Clinical trial NCT02249091
Conditions: Acute Myeloid Leukemia (Relapsed/Refractory)
Sponsor: GSO Global Clinical Research BV
Start date: 2014-09-01; Completion date: 2018-07-31
Enrollment: 42 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Acute Myeloid Leukemia (AML) is currently treated with chemotherapy by combining several drugs with different ways of inhibiting the cell growth. In this trial, standard chemotherapeutics that have proven their effectiveness for years, Ara-C and Idarubicin, will be combined with a new drug called Selinexor.

Selinexor inhibits the growth of cancer cells by keeping certain proteins in the nucleus which control the cell growth.

Detailed description:

Arms: arm 1: All enrolled patients are treated with cytarabine at a dose of 100 mg/m² continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m\^2 iv (day 1,3,5) every 4 weeks and selinexor for up to 2 induction cycles. If a second cycle is applied idarubicin is only given on day 1 and 3.

Selinexor is administered at a dose of 40 mg/m\^2 twice weekly orally starting on day 2 (total of 8 doses per induction cycle). arm 2: All enrolled patients are treated with cytarabine at a dose of 100 mg/m\^2 continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m\^2 iv (day 1,3,5) every 4 weeks and selinexor for up to 2 induction cycles. If a second cycle is applied idarubicin is only given on day 1 and 3.

Selinexor is administered at a flat dose of 60 mg twice weekly orally in weeks 1-3 of a 4-week cycle starting on day 2 (total of 6 doses per induction cycle).
Interventions: intervention 1: Selinexor intervention 2: Idarubicin intervention 3: Cytarabine
Intervention descriptions: intervention 1: Patients receive Selinexor as specified in arm/group description (8 doses of 40 mg/m\^2 or 6 doses of 60 mg per induction cycle). intervention 2: Infusion, iv, 10 mg/m\^2, on days 1,3,5 in cycle 1, on days 1,3 in cycle 2 intervention 3: Continuous infusion day 1 to 7, 100 mg/m\^2, iv,

Protocol documents:
Prot_000.pdf: 
SAIL 
 
 
 
 
 
 
 
 
 
 
Page 1/87 
 
Current version: Version 3.1, 13.01.2017 
 
An Investigator-Initiated Study To Evaluate Ara-C and Idarubicin in 
Combination with the Selective Inhibitor Of Nuclear Export (SINE)  
Selinexor (KPT-330) in Patients with Relapsed Or Refractory AML 
 
 
 
Protocol code 
SAIL 
 
 
EudraCT Number 
2014-000526-37 
 
 
 
 
Sponsor: 
GSO Global Clinical Research B.V. 
 
 
LKP according to §4 Abs. 
25 and §40 Abs. 1 Nr. 5 
AMG:  
Professor Dr. Michael Heuser, Hannover  
 
 
 
 
 
 
 
Confidentiality 
The contents of the protocol are confidential and may neither be communicated verbally 
nor in writing without the agreement of the study sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 2/87 
 
Current version: Version 3.1, 13.01.2017 
CONTACT ADDRESSES 
 
 
Sponsor 
GSO Global Clinical Research B.V.  
EBC Amsterdam 
Keizersgracht 62-64 
1015CS Amsterdam 
The Netherlands 
 
LKP according to §4 
Abs. 25 and $40 Abs. 1 
Nr. 5 AMG  
Professor Dr. Michael Heuser  
Medizinische Hochschule Hannover 
 
Coordinating CRO 
GSO Gesellschaft für Studienmanagement und 
Onkologie mbH 
Harvestehuder Weg 21 
20148 Hamburg 
Phone +49 (0) 40 44 19 54 60 
Fax +49 (0) 40 44 19 54 78 
E-mail: kranich@gsoglobal.com 
 
Drug Supply 
Karyopharm Therapeutics, Inc.  
85 Wells Ave  
Newton MA 02459 
USA 
 
 
 
 
 
 
 




SAIL 
 
 
 
 
 
 
 
 
 
 
Page 4/87 
 
Current version: Version 3.1, 13.01.2017 
APPROVAL OF THE PROTOCOL BY LKP ACCORDING TO §4 ABS. 25 AND §40 
ABS. 1 NR. 5 AMG 
 
Protocol code 
SAIL 
 
 
EudraCT Number 
2014-000526-37 
 
 
 
Title: 
An Investigator-Initiated Study To Evaluate Ara-C 
and Idarubicin in Combination with the Selective 
Inhibitor Of Nuclear Export (SINE) Selinexor (KPT-
330) in Patients with Relapsed Or Refractory AML 
 
 
Version  
Version 3.1, 13.01.2017 
 
 
 
Michael Heuser, MD, PhD  
Physician, Department of Hematology, Hemostasis, Oncology and Stem Cell 
Transplantation (Hannover Medical School) 
 
 
 
 
 
 
  
Signature  
  
Date (DD Month YYYY)  
 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 5/87 
 
Current version: Version 3.1, 13.01.2017 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled: 
“An Investigator-Initiated Study to Evaluate Ara-C and Idarubicin in Combination 
with the Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) in Patients 
with relapsed or refractory AML”, version 3.1 dated 13.01.2017.  
and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline 
on Good Clinical Practice, all applicable national regulations as well as the requirements 
of the appropriate Institutional Review Board/Independent Ethics Committee and any 
other institutional requirements. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the study sponsor. 
 
 
 
 
Signature  
  
Date (DD Month YYYY)  
Investigator  
  
Investigator’s Institution 
 
  
  
 
 
 
 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 6/87 
 
Current version: Version 3.1, 13.01.2017 
SYNOPSIS 
Protocol code. 
SAIL 
Protocol version 
(Date) 
Version 3.1, dated 13.01.2017 
Detailed title 
Evaluation of Ara-C and Idarubicin in Combination with the 
Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) in 
Patients with relapsed or refractory AML 
EudraCT no. 
2014-000526-37 
LKP according to §4 
Abs. 25 and §40 Abs. 
1 Nr. 5 AMG 
Professor Dr. Michael Heuser, Hannover 
Sponsor 
GSO Global Clinical Research B.V.  
EBC Amsterdam 
Keizersgracht 62-64 
1015CS Amsterdam 
The Netherlands 
Study design 
Multi center, open-label, non-randomized Phase 2 trial. 
Patients with relapsed/refractory Acute Myeloid Leukemia (AML) 
will receive standard chemotherapy cytosine arabinose (Ara-C) 
100mg/m² days 1-7 and Idarubicin 10 mg/m² days 1, 3, 5 every 4 
weeks (max. 2 cycles) and Selinexor as a flat dose of 60 mg twice 
weekly during weeks 1-3 of a 4-week cycle starting on Day 2 of 
week 1 (total of 6 doses per induction cycle).  
If a bone marrow CR or CRi was achieved the patient will be 
recommended for stem cell transplantation, which represents the 
end of study treatment.  
If a partial remission was achieved an additional induction cycle will 
be initiated.  
Patients achieving CR or CRi, who are not eligible for SCT will 
receive consolidation therapy with AraC (3 cycles) in parallel to 
maintenance with Selinexor until relapse.  
Patients with >50% blast reduction after 2 cycles will continue 
maintenance with Selinexor until PD. 
Patients will be evaluated for disease status at the end of each 4-
weeks induction cycle and approximately every 3 months after 
allogeneic SCT or CR (or CRi) has been achieved until relapse or 
death, whichever is first. 
Duration of study 
 
The planned number of 40 patients was reached.  
End of enrolment period: June 2016.  
End of study is defined as 2 years after registration of last patient 
Total number of sites 
6-8 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 7/87 
 
Current version: Version 3.1, 13.01.2017 
Study population 
Patients with relapsed/refractory Acute Myeloid Leukemia (AML) 
according to the inclusion and exclusion criteria will be enrolled in 
this study trial. 
Objectives 
 
Primary objective 
 
 
To determine the efficacy of Selinexor in combination with 
standard chemotherapy in patients with relapsed/ refractory 
AML by determination of rate of complete remission (CR) or 
morphologic complete remission with incomplete blood count 
recovery (CRi), as defined by the recommendations on 
diagnosis and management of AML in adults from an 
international expert panel, on behalf of the European 
LeukemiaNet(1) 
Secondary objectives 
 
To determine the efficacy of Selinexor in combination with 
standard chemotherapy in patients with relapsed/ refractory 
AML by  
o Rate of partial remissions 
o Percentage of patients being transplanted after 
induction therapy 
o Early death rate 
o Overall survival (OS) 
o Event-free survival  
 
To evaluate overall safety and tolerability of Selinexor 
characterized by type, frequency, severity (graded using the 
National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] Version 4.03), timing and 
relatedness 
of 
adverse 
events 
(AEs) 
and 
laboratory 
abnormalities observed during the treatment within this study. 
Exploratory objectives To identify the Pharmacokinetics and Pharmacodynamics of 
Selinexor in patients with relapsed/refractory AML 
 
Planned sample size 
A sample size of 40 patients is planned and all patients receive 
standard chemotherapy with Selinexor. If a CR is achieved patients 
are intended to receive stem cell transplantation. 
Inclusion criteria 
To be eligible for this trial, patients must meet the following criteria: 
1. Cytological or histological diagnosis of AML with the 
exception of promyelocytic leukemia (AML M3) 
2. Patients must have relapsed/refractory disease (relapse 
after stem cell transplantation is permitted) as defined as: 
patients 
with 
<PR 
after 
first 
cycle 
of 
induction 
chemotherapy, or 
b. patients with <CR(i) after second cycle of induction 
chemotherapy, or 
c. patients 
who 
relapse 
after 
conventional 
chemotherapy or 
d. patients who have undergone a single stem cell 
transplantation and who have relapse of their AML. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 8/87 
 
Current version: Version 3.1, 13.01.2017 
3. Men and women aged ≥18 years and eligible for standard 
dose of chemotherapy (7+3);  
4. A period of at least 3 weeks needs to have elapsed since 
last treatment (with the exception of hydroxyurea) before 
participating in this study. Hydroxyurea induction therapy to 
reduce peripheral blast counts is permitted prior to initiation 
of treatment on protocol.  Treatment may begin in <3 weeks 
from last treatment if deemed in the best interest of the 
patient after discussion with the PI of the study;  
5. ECOG performance status ≤ 2  
6. Serum biochemical values with the following limits unless 
considered due to leukemia: creatinine ≤2 mg/dl; total 
bilirubin ≤2x ULN, unless increase is due to hemolysis or 
congenital disorder; transaminases (SGPT or SGOT) ≤2.5x 
ULN. 
7. Ability to swallow and retain oral medication 
8. Ability to understand and provide signed informed consent;  
9. Cardiac 
ejection 
fraction 
must 
be 
>/=50% 
(by 
echocardiography).  
10. Willingness and ability to comply with scheduled visits, 
treatment plans, laboratory tests, and other study 
procedures. 
 
Exclusion criteria 
Patients with any of the following will not be eligible for participation: 
1. Treatment with any investigational agent within four weeks. 
2. Cumulative anthracycline dose (daunorubicin or equivalent) 
>360 mg/m² 
3. HIV infection 
4. Presence of any medical or psychiatric condition which may 
limit full compliance with the study, including but not limited 
to:  
5. Presence of CNS leukemia 
6. Unresolved toxicity from previous anti-cancer therapy or 
incomplete recovery from surgery. 
7. For patients after SCT as part of prior treatment:  
a. Necessity of immunosuppressive drugs 
b. GvHD > grade 1 
8. Any of the following within the 12 months prior to study drug 
administration: 
myocardial 
infarction, 
severe/unstable 
angina, 
coronary/peripheral 
artery 
bypass 
graft, 
symptomatic congestive heart failure, cerebrovascular 
accident or transient ischemic attack, pulmonary embolism, 
deep vein thrombosis, or other thromboembolic event. 
9. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2. 
10. Other severe acute or chronic medical or psychiatric 
condition, or laboratory abnormality that may increase the 
risk associated with study participation or study drug 
administration, or may interfere with the interpretation of 
study results, and in the judgment of the investigator would 
make the patient inappropriate for entry into this study. 
11. Clinically significant bleeding within 1 month  


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 9/87 
 
Current version: Version 3.1, 13.01.2017 
Treatment scheme 
 
All enrolled patients may participate in an optional baseline 
translational research study. Patients will receive single dose of 
Selinexor (60 mg) after registration and before first induction cycle. 
Bone marrow aspirate samples will be collected pre-dose and 24 
hour post-dose. 
All enrolled patients will be treated with Ara-C at a dose of 100 
mg/m² continuous infusion (day 1-7) and idarubicin at a dose of 10 
mg/m² iv (day 1,3,5) every 4 weeks and Selinexor. If a second 
cycles is applied idarubicin is only given on day 1 and 3). 
Selinexor will be administered at a dose of 60 mg twice weekly 
orally during weeks 1-3 of a 4-week cycle (day 2,4,9,11,16,18) 
(total of 6 doses per induction cycle). 
If a CR was achieved the patient will be recommended for stem cell 
transplantation and will have his/her end of treatment and will be 
followed for event-free and overall survival. 
If patient has achieved a PR an additional cycle (4 weeks) will be 
initiated. If a CR was achieved the patient will be recommended for 
stem cell transplantation and will be followed for event-free and 
overall survival. 
In patients achieving CR or CRi after 1 or 2 4-week cycles who are 
not eligible or do not undergo additional stem cell transplantation, 
but, in the opinion of the investigator, are benefiting from Selinexor, 
then oral Selinexor dosed twice weekly may be continued parallel 
to consolidation therapy with Ara-C until relapse or toxicity 
develops.  The dose of Ara-C is 3 g/m² IV for 2h every 12 hours at 
3 consecutive days for patients with good performance status and 
younger than 60 years (in total 6 doses). If patients are older than 
60 years the dose is 1 g/m² IV for 2h every 12 hours at 3 
consecutive days. Consolidation with AraC will consist of 3 4-week 
cycles. During consolidation Selinexor dosing (60 mg) will start on 
day 2 and continue twice weekly in weeks 1-3 of a 4-week cycle 
(total of 6 doses per cycle). Selinexor twice weekly (with ~48 hours 
between two consecutive doses) in weeks 1-3 of a 4-week cycle at 
a dose of 60 mg (total of 6 doses per 4-week cycle) may continue 
until relapse or for maximally 1 year of treatment.  
Patients achieving a > 50% blast reduction after the end of 2 
induction cycles, not candidates for SCT, and in the opinion of the 
investigator, are benefiting from Selinexor, oral Selinexor dosed 
twice weekly may be continued until PD or for maximally 1 year of 
treatment. Drug administration will occur twice weekly with ~48 
hours between two consecutive doses at a dose of 60 mg. One 
cycle is 4 weeks with 6 doses of Selinexor during weeks 1-3. (e.g. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 10/87 
 
Current version: Version 3.1, 13.01.2017 
on Monday and Wednesday or on Tuesday and Thursday or on 
Wednesday and Friday).  
Treatment will continue until progression of disease (PD) or 
unacceptable toxicity, withdrawal of consent by the patients, or 
non-compliance by the patient with protocol requirements. 
Patients for whom none of the above mentioned is achieved after 
2 4-week induction cycles will have their end of treatment and will 
be followed for overall survival. 
Primary Endpoint 
Percentage of patients achieving a complete response (CR) or CRi 
(complete remission without normalization of peripheral blood 
counts) 
Secondary Endpoints 
 
Partial response rate 
 
Percentage of patients undergoing subsequent allogeneic stem 
cell transplant 
 
Early death rate 
 
Overall survival (OS) 
 
Event-free survival (Events are defined as Death, not achieving 
a CR or CRi, Relapse after CR or CRi) 
 
Toxicity (acc. to NCI CTC AE v4.03) 
Exploratory Endpoints 
(Optional Studies)  
 
Limited pharmacokinetics to measure plasma concentration of 
Selinexor 
 
Selinexor-induced changes in mRNA levels of XPO1 and tumor 
suppressor markers 
 
Selinexor-induced changes in plasma cytokine levels 
 
Selinexor-induced changes in gene expression profiling of 
leukemic blasts isolated from patients 
 
Expansion of leukemic blasts in mice for therapeutic studies 
Efficacy assessment 
Clinical and Bone Marrow Aspirate examinations and safety 
assessments are performed at baseline, at the End of induction 
cycles and if applicable at the end of each consolidation cycle. 
Disease status during maintenance will be evaluated at the end of 
each cycle and Follow-up after SCT every 3 months ± 28 days  
If a patient discontinues treatment due to any other reason than 
disease progression/ death/ withdrawal of informed consent, the 
disease evaluations shall continue until definition of relapse-free 
survival are met. This includes patients who wish to discontinue 
treatment, but agree that further data is captured for the purpose of 
the study (partial withdrawal). 
Safety assessment 
All adverse events occurring during the course of the trial and for 
up to 30 days after the last dose of study medication will be 
captured, documented and reported. Toxicity will be graded twice 
weekly during treatment. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 11/87 
 
Current version: Version 3.1, 13.01.2017 
Until recovery of platelets and ANC, hematology assessments are 
done as often as necessary to determine the exact date of recovery 
of platelets and ANC. 
Safety laboratory assessments include complete blood count, time 
to recovery of platelets ≥ 50x 109/L and ≥ 100x 109/L, ANC recovery 
≥ 0.5x 109/L and ≥ 1.0x 109/L, clinical chemistry, including liver 
function test, coagulation, and 12-lead electrocardiogram as well 
as cardiac ultrasound. 
Statistical 
considerations 
Primary Efficacy Parameter 
The primary efficacy measure will be the rate of complete 
responders (CR). 
Secondary Efficacy Parameters 
The secondary efficacy measures: 
 
Rate of partial remissions 
 
Percentage of patients being transplanted after induction 
therapy 
 
Early death rate 
will be analyzed as rates. 
 
Overall survival (OS); 
 
Event-free survival (Events are defined as Death, not 
achieving a CR or CRi, Relapse after CR or CRi) 
will be described by median survival time and respective 95%-
confidence intervals. 
Sample size 
calculation 
The sample size calculation is based on the evaluation of response 
rates according to Fleming for single-stage phase II designs. For 
the Fleming's procedure the two response levels p0 (expected CR 
rate) and p1 (meaningful increase in CR rate) are specified as 
p0=30% and p1=60%: 
N=25 patients should participate in the study to ensure a power of 
1–=0.90 for the discrimination of p0 and p1. According to Fleming 
the null hypothesis should be rejected if at least 
 
r =

)
1(
0
0
1
0
p
Np
Z
Np



* 1
 
responses are observed (x* denotes the nearest integer to). With 
p0 and N defined as above and Z1– = (1 – )-quantile of the 
normal distribution = 1.645 at least 12 responders should be 
observed to show the efficacy as postulated. 
Using the same approach in the 15 additional patients, submitted 
to an adapted drug regimen, the power will be 80% to discriminate 
a p0=30% (expected CR rate) from a p1=65% (meaningful increase 
in CR rate), if 8 out of 14 completed patients are considered as 
responders, with a one-tailed alpha error of 5%. Alternatively, the 
power will be 90% to discriminate a p0=30% from a p1=70% again 
if 8 out of 14 completed patients are considered as responders, with 
a one-tailed alpha error of 5%. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 12/87 
 
Current version: Version 3.1, 13.01.2017 
Accompanying 
baseline translational 
study (optional) 
Leukemic blast cells will be isolated pre- and 24 hr post- a single 
Selinexor dose (60 mg) given at baseline (after registration and 
before first induction cycle). Blast cells will be used for leukemic 
stem cell gene expression profiling and in mouse model studies to 
define parameters associated with clinical responsiveness to 
Selinexor.    
Data 
Monitoring 
Committee 
An independent Data Monitoring Committee (DMC) will be 
implemented that reviews accumulating data of the clinical trial with 
respect to any potential safety issues, study progress and critical 
efficacy endpoints.  
The DMC will be an independent board consisting of 2-3 physicians 
with special expertise in AML. A physician is not allowed to 
participate in this clinical trial while serving on the DMC. The DMC 
will be supported by an independent statistician, if necessary. 
The DMC will review safety data, recovery times and efficacy of the 
clinical trial and support the interpretation of clinical trial results.   
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 13/87 
 
Current version: Version 3.1, 13.01.2017 
INFORMATION TO BE PROVIDED REGARDING SAES/PREGNANCY 
 
In the case of a serious adverse event (SAE) or pregnancy, the following 
person must be contacted by fax within 24 hours: 
Clinical Trial Manager 
Dr. Anne L. Kranich 
Address: 
GSO mbH 
Gesellschaft für Studienmanagement und 
Onkologie mbH 
Harvestehuder Weg 21 
20148 Hamburg 
 
 
Phone: 
+49  40 44 19 54 60 
Fax: 
+49  40 44 19 54 78 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 14/87 
Current version: Version 3.1, 13.01.2017 
 
List of Abbreviations  
 
-HCG 
Beta human chorionic gonadotropin 
AE 
AESI 
Adverse event 
Adverse event of special interest 
ACS 
Acute Cerebellar Syndrome 
ALT 
(SGPT) 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolut Neutrophil Count 
aPTT 
Activated partial thromboplastin time 
AraC 
Cytarabin 
AST 
(SGOT) 
Aspartate aminotransferase 
BP 
Blood pressure 
BSA 
Body surface area 
CLL 
Chronic lymphocytic leukemia 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organisation 
CT 
Computer tomography 
CTCAE 
Common terminology criteria for adverse events 
D 
Day 
DLBCL 
DMC 
Diffuse large B-Cell lymphoma 
Data Monitoring Committee 
DNA 
Desoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
FU 
Follow-Up 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GRP 
Growth regulatory protein 
GvHD 
Graft-versus-Host Disease 
h 
Hour 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
ITT 
Intent to treat 
IV 
Intravenous 
LCS 
Leucemia stem cells 
LDH 
Lactate dehydrogenase 
LIC 
Leucemia-initiating cells 
LVEF 
Left ventricular ejection fraction 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 15/87 
Current version: Version 3.1, 13.01.2017 
m² 
Square metre (body surface area) 
MCL 
Mantle cell lymphoma 
mg 
Milligram 
MI 
Myocardial infarction 
min 
Minute 
mL 
Millilitre 
mRNA 
Messenger Ribonucleic acid 
NCI 
National Cancer Institute  
NHL 
Non-Hodgkin lymphoma 
OS 
Overall survival 
PD 
Progressive disease 
PK 
Pharmacokinetics 
PP 
Per protocol  
PR 
Partial response 
PT 
Prothrombin time 
RBC 
Red blood count 
SAE 
Serious adverse event 
SCT 
Stem cell transplantation 
SD 
Stable disease 
SINE 
Selective inhibitor of nuclear export 
SADR 
Serious adverse drug reaction 
SUSAR 
Suspected unexpected serious adverse reaction 
T-ALL 
T- Acute lymphoblastic leukemia 
TSP 
Tumor suppressor protein 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
XPO1 
Exportin 1 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 16/87 
Current version: Version 3.1, 13.01.2017 
 
Confidentiality .............................................................................................................. 1 
CONTACT ADDRESSES .............................................................................................. 2 
APPROVAL OF THE PROTOCOL ................................................................................ 3 
Investigator’s Agreement ............................................................................................ 5 
Synopsis ....................................................................................................................... 6 
Information to be PROVIDED REGARDING SAEs/Pregnancy ................................ 13 
1 
Background and Rationale ............................................................................ 19 
1.1 
Background .................................................................................................................. 19 
1.1.1 
Acute myeloid leukemia .................................................................................... 19 
1.1.2 
Selinexor .......................................................................................................... 20 
1.2 
Study Rationale ............................................................................................................ 24 
2 
Objectives of the Study ................................................................................. 25 
2.1 
Primary Objective ......................................................................................................... 25 
2.2 
Secondary Objectives.................................................................................................. 25 
2.3 
Exploratory Objectives (Optional Studies) ............................................................... 25 
3 
Study design................................................................................................... 26 
3.1 
Overview of Study Design and Dosing Regimen ..................................................... 26 
3.1.1 
Baseline Translational Research Study (optional) .............................................. 26 
3.1.2 
Definition of Treatment Cycle ............................................................................ 26 
3.1.3 
Treatment Duration ........................................................................................... 29 
3.1.4 
End of treatment Visit........................................................................................ 29 
3.1.5 
Follow-up Phase ............................................................................................... 29 
3.2 
Study timelines ............................................................................................................. 29 
4 
Selection of the Study Population ................................................................ 30 
4.1 
Target Population ......................................................................................................... 30 
4.2 
Inclusion Criteria .......................................................................................................... 30 
4.3 
Exclusion Criteria ......................................................................................................... 30 
4.4 
Registration of Patients ............................................................................................... 31 
5 
Schedule of Assessment and Procedures ................................................... 32 
5.1 
Study Assessments ..................................................................................................... 32 
5.1.1 
Response Assessments.................................................................................... 32 
5.1.2 
Translational, Pharmacodynamic and Pharmacokinetic Analyses (Optional) ...... 32 
5.1.3 
Safety Assessments ......................................................................................... 33 
5.1.4 
Laboratory Assessments ................................................................................... 33 
5.2 
Study Procedures ........................................................................................................ 33 
5.2.1 
Prophylactic Therapy for All Patients ................................................................. 37 
5.2.2 
Screening Procedures ...................................................................................... 37 
5.2.3 
Baseline Procedures (after registration but before Day 1 of first induction cycle, 
optional)  ........................................................................................................................ 38 
5.2.4 
Treatment Phase .............................................................................................. 39 
5.2.5 
End of Treatment .............................................................................................. 39 
5.2.6 
Follow-Up ......................................................................................................... 40 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 17/87 
Current version: Version 3.1, 13.01.2017 
5.2.7 
End of Study ..................................................................................................... 40 
5.3 
Planned Treatment of the Patient after End of Treatment Phase ........................... 41 
5.4 
Removal of Patients from Treatment ......................................................................... 41 
5.5 
Study Discontinuation ................................................................................................. 42 
6 
Treatment ........................................................................................................ 43 
6.1 
Investigational medicinal product (IMP) .................................................................... 43 
6.2 
Preparation and Administration of Selinexor ........................................................... 43 
6.2.1 
Drug Name, Formulation and Storage ............................................................... 43 
6.2.2 
Route of Administration ..................................................................................... 44 
6.2.3 
Compliance ...................................................................................................... 44 
6.3 
Dose modification of Selinexor .................................................................................. 44 
6.3.1 
Dose Adjustment Guidelines for Selinexor Related Toxicities ............................. 45 
6.3.2 
Selinexor Dose Reduction for Decreased Glomerular Filtration Rate (GFR) ....... 51 
6.3.3 
Selinexor Dose Adjustment in the Setting of Infection ........................................ 51 
6.3.4 
Conditions not Requiring Selinexor Dose Reduction .......................................... 51 
6.3.5 
Missed doses ................................................................................................... 52 
6.3.6 
Vomited doses .................................................................................................. 52 
6.4 
Concomitant Medication and Treatment ................................................................... 52 
6.4.1 
Permitted Concomitant Medication .................................................................... 52 
6.4.2 
Prohibited Medications ...................................................................................... 52 
6.5 
Supportive Care Guidelines ........................................................................................ 53 
6.5.1 
Anorexia ........................................................................................................... 53 
6.5.2 
Fatigue ............................................................................................................. 54 
6.5.3 
Emesis ............................................................................................................. 54 
6.5.4 
Acute Emesis ................................................................................................... 54 
6.5.5 
Delayed Emesis - > 24h after treatment............................................................. 54 
6.5.6 
Diarrhea ........................................................................................................... 55 
6.5.7 
Hyponatremia ................................................................................................... 55 
6.5.8 
Liver enzyme increase ...................................................................................... 55 
7 
Safety Reporting ............................................................................................ 56 
7.1 
Adverse Events and Laboratory Abnormalities Reporting ..................................... 56 
7.1.1 
Adverse Event .................................................................................................. 56 
7.1.2 
Adverse Drug Reaction ..................................................................................... 56 
7.1.3 
Serious Adverse Event ..................................................................................... 56 
7.1.4 
NOT to be reported as SAEs ............................................................................. 57 
7.1.5 
Adverse events of special interest (AESI) .......................................................... 57 
7.1.6 
SUSAR/ Unexpected Serious ADR ................................................................... 57 
7.2 
Reporting of SAEs ....................................................................................................... 58 
7.3 
Reporting of SUSARs/ Expedited Reporting of Unexpected Serious ADRs ......... 59 
7.4 
Recording of Adverse Events ..................................................................................... 59 
7.5 
Laboratory Test Abnormalities ................................................................................... 60 
7.6 
Pregnancy ..................................................................................................................... 60 
7.7 
Adverse Drug Reactions with Concomitant Medication ......................................... 60 
8 
Biostatistics .................................................................................................... 61 
8.1 
Trial Design and Hypotheses...................................................................................... 61 
8.2 
Sample Size Calculation .............................................................................................. 61 
8.3 
Evaluation Categories for Patients ............................................................................ 62 
8.3.1 
Intent-to-Treat Population ................................................................................. 62 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 18/87 
Current version: Version 3.1, 13.01.2017 
8.3.2 
Per Protocol Population .................................................................................... 62 
8.3.3 
Safety Population ............................................................................................. 62 
8.4 
Methods of Statistical Analysis .................................................................................. 62 
8.4.1 
General Statistical Considerations ..................................................................... 62 
8.4.2 
Demographics and Baseline Characteristics ...................................................... 63 
8.4.3 
Efficacy Evaluation ........................................................................................... 63 
8.4.4 
Safety Evaluation .............................................................................................. 64 
8.5 
Interim and Final Analysis .......................................................................................... 64 
9 
Data Quality Assurance ................................................................................. 65 
10 
Data Monitoring Committee ........................................................................... 66 
11 
Ethical Aspects .............................................................................................. 67 
11.1 Declaration of Helsinki / Good Clinical Practice ...................................................... 67 
11.2 Patient Information and Informed Consent .............................................................. 67 
11.3 Independent Ethics Committees and Regulatory Authorities ................................ 67 
11.3.1 
Approval of the Study by the Regulatory Authority and Independent Ethics 
Committees .................................................................................................................... 67 
11.3.2 
Notification of the Study .................................................................................... 68 
11.3.3 
Obligation to Report and Document................................................................... 68 
12 
Conditions for Modifying the Protocol ......................................................... 69 
13 
Study Documentation, CRFs and Record-Keeping ...................................... 70 
13.1 Investigator’s Files / Retention of Documents ......................................................... 70 
13.2 Source Documents and Background Data ................................................................ 70 
13.3 Audits and Inspections................................................................................................ 70 
13.4 Case Report Forms ...................................................................................................... 71 
14 
Monitoring the Study ..................................................................................... 72 
15 
Confidentiality of Trial Documents and Patient Records ............................ 73 
16 
Study Report and Publication Policy ............................................................ 74 
17 
Appendices ..................................................................................................... 75 
17.1 Appendix 1 – Overview of current relapsed/refractory AML treatment studies ... 76 
17.2 Appendix 2 - Adverse Event Categories for Determining Relationship to Test 
Drug  ........................................................................................................................................ 77 
17.3 Appendix 3 – Definitions According to ICH Topic E2A Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, (CPMP/ICH/377/95).... 
 
78 
17.4 Appendix 4 – ECOG Performance Status .................................................................. 80 
17.5 Appendix 5 – Cockroft-Gault Formula ....................................................................... 81 
17.6 Appendix 6 – NCI-CTCAE version 4.03 ...................................................................... 82 
17.7 Appendix 7- Response criteria in AML ...................................................................... 83 
18 
References ...................................................................................................... 85 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 19/87 
Current version: Version 3.1, 13.01.2017 
1 
BACKGROUND AND RATIONALE 
1.1 
Background 
1.1.1 Acute myeloid leukemia 
Acute myeloid leukemia (AML) is a malignancy of hematopoietic progenitor cells (2).  Patients 
below an age of 60 years are treated with 1-2 cycles of standard chemotherapy usually with 
cytosine arabinoside (Ara-C) and daunorubicin according to the 7 + 3 schedule. Between 70-80% 
of patients achieve a complete remission. Both American (3, 4) and European (5) cooperative group 
studies have found that the choice of anthracycline (daunorubicin or idarubicin, or the 
anthracenedione mitoxantrone) is of little consequence, assuming equitoxic doses are 
administered. Thereafter, patients receive consolidation therapy which is guided by the European 
LeukemiaNet (ELN) risk criteria (6, 7). Patients with good risk receive several cycles high dose Ara-
C(8, 9), patients with intermediary risk I and II and patients with unfavorable prognosis are 
transplanted in first CR if a suitable donor is available and no contraindications to stem cell 
transplant exist. In Germany, up to two thirds of patients receive an allotransplant in first 
remission. With this strategy 70-80% of patients are cured in the good risk category (10, 11), 50% in 
the intermediary risk and 20-40% in the high risk category (12).  
Recurrent/ Relapsed AML 
Patients with relapsed AML usually have a dismal prognosis(13). The best outcome is achieved in 
patients who receive an allotransplanting with about 20% - 40% of patients being long term 
survivors (14). The best results with allografting are achieved in patients who have achieved a 
second remission (15). The chance of a second CR depends of the duration of the first remission, 
the karyotype and the performance status of the patient.  
No standard regimen exists for the treatment of patients with relapsed acute myeloid leukemia 
(AML), particularly in patients with a first remission duration of less than 1 year (16). A number of 
agents have activity in recurrent/relapsed with an overall response rate of 20-80%, depending on 
study design and treatment (see Table 1, Appendix 1). Re-induction with Ara-C and daunorubicin 
will result in a 50% CR rate in patients who had a first remission lasting longer than 1 year (17-19). 
In a trial of mitoxantrone in combination with Ara-C in patients with refractory or relapsed AML 
with 49 patients 62.5% with first relapse AML achieved complete remission while none of the four 
patients with more than one prior remission responded (20). A triple combination of mitoxantrone, 
etoposide, and cytarabine (MEC) demonstrated a CR induction rate of 55% in a population 
including 30 patients with relapsed AML, 28 patients with primary refractory AML, and 16 patients 
with secondary AML(21). A phase 1-2 study of clofarabine plus Ara-C in 25 patients with relapsed 
acute myeloid leukemia 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR 
with incomplete platelet recovery (CRi), for an overall response rate of 38%(22). For patients not 
achieving a complete remission the only potentially curative treatment option is allogeneic 
transplantation with up to 20% of patients being long term survivors(14). 
Therefore, the combination of Ara-C and idarubicin was chosen for standard induction therapy 
and if the patient receives complete remission transplantation is recommended.  
In the light of a dismal prognosis for patients with relapsed/rectory AML a great clinical need exists 
for new treatment options. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 20/87 
Current version: Version 3.1, 13.01.2017 
1.1.2 Selinexor 
Over 10 major tumor suppressor pathways have evolved in order to prevent the development and 
progression of neoplasia. Because the vast majority of tumor suppressor (TSP) and growth 
regulatory (GRP) proteins require nuclear localization in order to carry out their antineoplastic 
activities, enhancing their nuclear export leads to their functional inactivation. The major 
TSP/GRP are exported exclusively by the protein CRM1 (also called XPO1), and tumors showing 
elevated CRM1 levels with cytoplasmic mislocalization of TSP/GRP. 
Additional detailed information is provided in the Investigator’s Brochure.  
Selinexor is an orally available, irreversible, potent and Selective Inhibitor of Nuclear Export 
(SINE) that specifically blocks XPO1. It is selectively cytotoxic for cells with genomic damage, i.e., 
for tumor cells, both in vitro and in vivo.  Normal cells, with minimal or no DNA damage, 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.   
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 21/87 
Current version: Version 3.1, 13.01.2017 
1.1.2.1 Preclinical Efficacy 
In vitro experiments with continuous (~72 hour) exposure to Selinexor demonstrated potent pro-
apoptotic activity across a broad panel of tumor-derived cell lines and patient samples in culture 
including multiply-resistant cancers, with the majority of IC50s for cytotoxicity <800 nM and most 
hematologic tumor lines having IC50s of 20-400 nM for Selinexor.  In contrast, normal cells 
typically underwent (or remained in) cell cycle arrest but were resistant to apoptosis-induction; 
cytotoxicity IC50s were typically >5 µM.  Efficacy was demonstrated in mouse models of myeloma, 
mantle cell lymphoma (MCL), and T-cell acute lymphocytic leukemia (T-ALL) xenografts. 
Moreover, efficacy including significant survival advantages was demonstrated in acute myeloid 
leukemia (AML) [MV4-11 (FLT3-ITD)] (23, 24) and chronic lymphocytic leukemia (CLL) (TCL-1) 
leukemografts. Efficacy was also demonstrated in solid tumor xenografts including prostate, 
breast, liver, glioblastoma, kidney and colon cancers. KPT-276 and KPT-335, SINEs closely 
related to Selinexor, have been given orally to several dogs with various cancers in ongoing pilot 
studies, and clear evidence of antitumor activity with acceptable tolerability has been obtained in 
dogs with both de novo newly diagnosed and chemotherapy (e.g. CHOP- (cyclophosphamide, 
hydroxydaunorubicin, oncovin and prednisone-resistant diffuse large B cell non-Hodgkin’s 
lymphoma (DLBCL) in dogs. In a Phase 2b study of newly diagnosed or first relapsed NHL (mainly 
DLBCL) in dogs, KPT-335 induced a 34% objective response rate (≥50% tumor shrinkage) as a 
single agent. Reduced food intake, which can be accompanied by weight loss, was observed; 
food supplementation can largely overcome this and dosing has been maintained for over 6 
months in dogs with cancer.  
1.1.2.1.1 Preclinical Efficacy:  AML 
AML cells overexpress the nuclear exporter, Exportin 1 (XPO1/CRM1) and higher XPO1 levels 
correlate with poor outcome (28). The novel selective inhibitor of nuclear transport (SINE), 
Selinexor, antagonizes XPO1 and shows potent cytotoxicity for AML and ALL cells in vitro, 
independent of genotype.  
 
Selinexor show 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 (23).  
Mechanistic studies show that SINE 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 treatment in both FLT3- 
ITD and wild-type cell lines (23). 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 (23,24,29). 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 22/87 
Current version: Version 3.1, 13.01.2017 
1.1.2.2 Preclinical Safety 
In the Selenixor nonclinical safety program in Spegue-Dawley rats and cynomolgus monkeys, the 
primary effects of oral Selinexor were dose-dependent reductions in food intake and body weight 
(or reductions in body weight gain), with minimal clinical symptoms (no or mild non-bloody 
diarrhea), associated primarily with gastrointestinal atrophy.  Similar effects are observed in mice 
and dogs.  At high repeated doses of Selinexor associated with marked weight loss, there were 
changes in cerebellar granular layer neurons in both rats (≥300 mg/m²) and monkeys (≥72 mg/m²), 
but only monkeys showed any CNS symptoms.  No central nervous system (CNS)-related 
adverse side effects were observed in the GLP, rat and monkey 4-cycle toxicity studies.  
A GLP, rat neurofunctional study (Irwin test) has also been performed at dose levels of 12, 60, or 
300 mg/m² (2, 10, and 50 mg/kg).  No behavioral changes were observed at all doses tested.   
In the pivotal, GLP, 4-week monkey study, there was no evidence of a direct or indirect effect of 
Selinexor on the morphology and intervals of the ECG at up to 36 mg/m² (3 mg/kg).  Based on 
these results, QT prolongation or other cardiac effect does not appear to be a safety concern for 
Selinexor.  
In summary, dose limiting toxicity (DLT)/mortality in both rats and monkeys is related primarily to 
marked weight loss with atrophy of the gastrointestinal (GI) tract and noncritical effects on other 
major organs.  
Further detailed information is provided in the Investigator’s Brochure. 
1.1.2.3 Clinical Efficacy 
Karyopharm Therapeutics is currently conducting three open label Phase 1 clinical trials to assess 
the safety, tolerability and efficacy of Selinexor given orally 2-3 times per week. The first study 
(KCP-330-001) is a dose escalation study in patients with advanced hematological malignancies, 
the second (KCP-330-002) is a dose escalating study in patients with advanced or metastatic 
solid tumor malignancies and the third (KCP-330-003), a food effect study, is in patients who have 
metastatic, locally advanced or locally recurrent soft tissue or bone sarcomas. All patients entering 
these single-agent phase 1 studies have relapsed after available therapies and have objectively 
progressing tumors at time of study drug initiation. To date Selinexor has been administered to 
over 130 patients. The food effect study was initiated in July 2013, so preliminary safety or efficacy 
data are not yet available. 
In the Phase 1 study (KCP-330-001) a total of 39 patients with relapsed AML have been enrolled. 
As of December 4, of 33 pts who were evaluable for response, complete response (CR) with full 
hematological recovery was achieved in 4 patients (11%), and CR without hematological recovery 
(CRi) in 1 patient (3%). Partial Response (PR) was achieved in 2 patients (6%). Morphological 
leukemia free state was achieved in 1 patient (3%). Ten (29%) of the remaining patients have had 
stable disease for > 30 days, and 13 (34%) have had progressive disease. 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 23/87 
Current version: Version 3.1, 13.01.2017 
Table 1: Responses in Arm 2 (AML) [16.8 mg/m² to 40 mg/m²] (Study KCP-330-001)  
as of December 4, 2013    
Abbreviations: N=number of patients, CR=complete remission, CRi=complete remission without 
platelet recovery, PR=partial response, MLFS=morphological leukemia free state, SD=stable 
disease, PD=progressive disease, NE=not evaluable, WC=withdrew consent.   
1.1.2.4 Clinical Safety 
Gastrointestinal adverse events and fatigue are the most common types of AEs seen in Arm 2 
(AML) patients.  As of 8 November 2013, Karyopharm has reports of AEs in 36 of the 38 patients 
enrolled in this arm and the AE prevalence percentages below are based upon 38 patients.  As 
of 8 November 2013, the gastrointestinal adverse events typically consist of nausea in 22 patients 
(58%), anorexia in 17 patients (45%), vomiting in 13 patients (34%) and weight loss in 10 patients 
(26%).  The gastrointestinal events are primarily Grade 1 or Grade 2 events that are generally 
responsive to standard supportive care.  Fatigue was observed in 18 patients in this arm (47%) 
as of 8 November 2013, including Grade 3 fatigue in three patients (8%) and Grade 1 or Grade 2 
fatigue in 15 patients (39%).  Karyopharm has also observed Grade 4 thrombocytopenia in three 
patients (8%) in this arm as of 8 November 2013.  Karyopharm expects that the thrombocytopenia 
is primarily a result of patients entering this arm with marked bone marrow suppression due to 
both disease and prior therapies.  
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.   
To date, over 1,800 patients have received Selinexor in clinical studies. Of these, 1,175 patients 
were evaluable for safety as of 31 May 2016. 
Since the beginning of this study new safety data were revealed from other ongoing clinical trials 
with Selinexor. Four cases of Nervous System Disorders are described below. The necessity to 
report all cases of cerebellar toxicity ≥ 3 as SAE is included in the Safety Reporting Procedures 
in chapter 7. 
  
One patient, heavily pre-treated for recurrent pancreatic cancer, developed acute cerebellar 
syndrome (ACS) following 3 doses of selinexor at 85 mg/m2 twice weekly. The patient 
experienced abnormal speech, loss of coordination, and was unable to walk. Selinexor was 
permanently discontinued, and the patient recovered to near baseline over ~6 weeks.  
 
A five-year-old male patient with refractory AML and prior stem cell transplant (SCT) had severe 
body pain, followed the next day by irritability, aphasia, and lower extremity weakness after 
receiving 4 doses of selinexorr (70 mg/m2) and 5 days fludarabine and cytarabine. The event was 
considered to be ACS. Selinexor was permanently discontinued and the patient recovered 
completely after 6 weeks.  
 
A 19-month-old patient with relapsed AML and without prior SCT was unable to hold his trunk or 
head straight and demonstrated erratic use of his hands on study day 13, after receiving 4 doses 
Numberof
PtsEvaluated
TotalCRs,CR(i)s,
PRs,andSD(%)
CR(%)
CR(i)(%)
PR(%)
MLFS(%)
SD(%)
PD
WC
33
18(55%)
4(12%)
1(3%)
2(6%)
1(3%)
10(30%)
11(33%)
4(12%)
ResponsesinArm2AcuteMyeloidLeukemiaPatientsas4-Dec-2013


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 24/87 
Current version: Version 3.1, 13.01.2017 
of Selinexor (70 mg/m2) and prior to receiving fludarabine or cytarabine. The event was 
considered to be ACS. Selinexor dosing was permanently discontinued and his ataxia improved 
over the course of two weeks. 
 
An 18-year old female patient with heavily pre-treated, refractory AML developed cognitive 
disturbance Grade 3 after receiving 4 doses of Selinexor 56 mg/m² twice weekly. Symptoms 
included flat affect and brief episodes of non-responsiveness, but not focal or gait disturbances. 
Selinexor was held and the symptoms resolved within one week,however, after  restarting 
treatment and receiving two additional doses , the symptoms returned and selinexor was 
permanently discontinued. The symptoms returned to near baseline. The event differs from ACS 
seen in the other patients, as the patient had pre-existing MRI abnormalities, including cerebellar 
disease, but did not develop focal abnormalities or gait disturbances. 
 
ACS is defined as Adverse Event of Special Interest (AESI), see section 7.1.5. A further AESI is 
the development of (or worsening of existing) cataracts during treatment with Selinexor. In 30 
patients (3%), a cataract (or worsening of existing cataract) occurred, but in all cases, prior or 
ongoing use of other drugs associated with cataracts, diabetes or age-related progression have 
been implicated in cataract worsening. Most of the cases were worsening of existing cataracts.  
 
  
1.2 
Study Rationale 
Selective inhibition of nuclear export (SINE) is a novel therapeutic strategy that could potentially 
be applicable to many cancers. Tumors of hematopoietic lineage are particularly susceptible to 
induction of apoptosis by XPO1 inhibition; normal hematopoietic cells and their functions are 
largely spared.  In vivo efficacy was observed with Selinexor treatment groups in mouse models 
of different types of cancer. Moreover, efficacy including significant survival advantages was 
demonstrated in acute myeloid leukemia (AML) [MV4-11 (FLT3-ITD)] (23, 24), and chronic 
lymphocytic leukemia (CLL) (TCL-1) leukemografts. These studies demonstrate potent in vitro 
and in vivo efficacy of Selinexor against a variety of cancer tumor models as a standalone agent 
or in combination with a variety of anti-cancer modalities.  
In a recent study the safety and efficacy of Selinexor and Ara-C as single agent or in combination 
was tested in vivo. Treatment with AraC or Selinexor alone significantly prolonged the survival of 
leukemic mice from a median survival of 24 days (APL + vehicle) to 33 days or 39 days, 
respectively (P < 0.0001). Encouragingly, combination therapy with AraC + KPT-330 further 
prolonged survival compared to monotherapy (P < 0.0001), with some mice being cured of the 
disease. 
In the Phase 1 study (KTP-330-001) 5 out of the 33 AML patients (15%) have experienced a 
complete remission (CR)/ complete remission without platelet recovery (CRi).    
Because of the encouraging efficacy, unique mechanism of action and clinical safety, it is 
considered to be a suitable agent to study in the combination with Ara-C and Idarubicin. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 25/87 
Current version: Version 3.1, 13.01.2017 
2 
OBJECTIVES OF THE STUDY 
2.1 
Primary Objective 
The primary objective is to determine the efficacy of Selinexor in patients with relapsed/ refractory 
AML by complete response rate (CR) or CRi), as defined by the recommendations on diagnosis 
and management of AML in adults from an international expert panel, on behalf of the European 
LeukemiaNet(1). 
2.2 
Secondary Objectives  
Secondary objectives of the study are:  
 
To determine the efficacy of Selinexor in combination with standard chemotherapy in patients 
with relapsed/ refractory AML by:  
o Rate of partial remissions 
o Percentage of patients being transplanted after induction therapy 
o Early death rate 
o Overall survival (OS) 
o Event-free survival (Events are defined as Death, not achieving a CR or CRi, 
Relapse after CR or CRi) 
 
To evaluate overall safety and tolerability of Selinexor characterized by type, frequency, 
severity (graded using the National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] Version 4.03), timing and relatedness of adverse events (AEs) 
and laboratory abnormalities observed during the treatment within this study 
 
2.3 
Exploratory Objectives (Optional Studies) 
 
Translational Research on Patient Leukemic Blast Cells 
o Selinexor-induced changes in gene expression profile of leukemic blasts isolated from 
patients 
o Expansion of leukemic blasts in mice for therapeutic studies 
 
Pharmacokinetics and Pharmacodynamics of Selinexor in patients with relapsed/refractory 
AML will be assessed in an explorative manner.  
o Limited PK to assess Selinexor plasma level  
o Pharmacodynamic assessments  
 
Selinexor-induced changes in mRNA levels of XPO1 and tumor suppressor 
markers from leukocytes 
 
Selinexor-induced changes in plasma cytokine levels 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 26/87 
Current version: Version 3.1, 13.01.2017 
3 
STUDY DESIGN 
3.1 
 Overview of Study Design and Dosing Regimen 
This is a multi center, open-label, non-randomized phase II trial study. 
Patients are informed, screened and enrolled in the study at the time of progression of disease 
on prior chemotherapy documented by Bone Marrow Aspirate. Treatment should start within two 
weeks after enrolment.  
The study design is displayed in Figure 1. 
3.1.1 Baseline Translational Research Study (optional) 
All enrolled patients may participate in an optional baseline translational research study. Patients 
will receive single dose of Selinexor (60 mg) after registration and before first induction cycle. 
Bone marrow aspirate samples will be collected pre-dose and 24 hour post-dose. Blast cells will 
be used for leukemic stem cell gene expression profiling and in mouse model studies to define 
parameters associated with clinical responsiveness to Selinexor. See 5.1.2.1 for more details. 
3.1.2 Definition of Treatment Cycle 
All enrolled patients will be treated with cytosine arabinoside (Ara-C) at a dose of 100 mg/m² 
continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m² i.v. (days 1,3,5) every 4 weeks 
and Selinexor for a maximum of 2 cycles. During the second cycle the idarubicin dose is restricted 
to 2 administrations on day 1 and 3.  
Patients will receive oral Selinexor 60 mg twice weekly in weeks 1-3 of a 4-week cycle (Monday/ 
Wednesday or Tuesday/ Thursday or Wednesday/Friday) starting on day 2 of week 1 (total of 
6doses per induction cycle).  
If a CR or CRi was achieved, patients will be recommended for stem cell transplantation. If a PR 
is achieved patients can undergo a second, identical treatment cycle. 
In patients who are not eligible or do not undergo additional stem cell transplantation, but, in the 
opinion of the investigator, are benefiting from Selinexor, then oral Selinexor dosed twice weekly 
in weeks 1-3 of a 4-week cycle may be continued parallel to 3 cycles of consolidation therapy with 
Ara-C until relapse or toxicity develops.  The dose of Ara-C is 3 g/m² IV for 2h every 12 hours at 
3 consecutive days for patients with good performance status and younger than 60 years (in total 
6 doses). If patients are older than 60 years the dose is 1 g/m² IV for 2h every 12 hours at 3 
consecutive days. During consolidation Selinexor dosing (60 mg) will start on day 2 of week 1 of 
a 4-week cycle and will be continued twice weekly during weeks 1-3 of a 4-week cycle  (total of 6  
doses per cycle). Selinexor twice weekly (Monday/ Wednesday or Tuesday/ Thursday or 
Wednesday/Friday) in weeks 1-3   at a dose of 60 mg (total of 6 doses per 4-week cycle) may 
continue until relapse or for maximally 1 year of treatment. 
Patients achieving a > 50% blast reduction after the end of 2 induction cycles and in the opinion 
of the investigator, are benefiting from Selinexor and are not candidates for Stem cell 
transplantation, oral Selinexor dosed twice weekly in weeks 1-3 may be continued. Drug 
administration will occur twice weekly, on days 1 and 3 of weeks 1-3 of a 4-week cycle at a dose 
of 60 mg (e.g. on Monday and Wednesday or on Tuesday and Thursday or on Wednesday and 
Friday). One cycle is 4 weeks with 6 doses of Selinexor.  


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 27/87 
Current version: Version 3.1, 13.01.2017 
Safety assessments are performed at baseline visit, twice weekly during induction treatment, at 
the End of Cycle and at the End of Treatment visit. Clinical and Bone Marrow Aspirate for disease 
status are performed at baseline, at the end of the cycle during induction and consolidation. During 
maintenance and follow-up after SCT bone marrow aspirate is required in case of suspicious 
blood counts. If a patient discontinues treatment due to any other reason than disease 
progression/ death/ withdrawal of informed consent, the disease evaluations shall continue until 
disease progression. This includes patients who wish to discontinue treatment, but agree that 
further data is captured for the purpose of the study (partial withdrawal).


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 28/87 
Current version: Version 3.1, 13.01.2017 
Figure 1: Study Flow Chart 
 
 
 
 
Recommend:  
Allogeneic stem cell 
transplantation (SCT) 
D 2, 4, 9,11,16,18. 
Selinexor (twice weekly in 
weeks 1-3) 
Baseline translational research 
prior to first induction cycle (optional): 
Bone marrow aspirates pre- and 24 h-
post single Selinexor dose  
EOT 
EOT 
Maintenance 
Selinexor (twice weekly in 
weeks 1-3 of a 4-week cycle) 
until relapse or maximal 1 year 
after start of treatment 
CR/CRi 
PR 
CR 
CR and not 
eligible for 
allogeneic 
SCT 
Non-responders/PD 
Any other 
D1-3: 6 doses  
of AraC 
Consolidation (3 x 4 
weeks) 
D1-7 continuous 
AraC  
D1, 3 Idarubicin 
D2, 4, 9, 11, 16, 18 
Selinexor (twice weekly in weeks 1-3) 
 2. Induction 4 weeks 
> 50% blast 
reduction 
PD 
Maintenance 
Selinexor (twice weekly in 
weeks 1-3 of a 4-week cycle) 
until relapse or maximal 1 year 
after start of treatment 
PD 
EOT 
D1-7 continuous 
AraC  
D1, 3, 5  
Idarubicin 
D2, 4, 9, 11, 16, 18; 
Selinexor (twice weekly in weeks 1-3) 
 1. Induction 4 weeks 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 29/87 
Current version: Version 3.1, 13.01.2017 
3.1.3 Treatment Duration 
Treatment duration for patients achieving CR or CRi during induction will be 1 or 2 cycles of 4 
weeks each. These patients will be recommended for stem cell transplantation and have their end 
of treatment prior to SCT and will be followed for event-free and overall survival. 
For patients achieving CR or CRi but who are not eligible or do not undergo additional stem cell 
transplantation, will continue in consolidation/maintenance therapy with 3 cycle of AraC combined 
with 4-week cycles with twice-weekly Selinexor during weeks 1 and 3 until relapse (for maximally 
1 year of treatment).  
Patients with a > 50% blast reduction at the end of 2 induction cycles and in the opinion of the 
investigator, are benefiting from Selinexor, will in maintenance therapy with 4-week cycles with 
twice-weekly Selinexor in weeks 1-3 until progression of disease (for maximally 1 year of 
treatment).  
For patients for whom none of the above mentioned is achieved after 2 4-week induction cycles 
will discontinue study and will be followed for overall survival. 
In any case, treatment will be discontinued upon progression of disease (PD) or unacceptable 
toxicity, withdrawal of consent by the patients, or non-compliance by the patient with protocol 
requirements.  
3.1.4 End of treatment Visit 
Patients that discontinue from treatment will undergo an end of treatment visit, regardless of the 
reason of discontinuation, approximately 30 days (±7 days) after the last dose of study medication. 
In case of allogeneic SCT the end of treatment visit should be performed prior to SCT.   
3.1.5 Follow-up Phase 
Patients who discontinued for reasons other withdrawal of consent for participation in the trial will 
be followed every 3 months ± 28 days for event free- and/or overall survival. 
A patient may decide to discontinue study treatment. This is not the same as fully withdrawal of 
consent to participate in the trial and these patients should be encouraged to continue to be 
followed for event-free and overall survival. If a patient chooses to have no further interaction 
regarding the study (fully withdrawal of consent), the investigator must provide written 
documentation of the patient’s decision to fully withdraw from the study. 
 
3.2 
Study timelines 
The planned number of 40 patients was reached. The end of the enrolment period was June 
2016. End of study will be defined 2 years after registration of the last patient.  


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 30/87 
Current version: Version 3.1, 13.01.2017 
4 
SELECTION OF THE STUDY POPULATION 
4.1 
Target Population 
Patients with relapsed/refractory Acute Myeloid Leukemia (AML) according to the inclusion and 
exclusion criteria below will be enrolled in this study trial. Both male and female patients are 
enrolled. 
The baseline leukemia assessment must have taken place within 2 weeks prior to start of 
treatment. Under no circumstances are patients, who were once enrolled in this study, permitted 
to be re-enrolled into the same study. 
 
4.2 
Inclusion Criteria 
To be eligible for this trial, patients must meet the following criteria: 
1. Cytological or histological diagnosis of AML with the exception of promyelocytic leukemia 
(AML M3) 
2. Patients must have relapsed/refractory disease (relapse after stem cell transplantation is 
permitted) as defined as: patients with <PR after first cycle of induction chemotherapy, or 
b. patients with <CR(i) after second cycle of induction chemotherapy, or 
c. patients who relapse after conventional chemotherapy or 
d. patients who have undergone a single stem cell transplantation and who have relapse 
of their AML. 
3. Men and women aged ≥18 years and eligible for standard dose of chemotherapy (7+3);  
4. A period of at least 3 weeks needs to have elapsed since last treatment (with the exception 
of hydroxyurea) before participating in this study. Hydroxyurea induction therapy to reduce 
peripheral blast counts is permitted prior to initiation of treatment on protocol.  Treatment 
may begin in <3 weeks from last treatment if deemed in the best interest of the patient 
after discussion with the PI of the study;  
5. ECOG performance status ≤ 2  
6. Serum biochemical values with the following limits unless considered due to leukemia: 
creatinine ≤2 mg/dl; total bilirubin ≤2x ULN, unless increase is due to hemolysis or 
congenital disorder; transaminases (SGPT or SGOT) ≤2.5x ULN 
7. Ability to swallow and retain oral medication 
8. Ability to understand and provide signed informed consent;  
9. Cardiac ejection fraction must be >/=50% (by echocardiography).  
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures. 
4.3 
Exclusion Criteria 
Patients with any of the following will not be eligible for participation: 
1. Treatment with any investigational agent within four weeks. 
2. Cumulative anthracycline dose (daunorubicin or equivalent) >360 mg/m² 
3. HIV infection 
4. Presence of any medical or psychiatric condition which may limit full compliance with the 
study, including but not limited to:  
5. Presence of CNS leukemia 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 31/87 
Current version: Version 3.1, 13.01.2017 
6. Unresolved toxicity from previous anti-cancer therapy or incomplete recovery from 
surgery. 
7. For patients after SCT as part of prior treatment:  
a. Necessity of immunosuppressive drugs 
b. GvHD > grade 1 
8. Any of the following within the 12 months prior to study drug administration: myocardial 
infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary 
embolism, deep vein thrombosis, or other thromboembolic event. 
9. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2. 
10. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or study drug administration, 
or may interfere with the interpretation of study results, and in the judgment of the 
investigator would make the patient inappropriate for entry into this study. 
11. Clinically significant bleeding within 1 month  
4.4 
Registration of Patients  
Patients will be screened for eligibility and eligibility check form/Patient Registration Form will be 
sent to GSO mbH, Hamburg.  
Patient eligibility will be reviewed by GSO mbH for all patients participating in the study prior to 
receiving study treatment. 
PROTOCOL SPECIFIC QUESTIONS: 
 
All eligibility criteria will be checked one by one 
 
Actual values for the eligibility parameters will be requested when applicable 
 
Date of written informed consent (day/month/year) 
Patient eligibility will be checked by GSO mbH once all screening procedures are completed. 
There will be no exceptions. Any questions should be addressed to GSO mbH prior to registration.  
The eligibility check form/Patient Registration Form will be sent from the site to GSO mbH by 
email or by fax for evaluation at the following: 
GSO mbH 
Email: kranich@gsoglobal.com 
Telephone: +49  40 44 19 54 60 
Fax: +49  40 44 19 54 78 
Upon confirmation of eligibility, GSO mbH will assign a patient number and return the signed 
eligibility check form/Patient Registration Form via fax or email to the site. The Patient Registration 
Form will confirm the treatment arm in which the patient will participate. 
The first planned dose of study drug will be administered within 2 weeks after bone marrow 
aspirate verification of disease progression.  
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 32/87 
Current version: Version 3.1, 13.01.2017 
5 
SCHEDULE OF ASSESSMENT AND PROCEDURES 
5.1 
Study Assessments 
5.1.1 Response Assessments 
Disease status will be assessed by bone marrow and peripheral blood analysis at the end of each 
4-weeks induction and consolidation cycle. Disease status during maintenance will be evaluated 
by peripheral blood analysis at the end of each cycle and during follow-up after SCT every 3 
months ± 28 days. Bone marrow aspirate during maintenance and FU is required in case 
peripheral blood analysis is suspicious for progression of disease/relapse. Response is evaluated 
according to Döhner et al. criteria1. 
5.1.2 Translational, Pharmacodynamic and Pharmacokinetic Analyses (Optional) 
5.1.2.1 Baseline Translational Studies  
5.1.2.1.1 Leukemic Blast Cell Expansion in Mice 
The leukemic blasts isolated from bone marrow aspirates of patients will be expanded in 2-3 NSG 
mice and then retransplanted into 20 NSG mice for therapeutic experiments. The resulting mouse 
models of patient leukemias will be used to determine the activity of Selinexor against both the 
bulk leukemia population and leukemia-initiating cells (LICs) of patient AML cells. Mice 
transplanted with patient AML cells will be treated with either vehicle control or Selinexor to assess 
the drug response of the bulk AML population and will then re-transplant at limiting cell dilutions 
the bone marrow AML cells of the vehicle and Selinexor treated mice into new recipient mice in 
order to calculate the fold reduction of LICs in response to therapy. The therapeutic response of 
mouse primagrafts of patient leukemias will be correlated with clinical outcomes of patients 
enrolled in the trial.  
5.1.2.1.2 Leukemic Stem Cell Gene Expression 
Recent studies by Eppert et al., 2011 and Metzeler et al., 2013 identified AML stem cell prognostic 
(42 gene) signature by correlating enrichment for the leukemia stem cell (LCS) expression 
signature with the clinical outcome.25, 26 To analyze the extent of “stemness” of patient AML blasts 
in response to treatment with Selinexor, we will perform gene expression profiling of leukemic 
blasts isolated from patients before the start of therapy and 24 hour after the first drug dose. The 
LSC scores will be calculated based on the extent of the enrichment in the 42 LSC-specific gene 
signature for patient leukemias and will be used to predict clinical outcome. These experiments 
will be critical for defining the anti-leukemic activity of Selinexor against LICs of specific patient 
AML cells and predicting patients’ long-term response to the Selinexor therapy. 
 
5.1.2.2 Pharmacodynamic Studies 
5.1.2.2.1 XPO1 Inhibition 
Leukocytes will be isolated from patient blood samples collected pre- and post-dosing (≥ 4hr) and 
total RNA will be isolated to study changes in gene expression before and after exposure to 
Selinexor. Inhibition of XPO1 (Selinexor target) will be assessed by qRT-PCR of XPO1 and other 
genes, which are upregulated once XPO1 is inactivated (based on Karyopharm gene chip 
studies)(e.g., ARRDC3, NGFR, SLC family, PCLO). 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 33/87 
Current version: Version 3.1, 13.01.2017 
5.1.2.2.2 Cytokines 
Blood samples will be collected pre- and post-dosing and analyzed for plasma cytokine 
concentrations. Cytokines include: interleukin 1 alpha (IL1α), tumor necrosis factor alpha (TNFα), 
interleukin 6(IL-6), MCP1, interferon gamma (IFNγ), vascular endothelial growth factor alpha 
(VEGFα), interleukin 8 (IL-8), interferon alpha (IFNα), interleukin 10 (IL-10). 
5.1.2.3 Pharmacokinetics of Selinexor 
Blood samples will be obtained pre- and post-first Selinexor dose of induction cycle 1 to determine 
Selinexor plasma concentrations. 
 
5.1.3 Safety Assessments 
Throughout the treatment period until one month after the last dose of study medication, patients 
will be assessed for all adverse events. Common terminology criteria for adverse events (CTCAE 
v4.03, see Appendix 7) will be used for grading. If necessary, the patient may be withdrawn from 
the study treatment.  
Medical history including leukaemia and treatment history will be reviewed and recorded at the 
screening visit.  
Concomitant medications will be documented throughout treatment phase until the EOT visit.  
Adverse events (see also Section 7.1): All patients will be closely monitored for adverse events 
from start of treatment, i.e. cycle 1 day 1, until 30 days after the last dose of study medication. 
Adverse events for which the relationship to test drug is not “unrelated” should be followed up 
until they have returned to baseline status or stabilised.  Adverse events will be recorded at each 
visit.   
5.1.4 Laboratory Assessments 
Safety blood samples include complete blood count, time of recovery of platelets ≥ 50x 109/L and 
≥ 100x 109/L, ANC recovery ≥ 0.5x 109/L and ≥ 1.0x 109/L, clinical chemistry, including liver 
function test and coagulation. 
5.2 
Study Procedures 
The Schedule of Study Events is displayed in tabular form as Table 2. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 34/87 
Current version: Version 3.1, 13.01.2017 
  Table 2: Schedule of Assessments during the study 
 
Assessments by Visit 
Screening 
Baseline 
Induction cycle(s) Consolidation 
(if applicable) 
Maintenance 
(if 
applicable) 
End of 
treatment 
Follow-
up19 
Time window 
Within 14 
days prior 
to 
registration 
After 
registration, 
before 
Day1 of 
induction 
During 
Treatment 
Twice 
weekly 
End of 
Cycles 
weekly 
(D2,8,15,21 ± 
2 days) 
Twice per 
cycle 
D1,15 ± 2 
days) 
30-days 
after last 
dose/prior 
to SCT 
Every 3 
months 
± 28 
days 
Informed consent 1 
X 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 2 
X 
 
 
 
 
 
 
 
Pregnancy test (if 
applicable) 3 
X 
 
 
 
 
 
 
 
Physical examination and 
ECOG4 
X 
 
X 
X 
X 
X 
X 
 
Body height and weight 5 
X 
 
 
X 
X 
X 
X 
 
BSA 
X 
 
 
 
 
 
 
 
Vital signs 6 
X 
 
X 
X 
X 
X 
X 
 
Standard clinical neurologic 
examination 
X 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
X 
X 
X 
 
 
Cardiac ultrasound7 
X 
 
 
X 
 
 
X 
 
Hematology 8 
X 
 
X 
X 
X 
X 
X 
X 
Hematological Recovery 
status 21 
 
 
X21 
X21 
X21 
X21 
X21 
X21 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 35/87 
Current version: Version 3.1, 13.01.2017 
Assessments by Visit 
Screening 
Baseline 
Induction cycle(s) Consolidation 
(if applicable) 
Maintenance 
(if 
applicable) 
End of 
treatment 
Follow-
up19 
Calculation 9 (or 
measurement) of GFR 
X 
 
 
X 
X 
 
X 
 
Clinical Chemistry 10 
X 
 
 
X 
X 
X 
X 
 
Urine analysis 11 
X 
 
 
X 
X11 
X11 
 
 
Coagulation test 12 
X 
 
X 
X 
X12 
X12 
 
 
HIV testing13 
X 
 
 
 
 
 
 
 
Assessment of signs and 
symptoms, AE 
X 
 
X 
X 
X 
 
X 
 
CTCAE v 4.03 scale toxicity 
 
 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
 
X 
X 
X 
X 
X 
 
Bone Marrow Aspirate14 
X 
 
 
X 
X 
X14 
 
X14 
Survival 
 
 
 
 
 
 
 
X 
Selinexor baseline dose15 
 
X 
 
 
 
 
 
 
Bone Marrow aspirates for 
translational 
research16(optional) 
 
X 
 
 
 
 
 
 
Blood draws for translational 
research17(optional) 
 
 
X 
 
X 
 
 
 
Blood draws for 
Pharmacokinetics18(optional) 
 
 
X 
 
 
 
 
 
Ophthalmological 
examination20 
X 
 
 
 
 
 
 
 
Notes 
1 Prior to the first study-specific measures 
2 Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including start and stop dates, response of 
prior cancer therapies, disease progression during or after therapy, as well as discontinuations due to intolerability or any other serious illness. 
3  Applicable for women of childbearing potential. Serum -HCG test within 7 days before the first dose of study drug. To be repeated by urine test, 
if date of first result exceeds the 7-day window 
4 Full physical examination for baseline and end of study visit. Physical examinations during the study should be symptom directed. 
5  Body height will be measured at screening only. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 36/87 
Current version: Version 3.1, 13.01.2017 
6  Vital signs: blood pressure, pulse and temperature 
7  Echocardiography of left ventricular ejection fraction (LVEF) to observe cardiac toxic city of idarubicin. at baseline, before a second facultative 
induction course and before first consolidation therapy. Maybe repeated if clinically indicated. 
8 Hematology: hemoglobin,red blood cell (RBC) count, platelets, white blood cell (WBC) count and WBC differential (neutrophils, lymphocytes), 
leukemic blasts. 
9 Calculated GFR according to the formula of Cockroft and Gault. 
10 Clinical chemistry: Sodium, Potassium, Calcium, Creatinine, Total Bilirubin, Alkaline Phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), Total Protein, Albumin, LDH 
11 Urine analysis will include urine bilirubin, glucose, hemoglobin, ketones, pH, protein (once per cycle in consolidation/maintenance) 
12 Coagulation test include prothrombin time (PT) and activated partial thromboplastin time (aPTT) (once per cycle in consolidation/maintenance) 
13 If not performed within the last 6 months 
14  Including cytogenetic, flow cytometry and molecular analysis (FLT3 ITD or TKD mutation or NPM-1 mutation, FLT3 ITD at baseline only) at 
baseline, end of each induction and consolidation cycle. In maintenance and FU after SCT if blood count is suspicious for progression of 
disease/relapse. 
15 Baseline Selinexor dosing:  single dose given after registration but before beginning of first induction cycle. 
16 Bone marrow aspirates for translational research will be taken prior to baseline Selinexor dose and 24 hour post-baseline dose.   2 ml of each 
aspirate will be used to isolate viable cells for mouse studies; 2 ml of each aspirate will be processed to isolate RNA for stem cell expression array 
analysis. 
17 Blood draws for translational research (exploratory pharmacodynamic analysis):  (2 x 2.5 ml for XPO1 inhibition in leukocytes, 2 ml for cytokines) 
will be collected on day of first in-clinic dose of Selinexor during each induction and consolidation cycle. 2 x 2.5 ml, plus 2 ml blood will be collected 
pre-dose and 2 x 2.5 ml will be collected 4 hr post-dose.  
18Blood draws (2 ml) for PK analysis will be performed during first induction cycle on day of first in-clinic dose of Selinexor:  pre-dose, 2 hr and 4 hr 
post-dose. 
19 Follow-up is to include all patients, including those having undergone SCT 
20 required at screening and if clinically indicated during the treatment phase. Ophthalmologic examination 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 exam, cataract will be graded 
according to the Lens Opacities Classification System III (LOCS III) 
21 Hematological Recovery status: platelet recovery ≥ 50x 109/L and ≥ 100x 109/L, ANC recovery ≥ 0.5x 109/L and ≥ 1.0x 109/L reached and date of 
recovery. Until recovery of platelets and ANC, hematology assessments are done as often as necessary to determine the exact date of recovery of 
platelets and ANC 
 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 37/87 
Current version: Version 3.1, 13.01.2017 
5.2.1 Prophylactic Therapy for All Patients 
Patients may receive prophylactic treatment to prevent anorexia and nausea, which includes: 
 
Megesterol acetate 160-400 mg daily, 0-3 days before the first dosing day of Selinexor  
 
AND 
 
Olanzapine 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/qhs), 0-3 days before the first dosing day of Selinexor  
If the patient is on steroids coming on the study, megesterol acetate should be added 
prophylactically to prevent anorexia. If an increased risk of adverse effects due to olanzapine is 
anticipated, olanzapine can be omitted. However, it is recommended that mirtazapine or other 
appetite stimulating serotonergic agent be used.  Additional standard supportive care agents may 
be used as needed (prn). 
Supportive care may be tapered or discontinued in Cycle 2 or later in patients who tolerate 
Selinexor well in Cycle 1. 
5.2.2 Screening Procedures  
All patients will be screened and screening procedures performed within 14 days prior to the start 
of induction treatment unless specified otherwise below. These include the following:  
Signed written informed consent 
Obtained prior to any study specific assessments 
Demographics 
and 
medical 
history 
 
Age, gender, ethnic background 
 
Details on leukemia diagnosis including WHO 
subtype, cytogenetics and molecular investigations 
such as FLT3 and NPM-1 mutations 
 
Details on prior therapy, including start and stop 
dates, response of prior cancer therapies, disease 
progression during or after therapy, as well as 
discontinuation due to toxicities 
 
Previous and concurrent relevant diseases 
 
Current symptoms and/ or residual toxicities from 
prior therapies 
Pregnancy test (if applicable) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years. In case the sampling date for 
the serum pregnancy test exceeds 7 days before 
treatment start, a urine test is required for confirmation 
Physical examination and vital 
signs  
 
Body height and weight 
 
BSA 
 
Blood pressure, pulse, temperature 
 
Physical examination 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 38/87 
Current version: Version 3.1, 13.01.2017 
ECOG performance status  
Please refer to 17.4 
Standard clinical neurological 
examination  
A neurological exam will be performed to assess motor, 
sensory and balance functions 
Cardiac evaluation  
12-lead ECG, cardiac ultrasound 
Calculation (or measurement) of 
GFR 
Please refer to Appendix 6 
Urine analysis  
Urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein 
Hematology  
Hemoglobin, red blood cell (RBC) count, platelets, white 
blood cell (WBC) count, WBC differential (neutrophils, 
lymphocytes), leukemic blasts 
Clinical chemistry  
Sodium, Potassium, Calcium, Creatinine, Total Bilirubin, 
Alkaline Phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), Total Protein, 
Albumin, LDH 
Coagulation tests 
prothrombin 
time 
(PT) 
and 
activated 
partial 
thromboplastin time (aPTT) 
Ophthalmological examination 
Required at screening and if clinically indicated during 
the treatment phase. Ophthalmologic examination 
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 
exam, cataract will be graded according to the Lens 
Opacities Classification System III (LOCS III) 
HIV testing 
Required, if not done within 6 months prior to study. 
Assessment of disease status  
Bone Marrow Aspirate including cytogenetic, flow 
cytometry and molecular analysis (FLT3 ITD or TKD 
mutation or NPM-1 mutation) 
Concomitant medication 
Concomitant medication currently used 
 
5.2.3 Baseline Procedures (after registration but before Day 1 of first induction cycle, optional) 
 
Selinexor dose : 
Single Selinexor (60 mg) 
Bone Marrow aspirates for 
translational research: 
Aspirate collected pre- and 24 hour post-Selinexor dose, 
for isolation of live cells and RNA 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 39/87 
Current version: Version 3.1, 13.01.2017 
5.2.4 Treatment Phase 
During the treatment phase the following assessments are to be performed according to the study 
flow chart within the allowed visit windows: 
Physical examination and vital 
signs 
 
Body weight 
 
BSA 
 
Blood pressure, pulse, temperature 
 
Physical examination (symptom directed) 
ECOG performance status  
Please refer to Appendix 4 
Cardiac evaluation  
12-lead ECG, cardiac ultrasound 
Urine analysis  
Urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein 
Hematology  
Hemoglobin, white blood cell (WBC) count, neutrophils, 
lymphocytes, platelets, leukemic blasts 
Clinical chemistry  
 
Sodium, Potassium, Calcium, Creatinine, Total Bilirubin, 
Alkaline Phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), Total Protein, 
Albumin, LDH 
Coagulation tests 
prothrombin 
time 
(PT) 
and 
activated 
partial 
thromboplastin time (aPTT) 
Assessment of disease status 
Bone Marrow Aspirate, peripheral blood analysis as 
above 
Assessment of  hematological 
recovery status 
Platelet recovery ≥ 50x 109/L and ≥ 100x 109/L, ANC 
recovery ≥ 0.5x 109/L and ≥ 1.0x 109/L reached and date 
of recovery 
Adverse events and concomitant 
medication 
Assessed on an ongoing basis.  
Blood draws for translational 
research (optional) 
2 x 2.5 ml for XPO1 inhibition in leukocyte assays and 1 
ml for cytokine assays will be collected on day of first in-
clinic dose of Selinexor during each induction and 
consolidation cycle. 2 x 2.5 ml, plus 1 ml blood will be 
collected pre-dose and 2 x 2.5 ml will be collected 4 hr 
post-dose 
Blood draws for 
pharmacokinetics (PK, optional) 
Blood draws (2 ml) for PK analysis will be performed 
during first induction cycle on day of first in-clinic dose 
of Selinexor:  pre-dose, 2 hr and 4 hr post-dose. 
 
5.2.5 End of Treatment 
Patients who discontinue therapy for any reason must have and end of treatment (EOT) visit 
completed 30 days (± 7 days) after the last application of study drug. In case of allogeneic SCT 
the end of treatment visit should be performed prior to SCT. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 40/87 
Current version: Version 3.1, 13.01.2017 
At the EOT visit, the patients will undergo the following assessments: 
Physical examination and vital 
signs 
 
Body weight 
 
Blood pressure, pulse, temperature 
 
Physical examination 
ECOG performance status  
Please refer to Appendix 4 
Standard clinical neurological 
examination  
A neurological exam will be performed to assess motor, 
sensory and balance functions 
Cardiac evaluation  
cardiac ultrasound 
Hematology  
Hemoglobin, white blood cell (WBC) count, neutrophils, 
lymphocytes, platelets, leukemic blasts 
Assessment of hematological 
recovery status 
Platelet recovery ≥ 50x 109/L and ≥ 100x 109/L, ANC 
recovery ≥ 0.5x 109/L and ≥ 1.0x 109/L reached and date 
of recovery 
Clinical chemistry  
Sodium, Potassium, Calcium, Creatinine, Total Bilirubin, 
Alkaline Phosphatase, alanine aminotransferase (ALT), 
aspartate 
aminotransferase 
(AST), 
Total 
Protein, 
Albumin, LDH 
Coagulation tests 
prothrombin 
time 
(PT) 
and 
activated 
partial 
thromboplastin time (aPTT) 
Adverse events and concomitant 
medication 
Assessed on an ongoing basis 
 
5.2.6 Follow-Up  
Patients who discontinued for reasons other withdrawal of consent for participation in the trial will 
be followed every 3 months ± 28 days event free and overall survival to assess the following:  
 
Relapse after CR or CRi 
 
Progression of disease in case of PR and non-responders  
 
Death 
 
Assessment of hematological recovery status until Platelet recovery ≥ 50x 109/L and ≥ 
100x 109/L, ANC recovery ≥ 0.5x 109/L and ≥ 1.0x 109/L is reached and date of recovery. 
Follow-Up will be continued for maximum of 24 months per patient or end of study as defined 
below, whichever is first. 
5.2.7 End of Study 
The primary statistical analysis will be performed when all patients have discontinued treatment 
with study medication, i.e. 30 days after the last patient last dose. End of study will be defined 2 
years after registration of last patient. 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 41/87 
Current version: Version 3.1, 13.01.2017 
5.3 
Planned Treatment of the Patient after End of Treatment Phase 
After completion of the study at routine follow-up (EOT), patients will generally be treated at the 
discretion of the investigator according to medical routine, although stem cell transplantation is 
recommended if a donor is available and no contra-indications exist.  
 
 
5.4 
Removal of Patients from Treatment 
Subjects will be free to discontinue treatment or withdraw from the study at any time, for any 
reason.  Or they may be withdrawn/ removed if necessary in order to protect their health (see 
reasons for withdrawal below).  It is understood by all concerned that an excessive rate of 
withdrawals can render the study uninterpretable; therefore, unnecessary withdrawal of subjects 
should be avoided. Patients who are withdrawn from the study will not be replaced. 
Patients will be removed from further treatment for the following reasons: 
 
Disease progression 
 
Non-compliance 
 
Need of treatment with medications not allowed by the study protocol 
 
Patient no longer consents to participate in the study 
 
Intercurrent illness that interferes with study assessments 
 
Incidence or severity of AEs in this study indicates a potential health hazard to the patient 
 
Investigator discretion 
 
Pregnancy 
 
Termination of the study by the sponsor 
 
If there is a medical reason for withdrawal of treatment, the patient will remain under the 
supervision of the investigator until the AEs have been resolved or declined to baseline values. 
If a patient has failed to attend scheduled assessments in the study, the investigator must 
determine the reasons and circumstances as completely and accurately as possible.  
In case of premature discontinuation of the study treatment, the investigations scheduled for the 
EOT and the follow-up visits should be performed, if possible. The CRF section entitled “End of 
Treatment” must be completed in all cases. Should a patient decide to withdraw, every effort will 
be made to complete and report the observations as thoroughly as possible. The investigator 
should contact the patient to determine as completely as possible the reason for the withdrawal. 
A complete final evaluation at the time of the patient’s withdrawal should be made, with an 
explanation of why the patient is withdrawing from the study. If the reason for removal of a patient 
from the study is an adverse event or an abnormal laboratory test result, the principal specific 
event or test will be recorded on the case report form. 
If a patient withdraws consent for further study treatment, the patient should still be followed for 
disease progression and overall survival. If a patient withdraws consent for further participation in 
the study, follow-up assessments will be discontinued. 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 42/87 
Current version: Version 3.1, 13.01.2017 
5.5 
Study Discontinuation 
The whole study may be discontinued at the discretion of the sponsor in the event of any of the 
following: 
 
Medical or ethical reasons affecting the continued performance of the study 
 
Difficulties in the recruitment of patients 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 43/87 
Current version: Version 3.1, 13.01.2017 
6 
TREATMENT 
6.1 
Investigational medicinal product (IMP) 
An investigational medicinal product is a pharmaceutical form of an active substance or placebo 
being tested or used as a reference in a clinical trial, including products already with a marketing 
authorisation but used or assembled (formulated or packaged) in a way different from the 
authorised form, or when used for an unauthorised indication, or when used to gain further 
information about the authorised form. 
The IMP in this study is Selinexor. AraC and Idarubicin are not considered IMP as the treatment 
is according standard of care. Any AraC or Idarubicin with marketing authorisation in the member 
state can be administered according to protocol.  
The investigator or other appropriate individual, who is designated by the local principal 
investigator, should maintain records of the inventory at the site, the use for each patient and 
delivery, storage and destruction. Investigators should maintain records that adequately 
document that patients were provided the doses specified in the protocol and reconcile all 
investigational product(s) received from the sponsor. 
 
6.2 
Preparation and Administration of Selinexor 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drug as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF. 
Tablets, including instructions for administration, are dispensed by study personnel on an 
outpatient or inpatient basis. 
Patients will be provided with an adequate supply of study drug for self-administration at home 
until at least their next scheduled study visit. 
6.2.1 Drug Name, Formulation and Storage 
INN:  Selinexor 
Company´s Drug ID KPT-330 
Chemical name: 
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-   
                            
(pyrazin-2-yl)acrylohydrazide 
Classification:  
Cell biological modifier: Apoptosis inducing agent 
Mechanism of action: Selinexor is a Selective Inhibitor of Nuclear Export (SINE) that specifically 
blocks nuclear export by binding irreversibly to XPO1 protein. 
Molecular formula: 
C17H11F6N7O 
Molecular weight: 
443.31 
Approx. solubility:  
<0.03 mg/mL in water (pH 2-8) 
>10 mg/mL in dimethylsulfoxide 
<2 mg/mL in 40% v/v PEG-400/H2O 
<2 mg/mL in 15% v/v EtOH/H2O 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 44/87 
Current version: Version 3.1, 13.01.2017 
6.2.1.1 Tablets 
Selinexor (KPT-330) for oral administration will be supplied as 10 mg tablets. Bottles of 50 tablets 
per bottle will be supplied. 
6.2.1.2 Labelling 
Each bottle of Selinexor tablets will be labelled in accordance with current ICH GCP and specific 
national requirements. 
6.2.1.3 Storage 
Selinexor tablets will be stored at ambient temperatures between 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.  
6.2.2 Route of Administration 
Selinexor tablets will be taken orally twice weekly during weeks 1-3 of a 4-week cycle, either on 
Monday and Wednesday or on Tuesday and Thursday or on Wednesday and Friday. 
Selinexor is to be taken within approximately 30-minutes of solid food consumption together with 
240 mL (8 ounces) of water. 
Each dose will consist of Selinexor for oral administration with a dose of 60 mg.  
6.2.3 Compliance 
The investigator should ensure that the investigational product is used only in accordance with 
the protocol. All doses given are to be documented in the CRF, including exact dose, number of 
tablets, time and date administered. The principal investigator or the designee will account for the 
number of tablets dispensed against those stored at the site. Any deviations and missed doses 
will be recorded in the CRF and drug accountability logs for verification with the reasons for 
missed doses. The investigator/ designee will try to ensure complete compliance with the dosing 
schedule by providing timely instructions to the patients. It will be requested from patients to 
document intake of Selinexor in a patient diary. 
The investigational product should be stored as specified by the sponsor and in accordance with 
applicable regulatory requirements. 
 
6.3 
Dose modification of Selinexor 
Toxicity will be graded according to NCI CTCAE, version 4.03; the therapy modifications 
described below are applied according to this severity grading. 
Each dose modification or treatment delay has to be documented in the CRF, including the 
respective reason. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 45/87 
Current version: Version 3.1, 13.01.2017 
Based on observations from the ongoing Phase 1 studies in patients with advanced hematological 
and solid tumors, Selinexor (KPT-330) shows a wide therapeutic range, with documented anti-
leukemic activity from ~17mg/m² to ≥55mg/m² orally twice weekly. At the present time, we cannot 
predict which patient's leukemia will respond to lower doses, nor can tolerability be predicted. 
Therefore, in order to individualize and optimize therapeutic benefit with this oral SINE XPO1 
antagonist, initiation of study therapy will be with a relatively high dose (60 mg twice weekly in 
weeks 1-3 of a 4-week cycle by mouth) of Selinexor. Although this is a high dose, it is below the 
MTD of oral Selinexor, and we believe will maximize early disease control with good tolerability in 
the majority of patients.  Flexible dose reductions and/or schedule modifications will be permitted. 
In patients with tolerability issues on Selinexor, it is recommended either: (1) reducing Selinexor 
dose by 30% or (2) reducing Selinexor dosing frequency to once weekly.  
6.3.1 Dose Adjustment Guidelines for Selinexor Related Toxicities 
Toxicity will be graded according to NCI CTCAE, version 4.03; the therapy modifications 
described below are applied according to this severity grading. 
If more than one different type of toxicity occurs concurrently, the most severe grade will 
determine the modification. 
Re-escalation of the study drug is allowed as outlined in the sections that apply for the specific 
toxicity. If drug-related toxicity requires a treatment delay of more than 28 days the patient is taken 
off protocol treatment. 
Each dose modification or treatment delay has to be documented, including the respective 
reason. 
Table 2: Prespecified dose/schedule modifications for adverse events related to study 
drug 
 
Dose level 
Dose of Selinexor 
Dose level 0 
60 mg twice weekly (D1, D3) 
Dose level -1 
50 mg twice weekly (D1, D3) 
Dose level -2 
40 mg once weekly (D1) 
Dose level -3 
30 mg once weekly (D1) 
Dose level -4  
Discontinue dosing 
 
Based on observations from the ongoing Phase 1 studies in patients with advanced hematological 
and solid tumors, we note that selinexor shows a reasonably wide therapeutic range, with 
activities from ~10mg/m2 to ≥50mg/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. 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 46/87 
Current version: Version 3.1, 13.01.2017 
Table 3: Criteria for dose adjustments of Selinexor-related toxicities  
Toxicity and Intensity 
Dose Modification 
Fatigue (common) 
Grade 1 
Insure adequate caloric intake and assess volume status. Adjust 
other medications. Consider addition of low dose corticosteroids 
(e.g., 4 mg dexamethasone with each dose of Selinexor or 10 
mg prednisone per day every day).  Rule out other causes of 
fatigue such as adrenal insufficiency.  
Grade 2 
Insure adequate caloric and fluid intake and assess volume 
status.  Add corticosteroids on day of Selinexor (e.g., 4 mg 
dexamethasone), or give or 10-15mg prednisone every other 
day.  If fatigue dose not resolve to Grade 1, increase 
corticosteroids to the day of and the day after Selinexor dosing, 
and/or reduce dose of Selinexor by one level (Table 2). 
Grade 2 lasting ≥7 days 
and Grade 3 
Insure adequate caloric and fluid intake and assess volume 
status.  Interrupt Selinexor dosing until resolved to Grade ≤ 1, 
reduce dose of Selinexor by 1 level (Table 2), and add 
corticosteroids on day of (± day after) Selinexor dosing. 
Anorexia or weight loss 
(common) 
 
Grade 1 
Assess dietary options (e.g., try a variety of other foods). Add 
high-calorie supplements (e.g., Ensure®). If fatigue or nausea 
also present, consider low doses of corticosteroids (as for 
fatigue) on day of ± day after Selinexor dosing. 
Grade 2 
Add high-calorie supplements (e.g., Ensure®). Consider 
olanzapine 2.5-5 mg po qhs (especially if nausea or sleep 
disturbance present).  Consider megesterol acetate 400-800 mg 
daily.  Consider low dose corticosteroids (see fatigue).  Consider 
anabolic steroids such as oxandrolone. Consider dronabinol 
(Marinol®).  Skip intermittent doses of Selinexor while supportive 
medications are instituted. If Grade 2 anorexia does not resolve 
after institution of supportive medications, reduce Selinexor dose 
by 1 level (Table 2). 
Grade 3 
Interrupt dosing with Selinexor.  Add high calorie supplements.  
Use supportive medications alone or in combinations.  Restart 
Selinexor at 1 dose level reduction (Table 2) once anorexia 
resolves to Grade ≤ 2 and weight stabilized.  If Grade 2 anorexia 
persists with supportive medications, reduce dose of Selinexor 
another level (Table 2). 
Nausea/Emesis (common) 
 
Grade 1 
5-HT3 antagonists, D2 antagonists, olanzapine 5mg qhs or 
2.5mg bid, corticosteroids (e.g., 4-10 mg dexamethasone with 
each dose of Selinexor ± the day after dosing), NK1 antagonists, 
or dronabinol (Marinol) or combinations can prevent nausea in 
the majority of patients. 
Grade 2 
Implement one or more combinations of anti-nausea 
medications.  If nausea does not resolve to Grade ≤ 1, reduce 
dose of Selinexor by one dose level (Table 2). 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 47/87 
Current version: Version 3.1, 13.01.2017 
Toxicity and Intensity 
Dose Modification 
Grade 3 
Implement one or more combinations of anti-nausea 
medications and interrupt dosing of Selinexor.  Selinexor may be 
restarted with one dose level reduction (Table 2) when nausea is 
Grade ≤ 2 and adequate caloric and fluid intake have been 
achieved. 
Hyponatremia (common) 
Grade 1 (Lower Limit of 
Normal to 130 nM) 
 
Maintain dose level, assure adequate fluid, electrolyte and 
caloric intake, adjust other medications, consider salt 
supplementation, rule out other causes. 
Be certain that reported sodium level is corrected for concurrent 
hyperglycemia (serum glucose > 150mg/dL). 
Grade 3 (120-130 nM) 
without symptoms 
First Occurrence: Discontinue Selinexor until resolved to Grade 
≤ 1 then reinstate starting dose.  Check renal function, serum 
and urinary electrolytes, and rule out other causes. Reinforce 
patient education regarding fluid intake. 
Be certain that reported sodium level is corrected for concurrent 
hyperglycemia (serum glucose > 150mg/dL). 
 
Subsequent Occurences: Discontinue Selinexor until resolved to 
Grade ≤ 1 then reduce dose by 1 level (Table 2).  Check renal 
function, serum and urinary electrolytes, and rule out other 
causes. 
Grade 3 (120-130 nM with 
symptoms) or Grade 4 
(<120 nM) 
Check renal function, serum and urinary electrolytes, and rule 
out other causes. Be certain that reported sodium level is 
corrected for concurrent hyperglycemia (serum glucose > 
150mg/dL). 
 
Discontinue Selinexor until resolved to Grade ≤ 1 then reduce 
dose by 1 level (Table 2).  Check renal function, serum and 
urinary electrolytes, and rule out other causes. 
Renal (rare) 
Serum creatinine 
Calculated or measured 
creatinine clearance 
≥ 20 cc/min 
Maintain dose level 
Calculated or measured 
creatinine clearance 
< 20 cc/min 
Maintain dose level as Selinexor is not eliminated by the kidney. 
Hepatic (rare) 
Bilirubin 
Total bilirubin < 1.5 x ULN 
Maintain dose level 
Total bilirubin 1.5-3 x ULN 
Reduce Selinexor to once weekly dosing at the same dose until 
resolved to ≤ Grade 1, then restart twice weekly dosing 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 48/87 
Current version: Version 3.1, 13.01.2017 
Toxicity and Intensity 
Dose Modification 
Grade 3 (> 3.0-10.0 x ULN) 
Grade 4 (> 10.0 x ULN) 
Discontinue Selinexor until resolved to Grade ≤ 2, then follow 
guidelines above. 
Note: If Grade 3 or Grade 4 hyperbilirubinemia is due to the 
indirect component only, and hemolysis as the etiology has been 
ruled out as per institutional guidelines (e.g. review of peripheral 
blood smear and haptoglobin determination), then reduce 
Selinexor dose by 1 level (Table 2) and continue treatment at 
the discretion of the investigator. 
Discontinuation of Selinexor is required if concurrent elevations 
of total bilirubin > 2.0 X upper limit of normal (ULN) and ALT or 
AST > 3.0 X ULN are observed and other causes have been 
ruled out. 
In order to characterize hepatic toxicity more precisely, 
fractionation of bilirubin and alkaline phosphatases will be 
required for elevated values > 2.0 X ULN and ≥ CTCAE Grade 
2, respectively. 
AST or ALT (rare) 
Grade 1 (> ULN-2.5 x ULN) 
Maintain dose level 
Grade 2 (> 2.5-5.0 x ULN) 
Delay Selinexor until resolved to Grade ≤ 1, then maintain dose 
level.  Consider addition of S-adenosylmethionine (SAM) 400mg 
qd-bid. 
Grade 3 (> 5.0-20.0 x ULN) 
Delay Selinexor until resolved to ≤ Grade 2, then reduce by 1 
dose level (Table 2). 
Consider addition of S-adenosylmethionine (SAM) 400mg qd-
qid. 
If no further AST or ALT elevations occur during one cycle 
(4 weeks) at the reduced dose level, then dose may be 
continued at the reduced dose. 
Discontinuation of Selinexor is required if concurrent elevations 
of direct bilirubin > 2.0 X upper limit of normal (ULN) and ALT or 
AST > 3.0 X ULN are observed. 
In order to characterize hepatic toxicity more precisely, 
fractionation of bilirubin and alkaline phosphatases will be 
required for elevated values > 2.0 X ULN and ≥ CTCAE Grade 
2, respectively. 
Grade 4 (> 20.0 x ULN) 
Delay Selinexor until resolved to ≤ Grade 2, then reduce by 2 
dose levels (Table 2). 
Cardiac (rare) 
Hypertension 
Treatment-emergent hypertension should be treated as per 
standard cardiology practice. Recommended agents for the 
management of blood pressure elevations on Selinexor include 
angiotensin-converting enzyme inhibitors and calcium channel 
blockers. 
Grade 1 
Maintain dose level 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 49/87 
Current version: Version 3.1, 13.01.2017 
Toxicity and Intensity 
Dose Modification 
Grade 2 / 3 
Delay Selinexor and initiate/intensify antihypertensive therapy. 
Selinexor may be restarted in conjunction with standard anti-
hypertensive medication if BP is controlled (i.e., BP ≤ 150/100 
mmHg). 
If BP is controlled ≤ 7 days after suspending Selinexor, maintain 
dose level 
If BP is controlled > 7 days after suspending Selinexor , then 
reduce by 1 dose level (Table 2). 
Grade 4 
Delay the Selinexor and initiate/intensify antihypertensive 
therapy, then reduce by 1 dose level (Table 2). 
Selinexor may be restarted in conjunction with anti-hypertensive 
medication if BP is controlled (i.e., BP ≤ 150/100 mmHg).  
Cardiac – Other (rare) 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Delay Selinexor until resolved to ≤ Grade 1, then reduce by 1 
dose level (Table 2). 
Grade 4 
Discontinue study treatment 
Diarrhea (common) 
Grade 1 (despite maximal 
anti-diarrheal medication) 
At the first sign of abdominal cramping, loose stools, or onset of 
diarrhea, it is recommended that the patient be treated 
according to institutional standard of care. Maintain dose level of 
Selinexor. 
Grade 2 (despite maximal 
anti-diarrheal medication) 
 
Reduce to Selinexor to one weekly until resolved to ≤ Grade 1, 
then re-start twice weekly at the current dose level.  
If diarrhea returns as ≥ Grade 2, then reduce Selinexor dose by 
one dose level and dose once weekly until resolved to ≤ Grade 
1, then re-start twice weekly at reduced dose level 
Grade 3/4  (despite 
maximal anti-diarrheal 
medication) 
Delay Selinexor until resolved to ≤ Grade 1 or baseline and 
patient is clinically stable, then follow guidelines above. 
Neurotoxicity (not observed to date) 
≥ 1 CTCAE grade level 
increase 
 
Grade 0 → Grade 1: maintain dose level 
Grade 0 or 1 → Grade 2: delay study treatment until resolved to 
≤ Grade 1, then reduce by 1 dose level (Table 2). 
≥ CTCAE Grade 3 
Discontinue study treatment until resolved to Grade ≤ 1 then 
reduce by 2 dose levels (Table 2). 
Amylase and/or lipase elevations (rare) 
Grade 1 or 2 
Maintain dose level 
Asymptomatic Grade 3 or 4 
Delay Selinexor until ≤ Grade 2, then restart at 1 dose level 
reduction (Table 2).  Rule out other causes of amylase/lipase 
elevation.  If levels have not returned to ≤ Grade 2 within 3 
weeks then no further Selinexor may be given and the patient 
should discontinue permanently from the study. A computed 
tomography (CT) scan or other imaging study to assess the 
pancreas, liver and gallbladder must be performed within 1 week 
of the first occurrence of any Grade 3 elevation of amylase 
and/or lipase. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 50/87 
Current version: Version 3.1, 13.01.2017 
Toxicity and Intensity 
Dose Modification 
Symptomatic Grade 3 or 4 
Selinexor must be stopped immediately and proper supportive 
care provided. Evaluate enzyme levels at least twice weekly until 
resolution to ≤ Grade 1. Clinical manifestations should be 
monitored as needed until resolution or stabilization of the 
disease condition. Selinexor may be re-started at 2 dose levels 
below (Table 2) after resolution to ≤ Grade 1. 
Pancreatitis (not observed to date) 
Grade 1 
Maintain dose level 
Grade 2, 3 or 4 
Discontinue study treatment. 
Thrombocytopenia 
Grade 1 or 2 
Maintain dose. Rule out other causes including drug effects. 
Grade 3 without bleeding 
Rule out other causes including drug effects. 
For first occurrence: continue dosing without interruption: 
however, reduce Selinexor by 1 dose level. 
For ≥ second occurrence: interrupt selinexor and check platelet 
counts weekly until recovers to Grade 2 or baseline and reduce 
selinexor by 1 dose level. If the occurrence falls on a Day 1 of a 
cycle: delay start of cycle, check platelet counts weekly until 
recovers to Grade 2 or baseline and reduce selinexor by 1 dose 
level when resuming. 
Grade 4 without bleeding 
Rule out other causes including drug effects. 
Interrupt Selinexor until recovers to Grade 2 or baseline and 
reduce selinexor by 1 dose level. If the occurrence falls on a Day 
1 of a cycle: delay start of cycle, check platelet counts weekly 
until recovers to Grade 2 or baseline and reduce selinexor by 1 
dose level when resuming. 
≥ Grade 3 with bleeding 
Interrupt selinexor dosing and check platelet counts weekly until 
the bleeding has stopped, patient is clinically stable and the 
platelets have recovered to Grade 2 or baseline. When resuming 
selinexor, reduce by 1 dose level. If the occurrence falls on a 
Day 1 of a cycle: delay start of cycle, check platelet counts 
weekly until the bleeding has stopped, patient is clinically stable 
and the platelets have recovered to Grade 2 or baseline. 
Reduce selinexor by 1 dose level when resuming. 
Neutropenia 
Grade 3 or 4 Neutropenia 
With (febrile neutropenia) 
OR Without fever 
Institute prophylactic antibiotics as clinically indicated per 
institutional guidelines. 
Interrupt selinexor and check neutrophils weekly until recovers 
to Grade 2 or baseline and without fever (if febrile) and the 
patient is clinically stable. Reduce selinexor by 1 dose level 
when resuming.  
If the occurrence falls on a Day 1 of a cycle: delay start of cycle, 
check neutrophils weekly until recovers to Grade 2 or baseline 
and without fever (if febrile) and the patient is clinically stable. 
Reduce selinexor by 1 dose level when resuming. 
Anemia 
Treat per institutional guidelines including blood transfusion. Consider transfusing for haemoglobin 
< 8 g/dL. If possible, maintain selinexor dose as long as patient is clinically stable, but if a dose 
reduction or interruption is desired, consult with the Medical Monitor.  


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 51/87 
Current version: Version 3.1, 13.01.2017 
Toxicity and Intensity 
Dose Modification 
Other Selinexor-related adverse events 
Grade 1 or 2 
Maintain dose level and initiate standard supportive care. 
Grade 3 
Delay dose until resolved to ≤ Grade 1, then reduce by 1 dose 
level (Table 2). 
Grade 4 
Discontinue Selinexor and rule out other causes.  If other causes 
of Grade 4 adverse event are uncovered, Selinexor may be re-
initiated at 1 dose level reduction (Table 2). 
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. 
Patients are allowed dose reductions to a minimum dose of 15 mg/m2 as described in Table 2.   
If a patient requires a dose interruption of > 28 days, then the patient must be discontinued 
from the study. Patients who discontinue the study for a study related adverse event or an abnormal 
laboratory value must be followed at least once a week for 28 days and subsequently at 28 day 
intervals until resolution or stabilization of the event, whichever comes first. 
a. Common Terminology Criteria for Adverse Events (CTCAE Version 4.03 ) otherwise specified 
values. 
 
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.   
6.3.2 Selinexor Dose Reduction 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.  
6.3.3 Selinexor Dose Adjustment in the Setting of Infection 
Patients with active uncontrolled or suspected infections should have Selinexor treatment 
withheld until infection has clinically resolved or the patient is clinically stabilized. 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. Note: Over 1,175 patients receiving selinexor were evaluated for 
safety as of 31 May 2016 in clinical studies. Opportunistic infections attributed to selinexor were 
not observed, even with long-term (> 6-month) dosing.  
6.3.4 Conditions not Requiring Selinexor Dose Reduction 
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 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 52/87 
Current version: Version 3.1, 13.01.2017 
6.3.5 Missed doses  
A maximum of three doses may be given per week. If the dose was missed for more than 24 
hours, the dose will be skipped and the next dose will be taken as per schedule. If the dose was 
missed within 24 hours, then it will be replaced. Doses should not be administered in less than 
36 hours apart and all missed doses should be documented in the patient diary and the CRF. 
6.3.6 Vomited doses 
If a dose is vomited within one hour of ingestion, it will be replaced. If vomiting occurs more than 
1 hour after dosing, it will still be considered a complete dose. 
 
6.4 
Concomitant Medication and Treatment 
Concomitant medication is defined as any prescription or over-the-counter preparation, including 
vitamins and supplements. Patients may continue their baseline medication(s). All concomitant 
medication(s) must be reported in the case report form (CRF). Any diagnostic, therapeutic or 
surgical procedure performed during the study period should be recorded, including the dates, 
description of the procedure(s) and any clinical findings. Patients should minimize the use of 
products containing acetaminophen to less than 1000 mg acetaminophen on dosing days. 
Acetaminophen can interfere with the metabolism of Selinexor. For combination painkillers 
containing acetaminophen it is recommended that single agent opiates or aspirin combinations 
(when clinically acceptable) be substituted. 
6.4.1 Permitted Concomitant Medication 
Patients will receive concomitant medications to treat symptoms, adverse events and intercurrent 
illnesses that are medically necessary as standard care. Medications to treat concomitant 
diseases like diabetes, hypertension, etc. are allowed. 
6.4.1.1 Prevention of Pregnancy 
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. 
6.4.1.2 Use of Blood Products 
During the administration of Selinexor, patients may receive red blood cell (RBC) or platelet 
transfusions, if clinically indicated, per institutional guidelines. Appropriate anti-coagulation is 
allowed during the study (eg: LMW heparin, direct factor Xa inhibitors, etc).  
6.4.2 Prohibited Medications 
Patients should minimize the use of products containing acetaminophen. For combination 
painkillers containing acetaminophen it is recommended that single agent opiates or metamizol 
combinations (when clinically acceptable) be substituted, particularly on the days of Selinexor 
dosing.   


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 53/87 
Current version: Version 3.1, 13.01.2017 
Concurrent therapy with an approved or investigational anticancer therapeutic, other than Ara-C, 
Idarubicin and glucocorticoids as specified herein, is not allowed.  
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. 
Inactivation of Selinexor by glutathione conjugation is a significant metabolic pathway in vitro and 
in vivo, including in humans. This process can be mediated in the absence of proteins, indicating 
that it is thermodynamically favorable. In vitro studies using human liver microsomes confirm in 
vivo findings that Selinexor undergoes minimal CYP450 metabolism. Therefore, administration of 
Selinexor with drugs which undergo substantial glutathione conjugation should be minimized or 
avoided. These drugs include acetaminophen (paracetamol) and ethyl alcohol. It should be noted 
that studies of Selinexor in combination with acetaminophen are to begin in late 2013 and 
therefore that these recommendations are empirical. 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. 
6.5 
Supportive Care Guidelines 
Supportive measures for optimal medical care shall be provided during participation in this clinical 
trial. Supportive care including anti-nausea / anti-emetic therapy, acid suppression (proton pump 
inhibitors and/or H2-blockers), glucocorticoids, and other standard treatments may be 
administered as per institutional guidelines for symptomatic patients. As needed and per 
individual study site institutional guidelines, prophylactic therapies, including antivirals, 
antifungals, and antibiotics, may be administered to ameliorate risks associated with non-
malignant disorders or of immune system compromise.  
All patients are required to receive prophylactic anti-emetics ondansetron 8 mg (or similar 5-HT3 
antagonist) before their first dose of Selinexor and continued two or three times daily, as needed. 
 
6.5.1 Anorexia 
Based on clinical observations in over 1,175 adult patients treated with selinexor as of 31 May 
2016, one of the most frequent treatment-emergent adverse event is anorexia (50%) with poor 
caloric and fluid intake leading to weight loss, fatigue and nausea. Therefore, it is strongly 
recommended that patients at risk for anorexia, weight loss, and/or fatigue receive strong 
nutritional counseling, high caloric beverages with adequate electrolyte levels (e.g., Ensure®), 
prophylaxis with appetite-stimulating agent(s), and anti-emetic agents. Patients with proper 
nutritional support and counseling have remained on Selinexor for >11 months. There is no 
correlation between initial BMI or weight and the development of anorexia. 
In patients with problematic food/liquid/caloric intake, a patient log of food and drink should be 
considered and monitored by the treatment team. 
Fresh juices, simple carbohydrates, as well as ginger can improve appetite before the meal; 
ginger may also improve dysgeusia. 
Since the duration of treatment is short and most of the patients are hospitalized during induction 
treatment patients with anorexia nutrition is usually provided by infusion directly into the circulatory 
system  
If constipation occurs, then laxatives should be given as constipation can contribute to anorexia 
and loss of appetite. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 54/87 
Current version: Version 3.1, 13.01.2017 
6.5.2 Fatigue    
Fatigue may be related to underlying malignancy, Selinexor side effects, side effects of other 
agents or concurrent morbidities. Fatigue may also be related to anorexia and/or dehydration, so 
caloric and fluid intake should be optimized in all patients (please see above aggressive 
guidelines for maintenance of food and fluid intake). Acid suppression (proton pump inhibitors 
and/or H2-blockers) may be beneficial in some patients with fatigue. 
6.5.3 Emesis    
Supportive care for nausea and vomiting should be given promptly. The site can consider 
prophylactic treatment in case of previous side effect of nausea and vomiting with prior anti-cancer 
therapy. The treatment should start with the first sign of nausea. Standard anti-emetics are 
allowed and strongly recommended. 
6.5.4 Acute Emesis 
Acute emesis is not a major observation with Selinexor but has been reported. Selinexor 
associated nausea/emesis generally responds to D2-antagonists, 5-HT3 antagonists, or 
combinations of agents. 
5-HT3 receptor antagonists (Zofran® 8 mg on days of dosing) — First-generation 5-HT3 receptor 
antagonists all appear equally effective at preventing nausea/emesis at the recommended doses. 
A single dose of a 5-HT3 receptor antagonist prior to therapy is equivalent to a multiple dose 
schedule. The efficacy of 5-HT3 receptor antagonists is significantly improved when they are 
combined with glucocorticoids.  As QTc prolongation is the main side effect, magnesium and 
potassium 
should 
be 
corrected 
prior 
to 
use. 
If 
first-generation 
5-HT3 
receptor 
antagonists+dexamethasone do not adequately control emesis, second generation 5-HT3 
receptor antagonists (e.g., palonosetron) should be considered. Second generation 5-HT3 
receptor antagonists also improve delayed nausea/emetic response. 
Neurokinin-1 receptor antagonists (e.g., aprepitant or fosaprepitant, Emend®) – should be 
considered in case of uncontrolled emesis with standard treatments as described above. 
Neurokinin-1 receptor antagonists should be given with combination of dexamethasone and first 
or second generation 5-HT3 receptor antagonists. 
Additional treatment: Metoclopramide Hydrochloride 10mg, 30 min before meal (up to 4 time a 
day) or prochlorperazine (standard doses) have been effective in many patients.  Dronabinol 
(Marinol) has shown some activity in both nauea/emesis and anorexia in patients treated with 
Selinexor. Lorazapeam can be added to the combination treatment of 5-HT3 receptor 
antagonists +dexamethasone, e.g., at night, but has been less effective in Selinexor associated 
nausea/emesis. 
6.5.5 Delayed Emesis - > 24h after treatment 
Management — Selinexor is infrequently associated with delayed, resistant emesis. Many of the 
regimens associated with delayed emesis are classified as high-emetic risk, and professional 
guidelines recommend the use of an NK1 receptor antagonist (either NK-1 blockers e.g., 
aprepitant on days 1 to 3 or fosaprepitant on day 1 only), plus a glucocorticoids on days 1 to 4, 
along with a 5-HT3 receptor antagonist (particularly second generation agents) on day 1. This 
regimen is effective against both acute and delayed emesis. The data supporting the individual 
components of this regimen are reviewed below. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 55/87 
Current version: Version 3.1, 13.01.2017 
Olanzapine — Conventional antiemetics are more successful at preventing emesis than in 
preventing nausea, particularly delayed nausea. Olanzapine at the dose of 2.5 to 5 mg once daily 
(typically given at night to mitigate sedative effects) was proven effective in both anti emesis and 
nausea control. It may also be useful for management of breakthrough emesis, and to improve 
food intake in patients with anorexia. 
Glucocorticoids are also consistently useful and should be administered as described above. 
Granisetron transdermal patch — A transdermal preparation of granisetron should be consider in 
patients that have uncontrolled emesis/nausea >grade 2 under best supportive treatment 
Ginger — Supplemental ginger added to foods or at doses of 0.5, 1.0gm powder daily total dose, 
usually in divided doses. Ginger may also improve dysgeusia. 
Additional agents can be added, including lorazepam or alprazolam, a dopaminergic D2-
antagonist (eg, prochlorperazine, thiethylperazine, haloperidol), or substituting high-dose 
intravenous metoclopramide for the 5-HT3 antagonist. 
6.5.6 Diarrhea    
Diarrhea is common at up to 27 % as of 31 May 2016 (mostly Grade 1), which responds to 
standard anti-diarrheal agents. Fluid replacement is important to prevent dehydration, fatigue and 
electrolyte abnormalities (e.g., hyponatremia). 
6.5.7 Hyponatremia   
Hyponatremia Grade 3 (plasma sodium < 130 nM) has been reported in 283 patients (24%) of 
patients treated with selinexor as of 31 May 2016: (please note that Grade 2 hyponatremia is not 
recognized in the CTCAE, v. 4.03; Grade 1 hyponatremia includes any plasma level between 
normal and 130 nM). None of the cases of Grade 3 hyponatremia was symptomatic and all were 
rapidly correctable with standard measures. No instances of Grade 4 hyponatremia have been 
seen. One case was pseudohyponatremia due to hyperglycemia (not associated with Selinexor).  
Most of the patients had anorexia, nausea, vomiting and/or diarrhea. Two of the patients with 
Grade 3 hyponatremia had third-space fluid accumulation or resolution (e.g., ascites, edema). 
Adequate fluid and caloric intake, including electrolyte rich beverages rather than free water, has 
led to reversal of the hyponatremia. 
6.5.8 Liver enzyme increase   
Liver toxicities in rodents and monkeys were not observed in the GLP toxicology studies. To date, 
significant liver toxicity has not been reported in patients treated with Selinexor.  Patients should 
minimize their use of alcohol and acetaminophen as these drugs may deplete hepatic glutathione 
which could alter Selinexor metabolism. Studies of low dose acetaminophen administered just 
prior to Selinexor (in order to boost hepatic and gastrointestinal levels of Selinexor as 
demonstrated in rat nonclinical studies) are ongoing and will clarify any potential drug-drug 
interactions and/or liver toxicities of this combination.  The secondary goal of these studies is to 
boost hepatic Selinexor levels in order to enhance hepatic anti-tumor activity. Glutathione (GSH) 
replacing agents such as N-acetylcysteine or S-adenosylmethionine may be considered if 
Selinexor induced liver dysfunction is suspected. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 56/87 
Current version: Version 3.1, 13.01.2017 
7 
SAFETY REPORTING 
The Investigator’s Brochure will be used as reference document for KPT-330 (selinexor) and will 
be provided to the investigators in the investigator’s file. 
 
7.1 
Adverse Events and Laboratory Abnormalities Reporting 
7.1.1 Adverse Event 
An adverse event is defined in the International Conference on Harmonization (ICH) Guideline for 
Good Clinical Practice as “any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment” (ICH E6:1.2). 
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of a 
medicinal product, whether or not it is considered related to the medicinal product. 
7.1.2 Adverse Drug Reaction 
All untoward and unintended responses to a medicinal product related to any dose administered. 
The phrase “responses to a medicinal product” means that a causal relationship between the 
medicinal product and the adverse event is at least a reasonable possibility, i.e. the relationship 
cannot be ruled out. 
A serious ADR (SADR) is an ADR that meets the definition of serious (provided below). 
7.1.3 Serious Adverse Event 
A serious adverse event (SAE) is defined as an adverse event that meets one or more of the 
following: 
 
is fatal 
 
is life threatening (places the subject at immediate risk of death) 
 
requires in-patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect 
 
other important medical events 
 
A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a healthcare facility. Any 
adverse event that does not meet one of the definitions of serious (e.g. visit to A&E, 
outpatient surgery, or requires urgent investigation) may be considered by the investigator 
to meet the “other significant medical hazard” criterion for classification as a serious 
adverse event. Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias. 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. Medical 
judgment should be exercised in deciding whether such an AE should be considered serious. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 57/87 
Current version: Version 3.1, 13.01.2017 
7.1.4 NOT to be reported as SAEs 
For this study, the following is not classified as serious adverse event: 
 
Progression or deterioration of the malignancy under study (including new metastatic 
lesions) or death due to progression. 
 
Hospitalization for the performance of protocol-required procedures or administration of 
study treatment. However, hospitalization or a prolonged hospitalization for a complication 
of therapy administration will be reported as an SAE. 
 
Hospitalization or procedures planned prior to study start. A pre-planned procedure must 
be documented in the source documents. However, hospitalization or prolonged 
hospitalization for a complication remains to be reported as an SAE. 
 
An elective hospitalization for a pre-existing condition unrelated to the studied indication. 
 
Hospital admission that is not associated with an adverse event (e.g. social hospitalization 
for purpose of respite care). 
 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
 
The administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication of such 
transfusions remains to be reported as an SAE. 
 
Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
7.1.5 Adverse events of special interest (AESI) 
The occurrence of acute cerebellar syndrome (ACS) and development of (or worsening of 
existing) cataracts during treatment with Selinexor are closely monitored as AESIs. 
All cases of cerebellar toxicity ≥ Grade 3 must be captured as an SAE and reported in an 
expedited Safety Report within 24 hours of awareness of the event. 
7.1.6 SUSAR/ Unexpected Serious ADR 
A SUSAR/ Unexpected Serious ADR is a suspected unexpected serious adverse reaction. A 
suspected adverse reaction is an adverse event for which there is a reasonable possibility that 
the drug caused the event. An unexpected adverse reaction is any adverse reaction with a 
reasonable possibility that the study drug caused the event and the specificity or severity is not 
consistent with the current investigator’s brochure for Selinexor. Also, reports that provide 
significant information on the specificity or severity of a known, already documented adverse 
event constitute unexpected adverse events. An event more specific or more severe than 
described in the investigator’s brochure would be considered “unexpected”. All suspected adverse 
reactions related to Selinexor which occur in the trial and that are both unexpected and serious 
(SUSARs/ Unexpected Serious ADR) are subject to expedited reporting. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 58/87 
Current version: Version 3.1, 13.01.2017 
7.2 
Reporting of SAEs 
Any clinical adverse event or abnormal laboratory test value that is serious occurring during the 
course of the study from the date of signing the informed consent, irrespective of the treatment 
received by the patient, must be reported to the sponsor (via coordinating CRO) within 24 hours 
(expedited reporting). For each patient, all serious adverse events must be reported up to 30 days 
after the last dose of investigational product. Serious adverse events occurring more than 30 days 
after a patient is discontinued from the study treatment may be reported at the discretion of the 
investigator. 
The completed SAE form must be faxed to: 
GSO mbH 
Fax: +49  40 44 19 54 78 
 
The following detailed information must be recorded for each serious adverse event in the SAE 
report form: 
 
A description of the AE in medical terms according to NCI-CTC Version 4.03, not as 
reported by the subject 
 
The severity grade as assessed by the investigator according to the definitions in NCI-
CTC Version 4.03 
 
The date of becoming serious and the date of becoming known (if different) 
 
The reason for seriousness 
 
The outcome of the SAE at the time of the report 
 
Information on administration of the study drug and chemotherapy and any action taken 
 
Information on any treatment procedures necessary for the SAE, concomitant 
medications, relevant lab tests and relevant medical history 
If in any one subject the same SAE occurs on several occasions, then the SAE in question 
must be documented and assessed anew each time. 
The investigator is required to submit SAE Follow-up reports until the SAE has resolved 
or stabilized and all queries have been answered. 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 59/87 
Current version: Version 3.1, 13.01.2017 
7.3 
Reporting of SUSARs/ Expedited Reporting of Unexpected Serious ADRs 
The sponsor will via coordinating CRO ensure the notification of the appropriate ethics 
committees, competent authorities and participating investigators of all SUSARs events occurring 
at the sites in accordance with local legal requirements, statutes and the European Clinical Trial 
Directive as follows: 
 
Reporting of the SUSAR to the Competent Authorities and Ethics Committees within 15 
days (or within 7 days for fatal and life-threatening events) 
 
Sending the event to all participating Investigators for information (with confirmation of 
receipt). 
 
In addition, all events that require a new assessment of the risk-benefit ratio will be 
reported to the Ethics Committee and the Competent Authority of each concerned Member 
State within 15 days. This includes: 
 
Single reports of expected serious adverse reactions with unexpected outcome.  
 
An increase in the rate of occurrence of expected serious adverse reactions which is 
judged to be clinically relevant 
 
Post-study SUSARs that occur after the patient has completed a clinical trial 
 
New events related to the conduct of the trial or the development of the investigational 
medicinal products and likely to affect the safety of the subjects 
 
The sponsor is responsible to ensure that the latest investigator's brochure is used as the source 
document for determining the expectedness of an SAE. 
 
7.4 
Recording of Adverse Events 
The investigator is responsible for ensuring that all adverse events observed by the investigator 
or reported by subjects are properly recorded in the subjects’ medical records and the electronic 
case report form.  
The following adverse event attributes must be assigned by the investigator:  
 
Adverse event term according to the NCI-CTC criteria Version 4.03 
 
Severity grade according to the NCI-CTC criteria Version 4.03 
 
Start date and stop date (or date of last assessment) 
 
Outcome 
 
Causality to study drug and chemotherapy (to be assessed as either related or unrelated) 
 
Any action taken 
Adverse events will be followed until they resolve to baseline or considered stable. It will be left 
to the investigator’s clinical judgment to determine whether an adverse event is related and of 
sufficient severity to require the subject’s removal from treatment or from the study. A subject may 
also voluntarily withdraw from treatment due to what he or she perceives as an intolerable adverse 
event. If either of these situations arises, the subject should be strongly encouraged to undergo 
an end-of-study assessment and be under medical supervision until symptoms cease or the 
condition becomes stable. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 60/87 
Current version: Version 3.1, 13.01.2017 
Pre-existing diseases, when worsening during study therapy, have to be considered as adverse 
events. They can lead to serious adverse events, if the meet the criteria described in section 
7.1.3. 
Intensity of adverse events will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. If an adverse event occurs which 
is not described in the CTCAE version 4.03, the four-point scale below will be used. 
 
Mild 
Discomfort noticed but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect daily activity 
Severe 
Inability to work or perform normal daily activity 
Life-threatening Represents an immediate threat to life 
 
7.5 
Laboratory Test Abnormalities 
Laboratory test results will be recorded on the laboratory results pages of the CRF. In the event 
of unexplained abnormal laboratory test values, the tests should be repeated immediately and 
followed up until they have returned to the normal range and/or an adequate explanation of the 
abnormality is found. Laboratory test value abnormalities as such should not be reported on the 
AE page of the CRF as adverse events unless they are judged clinical significant by the 
investigator. 
7.6 
Pregnancy 
Female patients must be instructed to immediately inform the investigator if they become pregnant 
during the study. The study treatment must immediately be stopped and the patient must be 
withdrawn from the study. Pregnancies occurring up to 6 months after the completion of the last 
treatment cycle must also be reported to the investigator. The investigator must report all 
pregnancies within 24 hours to GSO mbH. GSO mbH will forward all pregnancy reports to the 
sponsor within 24 hours. The investigator should counsel the patient; discuss the risks of 
continuing the pregnancy and the possible effects on the fetus. The patient should be monitored 
until the conclusion of the pregnancy. 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the investigator, the sponsor and the CRO. The partner should be counseled and followed as 
described above. 
7.7 
Adverse Drug Reactions with Concomitant Medication 
The investigators must be aware that for all concomitant medications the regulations of post-
marketing reporting for suspected adverse drug reactions apply, i.e. reporting to the marketing 
authorization holder or the local regulatory bodies. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 61/87 
Current version: Version 3.1, 13.01.2017 
8 
BIOSTATISTICS 
8.1 
Trial Design and Hypotheses 
This is a single-arm trial to evaluate efficacy of Selinexor in patients with relapsed/ refractory AML 
by complete response rate (CR) or CRi), as defined by the revised recommendations of the 
International Working Group for diagnosis, standardization of response criteria in Acute Myeloid 
Leukemia for AML. 
The trial tests the null hypothesis that the observed response rate is less or equal than the 
predefined limit of 30% versus the alternative hypothesis that the response rate is at least 60%.: 
 
 
H0 
: 
p ≤ p0  against the alternative hypothesis   H1 
: 
p ≥ p1. 
8.2 
Sample Size Calculation 
The sample size calculation is based on the evaluation of response rates according to Fleming 
using the  A'Hern (Sample size tables for exact single-stage phase II designs. Statist. Med. 
2001;20:859-866.) extension. 
In Fleming's procedure two response levels p0 and p1 are specified: 
 the largest response proportion p0 which, if true, would clearly imply that the treatment does 
not warrant further investigations (except for other types of administration, e.g. in standardized 
combinations); and 
 the minimum required response level p1 that would imply the treatment warrants further 
investigations. 
The following characteristics were specified  
 p0 = 0.30 
 p1 = 0.60 
  = 0.05   (one-tailed) and 
 β = 0.10 
N=25 patients should participate in the study to ensure a power of 1–=0.90 for the discrimination 
of p0 and p1. According to Fleming the null hypothesis should be rejected if at least 
 
r =

)
1(
0
0
1
0
p
Np
Z
Np



* 1
 
responses are observed (x* denotes the nearest integer to). With p0 and N defined as above and 
Z1– = (1 – )-quantile of the normal distribution = 1.645 at least 12 responders should be 
observed to show the efficacy as postulated. 
 
Using the same approach in the 15 additional patients, submitted to an adapted drug regimen, 
the power will be 80% to discriminate a p0=30% (expected CR rate) from a p1=65% (meaningful 
increase in CR rate), if 8 out of 14 completed patients are considered as responders, with a one-
tailed alpha error of 5%.  
Alternatively, the power will be 90% to discriminate a p0=30% from a p1=70% again if 8 out of 14 
completed patients are considered as responders, with a one-tailed alpha error of 5%. 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 62/87 
Current version: Version 3.1, 13.01.2017 
8.3 
Evaluation Categories for Patients 
A Data Review will be performed prior to the data base lock. In this meeting the patients will be 
assigned to the respective analysis set depending on the observed protocol deviations.. 
 
8.3.1 Intent-to-Treat Population 
Intent-to-Treat Analysis Set (ITT):  The ITT-population includes all subjects who have received 
study medication at least once and for whom efficacy data upon treatment are available. 
 
8.3.2 Per Protocol Population 
Per Protocol Set (PP):  The PP population includes all patients who completed the treatment 
section (up to Visit 9) without any major protocol deviation. 
 
8.3.3 Safety Population 
Safety Analysis Set (SAS):  The SAS- Set will comprise all subjects who received at least one 
administration of study medication at any dosage and for any period of time. 
 
8.4 
Methods of Statistical Analysis 
8.4.1 General Statistical Considerations 
All statistical analyses will be performed and all summary tables and data listings will be prepared 
using the most recently installed version of the Statistical Analysis System® (SAS) software at 
the time of statistical analysis. For continuous variables, summary statistics (mean, standard 
deviation, median, minimum and maximum values) will be tabulated. For discrete variables, the 
frequency distribution will be tabulated. Statistical tests will be of descriptive nature only except 
for the analysis of the responder rate. 
The following chapter describes the planned statistical analyses at the time of writing the study 
protocol. More details about the statistical analyses will be provided in the separate Statistical 
Analysis Plan (SAP), which will be finalized before enrolment of the first subject. Any changes in 
the statistical methods compared to the final SAP will be documented in the integrated Clinical 
Study Report. 
 
 
 
 
 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 63/87 
Current version: Version 3.1, 13.01.2017 
8.4.2 Demographics and Baseline Characteristics 
The following baseline conditions will be analyzed and described: 
 
Age, gender, ethnic background 
 
Details on leukemia diagnosis including WHO subtype, cytogenetics and molecular 
investigations such as FLT3 and NPM-1 mutations 
 
Details on prior therapy, including start and stop dates, disease progression during or after 
therapy, as well as discontinuation due to toxicities 
 
Previous and concurrent relevant diseases 
 
Current symptoms and/ or residual toxicities from prior therapies 
 
Body height and weight, BSA 
 
ECOG performance status  
 
Standard clinical neurological examination  
 
Cardiac evaluation  
 
Calculation (or measurement) of GFR 
 
HIV testing 
 
Assessment of disease status  
 
Concomitant medication 
 
8.4.3 Efficacy Evaluation 
Primary Efficacy Parameter 
The primary efficacy measure will be the rate of complete responders (CR). Disease status will 
be assessed by bone marrow and peripheral blood analysis at the end of each 4-weeks induction 
and consolidation cycle. Disease status during maintenance will be evaluated by peripheral blood 
analysis at the end of each cycle and during follow-up after SCT every 3 months ± 28 days. Bone 
marrow aspirate during maintenance and FU is required in case peripheral blood analysis is 
suspicious for progression of disease/relapse. Response is evaluated according to Döhner et al. 
criteria1. 
 
Secondary Efficacy Parameters 
The secondary efficacy measures will be: 
 
Rate of partial remissions 
 
Percentage of patients being transplanted after induction therapy 
 
Early death rate 
 
Overall survival (OS) 
 
Event-free survival (Events are defined as Death, not achieving a CR or CRi, Relapse 
after CR or CRi) 
 
 
 
 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 64/87 
Current version: Version 3.1, 13.01.2017 
8.4.4 Safety Evaluation 
Safety evaluation will comprise the following variable and their change from baseline: 
 
Blood pressure, pulse, temperature 
 
Physical examination 
 
Urine analysis  
 
Hematology  
 
Clinical chemistry  
 
Time of recovery of platelets and ANC 
 
Coagulation tests 
 
The number of patients developing adverse experiences will be tabulated [NCI CTCAE] Version 
4.03. The CTC v4.03 will be the basis for grading the laboratory changes. Additionally, the subset 
of adverse experiences considered treatment-related will be summarized. Listings of adverse 
experiences leading to treatment discontinuation and those identified as 'severe' or of 'maximal' 
severity will be provided. 
 
8.5 
Interim and Final Analysis 
No formal interim analyses are planned.  
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 65/87 
Current version: Version 3.1, 13.01.2017 
9 
DATA QUALITY ASSURANCE 
 
Accurate and reliable data collection will be assured by verification and cross–check of the CRFs 
against the investigator’s records by the study monitor (source document verification), and the 
maintenance of a drug–dispensing log by the investigator. Data for this study will be recorded via 
CRF. It will be transcribed by the site from the source documents onto the CRF. Data are reviewed 
and checked for omissions, apparent errors, and values requiring further clarifications using 
computerized and manual procedures. Data queries requiring clarification are communicated to 
the site for resolution. Only authorized personnel will make corrections to the clinical database 
and an audit trail will document all corrections. 
 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 66/87 
Current version: Version 3.1, 13.01.2017 
10 DATA MONITORING COMMITTEE 
 
An independent Data Monitoring Committee (DMC) will be implemented that reviews 
accumulating data of the clinical trial with respect to any potential safety issues, study progress 
and critical efficacy endpoints. The DMC will function in accordance with the principles of the 
following 
documents: 
EMA 
guideline 
on 
data 
monitoring 
committees 
(EMEA/CHMP/EWP/5872/03 Corr), ICH Note for guidance E3 (structure and content of clinical 
study reports), ICH Note for guidance E6 (Good Clinical Practice), ICH Note for Guidance E9 
(Statistical Principles for Clinical Trials) and Directive 2001/20/EC relating to the implementation 
of good clinical practice in the conduct of  clinical trials on medical products for human use. 
The DMC will be an independent board consisting of 2-3 physicians with special expertise in AML. 
A physician is not allowed to participate in this clinical trial while serving on the DMC. The DMC 
will be supported by an independent statistician, if necessary. 
The DMC will review safety data, recovery times and efficacy of the clinical trial and support the 
interpretation of clinical trial results.   
A DMC charter will be set up which defines the roles and responsibilities of the DMC. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 67/87 
Current version: Version 3.1, 13.01.2017 
11 ETHICAL ASPECTS 
 
11.1 Declaration of Helsinki / Good Clinical Practice 
The Declaration of Helsinki is the accepted basis for clinical study ethics, and must be fully 
followed and respected by all those engaged in research on human beings. Any exceptions must 
be justified and stated in the protocol. The latest version of the Declaration of Helsinki is available 
at www.wma.net. 
Additionally it is the responsibility of all those engaged in research on human beings to ensure 
that the study is performed in accordance with the international standards of Good Clinical 
Practice and according to all local laws and regulations concerning clinical studies. 
 
11.2 Patient Information and Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from each patient 
participating in this study, after an adequate explanation of the aims, importance, anticipated 
benefits, potential hazards and consequences of the study according to applicable local laws. 
Written informed consent must be obtained before any study-specific procedures are performed. 
It must be also explained to the patient that they are completely free to refuse to enter the study 
or to withdraw from it at any time, for any reason, without incurring any penalty or withholding of 
treatment on the part of the investigator.  
With the declaration of consent, the patient agrees to data about his/ her disease being recorded 
within the context of the clinical trial and that it may be transferred to the sponsor in 
pseudonymized form. 
The subject/ patient also agrees to allow the monitor/ auditor/ health authorities to verify the 
patient data collected against the subject’s/ patient’s original medical records for the purpose of 
source data verification.  
The informed consent form personally signed and dated by the patient must be kept on file by the 
investigator(s) and documented in the CRF and the subject’s medical records. The investigator 
must confirm with the sponsor/coordinating CRO that he/ she has obtained written informed 
consent. 
If new safety information results in significant changes to the risk/ benefit assessment, the consent 
form should be reviewed and updated if necessary. All patients (including those already being 
treated) should be informed of the new information and must give their written informed consent 
to continue in the study. 
If family doctors are to be informed of their patients’ participation in the clinical study, this should 
be mentioned in the consent form. 
 
11.3 Independent Ethics Committees and Regulatory Authorities 
11.3.1 Approval of the Study by the Regulatory Authority and Independent Ethics Committees 
It is the responsibility of the sponsor to obtain and maintain independent approval from the 
applicable regulatory authority and a positive opinion from the competent ethics committees to 
conduct the study in accordance with local legal requirements and statutes.  
Indemnity insurance will be arranged for the trial subjects in accordance with the applicable local 
law.  


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 68/87 
Current version: Version 3.1, 13.01.2017 
11.3.2 Notification of the Study 
The sponsor is responsible for notifying the competent regional authority about the study and all 
principal investigators at the participating investigational sites, if applicable by local law. 
11.3.3 Obligation to Report and Document 
The sponsor and the investigator are responsible for complying with the requirements for reporting 
and documentation in accordance with local legal requirements and statutes. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 69/87 
Current version: Version 3.1, 13.01.2017 
12 CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made via amendment. The sponsor is 
responsible for obtaining independent approval for substantial amendments from the applicable 
regulatory authority and a positive opinion from the competent ethics committees in accordance 
with local legal requirements, statutes and the European Clinical Trial Directive. Approval must 
be obtained before any changes can be implemented, except for changes necessary in order to 
eliminate an immediate hazard to trial subjects or when the changes are non-substantial and 
involve only logistical or administrative aspects of the trial (e.g. change of telephone numbers). 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 70/87 
Current version: Version 3.1, 13.01.2017 
13 STUDY DOCUMENTATION, CRFS AND RECORD-KEEPING 
 
13.1 Investigator’s Files / Retention of Documents 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into two separate categories: investigator’s study file and subject/ patient data. 
The investigator’s study file will contain all essential documents such as the protocol/ 
amendments, case report and query forms, patient information and informed consent form, ethics 
committee and regulatory authority approval, notification of the federal regulatory authority and 
competent regional authorities (if applicable), drug records, staff curriculum vitae and 
authorisation forms, and other appropriate documents/correspondence, etc. 
Patient data includes patient hospital/clinic records (e.g. medical reports, surgery reports 
appointment book, medical records, pathology and laboratory reports, ECG, EEG, X-ray, etc.), 
signed informed consent forms and patient screening and eligibility screening forms.  
The investigator must keep these two categories of documents on file for at least 15 years (or 
longer, as legally required) after completion or discontinuation of the study. The documents must 
be archived in a secure place and treated as confidential material.  
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the investigational site for any 
or all of the documents, special arrangements must be made between the investigator and the 
sponsor to store these in sealed containers outside of the site so that they can be returned sealed 
to the investigator in the event of a regulatory audit. Where source documents are required for 
the continued care of the patient, appropriate copies should be made for storing outside of the 
site. 
All documents must be archived in a secure place and treated as confidential material. 
 
13.2 Source Documents and Background Data 
The investigator shall supply the sponsor on request with any required background data from the 
study documentation or clinic records. This is particularly important when case report forms are 
illegible or when errors in data transcription are suspected. In the event of special problems and/or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that patient confidentiality is protected. According to the 
standards of the data protection law, all data obtained in the course of a clinical study must be 
treated with discretion in order to guarantee the rights of the patient’s privacy. 
13.3 Audits and Inspections 
This study may be audited by the sponsor, any person authorised by the sponsor, or the 
competent health authority in order to determine the authenticity of the recorded data and 
compliance with the study protocol.  


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 71/87 
Current version: Version 3.1, 13.01.2017 
The investigator must be aware that source documents for this trial should be made available to 
appropriately qualified personnel working on behalf of the sponsor/monitor/auditor/health 
authority inspectors after appropriate notification for the purposes of source data verification and 
proper review of the study progress. The verification of the case report form data must be done 
via direct inspection of the source documents. The investigator agrees to comply with the sponsor 
and regulatory authority requirements regarding the auditing of the study. 
All materials used in clinical studies are subjected to quality control. 
 
13.4 Case Report Forms 
For each patient enrolled, acase report form must be completed and signed by the principal 
investigator or an authorised delegate from the study team. This also applies to records for those 
patients who fail to complete the study. If a patient withdraws from the study, the reason must be 
noted in the CRF. If a patient is withdrawn from the study because of a treatment-limiting adverse 
event, thorough efforts should be made to document the outcome clearly. 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 72/87 
Current version: Version 3.1, 13.01.2017 
14 MONITORING THE STUDY 
 
The monitor is responsible for familiarising the investigator(s) and the entire centre staff involved 
in the study with all study procedures, including the administration of the study drug. 
The monitor will visit the clinical study centre before the first patient has been enrolled (initiation 
visit). During the study, the monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the CRFs (source data verification), the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study drug is 
being stored, dispensed, and accounted for according to specifications.  
Key study personnel must be available to assist the monitor during these visits. The investigator 
(or his/her deputy) agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 73/87 
Current version: Version 3.1, 13.01.2017 
15 CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS 
 
The investigator and the sponsor (or designated person) must ensure that all data obtained in the 
course of a clinical study is treated with discretion in order to guarantee the rights of the patient’s 
privacy, according to the standards of the data protection law. CRFs or other documents should 
be submitted to the sponsor in pseudonymised form. The investigator should keep a patient 
identification log showing codes and names. The investigator should maintain documents not 
intended for submission to the sponsor, e.g. patients’ written consent forms, in the strictest 
confidence. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 74/87 
Current version: Version 3.1, 13.01.2017 
16 STUDY REPORT AND PUBLICATION POLICY  
 
This study will be entered into a clinical trial protocol registry and clinical results database. The 
sponsor is responsible for the timely reporting of study data. An integrated clinical study report 
(CSR) has to be completed one year after the end of the study (whether completed or prematurely 
terminated). The report has to be approved by the responsible specialist chosen by the sponsor, 
the project manager of the CRO, the statistician and the coordinating investigator by provision of 
their signatures. In this multi-centre study, the main publication will be a full publication of all data 
from all sites. Any publication of the results, either in part or in whole (abstracts in journals, oral 
presentations, etc.) by investigators or their representatives will require a pre-submission review 
by the sponsor and the coordinating investigator. This requirement only serves the information of 
the sponsor and does not imply any claim to any editing or restriction of the content of publications 
and presentations. The coordinating investigator will be the first author. The senior author of the 
study will be the last author. The remaining positions will be based on recruitment, good data 
quality and scientific input to the study. The final author list will be a joint agreement between the 
coordinating investigator and the sponsor. For all other publications, the order of the authors will 
be determined according to recruitment, data quality and significant scientific input to the study, 
after consulting the coordinating investigator. 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 75/87 
Current version: Version 3.1, 13.01.2017 
17 APPENDICES 
 
Appendix 1 
 Overview of current relapsed/refractory AML treatment studies 
Appendix 2 
Adverse Event Categories for Determining Relationship to Test Drug 
Appendix 3 
Definitions According to ICH Topic E2A Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, (CPMP/ICH/377/95) 
Appendix 4 
ECOG Performance Status 
Appendix 5 
Cockroft-Gault Formula  
Appendix 6 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03   
Appendix 7 
RESPONSE CRITERIA IN AML 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 76/87 
Current version: Version 3.1, 13.01.2017 
 
17.1 Appendix 1 – Overview of current relapsed/refractory AML treatment studies 
Table 4:  Overview of current relapsed/refractory AML treatment studies 
Source 
Indication 
No 
of 
patients 
enrolled 
(evaluab
le) 
Drug 
Dose 
ORR 
(CR / 
PR) 
SD 
PFS 
(months
) 
OS 
(months
) 
Breems et al(17) 
Relapsed/ 
refractory 
AML 
667 
Cytarabine + 
daunorubicin 
or idarubicin 
200 mg/m² 7 
days + 
46% 
 
 
 
Paciucci et al. (20) 
Relapsed/ 
refractory 
AML 
49 
Cytorabine + 
mitoxanthine 
100 mg/m² 7 
days + 
10 mg/m² 3 
days 
50-
60% 
 
8 
 
Haroussea 
et 
al.(19) 
Relapsed/ 
refractory 
AML 
35 
Cytorabine + 
Idarubicine 
1 mg/m² + 
8 mg/m² 2 
days every 
12h 6 doses 
50-
60% 
 
16 
 
Spadea et al. (21) 
Relapsed/ 
refractory 
AML 
44 
Cytorabine + 
Mitoxanthrone 
+ Etopsid 
(MEC) 
1 g/m² + 
6 mg/m² + 
80 mg/m² 
days 1 to 6 
55% 
 
 
 
Greenberg et al. 
(27) 
Relapsed/ 
refractory 
AML 
63 
MEC 
 
17% 
 
10 
 
66 
MEC 
+ 
valspodar 
(PSC388) 
 
25% 
 
9 
 
Faderl et al. (22) 
Relapsed/ 
refractory 
AML 
32 
Cytarabine + 
Clofarabine 
1 g/m²  + 
40 mg/m² 
5 days 
48% 
 
 
 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 77/87 
Current version: Version 3.1, 13.01.2017 
17.2 Appendix 2 - Adverse Event Categories for Determining Relationship to Test Drug 
 
Related (must have one of them) 
 
This category applies to those adverse events that are considered to be related to the test 
drug. An adverse event may be considered related if: 
 
It follows a reasonable temporal sequence from administration of the drug 
 
It cannot be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors or other modes of therapy administered to the subject 
 
It disappears or decreases on cessation or reduction in dose. (There are important excep-
tions when an adverse event does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists: e.g. (1) bone marrow depression, (2) tardive dyskinesias.) 
 
It follows a known pattern of response to the suspected drug 
 
It reappears upon rechallenge 
 
Unrelated 
This category is applicable to those adverse events which are judged to be clearly and incon-
trovertibly due only to extraneous causes (disease, environment, etc.) and do not meet the criteria 
for drug relationship listed under related. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 78/87 
Current version: Version 3.1, 13.01.2017 
17.3 Appendix 3 – Definitions According to ICH Topic E2A Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, (CPMP/ICH/377/95) 
An adverse event is any untoward medical occurrence in a patient or clinical investigation subject 
who has been administered a pharmaceutical product, and which does not necessarily have to 
have a causal relationship with this treatment. 
Adverse reactions are defined as all untoward and unintended responses to an investigational 
medicinal product related to any dose administered. The phrase "responses to a medicinal 
products" means that a causal relationship between a medicinal product and an adverse event is 
at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
A serious adverse event or serious adverse reaction is any experience that suggests a significant 
hazard, contraindication, side effect or precaution. It is any adverse event that at any dose fulfils 
at least one of the following criteria: 
 
is fatal (results in death) (NOTE: Death is an outcome, not an event) 
 
is life-threatening (NOTE: The term “life-threatening” refers to an event in which the patient 
was at immediate risk of death at the time of the event; it does not refer to an event which 
could hypothetically have caused a death had it been more severe) 
 
required in-patient hospitalisation or prolongation of existing hospitalisation 
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect 
 
is medically significant or requires intervention to prevent one or other of the outcomes 
listed above 
Medical and scientific judgement should be exercised in deciding whether expedited reporting to 
the sponsor is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or 
may require intervention to prevent one of the outcomes listed in the definitions above. These 
situations should also usually be considered serious. 
Examples of such events are intensive treatment in A&E or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse. 
An unexpected adverse event, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator's Brochure for an unapproved investigational medicinal 
product) 
Causality is initially assessed by the investigator. With respect to the obligation to report and 
document (regulatory authorities, ethics committees and other investigators) serious adverse 
events, causality can be one of two possibilities: 
 
No (unrelated; equals not drug-related) 
 
Yes (remotely, possibly or probably drug-related) 
All adverse events not assessed as definitively “not drug-related” by the investigator will be 
considered as adverse drug reactions. 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction whose 
nature or severity is not consistent with the applicable product information. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 79/87 
Current version: Version 3.1, 13.01.2017 
It is important that the severity of an adverse event is not confused with the seriousness of the 
event. For example, vomiting which persists for many hours may be severe, but is not necessarily 
a serious adverse event. On the other hand, stroke which results in only a limited degree of 
disability may be considered a mild stroke, but would be a serious adverse event. 
A serious adverse event occurring during the study or which comes to the attention of the 
investigator within three weeks of stopping the treatment or during the protocol-defined follow-up 
period, if this is longer, must be reported, whether considered treatment-related or not. In addition, 
serious adverse events occurring after this time should be reported if considered related to test 
“drug”. 
Such preliminary reports will be followed by detailed descriptions later that will include copies of 
hospital case reports, autopsy reports and other documents. 
For serious adverse events, the following must be assessed and recorded on the adverse events 
page of the case report form: intensity, relationship to test substance, action taken, and outcome 
to date. 
The obligation to document and report must be adhered to according to the national and inter-
national laws and regulations.  
For contact details and fax no. for SAE and pregnancy reporting, please refer to Section 7.2.  


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 80/87 
Current version: Version 3.1, 13.01.2017 
17.4 Appendix 4 – ECOG Performance Status 
GRADE 
SCALE 
0 
Fully active, able to carry out all pre-disease performance without restriction  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all self-care, but unable to carry out work activities. Up 
and about more than 50% of waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or 
chair. 
5 
Dead  
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 81/87 
Current version: Version 3.1, 13.01.2017 
17.5 Appendix 5 – Cockroft-Gault Formula 
 
Calculated CLCR (ml/min) =  
[(140 – subject’s age in years) x subject’s actual body weight in kilograms] * 
72 x subject’s serum creatinine (in mg/dL) 
 
*: x 0.85 for females 
 
Calculated CLCR (ml/min) =  
[(140 – subject’s age in years) x subject’s actual body weight in kilograms] x K* 
subject’s serum creatinine (in µmol/L) 
 
K*: 1.23 for males, 1.05 for females 
 
 
 
 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 82/87 
Current version: Version 3.1, 13.01.2017 
17.6 Appendix 6 – NCI-CTCAE version 4.03 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 83/87 
Current version: Version 3.1, 13.01.2017 
 
17.7 Appendix 7- Response criteria in AML  
Definitions of response criteria are based primarily on those given by Döhner et al.(1) 
 
Response 
criteria 
Absolute 
Neutrophil 
count 
Absolute 
Platelets 
count 
Bone 
marrow 
Blasts (%) 
Comments 
Complete 
remission (CR)* 
>1.0 x 109/L 
(1000/µL) 
>100 x 109/L 
(100.000/µL) <5 
Absence of blasts with Auer 
rods; 
Absence 
of 
EMD; 
independence of red cell 
transfusion 
CR 
with 
incomplete 
recovery (CRi)† 
<1.0 x 109/L 
(1000/µL) 
<100 x 109/L 
(100.000/µL) <5 
All CR criteria except for 
residual 
neutropenia 
or 
thrombocytopenia. 
Morphologic 
leukemia-free 
state‡ 
NA 
NA 
<5 
Absence of blasts with Auer 
rods; Absence of EMD; no 
hematologic 
recovery 
required 
Partial remission 
(PR) 
>1.0 x 109/L 
(1000/µL) 
>100 x 109/L 
(100.000/µL) 5 to 25 
Relevant in the setting of 
phase 1 and 2 clinical trials 
only; 
decrease 
of 
pretreatment bone marrow 
blast percentage by at least 
50% 
Cytogenetic CR 
(CRc)§ 
>1.0 x 109/L 
(1000/µL)  
or 
<1.0 x 109/L 
(1000/µL) 
>100 x 109/L 
(100.000/µL) 
or 
<100 x 109/L 
(100.000/µL) 
<5 
Reversion 
to 
a 
normal 
karyotype at the time of 
morphologic CR (or CRi) in 
cases 
with 
an 
abnormal 
karyotype at the time of 
diagnosis; based on the 
evaluation of 20 metaphase 
cells from bone marrow 
Molecular 
CR 
(CRm)i 
No standard definition; depends on molecular target 
 
 
 
 
 
Treatment 
failure 
 
 
 
 
Resistant 
disease (RD) 
Failure to achieve CR or CRi (general practice; phase 2/3 trials); 
or failure to achieve CR, CRi, or PR (phase 1 trials);  
only includes patients surviving ≥ 7 days following completion of initial 
treatment, with evidence of persistent leukemia by blood and/or bone 
marrow examination 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 84/87 
Current version: Version 3.1, 13.01.2017 
Death in aplasia 
Deaths occurring ≥ 7 days following completion of initial treatment while 
cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7 
days of death, without evidence of persistent leukemia 
Death from 
indeterminate 
cause 
Deaths occurring before completion of therapy; or < 7 days following its 
completion; or deaths occurring ≥ 7 days following completion of initial 
therapy with no blasts in the blood, but no bone marrow examination 
available 
Relapse¶ 
Bone marrow blasts ≥ 5%;  
or reappearance of blasts in the blood;  
or development of extramedullary disease 
EMD  extamedullary disease 
* All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 
nucleated cells in an aspirate with spicules; if ambiguous, consider repeat exam after 5 to 
7 days; flow cytometric evaluation may help to distinguish between persistent leukemia and 
regenerating normal marrow; a marrow biopsy should be performed in cases of dry tap, or 
if no spicules are obtained; no minimum duration of response required. 
† The criterion of CRi is of value in protocols using intensified induction or double induction 
strategies, in which hematologic recovery is not awaited, but intensive therapy will be 
continued. In such protocols, CR may even not be achieved in the course of the entire 
treatment plan. In these instances, the overall remission rate should include CR and CRi 
patients. Some patients may not achieve complete hematologic recovery upon longer 
observation times. 
‡  This category may be useful in the clinical development of novel agents within phase 1 
clinical trials, in which a transient morphologic leukemia-free state may be achieved at the 
time of early response assessment. 
§  Four studies showed that failure to convert to a normal karyotype at the time of CR predicts 
inferior outcome. 
i   As an example, in CBF AML low-level PCR-positivity can be detected in patients even in 
long-term remission. Normalizing to 104 copies of ABL1 in accordance with standardized 
criteria, transcript levels below 12 to 10 copies appear to be predictive for long-term 
remission. 
¶  In cases with low blast percentages (5-10%), a repeat marrow should be performed to 
confirm relapse. Appearance of new dysplastic changes should be closely monitored for 
emerging relapse. In a patient who has been recently treated, dysplasia or a transient 
increase in blasts may reflect a chemotherapy effect and recovery of hematopoiesis. 
Cytogenetics should be tested to distinguish true relapse from therapy-related MDS/AµL. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 85/87 
Current version: Version 3.1, 13.01.2017 
18 REFERENCES 
 
 
1. 
Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner, Burnett MS, Dombret H, 
Fenaux P, Grimwade D, Larson RA, Lo-Coco F, T, Tomoki Naoe AK, Niederwieser D, 
Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B and Bloomfield CD. 
Diagnosis and management of acute myeloid leukemia in adults: recommendations from 
an international expert panel, on behalf of the European LeukemiaNet. Blood, 2010  Jan 
21;115 (3): 453-474  
2. 
Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. The New England journal 
of medicine. 1999 Sep 30;341(14):1051-62. 
3. 
Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, et al. A phase 
3 study of three induction regimens and of priming with GM-CSF in older adults with acute 
myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004 Jan 
15;103(2):479-85. 
4. 
Anderson JE, Kopecky KJ, Willman CL, Head D, O'Donnell MR, Luthardt FW, et al. 
Outcome after induction chemotherapy for older patients with acute myeloid leukemia is 
not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: 
a Southwest Oncology Group study. Blood. 2002 Dec 1;100(12):3869-76. 
5. 
Gardin C, Turlure P, Fagot T, Thomas X, Terre C, Contentin N, et al. Postremission 
treatment of elderly patients with acute myeloid leukemia in first complete remission after 
intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia 
French Association (ALFA) 9803 trial. Blood. 2007 Jun 15;109(12):5129-35. 
6. 
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. 
European LeukemiaNet recommendations for the management of chronic myeloid 
leukemia: 2013. Blood. 2013 Aug 8;122(6):872-84. 
7. 
Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis 
and management of acute myeloid leukemia in adults: recommendations from an 
international expert panel, on behalf of the European LeukemiaNet. Blood. 2010 Jan 
21;115(3):453-74. 
8. 
Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, et al. Intensive 
postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia 
Group B. The New England journal of medicine. 1994 Oct 6;331(14):896-903. 
9. 
Byrd JC, Ruppert AS, Mrozek K, Carroll AJ, Edwards CG, Arthur DC, et al. Repetitive 
cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and 
inv(16)(p13q22) or t(16;16)(p13;q22): results from CALGB 8461. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2004 Mar 
15;22(6):1087-94. 
10. 
Lowenberg B, Griffin JD, Tallman MS. Acute myeloid leukemia and acute promyelocytic 
leukemia. Hematology / the Education Program of the American Society of Hematology 
American Society of Hematology Education Program. 2003:82-101. 
11. 
Estey E, Dohner H. Acute myeloid leukaemia. Lancet. 2006 Nov 25;368(9550):1894-907. 
12. 
Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, et al. Allogeneic 
stem cell transplantation for acute myeloid leukemia in first complete remission: 
systematic review and meta-analysis of prospective clinical trials. JAMA : the journal of 
the American Medical Association. 2009 Jun 10;301(22):2349-61. 
13. 
Ofran Y, Rowe JM. Treatment for relapsed acute myeloid leukemia: what is new? Current 
opinion in hematology. 2012 Mar;19(2):89-94. 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 86/87 
Current version: Version 3.1, 13.01.2017 
14. 
Burnett AK, Wheatley K, Goldstone AH, Stevens RF, Hann IM, Rees JH, et al. The value 
of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing 
risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol. 2002 Aug;118(2):385-
400. 
15. 
Appelbaum FR. Allogeneic hematopoietic stem cell transplantation for acute leukemia. 
Seminars in oncology. 1997 Feb;24(1):114-23. 
16. 
Ferrara F, Palmieri S, Mele G. Prognostic factors and therapeutic options for relapsed or 
refractory acute myeloid leukemia. Haematologica. 2004 Aug;89(8):998-1008. 
17. 
Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF, 
et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
2005 Mar 20;23(9):1969-78. 
18. 
Giles FJ, Borthakur G, Ravandi F, Faderl S, Verstovsek S, Thomas D, et al. The 
haematopoietic cell transplantation comorbidity index score is predictive of early death 
and survival in patients over 60 years of age receiving induction therapy for acute myeloid 
leukaemia. Br J Haematol. 2007 Feb;136(4):624-7. 
19. 
Harousseau JL, Reiffers J, Hurteloup P, Milpied N, Guy H, Rigal-Huguet F, et al. 
Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose 
cytarabine. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 1989 Jan;7(1):45-9. 
20. 
Paciucci PA, Dutcher JP, Cuttner J, Strauman JJ, Wiernik PH, Holland JF. Mitoxantrone 
and ara-C in previously treated patients with acute myelogenous leukemia. Leukemia. 
1987 Jul;1(7):565-7. 
21. 
Spadea A, Petti MC, Fazi P, Vegna ML, Arcese W, Avvisati G, et al. Mitoxantrone, 
etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute 
myeloid leukemia. Leukemia. 1993 Apr;7(4):549-52. 
22. 
Faderl S, Gandhi V, O'Brien S, Bonate P, Cortes J, Estey E, et al. Results of a phase 1-2 
study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory 
acute leukemias. Blood. 2005 Feb 1;105(3):940-7. 
23. 
Ranganathan P, Yu X, Na C, Santhanam R, Shacham S, Kauffman M, et al. Preclinical 
activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood. 2012 August 30, 
2012;120(9):1765-73. 
24. 
Etchin J, Sun Q, Kentsis A, Farmer A, Zhang ZC, Sanda T, et al. Antileukemic activity of 
nuclear export inhibitors that spare normal hematopoietic cells. Leukemia. 2013 
01//print;27(1):66-74. 
25. 
Eppert, K., Takenaka, K., Lechman, E.R., Waldron, L., Nilsson, B., van Galen, P., 
Metzeler, K.H., Poeppl, A., Ling, V., Beyene, J., Canty, A.J., Danska, J.S., Bohlander, 
S.K., Buske, C., Minden, M.D., Golub, T.R., Jurisica, I., Ebert, B.L. & Dick, J.E. (2011) 
Stem cell gene expression programs influence clinical outcome in human leukemia. Nat 
Med, 17, 1086-1093. 
26. 
Metzeler, K.H., Maharry, K., Kohlschmidt, J., Volinia, S., Mrozek, K., Becker, H., Nicolet, 
D., Whitman, S.P., Mendler, J.H., Schwind, S., Eisfeld, A.K., Wu, Y.Z., Powell, B.L., 
Carter, T.H., Wetzler, M., Kolitz, J.E., Baer, M.R., Carroll, A.J., Stone, R.M., Caligiuri, M.A., 
Marcucci, G. & Bloomfield, C.D. (2013) A stem cell-like gene expression signature 
associates with inferior outcomes and a distinct microRNA expression profile in adults with 
primary cytogenetically normal acute myeloid leukemia. Leukemia, 27, 2023-2031.  
 
27. 
Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, et al. Mitoxantrone, 
etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory 
acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). 


SAIL 
 
 
 
 
 
 
 
 
 
 
Page 87/87 
Current version: Version 3.1, 13.01.2017 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
2004 Mar 15;22(6):1078-86. 
 
28.  Kojima, K, Kornblau, SM, Ruvolo, V, et al. Prognostic impact and targeting of CRM1 in acute 
myeloid leukemia. Blood. 2013; 121(20): 4166–4174. doi:10.1182/blood-2012-08-447581. 
 
29.  Etchin J, Sanda T, Mansour MR, Kentsis A, Montero J, Le BT, Christie AL,McCauley D, Rodig 
SJ, Kauffman M, Shacham S, Stone R, Letai A, Kung AL, ThomasLook A. KPT-330 
inhibitor of CRM1 (XPO1)-mediated nuclear export has selectiveanti-leukaemic activity in 
preclinical models of T-cell acute lymphoblasticleukaemia and acute myeloid leukaemia. 
Br J Haematol. 2013a Apr;161(1):117-27. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
An Investigator-Initiated Study To Evaluate Ara-C and Idarubicin in 
Combination with the Selective Inhibitor Of Nuclear Export (SINE) 
Selinexor (KPT-330) in Patients with Relapsed Or Refractory AML 
 
 
Study code: SAIL 
 
Phase II study 
 
 
 
STATISTICAL ANALYSIS PLAN 


 
Statistical Analysis Plan 
            Page 2 (15) 
 
Sponsor: GSO 
Final 25.8.2017 
Study: SAIL 
 
 
 
 
 
Signatures: 
 
 
Statistical Analysis Plan was prepared by: 
 
 
 
Jouni Junnila 
Date 
Study Statistician 
 
4Pharma Ltd 
 
 
Statistical Analysis Plan was reviewed/approved by: 
 
 
 
Teppo Huttunen 
Date 
Senior Statistician 
 
4Pharma Ltd 
 
 
 
Anne Kranich 
Date 
Responsible person from the Sponsor 
 
GSO 
 
 
 
Walter Fiedler 
Date 
Principal Investigator 
 
 


 
Statistical Analysis Plan 
            Page 3 (15) 
 
Sponsor: GSO 
Final 25.8.2017 
Study: SAIL 
 
 
 
 
 
Table of Contents 
 
1 
Abbreviations ................................................................................................................................. 4 
2 
Study objective(s) .......................................................................................................................... 4 
3 
Design and type of the study .......................................................................................................... 5 
4 
Study variables ............................................................................................................................... 5 
5 
Sample size considerations ............................................................................................................ 5 
6 
Statistical hypotheses ..................................................................................................................... 6 
7 
Analysis sets .................................................................................................................................. 6 
7.1 
Intention-to-treat (ITT) set ...................................................................................................... 6 
7.2 
Per protocol (PP) set ............................................................................................................... 6 
7.3 
Safety set ................................................................................................................................. 6 
8 
General statistical considerations .................................................................................................. 6 
9 
Demographic and other baseline characteristics ............................................................................ 7 
10 
Concomitant medication/treatment ............................................................................................ 7 
11 
Extent of exposure and compliance ........................................................................................... 7 
12 
Analysis of efficacy .................................................................................................................... 7 
12.1 
Primary efficacy variables ................................................................................................ 7 
12.2 
Secondary efficacy variables ............................................................................................ 8 
12.3 
Additional analyses .......................................................................................................... 8 
13 
Analysis of safety ....................................................................................................................... 8 
13.1 
Adverse events ................................................................................................................. 8 
13.2 
Laboratory safety variables ............................................................................................... 9 
13.3 
Other safety variables ....................................................................................................... 9 
14 
Completion and premature discontinuation ............................................................................... 9 
15 
Deviations from the analyses planned in the study protocol ...................................................... 9 
16 
Execution of statistical analyses ................................................................................................. 9 
17 
Hardware and software ............................................................................................................... 9 
18 
References .................................................................................................................................. 9 
19 
Appendices ................................................................................................................................. 9 
19.1 
Schedule of assessments ................................................................................................. 10 
19.2 
Table and figure plan ...................................................................................................... 13 
 


 
Statistical Analysis Plan 
            Page 4 (15) 
 
Sponsor: GSO 
Final 25.8.2017 
Study: SAIL 
 
1 
Abbreviations 
AE 
 
Adverse event 
AML  
Acute myeloid leukemia 
ATC  
Anatomical Therapeutic Chemical 
CI 
 
Confidence Interval 
CR 
 
Complete Response 
CRi 
 
Complete Response with incomplete blood recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG  
Eastern Cooperative Oncology Group 
EFS 
 
Event-free-survival 
GFR 
 
Glomerular filtration rate 
ITT 
 
Intent-to-treat 
KM 
 
Kaplan-Meier 
OS 
 
Overall Survival 
RFS 
 
Recurrence-free-survival 
SAE 
 
Serious adverse event 
SCT 
 
Stem Cell Transplant 
PP 
 
Per-protocol 
2 
Study objective(s) 
The primary objective is to determine the efficacy of Selinexor in patients with relapsed/ refractory 
AML by complete response rate (CR or CRi), as defined by the revised recommendations of the 
International Working Group for diagnosis, standardization of response criteria in Acute Myeloid 
Leukemia for AML (Cheson et al 2003). 
Secondary objectives of the study are 1) To determine the efficacy of Selinexor in combination with 
standard chemotherapy in patients with relapsed/ refractory AML by: 
• Rate of partial remissions 
• Percentage of patients being transplanted after induction therapy 
• Early death rate 
• Overall survival (OS) 
• Event-free survival (Events are defined as Death, not achieving a CR or CRi, 
 
Relapse after CR or CRi) and  
2) To evaluate overall safety and tolerability of Selinexor. 


 
Statistical Analysis Plan 
            Page 5 (15) 
 
Sponsor: GSO 
Final 25.8.2017 
Study: SAIL 
 
3 
Design and type of the study 
This is a phase II non-randomized, single-arm, open-label, multicentre study in patients with 
relapsed or refractory AML. 
4 
Study variables 
The following variables will be evaluated. 
The demographic and baseline variables: 
Gender, age, race, details on leukemia diagnosis, prior therapy, medical history, current symptoms 
and residual toxicities form prior therapies, ECOG performance status, clinical neurological 
examination, cardiac evaluation, disease status, concomitant medication, prior transplantation, 
primary or secondary AML, early/late relapse from first therapy, mutation, karyotype risk category. 
The primary efficacy variable: 
The rate of complete responders according to the Cheson criteria. 
The secondary efficacy variables: 
Rate of partial remissions, percentage of patients being transplanted after induction therapy, early 
death rate, Overall survival (OS), Event-free survival (EFS), Recurrence-free-survival (RFS) 
The safety variable: 
Adverse events (AE), blood pressure, pulse, temperature, physical examination, urine analysis, 
hematology, clinical chemistry, coagulation tests. 
5 
Sample size considerations 
The sample size calculation is based on the evaluation of response rates according to Fleming using 
the A'Hern extension (Sample size tables for exact single-stage phase II designs. Statist. 
Med.2001;20:859-866). In Fleming’s procedure to response levels p0 and p1 are specified, where p0 
is the largest proportion of responders, which would clearly imply that the treatment does not 
warrant further investigations and p1 the minimum required proportion of responders that would 
imply that the treatment warrant further investigations. The following characteristics were specified 
in the sample size calculation: 
• p0 = 0.30 
• p1 = 0.60 
• α = 0.05 (one-tailed) and 
• β = 0.10 
 
The sample size calculation ended up in 25 patients to be recruited to ensure a power of 90 % for 
the discrimination of p0 and p1. In addition, 15 additional patients were submitted to an adapted 
drug regimen (flat dose 60mg of Selinexor instead of 40 mg /m2 of Selinexor). Using a similar 
approach, the power will be 80 % to discriminate a p0=30 % from a p1=65 %, with a one-tailed α of 
0.05 %. 


 
Statistical Analysis Plan 
            Page 6 (15) 
 
Sponsor: GSO 
Final 25.8.2017 
Study: SAIL 
 
6 
Statistical hypotheses 
The purpose of this study is to evaluate efficacy of Selinexor in patients with relapsed/ refractory 
AML by complete response rate (CR or CRi). The null-hypothesis to be tested is 
H0 : The observed response rate is less or equal than 30 % 
against the alternative hypothesis 
H1 : The observed response rate is over 30 % 
7 
Analysis sets 
A detailed subject classification document will be prepared in a Data Review meeting prior database 
lock. The document will assign patients to the respective analysis sets depending on the observed 
protocol violations. 
7.1 
Intention-to-treat (ITT) set 
The ITT set includes all subjects who have received study medication at least once and for whom 
efficacy data upon treatment are available. 
7.2 
Per protocol (PP) set 
The PP set will consist of all randomized subjects who completed the treatment section (up to Visit 
9) with no relevant protocol violations, detailed in the subject classification document. 
7.3 
Safety set 
The Safety set will comprise all subjects who received at least one administration of the study 
medication at any dosage and who have a subsequent safety measurement available. 
8 
General statistical considerations 
The aim of the study is to evaluate the effect of Selinexor in patients with relapsed / refractory AML 
by complete response rate (CR or CRi). 
All background, primary and secondary efficacy variables, and safety variables will be summarized 
by visit and treatment group. In addition to absolute values, changes from baseline values will be 
summarized, if feasible. 
Summary statistics will include at least the number of patients, mean, standard deviation, median, 
minimum and maximum for continuous variables, and frequencies and percentages for categorical 
variables. The results of statistical tests (including 95% CIs) will be included in the tables, when 
appropriate. 
If the assumptions of the parametric statistical test are not met, the use of common transformations 
(e.g. logarithmic, square root) will be considered. Appropriate non-parametric methods will be used 
if normality assumptions are not met even after transformations.  


 
Statistical Analysis Plan 
            Page 7 (15) 
 
Sponsor: GSO 
Final 25.8.2017 
Study: SAIL 
 
In the statistical analyses a p-value less than 0.05 will be considered as statistically significant. If not 
stated otherwise, all tests will be performed as two-sided and two-sided 95% CIs will be produced 
for the treatment differences. No adjustments for the p-values will be made. Missing values will not 
be imputed in the analyses. 
Subgroup analyses by dosing schedule (Selinexor / mm2 vs. flat dose of Selinexor) will be 
conducted for all study data.  
The table and figure plan is presented in Appendix 18.2. 
9 
Demographic and other baseline characteristics 
All background and other baseline characteristics will be tabulated with descriptive statistics. 
Medical history and other medication will be summarized with frequency distributions. Tabulations 
will be conducted overall and by dosing schedule. No statistical tests will be carried out for any 
baseline measures between the dosing schedules. 
10 Concomitant medication/treatment 
Concomitant medication and treatments will be summarized overall and by dosing group using 
ATC classification. 
11 Extent of exposure and compliance 
The extent of exposure and treatment compliance will be summarized descriptively overall and by 
dosing schedule. 
12 Analysis of efficacy 
 
Descriptive statistics of all of the efficacy data will be presented overall and by dosing schedule and 
visit for the ITT and PP analysis sets. 
12.1 
Primary efficacy variables 
The primary efficacy variable is the response rate based on the Cheson criteria. The response rate 
will be presented in percentages together with 95 % confidence interval (CI) calculated using the 
Wilson score method. 
The analysis will be conducted both for the overall population and separately by the dosing 
schedule. 
The response rate will also be presented in several subgroups, if feasible. Following subgroups will 
be investigated for the primary endpoint: primary vs. secondary AML, remission >12 Months vs. 
remission <12 months, relapse after SCT vs. no prior SCT, karyotypic risk group, FLT3 vs. NPM1 
mutation. 


 
Statistical Analysis Plan 
            Page 8 (15) 
 
Sponsor: GSO 
Final 25.8.2017 
Study: SAIL 
 
12.2 
Secondary efficacy variables 
The secondary efficacy variables; rate of partial remissions, percentage of patients being 
transplanted after induction therapy and early death rate will be analysed using similar methods as 
with the primary analysis. 
Overall survival, recurrence-free-survival and event-free survival will be analysed applying the 
Kaplan-Meier-method (KM). OS is calculated from the date of informed consent to the date of 
death, the patients still alive will be censored at the last date of follow-up. RFS is calculated from 
the date of informed consent to the date of recurrence or death, whichever occurs first, censoring 
patients who were alive without recurrence on the date of last follow-up visit. EFS is calculated 
from the date of CR/CRi until death or relapse, whichever occurs first. Patients are censored on the 
date of last follow-up visit if they are alive without relapse.  
The survival curves will be displayed graphically for the overall population and by dosage schedule. 
In addition median survival and follow-up times (including interquartile range and 95 % CI if 
feasible) will be calculated.  
12.3 
Additional analyses 
The survival analyses (OS, RFS, EFS) will be repeated using a different censoring approach than 
presented in 12.2. The calculation will be otherwise similar as previously presented, except for 
patients receiving a stem cell transplant (SCT). For these patients, the patient is censored at the time 
of the SCT.   
13 Analysis of safety 
All subjects who have participated in the study will be included in the safety analysis. 
13.1 
Adverse events 
All adverse events occurring during the course of the trial and for up to 30 days after the last dose of 
study medication will be captured, documented and reported. The number of patients developing 
adverse experiences will be tabulated using [NCI CTCAE] Version 4.03. The CTC v4.03 will be the 
basis for grading the laboratory changes. Additionally, the subset of adverse experiences considered 
treatment-related will be summarized. Listings of adverse experiences leading to treatment 
discontinuation will be provided. 
 
Clinical adverse events and laboratory adverse events will be reported in separate tables. The 
adverse events will be reported as a whole and additionally based on the severity grading (separate 
table for grade 3-5 AEs). 
Adverse events classified as serious adverse events (SAEs) will be listed separately. Deaths together 
with the reason for death and the possible relation to study treatment will be summarized. 


 
Statistical Analysis Plan 
            Page 9 (15) 
 
Sponsor: GSO 
Final 25.8.2017 
Study: SAIL 
 
13.2 
Laboratory safety variables 
Descriptive statistics of laboratory safety variables (hematology, clinical chemistry, urine analysis, 
coagulation tests) will be computed, together with the changes from baseline values. The changes 
from baseline will be analyzed by ANOVA method if feasible.  
13.3 
Other safety variables 
Vital signs (blood pressure, heart rate, temperature) will be summarized with descriptive statistics 
by visit and dosing group. In addition, the changes from baseline values will be given. The changes 
from baseline will be analyzed by ANOVA method if feasible. Physical examination, ECG and 
ECOG results will be summarized with frequency tables.  
14 Completion and premature discontinuation 
Completion and premature discontinuation will be listed. The reasons for premature discontinuation 
will be presented. 
15 Deviations from the analyses planned in the study protocol 
The primary hypothesis of the study was clarified in the Statistical Analysis Plan compared to the 
definition in the protocol.  
16 Execution of statistical analyses 
Statistical analyses will be performed by 4Pharma Ltd. 
17 Hardware and software 
Statistical analysis, tables and patient data listings will be performed with SAS® version 9.3 for 
Windows (SAS Institute Inc., Cary, NC, USA). 
18 
References 
Clinical Study Protocol, Final Protocol, Version 2 (25.08.2015)  
19 
Appendices


 
 
Statistical Analysis Plan 
            Page 10 (15) 
 
Sponsor: GSO 
Draft 23.8.2017 
Study: SAIL 
 
19.1 
Schedule of assessments 
Assessments by visit 
Screening 
Baseline 
Induction cycle(s) 
Consolidation 
Maintenance End of 
treatment 
Follow-
up 
Time window 
Within 14 
days prior 
registration 
Before 
Day 1 of 
induction 
During 
treatment, 
twice 
weekly 
End of 
cycles 
Weekly (D2,8, 
15,21 ± 2 days) 
Twice per cycle 
(D1,15 ± 2 
days) 
30 days after 
last 
dose/prior to 
SCT 
Every 3 
months ± 28 
days 
Informed consent1 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
 
Pregnancy test3 
X 
 
 
 
 
 
 
 
Physical examination and ECOG4 
X 
 
X 
X 
X 
X 
X 
 
Body height and weight5 
X 
 
 
X 
X 
X 
X 
 
BSA 
X 
 
 
 
 
 
 
 
Vital signs6 
X 
 
X 
X 
X 
X 
X 
 
Standard clinical neurological examination 
X 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
X 
X 
X 
 
 
Cardiac ultrasound7 
X 
 
 
X 
 
 
X 
 
Hematology8 
X 
 
X 
X 
X 
X 
X 
X 
Calculation of GFR9 
X 
 
 
X 
X 
 
X 
 


 
 
Statistical Analysis Plan 
            Page 11 (15) 
 
Sponsor: GSO 
Draft 23.8.2017 
Study: SAIL 
 
Clinical chemistry10 
X 
 
 
X 
X 
X 
X 
 
Assessments by visit 
Screening 
Baseline 
Induction cycle(s) 
Consolidation 
Maintenance End of 
treatment 
Follow-
up 
Urine analysis11 
X 
 
 
X 
X 
X 
 
 
Coagulation test12 
X 
 
X 
X 
X 
X 
 
 
HIV testing13 
X 
 
 
 
 
 
 
 
Assessment of signs and symptoms, AE 
X 
 
X 
X 
X 
 
X 
 
CTCAE v 4.03 scale toxicity 
 
 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
 
X 
X 
X 
X 
X 
 
Bone Marrow Aspirate14 
X 
 
 
X 
X 
X 
 
X 
Survival 
 
 
 
 
 
 
 
X 
Selinexor baseline dose15 
 
X 
 
 
 
 
 
 
Bone marrow aspirates for translational 
research16 (optional) 
 
X 
 
 
 
 
 
 
Blood draws for translational research17 
(optional) 
 
 
X 
 
X 
 
 
 
Blood draws for Pharmcokinetics18 
(optional) 
 
 
X 
 
 
 
 
 
Opthalmological examination20 
X 
 
 
 
 
 
 
 
Notes 
1 Prior to the first study-specific measures 
2 Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including start and stop dates, disease 
progression during or after therapy, as well as discontinuations due to intolerability or any other serious illness. 


 
 
Statistical Analysis Plan 
            Page 12 (15) 
 
Sponsor: GSO 
Draft 23.8.2017 
Study: SAIL 
 
3 Applicable for women of childbearing potential. Serum β-HCG test within 7 days before the first dose of study drug. To be repeated by urine test, if date of first 
result exceeds the 7-day window 
4 Full physical examination for baseline and end of study visit. Physical examinations during the study should be symptom directed. 
5 Body height will be measured at screening only. 
6 Vital signs: blood pressure, pulse and temperature 
7 Echocardiography of left ventricular ejection fraction (LVEF) to observe cardiac toxic city of idarubicin. at baseline, before a second facultative induction 
course and before first consolidation therapy. Maybe repeated if clinically indicated. 
8 Hematology: hemoglobin,red blood cell (RBC) count, platelets, white blood cell (WBC) count and WBC differential (neutrophils, lymphocytes), leukemic 
blasts. 
9 Calculated GFR according to the formula of Cockroft and Gault. 
10 Clinical chemistry: Sodium, Potassium, Calcium, Creatinine, Total Bilirubin, Alkaline Phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), Total Protein, Albumin, LDH 
11 Urine analysis will include urine bilirubin, glucose, hemoglobin, ketones, pH, protein (once per cycle in consolidation/maintenance) 
12 Coagulation test include prothrombin time (PT) and activated partial thromboplastin time (aPTT) (once per cycle in consolidation/maintenance) 
13 If not performed within the last 6 months 
14 Including cytogenetic, flow cytometry and molecular analysis (FLT3 ITD or TKD mutation or NPM-1 mutation, FLT3 ITD at baseline only) at baseline, end of 
each induction and consolidation cycle. In maintenance and FU after SCT if blood count is suspicious for progression of disease/relapse. 
15 Baseline Selinexor dosing: single dose given after registration but before beginning of first induction cycle. 
16 Bone marrow aspirates for translational research will be taken prior to baseline Selinexor dose and 24 hour post-baseline dose. 2 ml of each aspirate will be 
used to isolate viable cells for mouse studies; 2 ml of each aspirate will be processed to isolate RNA for stem cell expression array analysis. 
17 Blood draws for translational research (exploratory pharmacodynamic analysis): (2 x 2.5 ml for XPO1 inhibition in leukocytes, 2 ml for cytokines) will be 
collected on day of first in-clinic dose of Selinexor during each induction and consolidation cycle. 2 x 2.5 ml, plus 2 ml blood will be collected pre-dose and 2 x 
2.5 ml will be collected 4 hr post-dose. 
18Blood draws (2 ml) for PK analysis will be performed during first induction cycle on day of first in-clinic dose of Selinexor: pre-dose, 2 hr and 4 hr post-dose. 
19 Follow-up is to include all patients, including those having undergone SCT 
20 required at screening and if clinically indicated during the treatment phase. Ophthalmologic examination 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.


 
 
Statistical Analysis Plan 
            Page 13 (15) 
 
Sponsor: GSO 
Draft 23.8.2017 
Study: SAIL 
 
19.2 
Table and figure plan 
14.1 Demographic data 
Table 14.1.1 Number of randomized patients per center 
Table 14.1.2 Disposition of patients 
Table 14.1.3 Analysis datasets 
Table 14.1.4 Descriptive statistics of demographics variables 
Table 14.1.5 Details on leukemia diagnosis 
Table 14.1.6 Details of prior therapy 
Table 14.1.7 Current symptoms and / or residual toxicities from prior therapies 
Table 14.1.8 Summary of other medical history 
Table 14.1.9 Results of HIV and pregnancy tests 
Table 14.1.10 Summary of concomitant medication 
 
14.2 Efficacy data 
Figure 14.2.1 Kaplan-Meier curves for Overall survival (ITT) 
Figure 14.2.2 Kaplan-Meier curves for Recurrence-free survival (ITT) 
Figure 14.2.3 Kaplan-Meier curves for Event-free survival (ITT) 
Figure 14.2.4 Kaplan-Meier curves for Overall survival (censoring at time of SCT) (ITT) 
Figure 14.2.5 Kaplan-Meier curves for Recurrence-free survival (censoring at time of SCT) (ITT) 
Figure 14.2.6 Kaplan-Meier curves for Event-free survival (censoring at time of SCT) (ITT) 
14.2.1 Analysis of treatment Response 
Table 14.2.1.1 Frequency table for best treatment response overall and by dosing schedule (ITT) 
Table 14.2.1.2 Frequency table for best treatment response overall and by dosing schedule (PP) 
Table 14.2.1.3 Response rates (CR/CRi) overall and by dosing schedule (ITT) 
Table 14.2.1.4 Response rates (CR/CRi) overall and by dosing schedule (PP) 
14.2.2 Secondary efficacy analysis 
Table 14.2.2.1 Rate of partial remission overall and by dosing schedule (ITT) 
Table 14.2.2.2 Rate of partial remission overall and by dosing schedule (PP) 
Table 14.2.2.3 Percentage of patients being transplanted after induction therapy (ITT) 
Table 14.2.2.4 Percentage of patients being transplanted after induction therapy (PP) 
Table 14.2.2.5 Early death rate (ITT) 
Table 14.2.2.6 Early death rate (PP) 
Table 14.2.2.7 Summary statistics for overall survival endpoint (ITT) 


 
 
Statistical Analysis Plan 
            Page 14 (15) 
 
Sponsor: GSO 
Draft 23.8.2017 
Study: SAIL 
 
Table 14.2.2.8 Summary statistics for overall survival endpoint (PP) 
Table 14.2.2.9 Summary statistics for recurrence-free survival endpoint (ITT) 
Table 14.2.2.10 Summary statistics for recurrence-free survival endpoint (PP) 
Table 14.2.2.11 Summary statistics for event-free survival endpoint (ITT) 
Table 14.2.2.12 Summary statistics for event-free survival endpoint (PP) 
14.2.3 Additional efficacy analyses 
Table 14.2.3.1 Summary statistics for overall survival endpoint, censoring at time of SCT (ITT) 
Table 14.2.3.2 Summary statistics for recurrence-free survival endpoint, censoring at time of SCT 
(ITT) 
Table 14.2.3.3 Summary statistics for event-free survival endpoint, censoring at time of SCT (ITT) 
14.2.4 Subgroup analyses 
Table 14.2.4.1 Response rates (CR/CRi) by primary vs. secondary AML 
Table 14.2.4.2 Response rates (CR/CRi) by length of remission 
Table 14.2.4.3 Response rates (CR/CRi) by prior SCT 
Table 14.2.4.4 Response rates (CR/CRi) by karyotypic risk group 
Table 14.2.4.5 Response rates (CR/CRi) by mutation (FLT3 vs NPM1) 
14.3 Safety data 
14.3.1 Extent of exposure 
Table 14.3.1.1 Extent of exposure 
14.3.2 Adverse events 
Table 14.3.2.1 Summary of all adverse events 
Table 14.3.2.2 Number of patients with adverse events, by clinical/laboratory event category and 
CTC term 
Table 14.3.2.3 Number of patients with adverse events of grades 3 and 4(5), by decreasing 
frequency of CTC term 
Table 14.3.2.4 Number of patients with adverse events, by clinical/laboratory event category, CTC 
term and maximum severity 
Table 14.3.2.5 Number of patients with related adverse events by clinical/laboratory event category 
and CTC term 
Table 14.3.2.6 Number of patients with non-related adverse events by clinical/laboratory event 
category and CTC term 
Table 14.3.2.7 Adverse events leading to treatment discontinuation 
Table 14.3.2.8 Number of Serious adverse events 
Table 14.3.2.9 Number and reasons for death 
14.3.3 Laboratory safety variables 


 
 
Statistical Analysis Plan 
            Page 15 (15) 
 
Sponsor: GSO 
Draft 23.8.2017 
Study: SAIL 
 
Table 14.3.3.1 Review of safety laboratory variables, hematology 
Table 14.3.3.2 Abnormal/Normal safety laboratory variables; hematology 
Table 14.3.3.3 Review of safety laboratory variables, clinical chemistry 
Table 14.3.3.4 Abnormal/Normal safety laboratory variables; clinical chemistry 
Table 14.3.3.5 Review of safety laboratory variables, urine analysis 
Table 14.3.3.6 Abnormal/Normal safety laboratory variables; urine analysis 
Table 14.3.3.7 Review of safety laboratory variables, coagulation tests 
Table 14.3.3.8 Abnormal/Normal safety laboratory variables; coagulation tests 
14.3.4 Other safety variables 
Table 14.3.4.1 Descriptive statistics of vital signs by visit 
Table 14.3.4.2 Change from baseline in vital signs 
Table 14.3.4.3 Descriptive statistics of body weight by visit 
Table 14.3.4.4 Change from baseline in body weight 
Table 14.3.4.5 Review of physical examination 
Table 14.3.4.6 Frequency tables for ECG by visit 
Table 14.3.4.7 Frequency tables for ECOG by visit 
 
 
 




EudraCT No.:  
Study Code:  
Study Title:  
2014-000526-37 
SAIL 
An Investigator-Initiated Study To Evaluate Ara-C and Idarubicin in 
Combination with the Selective Inhibitor Of Nuclear Export (SINE) 
Selinexor (KPT-330) in Patients with Relapsed Or Refractory AML 
 
Addendum to Statistical Analysis Plan dated 2017Aug25 
 
 
Version 1, 2018Apr04 
 
Page 2 of 3 
 
1. Purpose of the addendum to SAP 
The purpose of this addendum to the Statistical Analysis Plan (SAP) dated 2017Aug25 is to 
clarify the analysis of the primary endpoint and to add an analysis of the difference between 
the subgroups.  
 
2. Analysis of the primary endpoint 
The primary objective of the clinical trial is to determine the efficacy of Selinexor in combination 
with standard chemotherapy in patients with relapsed/refractory acute myeloid leukemia (AML) 
by determination of rate of complete remission (CR) or morphologic complete remission with 
incomplete blood count recovery (CRi), as defined by the recommendations on diagnosis and 
management of AML in adults from an international expert panel, on behalf of the European 
LeukemiaNet. 
The primary endpoint is defined as the percentage of patients achieving a CR or CRi. Patients 
with morphologic leukemia free-state (MLFS) shall be included into the group of responders. 
To determine to efficacy of Selinexor in combination with standard chemotherapy, the best 
response after Selinexor treatment shall be analysed, thus the best response after the 
induction cycle(s).  
A response achieved after stem cell transplantation or in the follow-up period after the patient 
has received another treatment cannot be used to determine the efficacy of Selinexor in 
combination with standard chemotherapy as the response may be attributable to the stem cell 
transplantation or a subsequent therapy.  
 
3. Subsequent updates of the analysis 
For the initial analysis of the clinical trial, the best response of each patient throughout the 
whole study period was used, not the best response obtained after the induction cycle(s).  
Therefore, the following tables are required to be updated: 
 
Frequency tables for best response after Selinexor treatment 
 
Response rates after Selinexor treatment 
 
Summary statistics and Kaplan-Meier curves for relapse-free and event-free survival 
 
Subgroup analyses: Response rates by 
o Primary vs. secondary AML 
o Length of remission: remission < 12 months vs. remission > 12 months 
o Prior SCT: yes vs. no 
o Karyotypic risk group: favourable/intermediate vs. unfavourable vs. unknown 
karyotypic group 


EudraCT No.:  
Study Code:  
Study Title:  
2014-000526-37 
SAIL 
An Investigator-Initiated Study To Evaluate Ara-C and Idarubicin in 
Combination with the Selective Inhibitor Of Nuclear Export (SINE) 
Selinexor (KPT-330) in Patients with Relapsed Or Refractory AML 
 
Addendum to Statistical Analysis Plan dated 2017Aug25 
 
 
Version 1, 2018Apr04 
 
Page 3 of 3 
 
o FTL3 mutation: mutation vs. wildtype 
o NPM1 mutation: mutation vs. wildtype  
For the updated analysis, the table in attachment 1 shall be used. This table includes  
 
response data after the induction cycle, updated, 
 
updated survival data,  
 
updated data on relapse in the follow-up, and  
 
updated data on length of remission prior to the SAIL study (for subgroup analysis 
“length of remission”). 
Overall survival shall be re-calculated by the current data on survival. 
 
4. Subgroup analysis: Addition of analysis of the difference between the 
subgroups 
Subgroup analysis has currently been conducted separately by subgroup. Additionally, a p-
value for the difference between the groups (e.g. patients with early vs. late relapse) shall be 
provided. 
 
 
 
 
 
 
 
 
 
Attachment 1: SAIL Data table response_survival_relapse_length of remission dated 
2018Mar27