10 ECG on Day 1 of each cycle only 
11 Urine analyses will include appearance, color, urine bilirubin, glucose, hemoglobin, ketones, pH, protein, specific gravity, and urobilinogen. Microscopy will only be performed 
if clinically indicated. 


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CCI


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 14 
24 Patient is to take their temperature each morning and record their temperature on the diary card that has been provided. The temperature diary will be reviewed with site personnel 
during each site visit or phone call. 
25 A visit (Visit 4) at Cycle 1 Day 4 (+1 day) is required to monitor adverse events (including infections), to review temperature diaries, to evaluate supportive care medications, and 
to adjust supportive care as appropriate. Weekly phone calls to the patient may be done in place of visits at Day 4 (+1 day) for all other weeks during Cycles 1-3. 
26 Hematology and complete serum chemistry will be done only if fever and suspected infection are present. 
27 By phone (or a visit, if possible), assess overall medical condition of the patient and status of his/her AML, follow-up on any AEs that were not resolved at the Final Study Visit, 
and information on any antineoplastic therapies utilized since discontinuation of study treatment. 
28 After treatment discontinuation, a call will be made to the patient (or the patient’s family) every 3 months until the End of Study (Section 11.3) to inquire about the patient’s 
AML status, well-being, and information on any antineoplastic therapies utilized since discontinuation of  study treatment. 
 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 15 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................ 4 
TABLE OF CONTENTS ........................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................. 20 
1. 
OVERVIEW ........................................................................................... 26 
2. 
NUCLEAR EXPORT ............................................................................. 27 
3. 
ACUTE MYELOID LEUKEMIA (AML) ............................................. 28 
4. 
SELINEXOR (KPT-330) ........................................................................ 29 
4.1. 
Introduction ............................................................................................. 29 
4.2. 
Preclinical Data ....................................................................................... 29 
4.2.1. 
Pharmacology Studies ............................................................................ 29 
4.3. 
Clinical Experience ................................................................................. 30 
4.3.1. 
Potential Risks ........................................................................................ 31 
5. 
RATIONALE FOR THE STUDY .......................................................... 34 
5.1. 
Rationale for the Doses and the Dosing Regimen .................................. 34 
6. 
STUDY OBJECTIVES .......................................................................... 36 
6.1. 
Primary Objective ................................................................................... 36 
6.2. 
Secondary Objectives ............................................................................. 36 
7. 
STUDY DESIGN ................................................................................... 37 
7.1. 
Study Design Overview .......................................................................... 37 
7.2. 
Data Safety Monitoring Board ................................................................ 38 
7.3. 
Stopping Rules ........................................................................................ 39 
7.4. 
Study Endpoints ...................................................................................... 39 
7.4.1. 
Primary Endpoint(s) ................................................................................ 39 
7.4.2. 
Secondary Endpoints .............................................................................. 39 
7.5. 
Blinding and Randomization .................................................................. 39 
8. 
SELECTION OF PATIENTS................................................................. 41 
8.1. 
Number of Patients ................................................................................. 41 
8.2. 
Recruitment ............................................................................................. 41 
8.3. 
Inclusion Criteria .................................................................................... 41 
8.4. 
Exclusion Criteria ................................................................................... 42 


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CCI


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10.10. 
Correlative Procedures ............................................................................ 53 
10.11. 
Correlative Endpoints ............................................................................. 53 
10.12. 
blood Collection for PK, PD AND CORRELATIVE STUDIES ........... 55 
10.13. 
Efficacy Procedures ................................................................................ 56 
10.14. 
Efficacy Endpoints .................................................................................. 56 
11. 
DISCONTINUATION CRITERIA ........................................................ 57 
11.1. 
Early Discontinuation of the Study......................................................... 57 
11.2. 
Early Discontinuation of Individual Patients .......................................... 57 
11.3. 
End of Study ........................................................................................... 57 
12. 
TREATMENT ........................................................................................ 59 
12.1. 
Dosing and Administration of Physician’s Choice Study Medication 
(Reference Therapy) ............................................................................... 59 
12.2. 
Dosing and Administration of Selinexor ................................................ 59 
12.2.1. 
Labelling ................................................................................................. 59 
12.2.2. 
Dispensing Directions ............................................................................. 59 
12.2.3. 
Dosing Information ................................................................................. 59 
12.2.4. 
Dosing Instructions for the Study Participants ....................................... 59 
12.3. 
Dose Reduction and Supportive Care Guidelines .................................. 60 
12.3.1. 
Dose Modifications and Dose Delay ...................................................... 60 
12.3.2. 
Supportive Care and Concomitant Treatments ....................................... 67 
12.3.3. 
Concomitant Medication and Treatment ................................................ 68 
12.3.4. 
Prohibited Medication ............................................................................ 69 
12.4. 
Selinexor Storage and Accountability .................................................... 69 
12.5. 
Treatment Compliance ............................................................................ 70 
13. 
ADVERSE EVENTS.............................................................................. 71 
13.1. 
Serious Adverse Events, Overdose ......................................................... 72 
13.1.1. 
AE and SAE Follow-up .......................................................................... 73 
13.1.2. 
Post-Study Adverse Events and Serious Adverse Events ....................... 73 
13.1.3. 
Overdose ................................................................................................. 73 
13.1.4. 
Pregnancies ............................................................................................. 74 
13.1.5. 
Serious Adverse Event Reporting ........................................................... 74 
14. 
STATISTICAL METHODS ................................................................... 76 


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14.1. 
General Considerations ........................................................................... 76 
14.1.1. 
Statistical and Analytical Plans .............................................................. 76 
14.1.2. 
Determination of Sample Size ................................................................ 76 
14.1.3. 
Disposition of Patients ............................................................................ 77 
14.1.4. 
Blinding and Randomization .................................................................. 77 
14.2. 
Analysis Datasets .................................................................................... 77 
14.2.1. 
Population to be Analyzed ...................................................................... 77 
14.3. 
Data Analysis and Presentation .............................................................. 78 
14.3.1. 
Demographic Characteristics .................................................................. 79 
14.3.2. 
Baseline Characteristics and Medical History ........................................ 79 
14.3.3. 
Primary Endpoint .................................................................................... 79 
14.3.4. 
Secondary Endpoints .............................................................................. 80 
14.3.5. 
Pharmacokinetic Data ............................................................................. 81 
14.3.6. 
Safety Data .............................................................................................. 81 
14.3.7. 
Procedures for Handling Missing Data ................................................... 83 
14.4. 
Changes in the Conduct of the Study or Planned Analysis .................... 83 
15. 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS .............. 84 
15.1. 
Declaration of Helsinki ........................................................................... 84 
15.2. 
Good Clinical Practice ............................................................................ 84 
15.3. 
Institutional Review Boards/Ethics Committees .................................... 84 
15.4. 
Regulatory Authority Approval .............................................................. 84 
15.5. 
Pre-study Documentation Requirements ................................................ 84 
15.6. 
Informed Consent ................................................................................... 84 
15.7. 
Patient Confidentiality and Disclosure ................................................... 84 
15.8. 
Collection, Monitoring and Auditing Study Documentation, and Data 
Storage .................................................................................................... 85 
15.8.1. 
Collection of Data and Monitoring Procedures ...................................... 85 
15.8.2. 
Auditing Procedure ................................................................................. 86 
15.8.3. 
Retention of Documents ......................................................................... 86 
15.9. 
Disclosure of Information ....................................................................... 86 
15.10. 
Discontinuation of the Study .................................................................. 86 
15.11. 
Study Report, Publication Policy and Archiving of Study 
Documentation ........................................................................................ 86 


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15.11.1. 
Study Report and Publication Policy ...................................................... 86 
15.11.2. 
Data Capture ........................................................................................... 87 
15.11.3. 
Study Documents .................................................................................... 87 
15.11.4. 
Archiving of Documents ......................................................................... 88 
16. 
REFERENCES ....................................................................................... 89 
17. 
APPENDICES ........................................................................................ 93 
 
LIST OF IN-TEXT TABLES 
Table 1: 
Schedule of Assessments and Study Activities ...................................... 10 
Table 2: 
Effect of XPO1 Inhibition on Oncogenic and Inflammatory Pathways . 27 
Table 3: 
Best Responses in AML Patients as of 10 June 2014 ............................. 31 
Table 4: 
Blood Collection Time Points and Volumes for PK, PD and Correlative 
Studies..................................................................................................... 55 
Table 5: 
Prespecified Dose/Schedule Modifications for Adverse Events Related to 
Study Drug .............................................................................................. 61 
Table 6: 
Supportive Care and Dose Adjustment Guidelines for Non-Hematologic 
Selinexor-Related Toxicities .................................................................. 61 
Table 7: 
Classification of Adverse Events by Causality ....................................... 72 
 
LIST OF APPENDICES 
APPENDIX 1 Disease Risk Assessment According to the European LeukemiaNet 
(ELN) ...................................................................................................... 94 
APPENDIX 2 International Working Group Guidelines for AML ........................ 95 
APPENDIX 3 Ophthalmic Examination:  Assessments and Grade 1-4 Grading 
System for Cataracts ............................................................................... 98 
APPENDIX 4 NCCN Clinical Practice Guidelines in Oncology:  Antiemesis ...... 99 
APPENDIX 5 NCCN Clinical Practice Guidelines in Oncology:  
Anorexia/Cachexia ............................................................................... 102 
APPENDIX 6 Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-
acetylcysteine (NAC)-containing products (representative List) ......... 103 
APPENDIX 7 Protocol amendments:  Rationales and Summaries of changes .... 104 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase (SGPT) 
AML 
Acute Myeloid Leukemia 
AML M3 
acute promyelocytic leukemia 
APL 
acute promyelocytic leukemia  
aPTT 
activated partial thromboplastin time 
AR 
adverse risk 
AraC 
cytosine arabinoside 
AST 
aspartate transaminase (SGOT) 
AUClast 
Area under the Curve, first-last measurement 
AV 
atrioventricular 
bid 
twice daily 
BM 
bone marrow 
BMI 
BMSC 
body mass index 
bone marrow stroma cells 
BP 
blood pressure 
BSA 
body surface area 
BSC 
best supportive care 
BUN 
blood urea nitrogen 
°C 
degrees Centigrade 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
cm 
centimeter 
Cmax 
maximum serum concentration 
CMH 
Cochran Mantel-Haenszel 
CML 
chronic myeloid leukemia 
CNS 
central nervous system 
CR 
complete remission 


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Abbreviation 
Definition 
CRA 
clinical research associate 
CRF 
case report form 
CRi 
complete remission with incomplete hematological recovery 
CRM1 
chromosome region maintenance 1 
CRp 
complete remission with incomplete platelet recovery 
CRR 
complete remission rate 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCL 
cutaneous T-cell lymphoma 
DCR 
disease control rate (CR, CRi, PR, SD ≥ 4 weeks) 
DFS 
disease-free survival 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSMB 
Data Safety Monitoring Board 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDC 
electronic data capture 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
ELN 
European LeukemiaNet 
EQ-5D-5L 
European Quality of Life Five Dimension Five Level Scale 
F% 
oral bioavailability 
°F 
degrees Fahrenheit 
FACT-Leu 
Functional Assessment of Cancer Therapy - Leukemia 
FDA 
Food and Drug Administration 
FR 
favorable risk 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GM-CSF 
granulocyte macrophage-colony stimulating factor 


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Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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Abbreviation 
Definition 
GRAS 
generally regarded as safe 
GRP 
growth regulatory protein 
GSH 
glutathione 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDPE 
high density polyethylene 
HIV 
human immunodeficiency virus 
HPLC/MS-MS 
high performance liquid chromatography/tandem mass spectrometry 
HR 
hazard ratio 
hr 
hour 
IB 
Investigator’s Brochure 
IBD 
irritable bowel disease 
IC50 
inhibitory concentration, 50% (half maximal inhibitory concentration) 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IFNα 
interferon alpha 
IFNγ 
interferon gamma 
IL1α 
Interleukin 1 alpha 
IL-6 
Interleukin 6 
IL-8 
Interleukin 8 
IL-10 
Interleukin 10 
INR 
international normalization ratio 
IR 
intermediate risk 
IRB 
institutional review board 
ITT 
IV 
intent-to-treat 
intravenous 
IWG 
International Working Group 
IWRS 
interactive web response system 
kg 
kilogram 
KM 
Kaplan-Meier 
LAFB 
left anterior fascicular block 
LD 
low dose 
LDH 
lactic dehydrogenase 


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Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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Abbreviation 
Definition 
LMW 
low molecular weight 
LOCS III 
Lens Opacities Classification System III 
MCP1 
monocyte chemoattractant protein-1 
mCRR 
modified complete remission rate 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MLFS 
morphologically leukemia-free state 
mg 
milligram 
MI 
myocardial infarction 
MIC-1 
Macrophage inhibitory chemokine-1 
min 
minute 
mITT 
modified  intent-to-treat 
mL 
milliliter 
MM 
multiple myeloma 
mmHg 
millimeters of mercury 
MMRM 
mixed model repeated-measures analysis of variance 
MTD 
maximum tolerated dose 
mRNA 
messenger ribonucleic acid 
5'NT 
5'-nucleotidase 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
NK1R 
NYHA 
neurokinin 1 receptor 
New York Heart Association 
ORR 
overall response rate (CR, CRi) 
OS 
overall survival 
OS3.0 
overall survival at least 3 months 
PC 
Physician’s choice 
PDn 
pharmacodynamics 
PFS 
progression-free survival 
PI 
principal investigator 
PK 
pharmacokinetic 
po 
by mouth 


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Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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Abbreviation 
Definition 
PP 
per protocol 
PR 
partial remission 
PT 
prothrombin time 
PTCL 
peripheral T-cell lymphoma 
PTT 
partial thromboplastin time 
qd 
once daily 
qhs 
at bedtime 
QoL 
quality of life 
qRT-PCR 
quantitative real time polymerase chain reaction 
RBBB 
right bundle branch block 
RBC 
red blood cell 
rIL-11 
recombinant Interleukin-11 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAM 
S-adenosylmethionine 
sc 
subcutaneous 
SCT 
stem cell transplantation 
SD  
stable disease (within clinical context) 
standard deviation (within statistical context) 
SEER 
surveillance, epidemiology, and end result 
SIADH 
syndrome of inappropriate antidiuretic hormone secretion 
SINE 
selective inhibitor of nuclear export 
SOC  
standard of care (within treatment context) 
system organ class (within adverse event context) 
SOP 
standard operating procedure 
SPC 
Summary of Product Characteristics 
TK 
toxicokinetic 
Tmax 
time to maximum serum concentration 
TNFα 
tumor necrosis factor alpha 
TSH 
thyroid-stimulating hormone 
TSP 
tumor suppressor protein 
TOI 
trial outcomes index 


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Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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Abbreviation 
Definition 
μL 
ULN 
microliter 
upper limit of normal 
VEGFα 
vascular endothelial growth factor alpha 
WBC 
white blood cell 
WC 
withdrew consent 
WHO 
World Health Organization 
WM 
Waldenström’s Macroglobulinemia 
XPO1 
exportin 1 
 


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1. 
OVERVIEW 
The nuclear export of most tumor suppressor proteins (TSP) and other growth modulators 
inactivates their anti-cancer and regulatory functions. The vast majority of TSPs are exported 
from the nucleus exclusively by exportin 1 (XPO1, also called CRM1). Selinexor (KPT-330) 
is an orally bioavailable, selective inhibitor of nuclear export (SINE) that specifically blocks 
XPO1, leading to the nuclear accumulation and re-activation of TSP and other growth 
modulators. The reactivation of multiple tumor suppressor and growth regulatory pathways 
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. 
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, 
accounting for over 80% of all acute leukemias in individuals aged > 18 years. AML is 
predominantly a disease of older adults, with a median age at diagnosis of over 65 years. For 
the growing number of older patients with AML where intensive chemotherapy is associated 
with unacceptable mortality, therapeutic options are severely limited and median overall 
survival (OS) is < 1 year. Single agent ‘low-dose’ cytosine arabinoside (LD-AraC) is the only 
agent to show a clear reduction in mortality in this population of AML patients. The 
hypomethylating agent decitabine has shown a trend to improved OS (7.7 months) versus best 
supportive care ± LD-AraC (5.0 months). The related hypomethylating agent azacitidine has 
also shown activity in older patients with AML, with improved OS (10.4 months) versus 
conventional care regimens (6.5 months) (Dombret 2014). Despite some increases in response 
rates, no other agent has shown a clear improvement in OS in this population, where both 
efficacy and low rates of side effects are critical. 
Selinexor (oral) has shown single-agent, durable, anti-cancer activity in patients with multiply 
relapsed or refractory hematologic and solid tumor malignancies in initial Phase 1 dose 
escalation studies. Elderly patients (median age 68 years) with heavily pretreated AML whose 
life expectancy is very short were included in the initial phase 1 studies, and durable complete 
remissions (CR), complete remissions with incomplete hematologic recovery (CRi/p), partial 
remissions (PR) and stable disease (SD) were observed in these patients. With standard 
supportive care for selinexor-induced anorexia and fatigue, long-term tolerability has been 
adequate with no acute toxicities or major organ damage, even in patients > 70 years of age. 
Therefore, oral selinexor may represent a novel treatment for AML in this difficult-to-treat 
population. 
This randomized, open label study has been designed to assess whether oral, single agent 
selinexor can improve the OS in patients with relapsed or refractory AML who are not 
candidates for intensive chemotherapy. 


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Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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2. 
NUCLEAR EXPORT 
Neoplasms must inactivate most or all of the > 10 major tumor suppressor pathways in order 
to perpetuate their phenotypes (Sharpless 2007). Since the vast majority of tumor suppressor 
(TSP) and other growth modulators require nuclear localization in order to carry out their 
antineoplastic activities, enhancing their nuclear export leads to their functional inactivation. 
The control of nuclear import and export is tightly regulated by shuttle proteins in eukaryotic 
cells. There are over 15 nuclear import proteins, or importins, but only seven (7) nuclear export 
proteins, or exportins (Exportins 1-7). Despite their marked diversity of sequence, size, and 
3-dimensional structures, the major TSP/growth regulatory proteins (GRP) are exported 
exclusively by the protein Exportin 1 (XPO1), also called chromosome region maintenance 1 
(CRM1). All malignancies studied to date, including acute myeloid leukemia (AML), show 
elevated XPO1 levels, and increasing levels often correlate with poorer prognosis (Huang 
2009, Yao 2009, van der Watt 2009, Liu 2009, Kojima 2013, Tai 2014, Lapalombella 2012). 
Elevated XPO1 levels lead to cytoplasmic mislocalization and functional inactivation of 
TSP/GRP. It appears that tumor cells have co-opted XPO1 to move TSP/GRP out of the 
nucleus, thereby neutralizing their anti-neoplastic functions. 
XPO1 inhibitors have been shown to block the nuclear export of key TSP, leading to 
accumulation of these proteins in the nucleus, as nuclear import appears to proceed unimpeded. 
Moreover, nuclear retention appears to prevent proteasome-mediated degradation (which is 
typically cytoplasmic). Forced nuclear retention of TSP can counteract a multitude of 
oncogenic (and inflammatory) pathways that perpetuate the neoplastic phenotype (Table 2). 
Moreover, certain proteins such as survivin (Stauber 2007) and p21CIP1 (Gartel 2002) can be 
anti-apoptotic when in the cytoplasm; forcing their nuclear retention by XPO1 inhibition can 
prevent their anti-apoptotic functions and, for p21, expose its antitumor activities. 
Table 2: 
Effect of XPO1 Inhibition on Oncogenic and Inflammatory Pathways 
Pathway Affected 
Effect of XPO1 Inhibition 
Reference 
p53 mutation 
p73 activation, p21 activation 
Ranganathan 2012 
MDM2 activation 
Nuclear p53 retention and activation 
Kojima 2013 
NPM1 mutation 
Restoration of nuclear NPM1 
Falini 2007 
CEBPA down-regulation Nuclear retention and activation 
Ranganathan 2012 
XPO1 overexpression 
XPO1 reduction 
Walker 2013 
FLT3 activation 
FLT3 reduction 
Ranganathan 2012 
KIT activation 
KIT reduction 
Ranganathan 2012 
NF-κB activation 
IκB nuclear retention and activation 
Lapalombella 2012 
PIK3 or AKT activation 
FOXO1, -3, -4 activation 
Lapalombella 2012 
Survivin – cytoplasmic 
Survivin nuclear retention 
Altura 2003 
Bcr-Abl activation 
PP2A activation 
Walker 2013 
 


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Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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3. 
ACUTE MYELOID LEUKEMIA (AML) 
AML is the most common form of acute leukemia in adults, accounting for over 80% of all 
acute leukemias in individuals aged > 18 years (Thein 2013). An estimated 20,830 people will 
be diagnosed with AML in the United States in 2015 and 10,460 patients will die of the disease 
(American Cancer Society 2015). Although survival rates have almost doubled for AML in the 
youngest age group, there has been little improvement in survival for adults in the older age 
groups, with overall 5-year survival rates still less than 5% (Xie 2003). A subsequent analysis 
based on the National Cancer Institute’s Surveillance, Epidemiology, and End Result (SEER) 
dataset including 19,000 AML patients provided similar results; although overall survival 
improved consistently over the past three decades in patients ages 65 to 74 years, with 
improvements in 12-month survival from 20% (1977-1986), to 25% (1987-1996), to 30% 
(1997-2006), respectively, survival rates did not improve in patients aged ≥ 75 years. In this 
study, the highest age group (≥ 85 years) had the lowest survival rates, with no apparent 
improvement compared to previous years (Thein 2013). 
Consistent with the aging of the US population, the median age of AML patients at diagnosis 
has increased from 68 to 72 years (Motyckova 2011). AML is a heterogeneous disease with a 
wide variety of genetic abnormalities, rapid and diverse clonal evolution, and rapid generation 
of resistance to standard agents. Comorbid conditions and general health make therapeutics 
options in older patients very limited. Because standard chemotherapy (typically an 
anthracycline plus standard dose AraC) for AML is quite toxic, only 30-35% of older adults 
are even considered for this treatment (Isidori 2013). For those older adults with AML who do 
receive standard chemotherapy, compared with younger patients, there is a higher incidence of 
therapy-associated early death (~20% versus < 10%), a lower rate of complete remission 
(45-65% versus ~80%), and a reduced chance of long-term survival (Yanada 2012). Despite 
the achievement of CR in approximately half of the older patients receiving standard induction 
chemotherapy, the overall survival from diagnosis remains < 1 year. Moreover, the increased 
morbidity and mortality during induction appear to be directly related to age. 
For older patients who are deemed unfit to receive standard intensive induction chemotherapy 
due to expected therapy-related mortality >30%, survival is very poor. Single agent LD-AraC 
is the only agent to show a clear reduction in mortality in this population of AML patients 
(Burnett 2007). The hypomethylating agent decitabine has shown a trend to improved OS 
(7.7 months) versus best supportive care ± LD-AraC (5.0 months). The related 
hypomethylating agent azacitidine has shown activity in older patients with AML, with 
improved OS (10.4 months) versus conventional care regimens (6.5 months) (Dombret 2014). 
Despite some increases in response rates, no other agent has shown a clear improvement in OS 
in this population, where both efficacy and low rates of side effects are critical (see e.g., 
Burnett 2013). The treatment of older patients with AML following initial relapse from or 
progression on front-line therapy is even more challenging. 
An oral agent that can be administered in the outpatient setting, shows anti-leukemic activity 
with acceptable tolerability, low incidence of induction-associated death and other acute 
toxicities would be welcomed in the treatment of elderly patients with relapsed/refractory 
AML. 


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Karyopharm Therapeutics, Inc. 
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4. 
SELINEXOR (KPT-330) 
4.1. 
Introduction 
Selinexor is an oral, first in class, irreversible, potent and Selective Inhibitor of Nuclear Export 
(SINE) compound that specifically blocks Exportin 1 (XPO1/CRM1). Selinexor restores many 
of the tumor suppressor (TSP) and growth regulatory (GRP) proteins to the nucleus where they 
can carry out their normal functions. It is selectively cytotoxic for cells with genomic damage, 
i.e., for tumor cells, both in vitro and in vivo. All cell types exposed to SINE compounds in 
vitro undergo G1/S ± G2/M cell cycle arrest, followed by a ‘genomic fidelity’ review, and cells 
with damaged genomes are induced to undergo apoptosis. Normal cells, with an intact genome, 
remain in transient, reversible cell cycle arrest until the export block is relieved. Selinexor and 
other SINE compounds are not intrinsically cytotoxic; rather, they can restore the highly 
effective tumor suppressing pathways that lead to selective elimination of genomically 
damaged (i.e., neoplastic) cells. Tumors of hematopoietic lineage are particularly susceptible 
to induction of apoptosis by XPO1 inhibition; normal hematopoietic cells and their functions 
are largely spared. 
4.2. 
Preclinical Data 
In this section a short summary of preclinical data is provided. More detailed information is 
presented in the Selinexor/KPT-330 Investigator’s Brochure (IB). 
4.2.1. 
Pharmacology Studies 
AML cells overexpress the nuclear exporter, Exportin 1 (XPO1/CRM1) and higher XPO1 
levels correlate with poor outcome (Kojima 2013). The novel SINE compound selinexor, 
antagonizes XPO1 and shows potent cytotoxicity for AML and ALL cells in vitro, independent 
of genotype. 
Selinexor shows potent antiproliferative effect and induced apoptosis, cell cycle arrest and 
myeloid differentiation in AML cell lines and patient blasts, including those from patients with 
NPM1 and FLT3-ITD mutations (Ranganathan 2012). 
Mechanistic studies show that SINE compounds induces nuclear localization and activation of 
multiple tumor suppressor proteins (TSPs), leading to rapid apoptosis of AML cells. In 
addition, a strong down-regulation of the oncogenes FLT3 and c-KIT were observed after 
SINE compounds treatment in both FLT3-ITD and wild-type cell lines (Ranganathan 2012). 
Selinexor treatment also restored the localization of cytoplasmic mutant NPM1 into the 
nucleus. 
In murine AML and ALL models, selinexor showed potent antileukemic activity without 
toxicity to normal hematopoietic cells (Etchin 2013a, Etchin 2013b; Ranganathan 2012). 
In vitro experiments with continuous (~72 hour) exposure to selinexor demonstrated potent 
proapoptotic activity across a broad panel of tumor-derived cell lines and patient samples in 
culture including multiply-resistant cancers, with the majority of inhibitory concentrations, 
50% (IC50s) for cytotoxicity < 800 nM and most hematologic tumor lines having IC50s of 
20-400 nM for selinexor. Moreover, selinexor demonstrated cytotoxicity in multiple myeloma 


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(MM) and chronic lymphocytic leukemia (CLL) cells in the absence or presence of bone 
marrow stroma cells (BMSC). In contrast, normal cells typically underwent (or remained in) 
cell cycle arrest but were resistant to apoptosis-induction; cytotoxicity IC50s were typically 
> 5 μM. As noted above, selinexor had little effect on normal (nonmalignant) lymphocytes or 
other nontransformed cells, which correlated with the low incidence in animals of the typical 
side effects seen with most anti-cancer therapies such as significant myelosuppression, 
alopecia, mucositis and other gastrointestinal (GI) dysfunction. 
Preclinical parameters were assessed in three species:  mouse (CD1), rat (Sprague-Dawley), 
and monkey (cynomolgus). While pharmacokinetic (PK) studies were limited to male animals 
for all three species, toxicokinetic (TK) evaluations were conducted in both sexes for rats and 
monkeys as part of the KPT-330 toxicology studies, and no consistent sex-related differences 
were observed in either species. No accumulation was observed in any of the multi-dose 
toxicology studies with an every other day dosing regimen for KPT-330. Overall, systemic 
exposure was generally dose-proportional in all TK studies that involved multiple dose levels. 
Higher maximum concentration (Cmax) and earlier time to maximum concentration (Tmax) 
values were observed in monkeys that were fasted versus fed prior to dosing. Systemic 
exposure (area under the curve from first to last plasma measurement, AUClast) to KPT-330 
achieved with gelatin capsules was comparable to that achieved with oral suspension dosing, 
with lower Cmax and later Tmax values observed with capsules, and was not affected by the 
feeding status in monkeys. Oral bioavailability (F%) of KPT-330 was remarkably consistent 
among the three species, with average values of 66.5%, 61.2%, and 67.5% in mice, rats, and 
monkeys, respectively. See the Selinexor/KPT-330 IB for more information. 
4.3. 
Clinical Experience 
Study KCP-330-001 is a Phase 1, open-label, dose-escalation study to evaluate the safety and 
tolerability of oral selinexor and determine the RP2D in patients with hematological 
malignancies with three arms. Arm 1 includes patients with “chronic” hematological 
malignancies multiple myeloma (MM), Waldenström’s Macroglobulinemia (WM), non-
Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). This trial enrolled 
2 patients in cohort 1 with dose escalation of 100% increase from Cohort 1 to 2. Cohort 2 
enrolled at least 3 patients with dose escalation of 100% increase from Cohort 2 to 3. For 
cohorts 3 and beyond, the standard 3+3 design was used with dose escalation increase of 
30-40% from previous cohort. Arm 2 includes patients with acute myeloid leukemia (AML) 
of any subtype except M3. Because of the rapidly progressive nature of AML, Arm 2 began 
dosing at 16.8 mg/m2 after dose limiting toxicity (DLT) clearance in cohort 3 (12 mg/m2) and 
initiation of 16.8 mg/m2, corresponding to Cohort 4 of the Chronic Hematological 
Malignancies portion of the study. The standard 3+3 design was used with dose escalation 
increase of 30-40% from previous cohort. Arm 3 includes up to 12 patients with 
relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma 
(CTCL) treated at a dose of 30 mg/m2 twice weekly. 
A dose of 70 mg/m2 (~120 mg fixed dose) cleared DLT in patients with relapsed/refractory 
AML in Study KCP-330-001. An ~55 mg/m2 twice weekly dose was initially used in this study 
(Protocol Versions< 5.0) as this was <MTD. However, the dose has been reduced to a 60 mg 
fixed dose in response to a possible increase in sepsis related SAEs for selinexor ~55 mg/m2 


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(8 sepsis events) versus PC (2 sepsis events) (a ratio of 4:1 and not the expected 2:1) that was 
detected during an annual review of clinical safety data (29 July 2015). Clinical safety data 
supporting the 60 mg fixed dose are provided in Section 4.3.1.1. 
Overview of Clinical Efficacy in AML. Sixty-five heavily pretreated patients with progressive 
RR AML, most with ≥ 3 prior lines of treatment, were enrolled in the KCP-330-001 AML 
treatment arm and received selinexor 16.8-70 mg/m2 in four-week cycles. 
Among 48 evaluable patients (of 65 patients enrolled), the CR rate, with or without full 
hematologic recovery, was 8%, ORR was 15%, and DCR was 49%. (Note:  17 patients [26%] 
were non-evaluable but were included in the AML response rate calculation, based on the 
ITT approach.) Best response results as of 10 June 2014 are shown in Table 3 (Garzon 2014). 
Patients could be deemed non-evaluable due to either lack of post-dosing bone marrow 
assessments, failure to take the required number of doses of study medication, withdrawal of 
consent, or death during Cycle 1 prior to response determination. During this study, sixteen 
patients died during Cycle 1, including patients who were evaluable due to PD prior to death. 
Table 3: 
Best Responses in AML Patients as of 10 June 2014 
Number Enrolled 
DCR 
(%) 
ORR 
(%) 
CR 
(%) 
CR(i/p) 
(%) 
PR 
(%) 
MLFS 
(%) 
SD 
(%) 
PD 
(%) 
NE 
(%) 
65 
31 
10 
5 
2 
1 
2 
22 
16 
17 
(100%) 
(49%) 
(15%) 
(8%) 
(3%) 
(2%) 
(3%) 
(34%) 
(25%) 
(26%) 
Abbreviations:  N=number of patients, CR=complete remission, CR(i/p)=complete remission without 
hematological recovery, PR/MLFS= partial remission / morphologic leukemia free state, SD=stable disease, 
PD=progressive disease, NE=non-evaluable. 
 
Overview of Clinical Safety in AML. As of the 31 May 2015 clinical safety analysis for 
selinexor studies in patients with hematological malignancies, Grade 3/4 TEAEs that were 
reported in ≥ 5% of patients include:  anemia (13%) and fatigue (11%). Grade 3/4 
thrombocytopenia (27%) and neutropenia (15%) were observed, however all patients enrolled 
in selinexor clinical studies had advanced stages of cancer and have been heavily pre-treated 
with chemotherapy and other marrow-suppressive agents, which may contribute to reported 
instances of myelosuppression. The most common Grade 1/2 TEAEs were nausea (50%), 
fatigue (40%), anorexia (36%), and vomiting (28%). 
It is anticipated that fewer and more mild gastrointestinal events and reduced fatigue will be 
observed in the future as a result of the initiation of supportive care and medications prior to 
beginning selinexor therapy.  
Please refer to the Selinexor/KPT-330 IB for the most current clinical experience information. 
4.3.1. 
Potential Risks 
Selinexor is currently in clinical development and has not been approved by the Food and Drug 
Administration (FDA) for commercial use. Human experience with selinexor is currently 
limited and the entire safety profile is not known at this time. Measures will be taken to ensure 
the safety of the patients participating in this trial, including the use of stringent inclusion and 


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exclusion criteria and close monitoring. Toxicity grading will be performed in accordance with 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
V4.03. If more than one different type of toxicity occurs concurrently, the most severe grade 
will determine the modification. 
If toxicities are encountered, adjustments will be made to the study treatment as detailed in the 
sections below. All AEs and serious adverse events (SAEs) will be recorded during the trial 
and for up to 30 days after the last dose of study treatment or until the initiation of another anti-
cancer therapy, whichever occurs first. 
As of the 31 May 2015 clinical safety analysis for all selinexor studies, the most common AEs 
suspected to be related to selinexor (incidences in parentheses) have been nausea (55%), 
fatigue (54%), anorexia (43%), vomiting (35%), and  thrombocytopenia (30%). Most of these 
effects can be managed effectively with dose modification and/or supportive care initiated 
prior to first dosing. 
Low-grade blurred vision was reported in 12% of patients treated with selinexor. In patients 
without pre-existing cataracts, blurred vision was not associated with objective findings of lens 
opacity (or other abnormalities) on expert ophthalmic examination. The cases have generally 
been self-limiting without progression, even when selinexor dosing was continued. 
In a previous study, one patient, heavily pre-treated for recurrent pancreatic cancer, developed 
acute cerebellar syndrome following 3 doses of selinexor at 85 mg/m2 BSA twice weekly. The 
patient experienced abnormal speech, loss of coordination, and was unable to walk. Since the 
date of the initial reported event, this patient is recovering, with both speech and mobility 
recovered to near baseline over ~6 weeks. No other patients have reported similar symptoms 
to date. 
Cognitive disturbance (Grade 3) was experienced by an 18-year-old female patient with 
relapsed AML after receiving four doses of selinexor 56 mg/m2 twice weekly in the dose-
escalation phase of a pediatric investigator sponsored trial. 
Please refer to the Selinexor/KPT-330 IB for the most current safety information. 
4.3.1.1. 
Risk of Sepsis in AML 
During an annual review of clinical safety data (29 July 2015), a possible increase in 
sepsis-related SAEs for selinexor ~55 mg/m2 (8 sepsis events) versus PC (2 sepsis events) in 
AML was detected in the patient population for this study. 
The incidence of febrile neutropenia was similar on the two arms of the study (17 vs 9 events 
on selinexor and PC arms, respectively), although pneumonia/lung infections may be 
increased on the selinexor arm (8 vs 2 events on selinexor and PC arms, respectively). Seven 
of the 8 sepsis events on the selinexor arm occurred in patients receiving 100 mg of 
selinexor; the other patient received 80 mg of selinexor. Although the numbers are small, 
these observations suggest that doses above 80 mg of selinexor should not be given to older 
patients with relapsed/refractory AML. 


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In parallel with these observations and with the preparation of the Phase 1 study updates for 
the selinexor annual report, AE rates were compiled across dose levels for patients with 
AML in the initial Phase 1 study (Study KCP-330-001). Rates of sepsis, but not other 
infections, appear to be higher at doses > 300 mg/m2/cycle than at doses ≤ 300 mg/m2/cycle. 
Similar findings were not observed for other indications in other studies across other 
hematologic and solid tumor malignancies.  
Based on these safety analyses, the dose of selinexor in this study has been reduced from an 
oral fixed milligram (mg) dose equivalent to ~55 mg/m2 (60, 80, 100 or 120 mg based on 
body surface area (BSA); ~ 440 mg/m2/cycle) dosed twice weekly during each 4-week cycle 
to a fixed dose of 60 mg (~35 mg/m2, ~280 mg/m2/cycle) dosed twice weekly during each 
4-week cycle. 
4.3.1.2. 
Reproductive Risks 
Macroscopic and microscopic changes in reproductive organs were noted during rat and 
monkey toxicology studies; most resolved or partially resolved during the recovery period. The 
long term 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 12.3.3.1 Prevention of 
pregnancy) during the study and for 3 months after the end of treatment. 


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5. 
RATIONALE FOR THE STUDY 
Selinexor is a first in class SINE compound that specifically blocks the karyopherin protein 
Exportin 1 (XPO1/Exportin 1, also called CRM1). XPO1 is a non-redundant, key regulatory 
protein responsible for the nuclear export and therefore functional inactivation of tumor 
suppressor proteins (TSPs). XPO1 is up-regulated in AML and correlated with poor prognosis 
(Kojima 2013). Selinexor, given orally, has demonstrated potent anti-leukemic activity in 
animal models of AML with minimal toxicity to normal hematopoietic cells 
(Ranganathan 2012; Etchin 2013a; Etchin 2013b). 
As of 10 June 2014, 65 patients with relapsed/refractory AML (median prior therapies 3) were 
enrolled in the ongoing Phase 1 study (KCP-330-001) at doses of 16.8 mg/m2 to 70 mg/m2. 
The median age was 67 years. The most common toxicities have been diarrhea, nausea, 
anorexia and fatigue. Nausea, anorexia and fatigue were manageable with oral supportive care 
agents. Diarrhea generally responded rapidly to standard anti-diarrheal agents. As of 
10 June 2014, there has been no DLT. Along these lines, selinexor-associated deaths have not 
been reported. Of the 48 patients (out of 65 patients enrolled) who were evaluable for response, 
complete remission (CR) with full hematological recovery was achieved in 5 patients (8%), 
and CR without hematological recovery (CRi) in 2 patients (3%). Partial remission (PR) was 
achieved in 1 patient (2%). A morphological leukemia free state was achieved in 2 patients 
(3%). Twenty-two (34%) patients have had stable disease (SD) and 16 (25%) have had 
progressive disease (PD) (Garzon 2014). 
The goal of this trial is to evaluate the potential for an overall survival (OS) benefit associated 
with oral selinexor administration in patients ≥ 60 years of age that are ineligible for intensive 
chemotherapy or stem cell transplantation (SCT). 
5.1. 
Rationale for the Doses and the Dosing Regimen 
A MTD of 65 mg/m2 (~110 mg) twice weekly (Days 1 and 3) has been determined in the 
ongoing Phase 1 study of selinexor in patients with advanced solid tumors (KCP-330-002). 
Two dose-limiting toxicities (DLTs) occurred in 2 patients in the solid tumor study 
(KCP-330-002) treated at 85 mg/m2 (~145 mg) twice weekly and included ‘probably related’ 
asymptomatic Grade 3 hyponatremia and ‘possibly related’ acute cerebellar syndrome with 
ataxia and dysarthria. Of note, asymptomatic hyponatremia had been observed in other patients 
treated with selinexor, but only this one case of acute cerebellar syndrome was observed across 
any of the selinexor trials (730 patients evaluable for safety as of 31 May 2015). 
A dose of 70 mg/m2 (~120 mg fixed dose) cleared DLT in patients with relapsed/refractory 
AML. Therefore the ~55 mg/m2twice weekly dose used in Protocol Versions< 5.0 was <MTD. 
However, the dose has been reduced in response to a possible increase in sepsis related SAEs 
for selinexor ~55 mg/m2 (8 sepsis events) versus PC (2 sepsis events) (a ratio of 4:1 and not 
the expected 2:1) that was detected during an annual review of clinical safety data (29 July 
2015). Clinical safety data supporting the 60 mg fixed dose are provided in Section 4.3.1.1. 
Selinexor will be initiated at a fixed oral dose of 60 mg (equivalent to ~35 mg/m2 mg/m2) twice 
weekly (e.g., Monday and Wednesday or Tuesday and Thursday or Wednesday and Friday). 


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Patients who were randomized to selinexor (~55 mg/m2) under Protocol Versions < 5.0 will be 
switched to the 60 mg fixed dose. 
No patients in any study may receive doses above 70 mg/m2. Therefore, BSA will be 
monitored to ensure that no patient exceeds the maximum allowable dose. 


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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
To determine overall survival (OS) of selinexor as compared to physician’s choice (PC) in 
patients ≥ 60 years old with relapsed/refractory AML that requires treatment and are ineligible 
for intensive chemotherapy and/or transplantation. 
6.2. 
Secondary Objectives 
• To determine the proportion of patients whose OS is at least 3 months (OS3.0) 
• To determine the complete remission rate (CRR), including complete remission with  
full hematologic recovery (CR), and median disease free survival (DFS) for patients 
who achieve CR 
• To determine the modified CRR (mCRR), including CR or complete remission with 
incomplete hematologic recovery (CRi) (including complete remission with 
incomplete platelet recovery [CRp]), and median DFS for patients who achieve CR or 
CRi (including CRp) 
• To determine the overall response rate (ORR) and duration of overall response 
(DOR), including CR, CRi, morphologic leukemia-free state (MLFS), and partial 
remission (PR) 
• To determine the disease control rate (DCR) defined as ORR + stable disease for 
≥ 4 weeks (SD), and duration of DCR 
• To assess the safety and tolerability of selinexor (KPT-330), as compared to 
physician's choice (PC) 
• Quality of life and patient reported outcomes (FACT-Leukemia and EQ-5D-5L) 
(QoL) 
 


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7. 
STUDY DESIGN 
7.1. 
Study Design Overview 
This is a randomized, multicenter, open-label Phase 2 study of the SINE compound selinexor 
given orally versus restricted investigator choice (i.e., one of three potential salvage therapies). 
Patients who have never been transplant-eligible, are currently deemed unfit for intensive 
chemotherapy, ≥ 60 years old, who have AML (except acute promyelocytic leukemia: APL, 
AML M3) who have poor prognosis (intermediate or adverse risk) cytogenetics, with relapsed 
or refractory AML, after at least one prior AML therapy including at least an adequate trial of 
a hypomethylating agent with at least 2 cycles, and are meeting the inclusion and exclusion 
criteria will be randomized to receive either oral selinexor or physician's choice (one of three 
potential treatments:  best supportive care (BSC) alone, or BSC + hypomethylating agent, or 
BSC + low dose AraC) until disease progression, death or intolerance has occurred. 
Patients will be stratified for randomization using three criteria:  (1) duration of their first CR 
on prior therapy, > 6 months versus ≤ 6 months or never achieved CR; (2) number of prior 
therapies, 1 versus >1; (3) peripheral leukemic blast counts ≥ 10,000/μL versus < 10,000/μL. 
Patients can be randomized within 3 calendar days of Cycle 1 Day 1. Any patient randomized 
into this trial cannot be re-randomized for any reason. Selinexor will be given orally twice 
weekly (e.g., Monday and Wednesday, Tuesday and Thursday, or Wednesday and Friday) at 
a dose of 60 mg. Patients who were randomized to selinexor (~55 mg/m2) under Protocol 
Versions < 5.0 will be switched to the 60 mg fixed dose. Clinical safety data supporting the 
60 mg fixed dose are provided in Section 4.3.1.1. 
Hydroxyurea may be used at any time during the study, typically in patients with WBC 
≥ 30,000/μL or per institutional guidelines. Prior to the initiation of hydroxyurea, please 
consider the contraindications in the Summary of Product Characteristics (SPC), including 
leukocytopenia (< 2.5 x 109 leukocytes/L), thrombocytopenia (< 100 x 109 platelets/L) or 
severe anemia. 
One of the following three conventional care regimens will be selected by the treating 
physician:  (1) best supportive care (BSC) including blood product transfusions, 
antimicrobials, growth factors as needed, and hydroxyurea; or (2) BSC + low dose AraC, 
20 mg bid by subcutaneous (sc) injection daily on days 1-10/14 days (20/28 doses) to be 
repeated at 28 to 42 day intervals; or (3) BSC + hypomethylating agent:  azacitidine 75 mg/m2 
by sc injection daily on Days 1-7 or Days 1-5, 8-9 (7 doses) to be repeated at ≥ 28 day intervals, 
or decitabine (20 mg/m2 IV over 1 hour daily on days 1-5 or days 1-10 to be repeated at 
≥ 28 day intervals). 
Patients on the selinexor arm can receive appropriate anti-leukemia therapy following 
progression on or withdrawal from the selinexor arm.  


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Treatment with selinexor or the physician's choice will continue until the patient is removed 
from the study. At the discretion of the investigator, the investigator may remove a patient 
from study treatment for the following reasons: 
• Disease progression defined as an increase in blast counts and absence of hematologic 
recovery (one or more lineages) 
• Unacceptable AEs or failure to tolerate the study treatment 
• Patients decides to discontinue study therapy 
• Significant deviation from entry criteria (e.g., non-relapsed or non-refractory AML) 
• Misuse of study medication (e.g., deliberate overdosing by patient)  
• Missed / unscheduled / off-schedule / incomplete / incorrect assessments that result in 
patients being put at risk 
• Any other medically appropriate reason or significant protocol violation, in the 
opinion of the investigator. 
 
The investigator must determine the primary reason for a patient’s discontinuation of study 
treatment and record this information on the eCRF. Patients who are prematurely withdrawn 
from study treatment are not eligible to re-initiate study treatment at a later date. 
Patients may decide to discontinue study treatment for any reason. Patients who elect not to 
initiate study treatment or to discontinue study treatment should be encouraged to continue in 
the study so that follow-up information on disease progression and survival status may be 
obtained. However, patients may elect to withdraw consent and decline further participation in 
the trial. 
Patients will be followed for survival until the last patient has been followed for 6 months from 
the end of treatment, disease progression, another withdrawal criterion is met, or until death, 
whichever comes first. 
7.2. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will be set up to review the safety of 
selinexor and to review any SAEs that occur during the study. 
The DSMB will be composed of at least two physicians (at least one of whom is an oncologist) 
and a statistician. The DSMB will be provided with all reports of SAEs regardless of 
investigator causality assessments. 
Two interim analyses will be conducted on the ITT population (see Section 14.2.1.4 for further 
details). The first interim analysis will take place after 31 (25%) OS events have occurred, and 
will be conducted to assess futility only (non-binding). Futility would be concluded if the 
p-value from the log-rank test is ≥ 0.8084. The second interim analysis will take place after 
62 (50%) deaths, and will allow for a conclusion of significant efficacy at an α-level < 0.0015, 
and stopping for futility (non-binding) at an α-level ≥ 0.2879. The DSMB will be given the 
results of the interim analyses for review and will provide to Karyopharm the recommendation 
of stopping the trial for significant efficacy or futility, or continuing the study. 


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In addition to the interim analyses performed on the ITT population, a review of safety data 
for all patients will also be conducted at each interim analysis. 
Following the initial meeting, DSMB meetings will occur on a periodic basis in accordance 
with the DSMB charter. The chairperson of the DSMB will also be immediately provided with 
the report of any SAE that is judged as possibly, probably, or definitely attributable to treatment 
with study drug. 
The charter of the DSMB will specify that this committee is charged with providing periodic 
reports to Karyopharm that contain recommendations that include, but are not limited to, 
(a) continuation of the study, and (b) termination of the study.  
7.3. 
Stopping Rules 
The entire study or treatment of individual patients may be stopped under defined 
circumstances as outlined in Section 11:  Discontinuation Criteria. 
7.4. 
Study Endpoints 
7.4.1. 
Primary Endpoint(s) 
Overall survival (OS) is the primary efficacy endpoint of this study. 
7.4.2. 
Secondary Endpoints 
Secondary efficacy endpoints will include the following, assessed in hierarchical fashion in the 
order presented below: 
• The proportion of patients whose OS is at least 3 months (OS3.0) 
• The complete remission rate (CRR), including complete remission with full 
hematologic recovery (CR), and median disease free survival (DFS) for patients who 
achieve CR 
• The modified CRR (mCRR), including CR or CRi (including CRp), and median DFS 
for patients who achieve CR or CRi (including CRp) 
• The overall response rate (ORR) and duration of overall response (DOR), including 
CR, CRi, MLFS, and partial remission (PR) 
• The disease control rate (DCR) defined as ORR + stable disease for ≥ 4 weeks (SD), 
and duration of DCR 
• Quality of life and patient reported outcomes (FACT-Leukemia and EQ-5D-5L) 
(QoL) 
 
The safety and tolerability of selinexor and PC will be evaluated by means of drug-related AE 
reports, physical examinations, and laboratory safety evaluations. 
7.5. 
Blinding and Randomization 
This is an open-label study and is, therefore, not blinded. 
Patients will be randomized into the selinexor or PC treatment arms in a 2:1 allocation, within 
each of the 2 x 2 x 2 stratification levels. Patients will be stratified for randomization using 


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three criteria:  (1) duration of their first CR on prior therapy, > 6 months versus ≤ 6 months or 
never achieved CR; (2) number of prior therapies, 1 versus >1 (3) peripheral leukemic blast 
counts ≥ 10,000/μL versus < 10,000/μL. Patients should be randomized within 3 calendar days 
of Cycle 1 Day 1. 
Any patient randomized into this trial cannot be re-randomized for any reason. 
 


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8. 
SELECTION OF PATIENTS 
8.1. 
Number of Patients 
Approximately 300 patients will be randomized into the selinexor or PC treatment arms in a 
2:1 allocation, with the 2:1 allocation performed within each of the 2 x 2 x 2 stratification 
levels. Two separate cohorts will be randomized. To date, approximately 110 patients were 
randomized to selinexor at a fixed dose of ~55 mg/m2 versus PC under Protocol Versions < 5.0; 
enrollment will continue until Protocol Version 5.0 is approved. Due to dose and inclusion 
criteria changes in Version 5.0, the patients enrolled under Protocol Versions < 5.0 will not be 
included in the ITT population. Approximately 171 additional patients will be randomized 
under Protocol Versions ≥ 5.0, to either 60 mg of selinexor (flat dose) or PC, again in a 2:1 
randomization allocation within strata.  
8.2. 
Recruitment 
This study will be conducted at approximately 60 sites in North America, Europe, and the rest 
of the world. 
8.3. 
Inclusion Criteria 
In order for a patient to be included in the study, the patient must meet all the following criteria: 
1. Signed, written informed consent in accordance with federal, local, and institutional 
guidelines 
2. Patients age ≥ 60 years with relapsed/refractory AML (defined using WHO criteria) of 
any type except for acute promyelocytic leukemia (APL; AML M3), after at least one 
prior AML therapy, who have never undergone and who are not currently eligible for 
stem cell transplantation, and are currently deemed unfit for intensive chemotherapy.  
3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
4. Diagnosis of AML (WHO classification definition of ≥ 20% blasts) with the exception 
of acute promyelocytic leukemia (APL; AML M3); patients must have available 
archival or recently acquired bone marrow biopsy/aspiration or tumor tissue for central 
review to be eligible. 
5. Relapsed or refractory AML, defined as either:  
1) recurrence of disease after a complete remission (CR), or  
2) failure to achieve CR with initial therapy.  
6. All patients must have received at least one prior line of AML therapy given at standard 
doses and must have progressed after their most recent therapy. Prior therapy must have 
included an adequate trial of a hypomethylating agent with at least 2 cycles. 
7. A period of at least 2 weeks must have elapsed since the last anti-leukemia treatment 
(with the exception of hydroxyurea) before first dose in this study. 
8. Objective, documented evidence of disease progression or failure to respond to a 
reasonable trial of their most recent previous therapy prior to study entry.  
9. Serum biochemical values with the following limits unless due to leukemia:  creatinine 
clearance > 30 cc/min calculated using the Cockcroft and Gault (Cockcroft and Gault 
1976) formula or measured; total bilirubin ≤ 2 x upper limit of normal (ULN) (except 
patients with Gilbert’s syndrome [hereditary indirect hyperbilirubinemia] who must 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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have a total bilirubin of ≤ 3 x ULN); transaminases (AST and ALT) ≤ 2.5 x ULN 
(except patients with known liver involvement of their AML who must have an AST 
and ALT ≤ 5 x ULN). 
10. Coagulation time (Prothrombin time [PT] and partial thromboplastin time [PTT]) 
≤ 1.5 x ULN (PTT elevation for known lupus anticoagulant is allowed). Coagulation 
may also be measured using thromboplastin time (Quick test) if measurement of 
PT/PTT is not feasible. 
11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests and other study procedures. 
12. Male patients with partners of childbearing potential must agree to use effective 
contraception during the study period and a period of 3 months after the last dose of 
study drug. 
8.4. 
Exclusion Criteria 
A patient will not be included in the study if any of the following criteria are met: 
1. Treatment with any investigational agent within three weeks prior to first dose in this 
study. 
2. Presence of central nervous system (CNS) leukemia. 
3. Patients with AML M3 or who are in blast transformation of chronic myeloid leukemia 
(CML). Prior myelodysplastic syndrome (MDS) is acceptable; prior treatment for 
MDS does not count as an AML therapy. 
4. Patients whose AML is classified as favorable according to the European LeukemiaNet 
(ELN) disease risk assessment (Appendix 1). 
5. Major surgery within 2 weeks of first dose of study drug. Patients must have recovered 
from the effects of any surgery performed greater than 2 weeks previously. 
6. Patient has a concurrent active malignancy. 
7. Unstable cardiovascular function: 
• symptomatic ischemia, or  
• uncontrolled clinically significant conduction abnormalities (i.e., ventricular 
tachycardia on antiarrhythmic agents are excluded; 1st degree atrioventricular (AV) 
block or asymptomatic left anterior fascicular block/right bundle branch block 
(LAFB/RBBB) will not be excluded), or 
• congestive heart failure (CHF) NYHA Class ≥ 3, or 
• myocardial infarction (MI) within 3 months. 
8. Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within 
one week prior to first dose. Infections controlled on concurrent anti-microbial agents 
are acceptable, and anti-microbial prophylaxis per institutional guidelines are 
acceptable. 
9. Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be 
positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen). 
10. Known human immunodeficiency virus (HIV) infection. 
11. Any medical condition which, in the investigator's opinion, could compromise the 
patient's safety. 


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Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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12. Patients unable to swallow tablets, or patients with malabsorption syndrome, or any 
other disease significantly affecting gastrointestinal function. 
8.5. 
Screen Failures 
Patients who sign an informed consent form, are not assigned to a treatment, and do not receive 
test article are defined as screen failures. For all screen failures, the investigator will enter the 
screening number, patient initials and reason(s) for screen failure into the electronic data 
capture (eDC) system. These data will also be retained in the investigator’s study files and can 
be printed by the site in log format at the end of the study. Screen failures are to be replaced. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 44 
9. 
STUDY PLAN AND PROCEDURES 
This is a randomized, multicenter, open-label Phase 2 study of the SINE compound selinexor 
given orally versus investigator choice (one of three potential salvage therapies). 
Patients age ≥ 60 years with relapsed/refractory AML (defined using WHO criteria) of any 
type except for APL (AML M3), who have poor prognosis (intermediate or adverse risk) 
cytogenetics, with relapsed or refractory AML, after at least one prior AML therapy (must 
have included an adequate trial of a hypomethylating agent with at least 2 cycles), who have 
never undergone, and who are not currently eligible for, stem cell transplantation, and are 
currently deemed unfit for intensive chemotherapy, and are meeting the inclusion and 
exclusion criteria will be randomized to receive either oral selinexor or investigator choice 
(one of three potential treatments:  best supportive care (BSC) alone, or BSC + 
hypomethylating agent, or BSC + low-dose AraC until disease progression, death, or 
intolerance has occurred. 
Patients on the selinexor arm can receive appropriate anti-leukemia therapy following 
progression on or withdrawal from the selinexor arm.  
9.1. 
Study Patient Number 
Approximately 300 patients will be randomized into the selinexor or PC treatment arms in a 
2:1 allocation, with the 2:1 allocation performed within each of the 2 x 2 x 2 stratification 
levels. Two separate cohorts will be randomized. To date, approximately 110 patients were 
randomized to selinexor at a fixed dose of ~55 mg/m2 versus PC under Protocol Versions < 5.0; 
enrollment will continue until Protocol Version 5.0 is approved. Due to dose and inclusion 
criteria changes in Version 5.0, the patients enrolled under Protocol Versions < 5.0 will not be 
included in the ITT population. Approximately 171 additional patients will be randomized 
under Protocol Versions ≥ 5.0, to either 60 mg of selinexor (flat dose) or PC, again in a 2:1 
randomization allocation within strata. Patients will be stratified for randomization using three 
criteria:  (1) duration of their first CR on prior therapy, > 6 months versus ≤ 6 months or never 
achieved CR; (2) number of prior therapies, 1 versus >1; (3) peripheral leukemic blast counts 
≥ 10,000/μL versus < 10,000/μL. 
Each patient is identified in the study by a patient number that is assigned when the patient is 
first screened and is retained as the primary identifier for the patient for the duration of the 
study. Patient numbers will not be reassigned or reused for any reason. The patient number 
consists of the last 3 digits of the protocol number, center number as assigned by Karyopharm 
or the eDC vendor, with a sequential patient number suffixed to it, so each patient is numbered 
uniquely across the entire database. The investigator must maintain a patient master log. 
9.2. 
Description of Study Days 
9.2.1. 
Visit 1 (within 14 days prior to start of therapy); Screening #1 
Study procedures will be performed within 14 days prior to the start of therapy, as specified in 
Table 1. The study site should not repeat procedures completed as standard of care (SOC) if 
they are within the Screening window, and prior to signing the Informed Consent Form (ICF). 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 45 
The data from these procedures are part of the medical history and can be used for study 
purposes. 
• Sign Informed Consent 
• Demographics 
• Complete medical history 
• Full ophthalmic examination (See Appendix 3 for a detailed description). 
• Bone Marrow Aspirate (or Biopsy if aspirate is not adequate) including 
immunophenotyping, cytogenetic and molecular analysis (FLT3 ITD or TKD mutation 
or NPM1 mutations)(requires approval of the sponsor to perform between 14 and 
8 days prior to Day 1 Cycle 1 Days;  typical is ≤7 days prior to Day 1 Cycle 1) 
• 12-lead electrocardiogram (ECG) 
• Baseline symptoms 
• Concomitant medication assessments 
• Chest radiograph 
• Disease risk assessment, based on patient disease history, according to the European 
LeukemiaNet (ELN):  Favorable Risk (FR), Intermediate Risk (IR), and Adverse Risk 
(AR) (Rollig 2011) (See Appendix 1) 
9.2.2. 
Visit 2 (within 7 days prior to start of therapy); Screening #2 
Study procedures will be performed within 7 days prior to the start of therapy, as specified in 
Table 1: 
• Review of inclusion and exclusion criteria 
• Complete physical examination 
• ECOG Performance Status 
• Body Surface Area (BSA) calculated by Dubois (Dubois and Dubois, 1916) or 
Mosteller (Mosteller 1987) method 
• Weight, height 
• Vital signs (blood pressure, heart rate, body temperature  
• Oxygen saturation [Pulse Oximetry]) 
• Urine dipstick 
• Complete serum chemistry 
• Coagulation parameters 
• Hematology (CBC with differential) 
• Bone Marrow Aspirate (or Biopsy if aspirate is not adequate) including 
immunophenotyping, cytogenetic and molecular analysis (FLT3 ITD or TKD mutation 
or NPM1 mutations)(if not done during Visit 1) 
• Blood draw for correlative studies using peripheral blasts 
• Baseline symptoms 
• Concomitant medication assessments 
• Disease risk assessment according to the European LeukemiaNet (ELN):  Favorable 
Risk (FR), Intermediate Risk (IR) and Adverse Risk (AR) (Rollig 2011) (See Appendix 
1) (if not done at Visit 1) 


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Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 47 
• Weight 
• Vital signs (blood pressure, heart rate, body temperature) 
• Oxygen saturation [Pulse Oximetry]) 
• 12-lead electrocardiogram (ECG) (Day 1 of Week 1 of the cycle only) 
• Urine dipstick 
• Limited serum chemistry 
• Coagulation parameters 
• Hematology (CBC with differential) 
• Bone Marrow Aspirate (or Biopsy if aspirate is not adequate) for disease status 
assessment as specified in Section 10.13 
• Selinexor dosing or physician's choice treatment 
• Blood draw for pharmacokinetic testing (selinexor group only) on Day 1 of each cycle 
only 
• Blood draw for correlative studies using peripheral blasts (Day 1 Cycle 2 only) 
• AEs 
• Concomitant medication assessments 
• Quality of Life (FACT-Leu and EQ-5D-5L) questionnaires will be filled out on Day 1 
of Cycles 2-5 
• Review of temperature diary 
 
9.2.6. 
Visits 9 and 11 (Day 8 and 22 of each Cycle 2 Only; Return to the Clinic 
Study procedures will be performed on Day 8 and Day 22 (± 2 days) of Cycle 2, as specified 
in Table 1: 
• Vital signs (blood pressure, heart rate, body temperature) 
• Complete serum chemistry (only if fever and suspected infection are present) 
• Hematology (CBC with differential)(only if fever and suspected infection are present) 
• Selinexor dosing or physician's choice treatment 
• AEs 
• Concomitant medication assessments 
• Review of temperature diary 
9.2.7. 
Visit 18 + (Day 1 of each Cycle - Cycles ≥ 6); Return to the Clinic 
Study procedures will be performed on Day 1 (± 2 days) of each cycle, as specified in Table 1: 
• Symptom-directed physical examination 
• ECOG Performance Status 
• Body Surface Area (BSA) 
• Weight 
• Vital signs (blood pressure, heart rate, body temperature  
• Oxygen saturation [Pulse Oximetry]) 
• 12-lead electrocardiogram (ECG) 
• Urine dipstick 
• Limited serum chemistry 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 48 
• Coagulation parameters 
• Hematology (CBC with differential) 
• Bone Marrow Aspirate (or Biopsy if aspirate is not adequate) for disease status 
assessment as specified in Section 10.13 
• Selinexor dosing or physician's choice treatment 
• Blood draw for pharmacokinetic testing (selinexor arm only) on Day 1 only  
• AEs 
• Concomitant medication assessments 
• Quality of Life (FACT-Leu and EQ-5D-5L) questionnaires 
• Review of temperature diary 
9.2.8. 
Final Visit (within 30 Days after last dose of study medication); Return to the 
Clinic 
Study procedures will be performed 30 days (± 7) after the last dose of study medication for 
all patients, including early termination patients, as specified in Table 1: 
• Complete physical examination 
• ECOG Performance Status 
• Full ophthalmic examination (See Appendix 3 for a detailed description). 
• Weight 
• Vital signs (blood pressure, heart rate, body temperature 
• Oxygen saturation [Pulse Oximetry]) 
• 12-lead electrocardiogram (ECG) 
• Urine dipstick 
• Complete serum chemistry 
• Hematology (CBC with differential) 
• AEs 
• Concomitant medication assessments 
• Quality of Life (FACT-Leu and EQ-5D-5L) questionnaires 
• Review of temperature diary 
• Information on any antineoplastic therapies utilized since discontinuation of selinexor 
or PC study treatment 
9.2.9. 
30-Day Patient Safety Follow-up (within 30 Days after the final study visit 
± 7 days); Return to the Clinic, if possible 
During this patient contact either in the clinic or by phone, the most important information to 
be obtained includes: 
• Overall medical condition of the patient and status of his/her AML 
• Follow-up on any AEs that were not resolved at the Final Study Visit 
• Information on any antineoplastic therapies utilized since discontinuation of study 
treatment 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 49 
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.  
9.2.10. 
Survival Follow-up 
After study discontinuation, a call will be made to the patient (or the patient’s family) every 
3 months to inquire about the patient’s AML status, well-being, and information on any 
antineoplastic therapies utilized since discontinuation of study treatment. If the patient has 
died, the patient’s date of death will be collected, together with the reason for death, if possible. 
9.2.11. 
Restrictions and Precautions 
Alcohol: 
Ethanol should be avoided on selinexor dosing days as it may compete for 
glutathione mediated metabolism. 
Fasting: 
Patients on the selinexor arm should maintain an adequate diet. 
Medications: 
Acetaminophen on days of selinexor dosing will not exceed a total daily 
dose of 1 gram. Acetaminophen use on other days is not restricted (see 
Section 12.3.4). 
 
Patients should not take glutathione (GSH)-, S-adenosylmethionine 
(SAM)-, or N-acetylcysteine (NAC)-containing products during their 
participation in this study as these products may enhance the metabolism 
of selinexor. Please see Appendix 6 for a list of representative products.  
Diet: 
There are no dietary restrictions on this study. Patients on the selinexor 
arm should maintain adequate caloric and fluid intake. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 50 
10. 
METHODS OF ASSESSMENT AND ENDPOINTS 
10.1. 
Demographic Data 
At Visit 1 (Screening #1), patient demographic data will be collected. These include year of 
birth, age, gender, race, and AML disease parameters. 
10.2. 
Medical History 
At Visit 1 (Screening #1), a complete medical history will be obtained from each patient. 
Medical history includes baseline symptoms as well as a detailed history of prior procedures 
and prior cancer therapies including start and stop dates, best response, disease progression 
during or after therapy, as well as discontinuations due to intolerability or toxicity. Smoking 
history will be recorded. Data will be reviewed at Visit 2 (baseline) and updated at subsequent 
visits. 
10.3. 
Concomitant Medications 
A detailed history of medications will be documented for each patient at Visit 1 (Screening 
#1), Visit 2 (Screening #2) and Visit 3 (Day 1, Cycle 1 baseline). Concomitant medications 
(especially changes in medication) will be documented for each patient at each scheduled visit. 
Necessary supportive care such as anti-emetics and anti-diarrheals etc., will be allowed (see 
Section 12.3.2). 
10.4. 
Physical Examination and ECOG Score 
Full physical examination evaluations at Screening #2 and the Final Study Visit should include 
general appearance, dermatologic, head, eyes, ears, nose, throat, respiratory, cardiovascular, 
abdominal, lymph nodes, musculoskeletal, and neurological examinations. Subsequent 
symptom-directed targeted physical exams should include body systems as appropriate. 
All physical exams will include: 
• Height in centimeters (cm) will be measured at Visit 2 (Screening #2) only. 
• Body weight in kilogram (kg) will be measured at Screening #2 and at each visit. 
• Body temperature will be measured at each visit. 
• Systolic and diastolic blood pressure (BP) and pulse rate will be measured at each visit 
after the patient has been in a supine or sitting position for 5 minutes. Blood pressure 
should be assessed on the same arm at each visit during the study, if possible. 
 
Information about the physical examination must be present in the source documentation at the 
study site. Clinically relevant findings made after the start of study drug, which meet the 
definition of an AE, must be recorded on the AE CRF. 
10.5. 
Safety Assessments 
Safety evaluations will be conducted at Cycle 1, Day 1 baseline, on Day 1 of each week for 
Cycle 1, Days 1 and 15 (± 2 days) for Cycles 2-5, Day 1 (± 2 days) for Cycle ≥ 6, and at the 
Final Study Visit. These evaluations will include a physical examination and ECOG score 
assessment, and a 12-lead ECG. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 51 
A full ophthalmic examination will be conducted on all patients by an optometrist or 
ophthalmologist at screening, at the Final Visit, and at other visits if clinically indicated. The 
full ophthalmic assessment includes 1) prior to dilation:  best corrected visual acuity and slit 
lamp examination including tonometry and 2) following dilation:  fundoscopy and a slit lamp 
exam to document lens clarity. If a cataract is seen during the examination for newly enrolling 
patients or enrolled patients for whom no cataracts have been detected to date, the cataract will 
be graded using a Grade 1-4 scale (Appendix 3). 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. 
The following clinical laboratory tests will be performed: 
• Hematology (blood sample:  EDTA) – hemoglobin, hematocrit, mean corpuscular 
volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
white blood cell (WBC) count, WBC differential, red blood cell count, lymphocytes, 
monocytes, neutrophils, band neutrophils, eosinophils, basophils, platelets. WBC 
differential may be automated or manual as per institutional standards. Reticulocytes may 
be done only when clinically indicated. 
 
• Serum Chemistry (blood sample:  serum) 
 
o 
Complete Serum Chemistry for baseline, Cycles 1 Weeks 1, 2, 3, and 4, 
and at the Final Study Visit including sodium, potassium, chloride, 
bicarbonate, BUN or urea, creatinine, glucose, calcium, phosphate, 
magnesium, ALT, AST, alkaline phosphatase, total bilirubin, LDH, total 
protein, albumin, pancreatic amylase, lipase, creatine kinase, TSH, and uric 
acid. 
 
o 
Limited Serum Chemistry for Days 1 and 15 of Cycles 2 through 5 and 
Day 1 of Cycles ≥ 6 including sodium, potassium, chloride, bicarbonate, 
BUN or urea, creatinine, glucose, ALT, AST, alkaline phosphatase, total 
bilirubin, TSH, and LDH.  
 
o 
If the total bilirubin concentration is increased above 1.5 times the upper 
normal limit, total bilirubin should be differentiated into the direct and 
indirect reacting bilirubin. 
 
• Coagulation – prothrombin time (PT), international normalization ratio (INR), and 
activated partial thromboplastin time (aPTT). Coagulation may also be measured using 
thromboplastin time (Quick test) if measurement of PT/PTT is not feasible. 
 
• Urinalysis – appearance, color, urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein, specific gravity, urobilinogen. Microscopy will only be performed if clinically 
indicated. 


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Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 57 
11. 
DISCONTINUATION CRITERIA 
11.1. 
Early Discontinuation of the Study 
The study may be discontinued at the sole discretion of the sponsor for any reason, including 
medical or ethical reasons affecting the continued performance of the study, or difficulties in 
the recruitment of patients. The results of the two interim analyses, to take place after 
approximately one- quarter and one-half the required number of OS events have occurred, may 
result in a statistical conclusion of futility (see Section 14.1.2), and this would be taken into 
consideration in the decision to potentially stop the trial. Note also that a sample size 
re-assessment may also be performed at the second interim analysis, in order to maintain 
sufficient conditional power (see Section 14.1.2). 
11.2. 
Early Discontinuation of Individual Patients 
At the discretion of the investigator, the investigator may remove a patient from study 
treatment for the following reasons: 
• Disease progression defined as an increase in blast counts and absence of hematologic 
recovery (one or more lineages) 
• Unacceptable adverse event(s) or failure to tolerate the study treatment 
• Patient decides to discontinue study therapy 
• Significant deviation from entry criteria (e.g., non-relapsed or non-refractory AML) 
• Misuse of study medication (e.g., deliberate overdosing by patient)  
• Missed/unscheduled/off-schedule/incomplete/incorrect assessments that result in 
patients being put at risk 
• Any other medically appropriate reason or significant protocol violation, in the 
opinion of the investigator. 
 
The investigator must determine the primary reason for a patient’s discontinuation of study 
treatment and record this information on the eCRF. Patients who are prematurely withdrawn 
from study treatment are not eligible to re-initiate study treatment at a later date. 
Patients may decide to discontinue study treatment for any reason. Patients who elect not to 
initiate study treatment or to discontinue study treatment should be encouraged to continue in 
the study so that follow-up information on disease progression and survival status may be 
obtained. However, patients may elect to withdraw consent and decline further participation in 
the trial. 
Patients will be followed for survival until the last patient has been followed for 6 months from 
the end of treatment, disease progression, another withdrawal criterion is met, or until death, 
whichever comes first. 
11.3. 
End of Study 
End of study (Last Patient Last Visit) will be upon completion of the follow up period for the 
last patient treated in the study. Completion of follow-up will occur when the last patient in 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 58 
the study has expired, has been followed for 6 months after the end of treatment, has been 
lost to follow-up, or has withdrawn consent, whichever occurs first. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 59 
12. 
TREATMENT 
Selinexor study medication will be in the form of a coated, immediate release tablet for oral 
administration. Selinexor tablets will be supplied in bottles or blister packs. Tablets in bottles 
will be provided in two coated tablet strengths:  10 and 25 mg. Study medication of 50 tablets 
per bottle will be supplied for each of the two strengths. Tablets in blister packs will be 
provided in a coated tablet strength of 20 mg. 
The study sites will use their own supply of physician's choice (PC) study medication, as per 
agreement with the site contract with Karyopharm. 
12.1. 
Dosing and Administration of Physician’s Choice Study 
Medication (Reference Therapy) 
Based on the patient’s performance status, organ function, and comorbid conditions, one of the 
following three conventional care regimens will be selected by the treating physician:  (1) best 
supportive care (BSC) including blood product transfusions, antimicrobials, growth factors as 
needed, and hydroxyurea; or (2) BSC + low dose AraC, 20 mg bid by subcutaneous (sc) 
injection daily on Days 1-10/14 (20/28 doses) to be repeated at 28 to 42 day intervals; or 
(3) BSC + hypomethylating agent:  azacitidine 75 mg/m2 by sc injection daily on Days 1-7 or 
1-5, 8-9 (7 doses) to be repeated at ≥28 day intervals, or decitabine (20 mg/m2 IV over 1 hour 
daily on days 1-5 or days 1-10 to be repeated at ≥ 28 day intervals). 
12.2. 
Dosing and Administration of Selinexor 
12.2.1. 
Labelling 
Selinexor tablets will be labeled in accordance with current International Conference on 
Harmonization (ICH), Good Clinical Practice (GCP), and specific national requirements. 
Medication labels will comply with local language and legal requirements of each country. 
Labels will include storage conditions. 
12.2.2. 
Dispensing Directions 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drug as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. 
12.2.3. 
Dosing Information 
Selinexor will be initiated at a fixed oral dose of 60 mg (equivalent to ~35 mg/m2 mg/m2) twice 
weekly (e.g., Monday and Wednesday or Tuesday and Thursday or Wednesday and Friday). 
Patients who were randomized to selinexor (~55 mg/m2) under Protocol Versions < 5.0 will be 
switched to the 60 mg fixed dose. 
In order to minimize nausea and vomiting, it is recommended that selinexor tablets be taken 
within 30-minutes of food consumption together with at least 120 mL (4 ounces) of fluids. 
12.2.4. 
Dosing Instructions for the Study Participants 
Selinexor dosing will occur on Day 1 and Day 3 of each week of a four week cycle. For doses 
on non-clinic days, patients will be provided doses to take home, one dose per container. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 60 
Compliance to study medication will be recorded by study personnel after discussion with the 
patient and drug accountability. Compliance to study medication will be done by the 
investigator or delegate and recorded in source documents. The date will be recorded as per 
study drug schedule. The principal investigator or the designee will account for the number of 
tablets dispensed against those returned by the patient. Any deviations and missed doses will 
be recorded in the CRF and drug accountability logs for verification with the reasons. The 
investigator / designee will try to ensure complete compliance with the dosing schedule by 
providing timely instructions to the patients.  
12.3. 
Dose Reduction and Supportive Care Guidelines 
12.3.1. 
Dose Modifications and Dose Delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The criteria for dose 
modifications for toxicities considered at least possibly related to the study medication 
treatment are outlined in Table 5 and Table 6. These changes must be recorded on the eCRF. 
If a patient requires a dose delay of > 21 days from the intended day of the next scheduled 
dose, then the patient should be discontinued from the study. (In exceptional situations, if the 
patient is clearly benefiting from the study treatment, and in the opinion of the investigator no 
safety concerns are present, after discussion with Karyopharm, the patient may remain in the 
study.) Re-escalation of the study drug is allowed as outlined in the sections that apply for the 
specific toxicity. Patients who discontinue from the study for a study-related AE or an 
abnormal laboratory value must be followed as described in Section 11.2. All interruptions or 
changes to study drug administration must be recorded on the eCRF. 
Toxicity will be graded according to NCI CTCAE, V 4.03; the therapy modifications described 
below are applied according to this severity grading. If more than one different type of toxicity 
occurs concurrently, the most severe grade will determine the modification. 
Based on observations from the ongoing Phase 1 studies in patients with advanced 
hematological and solid tumors, selinexor shows a reasonably wide therapeutic range, with 
activity at doses from ~10 mg/m2 to ≥ 50 mg/m2. 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. Patients should also be treated aggressively with supportive 
care to reduce toxicities. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 61 
Table 5: 
Prespecified Dose/Schedule Modifications for Adverse Events Related to 
Study Drug 
Dose Level 
Dose of Selinexor 
Dose level 0 
60 mg twice weekly (Day 1, Day 3) 
Dose level -1 
40 mg, twice weekly  
(Day 1, Day 3) 
Dose level -2 
20 mg, twice weekly  
(Day 1, Day 3) 
Dose level -3 
20 mg, once weekly (Day1) 
Dose level -4 
Discontinue Dosing 
 
Table 6 contains supportive care and selinexor dose adjustment guidelines for non-
hematologic selinexor-related toxicities. Additional supportive care guidance can be found in 
Section 12.3.2. 
Table 6: 
Supportive Care and Dose Adjustment Guidelines for Non-Hematologic 
Selinexor-Related Toxicities 
Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Fatigue (common) 
Grade 1 
Rule out other causes of fatigue. 
Insure adequate caloric intake 
and assess volume status. 
Maintain dose.  
Grade 2 
Rule out other causes of fatigue. 
Insure adequate caloric intake 
and assess volume status. 
Supportive care for fatigue per 
institutional guidelines and 
recommendations in NCCN 
guidelines:  Fatiguea. 
Maintain dose. 
Consult medical monitor for 
additional option such as 
temporary dose reduction or 
short dose interruptions. 
Grade 3 
See guidelines for Grade 2 
fatigue. 
Interrupt selinexor dosing until 
resolved to Grade ≤ 2, For first 
occurrence of Grade 3, if 
adequate supportive care 
resulted in fatigue improving to 
Grade ≤ 1 within 7 days, restart 
selinexor at current dose.  
Otherwise, restart selinexor at 
one dose level below (Table 5). 
 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 62 
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®).  
Strongly encourage a low dose 
appetite stimulating agent (e.g., 
megesterol acetate 40-80 mg 
bid, up to 200 mg bid daily) 
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®).  
Strongly encourage megesterol 
acetate 40-80 mg bid, up to 200 
mg bid daily. 
Strongly encourage anabolic 
steroids such as oxandrolone, or 
dronabinol (Marinol®) or other 
cannabinoid. 
For additional supportive care 
see NCCN guidelinesb 
(Appendix 5). 
Selinexor may be skipped 
intermittently 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 other 
contributing factors have been 
addressed.   
Nausea/ - acute  (common) 
Grade 1 
Insure adequate caloric intake 
and assess volume status. 
Consider alternate 5-HT3 
antagonists and/or D2 
antagonists as needed. Consider 
addition of NK1 antagonists. 
Maintain dose. 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 2 
See guidelines for Grade 1 
nausea. 
For additional options see 
NCCN guidelines for 
antiemesisc (Appendix 4). 
Selinexor may be skipped 
intermittently 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 (Appendix 4). 
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 
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 > 150 mmol/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 – 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 > 150 mmol/L).   
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-three times per day. 
Hold selinexor until Grade ≤ 1 
(≥ 130 nM), restart on the same 
dose level.  


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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 guideline. 
Initiate salt supplementation 
two-three times per day. 
Hold selinexor until resolved to 
Grade ≤ 1 (≥ 130nM) then 
reduce selinexor dose by 
1 level (Table 5) 
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 
Benson 2004d guidelines  
Institute standard anti-diarrheal 
therapy. 
After the first occurrence of 
diarrhea, loperamide 2 mg 
should be considered 
prophylactically approximately 
1-2 hours before the 
administration of selinexor and 
repeated every 4 hours for the 
first 12 hours. 
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 IV fluids  
Diet recommendation as per 
Benson 2004d guidelines. 
Institute standard anti-diarrheal 
therapy. 
Once the symptoms resolve to 
≤Grade 1, loperamide 2 mg 
should be considered 
prophylactically approximately 
1-2 hours before the 
administration of selinexor and 
repeated every 4 hours for the 
first 12 hours. 
Delay selinexor 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 until resolved 
to ≤ Grade 1, then reduce 
selinexor dose by one dose 
level (Table 5). 
Other selinexor-related adverse events* 
Grade 1 or 2 
Initiate standard supportive care 
and follow institutional 
guidelines. 
Maintain dose. 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3 
Initiate standard supportive care 
and follow institutional 
guidelines. 
Delay dose until resolved to 
Grade ≤ 1 or baseline, then 
reduce by one dose level 
(Table 5). 
Grade 4 
Initiate standard supportive care 
and follow institutional 
guidelines. 
Delay dose until resolved to 
Grade ≤ 1 or baseline, 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. 
aNational Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®):  Fatigue. Available at: http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf 
bNational Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®):  Palliative Care, version 1.2014. Fort Washington, NY. April 2014. Available at: 
http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/facts.p
df. 
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. 
dBenson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-
induced diarrhea. J Clin Onc 2004; 22:2918. 
 
 
For all ≥ Grade 3 hematological or non-hematological AEs that are NOT selinexor-
related: 
After consultation with the Medical Monitor and at the discretion of the treating physician, 
selinexor dosing may be maintained provided that the patient can continue to take the agent by 
mouth, or via other enteral route. 
12.3.1.1. Selinexor Dose Adjustments for Hematological Toxicities 
No dose adjustments or treatment interruptions for myelosuppression are required in the 
presence of residual leukemia. Treatment may be continued regardless of neutrophil and 
platelet count, with supportive care (e.g., transfusions) provided as needed. Treatment 
interruptions and dose adjustments may be considered according to the following guidelines 
only when there is no evidence of active leukemia (e.g., only if < 5% blasts in the bone marrow 
or cytopenias not considered to be related to leukemia).  
 
• Patients with a response (e.g., only if < 5% blasts in the bone marrow or cytopenias not 
considered to be related to leukemia) and pre-cycle counts of neutrophils > 1x 109/L and 
platelets > 50 x 109/L who have sustained low counts of neutrophils < 0.5 x 109/L or a 
platelet count < 20 x 109/L for more than 2 consecutive weeks in the current cycle, may 


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have the treatment with selinexor interrupted at the discretion of the treating physician until 
neutrophils recover to ≥ 1 x 109/L and platelets to ≥ 50 x 109/L. 
 
• Patients with a response (significant reduction in marrow blast count) and pre-cycle counts 
of neutrophils < 1 x 109/L and platelets < 50 x 109/L may be continued regardless of 
neutrophil and platelet count with supportive care as needed. Dose-interruptions in these 
patients should be considered on an individual case and discussed with the Sponsor. 
 
12.3.1.2. Selinexor Dose Adjustment for Decreased Glomerular Filtration Rate (GFR) 
Selinexor is not significantly eliminated by the kidney. Therefore, no dose alteration of 
selinexor is required with renal dysfunction.  
12.3.1.3. Selinexor Dose Adjustment in the Setting of Infection 
Patients with active uncontrolled infections should have selinexor treatment withheld until 
infection has clinically resolved or the patient is clinically stabilized. However, selinexor has 
not been associated with opportunistic infections in 730 patients evaluable for safety as of 
31 May 2015. Therefore, after the infection has resolved clinically or the patient’s clinical 
condition has stabilized, treatment with selinexor 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. 
12.3.1.4. Conditions not Requiring Selinexor Dose Adjustment 
The following conditions are exceptions to the above guidelines. Selinexor does not need to be 
held in the following cases: 
• Alopecia of any grade 
• Electrolyte or serum analyte (e.g., urate) abnormalities that are reversible with 
standard interventions 
12.3.1.5. Dose Adjustments with Changes in BSA 
Dose adjustments do not need to be made for weight losses of ≤ 20%. If a patient dose will 
exceed the maximum allowable dose of 70 mg/m2, the Investigator should contact the medical 
monitor prior to administration to discuss appropriate dosing. 
12.3.1.6. Missed or Vomited Doses 
12.3.1.6.1. Missed Doses 
A maximum of two doses may be given per week. Doses should not be administered in less 
than 36 hrs apart and all missed doses should be documented. Every effort should be made to 
avoid missed doses. 
If a patient missed a full week of dosing (e.g., a required medical procedure or an unanticipated 
personal emergency), the days missed will not be replaced. For example, if patient missed 
Cycle 2 Day 7 to Cycle 2 Day 14, then patient will start on Cycle 2 Day 15. 


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12.3.1.6.2. Vomited Doses 
If a dose is vomited within one hour of ingestion, it will be replaced. If vomiting occurs more 
than 1 hour after dosing, it will still be considered a complete dose. 
If a patient missed a full week of dosing for non-study drug related events (e.g., a required 
medical procedure or an unanticipated personal emergency), the days missed will not be 
replaced. For example, if patient missed Cycle 2 Day 7 to Cycle 2 Day 14, then patient will 
start on Cycle 2 Day 15. 
12.3.2. 
Supportive Care and Concomitant Treatments 
12.3.2.1. Required Supportive Care Medications 
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 twice daily (bid) – three times a day (tid) as needed (prn). 
12.3.2.2. Supportive Care Recommendations for Selinexor-Related Adverse Events 
Supportive measures for optimal medical care should be provided during participation in this 
clinical trial. Based on clinical observations in 730 adult patients treated with selinexor with 
evaluable safety data as of 31 May 2015, the main side effects are primarily related to anorexia 
with poor caloric and fluid intake, fatigue, and nausea. Thrombocytopenia also occurs, 
although it is rarely associated with bleeding. 
Besides the required 5-HT3, aggressive use of other supportive care including anti-nausea / 
anti-emetic therapy, acid suppression (proton pump inhibitors and/or H2-blockers) and other 
treatments as described below is strongly recommended: 
1. Appetite stimulants:  megesterol acetate at a starting dose of 40-160 mg bid, up to 
200 mg bid daily.  Aggressive and early use of appetite stimulants such as megesterol 
acetate is strongly recommended in any patient with selinexor-associated anorexia; 
these can often be tapered after the first 2-3 cycles of therapy. 
2. Centrally acting agents:  per National Comprehensive Cancer Network® [NCCN] 
Clinical Practice Guidelines® for antiemesis and anorexia/cachexia [palliative care]) 
see (antiemesis) and Appendix 5 (anorexia), respectively. 
3. NK1R antagonist:  aprepitant or equivalent should be considered and will be covered 
for selected patients who have severe nausea and vomiting. 
4. Supportive care for fatigue per institutional guidelines and NCCN guidelines:  
Fatigue (NCCN Guidelines for Fatigue). 
Additional information on supportive care and dose modifications for specific adverse events 
can be found in Table 6. 
12.3.2.3. Infection 
Patients with relapsed AML are at risk for developing serious infections (bacterial, invasive 
fungal disease). Prophylactic antimicrobials are strongly encouraged for patients with pre-


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cycle absolute neutrophil counts < 1 x 109/L, particularly if the neutropenia is prolonged. 
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. 
12.3.3. 
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.  
12.3.3.1. Permitted Concomitant Medication  
Patients will receive concomitant medications to treat symptoms, adverse events and 
intercurrent illnesses that are medically necessary as standard care. Medications to treat 
concomitant diseases like diabetes, hypertension, etc. are allowed. Acetaminophen on days of 
selinexor dosing is permitted but will not exceed a total daily dose of 1 gram. 
Hydroxyurea may be used at any time during the study, typically in patients with 
WBC ≥ 30,000/μL or per institutional guidelines. Prior to the initiation of hydroxyurea please 
consider the contraindications in the SPC, including leukocytopenia (< 2.5 x 109 leukocytes/L), 
thrombocytopenia (< 100 x 109 platelets/L) or severe anemia. 
12.3.3.1.1. Prevention of Pregnancy 
It is not anticipated that female patients enrolling in this study will be able to conceive. 
However, in the rare event that this is possible, female patients of child-bearing potential must 
agree to use dual methods of contraception and have a negative serum pregnancy test at 
screening, and male patients must use an effective barrier method of contraception if sexually 
active with a female of child-bearing potential. Acceptable methods of contraception are 
condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive 
patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is 
surgically sterilized or post-menopausal. For both male and female patients, effective methods 
of contraception must be used throughout the study and for three months following the last 
dose. 
12.3.3.1.2. Use of Blood Products 
During the administration of selinexor, patients may receive red blood cell (RBC) or platelet 
transfusions, if clinically indicated, per institutional guidelines. Patients who require repeated 
transfusion support should be discussed with the PI, Sponsor and Medical Monitor. 
Appropriate anti-coagulation is allowed during the study (e.g., low molecular weight [LMW] 
heparin, direct factor Xa inhibitors, etc.). Warfarin is allowed during the study provided that 
patients are monitored for INR twice a week during the first two cycles of therapy, then weekly 
to biweekly thereafter.  


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Patients may receive supportive care with erythropoietin, darbepoetin, granulocyte-colony 
stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF), 
pegylated growth factors, and platelet stimulatory factors, in accordance with clinical practice 
or institutional guidelines prior to entry and throughout the study. 
12.3.3.1.3. Radiation Treatment 
If clinically indicated, palliative radiation therapy to non-target lesions is permitted but study 
drug should be held for 3-5 days before the start of palliative radiation therapy and 3-5 days 
after palliative radiation therapy. Treatment with selinexor shall not be discontinued solely due 
to palliative radiation. 
12.3.4. 
Prohibited Medication 
Concurrent  
therapies:  
Concurrent therapy with any other approved or investigative anticancer 
therapeutic is not allowed in either arm. 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. 
Medications:  Acetaminophen There are no longer any restrictions on the use of 
acetaminophen or acetaminophen-containing products in combination with 
selinexor, EXCEPT on days on selinexor dosing, when acetaminophen must 
not exceed a total daily dose of 1 gram. 
 
Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-acetylcysteine 
(NAC)-containing products  Patients should not take GSH-, SAM-, or NAC-
containing products during their participation in this study as these products 
may enhance the metabolism of selinexor. Please see Appendix 6 for a list of 
representative products. Patients must report all prescription and non-
prescription medicines to their physicians during this study. 
12.4. 
Selinexor Storage and Accountability 
Selinexor tablets will be stored at ambient or refrigerated temperatures between (41-86°F) or 
(5-30°C) in a locked and secured area with restricted access to study staff. The tablets should 
not be stored at freezer temperatures or allowed to freeze. Tablets will be supplied in white 
high density polyethylene (HDPE) bottles. All medication must be stored in a secure area under 
the proper storage requirements with access restricted to the site staff pharmacist or 
designee(s). 
Selinexor for the study will be provided by Karyopharm Therapeutics, Inc. Medication labels 
will comply with the legal requirements of each country and will be printed in the local 
language as required. The investigator (or designee) will verify and acknowledge receipt of all 
study drug shipments by signing and returning all required forms.  


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Study drug accountability records will be maintained at the site pharmacy and will be available 
for review by the study monitor during each monitoring visit and at the close out visit. The 
study drug must be reviewed by the clinical research associate (CRA) prior to destruction or 
return shipment. 
The Investigational medicinal product should not be used for any purpose outside the scope of 
this protocol, nor can Investigational medicinal product be transferred or licensed to any party 
not participating in the clinical study. Data for Investigational medicinal product are 
confidential and proprietary and shall be maintained as such by the investigators. 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of unused material.  
All selinexor tablets must be kept in an appropriate, limited access, secure place until used or 
returned to Karyopharm Therapeutics, Inc. or designee for destruction. Drug supplies will be 
counted and reconciled at the site before being returned. The study site will be required to 
maintain a log of the temperature where the study medication is stored 
12.5. 
Treatment Compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the source 
documentation. This information must be captured in the source document at each patient visit. 
The respective dose for investigational drug and any changes in dosing must be captured in the 
eCRF. Additionally, the exact time and date of dosing will be captured on the days of PK 
sampling. 


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13. 
ADVERSE EVENTS 
An adverse event (AE) is defined as any undesired medical occurrence in a patient or clinical 
investigation patient receiving a pharmaceutical product and which does not necessarily have 
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 drug, whether or not related to the study drug. 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., 
meeting one or more of the following conditions, should be recorded as a single diagnosis on 
the adverse event page in the eCRF:  
1. Accompanied by clinical symptoms  
2. Leading to a change in study medication (e.g., dose modification, interruption or 
permanent discontinuation)  
3. Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 
It is the responsibility of the investigator to document all AEs that occur during the study. AE 
information will be elicited by asking the patient a non-leading question, for example, “Have 
you experienced any new or changed symptoms since we last asked/since your last visit?” AEs 
should be reported on the appropriate page of the eCRF. 
AEs should be reported for their actual grade and duration. 
• The term “severe” is used to describe the intensity of an AE; the event itself could be 
of relatively minor clinical significance (e.g., ‘severe’ headache). This is not the same 
as “serious”. Seriousness of AEs is based on the outcome of an AE and usually 
associated with events that pose a threat to a patient’s life or functioning. 
The severity of the AE will be graded according to the NCI CTCAE Grading Scale 
Version 4.03 (see the NCI CTCAE web page at http://ctep.cancer.gov for details). For AEs not 
covered by NCI CTCAE, the severity will be characterized as “mild”, “moderate”, or “severe” 
according to the following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily 
activities. 
• Moderate events introduce a low level of inconvenience or concern to the patient 
and may interfere with daily activities. 
• Severe events interrupt the patient’s usual daily activities. 
 


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The investigator will make a judgment regarding whether or not the AE was related to study 
drug, as outlined in Table 7: 
Table 7: 
Classification of Adverse Events by Causality 
Unrelated 
The adverse event is unlikely to have been caused by study drug. 
Possibly related 
It is unclear whether the adverse event may have been caused by 
study drug. 
Related 
The adverse event is likely to have been caused by study drug. 
 
13.1. 
Serious Adverse Events, Overdose 
A Serious Adverse Event (SAE) is any untoward medical occurrence that occurs at any dose 
(including after the Informed Consent Form [ICF] is signed and prior to dosing) that: 
• Results in death 
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires in-patient hospitalization (formal admission to a hospital for 
medical reasons) or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalization, or the development of drug 
dependency or drug abuse. 
Hospitalizations for elective surgery or other medical procedures that are not related to a 
treatment-emergent AE are not considered SAEs. 
Progression of the malignancy under study (including signs and symptoms of progression), 
including fatal outcomes if documented per IWG criteria, should not be reported as an SAE 
during the study or within the safety reporting period (see below). 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 


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13.1.1. 
AE and SAE Follow-up 
All AEs occurring during the study are to be followed up in accordance with good medical 
practice until they are resolved, stabilized or judged no longer clinically significant or, if a 
chronic condition, until fully characterized. Any AEs that are considered drug-related (possibly 
related, related) must be followed until resolution or until stabilization. Any AE of rash should 
be documented until resolution with photographs. 
13.1.2. 
Post-Study Adverse Events and Serious Adverse Events 
All unresolved AEs should be followed by the investigator until the events are resolved, the 
patient is lost to follow-up, or the AE is otherwise explained. At the last scheduled visit, the 
investigator should instruct each patient to report any subsequent event(s) that the patient, or 
the patient’s personal physician, believes might reasonably be related to participation in this 
study.   
For any patient who discontinues from treatment, a Survival Follow-Up telephone call (See 
Table 1 and Section 9.2.10) be made by study personnel every three months to the patient (or 
the patient’s family) to inquire about the patient’s AML status, initiation of anti-neoplastic 
therapies, and survival status.  
Prior to the conclusion of the study at the site the investigator should notify the Karyopharm 
Pharmacovigilance Department (see Section 13.1.5.1) of any death or AE occurring at any time 
after a patient has discontinued or terminated study participation that may reasonably be related 
to this study.  
After study conclusion, the investigator should notify the Karyopharm Pharmacovigilance 
Department of any death or AE he or she is aware of occurring at any time after a patient has 
discontinued or terminated study participation that may reasonably be related to this study. 
Karyopharm Therapeutics, Inc. should also be notified if the investigator should become aware 
of the development of cancer or of a congenital anomaly in a subsequently conceived offspring 
of a patient that has participated in this study. 
13.1.3. 
Overdose 
An overdose is defined as a deliberate or accidental administration of study medication to a 
study patient, at a dose above that which is assigned to that individual patient according to the 
study protocol. In the event of drug overdose, the investigator should be notified immediately 
and the patient observed closely for adverse effects. The patient should be treated 
symptomatically as appropriate, and the incident of overdose and related AEs and/or treatment 
documented in the patient's medical record. 
As selinexor is metabolized by glutathione (GSH) conjugation it is conceivable that hepatic 
GSH depletion can occur in case of overdose. Therefore, in patients who develop liver function 
test abnormalities, supportive measures such as S-adenosylmethionine (SAM) 400 mg po qd – 
qid or other drugs that can replace GSH should be considered. There have been no reports of 
selinexor overdose in > 1000 patients treated with selinexor to date. 


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13.1.4. 
Pregnancies 
Pregnancy per se is not considered an AE. A medical occurrence observed in the mother or 
fetus/newborn would be an AE. 
Each pregnancy in a partner of a patient on selinexor must be reported to the Sponsor within 
24 hours of learning of its occurrence. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. All attempts will be made to follow-up and document the course of pregnancy 
and birth. Follow-up and documentation must occur even if the patient withdraws from the 
study or the study is completed. 
The avoidance of fathering a child is suggested for 3 months following the discontinuation of 
selinexor therapy. No information is currently available regarding the effects of selinexor on 
fertility, gestation or subsequent child development. 
Any pregnancy within 3 months post-study should be reported to the study investigator and to 
the Karyopharm Pharmacovigilance Department. 
13.1.5. 
Serious Adverse Event Reporting 
13.1.5.1. Reporting Requirements 
ALL SAEs and cases of overdose occurring in any patient, must be notified to Karyopharm 
within 24 hours of first knowledge of the event by the principal investigator or assigned site 
personnel. The principal investigator or assigned site personnel are requested to provide 
following information: 
• Protocol number 
• Site and/or investigator number 
• Patient number 
• Brief description of the event 
• Onset date and time 
• Resolution date and time, if the event resolved 
• Any medication administered to treat the event 
• Investigator’s assessment of the SAE’s relationship to investigational product 
• Outcome of the event on the date of report 


Selinexor (KPT-330) 
 
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Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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This information will be captured in the protocol specific SAE report form and will be 
forwarded to: 
 Pharmacovigilance Department 
Karyopharm Therapeutics Inc. 
Email: pharmacovigilance@karyopharm.com 
   Fax:  +1-617-3347-617 (US) 
+49-89-9218-5650 (Germany) 
Karyopharm Therapeutics Inc. is responsible for submitting reports of AEs associated with the 
use of the study medication that are both serious and unexpected in compliance with the ICH 
Harmonized Tripartite Guidelines, to the regulatory agencies of the countries where this trial 
is being conducted, in accordance to country specific regulations.  
All investigators participating in ongoing clinical studies with the study medication will 
receive copies of these reports for prompt submission to their Institutional Review Board (IRB) 
or Ethics committee (EC), as applicable. Reporting of SAEs by the investigator to the IRB or 
EC will be done in accordance with the standard operating procedures and policies of the 
IRB/EC. Adequate documentation must be maintained showing that the IRB/EC was properly 
notified. 
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.  


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
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Page 76 
14. 
STATISTICAL METHODS  
14.1. 
General Considerations 
14.1.1. 
Statistical and Analytical Plans 
This is a randomized, multicenter, open-label phase 2 study of the SINE compound selinexor 
given orally versus investigator choice (one of three potential salvage therapies) in heavily 
pretreated, transplant ineligible patients of age ≥ 60 years, with relapsed/refractory AML. 
Formal hypothesis testing methods will be used for efficacy endpoint data, in order to evaluate 
if selinexor provides statistically significant improvement in efficacy over the control agents 
(collectively) used in this study. No formal hypothesis-testing will be used for other study data, 
such as demographics and safety data. 
Tabulations will be produced for appropriate disposition, demographic, baseline, efficacy and 
safety parameters. For categorical variables, summary tabulations of the number and 
percentage of patients within each category (with a category for missing data) of the parameter 
will be presented, as well as two-sided 95% confidence intervals (CI), unless otherwise stated. 
For continuous variables, the number of patients, mean, median, standard deviation (SD), 
minimum, and maximum values will be presented. Time-to-event data will be summarized 
using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% confidence intervals, as well as percentage of censored observations. 
14.1.2. 
Determination of Sample Size 
Patients enrolled under Protocol Versions < 5.0 will not be included in the efficacy analyses; 
therefore, sample size justification will refer to patients to be enrolled under Protocol Versions 
≥ 5.0.  
The sample size is designed to have 80% power to detect a median OS for patients treated with 
selinexor of ~5.2 months, versus investigator choice of ~3.0 months, using a one-sided alpha 
of 0.025 and allowing for two interim analyses. The follow up period for survival is up to 6 
months after the end of treatment for the last enrolled patient for the primary analysis, and a 
~20% drop out rate is assumed. Based on these statistical assumptions, a total of 123 events 
(deaths) are required for analysis. To achieve these events, a total of approximately 169 patients 
are required for enrollment; in order to maintain the 2:1 randomization allocation to 
selinexor:PC, this number is rounded up to 171 patients. Therefore, a total of approximately 
171 patients with relapsed or refractory AML will be enrolled into the study from 
approximately 60 sites in North America, Europe and the rest of the world. Patients will be 
randomized into the selinexor or PC treatment arms in a 2:1 allocation, within each of the 
2 x 2 x 2 stratification levels noted in Study Design.  
As described in Section 4.3.1.1, following a thorough evaluation of patient safety from the first 
approximately 110 patients enrolled under Protocol Versions < 5.0, a dose reduction for 
selinexor is being implemented. Under Protocol Versions < 5.0, the selinexor group was 
prescribed a dose equivalent to ~55 mg/m2 based on the patient’s BSA twice weekly. Under 
Protocol Versions ≥ 5.0, the selinexor group will receive a fixed dose of 60 mg (equivalent to 
~35 mg/m2) twice weekly. Patients enrolled under Protocol Versions < 5.0 will not be included 


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Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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in efficacy analysis. The total sample size of the study is expected to be approximately 300, as 
approximately 110 patients were enrolled under Protocol Versions < 5.0; enrollment will 
continue until Protocol Version 5.0 is approved.  
Two interim efficacy analyses are planned for patients enrolled under Protocol Versions ≥ 5.0 
as noted in Section 14.2.1.4.  
14.1.3. 
Disposition of Patients 
A tabulation of patient disposition will be presented, including the number in each analysis 
population, the number with non-evaluable disease according to the International Working 
Group (IWG) classic criteria, the number in each analysis population, the number censored at 
each of the PFS and OS analyses, the number lost to follow-up, the number that withdrew and 
reason(s) for withdrawal. 
A by-patient listing of study completion information, including the reason for premature study 
withdrawal, if applicable, will be presented. 
14.1.4. 
Blinding and Randomization 
Study drug will be administered in a non-blinded manner. Randomization will be performed 
centrally using an Interactive Web Response System (IWRS), and patients will be randomized 
with a 2:1 allocation to receive selinexor or control. The randomization will be stratified by (1) 
duration of their first CR on prior therapy, ≤ 6 months (including no CR on prior therapy) 
versus > 6 months; (2) number of prior therapies, 1 versus >1; (3) peripheral leukemic blast 
counts ≥ 10,000/μL versus < 10,000/μL. The randomization process will maintain the 2:1 
allocation between treatment groups within each of the stratification categories. 
The total number of patients enrolled within a randomization stratum will not be restricted 
overall or by site. 
14.2. 
Analysis Datasets 
14.2.1. 
Population to be Analyzed 
14.2.1.1. Intent-to-Treat Population 
The intent-to-treat (ITT) population will consist of all patients who are randomized to study 
therapy under Protocol Versions ≥ 5.0. Patients randomized under Protocol Versions < 5.0 will 
not be included for efficacy analyses. This population will include patients who have 
discontinued therapy due to toxicity or disease progression and patients who have died from 
any cause. This population will be used for primary analyses of efficacy, and such analyses 
will be based on the randomized treatment assignment. 
14.2.1.2. Per Protocol Population 
The per-protocol (PP) population will consist of all patients randomized to study therapy under 
Protocol Versions ≥ 5.0 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 


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Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
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Page 78 
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 ITT population, this will be taken into consideration in the decision to 
continue to later phase studies, or in the design of further studies. 
14.2.1.3. Safety Population 
The safety population will consist of all patients who have received any amount of study 
medication; analyses of safety will be performed based on treatment received, even if different 
from that randomized. Patients enrolled under all protocol versions will be included in the 
safety population. 
14.2.1.4. Interim Analyses 
Two interim efficacy analyses will be conducted on patients meeting the criteria to be included 
in the ITT population. The first interim analysis will take place after 31 (25%) OS events have 
occurred, and will be conducted to assess futility only (non-binding). Futility would be 
concluded if the p-value from the log-rank test is ≥0.8084. The second interim analysis will 
take place after 62 (50%) OS events, and will allow for a conclusion of significant efficacy at 
an α-level < 0.0015, and stopping for futility (non-binding) at an α-level ≥ 0.2957. The Sponsor 
may elect to continue the study even if the second interim analysis of OS demonstrates a 
p-value < 0.0015, in order to provide further safety data or to more fully explore secondary 
endpoints. The final hypothesis test will be performed after 123 OS events are observed with 
a one-sided significance level of 0.0245. Type I error adjustments were made using the 
O’Brien-Fleming approach. At the second interim analysis, a sample size re-assessment will 
be performed if the study is not stopped for futility, and significant superiority is not claimed. 
Sample size re-assessment would therefore only be performed conditionally on log-rank test 
results where 0.0015 ≤ p <0.2957, therefore alpha control is maintained. The sample size may 
be increased in order to ensure a minimum of 80% conditional power, where conditional power 
is calculated as the probability of a statistically significant result from the stratified log-rank 
test at the final analysis, conditional on the result at the interim. Complete details of the sample 
size re-assessment method are contained in the statistical analysis plan for this study. 
The statistical analyses of interim efficacy to determine a recommendation to stop the trial for 
significant efficacy or futility will be performed by the DSMB statistician, based on data 
provided to the DSMB by the biometrics CRO. The recommendation to stop or continue the 
trial will be provided to the Sponsor by the DSMB, after a thorough review of the efficacy 
results, in conjunction with an overall evaluation of safety. 
In addition to the interim analyses performed on the ITT population, a review of safety data 
for all patients will also be conducted at each interim analysis. 
14.3. 
Data Analysis and Presentation 
Summary tabulations will be provided for disposition as noted above, and for demographic, 
baseline, efficacy and safety data as noted in the following sections. All data collected on the 
electronic case report form (eCRF) will be provided in by-patient data listings. The primary 
presentation of all non-efficacy data will use a 4 treatment arm classification of:  selinexor at 
the 2 dose levels of ~55 mg/m2 (Protocol Versions < 5.0) and 60 mg (35 mg/m2) (Protocol 


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Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 80 
14.3.4. 
Secondary Endpoints 
In order to preserve the overall Type I error for the study, secondary efficacy variables will be 
assessed in hierarchical fashion in the following order, using the definitions presented above 
(Secondary Objectives): 
• OS3.0 
• CRR and DFS for CRR 
• mCRR and DFS for mCRR 
• ORR and DOR 
• DCR and duration of DCR 
• QoL 
 
The hierarchical assessment will proceed as follows, with all statistical tests performed at the 
one-sided, 0.025 level. OS3.0 will be assessed for statistical significance only if OS is 
statistically significant. Subsequent to a significant result for OS3.0, CRR will be assessed, and 
so forth for all remaining secondary variables, in order. 
For OS3.0, the difference in survival at 3 months post-randomization will be based on the 
stratified KM curves, using all available data at the time of analysis. 
CRR will be analyzed as the difference in the proportions of subjects with IWG results of CR 
and will be compared between the treatment arms, accounting for randomization strata, using 
a Cochran Mantel-Haenszel (CMH) chi-square test. The analysis of mCRR, ORR and DCR 
will be performed in a similar manner to CRR, using the CMH test.   
Duration of response will be calculated for each response rate: CRR, mCRR, ORR, and DCR. 
The duration of response for each respective type of response will not be used in the overall 
hierarchy used to maintain alpha-control, but will be regarded as descriptive adjuncts to the 
analyses of response rates. Analysis of duration of each response type will be performed using 
stratified KM methods. 
• For CRR and mCRR, the duration of response will be based on disease-free survival, 
defined as the duration from start of the complete response achieved based on IWG 
criteria until disease progression or death from any cause. 
• For ORR, duration of response will be calculated as the duration from the date when 
first evidence of overall disease response was achieved until the first date of 
documented disease recurrence or progression. Patients without documented disease 
recurrence or progression will be censored at the date of last disease assessment. 
• For duration of DCR, duration of response will be similar to that of ORR; however, the 
start of DCR will be based on the date of randomization. 
QoL will be assessed using the Functional Assessment of Cancer Therapy – Leukemia 
(FACT-Leu) and the European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L). 
FACT-Leu combines the General version of the Functional Assessment of Cancer Therapy 


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patients will be presented both overall and separately by patients enrolled under Protocol 
Versions < 5.0 and patients enrolled under Protocol Versions ≥ 5.0. 
14.3.6.1. Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and displayed in tables and listings using MedDRA system organ class (SOC) and 
Preferred Term. 
Analyses of AEs will be performed for those events that are considered treatment emergent, 
where treatment-emergent is defined as any AE with onset or worsening of a pre-existing 
condition on or after the first dose of randomized treatment through 30 days following the last 
dose of randomized treatment, or any event considered drug-related by the investigator through 
the end of the study. AEs with partial dates will be assessed using the available date 
information to determine if treatment-emergent; AEs with completely missing dates will be 
assumed to be treatment-emergent. No formal hypothesis-testing of AE incidence rates will be 
performed. 
AEs will be summarized by patient incidence rates, therefore, in any tabulation, a patient 
contributes only once to the count for a given AE (preferred term).The number and percentage 
of patients with any TEAE will be summarized for each treatment group, classified by SOC 
and preferred term. The number and percentage of patients with TEAEs assessed by the 
investigator as at least possibly related to treatment will also be tabulated. The number and 
percentage of patients with any Grade ≥ 3 treatment-emergent AE will be tabulated in the same 
manner. 
The causal relationship between the occurrence of an AE and the study drug will be judged by 
the investigator as unrelated, possibly related and related. In the event a patient experiences 
repeat episodes of the same AE, then the event with the highest severity and/or strongest causal 
relationship to treatment will be used for purposes of tabulations.   
Serious adverse events (SAEs) will also be tabulated. 
The incidence rates of selected treatment-emergent AEs, serious AEs, AEs of at least Grade 3 
in severity, related AEs, and AEs leading to withdrawal of treatment may be analyzed for 
treatment group differences using Fisher’s Exact test.  All AEs (treatment emergent and post-
treatment) will be listed in by-patient data listings, classified by treatment, patient and day on 
study. In addition, separate by-patient listings will be provided for the following:  patient 
deaths; serious AEs; and AEs leading to withdrawal. 
14.3.6.2. Laboratory Data 
Clinical laboratory values will be expressed using conventional SI units. 
For each treatment arm, the actual value and change from Baseline (Day 1, prior to the first 
administration of study drug) to each on study evaluation will be summarized for each clinical 
laboratory parameter, including hematology, clinical chemistry, coagulation and urinalysis. In 
the event of repeat values, the last non-missing value per study day/time will be used. In the 


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event that Day 1 data are unavailable for a given patient/parameter, the Screening value will 
substitute as the baseline value. 
Severity of select clinical lab measures will be determined using CTCAE criteria (e.g., those 
measures that have a corresponding CTCAE grade classification). Labs with CTCAE grades 
greater than or equal to 3 will be presented in a data listing. Shift tables that present changes 
from Baseline to worst on-study and Baseline to last on-study values relative to CTCAE 
classification ranges will be produced. 
14.3.6.3. Vital Signs and Physical Examinations 
The actual value and change from Baseline (Day 1) 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, and physical examination results changes during the 
study, will be summarized. All physical examination findings will be presented in by-patient 
data listings. 
14.3.6.4. Concomitant Medications 
The use of concomitant medications will be included in by-patient data listings. 
14.3.7. 
Procedures for Handling Missing Data 
No imputation of missing efficacy data is planned. For time to event analyses, patients who 
have no efficacy evaluations will be considered as censored at time 0. For PFS, patients who 
have not had disease progression or are non-evaluable at the interim or final analyses will be 
censored on the date they were last evaluated. For OS, patients will be followed until either 
lost to follow-up, withdrawal, or death. Patients will be censored on the date they were last 
known to be alive, regardless of disease status:  patients who discontinue post-randomization 
but receive no study treatment will be censored on the date of their last known vital status. 
For AEs, missing dates will not be imputed; however if partial dates are available, they will be 
used to assess if the AE occurred during the treatment period. Missing severities of AEs will 
not be imputed and will be considered missing in any tabulations of AE severity. If an AE is 
missing a response to the question regarding relationship to treatment, the event will be 
considered to be related. 
14.4. 
Changes in the Conduct of the Study or Planned Analysis 
Following an annual review of clinical safety data (29 July 2015), a dose reduction is being 
implemented. Under Protocol Versions < 5.0, the selinexor group was prescribed a dose 
equivalent to ~55 mg/m2 twice weekly based on the patient’s BSA. Under Protocol Versions 
≥ 5.0, the selinexor group will receive a fixed dose of 60 mg (equivalent to ~35 mg/m2) twice 
weekly. As described above, patients enrolled under Protocol Versions < 5.0 will not be 
included in the efficacy analysis, but will be included in the safety analyses. 
All deviations from the original statistical analysis plan will be documented and provided in 
the final clinical study report.  


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15. 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
15.1. 
Declaration of Helsinki 
The Study will be conducted in accordance with the ethical principles founded in the 
Declaration of Helsinki. 
15.2. 
Good Clinical Practice 
This study will be conducted according to the approved study protocol and Standard Operating 
Procedures (SOPs) that meet the guidelines provided by the International Conference on 
Harmonisation (ICH) E6 for Good Clinical Practice in clinical studies. 
15.3. 
Institutional Review Boards/Ethics Committees 
Before implementing this study, the protocol, the proposed patient informed consent forms and 
other information for the patients, must be reviewed by a properly constituted committee or 
committees responsible for approving clinical studies. The IRB/IEC written, signed approval 
letter/form must contain approval of the designated investigator, the protocol (identifying 
protocol title, date and version number), and of the patient informed consent form (date, 
version). 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the Sponsor, the IRB/IEC and the Health Authorities. 
15.4. 
Regulatory Authority Approval 
Before implementing this study, the protocol must be approved by the relevant regulatory 
authority. 
15.5. 
Pre-study Documentation Requirements 
To be provided. 
15.6. 
Informed Consent 
The investigator must fully inform the patient of all pertinent aspects of the trial including the 
written information approved/favorably assessed by the IRB/IEC. 
Prior to the start of the pre-study examination, the written informed consent form must be 
signed and personally dated by the patient and by the physician who conducted the informed 
consent discussion. One copy of the written information and signed consent form must be given 
to each patient and 1 copy must be retained in the investigator's study records. 
Additionally, consent will be requested to obtain/retain a blood sample for future analysis as 
warranted by our rapidly-advancing understanding in this field. Each patient’s Informed 
Consent document will reflect that samples collected may be used for pharmacogenomic 
investigations. 
15.7. 
Patient Confidentiality and Disclosure 
Data on patients collected on eCRFs during the trial will be documented in an anonymous 
fashion and the patient will only be identified by the patient number, and by his/her initials if 


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also required. If, as an exception, it is necessary for safety or regulatory reasons to identify the 
patient, all parties are bound to keep this information confidential. 
The investigator will guarantee that all persons involved will respect the confidentiality of any 
information concerning the trial patients. All parties involved in the study will maintain strict 
confidentiality to assure that neither the person nor the family privacy of a patient participating 
in the trial is violated. Likewise, the appropriate measures shall be taken to prevent access of 
non-authorized persons to the trial data. 
15.8. 
Collection, Monitoring and Auditing Study Documentation, and 
Data Storage 
15.8.1. 
Collection of Data and Monitoring Procedures 
This study will use a 21 CFR Part 11 compliant electronic data capture system (TEMPOTM) 
An electronic case report form (eCRF) is used for data recording All data requested on the 
eCRF must be entered and all missing data must be accounted for. Any observations must be 
reported to the sponsor. 
The data will be checked for completeness and correctness as it is entered by the real-time 
online checks applied by TEMPOTM. Off-line checks will also be run to perform any additional 
data review required. Discrepancy reports will be generated accordingly and transferred to the 
study center for resolution by the investigator or his/her designee. 
Accurate and reliable data collection will be assured by verification and cross–check of the 
eCRF against the investigator’s records by the study monitor (source document verification), 
and the maintenance of a study drug–dispensing log by the investigator. 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Sponsor 
representative will review the protocol and case report forms with the investigators and their 
staff. During the study a monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the case report forms, the adherence to the protocol 
and to Good Clinical Practice, the progress of enrollment. The monitor will ensure during on-
site visits that study medication is being stored, dispensed and accounted for according to 
specifications. Key trial personnel must be available to assist the monitors during these visits. 
All critical observation or compliance issues will be reported to sponsor Head of Quality and 
Regulatory Affairs. 
The investigator must give the monitor access to relevant hospital or clinical records to confirm 
their consistency with the case report form entries. No information in these records about the 
identity of the patients will leave the study center. Monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs and the recording of primary efficacy and safety variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. 


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15.8.2. 
Auditing Procedure 
In addition to the routine monitoring procedures the Sponsor or the regulatory authority can 
conduct an audit or an inspection (during the study or after its completion) to evaluate 
compliance with the protocol and the principles of Good Clinical Practice (GCP). 
The investigator agrees that representatives of the Sponsor and Regulatory Authorities will 
have direct access, both during and after the course of this study, to audit and review all study-
relevant medical records.  
In the event that a major compliance or regulatory issues arises, the sponsor may conduct an 
audit without prior schedule. 
15.8.3. 
Retention of Documents 
The investigator must maintain source documents for each patient in the study, consisting of 
all demographic and medical information, including laboratory data, electrocardiograms, etc., 
and keep a copy of the signed informed consent form. All information on case report forms 
must be traceable to these source documents in the patient's file. Data without a written or 
electronic record will be defined before trial start and will be recorded directly on the case 
report forms, which will be documented as being the source data. 
15.9. 
Disclosure of Information 
All information provided to the investigator by Karyopharm, or their designee, will be kept 
strictly confidential. No disclosure shall be made except in accordance with a right of 
publication granted to the investigator. 
No information about this study or its progress will be provided to anyone not involved in the 
study other than to Karyopharm, or its authorized representatives, or in confidence to the IRB, 
or similar committee, except if required by law. 
15.10. 
Discontinuation of the Study 
It is agreed that, for reasonable cause, either the investigator or Karyopharm, may terminate 
the investigator’s participation in this study after submission of a written notice. Karyopharm 
may terminate the study at any time upon immediate notice for any reason, including the 
Sponsor’s belief that discontinuation of the study is necessary for the safety of patients. 
15.11. 
Study Report, Publication Policy and Archiving of Study 
Documentation 
15.11.1. 
Study Report and Publication Policy 
An ICH-compliant integrated clinical and statistical report will be prepared upon completion 
of the study and data analysis. The results of the study will be published in a relevant peer- 
reviewed journal, with authorship status and ranking designated according to the 
acknowledged contributions of participating investigators, institutions and the Sponsor. 


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15.11.2. 
Data Capture 
The eDC vendor will be responsible for the design of the eCRF, monitoring the trial according 
to GCP guidelines, preparation of data queries and reports to assist the clinical monitoring, and 
training each study site staff member entering data in the eCRF. The eDC vendor will also be 
responsible for preparation of analysis files from the database prior to analyses, assisting with 
the statistical analyses and statistical report, and preparation of the integrated clinical study 
report. 
The eDC component of TEMPOTM will be used for electronic data acquisition and storage. 
TEMPOTM will provide electronic case report forms (eCRFs) for transfer of all research data 
by site personnel from data source documentation to the study database. Each responsible 
person at a site will have user access to TEMPOTM through their unique username and 
password, with permissions providing each person their needed access. Some personnel will 
have data entry, data review, and query resolution permissions, while others may only have 
data read permissions, based on their individual study roles. TEMPOTM is flexible to allow 
customizable permissions as needed for study personnel. 
Study data will be checked for completeness and correctness as it is entered by the real-time 
online checks applied by TEMPOTM. Off-line checks will also be run to perform any additional 
data review required. Any issues identified will be transferred to the study site via query for 
resolution by the investigator or his/her designee. All queries will be managed through 
TEMPOTM and audit trails of all queries and their resolution, along with any data changes, will 
be recorded. 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
Clinical research associates (CRAs) will monitor the data, verifying all captured data against 
its source. Monitoring will be enhanced by computer assisted data management identifying 
missing or possibly erroneous data as soon as data is entered into the system. This approach 
will allow initial remote monitoring, and communication between CRAs and site personnel 
before and between site visits, and will expedite data review and cleaning. Missing data and 
identified data errors (or possible errors) will be communicated by the CRAs to site 
investigators using the Query feature in TEMPOTM for correction or acknowledgement that 
data is correct as entered. As each subject’s data entry is completed and fully monitored with 
all queries resolved, that subject’s data will be locked by the CRA to only allow read access 
for the remainder of the study. 
TEMPOTM and all study data are housed in a secure computing environment. TEMPOTM 
further provides a complete audit trail of all data entry, monitoring, and query activity. 
TEMPOTM is compliant with HIPPA and meets all requirements for 21 CFR Part 11. 
15.11.3. 
Study Documents 
The investigator must maintain source documents for each patient in the study, consisting of 
all demographic and medical information, including laboratory data, electrocardiograms, etc., 


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and keep a copy of the signed informed consent form. All information on the e-case report 
forms must be traceable to these source documents in the patient's file. Data without a written 
or electronic record will be defined before trial start and will be recorded directly on the e-case 
report forms, which will be documented as being the source data. 
15.11.4. 
Archiving of Documents 
Essential documents, as listed below, must be retained by the investigator for as long as needed 
to comply with national and international regulations. The Sponsor will notify the 
investigator(s)/institution(s) when the study-related records are no longer required. The 
investigator agrees to adhere to the document retention procedures by signing the protocol. 
Essential documents include, but are not limited to: 
1. IRB/IEC/REB approvals for the study protocol and all amendments 
2. All source documents and laboratory records 
3. CRF copies (electronic copies on a CDROM) 
4.  Patients' informed consent forms (with study number and title of trial) 
5. FDA form 1572 
6.  Any other pertinent study document 
 


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16. 
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13. Liu J, Lu H, Ohgaki H, Merlo A, Shen Z. Alterations of BCCIP, a BRCA2 interacting 
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24. Thein, MS, Ershler, WB, Jemal, A, Yates, JW, Baer, MR. Outcome of older patients with 
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31. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. Results 
of a phase 3, multicenter, randomized, open-label study of azacitidine (AZA) vs 
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044552.pdf. Last accessed April 21, 2015. 
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Visani1 Alternative novel therapies for the treatment of elderly acute myeloid leukemia 
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35. Garzon R, Flinn I, Berdeja J, et al. A phase 1 dose escalation study of the oral selective 
inhibitor of nuclear export (sine) selinexor (kpt-330) in patients with relapsed/refractory 
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Hematology Association, June 12-15 2014, Milan, Italy. 


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17. 
APPENDICES 
 
 
 


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APPENDIX 1 
Disease Risk Assessment According to the European 
LeukemiaNet (ELN) 
 
Table from: 
Röllig C, Bornhäuser M, Thiede C, Taube F, Kramer M, Mohr B, Aulitzky W, Bodenstein H, Tischler 
HJ, Stuhlmann R, Schuler U, Stölzel F, von Bonin M, Wandt H, Schäfer-Eckart K, Schaich M, 
Ehninger G. Long-term prognosis of acute myeloid leukemia according to the new genetic risk 
classification of the EuropeanLeukemiaNet recommendations: evaluation of the proposed reporting 
system. J Clin Oncol. 2011 Jul 10;29(20):2758-65. 


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APPENDIX 2 
International Working Group Guidelines for AML 
Response Criteria for AML (modified from Cheson et al. 2003) 
Reference: Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Este EH, et al.  Revised recommendations 
of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec;21(24):4642-4649.  
Acute Myeloid Leukemia (AML) is a clonal expansion of myeloid blasts in bone 
marrow, blood, or other tissue (ICD-O code 961/3. The most significant change from the 
FAB classification is that the requisite blast percentage for a diagnosis of AML be ≥ 20% 
myeloblasts in the blood or marrow. 
There are two exceptions to the above rule. 
• Acute erythroleukemia (erythroid/myeloid subtype) is defined by the presence in 
the bone marrow of greater than or equal to 50% erythroid precursors in the entire 
nucleated cell population and greater than or equal to 20% myeloblasts in the non-
erythroid cell population. 
• Pure erythroid leukemia is defined as a neoplastic proliferation of immature cells 
committed exclusively to the erythroid lineage (> 80% of the marrow nucleated 
cells) with no evidence of a significant myeloblastic component. 
Diagnostic and Staging Criteria 
Definitions: 
1. Bone marrow cellularity:  The volume of hematopoietic nucleated cells, expressed
 as a percentage of marrow volume less volume of fibrosis. 
2. Blasts:  For AML, the following cell types are considered equivalent to blasts and
 are included in the calculation of blast percentages. (Note that erythroblasts are 
not counted as blasts in calculating blast percentages). 
a. Myeloblasts include both agranular and granular variants. 
b. Neoplastic promyelocytes, for Acute Promyelocytic Leukemia. 
Neoplastic promyelocytes are defined as promyelocytes with heavy 
granulation and irregular nuclei and/or primitive promyelocytes with very 
large numerous Auer rods. 
c. Monoblasts and promonocytes for Acute Monoblastic and Monocytic 
Leukemia 
d. Megakaryoblasts for Acute Megakaryoblastic Leukemia. 
3. Bone Marrow Blast Percentage is calculated as the percent of blasts among all 
nucleated marrow cells. 
 
 


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Table A4.1:  Response Criteria in AML 
Response 
Criterion 
Neutrophils 
(µL) 
Platelets 
(µL) 
Bone Marrow 
Blasts (%) 
Other 
Early treatment 
assessment 
NA 
NA 
< 5 
 
Morphologic 
leukemia—free 
state 
NA 
NA 
< 5 
Flow cytometry EMD 
Morphologic CR 
> 1,000 
> 100,000 
< 5 
Transfusion EMD 
Cytogenetic  
CR 
> 1,000 
> 100,000 
< 5 
Cytogenetics – normal  EMD 
Molecular  
CR 
>1,000 
> 100,000 
< 5 
Molecular-negative EMD 
Partial remission 
(PR) 
>1,000 
> 100,000 
≥ 50% decrease to 5-25% 
OR 
Blasts < 5% if Auer rod positive 
Abbreviations:  AML, acute myelogenous leukemia; EMD, extramedullary disease; CR, complete 
remission. 
 
Descriptive Definitions of Remission 
A. 
Morphologic complete remission (CR):  ANC ≥ 1,000/ µL, platelet 
count ≥ 100,000/µL, < 5% bone marrow blasts, no Auer rods, no evidence of 
extramedullary disease. (No requirements for marrow cellularity, hemoglobin 
concentration).  
B. 
Morphologic complete remission with incomplete blood count recovery 
(CRi):  Same as CR but ANC may be < 1,000/ µL and/or platelet count < 
100,000/ µL.  
C. 
Partial remission (PR):  ANC > 1,000/ µL, platelet count > 100,000/ µL, and at 
least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or 
marrow blasts < 5% with persistent Auer rods.  
D. 
Morphologic leukemia-free state (MLFS):  This designation requires less than 
5% blasts in an aspirate sample with marrow spicules and with a count of at least 
200 nucleated cells. There should be no blasts with Auer rods or persistence of 
extramedullary disease. The presence of a unique phenotype (by flow cytometry) 
identical to what was found in the pretreatment specimen (e.g., CD34, CD7 
coexpression) should be viewed as persistence of leukemia. 
E. 
Stable Disease (SD):  Not fulfilling criteria for CR, CRi, PR, MLFS, or disease 
progression 


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F. 
Disease Progression (PD):  Presence of > 50% increase in bone marrow blasts to 
a level of at least 50% and/or a doubling of the percentage of peripheral blood 
blasts to a level of at least 50%.  
G. 
Inevaluable (IN):  This box should be checked off if no hematologic evaluation 
done or if a bone marrow aspirate and/or biopsy was done and there were no 
spicules/fragments in the aspirate (and biopsy was not representative, if done).  
 
 


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APPENDIX 3 
Ophthalmic Examination:  Assessments and Grade 1-4 
Grading System for Cataracts 
An ophthalmic examination by an optometrist or ophthalmologist is required at screening, if 
clinically indicated during the study (e.g., monitoring of pre-existing cataracts, visual 
disturbances) and at the Final Visit.  
 
The examination is to include the following:  
Prior to dilation:   
• best corrected visual acuity  
• slit lamp examination 
• tonometry 
Following dilation:  
• fundoscopy 
• slit lamp examination to document lens clarity  
If a cataract/lens opacity is seen during the examination, the cataract/lens opacity will be 
graded according to a Grade 1-4 system (modified from Optometric Clinical Practice 
Guideline:  Care of the Adult Patient with Cataracts: available on the American Optometric 
Association website:  www.aoa.org). 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. 
 
 
 


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APPENDIX 4 
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. © 2014 National Comprehensive Cancer Network, Inc. All 
rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent 
and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN 
Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014. © 2014 National Comprehensive Cancer Network, Inc. All 
rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent 
and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN 
Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014. © 2014 National Comprehensive Cancer Network, Inc. All 
rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent 
and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN 
Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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APPENDIX 5 
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.1.2014. ©2014 National Comprehensive Cancer Network, Inc. 
All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most 
recent and complete version of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other 
NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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APPENDIX 6 
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 
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 
 
 
 
 
 
 


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APPENDIX 7 
Protocol amendments:  Rationales and Summaries of 
changes 
 
CLINICAL STUDY PROTOCOL 
KCP-330-008 
A RANDOMIZED, OPEN LABEL, PHASE 2 STUDY OF THE SELECTIVE 
INHIBITOR OF NUCLEAR EXPORT (SINE) SELINEXOR (KPT-330) VERSUS 
SPECIFIED PHYSICIAN’S CHOICE IN PATIENTS ≥ 60 YEARS OLD WITH 
RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA (AML) WHO ARE 
INELIGIBLE FOR INTENSIVE CHEMOTHERAPY AND/OR 
TRANSPLANTATION 
SOPRA Study:  Selinexor (KPT-330) in Older Patients with Relapsed AML 
Drug Development 
Phase: 
Phase 2 
Investigational Product: 
Selinexor (KPT-330) 
Indication: 
Acute Myeloid Leukemia 
EudraCT Number: 
2014-000920-26 
Sponsor: 
Karyopharm Therapeutics, Inc. 
85 Wells Avenue 
Newton, MA 02459 USA 
Protocol Date and 
Version: 
21 January 2014, Version 1.0 
03 July 2014, Version 2.0 (Amendment 1) 
30 September 2014, Version 2.1 
          (United Kingdom-specific Amendment 2) 
25 November 2014, Version 3.0 (Amendment 3) 
24 April 2015, Version 4.0 (Amendment 4) 
09 July 2015, Version 4.1 
           (Germany-specific Amendment 4.1) 
04 August 2015, Version 5.0 (Amendment 5) 
Conduct:  In accordance with the ethical principles that originate from the Declaration of 
Helsinki and that are consistent with International Conference on Harmonisation (ICH) 
guidelines on Good Clinical Practice (GCP) and regulatory requirements as applicable. 
 
 


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Amendment 5.0, Version 5.0 
Version 5.0 incorporates changes to Version 4.0, as well as Germany-specific 
changes in Version 4.1  
• Please note that Germany-specific Version 4.1 included Version 3.0 to 
4.0 changes; these changes were marked in the text of the Version 4.0 
redline and are not repeated in the Version 5.0 redline 
Amendment Rationale 
The major changes in this amendment of the protocol were made primarily to address an 
unexpected increase in the number of infection-related AEs in patients randomized to 
selinexor as compared with patients randomized to the Physician’s Choice arm. Minor 
updates to other safety assessment and guidance sections are also included. Specific major 
changes are as follows: 
• Reduction of selinexor dose from ~55 mg/m2 (~80-100 mg) to a fixed dose of 60 mg 
(~35 mg/m2) to reduce selinexor-related adverse events, especially sepsis and 
pneumonia/lung infections in this highly compromised patient population. 
• Revision of inclusion criteria to specify that prior AML therapy must have included 
an adequate trial of a hypomethylating agent with at least 2 cycles. 
• Addition of exclusion for patients who are classified as favorable according to the 
European LeukemiaNet (ELN) disease risk assessment. 
• Revision of statistical methods, including ITT and PP populations and presentation of 
non-efficacy data, to reflect exclusion of patients treated with ~55 mg/m2 of selinexor 
from the primary analysis population due to changes in the selinexor dose and the 
inclusion criteria. These patients will be included in the safety population. As such, 
the total number of patients in the study has been increased. 
• Changes to guidance on the use of hydroxyurea requested by German (Ulm EC) that 
were included in Version 4.1. 
 
Other changes, primarily editorial and administrative, were made for readability and clarity. 
These changes include updates to data and corrections in the Synopsis, Schedule of 
Assessments, body of the protocol and Appendices for consistency and accuracy. 
 
The revised protocol Version 5.0 dated 04 August 2015 will be submitted by the Principal 
Investigator(s) to all applicable Institutional Review Boards (IRBs), Independent Ethics 
Committees (IECs), or Research Ethics Boards (REBs), and by Karyopharm Therapeutics 
Inc. to all applicable Regulatory Authorities. 
A summary of the key changes that were made to Version 4.0 of the protocol, including the 
rationale for these changes, in Version 5.0 is provided below. 


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Changes to the protocol 
Administrative Changes 
• Internal changes to improve clarity and eliminate inconsistencies between sections; 
updated Table of Contents and hyperlinks (Modified sections:  Global). 
• Updated the version number and date of protocol Version 4.0 dated 24 April 2015 to 
Version 5.0 dated 04 August 2015 (Modified sections:  Global). 
• Updated abbreviations list, references, patient numbers and safety/response data 
(Modified sections:  Global). 
• Removed sample FACT-Leu QOL and EQ-5D-5L questionnaires from Appendices. 
The questionnaires will be located in the Investigator Site File. 
Clinical Experience 
• Addition of new subsection on risk of sepsis in AML with a summary of the clinical 
safety data reviewed in July 2015 (29 July 2015) that indicate an apparent increase in 
the rates of sepsis at higher doses of selinexor. 
o Modified Section:  4.3.1. 
o Rationale:  To reflect recent safety findings in this study regarding increased 
rate of sepsis and possibly pneumonia/lung infections in patients treated with 
selinexor. 
Study Design 
• Addition of daily temperature diary to be completed by all patients. 
o Modified Sections:  Sections 9.2.3, 9.2.4, 9.2.5, 9.2.6, 9.2.7, and 9.2.8, and 
Table 1. 
o Rationale:  To increase safety oversight of this highly compromised 
population in response to recent sepsis findings. 
• Addition of visit on Cycle 1 Day 4, weekly phone calls for all patients during all 
subsequent weeks in Cycles 1-3, and weekly visits on Days 8 and 22 of Cycle 2. 
o Modified Sections:  Sections 9.2.4, 9.2.5, 9.2.6, and 9.2.7, and Table 1. 
o Rationale:  To increase safety oversight of this highly compromised 
population in response to recent sepsis findings. 
• Removed the anticipated enrollment period of 15-18 months. 
o Modified Sections:  Synopsis (Study Duration and Statistical Methods) and 
Section 14.1.2. 
o Rationale:  This enrollment estimate is not informative to the investigators. 
• Addition of a review of safety data for all patients at each interim analysis. 
o Modified Sections:  Sections 7.2 and 14.2.1.4. 
o Rationale:  To allow for review of all patient safety data by the DSMB in 
conjunction with the interim analyses on the ITT population. 
• Revised the timing of completion of follow-up was also revised from 6 months after 
randomization to 6 months after the end of treatment.  
o Modified Sections:  Synopsis (Study Duration and Statistical Methods), 
Section 7.1, Section 11.2, Section 11.3, Section 14.1.2  


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o Rationale:  To more completely assess safety and survival for all patients. 
• Clarified the guidance on missed doses 
o Modified Sections:  Section 12.3.1.6.1. 
• Modified patient numbers:  total number of patients increased to 300 and the number 
of patients in the primary analysis was corrected from 170 patients to 171 patients. 
o Modified Sections:  Synopsis (Methodology), Section 8.1, Section 9.1, and 
Section 14.1.2. 
o Rationale:  To reflect changes to dosing, inclusion and exclusion criteria, and 
study populations. 
• Revised secondary objectives/endpoints to add morphologic leukaemia-free state 
(MLFS) and remove bone marrow CR from ORR 
o Modified Sections:  Synopsis (Objectives), Section 6.2, Section 7.4.2, 
Section 10.1.4. 
o Rationale:  To align nomenclature with response criteria for AML (IWG 
guidelines for AML). 
 
Inclusion Criteria 
• Revised inclusion criterion #6 to specify that prior AML therapy must have included 
an adequate trial of a hypomethylating agent with at least 2 cycles, and to clarify that 
patients must have progressed after their  most recent therapy. 
o Modified Sections: Synopsis (Diagnosis and Main Criteria for Inclusion) and 
Sections 7.1, 8.3, and 9. 
o Rationale: To align the study population globally. The requirement for prior 
AML treatment with both cytosine arabinoside and an adequate trial of a 
hypomethylating agent will account for differences in treatment practices 
between the US and Europe. 
• Revised inclusion criteria #8 to clarify that objective, documented evidence of disease 
progression is required for the most recent previous therapy prior to study entry. 
o Modified Section: Section 8.3. 
o Rationale: To align with the change to inclusion #6. 
• Revised inclusion criterion #9 to allow patients with liver involvement of their AML 
who have an AST and ALT ≤ 5 x ULN to enroll in the study, to increase the threshold 
levels for inclusion for bilirubin (≤ 2 x ULN), AST (≤ 2.5 x ULN), and ALT (≤ 2.5 x 
ULN), and to specify the threshold level (≤ 3 x ULN) for patients with high indirect 
bilirubin due to a congenital disorder (Gilbert’s syndrome). 
o Modified Section: Section 8.3. 
o Rationale: To enable patients with hepatic transaminase elevations due to 
liver involvement of their AML to enroll in the study and to align inclusion 
requirements for bilirubin, AST, and ALT with other Karyopharm clinical 
studies in hematological cancers. In addition, of note, liver function 
abnormalities are rarely associated with selinexor use. 
Exclusion Criteria 


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• Added an exclusion for patients whose AML is classified as favorable according to 
the European LeukemiaNet (ELN) disease risk assessment. 
o Modified Sections: Synopsis (Major Exclusion Criteria) and Section 8.4. 
o Rationale: To further define the appropriate patient population. Patients 
whose AML is classified as intermediate or adverse according to ELN are in 
greater need of treatment than patients whose AML is classified as favorable, 
who have a more benign course of disease. 
Treatment 
• Changed starting selinexor dose from ~55 mg/m2 (~80-100 mg) to 60 mg (~35 mg/m2) 
fixed dose for all patients. 
o Modified Sections:  Synopsis (Test Product, Dose and Mode of 
Administration) and Sections 4.3, 5.1, 7.1, 8.1, 9.1, 12.2.3, 12.3.1 (Table 5), 
14.1.2, and 14.4. 
o Rationale:  Reduction of selinexor dose from ~55 mg/m2 (~80-100 mg) to a 
fixed dose of 60 mg (~35 mg/m2) to reduce selinexor-related adverse events, 
especially sepsis and pneumonia/lung infections in this highly compromised 
patient population. 
• Deletion of hydroxycarbamide (hydroxyurea) guidance text from Test Product, Dose 
and Mode of Administration (synopsis) and Prohibited Medication Section 12.3.4) 
o Modified Sections:  Synopsis (Test Product, Dose and Mode of 
Administration) and Section 12.3.4 (Prohibited Medication). 
o Rationale:  Text removed to improve protocol consistency and clarity, as text 
is not appropriate for these sections (i.e., it does not belong in the named 
sections). Guidance regarding the use of hydroxycarbamide (hydroxyurea), 
including contraindications, is provided in Supportive Care and Concomitant 
Medications section of the synopsis and protocol Sections 7.1 and 12.3.3.1. 
Supportive Care and Concomitant Medications 
• Modification of text regarding the use of hydroxycarbamide (hydroxyurea), including 
additional guidance regarding contraindications (changes requested by German (Ulm) 
EC) 
o Original Text: 
 “Patients receiving selinexor will also receive BSC including blood 
product transfusions, antimicrobials, and (if appropriate) granulocyte 
colony-stimulating factors for neutropenic infection. Hydroxyurea may 
be used at any time during the study but only in patients with WBC 
≥ 30,000/μL.” [Section 7.1] 
AND 
 “Hydroxyurea may be used at any time during the study but only in 
patients with WBC ≥ 30,000/μL.”  [Synopsis, Section 12.3.4] 
o Amended Text:  “Hydroxyurea may be used at any time during the study, 
typically in patients with WBC ≥30,000/μL or per institutional guidelines. Prior 
to the initiation of hydroxyurea please consider the contraindications in the 


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Summary of Product Characteristic (SPC), including leukocytopenia (< 2.5 x 
109 leukocytes/L), thrombocytopenia (< 100 x 109 platelets/L) or severe 
anemia.”  
o Modified Sections:  Synopsis (Supportive Care and Concomitant Medications) 
and Sections 7.1, 12.3.3.1, and 12.3.4. 
o Rationale:  This change was made to address the two requests from the Ulm 
EC for modification of the guidance regarding the use of hydroxycarbamide 
(hydroxyurea), including contraindications. The specific wording requested by 
the ULM EC has been modified slightly for clarity. The requests for protocol 
changes, which, are summarized below: 
• Addition of text regarding thrombocytopenia and severe anemia as 
contraindications for the use of hydroxycarbamide (hydroxyurea) 
• Modification of the following text in Study Design, page 43, 
paragraph 6 (version 3.0 redline): 
“Patients receiving selinexor will also receive BSC including 
blood product transfusions, antimicrobials, and (if appropriate) 
granulocyte colony-stimulating factors for neutropenic 
infection and hydroxyurea (Cycle 1 only)” is to be deleted and 
replaced by: “Hydroxyurea may be used at any time during the 
study but only in patients with WBC ≥ 30,000 µl”. 
• Modification of guidance for anorexia and neutropenia to strongly encourage the use 
of megesterol for patients with anorexia and prophylactic antimicrobials for patients 
with neutropenia. 
o Modified Sections: Table 6 and Section 12.3.2.3. 
o Rationale: This change was made for patient safety to mitigate complications 
related to anorexia and neutropenia. 
• Modification of guidance in “Dose Adjustments with Changes in BSA”  
o Modified Sections: Section 12.3.1.5. 
o Rationale: This change was made to reflect the switch to the fixed 60 mg 
dose. 
Adverse Events 
• Modified pregnancy text to replace text relating to a drug-drug interaction (i.e., 
pregnancy due to study drug reduction of the effectiveness of a contraceptive 
medication) with text relating to adverse events (i.e., medical occurrence observed in 
the mother or fetus/newborn). 
o Modified Section: 13.1.4. 
o Rationale: Change was made to improve accuracy.  
Statistical Methods 
• Revised stratification:  replaced age < 70 versus age ≥ 70 years with number of prior 
therapies, 1 versus >1, added a stratum for peripheral leukemic blast counts 


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≥ 10,000/μL versus < 10,000/μL, and  reduced the duration of the first CR on prior 
therapy from 1 year to 6 months. 
o Modified Sections: Synopsis (Methodology, Diagnosis and Main Criteria for 
Inclusion) and Sections 7.1, 7.5, 9.1, 14.1.2, and 14.1.4. 
o Rationale: The stratum for age was replaced by stratum for number of prior 
therapies as number of prior therapies is a more relevant factor affecting 
potentially correlating with clinical outcome, given the change in inclusion 
criteria relating to number of prior therapies. The stratum for peripheral 
leukemic blast counts has been added to explore correlation between WBC 
count and clinical outcome. The duration of the first CR on prior therapy 
stratum has been reduced to reflect a more relevant cut off for older patients 
with relapsed AML for whom median OS is 7-9 months. 
• Revised statistical methods to increase the patient population, redefine the ITT and 
PP populations to exclude patients enrolled under Protocol Versions < 5.0, clarify the 
presentation of non-efficacy data, and revise the populations to be included in the 
interim analyses. 
o Modified Sections: Synopsis (Methodology; Reference Therapy Dose and 
Mode of Administration; Statistical Methods) and Sections 7.2, 8.1, 9.1, 
14.1.2, 14.2.1.1, 14.2.1.2, 14.2.1.3, 14.2.1.4, 14.3, 14.3.3, 14.3.6, and 14.4. 
o Rationale: To reflect the exclusion of patients treated with ~55 mg/m2 of 
selinexor from the primary analysis population due to changes in the selinexor 
dose and the inclusion criteria. 
• Revised secondary objectives/endpoints to add mCRR and remove bone marrow CR 
from CRR. 
o Modified Sections: Synopsis (Objectives, Criteria for Evaluation) and 
Sections 6.2, 7.4.2, 10.14, and 14.3.4. 
o Rationale: To align with updates to the SAP. 
• Added details on sample size re-assessment for the second interim analysis. 
o Modified Sections: Sections 14.1.2 and 14.2.1.4. 
o Rationale: FDA request. 
 
 
 


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Protocol Version 4.1 (Amendment 4.1) 
Amendment Rationale 
The major changes in this amendment of the protocol are as follows: 
• Address comments, dated 06.05.2015, from the Ethics Committee of Ulm (Ulm 
University) including requests for additional revisions to KCP-330-008 Version 3.0 
(Ulm reference number 122/14) to provide additional guidance regarding the use of 
hydroxycarbamide (hydroxyurea). Version 4.1 is for Germany only; these changes 
will be carried forward into a future global version of the protocol. 
• Increase in the assumed drop out rate to ~20% to align with the actual rate at study 
sites and increase in the sample size to 170 patients to maintain power with the 
increased drop out rate. 
• Addition of interim analysis after 25% of Overall Survival events in order to assess 
for early futility and prevent unnecessary exposure of patients to selinexor in the 
event futility is declared. 
• Expansion of exclusion criteria to exclude patients with concurrent active 
malignancies that are not being treated. 
• Addition of EQ-5D-5L Quality of Life questionnaire. 
• Addition of 20 mg tablets in blister packs as an option for selinexor drug product. 
• Removal of specific recommendation for the use of dexamethasone as a supportive 
care agent. 
 
Other changes, primarily editorial and administrative, were made for readability and clarity. 
These changes include updates to data and corrections in the Synopsis, Schedule of 
Assessments, and body of the protocol for consistency and accuracy. 
 
Version 4.1 is for Germany only. The revised protocol Version 4.1 dated 09 July 2015 will 
be submitted by the Principal Investigator(s) to all applicable German Institutional Review 
Boards (IRBs), Independent Ethics Committees (IECs), or Research Ethics Boards (REBs), 
and by Karyopharm Therapeutics Inc. to all applicable Regulatory Authorities. 
A summary of the key changes that were made to Version 4.1 of the protocol, including the 
rationale for these changes, in Version 3.0 is provided below. 
Changes to the protocol 
Administrative Changes 
• Internal changes to improve clarity and eliminate inconsistencies between sections; 
updated Table of Contents and hyperlinks (Modified sections:  Global). 
• Updated the version number and date of protocol from Version 3.0 dated 
24 November 2014 to Version 4.1 dated 09 July 2015 (Modified sections:  Global). 
• Updated references and patient and incidence data (Modified sections:  Global). 
• Removed sample FACT-leu QOL questionnaire from Appendix 2. The questionnaire 
will be located in the Investigator Site File. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 112 
Concurrent Therapies (Supportive Care and Concomitant Medications) 
• Modification of text regarding the use of hydroxycarbamide (hydroxyurea), including 
additional guidance regarding contraindications. 
Original Text: 
“Patients receiving selinexor will also receive BSC including blood 
product transfusions, antimicrobials, and (if appropriate) granulocyte 
colony-stimulating factors for neutropenic infection. Hydroxyurea may 
be used at any time during the study but only in patients with 
WBC ≥ 30,000/μL.” [Section 7.1] 
AND 
“Hydroxyurea may be used at any time during the study but only in 
patients with WBC ≥ 30,000/μL.” [Synopsis, Section 12.3.4] 
Amended Text: 
“Hydroxyurea may be used at any time during the study but only in 
patients with WBC ≥ 30,000/μL. Prior to the initiation of hydroxyurea 
please consider the contraindications in the Summary of Product 
Characteristic (SPC), including leukocytopenia (< 2.5 x 109 
leukocytes/L), thrombocytopenia (< 100 x 109 platelets/L) or severe 
anemia.” 
o Modified Sections:  Synopsis (Supportive Care and Concomitant 
Medications), Sections 7.1, 12.3.3.1, and 12.3.4. 
o Rationale:  This change was made to address the two requests from the Ulm 
EC for modification of the guidance regarding the use of hydroxycarbamide 
(hydroxyurea), including contraindications. The requests for protocol changes 
are summarized below: 
• Addition of text regarding thrombocytopenia and severe anemia as 
contraindications for the use of hydroxycarbamide (hydroxyurea) 
• Modification of the following text in Study Design, page 43, 
paragraph 6 (Version 3.0 redline): 
“Patients receiving selinexor will also receive BSC including 
blood product transfusions, antimicrobials, and (if appropriate) 
granulocyte colony-stimulating factors for neutropenic 
infection and hydroxyurea (Cycle 1 only)” is to be deleted and 
replaced by: “Hydroxyurea may be used at any time during the 
study but only in patients with WBC ≥ 30,000 µL”. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 113 
Test Product, Dose and Mode of Administration & Prohibited Medications Sections 
• Deletion of hydroxycarbamide (hydroxyurea) guidance text from the Test Product, 
Dose and Mode of Administration subsection of the Synopsis and the Prohibited 
Medication subsection (Section 12.3.4). 
o Modified Sections:  Synopsis (Test Product, Dose and Mode of 
Administration), Section 12.3.4 (Prohibited Medication). 
o Rationale:  Text was removed to improve protocol consistency and clarity, as 
text is not appropriate for these sections (i.e., it does not belong in the named 
sections). Guidance regarding the use of hydroxycarbamide (hydroxyurea), 
including contraindications, is provided in Supportive Care and Concomitant 
Medications subsection of the synopsis and Sections 7.1 and 12.3.3.1 of the 
protocol. 
Clinical Experience 
• AML efficacy and safety data:  Section describing efficacy and safety data from 
AML patients treated with selinexor in Phase 1 study KCP-330-001 was updated 
based on the presentation made at the EHA Annual Meeting 12-15 June 2014 
(Garzon R, Flinn I, Berdeja J, et al.) and on information in the Selinexor/KPT-330 IB  
v 4.0 (April, 2015). 
o Modified Sections:  Table 4-1 and Sections 4.3 and 5. 
o Rationale:  To present currently available efficacy and safety data from AML 
patients treated with selinexor. 
• Potential Risks:  Side effects were updated based on information in the 
Selinexor/KPT-330 IB v 4.0 (April, 2015). 
o Modified Section:  Section 4.3.1. 
o Rationale:  To present currently available safety data for patients treated with 
selinexor. 
• Reproductive Risks:  Modified section to include summary of animal reproductive 
toxicity findings and statement that, as human reproductive risks are not known, all 
patients must use effective contraception as defined in Section 12.3.3.1 – Prevention 
of Pregnancy. 
o Modified Section:  Section 4.3.1.1 (new section heading). 
o Rationale:  Former language in this section only dealt with risk mitigation 
(contraception) without describing existing reproductive toxicity data. 
Rationale for Dosing 
• Addition of maximum allowable dose. 
o Modified Sections:  Sections 5.1 and 12.3.1.5. 
o Rationale:  To ensure no patient exceeds the maximum allowable dose.  
Discontinuation Criteria 
• Addition of End of Study section. 
o Modified Sections:  Table 1-1, Section 11.3 (new sub-section). 
o Rationale:  Provide definition of End of Study. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 114 
Study Design 
• Increase in the assumed drop out rate from ~10% to ~20% and increase in the sample 
size from 150 patients to 170 patients. 
o Modified Sections:  Synopsis, Sections 8.1, 9.1, and 14.1.2. 
o Rationale:  Align with the actual drop out rate at the study sites and maintain 
power with the increased drop out rate. 
• Addition of an interim analysis after 25% of Overall Survival events. 
o Modified Sections:  Synopsis, Sections 7.2, 11.1, 14.1.2, and 14.2.1.4. 
o Rationale:  Assess for early futility and prevent unnecessary exposure of 
patients to selinexor in the event futility is declared. 
• Addition of BSA assessment at Days 1 and 15 of Cycles 2-5. 
o Modified Sections:  Section 9.2.4 and Table 1-1. 
o Rationale:  To ensure that none of the selinexor doses result in a dose 
> 70 mg/m2. 
• Increase in the anticipated enrollment period from 12 months to approximately 
15-18 months. 
o Modified Sections:  Synopsis and Section 14.1.2. 
o Rationale:  Provide realistic timeframe for enrollment of additional patients. 
• Clarification that patients who elect not to initiate study treatment should be 
encouraged to continue in the study so that follow-up information on disease 
progression and survival status may be obtained. 
o Modified Sections:  Synopsis, Sections 7.1 and 11.2. 
o Rationale:  Encourage patients who are randomized to physician’s choice to 
provide follow-up information even if they choose not to initiate study 
treatment. 
• Clarification of procedure for handling missing data for patients who are randomized 
but do not initiate study treatment. 
o Modified Section:  Section 14.3.7. 
o Rationale:  To account for missing data for randomized patients who do not 
receive study treatment. 
Inclusion Criteria 
• Revised inclusion criterion #9 to allow patients with liver involvement of their AML 
who have an AST and ALT ≤ 5 x ULN to enroll in the study, to increase the threshold 
levels for inclusion for bilirubin (≤ 2 x ULN), AST (≤ 2.5 x ULN), and ALT (≤ 2.5 x 
ULN), and to specify the threshold level (≤ 3 x ULN) for patients with high indirect 
bilirubin due to a congenital disorder (Gilbert’s syndrome). 
o Modified Section: Section 8.3. 
o Rationale: Changes were made to enable patients with hepatic transaminase 
elevations due to liver involvement of their AML to enroll in the study and to 
align inclusion requirements for bilirubin, AST, and ALT with other 
Karyopharm clinical studies in hematological cancers. In addition, of note, 
liver function abnormalities are rarely associated with selinexor use. 


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Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 117 
Amendment 4, Protocol Version 4.0 
Version 4.0 incorporates changes to Version 3.0 
Amendment Rationale 
The major changes in this amendment of the protocol are as follows: 
• Increase in the assumed drop out rate to ~20% to align with the actual rate at study 
sites and increase in the sample size to 170 patients to maintain power with the 
increased drop out rate. 
• Addition of interim analysis after 25% of Overall Survival events in order to assess 
for early futility and prevent unnecessary exposure of patients to selinexor in the 
event futility is declared. 
• Expansion of exclusion criteria to exclude patients with concurrent active 
malignancies that are not being treated. 
• Addition of EQ-5D-5L Quality of Life questionnaire. 
• Addition of 20 mg tablets in blister packs as an option for selinexor drug product. 
• Removal of specific recommendation for the use of dexamethasone as a supportive 
care agent. 
 
Other changes, primarily editorial and administrative, were made for readability and clarity. 
These changes include updates to data and corrections in the Synopsis, Schedule of 
Assessments, and body of the protocol for consistency and accuracy. 
 
The revised protocol Version 4.0 dated 24 April 2015 will be submitted by the Principal 
Investigator(s) to all applicable Institutional Review Boards (IRBs), Independent Ethics 
Committees (IECs), or Research Ethics Boards (REBs), and by Karyopharm Therapeutics 
Inc. to all applicable Regulatory Authorities. 
A summary of the key changes that were made to Version 3.0 of the protocol, including the 
rationale for these changes, in Version 4.0 is provided below. 
Changes to the protocol 
Administrative Changes 
• Internal changes to improve clarity and eliminate inconsistencies between sections; 
updated Table of Contents and hyperlinks (Modified sections:  Global). 
• Updated the version number and date of protocol from Version 3.0 dated 
25 November 2014 to Version 4.0 dated 24 April 2015 (Modified sections:  Global). 
• Updated references and patient and incidence data (Modified sections:  Global). 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 118 
Clinical Experience  
• AML efficacy and safety data:  Section describing efficacy and safety data from 
AML patients treated with selinexor in Phase 1 study KCP-330-001 was updated 
based on information in the Selinexor/KPT-330 IB  v 4.0 (April, 2015). 
o Modified Section:  Section 4.3. 
o Rationale:  To present currently available efficacy and safety data from AML 
patients treated with selinexor. 
• Potential Risks:  Side effects were updated based on information in the 
Selinexor/KPT-330 IB v 4.0 (April, 2015). 
o Modified Section:  Section 4.3.1. 
o Rationale:  To present currently available safety data for patients treated with 
selinexor. 
• Reproductive Risks:  Modified section to include summary of animal reproductive 
toxicity findings and statement that, as human reproductive risks are not known, all 
patients must use effective contraception as defined in Section 12.3.3.1 – Prevention 
of Pregnancy. 
o Modified Section:  Section 4.3.1.1 (new section heading). 
o Rationale:  Former language in this section only dealt with risk mitigation 
(contraception) without describing existing reproductive toxicity data. 
Rationale for Dosing 
• Addition of maximum allowable dose. 
o Modified Sections:  Sections 5.1 and 12.3.1.5. 
o Rationale:  To ensure no patient exceeds the maximum allowable dose.  
Discontinuation Criteria 
• Addition of End of Study section. 
o Modified Sections:  Table 1-1, Section 11.3 (new sub-section). 
o Rationale:  Provide definition of End of Study. 
Study Design 
• Increase in the assumed drop out rate from ~10% to ~20% and increase in the sample 
size from 150 patients to 170 patients. 
o Modified Sections:  Synopsis, Sections 8.1, 9.1, and 14.1.2. 
o Rationale:  Align with the actual drop out rate at the study sites and maintain 
power with the increased drop out rate. 
• Addition of an interim analysis after 25% of Overall Survival events. 
o Modified Sections:  Synopsis, Sections 7.2, 11.1, 14.1.2, and 14.2.1.4. 
o Rationale:  Assess for early futility and prevent unnecessary exposure of 
patients to selinexor in the event futility is declared. 
• Addition of BSA assessment at Days 1 and 15 of Cycles 2-5. 
o Modified Sections:  Section 9.2.4 and Table 1-1. 
o Rationale:  To ensure that none of the selinexor doses result in a dose 
> 70 mg/m2. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 119 
• Increase in the anticipated enrollment period from 12 months to approximately 
15-18 months. 
o Modified Sections:  Synopsis and Section 14.1.2. 
o Rationale:  Provide realistic timeframe for enrollment of additional patients. 
• Clarification that patients who elect not to initiate study treatment should be 
encouraged to continue in the study so that follow-up information on disease 
progression and survival status may be obtained. 
o Modified Sections:  Synopsis, Sections 7.1 and 11.2. 
o Rationale:  Encourage patients who are randomized to physician’s choice to 
provide follow-up information even if they choose not to initiate study 
treatment. 
• Clarification of procedure for handling missing data for patients who are randomized 
but do not initiate study treatment. 
o Modified Section:  Section 14.3.7. 
o Rationale:  To account for missing data for randomized patients who do not 
receive study treatment. 
Exclusion Criteria 
• Expansion of exclusion criteria to exclude patients with concurrent active 
malignancies that are not being treated. 
o Modified Section:  Section 8.4. 
o Rationale:  To avoid compromising the objectives of the trial. Certain 
malignancies (e.g., CLL or prostate cancer), even if untreated, could 
compromise the trial objectives. 
Treatment 
• Addition of description of 20 mg selinexor tablet formulation, packaging and 
administration. 
o Modified Sections:  Sections 12, 12.2.1, and 12.2.2. 
o Rationale:  Change reflects pending addition of 20 mg selinexor tablets in 
blister packs as an additional form of selinexor drug product. 
• Addition of new sub-section on Dose Modifications and Dose Delay (Section 12.3.1) 
to clarify criteria for dose modifications and discontinuation of patients due to dose 
delay.  
o Modified Section:  Section 12.3.1 (new sub-section). 
o Rationale:  Update of previous text to provide additional information and to 
improve clarity. 
• Clarifications on restrictions on use of acetaminophen and GSH-, 
S-adenosylmethionine (SAM)-, or N-acetylcysteine (NAC)-containing products. 
o Modified Sections:  Section 12.3.4, Appendix 8. 
o Rationale:  Minor revisions to improve clarity. 
• Revision of Treatment Compliance (Section 12.5)  
o Modified Section:  Section 12.5 
o Rationale:  Update of previous text to provide additional information and to 
improve clarity.  


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Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 122 
DESCRIPTION OF CHANGES 
1. Modification of hydroxyurea use during the study 
Change:  Old text indicated that hydroxyurea could only be used during Cycle 1. 
Protocol has been modified to allow hydroxyurea use at any time during the study but 
only in patients with WBC ≥30,000/μL. 
Rationale:  This change was made after discussions with study investigators regarding 
the appropriate use of hydroxyurea in this study. 
Modified Sections:  Synopsis, Section 7.1: Study Design Overview 
2. Modification of coagulation parameters 
Changes: Inclusion criterion #10 was modified to indicate that PTT elevation for 
known lupus anticoagulant is allowed. In addition, protocol has been modified to allow 
Thromboplastin Time for assessment of coagulation if necessary. 
Rationale: These changes were made because 1) the specified requirement for 
PTT≤1.5 ULN is not relevant for patients with lupus anticoagulation and 2) certain sites 
routinely use TT for coagulation testing and requested permission to use this method.   
Modified Sections: Table 1-1: Schedule of Assessments and Study Activities, Table 
and footnote 15; Section 8.3: Inclusion Criteria; Section 10.5: Safety Assessments 
3. Modification of acetaminophen use and restrictions on drugs affecting glutathione-
medicated metabolism 
Changes:   
• Modification of restriction on use of acetaminophen:  Patients should minimize 
the use of products containing acetaminophen (paracetamol) on the days of 
selinexor dosing. Acetaminophen (paracetamol) alone or in combination should 
not be taken within 2 hours before or after selinexor dosing. New text:  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 of up to 1 gm and selinexor up to 55 mg/m2 (approximately 80-
100 mg). Therefore, there are no longer any restrictions on the use of 
acetaminophen or acetaminophen-containing products in combination with 
selinexor, EXCEPT on days on selinexor dosing, when acetaminophen must 
not exceed a total daily dose of 1 gram.   
• Addition of restrictions on glutathione (GSH)-, S-adenosylmethionine (SAM), 
or N-acetylcysteine (NAC)-containing products (potentially enhance selinexor 
metabolism) and addition of list of representative products (Appendix 6). 
Rationale: Ongoing clinical safety evaluations on the use of selinexor in combination 
with acetaminophen have not shown any significant clinical or laboratory abnormalities 
with doses of acetaminophen up to 1 gram and selinexor up to 55 mg/m2 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 123 
(approximately 80-100 mg). However, in comments on another selinexor clinical 
protocol, the FDA requested that acetaminophen use be restricted to 1 gm total daily 
dose on days of selinexor dosing. Restrictions on drugs that may enhance selinexor 
metabolism reflect the primary mechanism of selinexor metabolism by glutathione 
conjugation. The list of glutathione (GSH)-, S-adenosylmethionine (SAM), or N-
acetylcysteine (NAC)-containing products added as a new Appendix (Appendix 6) was 
requested by the FDA. 
Modified Sections: Synopsis; Section 9.2.11:  Restrictions and Precautions; Section 
12.3.4:  Prohibited Medications  
4. Clarification of options for selinexor dosing days 
Change:  Added “e.g.,” before description of possible twice weekly dosing days, to 
indicate that the list is not all inclusive.   
Rationale:  This change was made to provide clinical sites more flexibility to schedule 
patient dosing days, including option to dose on Saturday or Sunday.   
Modified Sections: Synopsis; Section 5.1:  Rationale for the Doses and Dosing 
Regimen; Section 12.2.3:  Dosing Information   
5. Updated ophthalmologic exam procedures and required timing 
Change:  Removal of the visual field exam and requirement for all patients with 
cataracts at screening to be assessed every 3 months. Addition of requirement to grade 
any cataracts seen during exam using Lens Opacities Classification System III 
(included as new Appendix 3).  
Rationale: Changes were made following discussion with ophthalmologic expert 
regarding appropriate parameters to include in the exam, and appropriate frequency of 
assessment for all patients to effectively monitor for ophthalmological adverse events. 
All patients are assessed at screening and the Final Visit, and as clinically indicated at 
any time during the study.  
Modified Sections: Table 1-1: Schedule of Assessments and Study Activities, Table 
and footnote 8; Section 9.2:  Description of Study Days; Section 10.5: Safety 
Assessments; Appendix 3: Lens Opacities Classification System III. 
6. Bone marrow aspirate: expanded screening window under certain circumstances 
Change:  Expanded window for bone marrow aspirate/biopsy during screening to 
within 14 days of Day 1 of Cycle 1, after consultation with, and approval by, the 
sponsor. In addition, text was added within Schedule of Assessments table clarifying 
timing of bone marrow aspirates during the study. 
Rationale:  Change requested by investigators, as the expanded window may 
occasionally be required for certain patients. 
Modified Sections:  Table 1-1: Schedule of Assessments and Study Activities, Table 
and footnote 16; Section 9.2.1: Visit 1 (within 14 days prior to start of therapy); 
Screening #1. 


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CCI


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 125 
• Removed prophylactic therapy section and replaced with new sections (12.3.1 
and 12.3.2) describing required and recommended supportive care  
• Removed supportive care guidance text from the body of the protocol that is 
now included in Table 12-2. 
• Addition of two supportive care Appendices:  Appendix 4:  NCCN Clinical 
Practice Guidelines in Oncology: Antiemesis and Appendix 5:  NCCN Clinical 
Practice Guidelines in Oncology:  Anorexia/Cachexia. 
Rationale:  Changes reflect current recommendations for management of selinexor-
related adverse events, based on results from ongoing Phase 1 and Phase 2 clinical 
studies. Section 12 was re-ordered and supportive care and dose adjustment guidances 
were consolidated into a single table to improve clarity and flow of adverse event 
management sections. Appendices were added to provide investigators with additional 
AE management guidance. 
Modified Sections: Synopsis; Section 12.2.4:  Dosing Information for Study 
Participants;  Section 12.3:  Dose Reduction Guidelines; Section 12.3.1.1:  Selinexor 
Dose Adjustments for Hematological Toxicities;  Section 12.3.2: Supportive Care and 
Concomitant Treatments; Section 12.3.2.1: Required Supportive Care Medications;  
Section 12.3.2.2: Supportive Care Recommendations for Selinexor-Related Adverse 
Events.  
10. Clarified requirements for reporting acute cerebellar syndrome to regulatory authorities 
Change:  Updated requirement for reporting of all cases of cerebellar toxicities to 
include not only FDA and MHRA (as in Version 2.1) but also Health Canada or other 
appropriate national regulatory body.  
Rationale:  FDA and MHRA had requested specific reporting requirements for 
cerebellar toxicities. Change made to standardize global reporting of cerebellar 
toxicities.  
Modified Sections: Section 13.1.5.1 (Adverse Event) Reporting Requirements. 
11. Combined Rationales and Summaries of Changes for all amendments into a single 
Appendix 
Change:  Prior versions of the protocol had separate Summary of Change appendices 
for each amendment. All Summaries of Changes are now combined in Appendix 6: 
Protocol Amendments:  Rationales and Summaries of Changes. Amendment 
summaries are presented in reverse chronological order, starting with most recent 
amendment 
Rationale:  Simplify the protocol by including history of changes in one Appendix.  
Modified Section:  Appendix 6. 
 
 
 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 126 
AMENDMENT 2, VERSION 2.1 (UK-Specific; submitted only to MHRA)  
 
RATIONALE FOR THIS AMENDMENT 
The purpose of this protocol amendment is to address a comment received after review of the 
protocol by the Medicines and Healthcare Products Regulatory Agency.   
This change is: 
• All cases of cerebellar toxicities of grade 3 or higher will also be reported to the MHRA 
in an expedited manner within 7 days of the Sponsor, or designee, being notified of the 
event. 
 
Specific changes are displayed in Boldface. 
Section 13.1.5.1 Reporting Requirements 
Unexpected serious suspected adverse reactions are subject to expedited reporting to FDA. 
ALL SAEs must be entered into the eCRF and reported to the Sponsor within 24 hours of 
first knowledge of the event by study personnel. In addition, all cases of cerebellar toxicities 
of grade 3 or higher must be captured as an SAE and reported to the FDA and the MHRA 
(Medicines and Healthcare Products Regulatory Agency) in an expedited IND Safety 
Report within 7 days of the event. 
 
 
 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 127 
AMENDMENT 1, VERSION 2.0 
 
RATIONALE FOR THIS AMENDMENT 
The purpose of this protocol amendment is to address comments received from regulatory 
authorities and ethical committees following review of protocol Version 1 dated 21 January 
2014. 
Given that thrombocytopenia is expected in patients with this protocol regimen, it was 
recommended that the treatment goal for hypertension should be lower than 
BP = 150/100 mmHg, the original protocol limit, to reduce the risk of CNS bleeding. This 
observation is addressed in Section 3: Change 1. Additionally, it was recommended that the 
efficacy analysis be conducted in the intent-to-treat (ITT) population (all patients randomized; 
whether dosed or not) as opposed to the modified intent-to-treat (mITT) population described 
in the original protocol. This change in analysis methodology is addressed in Section 3: 
Change 5. 
Other changes included in this amendment are described in the approximate order they appear 
in the protocol in Changes ≥ 2. When a protocol change applies to multiple protocol sections, 
the later sections are identified where similar edits were applied.   
Minor sponsor-initiated changes were also made to the protocol for clarity. Administrative and 
typographical corrections were made as needed throughout the document. Clinical data from 
ongoing clinical studies have been updated as available throughout the protocol. 
Section numbers are provided for old text in protocol Version 1.0 dated 21 January 2014 and 
for amended text or added text in the protocol Version 2.0 dated 03 July 2014. 
SUMMARY OF CHANGES 
The substantive changes addressed in the following order include: 
1. Hypertension blood pressure (BP) treatment goal 
2. Clarification of dosing schedule options 
3. Revised description of third physician’s choice best supportive care (BSC) + 
hypomethylating agent 
4. Change from a 4-hour to a 2-hour window between administration of selinexor and 
acetaminophen (paracetamol)-containing medications 
5. Change in analysis from mITT patient population to ITT population 
6. Additions to the “Schedule of Assessments and Study Activities”  
a. Added Randomization with criteria to Visit 3 
b. Addition of Cycle 1 Day 3 only phone contact with patient to monitor AEs and 
concomitant medications 
c. Addition of 30-Day (after Final Visit) and Survival patient contacts 
7. Updated side effects information   
8. Update to Rationale for Dosing and the Dosing Regimen  
9. Deletion of instructions for patients who achieve CR and rationale for change 


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Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 129 
CHANGE 3: PROTOCOL SYNOPSIS, REFERENCE THERAPY, DOSE AND 
MODE OF ADMINISTRATION 
Old Text: Reference Therapy, Dose and Mode of Administration 
(3) BSC + hypomethylating agent: azacitidine 75 mg/m2 by sc injection daily on Days 1-7 
(7 doses) to be repeated at 28 day intervals, or decitabine (20 mg/m2 IV over 1 hour daily on 
Days 1-5 to be repeated at 28 day intervals). 
has been changed to: 
(3) BSC + hypomethylating agent: azacitidine 75 mg/m2 by sc injection daily on Days 1-7 or 
1-5, 8, 9 (7 doses) to be repeated at ≥28 day intervals, or decitabine (20 mg/m2 IV over 1 hour 
daily on days 1-5 or days 1-10 to be repeated at ≥28 day intervals). This identical change was 
made in Section 7.1: Study Design Overview and in Section 12.1: Dosing and Administration 
of Physician Choice’s Study Medication (Reference Therapy).   
CHANGE 4: PROTOCOL SYNOPSIS, CONCOMITANT MEDICATIONS 
Old Text: Protocol Synopsis, Concomitant Medications 
Acetaminophen (paracetamol) should not be taken within 4 hours before or after selinexor 
dosing, 
has been changed to: 
Acetaminophen (paracetamol) alone or in combination should not be taken within 2 hours 
before or after selinexor dosing. 
Similar text revisions reflecting the change in the dosing window for acetaminophen 
(paracetamol) products have been made in Section 9.2.11: Restrictions and Precautions, in 
Section 12.3.3: Concomitant Medication and Treatment and in Section 12.3.4: Prohibited 
Medication. 
CHANGE 5: PROTOCOL SYNOPSIS, STATISTICAL METHODS 
Old Text: Study Synopsis, Criteria for Evaluation, Efficacy 
The analysis of OS will be performed on the modified intent-to-treat (mITT) population as the 
primary analysis, and on the per-protocol (PP) population as a supportive analysis. 
has been changed to: 
The analysis of OS will be performed on the intent-to-treat (ITT) population as the primary 
analysis, and on the per-protocol (PP) population as a supportive analysis 
This significant change has also been made in the following protocol locations: 
Old Text: Protocol Synopsis, Statistical Methods 
The modified intent-to-treat population (mITT) will consist of all patients who are randomized 
to, and receive at least one dose of, study therapy. This population will be used for primary 
analyses of efficacy. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 130 
has been changed to: 
The intent-to-treat population (ITT) will consist of all patients who are randomized to study 
therapy. This population will be used for primary analyses of efficacy.  
Old Text: Statistical Methods, Section 14.2.1.1: Modified Intent-To-Treat Population  
The modified intent-to-treat population (mITT) will consist of all patients who are randomized 
and receive at least one dose of study therapy. This population will include patients with at 
least one dose of study drug who have discontinued therapy due to toxicity or disease 
progression and patients who have taken at least one dose of study drug and have died from 
any cause related to study drug or disease. This population will be used for primary analyses 
of efficacy. 
has been changed to: 
The intent-to-treat population (ITT) will consist of all patients who are randomized to study 
therapy. This population will include patients who have discontinued therapy due to toxicity 
or disease progression and patients who have died from any cause related to study drug or 
disease. This population will be used for primary analyses of efficacy, and such analyses will 
be based on the randomized treatment assignment.  
Old Text: Statistical Methods, Section 14.2.1.2: Per-Patient Population 
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. 
has been changed to: 
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 ITT 
population, this will be taken into consideration in the decision to continue to later phase 
studies, or in the design of further studies. 
Old Text: Statistical Methods, Section 14.2.1.3: Safety Population  
The safety population will consist of all patients who have received any amount of study 
medication; it is anticipated this population consist of the same patients as in the mITT 
population.  
 
has been changed to: 
The safety population will consist of all patients who have received any amount of study 
medication; analyses of safety will be performed based on treatment received, even if different 
from that randomized. 
CHANGE 6: ADDITIONS TO THE “SCHEDULE OF ASSESSMENTS AND STUDY 
ACTIVITIES” 
The following additions have been made in the “Schedule of Assessments and Study 
Activities” and corresponding sections in the body of the protocol. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 131 
The table title has been changed to “Table 1-1: Schedule of Assessments and Study Activities” 
for easier reference throughout the amended protocol. 
• Added Randomization Visit 3 with this footnote: Randomization must occur 
≤3 calendar days of Cycle 1 Day 1 
• Added “Nutritional consultation” procedure to Table 1-1 as described in Footnote 22: 
It is strongly recommended that patients be given nutritional consultation to discuss 
any food recommendations and strategies for managing potential nausea and appetite 
changes experienced with selinexor. This addition is similarly documented in Study 
Plans and Procedures, Section 9.2.2: Screening Visit 2.  
• Added another column to Table 1-1 for a telephone contact on Day 3 of Cycle 1 as well 
as a new Footnote 23 which reads “Cycle 1 Day 3 phone call with patient to evaluate 
supportive care medications and adverse events, and to adjust supportive care as 
appropriate. The phone contact with the patient must take place on Day 3 following the 
Cycle 1 Day 1 selinexor dosing”. The footnotes thereafter were re-numbered 
accordingly. This addition is similarly documented in Study Plans and Procedures, 
Section9.2.4: Cycle 1 Day 3 only. 
• Added a “30-Day Safety Follow-up Visit” procedure in Table 1-1 as described in 
Footnote 24: By phone (or a visit, if possible), assess overall medical condition of the 
patient and status of his/her AML, follow-up on any AEs that were not resolved at the 
Final Study Visit, and information on any antineoplastic therapies utilized since 
discontinuation of selinexor study treatment. This addition is similarly documented in 
Study Plans and Procedures, Section 9.2.9: 30 Day Patient Safety Follow-up. 
• Added a “Survival Follow-up Visit” procedure in Table 1-1 as described in 
Footnote 25:  After study discontinuation, a call will be made to the patient (or the 
patient’s family) every 3 months to inquire about the patient’s AML status, well-being, 
and information on any antineoplastic therapies utilized since discontinuation of 
selinexor study treatment. This addition is similarly documented in Study Plans and 
Procedures, Section 9.2.10: Survival Follow-up 
• Edited and clarified instructions about Complete and Limited Serum Chemistries on 
timing and inclusion of TSH in Table 1-1 Footnotes 12 and 13 and in Methods of 
Assessments and Endpoints, Section 10.5: Safety Assessments, Serum Chemistry and 
to allow for the collection of either Blood Urea Nitrogen (BUN) or urea to 
accommodate institutions that do not analyze BUN but do analyze urea as documented 
in Footnotes 12 and 13 and in Section10.5.  
CHANGE 7: SECTION 4.3 CLINICAL EXPERIENCE 
Old Text: Clinical Experience, Section 4.3.1, Potential Risks 
Side effects observed in patients include: 
Most common side effects:  


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 132 
• nausea  
• loss of appetite  
• fatigue  
• vomiting 
• weight loss 
Less common: 
• diarrhea  
• change in taste   
• changes in vision including blurred vision 
• low platelets without bleeding  
• decrease in red blood cells 
• low sodium 
Rare (< 5%): 
• worsening of existing cataracts   
• elevated levels of bilirubin 
• elevated levels liver enzymes (ALT and AST)  
 
has been changed to  
Side effects observed to date in patients are shown below. Please see KPT-330 for Oral 
Administration Investigator’s Brochure for most up-to-date information. 
Most common side effects:  
• nausea  
• loss of appetite  
• fatigue  
• vomiting 
• weight loss  
• diarrhea  
Less common: 
• change in taste   
• changes in vision including blurred vision 
• low platelets 
• decrease in red blood cells 
• low sodium without symptoms 
Rare (< 5%): 
• worsening of pre-existing cataracts   
• elevated levels of bilirubin 
• elevated levels of liver enzymes (ALT and AST)  
 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 133 
One patient, heavily pre-treated for recurrent pancreatic cancer, developed, ‘acute cerebellar 
syndrome’ following 4 doses of KPT-330 at 85 mg/m twice weekly. The patient experienced 
abnormal speech, loss of coordination, and was unable to walk. No other patients have reported 
such symptoms to date. 
CHANGE 8: SECTION 5: RATIONALE FOR THE STUDY 
Old Text Section 5.1: Rationale for Dosing and the Dosing Regimen 
Dose escalation on this twice-weekly schedule in KCP-330-001 in patients with B-cell 
malignancies is currently proceeding at 60 mg/m2 and in patients with rel/ref AML at 
70 mg/m2.   
has been changed to: 
A MTD of 65 mg/m2 twice weekly (Days 1 and 3) has been determined in the ongoing Phase 
1 study of selinexor in patients with advanced solid tumors (KCP-330-002). Two dose-limiting 
toxicities (DLTs) occurred in 2 patients in the solid tumor study (KCP-330-002) treated at 85 
mg/m2 twice weekly and included ‘probably related’ asymptomatic Grade 3 hyponatremia and 
‘possibly related’ acute cerebellar syndrome with ataxia and dysarthria. Of note, asymptomatic 
hyponatremia had been observed in other patients treated with selinexor, but only this one case 
of central nervous system (CNS) toxicity was observed across any of the selinexor trials (>300 
patients as of 15 May 2014) 
CHANGE 9: SECTION 12.2: DOSING AND ADMINISTRATION OF SELINEXOR  
Old Text: Section 12.3: Dosing Instructions for Patients who Achieve CR (see below) has 
been deleted. 
“For patients who achieve CR or CRi for ≥ 8 weeks (including two bone marrow [BM] biopsies 
confirming CR/CRi), dosing frequency may be reduced to once weekly at the same dose based 
on the treating Physician recommendation and following consultation with the Sponsor. In the 
event that patients show early evidence of relapse from CR or CRi, twice weekly dosing 
frequency may be reinstated.” 
The rationale for this change is that because of emerging data from the ongoing Phase 1 study, 
the physician can choose to reduce the dose based on dose modification guidelines. 
CHANGE 10: SECTION12.4: SELINEXOR STORAGE AND ACCOUNTABILITY 
Old Text: Treatment, Section 12.4, Selinexor Storage and Accountability 
Selinexor tablets will be stored at ambient or refrigerated temperatures between (36-86°F) or 
(2-30°C) in a locked and secured area with restricted access to study staff. 
has been changed to: 
Selinexor tablets will be stored at ambient or refrigerated temperatures between (41-86°F) or 
(5-30°C) in a locked and secured area with access restricted to study staff. 
This change documents a narrower temperature range in cold temperatures for best storage of 
selinexor. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 134 
CHANGE 11: SECTION 12.3.2: RESCUE MEDICATIONS AND CONCOMITANT 
TREATMENTS  
Old Text:  Treatment, Section 12.3.2.1, Required Prophylactic Therapy for Adverse Events 
Associated with Selinexor 
All patients will receive prophylactic treatment to prevent anorexia, fatigue and nausea, 
which includes: 
Megesterol acetate 160-400 mg daily, 0-3 days before the first dosing day of selinexor  
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 2.5-5.0 mg qhs or 2.5 mg bid, 0-3 days before the first dosing day of selinexor  
OR 
Mirtazapine 15 mg qd (qpm/phs), 0-3 days before the first dosing day of selinexor  
 
has been changed to: 
Two prophylactic medications (one from Group A and one from Group B shown below) must 
be used to minimize anorexia, nausea and fatigue and are required for Cycle 1, and may be 
tapered or discontinued after Cycle 2 as tolerated. If there is an adverse reaction to one of the 
prophylactic medications, it may be discontinued or omitted. In addition, medications from 
Group C and D may be used (optional). 
A. 
Dexamethasone 12mg will be given on the days of selinexor dosing. All patients must 
receive dexamethasone unless they cannot tolerate it or it is contraindicated. 
Optional: The day after selinexor dosing additional 4-8 mg dexamethasone (or 
equivalent glucocorticoid) may be given; maximum 40 mg dexamethasone or 
equivalent per week) 
 
 
OR 
Megesterol Acetate For patients with partial intolerance to glucocorticoids or for 
whom glucocorticoids are contraindicated (i.e., patients receiving < 4 mg 
dexamethasone on dosing days): patients must receive megesterol acetate 80-400 mg 
daily, starting 1-3 days before the first dosing day of selinexor.   
Optional: In addition, megesterol acetate 80-400 mg daily can be added for any patients 
as part of general supportive care for anorexia. 


Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 135 
B. 
5-HT3 Antagonists (ondansetron 8 mg or equivalent) starting before the first dose of 
selinexor and continued bid – tid prn.  
C. 
OPTIONAL:  Either olanzapine (preferred) 5.0 mg qhs or 2.5 mg bid, starting 
0-3 days before the first dosing day of selinexor –or– mirtazapine 7.5-15 mg daily 
(qpm or qhs), starting 0-3 days before the first dosing day of selinexor. Please note that 
olanzapine and mirtazapine can induce fatigue and should be discontinued in the case 
for fatigue grade >2. 
D. 
OPTIONAL:  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 in the first 2 doses. 
Table 12-3 
Sample Weekly Schedule for Selinexor, Dexamethasone and Prophylactic 
Therapy 
Compound 
Day Prior 
to first 
Selinexor 
Dose 
Day 1 
Day 
2 
Day 3 
Day 
4 
Day 5 
Day 
6 
Day 7 
Selinexor  
 
X 
 
X 
 
 
 
 
Dexamethasone 
(12 mg)*  
 
X 
 
X 
 
 
 
 
Dexamethasone – 
optional (4-8 mg) or 
equivalent 
glucocorticoid 
 
 
X 
 
X 
 
 
 
Megesterol acetate – 
optional 
X 
X 
X 
X 
X 
X 
X 
X 
5-HT3 Antagonist (e.g., 
ondansetron) 
 
X 
BID-TID prn 
Olanzapine or 
mirtazapine – optional 
X 
X 
X 
X 
X 
X 
X 
X 
NK1R antagonist (e.g., 
aprepitant) – optional 
 
X 
BID-TID prn 
* 
For patients with partial intolerance to glucocorticoids, a minimum dose of 4 mg dexamethasone is 
permitted on dosing days. 
 


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Selinexor (KPT-330) 
 
Karyopharm Therapeutics, Inc. 
Clinical Study Protocol:  KCP-330-008 
 
 
 
 
Version 5.0  04 August 2015 
CONFIDENTIAL 
Page 137 
CHANGE 14: SECTION 12.4.2: SUPPORTIVE CARE 
Old Text: Section12.4.2.7: Liver Enzyme Increase 
To date, significant liver toxicity has not been reported in patients treated with selinexor. 
Patients should minimize their use of alcohol and acetaminophen (paracetamol) as these drugs 
may deplete hepatic glutathione that could alter selinexor metabolism. Glutathione (GSH) 
replacing agents such as N-acetylcysteine or S-adenosylmethionine may be considered if 
selinexor induced liver dysfunction is suspected 
has been changed to: 
To date, significant liver toxicity has not been reported in patients treated with selinexor. 
Patients should minimize their use of alcohol and acetaminophen (paracetamol) as these drugs 
may deplete hepatic glutathione that could alter selinexor metabolism. 
Statement regarding glutathione replacing agents was removed as these agents could 
potentially influence selinexor metabolism and exposure in patients.  
CHANGE 15: SECTION 12.3.4: PROHIBITED MEDICATION 
Old Text: (Paragraph below) 
The primary metabolism of selinexor in humans is through glucuronidation. Inactivation of 
selinexor by glutathione conjugation is a secondary 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 
(paracetamol) are underway and preliminary data suggest the combination of low dose 
acetaminophen (paracetamol) and selinexor is not toxic. Therefore, these recommendations are 
empirical, and acetaminophen (paracetamol) should not be ingested 4 hours before through 4 
hours after selinexor dosing. It should also be noted that recreational ethanol ingestion is 
associated with glutathione depletion; therefore, the use of products containing ethanol should 
be minimized or avoided on selinexor dosing days. 
has been replaced by: 
Use of products containing ethanol should be minimized or avoided on selinexor dosing days. 
CHANGE 16: ADDITION OF APPENDIX 2: INTERNATIONAL WORKING GROUP 
GUIDELINES FOR AML 
This new appendix has been added to provide convenient access to the revised 
recommendations of the International Working Group for diagnosis, standardization of 
response criteria, treatment outcomes, and reporting standards for AML. 

SAP_001.pdf: 
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1. 
Information From the Study Protocol...................................................... 8 
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Study Analyses .......................................................................................... 25 
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5. 
Changes to Planned Analyses .................................................................. 39 
6. 
References ................................................................................................. 40 
 
 
 
 
 
 
 
 
 
 
8. 
Revision History ..................................................................................... 190 
9. 
Appendices .............................................................................................. 191 
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