Clinical trial NCT02228525
Conditions: Myelodysplastic Syndromes
Keywords: Selinexor (KPT-330) Selective Inhibitor of Nuclear Export (SINE) 14-005
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2014-08-27; Completion date: 2021-04-06
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see if selinexor will improve the blood counts and bone marrow function in people with your type of MDS.

Detailed description:

Arms: arm 1: Patients with myelodysplastic syndromes who are refractory to hypomethylating agents (decitabine or 5-azacytidine) will receive oral selinexor at a starting dose of 60 mg twice weekly for 2 weeks, followed by 1 week of no therapy. Dose reductions are permitted for patients who are benefiting from selinexor but have poor tolerance. After discontinuation from treatment, patients will be followed by the study staff for survival status approximately every three months.
Interventions: intervention 1: selinexor (KPT-330)
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
 
 
 
MSK PROTOCOL COVER SHEET 
 
A Phase II Study of the Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) in 
Patients with Myelodysplastic Syndromes 
 
 
 
Principal Investigator/Department: Virginia Klimek, MD/Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .......................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................... 7 
3.0 
BACKGROUND AND RATIONALE ......................................................................................... 8 
3.5. Study .......................................................................................................................................... 19 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ...................................................................... 20 
4.1 
Design .................................................................................................................................... 20 
4.2 
Objectives ............................................................................................................................... 20 
4.3 
Intervention ................................................................................................................................... 20 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................... 21 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .................................................................................. 23 
6.1 
Subject Inclusion Criteria ........................................................................................................ 23 
6.2 
Subject Exclusion Criteria ....................................................................................................... 24 
7.0 
RECRUITMENT PLAN ........................................................................................................................ 24 
8.0 
PRETREATMENT EVALUATION .......................................................................................... 25 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................... 25 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ......................................................... 35 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................................... 41 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ............................ 43 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................... 45 
14.0 
BIOSTATISTICS ................................................................................................................... 46 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 47 
15.1 Research Participant Registration ............................................................................................. 47 
15.2 
Randomization ....................................................................................................................... 47 
16.0 
DAT A M ANAGEMENT ISSUES ............................................................................................ 47 
16.1 
Quality Assurance .................................................................................................................. 48 
16.2 
Data and Safety Monitoring ......................................................................................................... 48 
17.0 
PROTECTION OF HUMAN SUBJECTS ................................................................................ 49 
17.1 
Privacy ................................................................................................................................... 51 
17.2 
Serious Adverse Event (SAE) Reporting .................................................................................... 51 
Reporting to Karyopharm (company holding cross-referenced IND)Error! Bookmark not defined. 
17.2.1 
Adverse Events Reporting ................................................................................................... 52 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................................... 52 
19.1 
REFERENCES .......................................................................................................................... 53 


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Memorial Sloan Kettering Cancer Center 
 
 
 
 
 
 
20.0 
 
 
 
 
1.0 
 
 
 
 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
APPENDICES ....................................................................................................................... 56
PROTOCOL SUMMARY AND/OR SCHEMA 
Synopsis 
Study Title: 
A Phase II Study of the Selective Inhibitor of Nuclear Export 
(SINE) Selinexor (KPT-330) in Patients with Myelodysplastic 
Syndromes 
Primary Objective: 
Best overall response rate (CR + marrow CR + PR + HI) of 
Selinexor in patients with myelodysplastic syndromes refractory 
to hypomethylating agents 
Secondary 
• To  determine  response duration  in  patients  with  MDS  who 
Objectives: 
achieve a response of stable disease, HI, mCR, PR, CR. 
• To describe the frequency of Stable Disease 
• To describe survival of MDS patients receiving Selinexor  after 
study enrollment 
• To assess the response rate and response duration in therapy- 
related MDS 
• To assess tolerability  of chronic Selinexor  therapy in patients 
with Myelodysplastic  Syndromes 
• To determine the pharmacodynamics (PDn) of Selinexor 
Study Design 
• 
Single-center, non-randomized, open-label, single-arm phase 
II study of oral Selinexor 
• 
Patients with myelodysplastic syndromes who are refractory 
to hypomethylating agents (decitabine or 5-azacytidine) will 
receive oral Selinexor at a starting dose of 60mg twice weekly 
for 2 weeks, followed by 1 week of no therapy. 
o Dose reductions are permitted for patients who are 
benefiting from Selinexor but have poor tolerance 
• 
Pharmacodynamic studies will be obtained to study the 
effects of Selinexor on key signalling pathways which affect 
cellular growth and differentiation. Patients may continue 
Selinexor indefinitely,  barring disease progression, excessive 
toxicity or patient, physican decision to terminate treatment. 
Sample Size: 
20 patients 
Study Duration 
With an estimated accrual rate of 1-2 patients per month, and a 
total number of 25 patients planned, the anticipated enrolment 
period will last 10-20 months. 
Inclusion / Exclusion 
Inclusions: 
Criteria: 
Patients must meet all of the following inclusion criteria to be 
eligible to enroll in this study. 


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IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
 
 
 
 
 
1. Written informed consent in accordance with federal, 
local, and institutional guidelines 
2. Age ≥18 years 
3. Patients with Myelodysplastic  Syndromes refractory 
(primary or acquired resistance) to hypomethylating 
agents(decitabine or 5-azacytidine). At least 4 1- 
month cycles of prior decitabine or SGI-110 OR 6 1- 
month cycles of 5-azacytidine (IV, subcutaneous, or 
oral is required unless the patient has progressive 
disease prior to completing the required number of 
cycles. 
4. Histologically confirmed diagnosis of a 
Myelodysplastic  Syndrome, meeting criteria for any 
subtype in the FAB or WHO classification systems 
with any IPSS score. 
5. Patients with MDS who relapse after allogeneic stem 
cell transplant are eligible if they received standard 
dose decitabine or 5-azacytidine prior to or after stem 
cell transplant as defined in inclusion criteria 3. 
6. If patient has undergone prior allogeneic stem cell 
transplant, they must be greater than 100 days post 
transplant and have ≤ grade 2 graft-versus-host 
disease 
7. There is no upper limit on the number of prior 
treatments provided all inclusion/exclusion criteria are 
met. 
8. Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0-2 (Appendix 1). 
9. Patients receiving erythropoietin (darbepoetin, epoetin 
alfa) must be on a stable dose and with stable 
transfusion requirement or hemoglobin level during the 
8 weeks prior to study entry. 
10. Adequate hepatic function within 21 days prior to 
C1D1: total bilirubin <2 times the upper limit of normal 
(ULN), asparate aminotransferase (AST) <2.5 times 
ULN and alanine aminotransferase (ALT) <2.5 times 
ULN. 
11. Adequate renal function within 21 days prior to C1D1: 
estimated creatinine clearance of ≥ 30 mL/min, 
calculated using the formula of Cockroft and Gault 
(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply 
by 0.85 if female. 
12. 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 


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IRB Number: 14-005 A(17) 
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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. 
 
 
Exclusions: 
1. Patients who are pregnant or lactating; 
2. Chemotherapy or immunotherapy or any other 
anticancer therapy ≤3 weeks  prior to cycle 1 day 1. 
Hydroxyurea may be continued until 72 hours prior to 
first dose and at least 24 hours before the baseline 
bone marrow aspiration is performed; 
3. Major surgery within four weeks before Day 1; 
4. Unstable cardiovascular function: 
• 
symptomatic ischemia, or 
• 
uncontrolled clinically significant conduction 
abnormalities (ie: ventricular tachycardia on 
antiarrhythmics are excluded and 1st  degree AV 
block or asymptomatic LAFB/RBBB will not be 
excluded), or 
• 
congestive heart failure (CHF) of NYHA Class ≥3, 
or 
• 
myocardial infarction (MI) within 3 months; 
5. Uncontrolled active infection requiring systemic 
antibiotics, antivirals, or antifungals within one week 
prior to first dose; Prophylactic antimicrobials are 
permitted. 
6. Known to be HIV seropositive; 
7. Known active hepatitis A, B, or C infection; or known 
to be positive for HCV RNA or HBsAg (HBV surface 
antigen); 
8. Patients with another active 
malignancy.  Asymptomatic sites of disease are not 
considered active.  Treated or untreated sites of 
disease may be considered inactive if they are stable 
for at least 2 months and are not expected to require 
therapy for 4 months. 
9. Patients with significantly diseased or obstructed 
gastrointestinal tract or uncontrolled vomiting or 
diarrhea. 
10. Grade ≥2 peripheral neuropathy at baseline. 
11. History of seizures, movement disorders or 
cerebrovascular accident within the past 1 year prior 
to cycle 1 day 1. 


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12. Patients with macular degeneration with markedly 
decreased visual acuity, or uncontrolled glaucoma. 
13. Patients who are significantly below their ideal body 
weigh (BMI < 17). 
14. Serious psychiatric or medical conditions that could 
interfere with treatment. 
Pharmacodynamic 
Assessments: 
Pharmacodynamic studies will be obtained to study the effects of 
Selinexor on signalling pathways which affect cellular growth and 
differentiation. 
Efficacy Assessment 
Efficacy will be assessed by evaluation of bone marrow aspirates 
and biopsies, complete blood counts, and transfusion records. 
Hematologic Improvement will be assessed continuously, with the 
use of CBC values and transfusion records. At the time of bone 
marrow aspirates and biopsies, full efficacy evaluations will be 
performed, taking into account blood and bone marrow 
parameters, and responses will be assessed using the 2006 
Modified  MDS International  Working Group Response Criteria. 
Safety Variables & 
Analysis: 
The safety and tolerability of Selinexor and ST will be evaluated 
by means of drug related AE reports, physical examinations, and 
laboratory safety evaluations.  Common Terminology Criteria for 
Adverse Events (CTCAE) V4.03 will be used for grading of AEs. 
Investigators will provide their assessment of causality as 1) 
unrelated, 2) possibly related, or 3) probably or definitely related 
for all AEs. 
Statistical Analysis: 
Primary endpoint evaluation 
The primary endpoint of this study is to investigate the efficacy of 
Selinexor in patients with MDS refractory to hypomethylating 
agents (decitabine and/or 5-azacytidine). The standard treatment 
in this setting is supportive care, where the response rate is 
assumed to be zero. Therefore, in this population, a response 
rate of 25% would be considered promising, whereas a 5% 
response rate would not be considered promising. For purposes 
of assessing the primary endpoint, response categories will 
include CR, PR, marrow CR (mCR), or Hematologic 
Improvement. Using a Simon’s two-stage minimax design, this 
trial will accrue a maximum of 20 patients who receive study 
drug. Early termination may occur if no responses are observed 
in the first 13 patients. If at least one response is observed, the 
trial will continue to the maximum sample size. At the end of the 
trial, the treatment strategy will be considered promising in this 
patient population if at least 3 patients achieve a response. The 
type I and type II errors are set at 0.10. 
The response evaluation cohort will include those patients who 
have completed one cycle of therapy and have undergone at 
least one full scheduled post-treatment disease assessment 
(informative bone marrow aspirate or biopsy, cytogenetics, and 


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IRB Number: 14-005 A(17) 
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CBC with differential) after 1 cycle of therapy. For patients who 
come off study after completing 1 cycle of therapy and are unable 
to undergo (or refuse) a bone marrow procedure, an assessment 
for Hematologic Improvement (based on CBC data) will be 
performed and described and an attempt will be made to obtain 
follow-up CBC data for the 8 weeks mandated to confirm 
Hematologic Improvement according to the MDS International 
Working Group response criteria. Patients who come off study 
after starting study drug because of toxicity, death, or withdrawal 
of consent prior to undergoing a response assessment will not be 
replaced and will be considered a treatment failure. Patients who 
enroll on study but do not receive study therapy will be replaced. 
 
Analysis  of secondary endpoints 
 
Secondary efficacy endpoints include response duration, as well 
as an assessment of the incidence of Stable Disease, given the 
finding that Stable Disease is associated with a survival benefit in 
MDS patients receiving up-front therapy with 5-azacytidine. The 
response rate and response duration will also be described for 
the generally poor-risk therapy-related MDS patients enrolled on 
this study (therapy-related MDS accruals may approach ~ 50%, 
as seen in MSKCC protocol 06-054). 
Survival will be described as a secondary endpoint, and will be 
calculated from the time of study entry. Also, since Selinexor may 
require chronic dosing to maintain its effect, we will also describe 
the overall tolerability of chronic Selinexor dosing by summarizing 
safety data collected on patients throughout all cycles of  
treatment who have received at least 1 dose of Selinexor. 
Descriptive statistics will be used to explore the relationship 
between therapeutic response or study entry disease parameters, 
and the results of the pharmacodynamics studies. 
 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective: 
• 
The primary objective is to determine the best overall response rate (CR + marrow 
CR + PR + HI) according to the modified MDS International Working Group response 
criteria (Cheson, 2006) of Selinexor in patients with myelodysplastic syndromes 
refractory to hypomethylating agents 
 
Secondary Objectives: 
 
• 
To determine response duration in patients with MDS who achieve a response of stable 
disease, HI, mCR, PR, CR. 
• 
To describe the frequency of Stable Disease 
• 
To describe survival of MDS patients receiving Selinexor after study enrollment. 
• 
To assess the response rate and response duration in therapy-related MDS 


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Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
 
 
 
 
 
• 
To assess tolerability  of chronic Selinexor  therapy  in patients  with Myelodysplastic 
Syndromes. 
• 
To study the pharmacodynamics (PDn) of Selinexor. 
 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
Cancer cells must inactivate their tumor suppressor proteins (TSPs) in order to perpetuate their 
neoplastic phenotype. TSPs require nuclear localization in order to function. Like most proteins, 
TSPs are shuttled into the nucleus by carrier proteins called importins, and they are carried out of 
the nucleus by exportins. Exportin 1 (XPO1), also called CRM1, is one of seven major nuclear 
exporters responsible for carrying ~220 cargo proteins out of the nucleus into the cytoplasm.  Nearly 
all TSPs are transported out of the nucleus exclusively by XPO1. Furthermore, XPO1 is 
overexpressed by 2-4 fold in nearly all cancer cells, and its levels correlate with poor prognosis 
and/or chemotherapy resistance. Current research suggests that cancer cells have co-opted XPO1 
in order to neutralize their TSPs. 
Selinexor (KPT-330) is a small molecule, drug-like, orally available Selective Inhibitor  of Nuclear 
Export (SINE) compound that is a slowly reversible covalent antagonist of XPO1.  By blocking 
XPO1, Selinexor induces the accumulation of TSPs in the cell nucleus, leading to activation of their 
tumor suppressing function.  Cells with marked  genomic (DNA) damage, including cancer cells, 
undergo apoptotic cell death; normal cells, with little or no genomic damage, undergo transient, 
reversible cell cycle arrest. Consistent with its novel mechanism of broadly inducing TSP function, 
Selinexor has shown broad anti-tumor in preclinical mouse models and spontaneous canine 
cancers. Selinexor is currently being studied in three Phase 1 clinical trials in patients with  
advanced hematolgic or solid tumor malignancies, or in patients with treatment refractory sarcomas. 
Preliminary evidence of anti-tumor activity in humans with a diverse set of cancers formed the basis 
for studying the effect of Selinexor on patients with MDS. 
3.1 
Selinexor: Mechanism of Action and Preclinical Summary 
 
A brief summary of key aspects the preclinical evaluation of Selinexor is presented below.  Further 
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.  Selinexor restores many of the TSP and other growth regulatory 
proteins to the nucleus where they can carry out their normal functions.  It is selectively cytotoxic for 
cells with genomic damage, i.e., for tumor cells, both in vitro and in vivo.  All cell types exposed to 
SINE in vitro undergo G1 ± G2 cell cycle arrest, followed by a ‘genomic fidelity’ review, and cells with 
significant genomic (DNA) damage are induced to undergo apoptosis.  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. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
 
 
 
 
Preclinical Safety 
 
Sprague-Dawley rats and cynomolgus monkeys were chosen as the toxicology species for the 
selinexor nonclinical safety program.  In both species, 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. 
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.  As noted above, Selinexor had little effect on normal (nonmalignant) 
lymphocytes or other nontransformed cells, which correlated with the low incidence in animals of the 
typical side effects seen with most anti-cancer therapies such as significant myelosuppression, 
alopecia, mucositis and other gastrointestinal (GI) dysfunction. 
Selinexor and other SINE analogs have been administered in efficacy studies to mice and dogs and 
in toxicology studies to rats and monkeys. 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)] (Ranganathan 2012, Etchin 2012) 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. 
3.2 
Selinexor:  Clinical Summary 
 
A brief summary of key aspects the clinical evaluation of Selinexor is presented below.  Further 
detailed information is provided in the Investigator’s Brochure. 
Study Designs 
 
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Karypoharm Therapeutics, Inc. (subsequently referred to as Karyopharm) 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 in patients with advanced 
hematological malignancies, the second (KCP-330-002) is 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. As of December 15, 2014 550 patients with 
tumors have been treated with selinexor, and the overall safety profile has not changed. The food 
effect study was initiated in July 2013, so preliminary safety or efficacy data is not yet available. 
KCP-330-001 is a dose escalation study in patients with advanced hematologic malignancies.  KCP- 
330-002 is a dose escalation study in patients with advanced metastatic solid tumors.  Dose 
escalation began at 3mg/m2 given at 10 doses per cycle (Monday/Wednesday/Friday on weeks 1 
and 3; Monday/Wednesday on weeks 2 and 4).  The dose limiting toxicities (DLTs) were 
anorexia/nausea and fatigue at 40mg/m2 (10 times per 4-week cycle) in KCP-330-002 and the 
maximum tolerated dose (MTD) was 30mg/m2. Based on similar adverse events in KCP-330-001, 
escalation beyond 30mg/m2  (10 times per cycle) was not performed. The recommended phase 2 
dose (RP2D) for 10 times per cycle dosing is 30mg/m2. Reduced intensity dosing at twice weekly (8 
times per cycle, Days 1 & 3 of each week) has shown improved tolerability.  Dose escalation on this 
schedule in KCP-330-002 is ongoing; Dose level 50mg/m2 cleared DLT.  Escalation on this twice- 
weekly schedule in KCP-330-001 is currently proceeding at 55mg/m2. In patients with relapsed AML, 
escalation is currently ongoing at 50mg/m2 on the twice weekly schedule. 
Clinical Evidence of Anti-Cancer Activity 
 
KCP-330-001: A Phase I Study of the Safety, Pharmacokinetics and Pharmacodynamics of 
Escalating Doses of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients with 
Advanced Hematological Malignancies 
This study includes patients with relapsed and refractory hematologic malignancies. KPT-330 is 
orally administered in escalating dose levels at 10 doses/cycle (Schedules 1and 2) or 8 doses/cycle 
(Schedule 3) as follows: 
• Schedules 1 and 2: selinexor is administrated PO 3 times a week every other day for weeks 
1 and 3 (QoDx3/wk). For weeks 2 and 4, drug is dosed on days 1 and 3 of each week (BIW). 
One cycle is 28 days or 10 doses. At doses > 12mg/m2, a “run in” week at 12 mg/m2 
QoDx3/wk precedes Cycle 1 (10 doses per 4 weeks); this 10-dose regimen with the run-in 
week is designated Schedule 2. 
 
• Schedule 3: selinexor is administrated PO on days 1 and 3 of each week (BIW). One cycle 
is 28 days or 8 doses. 
 
There are three Arms to this study: Arm 1 includes patients with the relatively indolent hematologic 
malignancies multiple myeloma (MM), Waldenström’s Macroglobulinemia (WM), Non-Hodgkin’s 
Lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Arm 2 includes patients with acute 
myeloid leukemia (AML). Because of the rapidly progressive nature of AML, Arm 2 began dosing at 
16.8mg/m2 after dose limiting toxicity (DLT) clearance in cohort 3 (12 mg/m2) and initiation of 


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IRB Number: 14-005 A(17) 
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16.8mg/m2 dosing in Arm 1, i.e., in the indolent hematologic malignancy patients. Arm 3 includes up 
to 12 patients with refractory PTCL or CTCL treated at a dose of 30mg/m2 on Schedule 3. No 
patients have been enrolled in this Arm to date. All patients entered study with documented disease 
progression having relapsed following all proven and many experimental therapies. Intrapatient  dose 
escalation is permitted once patients have cleared the next higher dose cohort. 
Arm 1: As of 01-July-2013, a total of 38 patients on Arm 1 (17 MM, 2 WM, 15 NHL and 4 CLL) have 
been enrolled at doses ranging from 3 to 30 mg/m2 on Schedule 1 and 2 (10 doses/cycle). As of 01- 
July-2013, 3 patients have been enrolled at 35 mg/m2 on Schedule 3. The maximum tolerated dose 
(MTD) has not yet been reached in this Arm, and as of 11/11/13 (personal communication with John 
McCartney, Karyopharm) dose level 40mg/m2 had not produced DLT and dosing is proceeding at 
55mg/m2 on schedule 3 (BIW dosing). 
Arm 2: As of 01-July-2013, a total of 27 patients on Arm 2 (AML) have been enrolled, all refractory to 
standard therapy (median number of prior therapies = 2; range 1-7), including hypomethylating 
agents, and treated at doses ranging from 16.8 mg/m2 to 30 mg/m2 on Schedule 2 (13 doses/cycle) 
and at a dose of 30 mg/m2 on Schedule 3. Three patients achieved a complete response (CR) 
without hematologic recovery and one patient achieved CR with recovery of ANC and platelets. No 
DLTs were observed in these cohorts and MTD has not yet been reached. As of 01-July-2013, no 
clinically significant cumulative drug toxicities have been observed in either Arm1 or Arm 2, with 5 
patients on study for >6 months. Currently, dosing is proceeding at 50 mg/m2 on schedule 3 (BIW 
dosing). 
 
Arm 3: One  patient has been enrolled on Arm 3 to date. 
 
 
 
KCP-330-002: A Phase I Study of the Safety, Pharmacokinetics and Pharmacodynamics of 
Escalating Doses of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients with 
Advanced or Metastatic Solid Tumor Malignancies 
This study includes patients with advanced, refractory solid tumors. Selinexor) is orally administered 
in escalating dose levels at 10 or 13 doses/cycle (Schedules 1 and 2) or 8 doses/cycle (Schedule 3) 
as described above for study KCP-330-001. 
As of 01-July-2013 68 patients received selinexor across 7 dose levels (3 to 40 mg/m2) on Schedule 
1 and two dose levels in Schedule 2 (35 and 40 mg/m2). Dosing at 50 mg/m2 on Schedule 3 (BIW) 
was completed without DLT as of 11/11/13 (11/11/13 personal communication with John McCartney, 
Karyopharm). 
No DLTs were observed in the initial six cohorts at doses ranging from 3 to 30 mg/m2 on Schedule 
1/2. Two DLTs were observed out of 3 patients at 40 mg/m2: one was Grade 3 anorexia with 
dehydration and fatigue, the other was Grade 3 fatigue with Grade 1-2 anorexia. Although neither of 
these patients with DLTs received optimal supportive care/medications (such as anti nausea, 
appetite stimulators and glucocorticoids), given the entire clinical picture, the decision was made to 
declare 30 mg/m2 the MTD for solid tumor patients treated on Schedules 1/2, and both of these 
patients with DLTs had their doses reduced from 40 mg/m2 to 30 mg/m2. A third patient treated at 
40 mg/m2 on Schedule 2 tolerated therapy well, but given the other patients, her dose was reduced 


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IRB Number: 14-005 A(17) 
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to 30mg/m2 as well. Twelve (12) additional patients were enrolled at this dose as part of the 
expansion phase on Schedule 2. 
Six patients were treated at 35 mg/m2 on Schedule 3. One DLT of Grade 3 nausea/vomiting, with 
fatigue was observed in patient (043-101) with melanoma who had concomitant C. difficile infection; 
this patient also had a partial response on CT scan after 2 cycles but the patient withdrew consent. 
Three patients have cleared DLT assessment in cycle 1 at 40 mg/m2 on Schedule 3 (July 25, 2013), 
and dose escalation to 50 mg/m2 is has opened. Based on the data to date, the Phase 2 
recommended starting dose was determined as 35 mg/m2 on Schedule 3 and 18 patients were 
enrolled to the study as part of the expansion phase on Schedule 3. Patients who tolerate 35 mg/m2 
on Schedule 3 may have their doses escalated to 40 mg/m2 if requested by their treating physician. 
Interim KCP-330-002 study results were presented at the 2013 ASCO annual meeting (Razak, 
2013). 
Preliminary evidence of clinical activity was appreciated in study KCP-330-002. One patient (043- 
805) with K-ras mutant colorectal cancer (CRC) treated with all approved agents (except 
regorafenib) showed a partial response (PR) by RECIST 1.1 criteria after 4 cycles of therapy. 
Several other patients with heavily pretreated CRC have also shown reduction in tumor mass, CEA 
levels, and/or ascites, on study for >4 months (043-001, 043-014, 043-016). Patients with cervical 
cancer have shown stable disease for ≥6 months (043-002, 043-007). Two patients with squamous 
cell cancers of the head and neck region have shown stable disease (043-804, 043-013). 
 
 
Phase 1 safety data for selinexor 
 
For the two ongoing clinical trials (KCP-330-001 and KCP-330-002), a total of 97 patients comprise 
the safety population as of the 31 May 2013 data cut-off (over 130 patients have been dosed to 
date, but the data sets reported here are through 31 May 2013). 
KCP-330-001: A Phase I Study of the Safety, Pharmacokinetics and Pharmacodynamics of 
Escalating Doses of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients with 
Advanced Hematological Malignancies 
The AEs for AML patients (Arm 2) in this study are summarized in the table below. 
 
 
KCP-330-001 (AML cohort, n = 16): Toxicities attributed to selinexor 


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Patients entering this study have heavily pretreated hematologic malignancies. The most common 
AEs, which are also observed in patients with advanced metastatic solid tumors, are gastrointestinal 
(GI) in nature. These are Grade 1-2 events are generally responsive to standard supportive care 
measures. Diarrhea is observed in some patients though relationship to study drug is unclear. 
Dysgeusia is primarily reported as a metallic taste. Thrombocytopenia is seen, but no bleeding 
events have been observed, and several patients with Grade 4 thrombocytopenia have remained on 
therapy for months with intermitted glucocorticoids and/or infrequent transfusions, and good disease 
control. Severe neutropenia has been relatively uncommon and there is only one case of possibly 
related febrile neutropenia to date. 
Blurry vision has been reported on this and the accompanying study KCP-330-002. The etiology of 
the blurry vision is not known, and no objective ophthalmological correlates have been observed. 
Dehydration leading to changes in the refractive index in the lens may be involved. Two of these 
cases have responded to changes in lens prescription, and all of the cases have resolved or are 
improving. Nearly all patients entering the study have baseline ophthalmological abnormalities. No 
drug-related neuroophthalmalogic abnormalities or CNS adverse events have been reported to date. 
Increases in liver function transaminases were reported in 3 patients (040-106 Grade 3 AST and  
ALT elevation, 040-007 Grade 1 ALT elevation, 040-109 Grade 1 AST elevation) without sequelae  
or total bilirubin elevations; relationship to study drug remains questionable. Patient 040-106’s 
increases rapidly resolved and no AST or ALT changes occurred on retreatment with the drug at the 
same dose for 5 additional doses; this patient then left the study due to progressive AML. Nonclinical 
toxicology studies showed no laboratory or pathological evidence of liver toxicity. Cumulative 
toxicities have not been significant to date, but data at this point are limited. No drug-associated 
deaths have been reported on study as of 01 July 2013. 


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KCP-330-002: A Phase I Study of the Safety, Pharmacokinetics and Pharmacodynamics of 
Escalating Doses of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients with 
Advanced or Metastatic Solid Tumor Malignancies 
The patients (N=50) compromising the current safety population were treated at escalated protocol 
doses of 3-40 mg/m2 on Schedule 1 or 2 and at 35-40 mg/m2 on Schedule 3. A summary of the 
reported related treatment-emergent adverse events that were considered at least possibly related 
to drug administration occurring in ≥2 patients is displayed in Table 14, pages 82-83 in the IB and in 
the table below. The most common AEs are GI in nature, typically grade1-2 anorexia, nausea and 
vomiting, which are generally responsive to standard supportive care measures. 
Diarrhea is observed in some patients though relationship to study drug is unclear. Dysgeusia is 
primarily reported as a metallic taste. Systemic AEs are primarily related to fatigue. 
Myelosuppression has generally been manageable. Platelet counts appear to be the most sensitive 
to treatment with selinexor, similar to (though less common) that observed on the hematologic 
cancer study KCP-330-001. Asymptomatic hyponatremia Grade 3 has been reported in 8 patients. 
Increases in liver function transaminases were reported in 3 patients. 
Ocular symptoms of various kinds have been reported by a number of patients. The most common 
is blurred vision. None of the ocular symptoms have been progressive, none have lead to therapy 
discontinuation, and professional ophthalmological examinations, instituted per protocol based on 
early reports, have disclosed no common findings. Many of the patients entering the study have 
unrecognized ophthalmological disorders that are discovered during these examinations. 
It should be noted that no reports of major organ dysfunction have occurred to date including in the 
patients with DLT. In particular, there has been no clinically significant renal, liver, pancreatic, 
cardiac or pulmonary dysfunction. No drug-associated deaths have been reported on study as of 01 
July 2013. Moreover, there have been no reports of central or peripheral neurological toxicities. 
Therefore, the primary side effects of selinexor in doses up to 40 mg/m2 on Schedules 1 (10 doses 
per cycle) and up to 50 mg/m2 3 on schedule 3 (BIW or 8 doses per cycle) are reversible anorexia, 
weight loss and fatigue which responds to aggressive supportive care measures. These side effects 
have been considerably more prominent in weeks 1 and 3 when patients receive 3 doses (M/W/F) 
as compared with weeks 2 and 4 when patients receive 2 doses only (M/W). These observations 
have led to the current amendment for twice weekly dosing schedule in planned phase 2 trials. 
In summary, the primary AEs associated with selinexor in patients with advanced solid tumor 
malignancies are GI in nature and respond to aggressive standard supportive care measures. 
Institution of prophylactic supportive medications and dietary counseling can greatly reduce or 
eliminate much of the anorexia, nausea, or weight loss associated with selinexor and permit long 
term dosin 


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KCP-330-002: Toxicity attributed to selinexor 


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KCP-330-002:  Toxicity attributed to selinexor (continued) 
 
 
 
Clinical Pharmacokinetics 
 
Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and serial tumor biopsies 
were performed in both studies and suggested a fairly proportional increase in Cmax and AUC with 
increasing dose, with no accumulation and without affecting half-life or clearance of Selinexor. At 30 
mg/m2, AUC0-last. (4375 ng*h/mL) was comparable to the anti-tumor exposure observed in mice and 
dogs.  Tmax  (~3 h) and T1/2 (6-7 h) were consistent across doses.  Significant increase (2-20x) in 
XPO1 messenger ribonucleic acid (mRNA) levels (PDn marker) in circulating leukocytes was 
observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA induction. 
Analysis of tumor biopsies confirmed nuclear localization of TSPs (e.g., p53, FOXO3A, IκB) and 
apoptosis of cancer cells following selinexor administration. 
 
 
3.3 
Rationale for use of Selinexor in Hematologic Malignancies 
 
Pre-clinical studies have demonstrated striking anti-leukemic activity in acute lymphoblastic 
leukemia and acute myelogenous leukemia for selinexor and similar, earlier compounds (Etchin, 
2013) with little effect on normal hematopoetic cells or myelosuppression. In an ongoing phase 1 
study, the dose of selinexor was escalated starting at 3 mg/m2 in patients with solid tumors, multiple 
myeloma, lymphoma, and leukemia. Activity has been noted in a variety of malignancies, including 
multiple myeloma, lymphoma, and leukemia. 
Therapy-related MDS/AML and poor risk de novo MDS/AML is characterized by an increased 
frequency of lost or mutated p53 (20-30% as we have shown in therapy-related MDS/AML and 5- 
10% in de novo MDS/AML)(Shih, 2013). We have also noted that both p53 alleles may be mutated 


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18 
 
 
 
 
and/or lost, but in this situation, the related TSP p73 can be engaged (Mass 2011). XPO1 blockade 
forces p53 and p73 nuclear retention and, even in cells harboring only one p53wt allele, activates its 
downstream cell cycle regulatory and apoptotic functions (Turner 2012). However, upregulated 
XPO1 can also promote p53 “mislocalization” and dysfunction in cancer cells even in the absence of 
mutation or allele loss. 
NFkB is also an important pathway in MDS/AML. The NFkB pathway is activated in MDS/AML as it  
is in other malignancies, as a means to enhance proliferation. Inhibition of NFkB by the proteosome 
inhibitor bortezomib has shown activity in multiple myeloma, and it’s use is being explored in AML 
(and MDS). We and others have shown that inhibition of NFkB leads to apoptosis in MDS/AML using 
sodium salicylate (Disalcid) (Klampfer, 1999). Upregulation  of NFkB is associated with  
chemotherapy resistance in AML (and MDS) due to either constitutive activation or chemotherapy- 
induced upregulation, Therefore, inhibition of NFkB may be effective, particularly for MDS or AML 
which can have constitutive or induced (during chemotherapy administration) NFkB upregulation, 
thereby promoting resistance to chemotherapy. Blockade of XPO1 prevents export of I-қp from the 
nucleus, and was shown to induce long term inhibition of NF-қB activity (Gupta 2010) and therefore 
Selinexor may induce apoptosis in MDS or AML, and/or may sensitize MDS/AML to standard 
chemotherapy. 
The Wnt signaling pathway plays a role in the maintenance of hematopoetic stem cells. Upregulated 
Wnt signaling results in accumulation of nuclear non-phosphorylated beta catenenin, leading to 
activation of MYC and CCND1 and is therefore known to be oncogenic. Nuclear non-phosphorylated 
beta catenin was seen in 18/44 (41%) of MDS BM biopsies and was associated with higher IPSS 
risk disease, -7/del(7q) (poor risk) karyotypes, and poor clinical outcomes (Xu, 2010). The effects of 
interrupted XPO1 activity on APC and nuclear beta catenin levels is unclear, especially since beta 
catenin can also undergo nuclear-cytoplasmic shuttling independent of APC and XPO1. However, 
Selienexor treatment was shown to reduce MYC levels in myeloma and HCC cells. 
Other clients for XPO1 which may be more relevant for AML include FOXO3 and NPM1 as 
discussed in section 1.1.2. The effects of selinexor on these TSPs are being evaluated in an 
ongoing study of selinexor in AML. 
Further information about the preclinical pharmacology and toxicology of selinexor is presented in 
the Investigator’s  Brochure. 
3.4. Rationale for dose and schedule 
 
In general, selinexor has been well tolerated across in patients with advanced cancer. Drug related 
grade 1-2 nausea, grade 1-2 vomiting (intermittent, rapidly responding to anti-emetics or self- 
resolving), grade 1-2 fatigue, grade 1 or 2 dysgeusia, grade 1-2 anorexia, grade 1 weight loss have 
been observed. These side effects have been considerably more prominent in weeks 1 and 3 when 
patients receive 3 doses (M/W/F) as compared with weeks 2 and 4 when patients receive 2 doses 
only (M/W). 
Based on the observed better tolerability in the twice weekly dosing compared with 3X/week dosing, 
an alternative twice weekly schedule consisting of 8 doses / 4 week cycle was explored (referred to 
as “Schedule 3”). 


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19 
 
 
 
 
In the solid tumor phase 1 study, six patients were treated at 35 mg/m2 on Schedule 3.  One DLT of 
Grade 3 nausea/ vomiting, with fatigue was observed in patient (043-101) with melanoma who had 
concomitant C. difficile infection; this patient also had a partial response on CT scan after 2 cycles 
but the patient withdrew consent. Three patients have cleared DLT assessment in cycle 1 at 40 
mg/m2 on Schedule 3 (July 25, 2013), and more recently, dose escalation to 50 mg/m2 has not 
resulted in dose limiting toxicity. .Based on the data to date, the Phase 2 recommended starting 
dose was determined as 35 mg/m2 on Schedule 3 and 18 patients were enrolled to the study as part 
of the expansion phase on Schedule 3. 
In the phase 1 hematologic malignancies study, as of 01-July-2013, patients were enrolled at doses 
of up to 40 mg/m2 on Schedule 3 without DLT and dosing is currently proceeding at 55 mg/m 2 
(indolent hematologic malignancies arm) without DLT. In the AML arm, MTD was not reached as of 
July 2013 at a dose of 30 mg/m2 and 4 CRs were seen in AML patients at doses below 35 mg/m2 
BIW (CRs seen at doses of 16.8-23 mg/m2 on TIW alternating with BIW schedule). Dosing for the 
AML arm (Arm 2) is currently proceeding at 50 mg/m2. 
It should be noted that no reports of major organ dysfunction have occurred to date, including in the 
patients with DLT. In particular, there has been no clinically significant renal, liver, pancreatic, 
cardiac or pulmonary dysfunction.  Moreover, there have been no reports of central or peripheral 
neurological toxicities.  Therefore, the primary side effects of selinexor in doses up to 40 mg/m2 on 
Schedules 1 (10 doses per cycle) and up to 50 mg/m2 3 (8 doses per cycle) are reversible anorexia, 
weight loss and fatigue. 
Data from phase I studies of selinexor indicate that prophylactic antiemetic and anti-anorexia 
therapy imporves the tolerance of selinexor. As a result, all patients will take two prophylactic 
medications during cycle 1 of Selinexor, and these medications may be tapered or discontinued 
during cycle 2 or later in treatment. See section 9.1.3 for details. 
Given the improved tolerability of twice weekly dosing compared to three times per week dosing,  
and the activity in hematologic malignancies at and below 70 mg/m 2 per week, selinexor for 8 doses 
in a 4 week cycle (i.e., 280mg/m2 in 4 weeks) was the initial starting schedule for this study. Impaired 
tolerance, due primarily to fatigue, was noted in the first two patients enrolled on this study, which is 
the first selinexor study in the MDS population. This impaired tolerance may be due to the advanced 
age of MDS patients combined with the anemia related to the MDS. Therefore, the dosing schedule 
was adjusted to provide a dosing break. Selinexor will be dosed twice per week for two weeks 
followed by 1 week of no therapy. 
Recent analysis of the existing PK data from Phase 1 trials KCP-330-001 and KCP-330-002 
supports the use of fixed rather than BSA-based dosing. The 5th and 95th percentile for BSA values 
encountered to date in Phase 1 trials KCP-330-001 and KCP-330-002 are 1.5 and 2.3 m2, 
respectively (N=331). PK values (Cmax and AUC(0-)) for a given flat (fixed) dose of selinexor were 
similar across this typical BSA range, indicating that exposure is not strongly correlated with BSA. 
Basedo n the analysis of this PK data, the recommended starting dose will be changed to a flat dose 
of 60mg (~35mg/m2) 
 
 
3.5. Study Rationale: Summary 


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Preclinical in vitro and in vivo data and phase 1 clinical data have shown that both hematologic and 
solid tumor cells are susceptible to single-agent cytotoxicity by selinexor, consistent with its 
restoration of multiple tumor suppressor gene functions and growth regulatory pathways leading to 
the death of cancer cells. The ongoing phase 1 study has demonstrated the safety of the proposed 
phase 2 dose (35 mg/m2) and activity in hematologic malignancies including MM, NHL and CLL. In a 
separate arm of the Phase 1 study heavily pretreated elderely AML patients were treated with 
selinexor at doses of 16.8 mg/m2 to 40 mg/m2. Three patients achieved CR (2 with complete 
hematological recovery and one bone marrow CR without hemetologic recovery) and several 
patients had stable diease.  Given the novel mechanism of action, the rationale for XPO1 inhibition 
by selinexor in AML/MDS, and the phase 1 safety and efficacy data, the risk benefit assessment 
favors further development of selinexor in hematologic malignancies, including MDS. 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a phase 2, single arm, open-label study designed to assess the activity of selinexor in 
patients with myelodysplastic syndromes who have progressed on or have not responded to an 
adequate trial of hypomethylating agents. 
4.3 
Objectives 
 
Primary Objective: 
 
• 
To evaluate the efficacy (overall response rate: CR+marrow CR + PR + HI) of 
Selinexor in patients with myelodysplastic syndromes 
SecondaryObjectives: 
 
• 
To determine response duration in patients with MDS who achieve a response of stable 
disease, HI, mCR, PR, CR. 
• 
To describe the frequency of Stable Disease 
• 
To describe survival of MDS patients receiving selinexor after study enrollment 
• 
To assess the response rate and response duration in therapy-related MDS 
• 
To assess tolerability  of chronic Selinexor  therapy  in patients  with Myelodysplastic 
Syndromes. 
• 
To study the pharmacodynamics (PDn) of Selinexor. 
 
 
4.4 
Intervention 
 
4.3.1. Rationale for the Study Design 
 
Various pathways which are aberrantly suppressed or activated in myeloid malignancies are 
modulated by the nuclear retention or export of transcriptional regulatory elements via XPO1. These 
pathways modulate the growth of myeloid malignancie and/or contribute to resistance to therapy 
(eg., NF-kβ). In in vitro studies, selinexor induces apoptosis in leukemia cell lines and in primary 
(patient-derived) AML cultures, which is correlated to nuclear retention of tumor suppressors which 


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are thought to have a role in the pathobiology of MDS. The goal of this study is to determine if 
selinexor can induce responses in this population, for whom best supportive care is the standard 
treatment option, and median survival is 4-6 months. 
4.3.2. Study Design 
 
Selinexor will be taken twice per week for 2 weeks, followed by 1 week of no therapy. Disease 
assessments will be performed after cycle 1 and 2, then every other month therafter until CR or 
maximal response is achieved, at time of disease progression or when clinically indicated, using the 
Modified  MDS International  Working Group response criteria. Treatment will be allowed indefinitely, 
barring disease progression, excessive toxicity, or withdrawal of consent. Pharmacodynamic studies 
will be performed at baseline, cycle 1 day 14 (for first 10 patients), after cycle 1, 2, and 4 to assess 
the biological activity of Selinexor. A total of 20 adult patients with myelodysplastic syndromes will be 
enrolled into this study. After treatment is stopped, patients will be followed indefinitely every three 
months for survival. The study will be conducted at Memorial Sloan-Ketteriing Cancer Center. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Product:   Selinexor (KPT-330) 
 
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 slowly-reversible covalent binding to XPO1 (also called CRM1) protein. 
5.1. Formulation 
 
Tablets for selinexor oral administration will be supplied in two (2) strengths: 10 and 25 mg of active 
ingredient per tablet, or 20mg tablets (supplied in blister packs). The initial drug product for the study 
will be the 10 and 25 mg tablets, with transition to the 20mg tablets as these supplies become 
available. Bulk bottles of 50 tablets per bottle will be supplied for each of the two strengths. The 
tablets are clear coated with Opadry II clear and prepared from a common blend prepared from a 
wet granulation of active compound (SELINEXOR), Kollidon® 30 (polyvinyl  pyrrolidone), sodium 
lauryl sulfate, croscarmellose sodium, and Avicel PH-101 (Microcrystalline cellulose). The  
granulation is adjusted to final compression blend with Avicel PH-102 (Microcrystalline cellulose), 
Aerosil® (colloidal silicon dioxide), magnesium stearate, and additional croscarmellose sodium. All 
tablet excipients are GRAS and suitable for use in pharmaceuticals. 
5.2. Labelling 
 
Each bottle of selinexor tablets will be labelled in accordance with current ICH GCP, FDA and 
specific national requirements. 
5.3. Storage 
 
10 and 25 mg Tablets on Bottles 


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Selinexor tablets will be stored at ambient or refrigerated temperatures between (36 – 86 °F) or (2– 
30 °C) in a locked and secured area with restricted access to study staff. The tablets should not be 
stored at freezer temperatures or allowed to freeze. Tablets will be supplied in white high density 
polyethylene (HDPE) bottles.  All medication must be stored in a secure area under the proper 
storage requirements with access restricted to the site staff pharmacist or designee(s). 
20 mg Tablets in Blister Packs 
 
• 
Selinexor tablets (20 mg) are currently in ongoing stability studies. The expiry will be based 
on concurrent stability studies and extended during the course of the study as further stability 
data becomes available. 
• 
All selinexor tablets must be kept in an appropriate, limited access, secure place until 
dispensed, destroyed or returned to Karyopharm Therapeutics, Inc. or designee for 
destruction. 
• 
Selinexor tablets can be stored at room temperature or refrigerated, at or below 86 ˚F or 30 
˚C, do not freeze.  Room temperature storage is recommended.  The study site will be 
required to maintain a log of the temperature where the study medication is stored. 
 
 
5.4. Selinexor Dosing Information 
 
After the initial screening visit and registration in the study, patients will receive selinexor twice 
weekly orally at a starting dose of 60mg. The dosing schedule is two doses per week for 2 weeks, 
followed by 1 week of no therapy. Dose reductions are permitted as described in section 9.2. In 
addition, patients will receive anorexia and nausea prophylactic medications prior to their first dose 
(detailed in section 9.1.3). 
 
Selinexor is to be taken with solid food consumption together with 240 mL (8 ounces) of water. 
 
5.5. Drug Product Accountability 
 
Study drug for the study are provided by the Karyopharm and will be labelled as per the applicable 
regulations.  Sites must request study drug by submitting an order form directly to the drug depot in 
order for the study drug to be shipped to the site pharmacy.  The Investigator (or designee) will verify 
and acknowledge receipt of all study drug shipments by signing and returning all required forms. 
Study drug accountability records will be maintained at the site pharmacy and will be available for 
review by the institutional study monitor during each monitoring visit and at the close out visit. 
All medication must be stored in a secure area under the proper storage requirements with access 
restricted to the site staff pharmacist or designee(s). 
The Investigational medicinal product should not be used for any purpose outside the scope of this 
protocol, nor can Investigational medicinal product be transferred or licensed to any party not 
participating in the clinical study. Data for Investigational medicinal product are confidential and 
proprietary and shall be maintained as such by the Investigators. 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful 
record of the inventory and disposition of unused material. 


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All clinical drug supplies must be kept in an appropriate, limited access, secure place until used or 
returned to Karyopharm or designee for destruction. Drug supplies will be counted and reconciled at 
the site before being returned. The study site will be required to maintain a log of the temperature 
where the study medication is stored. 
 
 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY. 
 
6.2 
Subject Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to be eligible to enroll in this study. 
 
1. Written informed consent in accordance with federal, local, and institutional guidelines 
2. Age ≥18 years 
3. Patients with Myelodysplastic  Syndromes refractory (primary or acquired resistance) 
to hypomethylating agents. At least 4 1-month cycles of prior decitabine or SGI-110 
OR 6 1-month cycles of 5-azacytidine (IV, subcutaneous, or oral) is required unless 
the patient has progressive disease prior to completing the required number of 
cycles. 
4. Histologically confirmed diagnosis of a Myelodysplastic Syndrome, meeting criteria for 
any subtype in the FAB or WHO classification systems with any IPSS score. 
5. Patients with MDS who relapse after allogeneic stem cell transplant are eligible if they 
received standard dose decitabine or 5-azacytidine prior to or after stem cell 
transplant as defined in inclusion criteria 3. 
6. If patient has undergone prior allogeneic stem cell transplant, they must be greater 
than 100 days post transplant and have ≤ grade 2 graft-versus-host disease. 
7. There is no upper limit on the number of prior treatments provided all 
inclusion/exclusion criteria are met. 
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 (Appendix 
1). 
9. Patients receiving erythropoietin (darbepoetin, epoetin alfa) must be on a stable dose 
and with stable transfusion requirement or hemoglobin level during the 8 weeks prior 
to study entry. 
10. Adequate hepatic function within 21 days prior to C1D1: total bilirubin <2 times the 
upper limit of normal (ULN), asparate aminotransferase (AST) <2.5 times ULN and 
alanine aminotransferase (ALT) <2.5 times ULN. 
11. Adequate renal function within 21 days prior to C1D1: estimated creatinine clearance 
of ≥ 30 mL/min, calculated using the formula of Cockroft and Gault. 
12. 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 


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24 
 
 
 
 
methods of contraception must be used throughout the study and for three months 
following the last dose 
6.3 
Subject Exclusion Criteria 
 
1. Patients who are pregnant or lactating; 
2. Chemotherapy or immunotherapy or any other anticancer therapy ≤3 weeks prior to 
cycle 1 day 1. Hydroxyurea may be continued until 72 hours prior to first dose and at 
least 24 hours before the baseline bone marrow aspiration is performed; 
3. Major surgery within four weeks before Day 1; 
4. Unstable cardiovascular function defined as symptomatic ischemia, uncontrolled 
clinically significant conduction abnormalities (ie: ventricular tachycardia on 
antiarrhythmics are excluded and 1st  degree AV block or asymptomatic LAFB/RBBB 
will not be excluded), congestive heart failure (CHF) of NYHA Class ≥3, or myocardial 
infarction (MI) within 3 months; 
5. Uncontrolled active infection requiring systemic antibiotics, antivirals, or antifungals 
within one week prior to first dose; Prophylactic antimicrobials are permitted. 
6. Known to be HIV seropositive; 
7. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or 
HBsAg (HBV surface antigen); 
8.   Patients with another active malignancy.  Asymptomatic sites of disease are not 
considered active.  Treated or untreated sites of disease may be considered inactive 
if they are stable for at least 2 months and are not expected to require therapy for 4 
months. 
9. Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled 
vomiting or diarrhea. 
10. Grade ≥2 peripheral neuropathy at baseline (within 21 days prior to cycle 1 day  1). 
11. History of seizures, movement disorders or cerebrovascular accident within the past 1 
years prior to cycle 1 day 1. 
12. Patients with macular degeneration with markedly decreased visual acuity, patients 
with markedly decreased visual acuity (no specific etiology) or uncontrolled 
glaucoma. 
13. Patients who are significantly below their ideal body weight (BMI < 17).. 
14. Serious psychiatric or medical conditions that could interfere with treatment. 
 
7.0 
RECRUITMENT PLAN 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. Potential 
candidates for this study will be discussed during the weekly Leukemia Service new patient 
conference. In addition, potential study participants will be identified by a member of the patient's 
treatment team, the principal investigator, or research team. If the investigator is a member of the 
treatment team he or she will screen their patient’s medical records and discuss the study with the 
patient. Potential study candidates identified during clinic visits or in clinical care meetings on other 


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services, such as the Stem Cell Transplant Service, will be referred to the principal investigator for 
screening and clinical management while on the study. 
 
 
8.1 
PRETREATMENT EVALUATION 
 
The investigator must not start any study related procedure before informed consent form is signed 
and dated by the patient (and impartial witness, if applicable), and investigator. The investigator is 
obliged to give the patient thorough information about the study and study related assessments, and 
the patient should be given ample time to consider his or her participation. If the screening physical 
exam (including vital signs, oxygen saturation) is done within five days of starting the study 
treatment, the exam does not need to be repeated to initiate treatment. 
 
 
W ithin 30 days of starting treatment: 
 
• 
Sign written informed consent 
W ithin 21 days of starting treatment: 
• 
Medical history and review of prior cancer treatment 
• 
Review of concomitant medications 
• 
Complete physical exam including oxygen, routine clinical neurologic examination, and visual 
acuity examination 
• 
12-lead electrocardiogram (baseline assessment) 
• 
Routine urinalysis and microscopic exam if indicated (baseline assessment) 
• 
Comprehensive metabolic panel, uric acid, thyroid stimulating hormone (TSH) 
• 
Coagulation panel (PT, INR, aPTT) 
• 
Serum pregnancy test 
• 
Chest radiograph (baseline – for subsequent comparison. If CT chest or chest X-ray done 
within 30-days prior to start of treatment, no chest X-ray is required) 
• 
Opthalmalogy exam 
• 
Bone marrow biopsy and aspirate (for baseline disease assessment and for research sample 
procurement) 
• 
Baseline blood samples for exploratory pharmacodynamics assessments 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1. Treatment Plan 
 
9.1.1. Treatment Dose and Schedule 
 
The starting dose of selinexor will be 60mg (PO) 2 times a week (+/- 1 day) with at least 36 hours 
between doses. Selinexor will be given for 2 weeks, followed by 1 week of no therapy. The 
scheduled dosing days should be the same days in each week.  One cycle is 21 days or 4 doses 
(plus 1 week off). The drug administration days will occur on the same days within a cycle (ie 
Tue/Thu) but may be adjusted as needed from cycle to cyle. Dosing is not required to start on Day 


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#1 of a given cycle, which will coincide with the patient’s clinic visit. Depending on patient preference 
for dosing days, and given the need to have results from day #1 laboratory evaluations, dosing can 
begin on days 1, 2, or 3 of a given cycle, but preferentially with consistency from one cycle to next. 
Patients will be required to keep a drug dosing diary and symptom diary. Doses should be taken at 
roughly the same time of day (morning, afternoon, or evening hours), ensuring there is at least 36 
hours between doses. Selinexor is taken with solid food consumption. Food should contain at least 
moderate fat content. Selinexor tablets should not be opened, chewed, or crushed. 
Compliance to study medication will be ascertained by use of patient diaries. The date, time and 
number of tablets consumed will be recorded as per study drug schedule. The principal investigator 
or the designee will account for the number of tablets dispensed against those returned by the 
patient. Any deviations and missed doses will be recorded in the medical record and drug 
accountability logs for verification with the reasons. The investigator / designee will try to ensure 
complete compliance with the dosing schedule by providing timely instructions to the patients. 
 
Dose reductions are allowed as decribed in section 9.2 (Table 1). 
 
Patients who come off study after starting study drug because of toxicity, death, or withdrawal of 
consent prior to undergoing a response assessment will not be replaced and will be considered a 
treatment failure. Patients who enroll on study but do not receive study therapy will be replaced. 
9.1.2. Treatment Duration 
 
Patients may continue on study indefinitely if they are experiencing clinical benefit, barring 
progression of disease, excessive toxicity,or withdrawal of consent. After discontinuation from 
treatment, patients will be followed by the study staff for survival status approximately evert three 
months. 
 
 
 
9.2 Dosing Adjustments 
 
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 21 days the patient is taken 
off protocol treatment. 
 
Each dose modification or treatment delay must be documented, including the respective reason. 
 
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 


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27 
 
 
 
 
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. 
9.2.1. Dose Modifications for Non-hematologic Toxicity Unrelated to Selinexor 
 
For all ≥ Grade 3 non-hematologic toxicitiies that are NOT selinexor related: 
 
• 
Hold selinexor dose until AEs resolves to ≤ Grade 1 or baseline (maximum 28 days). 
Exceptions to this include: Patients with grade ≥3 nausea, vomiting or diarrhea can continue 
selinexor unless optimal supportive therapies have already been administered for at least 3 
days days without improvement of the nausea, vomiting, or diarrhea. Optimal supportive 
therapies (see Supportive Care Guidelines, Section 9.1.3). 
• 
If the AEs resolve to ≤ Grade 1 or baseline within 28 days, restart Selinexor at the same dose. 
• 
If the AEs do not resolve to ≤ Grade 1 or baseline within 28 days of discontinuation of study 
drug, study drug will be discontinued permanently. 
 
In exceptional situations, if the patient has experienced objective evidence of clinical benefit, and in 
the opinion of the investigator no safety concerns are present and it is in the best interest of the 
patient to remain on study, the patient may continue to receive study treatment after the 28-day 
delay. The rationale for continuing study treatment will be documented in the patient’s medical 
record. 
 
9.2.2. Dose Modifications for Hematologic and Non-hematologic Toxicities Related to 
Selinexor 
The criteria for dose modification for toxicities at least possibly related to selinexor are outlined 
below in Table 1. Supportive care guidelines for management of selinexor-related toxicities and 
indications for dose modifications are described in Table 2. 
 
 
Table 1. Pre-specified Dose Modifications for AEs Related to Study Drug 
 
Dose  Level 
Starting Dose 
1 
60mg 
twice weekly 
Dose  Reductions 
-1 
40 mg 
twice weekly 
-2 
40 mg 
once weekly 


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Table 2. Supportive Care and Dose Modification Guidelines 
 
Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Fatigue (common) 
Grade 1 
Rule out other causes of fatigue. 
Consider addition of 4-8 mg dexamethasone or 
equivalent on the day after selinexor. 
Insure adequate caloric intake and assess 
volume status. 
Maintain dose. 
Grade 2 
Rule out other causes of fatigue. 
Consider addition of 4-8 mg dexamethasone or 
equivalent on the day after selinexor. 
Insure adequate caloric intake and assess 
volume status. 
For additional support see NCCN fatigue 
guidelines. 
Maintain dose. 
Consult medical monitor for additional 
option such as temporarydose reduction or 
short dose interruptions. 
Grade 3 
See above guidelines for Grade 2 fatigue 
Interrupt selinexor dosing until resolved to 
Grade ≤ 2, For first occurrence of Grade 3, 
if adequate supportive care resulted in 
fatigue improving to Grade ≤ 1 within 7 
days, restart selinexor at current dose. 
Otherwise, restart selinexor one dose level 
lower 
Anorexia or Weight loss 
Grade 1 
Rule out other causes of anorexia. 
Assess dietaryoptions (e.g., try a variety of 
other foods). 
Add high-calorie supplements (e.g., Ensure®). 
Consider addition of 4-8 mg dexamethasone or 
equivalent on the day after selinexor dosing. 
Maintain dose. 
Grade 2 
Rule out other causes of anorexia. 
Assess dietaryoptions (e.g., try a variety of 
other foods). 
Add high-calorie supplements (e.g., Ensure®). 
Consider addition of 4-8 mg dexamethasone or 
equivalent on the day after selinexor. 
Consider megesterol acetate 80-400 mg daily. 
Consider anabolic steroids such as 
oxandrolone, or dronabinol (Marinol®) or other 
cannabinoid, mainlyfor patients who cannot 
tolerate steroids or are at high risk to progress. 
For additional supportive care see NCCN 
guidelines (see Appendix 8). 
Selinexor may be skipped intermittently 
while supportive medications are instituted, 
usuallyfor < 1 week. 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3 
See guidelines for Grade 2 anorexia above 
Interrupt dosing with selinexor. 
Restart selinexor at 1 dose level reduction 
(see Table 1) once anorexia resolves to 
Grade ≤ 2 and patient is clinicallystable. 
Grade 4 (anorexia only) 
See guidelines for Grade 2 anorexia above 
Stop dosing of selinexor. 
Restart selinexor at 1 dose level reduction 
(see Table 1) only if anorexia resolves to 
Grade ≤ 2, patient is clinicallystable other 
contributing factors have been addressed. 
Nausea, Acute (common) 
Grade 1 
Ensure adequate caloric intake and assess 
volume status. 
Consider alternate 5-HT3 antagonists and/or D2 
antagonists as needed. Consider addition of 
NK1 antagonists. 
Consider addition of 4-8 mg dexamethasone or 
equivalent on the day after selinexor. 
Maintain dose. 
Grade 2 
See guidelines for Grade 1 nausea above. 
For additional options see NCCN guidelines for 
antiemesis (see Appendix 7). 
Selinexor may be skipped intermittently 
while supportive medications are instituted, 
usuallyfor <1 week. 
Grade 3 
See guidelines for Grade 1 nausea. 
For additional options see NCCN guidelines for 
antiemesis (see Appendix 7). 
Interrupt selinexor dosing until resolved to 
Grade ≤ 2. For first occurrence of Grade 3, 
if adequate supportive care resulted in 
nausea improve to Grade ≤ 1 within 3 days, 
restart selinexor at current dose. 
Otherwise, restart selinexor one dose level 
lower (see Table 1). If nausea stabilizes for 
at least 4 weeks at Grade ≤ 1, original dose 
of selinexor may be resumed. 
Hyponatremia (common) 
Grade 1 (sodium levels < 
Normal to 130 nM) 
Ensure that sodium level is corrected for 
hyperglycemia (serum glucose > 150 mmol/L). 
Rule out other causes of low sodium (e.g., 
cardiac, hepatic, adrenal, renal and thyroid 
diseases, SIADH, Fanconi Syndrome, 
hyperglycemia, diuretic use). 
Consider salt supplementation 1-2 times per 
day. 
Maintain dose. 
Grade 3 (sodium levels 
126-129 nM) without 
Symptoms 
Ensure that sodium level is corrected for 
hyperglycemia (serum glucose > 150 mmol/L). 
Rule out other causes of low sodium (e.g., 
cardiac, hepatic, adrenal, renal and thyroid 
diseases, SIADH, Fanconi Syndrome, 
hyperglycemia, diuretic use). 
Initiate salt supplementation 2-3 times per day. 
Hold selinexor until Grade ≤ 1 (≥ 130 nM), 
restart on the same dose level. 
Grade 3 (120-125 nM) or 
Grade 4 or Grade 3 with 
Symptoms 
Correct sodium as per institutional guideline 
Initiate salt supplementation 2-3 times per day. 
Hold selinexor until resolved to Grade ≤ 1  
(≥ 130nM) then reduce selinexor dose by1 
level (See Table 1). For Grade 3 
hyponatremia, if serum sodium stabilizes to 
grade ≤ 1 for at least 4 weeks, original dose 
of selinexor may be resumed. 
Diarrhea (common) 
Grade 1+2 
Diet recommendation as per guidelines 
(Benson, 2004)b. 
Institute standard anti-diarrheal therapy. 
After the first occurrence of diarrhea, 
loperamide 2 mg should be considered 
prophylacticallyapproximately1-2 hours before 
the administration of selinexor and repeated 
every 4 hours for the first 12 hours. 
For Grade 2 only, reduce selinexor one 
dose level (See Table 1) until resolved to 
≤ Grade 1, then re-start at the current dose 
level. 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3 
Institute IV fluids. 
Diet recommendation as per guidelines (Benson 
2004)b. 
Institute standard anti-diarrheal therapy. 
Once the symptoms resolve to ≤ Grade 1, 
loperamide 2 mg should be considered 
prophylacticallyapproximately1-2 hours before 
the administration of selinexor and repeated 
every 4 hours for the first 12 hours. 
Delay selinexor until resolved to ≤ Grade 1, 
then reduce selinexor dose by one dose 
level (See Table 1). If diarrhea stabilizes for 
at least 4 weeks at Grade ≤ 1, then original 
dose of selinexor maybe resumed. 
Grade 4 
Rule out other causes of diarrhea, including 
infectious agents. In case of opportunistic 
infection, withdraw all steroids (with tapering if 
medicallyappropriate) until culture is negative. 
Follow institutional guidelines for Grade 4 
diarrhea. 
Delay selinexor until resolved to ≤ Grade 1, 
then reduce selinexor dose by one dose 
level (See Table 1) 
Thrombocytopeniac 
Grade 1 
None 
Maintain dose. 
Grade 2 
Consider implementing platelet growth factors 
(eltrombopag or romiplostim +/- oprelvekin [IL- 
11]) and platelet transfusions, per institutional 
guidelines. 
Monitor platelet counts weekly. 
Grade 3 
Thrombocytopenia 
Without bleeding 
Initiate platelet growth factors (eltrombopag or 
romiplostim +/- oprelvekin [IL-11]) and platelet 
transfusions per institutional guidelines. 
Monitor platelet counts at least weekly. 
In general selinexor dose should be 
reduced one dose level (see See Table 1). 
In certain cases when there is significant 
disease involvement in the bone marrow 
(e.g., in heavily pretreated multiple 
myeloma) or pre-existing compromised 
marrow function (e.g., due to prior marrow- 
toxic therapy), the Investigator in 
consultation with the Sponsor maydecide 
to continue Selinexor dosing, provided that 
platelet counts and bleeding 
symptoms/signs are closelymonitored. 
Grade 4 
Thrombocytopenia 
Without bleeding 
Follow guidelines (above) for Grade 3 
thrombocytopenia without bleeding. 
Transfuse as per institutional guidelines. 
In general, hold selinexor dos until platelet 
counts >50,000/mm 3 or baseline, then 
resume selinexor dosing at one dose level 
lower (See Table 1). In certain cases when 
there is significant disease involvement in 
the bone marrow (e.g., in heavily pretreated 
multiple myeloma) or pre-existing 
compromised marrow function (e.g., due to 
prior marrow-toxic therapy), the Investigator 
in consultation with the Sponsor may 
decide to continue Selinexor dosing, 
provided that platelet counts and bleeding 
symptoms/signs are closelymonitored. 
≥ Grade 3 
Thrombocytopenia with 
bleeding 
Transfuse as per institutional guidelines. 
Follow guidelines for Grade 3 thrombocytopenia 
without bleeding. 
Hold selinexor dosing until platelet counts 
>50,000/ mm 3 or baseline, then resume 
selinexor dosing at one dose level below 
(See Table 1) 
Neutropenia 
Grade 3 Neutropenia 
without fever 
Implement growth factors per institutional 
guidelines until neutrophils are consistently 
> 1,500/mm 3. 
Maintain dose. 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 4 Neutropenia 
without fever 
Implement growth factors per institutional 
guidelines. 
Reduce selinexor dose byone level (See 
Table 1). 
After implementation of growth factors, for 
patients who achieve neutrophil levels > 
1,500/mm 3 for > 4 weeks (in the presence 
or absence of growth factors), selinexor 
dose maybe re-escalated, with frequent 
monitoring implemented. 
Grade 3 or 4 Neutropenia 
with fever (febrile 
neutropenia) 
Implement growth factors per institutional 
guidelines. 
Implement broad anti-microbial coverage per 
institutional guidelines. 
Please note that selinexor has not been 
associated to date with any opportunistic 
infections 
Hold selinexor until fever resolves and 
patient is clinicallystable. 
When patient is clinically stable, restart 
dosing one dose level lower (See Table 1) 
After implementation of growth factors, for 
patients who achieve neutrophil levels 
>1,500/mm 3 for >4 weeks, selinexor dose 
may be re-escalated, provided frequent 
monitoring is implemented. 
Other Selinexor-related Adverse Eventsd 
Grade 1 or 2 
Initiate standard supportive care per institutional 
guidelines. 
Maintain dose. 
Grade 3 
Initiate standard supportive care and follow 
institutional guidelines. 
Delay dose until resolved to Grade ≤ 1 or 
baseline, then reduce by one dose level 
(See Table 1) 
Grade 4 
Initiate standard supportive care and follow 
institutional guidelines. 
Delay dose until resolved to Grade ≤ 1 or 
baseline, then reduce by two dose levels 
(See Table 1) 
All dose modifications should be based on the worst preceding toxicity. 
a National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines®): 
Fatigue. Available at http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf 
b Benson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced 
diarrhea. J Clin Onc 2004; 22:2918. 
c 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. 


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9.2.3. Dose Reductions for Renal Impairment 
Because the impact of renal dysfunction on Selinexor is not known, patients with GFR <30mL/min are 
not eligible to enter the study. Refer to dose adjustment guidelines below for renal dysfunction that 
develops while on study and unrelated to Selinexor. 
 
 
Dose Adjustment Guideline for renal dysfunction while on study 
 
Renal  Dysfunction 
Recommended  Action 
Normal 
to 
Moderate 
(GFR ≥ 30 mL/min) 
• 
Full dose 
Severe 
(GFR < 30 mL/min) 
• 
Reduce Selinexor by 30% for at least two weeks 
• 
If reduced dose is well tolerated, or GFR increases to 
>30mL/min, then Selinexor may be increased to starting dose 
after consultation with the Principal Investigator. 
 
 
9.2.4. Selinexor Dose Adjustment in the Setting of Infection 
 
Patients with active uncontrolled infections should have selinexor treatment withheld until the 
infection has clinically resolved or is controlled. After the infection is controlled, treatment may 
continue at the original dose.  Missed doses will not be replaced. Patients may continue on 
antibiotics for prolonged periods while re-initiating their selinexor regimen at the discretion of the 
investigator but the infection must be clinically stabilized prior to restarting selinexor. 
 
For patients with recurrent episodes of complicated febrile neutropenia, follow the guidelines 
outlined in the table above: “Dose adjustment guidelines for hematologic selinexor-related 
toxicities”. 
 
 
9.2.5. 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: 
• 
Grade 3 nausea, vomiting or diarrhea (unless persisting > 3 days with adequate treatment of 
anti-emetics or anti-diarrheals 
• 
Alopecia of any grade 
• 
Weight loss of less than 20% 
• 
Electrolytes abnormalities that are reversible with oral supplements or brief intravenous 
infusions. 
 
9.2.6. Missed or Vomited Doses 
 
 
 
Missed doses during the week may be replaced within 24 hours. 
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.  Doses 


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should not be administered less than 36 hrs apart and all missed doses should be documented in 
the patient diary. 
If a dose is vomited within one hour of ingestion, it will be considered a missed dose and recorded 
as such on the patient diary.  The dose will not be repeated that same day but the patient will follow 
regular schedule starting the next study dosing day.  If vomiting occurs more than 1 hour after 
dosing, it will still be considered a complete dose. 
 
9.2.7. Delays, Modifications and Reintroduction 
 
All delays, modifications, and reintroductions of Selinexor dosing will be made in consultation with the 
Principal Investigator. 
9.3. Concommitant  Medications 
 
9.3.1. Medications for the 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. 
9.3.2. Use of Blood Products 
 
During the administration of Selinexor, patients may receive red blood cell (RBC) or platelet 
transfusions for disease or selinexor-related anemia or thrombocytopenia, if clinically indicated, and 
as per institutional guidelines.  Also see guidelines for managing grade 3/4 thrombocytopenia and 
bleeding complications in the table above (“Dose adjustment guidelines for hematologic selinexor- 
related toxicities”). 
9.3.3. Glucocorticoid Therapy 
 
Glucocorticoids ≤ 10 mg oral prednisone (or equivalent) per day are permitted for non-malignant 
conditions (i.e., asthma, IBD, etc.) as needed. 
9.3.4 Required 5-HT3 Antagonists 
 
In order to minimize nausea, unless contraindicated, all patients must receive 5-HT3 antagonists 
(ondansetron 8 mg or equivalent), starting before the first dose of selinexor and continued 2-3 times 
daily thereafter, as needed. 
9.3.5 Supportive Care for Anorexia, Nausea/Vomiting, and Fatigue 
 
Supportive measures for optimal medical care should be provided to patients during participation in 
this study. Based on clinical observations in over 550 adult patients treated with selinexor as of 
1 December 2014, the main side effects have been primarily related to anorexia with poor caloric 


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and fluid intake, fatigue, and nausea. .In addition to required 5-HT3 prophylaxis (see Section 9.3.4), 
anti-nausea/anti-emetic therapy, acid suppression (proton-pump inhibitors [PPI] and/or H2-blockers) 
and other treatments may be administered as follows: 
• 
Appetite stimulants: megesterol acetate at a dose of 400-800 mg daily. 
 
• 
Nausea/vomiting and anorexia: Management as per the National Comprehensive Cancer 
Network® [NCCN] Clinical Practice Guidelines. See Apendix 7 (NCCN Guidelines for use of anti- 
emetics) and Appendix 8 NCCN Guidelines for management of anorexia/cachexia). 
• 
Neurokinin-1 receptor antagonist (NK1R antagonist): Aprepitant or equivalent should be 
considered and will be covered for selected patients who have severe nausea and vomiting. 
 
Supportive care guidelines for managing AEs are provided in Section 9.2.2, Table . 
 
9.3.6 Dietary and Concomitant Medication Restrictions 
 
Medications: 
Although acetaminophen (paracetamol) use in combination with selinexor was 
restricted in previous selinexor studies based on theoretical interactions  with 
GSH, ongoing clinical safety evaluations on the use of these drugs together have 
not shown any significant clinical or laboratory abnormalities with doses of 
acetaminophen of up to 1 gm and selinexor up to 55 mg/m 2 (approximately 80- 
100 mg). Therefore, there are no longer any restrictions on the use of 
acetaminophen or acetaminophen-containing products in combination with 
selinexor, EXCEPT on days on selinexor dosing, when acetaminophen must not 
exceed a total daily dose of 1 gram. 
 
Diet: 
There are no dietary restrictions on this study. 
 
 
 
9.4.  Prohibited Concomitant medications 
 
Concurrent 
therapies: 
Concurrent therapy with glucocorticoids is allowed, as specified in Section 9.3.3. 
 
Concurrent 
therapy with any other approved or investigative anticancer 
therapeutic is not allowed. Other investigational agents should not be used during 
the study. Use of any immunosuppressive agents during the study must be 
confirmed by the Medical Monitor. 
 
Medications: 
Patients should not take glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N- 
acetylcysteine (NAC)-containing products during their participation in this study 
as these products may enhance the metabolism of selinexor.  Please see Section 
20.5 (Appendix 5) for a list of representative products. Patients must report all 
prescription and non-prescription medicines to their physicians during this study. 


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10.0 
EVALUATION  DURING TREATMENT/INTERVENTION 
 
Evaluation during treatment:  Screening and Cycle #1 
D- 
D1 D7 (+/-3 
D14(+/- 3 
D21 (+/- 
21 
Days) 
Days) 
1 D) 
to - 
1 
Written Informed Consent 
X 
Medical History & Prior Cancer Treatments 
(1) 
X 
Complete Physical Examination, Oxygen 
saturation 
X 
X 
X 
Weight, Blood Pressure, Pulse, 
Temperature 
X 
X 
X 
X 
X 
12-lead Electrocardiogram (ECG) (2) 
X 
X 
Serum Pregnancy Test (within 7 days of 
dosing) 
X 
Urinalysis (& microscopy if indicated) (3) 
X 
Complete Serum Chemistry (4) 
X 
X 
X 
X 
X 
Thyroid Stimulating Hormone (TSH) 
X 
Coagulation tests (PT, INR, aPTT) (5) 
X 
X 
X 
X 
CBC with Differential & Reticulocyte Count 
(6) 
X 
X 
X 
X 
X 
Chest Radiograph (7) 
X 
Ophthalmology exam(12) 
X 
Bone marrow samples for routine disease 
assessments (11) 
X 
X 
Blood samples for pharmacodynamic 
assays (10) 
X 
X 
X 
X 
X 
Bone marrow samples for 
pharmacodynamic assays (10) 
X 
X 
X 


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Selinexor dosing (8) 
2 doses per week for two weeks, followed 
by one week of no therapy 
Adverse Events 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
 
 
 
 
Evaluation during treatment:  Cycle 2, 3, 4, etc., and at End of Study 
D 1 
D 14 
(+/- 3 
days) 
D 21 (+/-1 day) 
End of Study 
Visit Within 30 
(±7) days post 
last dose 
Complete Physical 
Examination 
X 
X 
Weight 
X 
X 
X 
12-lead Electrocardiogram 
(ECG)(2) 
X 
Pregnancy Test (within 7 
days of dosing) 
X 
X 
Serum Chemistry 
X 
X 
X 
Coagulation tests (PT, INR, 
aPTT) 
X 
X 
CBC with Differential, 
reticulocyte count 
X 
X 
X 
X 
Blood and bone marrow tests 
for pharmacodynamic assays 
(blood and BM pre-dose and 
blood 4 hours post-dose) 
X (cycles 2 & 4) 
X 
Bone marrow tests for 
response assessment 
X (cycles 2, 4 then 
every other cycle 
until CR or max 
response, and 
when clinically 
indicated) 
X 
Selinexor dosing (8) 
2 doses per week for two weeks, followed by one 
week of no therapy 


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Adverse Events 
X 
X 
X 
Ophthalmology exam(12) 
-12 
-12 
-12 
-12 
Concomitant Medications 
X 
X 
X 
 
 
 
 
Treatment calendar notes and event windows 
 
Cycle 1 day 1 must begin within 5 working days of registration. 
 
All screening evaluations are to be performed within 21 days (Day -21 to -1) prior to cycle 1 day 1. 
 
All serum chemistry and CBC with differentials results must be reviewed and assessed by the 
investigator prior to all Selinexor administration for cycle 1. Chemistry labs do not have to be 
repeated if they have been performed within 1 week prior Selinexor administration (except for 
screening labs). 
For cycles 2 and beyond, day 1- a CBC must be completed and results must be reviewed by study 
investigator before patients take first dose for that cycle. 
End of Study visit is to be performed within 30 ± 7 days following patient’s last drug administration. 
If, in the judgment of the investigator, the patient requires immediate anti-cancer therapy, the final 
visit may be conducted earlier than 30 days and should preferably be completed prior to patient 
receiving any additional therapy. 
Patients will receive selinexor twice weekly, dosed at least 36 hours apart orally at a starting dose of 
60mg per dose. Selinexor will be given for 2 weeks, followed by 1 week of no therapy. 
Patients will undergo a baseline ophthalmologic exam by either their personal Ophthalmologist or by 
an MSKCC Ophthalmologist to document any pre-existing conditions. If vision changes occur on 
study, the baseline exam will be used to detect any new pathology, but serial exams are not mandated 
All physical examinations must be performed by an MD or Nurse Practitioner listed on the face sheet 
for this study. 


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38 
 
 
 
 
Study Assessments  Footnotes 
 
 
1. Medical History & Prior Cancer Treatments: includes detailed history of prior cancer 
therapies including start and stop dates, and disease progression during or after therapy, as 
well as discontinuations due to intolerability  or any other serious illness. 
 
2. ECGs: to be performed in a supine position at screening, then bi-weekly during cycle 1 (pre- 
dose). For cycles 2 and beyond, EKG will be done pre-dose on day 1 of each cycle. ECGs 
do not have be repeated if one was performed within 1 calendar day prior to visit. 
3. Urinalysis (& microscopic exam if clinically indicated): include appearance, color, urine 
bilirubin, glucose, hemoglobin, ketones, pH, protein, specific gravity, urobilinogen, and 
microscopic examinations if any of the preceding urinalysis tests are abnormal. Urine 
samples will be obtained at screening and during the study only if clinically indicated. Urine 
microscopy will be done only if urinalysis results are considered clinically significant by 
investigator. 
 
4. Complete Serum Chemistry: include Sodium, Potassium, Chloride, Bicarbonate, BUN, 
Creatinine, and Glucose, Calcium, Phosphate, Magnesium, ALT, AST, Alkaline Phosphatase, 
Total Bilirubin, LDH, Total Protein, Albumin, and Uric acid. Chemistry tests are                     
to be performed at screening, weekly during cycle 1, and every 2 weeks during cycle 2 and 
beyond, and at the off-study visit. May be performed at MSKCC or local laboratory. 
 
5. Coagulation: include Prothrombin Time (PT), international normalization ratio (INR), and 
activated Partial Thromboplastin Time (aPTT) which will be performed at screening,  during 
cycle 1 on days 7 (+/- 3 day), and 21 (+/- 3 day).  For cycles 2 and beyond, coagulation 
studies are to be performed on day 1 (+/- 3 days)  and at the final visit.  For patients being 
treated with warfarin (Coumadin), these coagulation tests are to be performed and monitored 
twice a week during the first two cycles and anytime the dose of Selinexor is adjusted.  If the 
INR is stable after the first two cycles, then monitoring may revert to once per cycle on day 1. 
May be performed at MSKCC or local laboratory. 
 
6. CBC with differential and reticulocyte count: include hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, white blood cell (WBC) count, WBC differential, red blood cell count, 
reticulocytes, lymphocytes, monocytes, neutrophils, band neutrophils, eosinophils, basophils, 
platelets.  WBC differential may be automated or manual. May be performed at MSKCC or 
local laboratory. 
 
CBC with differentials to be performed at screening, cycle 1 day 1, and on days 7, 14, 21 (+/- 
1 day ), cycles 2 and beyond on days 1, 14 (+/- 3 days), or more often as clinically indicated, 
and at the End of Study visit. 
 
7. Chest Radiograph: both posteroanterior and lateral films should be obtained at baseline. 
Note: this test does not need to be repeated if results are available from a CT of chest or 
chest X-ray (PA and laeteral views) performed 30 days prior to C1D1. This test is done to 
ensure the absence of active pulmonary disease prior to therapy and as a baseline for 
comparison in the event that patients develop pulmonary adverse effects during the study. 
 
8. Selinexor Drug Administration: patients will receive selinexor twice weekly 


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39 
 
 
 
 
 
orally at a starting dose of 60mg per dose. Selinexor will be given for 2 weeks, 
followed by 1 week of no therapy. The scheduled dosing days should be the same days in 
each week.  One cycle is 21 days or 4 doses (with the following week off). 
 
 
9. Blood and bone marrow tests for pharmacodynamics:  blood samples (7ml EDTA, 2ml 
EDTA, and/or PAXgene) 
and bone marrow samples will be obtained for research assessments at baseline, cycle 1 
day 7 (PB only; +/- 2 days, and after 2 doses of Selinexor), cycle 1 day 14 (PB and BM; +/- 3 
days), cycle 1 day 21 (PB and BM; +/- 3 days and before dosing starts for cycle #2), and PB 
and BM day 21of cycle 2 and 4, and at the time of the End of Study bone marrow. 
The day 14 bone marrow specimens will be obtained on the first 10 patients. For details 
regarding the samples and assays at these time points, see the Karyopharm Laboratory 
manual (for analyses done at Karyopharm), and see Section 10.4 for a description of the PD 
analyses to be done in the MSKCC Pathology Core Laboratory, and the laboratory of Dr. 
Andreef and Dr. Schwartz. In the event a patient is not dosed during a protocol visit, the visit 
will be rescheduled to reassess the patinet’s condition, and in order to obtain all required 
research samples.  The patient will continue their subsequent visits as planned. Additionally, 
if a patient’s dose is held to reassess their disease status, research pharmacodynamic 
samples will be held until disease status is confirmed, or at the discretion of the treating 
investigator. 
 
10. Bone marrow tests for disease assessments: Bone marrow aspirate and biopsy will be 
performed at baseline, on day 1 of cycle 2 (same as cycle #1, day 21), and on day 21 of 
cycles 2, and every other cycle therafter until CR or maximal response is achieved, at the 
time of disease progression, and at the End of Study visit (for patients coming off study for 
reasons other than disease progression). 
 
11. Ophthalmology exam: A full ophthalmological exam, by an ophthalmologist, is 
required of all patients at screening, and if clinically indicated during study. The 
following criteria will be followed: 
1. Prior to dilation: 
• Best corrected visual acuity 
• Slit lamp examination including tonometry 
2. Dilated: 
• Fundoscopy 
• Slit lamp examination to document lens clarity 
If a cataract is seen during the exam, it will be graded according to the Lens Opacities 
Classification System (LOCS III; (See Section 20.6, Appendix 6). 
 
 
 
10.2 Efficacy assessments 
 
Efficacy will be assessed by evaluation of bone marrow aspirates and biopsies, complete blood 
counts, and transfusion records. Hematologic Improvement will be assessed continuously, with the 
use of CBC values and transfusion records. At the time of bone marrow aspirates and biopsies, full 
efficacy evaluations will be performed, taking into account blood and bone marrow parameters, and 
responses will be assessed using the 2006 Modified  MDS International  Working Group Response 
Criteria. All efforts should be made to obtain bone marrow studies at the End of Study visit. 


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10.3 Safety assessments 
 
Safety will be assessed continuously by monitoring for new or worsening subjective symptoms, 
physical exam findings, and laboratory values. For details on Adverse Event collection and reporting, 
please see Section 17.2. 
 
 
10.4 Pharmacodynamic  (PD) Studies 
 
PD schedule: 
 
Blood samples and bone marrow samples will be obtained for research assessments at the following 
timepoints: 
Baseline, day -21 to -1: Blood and bone marrow samples for PD studies at time of routine disease 
assessment (for Karyopharm, Dr. Schwartz, Dr. Andreef, MSKCC Pathology Laboratory). 
Cycle 1 day 1: PD samples at pre-treatment, 4 hours, and 8 hours post dose (Karyopharm) 
 
Cycle 1 day 7 (+/-1 day):  Pre-dose blood samples (7ml EDTA x2) for PD studies at time of routine 
bloodwork (Dr. Schwartz) 
Cycle 1 day 14 (+/- 3 days): Blood samples at time of routine bloodwork for PD studies. BM aspirate 
and biopsy (for first 10 patients only) for PD research studies (for Karyopharm, Dr. Schwartz, Dr. 
Andreef, MSKCC Pathology Laboratory).. 
 
Cycle 1 day 21 (+/- 1 day): Before dosing starts for cycle #2 and at time of routine disease 
assessment.PB and BM aspirate and biopsy for PD studies (Karyopharm, Dr. Schwartz, Dr. Andreef, 
MSKCC Pathology Laboratory) 
Cycle 2 and 4, day 21 (+/-1 day): At time of routine disease assessment; PB and BM aspirate for PD 
studies  (Karyopharm, Dr. Schwartz, Dr. Andreef, MSKCC Pathology Laboratory) 
At the time of the End of Study bone marrow (At time of routine disease assessment): PB and BM 
aspirate for PD studies  (Karyopharm, Dr. Schwartz, Dr. Andreef, MSKCC Pathology Laboratory) 
 
 
Pharmacodynamic Studies: 
 
Dr. Gary Schwartz: blood and bone marrow aspirates will be shipped to Dr. Schwartz’s laboratory at 
Columbia University for studies to assess the mechanism of selinexor. His laboratory will perform  
the following analyses: Western blots for XPO1, p53, p21, PARP, and caspase. Specimens will be 
processed using ficoll-hypaque separation at the HOTB. Bone marrow and blood mononuclear cells 
will be viably cryopreserved (in DMSO) and stored until they are batch-shipped approxiamately once 


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each month on dry ice to the laboratory of Dr. Schwatrz at Columbia University c/o Shyamprasad 
Deraje Vasudeva via FedEx (account number 2346-5338-5).at the following address: 
Columbia University 
1130 Saint Nicholas Ave 
ICRC Room 207, Schwartz Lab 
New York, NY 10032 
 
MSKCC Surgical Pathology: 
Dr. Sen will direct the processing of bone marrow immunohistochemical (IHC) stains, which will be 
performed by the Pathology Core Laboratory at MSKCC to assess nuclear localization of beta 
catenin and p65, thereby assessing for evidence of WNT and NF-kB pathway signaling activation, 
respectively. Bone marrow specimens will be processed routinely for response assessment at the 
designated time points as per the protocol. Specimens will be directed to Dr. Filiz Sen. Extra 
sections will be obtained under the direction of Dr. Filiz Sen, and the Core Laboratory will 
perform.IHC for nuclear beta catenin and p65 using standard IHC techniques. . 
 
Dr. Michael Andreef (MD Anderson Cancer Center): 
 
Dr. Andreef will assess nuclear and cytoplasmic p53 localization on unstained bone marrow aspirate 
smears. Bone marrow aspirate slides are prepared at the time of the bone marrow procedure as per 
standard routine. No processing is required. These slides will be delivered to Dr. Klimek and will be 
stored at room temperature until they are batch-shipped by UPS approxiamately every three months 
at ambient temperature in plastic slide carriers to Dr. Andreef. Specimens will be sent to the  
attention of Teresa Mcqueen (using Fedex accout # 136495291) at the following address: 
Name: Teresa Mcqueen 
Company: MD Anderson Cancer Center 
Address: 6767 Bertner Ave. 
T6.3948 
Houston Tx 77030 
 
 
Karyopharm: 
Karyopharm will perform functional assays to assess NFkB and WNT pathway signaling and 
cytokine levels. Blood and bone marrow samples will be delivered to the MSKCC HOTB for 
centrifugation, aliquotting and storage to be batched-shipped to Karyopharm. Details are provided in 
the Karyopharm laboratory manual. 
 
 
11.1 TOXICITIES/SIDE EFFECTS 
 
Side effects observed in patients include: 
 
COMMON, SOME MAY BE SERIOUS 
 
In 100 people receiving selinexor, more than 20 and up to 100 may have: 
• 
Nausea and/or vomiting 
• 
Fatigue or loss of energy 
• 
Loss of appetite 
• 
Diarrhea 


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42 
 
 
 
 
• 
Weight loss 
• 
Low platelets 
• 
Decrease in red blood cells 
• 
Low sodium 
 
 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
 
In 100 people receiving selinexor, from 4 to 20 may have: 
• 
Change in taste 
• 
Dehydration 
• 
Dizziness 
• 
Constipation 
• 
Confusion 
• 
Shortness of breath 
• 
Visual changes including blurred vision 
• 
Low neutrophil count 
• 
Low white blood cell count 
• 
Increased creatinine 
• 
Dry mouth 
• 
Sepsis 
 
RARE, AND SERIOUS 
 
In 100 people receiving selinexor,  3 or fewer may have: 
• 
worsening cataract 
• 
Febrile neutropenia 
• 
Fainting 
• 
Cognitive disturbance 
• 
Altered balance 
• 
Acute cerebellar syndrome – symptoms can include a sudden loss of coordination 
• 
Pneumonia 
 
Reproductive risks 
 
Patients should not become pregnant or father a baby while on this study because the drugs in this 
study can affect an unborn baby.  Women should not breastfeed a baby while on this study.  It is 
important patients understand the need to use birth control while on this study. 
Adverse Events Reporting 
 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product whether or not it is related to the medicinal product. This 
includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. An abnormal laboratory value will not be assessed 


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43 
 
 
 
 
as an AE unless that value leads to discontinuation or delay in treatment, dose modification, 
therapeutic intervention, or is considered by the investigator to be a clinically significant change from 
baseline. 
 
 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The primary and secondary efficacy endpoints of this study will be assessed using the 2006 
Modified MDS International Working Group response criteria (Cheson et al., 2006). 
Patients will be eligible for the primary efficacy endpoint if they have undergone at least one cycle of 
therapy, and are evaluable for response. Patients will be evaluable for Hematologic Improvement 
with the availability of CBC parameters and transfusion records, and will be evaluable for all 
response categories if they undergo at least one bone marrow procedure (first planned marrow for 
response assessments is after dosing is completed for the first 21-day cycle). 
 
For the primary endpoint, overall CR, marrow CR, and PR, and HI responses will be tabulated. 
 
According to the 2006 Modified MDS International  Working Group response criteria, response 
categories include the following: 
 
 
Complete Remission (CR) 
Bone marrow evaluation: Repeat bone marrow showing  5% or less myeloblasts with normal 
maturation of all cell lines.  Persistent dysplasia will be allowed but noted. 
 
Blood: 
 
Hgb > 11 g/dL (untransfused, patient not on erythropoietin) 
Neutrophils > 1.0 x 109/L or more (not on myeloid growth factor) 
Platelets > 100 x 109/L or more (not on thrombopoietic factor) 
Blasts 0% 
CBC values must last at least 1 month. In some circumstances, protocol therapy may require the 
initiation of further treatment before the 1 month period. Such patients can be included in the 
response criteria into which they fit at the time therapy is started.  Transient cytopenias during 
repeated chemotherapy courses should not be considered as interrupting durability of response, 
as long as they recover to the improved counts of the pervious course. 
 
Partial Remission (PR) 
All the CR criteria except: 
Bone marrow evaluation: Blasts decreased by 50% or more over pretreatment, but  still more than 
5%. 
CBC values must last at least 1 month unless interrupted by therapy as described above. 
 
Marrow CR 
Bone Marrow: 5% myeloblasts or less and decreased by 50% or greater over pretreatment. 
Blood: if criteria for HI responses are met (see criteria below), they will be noted in addition to 
marrow CR 
 
Stable Disease 


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Failure to achieve at least a PR, but with no evidence of progression for at least 2 months 
Failure 
Death during treatment or disease progression characterized by worsening of cytopenias, or 
progression to AML. 
Relapse after CR or PR 
One or more of the following: 
- 
Return to pretreatment bone marrow blast percentage 
- 
Decrement of 50% or greater from maximum remission / response levels in  granulocytes 
or platelets 
- 
Reduction in hemoglobin concentration by at least 1.5 g/dL or new/recurrent transfusion 
dependence (in the absence of another explanation  such as treatment effect, acute 
infection, gastrointestinal bleeding, hemolysis, etc.) 
 
Disease Progression 
- 
For patient with less than 5% blasts: a 50% or more increase in blasts to more than 5% 
blasts 
- 
For patients with 5% to 10% blasts: a 50% or more increase to more than 10% blasts. 
- 
For patients with 10% to 20% blasts: a 50% or more increase to more than 20% blasts 
- 
For patients with 20% to 30% blasts: a 50% or more increase to more than 30% blasts. 
- 
One or more of the following: 50% or greater decrement from maximum 
remission/response levels in granulocytes or platelets, reduction in hemoglobin 
concentration by at least 2 g/dL, or transfusion dependence (in absence of another 
explanation such as acute infection, G.I. bleeding, hemolysis etc.) 
 
 
Hematologic Improvement (HI) 
 
Improvements must last at least 2 months in the absence of ongoing cytotoxic therapy. When 
protocol therapy requires the initiation of further treatment before the 2 month period, 
patients can be included in the response criteria into which they fit at the time therapy is re- 
started. 
Hematologic improvement should be described by the number of individual, positively 
affected cell lines (eg, HI-E; HI-E + HI-N; HI-E + HI-P + HI-N) 
Hematologic Improvement response categories include the following: 
 
• 
Erythroid response (HI-E) 
For patients with pretreatment hemoglobin less than 11g/dL: 
- 
Hemoglobin increase by > 1.5 g/dL 
- 
Relevant reduction of units of RBC transfusions by an absolute number of at least 4 
RBC/8wk compared with the pretreatment transfusion number in the pervious 8 wk. (*) 
 
(*) Only RBC transfusions given for Hgb < 9.0 g/dL will count in the RBC transfusion 
response evaluation. 
• 
Platelet response (HI-P) 
 
For patients with a pretreatment platelet count < 100 x 109/L: 


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An absolute increase of > 30 x 109/L or more for patients  starting with > 20 x 109/L platelets 
 
An increase from < 20 x 109/L to > 20 x 109/L, and by at least 100%. 
 
• 
Neutrophil response (HI-N) 
 
For patients with pretreatment neutrophil count < 1.0 x 109/L: At least a 100% increase and 
an absolute increase  > 0.5 x 109/L. 
Progression/relapse after HI 
 
One or more of the following: 
 
- 
A 50% or greater decrement from maximum response levels in granulocytes or platelets 
- 
A reduction in hemoglobin concentration by at least 1.5 g/dL 
- 
Transfusion dependence (in the absence of other explanation, such as hemolysis, 
hemorrhage, etc). 
 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
Patients may withdraw from the study at any time.  Patients who discontinue from the study will be 
encouraged to return to the study site to undergo the evaluations listed for the End of Treatment 
Visit. 
At the discretion of the Investigator, the investigator may remove a patient from the study for the 
following reasons: 
• 
Due to disease progression 
 
• 
Noncompliance with study procedures 
 
• 
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 
• 
For the third occurrence of the same Grade ≥3 non-hematological toxicity 
• 
For the third episode of clinically significant bleeding or fourth episode of complicated febrile 
neutropenia 
• 
Investigator  discretion 
 
• 
Other treatments become available which are more appropriate for the individual patient 
 
 
To the extent possible, patients must strictly follow the standard dosing schedule. Patients who miss 
3 doses or more (out of 4 doses) in a cycle in the absence of study drug related toxicity will be 
discontinued. 


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46 
 
 
 
 
If the reason for withdrawal is the occurrence of an AE, the patient will be followed by the  
Investigator until such events resolve, stabilize, and according to the Investigator’s judgment there is 
no need of further follow-up.  The reason for withdrawal from the study will be documented in the 
case report form. 
 
 
 
 
14.1 
BIOSTATISTICS 
 
Primary endpoint evaluation 
 
The primary endpoint of this study is to investigate the efficacy of Selinexor in patients with MDS 
refractory to hypomethylating agents (decitabine and/or 5-azacytidine). The standard treatment in 
this setting is supportive care, where the response rate is assumed to be zero. Therefore, in this 
population, a response rate of 25% would be considered promising, whereas a 5% response rate 
would not be considered promising. For purposes of assessing the primary endpoint, response 
categories will include CR, PR, marrow CR (mCR), or Hematologic Improvement. Using a Simon’s 
two-stage minimax design, this trial will accrue a maximum of 20 patients. Early termination may 
occur if no responses are observed in the first 13 patients. If at least one response is observed, the 
trial will continue to the maximum sample size. At the end of the trial, the treatment strategy will be 
considered promising in this patient population if at least 3 patients achieve a response. The type I 
and type II errors are set at 0.10. 
The response evaluation cohort will include those patients who have completed at least 3 of 4 
planned doses of their first cycle of therapy and have undergone at least one full scheduled post- 
treatment disease assessment (informative bone marrow aspirate or biopsy, cytogenetics, and CBC 
with differential). For patients who come off study after completing at least 3 of 4 planned doses of 
their first cycle of therapy and are unable to undergo (or refuse) a bone marrow procedure, an 
assessment for Hematologic Improvement (based on CBC data) will be performed and described 
and an attempt will be made to obtain follow-up CBC data for the 8 weeks mandated to confirm 
Hematologic Improvement according to the MDS International Working Group response criteria. 
Patients who come off study after starting study drug because of toxicity, death, or withdrawal of 
consent prior to undergoing a response assessment will not be replaced and will be considered a 
treatment failure. Patients who enroll on study but do not receive study therapy will be replaced. 
 
Analysis of secondary endpoints 
 
1. Response duration will be caluated among patients who achieve a response of HI, mCR, PR 
or CR using Kaplan-Meier methodology. Median duration of response and the corresponding 
95% confidence interval will be estimated. 
2. The frequency of stable disease will be tabulated and exact 95% confidence intervals will be 
estimated. 
3. The response rate and response duration will also be described for the generally poor-risk 
therapy-related MDS patients enrolled on this study (therapy-related MDS accruals may 
approach ~ 50%, as seen in MSKCC protocol 06-054). The response rate will be estimated 
along with an exact 95% confidence interval to evaluate the proportion of patients who have 


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47 
 
 
 
 
CR, PR, mCR or HI. Median  response duration and corresponding 95% confidence intervals 
will be estimated. 
4. Overall survival from the time of study enrollment will be caluated using Kaplan-Meier 
methodology. Overall survival curves will be displayed for the study population along with 
selected quantiles and corresponding 95% confidence intervals of survival. 
5. Since Selinexor may require chronic dosing to maintain its effect, the overall tolerability and 
safety of chronic Selinexor dosing will be described on patients throughout all cycles of 
treatment who have received at least 1 dose of selinexor. Tolerability will be assessed by 
calculating the proportion of patients who withdraw consent due to chronic low-grade (1/2) 
toxicity. Safety will be calculated by determining the proportion of patients who have any 
toxicity listed in section 11.0. This will be calculated overall at each treatment cycle and 
separately by the Selinexor dose received at the time of the selected toxicity. Proportions 
and exact 95% confidence intervals will be calculated. 
6. Descriptive statistics will be used to explore the relationship between the results of the 
pharmacodynamics studies and therapeutic response or study entry disease parameters. 
The Wilcoxon rank-sum statistic or Fisher’s exact test may be used to assess these 
associations. 
 
 
Accrual rates and study duration 
 
It is expected that the study will accrue 1-2 patients per month, resulting in completion of accrual in 
10-20 months. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
15.3 
Randomization 
 
This is an open-label phase 2 study.No randomization will be performed. 
 
16.1 
DATA MANAGEMENT ISSUES 


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A research study assistant (RSA) will be assigned to study. The responsibilities of the RSA 
include project compliance, data collection, extraction and data entry, data reporting, 
coordination of the activities of the protocol study team and, and of the flow of regulatory 
paperwork. Study accrual is estimated to to take 1.5 years, and it is estimated that the study 
will be complete approximately 9 months from the date of the last regis tration. 
 
 
The data collected for the study will be entered into a secure database (CRDB). All routine 
blood test results required per the protocol will be captured in CRDB in addition to baseline 
medical conditions and disease information, response assessments, off-study 
documentation, and toxicity grade and attribution. Source documentation will be available to 
support the computerized patient record. 
Lab toxicities will be routinely assessed by the PI. The following labs are considered common 
toxicities for the disease under study and therefore should be considered not clinically 
relevant for data entry purposes. 
• 
Total WBC Count 
 
The total WBC count is typically decreased due to the disease process. However, further 
reductions in the WBC count are not clinically relevant. Reductions in other WBC subsets 
may be clinically meaningful and will continued to be entered per MSK guidelines. 
MSKCC will cross-reference Karyopharm’s IND and will be responsible for all safety 
monitoring. All SAEs will be reported to the MSKCC IRB. The safety of the study will be 
monitored by the MSKCC Data and Safety Monitoring Committee. 
 
 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated by the RSA and reviewed by the PI to monitor 
patient accruals and completeness of registration data. Routine data quality reports will be 
generated to assess missing data and inconsistencies. 
 
 
Accrual rates and extent and accuracy of evaluations and follow up will be monitored 
periodically throughout the study. Recurrent lapses in data collection, deviations or violations 
will be disussed with the study team and a corrective plan will be generated. 
Accrual goals and factors impacting accrual goals will be discussed at the weekly New 
Patient/Protocol Leukemia meetings. 
 
 
16.3 
Data and Safety Monitoring 
 
The data and safety monitoring plan at Memorial Sloan-Kettering Cancer Center was 
approved by the National Cancer Institute in September 2001. The plan addressed the new 
policies set forth by the NCI and the document entitled "Policy of the National Cancer 
Institute for data and safety monitoring of clinical trials" which can be found at 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html. 


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The DSM plans at MSKCC were established and are monitored by the Office of Clinical 
Research. The MSKCC data and safety monitoring plan can be found on the MSKCC 
Internet at  
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring%  
20Plans.pdf 
 
Memorial Sloan-Kettering Cancer Center has set up three distinct monitoring processes for 
our clinical trials program. There are two sub-committees of the Center's Institutional Review 
Board/Privacy Board (IRB/PB) and Research Council (RC) that have the responsibility of 
data and safety monitoring. These are joint sub-committees with dual-reportin 
responsibilities. The Data and Safety Monitoring  Committee (DSMC) is the sub-committee 
responsible for monitoring all Phase I, II, I/II, pilot and non-phase clinical trials. The Data and 
Safety Monitoring Board (DSMB) is the sub-committee responsible for monitoring Phase III 
randomized clinical trials. The Therapeutic Response Review Committee (TRRC) is the sub- 
committee of Research Council responsible for the independent therapeutic response review 
for participants in IRB/PB approved clinical trials where therapeutic efficacy is a stated 
primary objective, typically phase II and III trials. Formal monitoring of such studies is 
designed to ensure that the interests of the participants are being scrutinized on a regular 
basis, and that the trial is progressing in a satisfactory manner. 
The Data and Safety Monitoring Committee (DSMC) convenes once per quarter and 
monitors the risk participants are exposed to, the progress of the study, the adequacy of the 
data storage and whether sufficient data are being entered into the CRDB. The DSMC 
monitors phase I, II, I/II, pilot and non-phase trials that are not being monitored by an 
industrial sponsor, and which meet the NCI definition of a Clinical Trial. This trial will qualify 
for monitoring by the DSMC. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required, and the monitoring procedures will be 
established at the time of protocol activation 
16.4 Regulatory Documentation 
 
Participating sites that are consulting and/or conducting specimen or data analysis should 
submit this protocol to their IRB according to local guidelines. Copies of any site IRB 
correspondence should be forwarded to MSKCC. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities and side  
effects. Alternative,  non-protocol, treatment options will be discussed with the patient. It will 
be reviewed that participation in this clinical trial is voluntary and that the patient may 
withdraw consent at any time. The study is designed with careful safety monitoring for toxicity 
including physician visits and serial safety monitoring. Specific guidelines for symptom 
management are in place to protect the study participant. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
50 
 
 
 
 
Human Subjects Involvement and Characteristics: All patients at MSKCC who meet the all of 
the inclusion and none of the exclusion criteria will be eligible. Both men and women and 
members of all ethnic groups are eligible for this trial. Pregnant and breast-feeding women 
are excluded from this study. This protocol does not include children because the number of 
children is expected to be limited for the patient population expected to be accrued onto this 
study. Also, the majority of children are already accessed by a nationwide pediatric cancer 
research network. This statement is based on exclusion 4b of the NIH Policy and Guidelines 
on the Inclusion of Children as Participants in Research Involving Human Subjects. 
Consent process: All patients at MSKCC who meet the inclusion criteria will be eligible. 
Participation in the trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to IRB guidelines. The informed consent procedure is 
described in Section 18.0. 
Possible Toxicities/Side-Effects: There are risks associated with treatment as described in 
Section 11.0; however, patients screened for enrollment will be deemed appropriate for 
treatment independent of this study. 
Benefits: It is unknown if selinexor can benefit patients with myelodysplastic syndromes. The 
goal of this study is to assess if selinexor has the potential to demonstrate objective 
response in patients with myelodysplastic syndromes. 
Costs:  Patients will be charged for physician visits, routine laboratory tests, and radiologic 
studies required for monitoring their condition. The cost of research-only pharmacodynamic 
studies will be covered by research funds. 
Alternatives: For patients considering this trial as second-line therapy, standard second-line 
treatments would include supportive care or another study drug in an alternate clinical trial, 
since for patients considering this trial, there are no standard treatment options. 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential. Patients’ names and any other identifying information will 
not be used in reports or publications resulting from this study. Other authorized agencies 
and appropriate internal personnel (e.g. qualified monitors from MSKCC) and external 
personnel (Karyopharm, the manufacturer of selinexor), its authorized agents, the FDA, 
and/or other governmental agencies) may review patient records as required. 
Patient safety: Patients are monitored by physicians and oncology nurses who are very 
familiar with clinical trials. In the case of an adverse reaction, immediate medical attention is 
available. In the evenings and weekends, we have a 24-hour urgent care facility for 
outpatients. The PI or co-PI will also be available at all times to organize any necessary 
intervention. 
Monitoring of data to ensure safety: This study is to be monitored by the institutional IRB. 
This incorporates an independent data and safety monitoring board established by 
arrangement with the National Cancer Institute. The analysis of safety will include all 
patients. Adverse events, including all toxic effects of treatment, will be tabulated individually, 
and summarized by severity and causality. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
51 
 
 
 
 
 
 
 
17.2 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
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52 
 
 
 
 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office 
 
17.2.1 
 
Reporting to Karyopharm (company holding cross-referenced IND) 
In addition to reporting to the FDA, Sponsor-Investigator will forward completed SAE and 
pregnancy forms to representatives of the Sponsor. Forms will be completed and emailed to  
pharmacovigilance@karyopharm.com 
 
 
 
17.4 Ethics and good clinical practice 
 
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s). The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the IB. 
 
 
17.5 Institutional Review Board 
The protocol, Investigator’s Brochure, Informed Cconsent Form, advertisements (if 
applicable), written information given to the patients (including diary cards), safety updates, 
progress reports, and any revisions to these documents will be provided to the MSKCC IRB 
by the Principal Investigator. Any amendment must be approved after review by the IRB. 
 
 
18.1 
INFORMED CONSENT PROCEDURES 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
53 
 
 
 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
REFERENCES 
 
 
 
Brown 2011. Reactivation of p53: from peptides to small molecules. Christopher J. Brown, Chit F. 
Cheok, Chandra S. Verma and David P. Lane. Trends in Pharmacological Sciences January 2011, 
Vol. 32, No. 1. Pg 53-62. 
Castro-Alcaraz 2002. NF-қB Regulation in Human Neutrophils by Nuclear I  B   : Correlation to 
Apoptosis. Susana Castro-Alcaraz, Veronika Miskolci, Bharati Kalasapudi, Dennis Davidson, and 
Ivana Vancurova. Journal of Immunology, Oct 1, 2002, 169(7): 3947–3953. 
Chapuis 2010. IқB kinase overcomes PI3K/Akt and ERK/MAPK to control FOXO3a activity in acute 
myeloid leukemia. Nicolas Chapuis, Sophie Park, Laurent Leotoing, Jerome Tamburini, Frederique 
Verdier, Valerie Bardet, Alexa S. Green, Lise Willems, Fabrice Agou, Norbert Ifrah, François 
Dreyfus, Georges Bismuth,  Veronique Baud, Catherine Lacombe, Patrick Mayeux,  and Didier 
Bouscary.  Blood. Nov 2010. 116(20):4240-50. 
Cheson 2006. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, 
Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian 
H. Clinical application and proposal for modification of the International Working Group (IWG) 
response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. Epub 2006 Apr 11. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
54 
 
 
 
 
Etchin, 2013. Etchin J, Sanda T, Mansour MR, Kentsis A, Montero J, Le BT, et al. KPT-330 inhibitor 
of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models 
of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia. Br J Haematol. 2013 
Apr;161(1):117-27. 
Golomb 2012. Importin 7 and Exportin 1 Link c-Myc and p53 to Regulation of Ribosomal 
Biogenesis. Golomb L, Bublik DR, Wilder S, Nevo R, Kiss V, Grabusic K, Volarevic S, Oren M.  Mol 
Cell. 2012 Jan 27;45(2):222-32. 
Grisendi S.  Nucleophosmin and cancer.  Grisendi S., Mecucci C, Falini B, Pandolfi PP. Nat Rev 
Cancer 2006; 6: 493–505. 
Gupta 2010. Inhibiting NF-қB activation by small molecules as a therapeutic strategy.  Subash C. 
Gupta, Chitra Sundaram, Simone Reuter, Bharat B. Aggarwal. Biochimica et Biophysica Acta 1799 
(2010) 775–787. 
Jang 2003. Leptomycin B, an Inhibitor of the Nuclear Export Receptor CRM1, Inhibits COX-2 
Expression.  Byeong-Churl Jang, Ursula Munoz-Najar, Ji-Hye Paik, Kevin Claffey, Minoru Yoshida, 
and Timothy Hla.  Journal of Biological Chemistry. 2003. 278(5):2773–2776. 
 
Kau 2003. A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead 
transcription factor in PTEN-deficient tumor cells. Tweeny R. Kau, Frank Schroeder, Shivapriya 
Ramaswamy, Cheryl L. Wojciechowski, Jean J. Zhao, Thomas M. Roberts, Jon Clardy, William R. 
Sellers, and Pamela A. Silver. Cancer Cell. Dec 2003. 4(6):463-76. 
Kau 2004. Nuclear Transport and Cancer: From Mechanism to Intervention.   Kau TR, Way JC, 
Silver PA. 2004. Nature Reviews Cancer.  4, 106-117 (February 2004). 
Klampfer 1999. Klampfer L, Cammenga J, Wisniewski HG, Nimer SD. Sodium salicylate activates 
caspases and induces apoptosis of myeloid leukemia cell lines. Blood. 1999 Apr 1;93(7):2386-94. 
Kloet 2011. The PKB/FOXO switch in aging and cancer. David E.A. Kloet, Boudewijn M.T. 
Burgering. Biochimica et Biophysica Acta. 2011. 1813:1926–1937. 
Kojima, 2012. Kojima K, Kornblau SM, Ruvolo V, Duvvuri S, Davis RE, Zhang M, et al. Prognostic 
Impact and Targeting of CRM1 in Acute Myeloid Leukemia. ASH Annual Meeting Abstracts. 2012 
November 16, 2012;120(21):870-. 
Maas 2011. Targeting p73 in cancer. Anna-Maria Maas, Anne Catherine Bretz, Elisabeth Mack, 
Thorsten Stiewe. Cancer Lett. 2011 Aug 22. [E-pub ahead of print]. 
Mutka 2009. Identification of Nuclear Export Inhibitors with Potent Anticancer Activity In vivo.  Sarah 
C. Mutka, Wen Qing Yang, Steven D. Dong, Shannon L. Ward, Darren A. Craig, Pieter B.M.W.M. 
Timmermans, and Sumati Murli. Cancer Res 2009; 69(2): 510-517. 
Navari 2010. Navari RM & Brenner MC. Treatment of cancer-related anorexia with olanzapineand 
megestrol acetate: a randomized trial. Support Care Cancer (2010) 18:951–956. 
Razak 2013.  Razak A, Soerensen MM, Mahipal A, Shacham S, Yau CYF, Lassen UN, McCauley D, Cooksey J, 
Tan DS, Saint-Martin J-R, Landesman Y, Pond G, Oza AM, Kauffman M, Siu LL, Mirza MR. First-in-class, first- 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
55 
 
 
 
 
 
in-human phase I trial of KPT-330, a selective inhibitor of nuclear export (SINE) in patients (pts) with 
advanced solid tumors. J Clin Oncol 31, 2013 (suppl; abstr 2505). 
 
Ryan 2013. Ryan JL, Heckler CE, JE Roscoe, Dakhil SR, Kirshner J, Flynn PJ, Hickok JT, & Morrow 
GR. Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP  
study of 576 patients. Support Care Cancer (2012) 20:1479–1489 
 
Shacham 2010.  KPT-0127 Induces Selective Apoptosis of Malignant  Cells by CRM1 Inhibition and 
Elevation of Regulatory Proteins p53, p21, FOXO and IkB. Sharon Shacham, Joel Turner, Raphael 
Nir, Giulio Draetta, Keith Stewart, Sharon Shechter, Vincent Sandanayaka, Dilara McCauley, 
Michael Kauffman and Daniel Sullivan; (ASH Annual Meeting Abstracts) 2010;116:Abstract 3012. 
Sharpless 2007.  Gone but not forgotten.  Norman E. Sharpless and Ronald A. DePinho. Nature. 8 
February 2007. 445(7128):606-7. 
Shih 2013. Shih AH, Chung SS, Dolezal EK, Zhang SJ, Abdel-Wahab OI, Park CY, et al. Mutational 
analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia. 
Haematologica. 2013 Jun;98(6):908-12. 
 
Siddiqui 2012. mRNA export and cancer. Nadeem  Siddiqui  and  Katherine L. B. Borden. 
Wiley 
Interdiscip Rev RNA. 2012 Jan;3(1):13-25. 
Turner 2008. CRM1-Mediated  Nuclear Export of Proteins and Drug Resistance in Cancer. Joel G. 
Turner and Daniel M. Sullivan. Current Medicinal  Chemistry, 2008. 15(26):2648-2655. 
Turner 2012. Nuclear export of proteins and drug resistance in cancer. Joel G. Turner, Jana Dawson, 
Daniel M. Sullivan. Biochemical Pharmacology. 2012. (epub as of 2/4/12). 
Vassiliou 2011. Mutant nucleophosmin and cooperating pathways drive leukemia initiation and 
progression in mice. George S Vassiliou, Jonathan L Cooper, Roland Rad, Juan Li, Stephen Rice, 
Anthony Uren, Lena Rad, Peter Ellis, Rob Andrews, Ruby Banerjee, Carolyn Grove, Wei Wang, 
Pentao Liu, Penny Wright, Mark Arends & Allan Bradley. Nature Genetics. May 2011.  43(5):470-475. 
Van der Watt 2011. The nuclear exporter, Crm1, is regulated by NFY and Sp1 in cancer cells and 
repressed by p53 in response to DNA damage.  Pauline J. van der Watt, Virna D. Leaner. Biochimica 
et Biophysica Acta. 2011. 1809(7):316–326. 
Xu 2010. Recognition of nuclear targeting signals by Karyopherin-ß proteins. Darui Xu, Alicia Farmer 
and Yuh Min Chook.  Current Opinion in Structural Biology. 2010. 20(6):782–790. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
56 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20.0 
APPENDICES 
 
20.1 Appendix 1 : Eastern Cooperative Oncology Group Performance Status Criteria 
 
ECOG  Performance Status Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on 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 any  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 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
57 
 
 
 
 
 
Completely  disabled.   Cannot  carry  on any self-care. 
Totally  confined  to 
bed or chair. 
5 
Dead. 
 
 
 
 
20.2 Appendix 2:  Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 
The CTC version 4.03 is published at the following web address:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010 -06-14_QuickReference_5x7.pdf 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
58 
 
 
 
 
20.3 APPENDIX 3: GLUTATHIONE (GSH)-, S-ADENOSYLMETHIONINE (SAM)-, OR N- 
ACETYLCYSTEINE (NAC)-CONTAINING PRODUCTS (REPRESENTATIVE LIST) 
 
Product Name 
Ingredient 
Manufacturer/Brand 
Strength 
Dose 
Form 
Other key 
ingredients 
Glutathione 
Glutathione 
glutathione 
NOW Foods 
500 mg 
Vcaps 
milk thistle, 
alpha lipoic 
acid 
Glutathione 
L-glutathione 
NOW Foods 
250 mg 
Vcaps 
Glutathione 
reduced 
glutathione 
Jarrow Formulas 
500 mg 
capsules 
Reduced 
glutathione 
sublingual 
complex 
glutathione 
Source Naturals 
50 mg 
sublingual 
Glutathione 
reduced 
glutathione 
Bulk Supplements 
10, 25, 50, 
100, 250, 
500, 1000 g 
powder 
Reduced 
glutathione with 
alpha lipoic acid 
Setria L-glutathione 
Viva Labs 
500 mg 
capsules 
alpha lipoic 
acid 
Glutathione, 
Cysteine & C 
glutathione, 50 mg 
L-cysteine, 200 mg 
vitamin C, 500 mg 
Life Extension 
750 mg 
capsules 
L-cysteine, 
vitamin C 
Liposomal 
Glutathione 
glutathione 
Empirical Labs 
4 mL 
liquid 
Lypospheric 
GSH 
glutathione 
LivOn Laboratories 
450 mg 
packet 
essential 
phospholipids 
from soy 
lecithin 
Ivory Caps 
Skin 
Enhancement 
Formula 
glutathione 
Princeton Nutritional 
Systems 
1500 mg 
capsules 
Glutathione 
GOLD 
S-acetyl glutathione 
Health Naturally 
200 mg 
capsules 
Mega-Liposomal 
Glutathione 
glutathione 
Aurora NutraScience 
750 mg 
liquid 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
59 
 
 
 
 
 
L-Glutathione 
500 
L-glutathione 
GNC 
500 mg 
capsules 
N-acetylcysteine (NAC) 
Acetadote 
for 
acetaminophen 
overdose 
acetylecysteine 
Cumberland 
Pharmaceutcals 
IV 
sterile 
solution, 
200 mg/mL 
CerefolinNAC 
medical food for 
age-related 
memoryloss 
L-methylfolate 
vitamin B12 
N-acetyl cysteine 
PAMLAB, LLC 
600 mg 
NAC 
caplets 
L- 
methylfolate 
vitamin B12 
NAC 
N-acetyl cysteine 
NOW Foods 
600 mg 
capsules 
selenium, 
molybdenum 
N-A-C Sustain 
N-acetyl L-cysteine 
Jarrow Formulas 
600 mg 
capsules 
Best NAC Detox 
Regulators 
N-acetyl cysteine 
Doctor’s Best 
600 mg 
capsules 
selenium, 50 
mg 
molybdenum, 
50 mg 
S-adenosylmethionine (SAM) 
SAM-e Complete 
S- 
Nature Made 
adenosylmethionine 
400 mg 
tablets 
SAMe 
S-adenosyl-L- 
methionine 
NOW Foods 
400 mg 
tablets 
Double Strength 
SAMe 400 
S- 
adenosylmethionine 
Doctor’s Best 
400 mg 
tablets 
SAM-e 200 
S- 
Jarrow Formulas 
adenosylmethionine 
200 mg 
tablets 
SAMe 
S-adenosyl-l- 
methionine 
Source Naturals 
400 mg 
tablets 
SAMe 
S-adenosyl-l- 
methionine 
Source Naturals 
200 mg 
tablets 
SAMe 
S- 
adenosylmethionine 
Natrol 
400 mg 
enteric 
coated 
tablets 
SAMe 
S-adenosyl- 
methionine 
NOW Foods 
200 mg 
tablets 
vitamin B-6, 
folic acid, 
vitamin B-12 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
60 
 
 
 
 
 
 
 
 
 
20.4 Appendix 4: Lens Opacities Classification System III (LOCS III) 
 
If a cataract is seen during the slit lamp examination to document lens clarity, the 
cataract will be graded according to the LOCS III. 
 
 
 
 
 
 


Memorial Sloan Kettering Cancer Center 
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61 
 
 
 
 
 
 
 
 
Paitent: 
MRN: 
 
 
Ophthamological Exam Assessments 
 
Best Corrected Visual Acuity (BCVA): 
Normal 
Abnormal 
Description 
Adnexa 
Lids 
Lashes 
Conjunctiva 
Cornea 
Ant. Chamber 
Iris 
Lens1 
Intraocular pressure 
Fundus 
Vitreous 
Optic Disc2 
Macula 
Retina 
1 
Does lens show cataract change? Follow grading system in description 
2 
Cup/disc ratio and any abnormalities, if observed 
 
 
Visit Checklist 
Prior to dilation: 
  Best corrected visual acuity 
  Slit lamp examination including tonometry 
Dilated:    Fundoscopy 
  Slit lamp examination to document lens clarity 


Memorial Sloan Kettering Cancer Center 
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62 
 
 
 
 
MD Signature  
 Date  
 
 
20.5 Appendix 5: NCCN Clinical Practice Guidelines in Oncology: Antiemesis 
 
 
Reproduced w ith permission fromthe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Antiemesis V.2.2014. © 
2014 National Comprehensive Cancer Netw ork, Inc. All rights reserved. The NCCN Guidelines ® and illustrations herein may not be 
reproduced in any form for any purpose w ithout the express written permission of the NCCN. To view the most recent and complete 
version of the NCCN Guidelines, go online to w ww.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN 
GUIDELINES®,  and all other NCCN Content are trademarks ow ned by the National Comprehensive Cancer Netw ork, Inc. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
63 
 
 
 
 
 
 
 
 
 
 
Reproduced w ith permission fromthe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Antiemesis V.2.2014. © 
2014 National Comprehensive Cancer Netw ork, Inc. All rights reserved. The NCCN Guidelines ® and illustrations herein may not be 
reproduced in any form for any purpose w ithout the express written permission of the NCCN. To view the most recent and complete 
version of the NCCN Guidelines, go online to w ww.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN 
GUIDELINES®,  and all other NCCN Content are trademarks ow ned by the National Comprehensive Cancer Netw ork, Inc. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
64 
 
 
 
 
 
 
 
 
 
Reproduced w ith permission fromthe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Antiemesis V.2.2014. © 
2014 National Comprehensive Cancer Netw ork, Inc. All rights reserved. The NCCN Guidelines ® and illustrations herein may not be 
reproduced in any form for any purpose w ithout the express written permission of the NCCN. To view the most recent and complete 
version of the NCCN Guidelines, go online to w ww.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN 
GUIDELINES®,  and all other NCCN Content are trademarks ow ned by the National Comprehensive Cancer Netw ork, Inc. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
65 
 
 
 
 
 
 
 
20.6 Appendix 6: NCCN Clinical Practice Guidelines in Oncology: Anorexia/Cachexia 
 
 
 
Reproduced w ith permission fromthe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Palliative Care V.1.2014. © 
2014 National Comprehensive Cancer Netw ork, Inc. All rights reserved. The NCCN Guidelines ® and illustrations herein may not be 
reproduced in any form for any purpose w ithout the express written permission of the NCCN. To view the most recent and complete 
version of the NCCN Guidelines, go online to w ww.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN 
GUIDELINES®,  and all other NCCN Content are trademarks ow ned by the National Comprehensive Cancer Netw ork, Inc. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
66 
 
 
 
 
 
 
 
20.7 Appendix 7: Sample Collection and Shipping Summary 
 
Karyopharm 
 
Karyopharm will perform functional assays to assess NFkB and WNT pathway signaling and cytokine levels. blood and 
bone marrow samples will be delivered to the MSKCC HOTB for centrifugation, aliquotting and storage. Details are 
provided in the Karyopharm laboratory manual. 
 
Sample Collected: 
 
No. 
TIME POINT 
TOTAL 
VOLUME 
OF BLOOD 
(mL) 
PDn 
Cytokines 
1 tube x 2 ml 
EDTA 
Leukocytes 
3 PAXgene Tubes 
x 
2.5 ml 
Bone 
Marrow* 
2 aliquots x 
1x106cells 
Baseline (Day -21 to -1) 
x 
Cycle 1, Day 1 
1 
Pre-dose (within 10 min before dosing) 
9.5 
2 ml 
3 x 2.5ml 
2 
4 hr (20 min) post dose 
9.5 
2 ml 
3 x 2.5ml 
3 
8 hr (20 min) post dose 
9.5 
2 ml 
3 x 2.5ml 
Cycle 1, Day 14 
4 
Pre-dose (within 10 min before dosing) 
x 
Cycle 1, Day 21 
5 
Pre-dose (within 10 min before dosing) 
9.5 
2 ml 
3 x 2.5ml 
x 
6 
4 hr (20 min) post dose 
9.5 
2 ml 
3 x 2.5ml 
Cycle 2, Day 21 
7 
Pre-dose (within 10 min before dosing) 
9.5 
2 ml 
3 x 2.5ml 
x 
8 
4 hr (20 min) post dose 
9.5 
2 ml 
3 x 2.5ml 
Cycle 4, Day 21 
9 
Pre-dose (within 10 min before dosing) 
9.5 
2 ml 
3 x 2.5ml 
x 
10 
4 hr (20 min) post dose 
9.5 
2ml 
3 x 2.5ml 
11 
Off study 
x 
*Not included in total volume of blood and may be collected any time pre -dose (not necessarilywithin 10 minutes before 
dosing). 
 
 
 
Shipping Schedule: 
 
Batched-shipped approximatelyonce each month on dry ice to Karyopharm via World Courier (account number 017300).at 
the following address: 
 
Dr. Yosef Landesman 
Karyopharm Therapeutics Inc. 
75 Wells Avenue 
Newton, MA 02459 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
67 
 
 
 
 
 
 
 
Columbia 
 
 
 
Dr. Gary Schwartz: blood and bone marrow aspirates will be shipped to Dr. Schwartz’s laboratory at Columbia University 
for studies to assess the mechanism of selinexor. His laboratorywill perform the following analyses: Western blots for 
XPO1, p53, p21, PARP, and caspase. Specimens will be processed using ficoll-hypaque separation at the HOTB. Bone 
marrow and blood mononuclear cells will be viablycryopreserved (in DMSO) and stored for shipping. 
 
 
 
Sample Collected: two 7mL EDTA tubes 
 
 
No. 
TIME POINT 
1 
Baseline (Day -21 to -1) 
2 
Cycle 1, Day 7 (±1 day) 
3 
Cycle 1, Day 14 (±3 day) 
4 
Cycle 1, Day 21 (±1 day) 
5 
Cycle 2, Day 21 (±1 day) 
6 
Cycle 4, Day 21 (±1 day) 
7 
End of Study 
 
 
 
 
Shipping Schedule: 
 
 
 
Batch-shipped approximatelyonce each month on dry ice to the laboratory of Dr. Schwatrz at Columbia Universityc/o 
Shyamprasad Deraje Vasudeva via FedEx (account number 2346-5338-5).at the following address: 
 
Dr. Gary Schwartz c/o Shyamprasad Deraje Vasudeva 
Columbia University 
1130 Saint Nicholas Ave 
ICRC Room 207, Schwartz Lab 
New York, NY 10032 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
68 
 
 
 
 
 
 
 
 
MSKCC Surgical Pathology 
 
 
 
Dr. Chiu will direct the processing of bone marrow immunohistochemical (IHC) stains, which will be performed by the 
Pathology Core Laboratory at MSKCC to assess nuclear localization of beta catenin and p65, thereby assessing for 
evidence of WNT and NF-kB pathway signaling activation, respectively. Bone marrow specimens will be processed 
routinely for response assessment at the designated time points as per the protocol. Specimens will be directed to Dr. April 
Chiu. Extra sections will be obtained under the direction of Dr. April Chiu, and th e Core Laboratory will perform.IHC for 
nuclear beta catenin and p65 using standard IHC techniques. 
 
 
 
Sample Collected: Bone Marrow Immunohistochemical Stains 
 
 
No. 
TIME POINT 
1 
Baseline (Day -21 to -1) 
2 
Cycle 1, Day 14 (±3 day) 
3 
Cycle 1, Day 21 (±1 day) 
4 
Cycle 2, Day 21 (±1 day) 
5 
Cycle 4, Day 21 (±1 day) 
6 
End of Study 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
69 
 
 
 
 
 
 
 
 
 
 
MD Anderson Cancer Center 
 
 
 
Dr. Andreef will assess nuclear and cytoplasmic p53 localization on unstained bone marrow aspirate smears. Bone marrow 
aspirate slides are prepared at the time of the bone marrow procedure as per standard routine. No processing is required. 
These slides will be delivered to Dr. Klimek and will be stored at room temperature until they are shipped. 
 
 
 
Sample Collected: Unstained Bone Marrow Aspirate Smears 
 
 
No. 
TIME POINT 
1 
Baseline (Day -21 to -1) 
2 
Cycle 1, Day 14 (±3 day) 
3 
Cycle 1, Day 21 (±1 day) 
4 
Cycle 2, Day 21 (±1 day) 
5 
Cycle 4, Day 21 (±1 day) 
6 
End of Study 
 
 
 
 
Shipping Schedule: 
 
Batch-shipped byUPS approximatelyevery three months at ambient temperature in plastic slide carriers to Dr. Andreef. 
Specimens will be sent to the attention of Teresa Mcqueen (using Fedex accout # 136495291) at the following address: 
 
 
 
Teresa Mcqueen 
MD Anderson Cancer Center 
6767 Bertner Ave. 
T6.3948 
Houston Tx 77030 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-005 A(17) 
Approval date: 25-Jan-2021 
70