A Phase I/II Trial of Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes
Phase: PHASE1
Conditions: Myelodysplastic Syndromes
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: DELTA-MDS
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Version Date: 10/30/2024
Abbreviated Title: DELTA-MDS
NIH Protocol #: IRB001541
Version Date: 10/30/2024
NCT Number: NCT05918055
Title: A Phase I/II Trial of Eltanexor (KPT-8602) with Inqovi (Decitabine-Cedazuridine) in 
High-Risk Myelodysplastic Syndromes
NCI Principal Investigator:
Alain Mina, MD
Immune Deficiency Cellular Therapy Program (IDCTP)
Building 10, Rm 6N119A
9000 Rockville Pike
Bethesda, MD 20892
Phone: 240-858-7625
Email:  alain.mina@nih.gov
Drug Name:
Eltanexor (KPT-8602)
Inqovi®
(decitabine-cedazuridine)
IND Number:
163958
Sponsor:
Center for Cancer Research
Manufacturer:
Karyopharm Therapeutics, Inc.
Generic
Supplier:
Karyopharm Therapeutics, Inc.
CC Pharmacy

Abbreviated Title: DELTA-MDS
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PRÉCIS
Background:
•
The myelodysplastic syndromes (MDS) are a group of clonal bone marrow neoplasms 
characterized by ineffective hematopoiesis, cytopenia, and high risk of transformation to 
acute myeloid leukemia (AML). 
•
The median survival of patients with newly-diagnosed higher-risk MDS (HR-MDS) 
according to the Revised International Prognostic Scoring System (IPSS-R) is 1.5 years.
•
Hypomethylating agents (HMAs), such as azacitidine and decitabine, are the standard of 
care therapy for HR-MDS. However, less than half of patients respond to HMAs, and even 
the best responses are transient and non-curative.
•
The only curative treatment for patients with MDS is allogeneic hematopoietic stem cell 
transplantation (HSCT); however only a small portion are eligible for transplant.
•
More effective therapies are needed for patients with HR-MDS.
•
A promising approach for improving HMA efficacy in the treatment of MDS is by 
exploiting therapeutic synergism in combinatorial approaches.
•
Inqovi (decitabine-cedazuridine) is an oral formulation of decitabine plus cytidine 
deaminase inhibitor that was recently FDA-approved for MDS, based on a similar safety 
and efficacy profile to decitabine for injection.
•
KPT-8602 (eltanexor) is an orally-available, second-generation selective inhibitor of 
nuclear export (SINE) that covalently binds to exportin 1 (XPO1).
•
XPO1 is a protein that mediates the nuclear export of molecules from the nucleus to the 
cytoplasm of the cell. Among affected molecules are tumor suppressor genes, mRNAs 
encoding oncogenes (including c-MYC), and newly assembled ribosomal subunits.
•
By interfering with c-MYC translation, KPT-8602 may diminish rebound methylation after 
decitabine cessation and improve treatment responses in patients with MDS.
•
Preliminary reports from a Phase 1/2 trial of KPT-8602 monotherapy in patients with 
higher-risk MDS who have failed HMAs show anti-tumor activity and an acceptable 
toxicity profile.
•
Sequential addition of KPT-8602 to Inqovi may improve treatment responses in patients 
with MDS by acting synergistically to inhibit further DNA methylation. 
Objective:
•
Phase I: To determine the recommended phase 2 dose (RP2D) of KPT-8602 in 
combination with Inqovi in adult participants with with higher-risk MDS
•
Phase II: To determine overall response rate (ORR) of KPT-8602 in combination with 
Inqovi in adult participants with with higher- risk MDS
Eligibility:
•
Participants must have histologically or cytologically confirmed MDS according to 2016 
WHO criteria (1), and for both Phase I and II:
o
have HR-MDS (IPSS-R > 3.5) with inadequate response to hypomethylating agent 
(HMA) therapy [(received  4 cycles of the standard dose (35 mg decitabine and 
100 mg cedazuridine) without prior dose-reductions, with failure to achieve at least 
a PR or experienced disease progression prior to completing 4 cycles)
•
Age  18 years

Abbreviated Title: DELTA-MDS
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•
ECOG performance status  2 (KPS  60)
Design:
•
Participants with HR-MDS will be enrolled in both Phase I and II.
•
Participants will be treated with Inqovi at a fixed dose of 1 tablet (35 mg decitabine and 
100 mg cedazuridine) daily on Days 1-5 of each 28-day cycle, followed by KPT-8602 at 
escalating doses (Phase I) or the RP2D (Phase II).
•
In Phase I, KPT-8602 will be dose-escalated following a standard 3+3 design, with a 
starting dose level of 10 mg for 10 days (staggered) within a cycle.  If tolerated, the dose 
will be escalated to 14 days per cycle, or dose de-escalated to 5 mg at 14 or 10 days. 
•
This study will be done at the NIH Clincal Center with an enrollment of up to 80 planned 
participants. 

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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ..............................................................................................10
1
INTRODUCTION ..............................................................................................................10
1.1
Study Objectives..........................................................................................................10
1.1.1
Primary Objective....................................................................................................10
1.1.2
Secondary Objectives ..............................................................................................10
1.1.3
Exploratory Objectives ............................................................................................10
1.2
Background and Rationale ..........................................................................................11
1.2.1
Myelodysplastic syndromes.....................................................................................11
1.2.2
Current treatment options for patients with HR-MDS ............................................13
1.2.3
KPT-8602 (eltanexor)..............................................................................................13
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................18
2.1
Eligibility Criteria........................................................................................................18
2.1.1
Inclusion Criteria .....................................................................................................18
2.1.2
Exclusion Criteria ....................................................................................................19
2.1.3
Recruitment Strategies.............................................................................................20
2.2
Screening Evaluation...................................................................................................20
2.2.1
Screening activities performed prior to obtaining informed consent ......................20
2.2.2
Screening activities performed after a consent for screening has been signed........20
2.3
Participant Registration and Status Update Procedures ..............................................21
2.3.1
Screen Failures.........................................................................................................21
2.3.2
Treatment Assignment (for Phase I and II) .............................................................22
3
STUDY IMPLEMENTATION ..........................................................................................22
3.1
Study Design ...............................................................................................................22
3.1.1
Dose Limiting Toxicity (DLT) ................................................................................24
3.1.2
Dose Escalation .......................................................................................................25
3.1.3
Dose Expansion .......................................................................................................26
3.1.4
Protocol Stopping Rules ..........................................................................................26
3.2
Drug Administration....................................................................................................27
3.2.1
KPT-8602 ................................................................................................................27

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3.2.2
Decitabine and Cedazuridine (Inqovi).....................................................................27
3.3
Dose Modifications .....................................................................................................27
3.3.1
Dose Levels for Toxicity Management ...................................................................28
3.3.2
Dose Modification Guidelines.................................................................................28
3.4
On Study Assessments/Evaluations ............................................................................33
3.4.1
Timing of Procedures ..............................................................................................33
3.4.2
Description of Procedures........................................................................................34
3.4.3
Correlative/Exploratory Assessments......................................................................35
3.5
Study Calendar ............................................................................................................39
3.5.1
Phase I and II – Screening & Cycle 1......................................................................39
3.5.2
Phase I and II – Cycle 2 – beyond ...........................................................................42
3.6
Cost and Compensation...............................................................................................44
3.6.1
Costs ........................................................................................................................44
3.6.2
Compensation ..........................................................................................................44
3.6.3
Reimbursement........................................................................................................44
3.7
Criteria for Removal from Protocol Therapy and Off Study Criteria .........................44
3.7.1
Criteria for removal from protocol therapy .............................................................44
3.7.2
Off-Study Criteria....................................................................................................44
3.7.3
Lost to Follow-up ....................................................................................................45
4
CONCOMITANT MEDICATIONS/MEASURES............................................................45
4.1
Allowed Concomitant Medications/Supportive Measures..........................................45
4.1.1
Antimicrobial Prophylaxis.......................................................................................45
4.1.2
Hematologic Support...............................................................................................45
4.1.3
Other Supportive Care .............................................................................................46
4.2
Drug Interactions.........................................................................................................46
4.3
Contraindicated Agents ...............................................................................................46
5
CORRELATIVE STUDIES FOR RESEARCH ................................................................46
5.1
Biospecimen Collection ..............................................................................................46
5.1.1
Peripheral Blood ......................................................................................................49
5.1.2
Bone Marrow Samples ............................................................................................49
5.2
Correlative Analyses ...................................................................................................49
5.2.1
PK Studies ...............................................................................................................50

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5.2.2
PD Studies ...............................................................................................................50
5.2.3
Methylation Studies.................................................................................................50
5.2.4
Proteomics Studies...................................................................................................50
5.2.5
Cytokine Studies......................................................................................................51
5.2.6
Gene Editing ............................................................................................................51
5.2.7
Microarrays/Immunohistochemistry........................................................................51
5.2.8
DNA Damage ..........................................................................................................51
5.2.9
Additional Studies ...................................................................................................51
5.3
Sample Storage, Tracking and Disposition .................................................................51
5.3.1
Dr. Figg’s Blood Processing Core (BPC)................................................................52
5.3.2
Protocol Completion/Sample Destruction ...............................................................52
5.4
Samples for Genetic/Genomic Analysis......................................................................53
5.4.1
Description of the scope of genetic/genomic analysis.............................................53
5.4.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized................................................................................................53
5.4.3
Management of Results ...........................................................................................53
5.4.4
Genetic counseling...................................................................................................53
6
DATA COLLECTION AND EVALUATION ..................................................................54
6.1
Data Collection............................................................................................................54
6.2
Data Sharing Plans ......................................................................................................54
6.2.1
Human Data Sharing Plan .......................................................................................54
6.2.2
Genomic Data Sharing Plan.....................................................................................55
6.3
Response Criteria ........................................................................................................55
6.3.1
Response Criteria.....................................................................................................55
6.4
Toxicity Criteria ..........................................................................................................58
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN58
7.1
Definitions...................................................................................................................58
7.2
OHSRP Office of Compliance and Training / IRB Reporting....................................58
7.2.1
Expedited Reporting ................................................................................................58
7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................58
7.3
NCI Clinical Director Reporting .................................................................................59
7.4
NIH Required Data and Safety Monitoring Plan ........................................................59
7.4.1
Principal Investigator/Research Team.....................................................................59

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SPONSOR PROTOCOL/SAFETY REPORTING.............................................................59
8.1
Definitions...................................................................................................................59
8.1.1
Adverse Event..........................................................................................................59
8.1.2
Serious Adverse Event (SAE) .................................................................................59
8.1.3
Life-threatening .......................................................................................................60
8.1.4
Severity....................................................................................................................60
8.1.5
Relationship to Study Product .................................................................................60
8.1.6
Adverse Events of Special Interest (AESI) .............................................................60
8.2
Assessment of Safety Events.......................................................................................60
8.3
Reporting of Serious Adverse Events .........................................................................61
8.4
Waiver of Expedited Reporting to CCR ......................................................................61
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................61
8.6
Reporting Pregnancy ...................................................................................................61
8.6.1
Maternal exposure ..................................................................................................62
8.6.2
Paternal exposure.....................................................................................................62
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ...............62
8.8
Sponsor Protocol Deviation Reporting........................................................................62
9
CLINICAL MONITORING...............................................................................................63
10
STATISTICAL CONSIDERATIONS ...............................................................................64
10.1
Objectives and Endpoints............................................................................................64
10.2
Statistical Hypothesis and Sample Size Determination ..............................................66
10.3
Populations for Analyses.............................................................................................66
10.3.1
Evaluable for toxicity ..............................................................................................66
10.3.2
Evaluable for objective response.............................................................................67
10.4
Statistical Analyses......................................................................................................67
10.4.1
General Approach....................................................................................................67
10.4.2
Analysis of the Primary Endpoints..........................................................................67
10.4.3
Analysis of the Secondary Endpoints......................................................................67
10.4.4
Safety Analyses .......................................................................................................67
10.4.5
Baseline Descriptive Statistics.................................................................................68
10.4.6
Planned Interim Analyses........................................................................................68
10.4.7
Sub-Group Analyses................................................................................................68

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10.4.8
Tabulation of individual Participant Data................................................................68
10.4.9
Exploratory Analyses...............................................................................................68
11
COLLABORATIVE AGREEMENTS...............................................................................69
11.1
Agreement Type..........................................................................................................69
12
HUMAN SUBJECTS PROTECTIONS.............................................................................69
12.1
Rationale For Participant Selection.............................................................................69
12.2
Participation of Children .............................................................................................70
12.3
Risk/Benefit Assessment.............................................................................................70
12.3.1
Known Potential Risks ............................................................................................70
12.3.2
Known Potential Benefits........................................................................................71
12.3.3
Assessment of Potential Risks and Benefits............................................................71
12.4
Consent and Assent Process and Documentation........................................................71
13
REGULATORY AND OPERATIONAL CONSIDERATIONS.......................................72
13.1
Study Discontinuation and Closure.............................................................................72
13.2
Quality Assurance and Quality Control ......................................................................73
13.3
Conflict of Interest Policy ...........................................................................................73
13.4
Confidentiality and Privacy.........................................................................................73
14
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION............74
14.1
KPT-8602 (IND # 163958) .........................................................................................74
14.1.1
Description...............................................................................................................74
14.1.2
Source/Acquisition and Accountability...................................................................75
14.1.3
Toxicity....................................................................................................................75
14.1.4
Formulation and preparation....................................................................................76
14.1.5
Stability and Storage................................................................................................76
14.1.6
Administration Procedures ......................................................................................76
14.1.7
Incompatibilities ......................................................................................................76
14.2
Inqovi® (Decitabine and Cedazuridine) .....................................................................77
14.2.1
Source/Acquisition and Accountability...................................................................77
14.2.2
Toxicity....................................................................................................................77
14.2.3
Formulation and preparation....................................................................................77
14.2.4
Stability and Storage................................................................................................78
14.2.5
Administration Procedures ......................................................................................78

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14.2.6
Incompatibilities ......................................................................................................78
15
REFERENCES ...................................................................................................................79
16
LIST OF ABBREVIATIONS.............................................................................................84
17
APPENDICES ....................................................................................................................86
17.1
Appendix A: Performance Status Criteria...................................................................86
17.2
Appendix B:  2016 WHO classification for Myelodysplastic Syndrome ...................87
17.3
Appendix C:  Revised International Prognostic Scoring System (IPSS-R) for 
Myelodysplastic Syndromes......................................................................................................88
17.4
Appendix D: The 2006 International Working Group response criteria with modified 
definitions for hematologic improvement by the 2018 International Working Group response 
criteria 89
17.5
Appendix E: Rockwood Frailty Index.........................................................................92
17.6
Appendix F: MDS-Specific Comorbidity Index (MDS-CI)........................................93
17.7
Appendix G: European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire = EORTC QLQC30 score ........................................94
17.8
Appendix H: Patient-Reported Outcomes (NIH Adult Psychosocial Assessment for 
MDS, CTCAE, Overall Side Effect Bother, PROMIS Physical Function, PGI-S, and PGI-C)95
17.9
Appendix I: Data Elements to Consider for CRF Entry in Clinical Database ............96
17.10
Appendix J: Blood Processing Core Procedures.........................................................98
17.11
Appendix K: Participant Medication Diary...............................................................100
17.12
Appendix L: Controlled Medications for HIV, Hepatitis B or Hepatitis C Disease 
Control (CYP Substrates) ........................................................................................................102

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
•
Phase I: To determine the recommended phase 2 dose (RP2D) of KPT-8602 in 
combination with Inqovi in adult participants with with higher-risk MDS
•
Phase II: To determine the overall response rate (ORR) of KPT-8602 in combination with 
Inqovi in adult participants with higher-risk MDS
1.1.2
Secondary Objectives
•
Phase I: To characterize the pharmacokinetic (PK) properties of KPT-8602 in combination 
with Inqovi (decitabine-cedazuridine) in MDS participants 
•
Phase II: To further evaluate the PK properties and safety of KPT-8602 in combination 
with Inqovi (decitabine-cedazuridine) in MDS participants
1.1.3
Exploratory Objectives
•
To evaluate the relationship between KPT-8602 exposure (PK) and response
•
To evaluate changes in XPO1 mRNA expression and other potential PD markers with 
treatment
•
To assess changes in DNA damage repair by evaluation of gammaH2AX levels
•
To evaluate compliance and feasibility of administering PRO in this patient population
•
To evaluate tolerability of treatment by assess symptomatic adverse events, physical 
function and side effect bother
•
To longitudinally describe and evaluate disease and treatment-related severity and 
functional well-being

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•
To determine meaningful change in disease and treatment-related symptoms and functional 
well-being by using anchors
•
To evaluate changes in DNA methylation status pre- and post-treatment
•
To evaluate changes in cell composition in the bone marrow and peripheral blood 
microenvironment pre- and post-treatment
•
To evaluate changes in genetic clonal diversity during treatment
•
To evaluate changes in gene expression patterns of tumor suppressor genes and 
oncogenes (including DNMT3B expression)
•
To evaluate the influence of splicing factor mutations (U2AF1, SRSF2, SF3B1, ZRSR2) 
on nuclear shuttling
•
To evaluate the degree of disruption of ribosome biogenesis after XPO1 inhibition
•
To evaluate changes in nuclear and cytoplasmic protein composition using  mass 
spectrometry
•
To evaluate additional clinical outcomes, such as overall improvement rate (OIR), 
transfusion-independence (TI), cytogenetic response rate, time to best response (CR, PR, 
marrow CR + HI, HI), disease-free survival (DFS; definition: time to relapse for 
participants who achieve CR), progression-free survival (PFS; definition: time to 
progression or death from MDS), leukemia-free survival (LFS; definition: time to 
progression to AML or death from any cause), and overall survival (OS; definition: time 
to death from any cause)
1.2
BACKGROUND AND RATIONALE
1.2.1
Myelodysplastic syndromes
The myelodysplastic syndromes (MDS) are a group of heterogenous clonal neoplasms of 
hematopoietic stem cells, characterized by dysplastic changes in at least one myeloid lineage, 
recurrent genetic aberrations, presence of up to 20% myeloblasts in the bone marrow, and high 
risk of evolution to acute myelogenous leukemia (AML).(1) Myelodysplasia results in ineffective 
hematopoiesis with consequential peripheral blood cytopenia(s). Anemia is the most common 
clinical presentation of MDS, but other cytopenias are also often present. Cytopenias, together 
with ineffective maturation of neutrophils and platelets, often result in severe and/or recurrent 
infections and/or bleeding episodes, respectively. In general, it is estimated that up to 1/3 of 
patients with MDS will die from cytopenia-related complications, up to 1/3 have disease 
progression into a secondary AML with poor prognosis, and the remaining 1/3 may die from causes 
unrelated to their MDS.(2, 3)
MDS is a disease of the elderly, with a median age at diagnosis of approximately 75 years, with 
~80% of patients being ≥65 years.(4) Based on cancer registry data, about 10,000 new MDS cases 
are diagnosed per year in the United States,(5, 6) but the number is probably underestimated,(7) 
and may be as high as >40,000 based on Medicare claims analyses.(8) There is a slight 
predominance of males.(4)
Most MDS patients (~90%) have sporadic disease and the remainder are therapy-related MDS (t-
MDS), the latter often presenting in patients younger than 60 years of age. In the last decade, 

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familial related myeloid neoplasia in persons with germ-line mutations (i.e., RUNX1, GATA2, 
DDX41, CEPBA, ANKRD26, ETV6) is recognized as a predisposing condition for earlier 
acquisition of additional MDS-related mutations and MDS development.(9) Additionally, MDS 
can also develop from the rare inherited bone marrow failure disorders, such as Fanconi and 
Diamond-Blackfan anemia, which can present in childhood and adolescence.(10)
A conceptual model of MDS evolution(11) presumes an initiating somatic driver mutation in the 
hematopoietic stem cell with subsequent formation of the mutant stem cell clone. The most 
commonly affected genes involve RNA splicing, DNA methylation, histone modification, 
transcription regulators, DNA-repair control, signaling and cohesin complex. Six genes are 
commonly affected and have been reported to be mutant in at least 10% of patients: SF3B1, TET2, 
SRSF2, DNMT3A, ASXL1, and RUNX1.(12) In the second phase, the mutant clone expands and 
when it reaches approximately 4% of the total hematopoiesis, clonal hematopoiesis of 
indeterminate potential (CHIP) can be diagnosed. The duration of the first phase and potential of 
further progression to the third phase (MDS or clonal cytopenia of undetermined significance 
[CCUS] – cytopenia with presence of a clonal population without morphologic evidence of 
dysplastic changes) seems to be related to the genes affected by mutations and the size of the clonal 
population.(13) Most patients with CHIP and mutations in DNMT3A, TET2, or ASXL1 will slowly 
progress to the third phase, while those harboring spliceosome gene mutations (i.e., SF3B1, SRSF2, 
U2AF1) will usually progress faster into MDS.(13) The spliceosome gene mutations are 
collectively present in more than 50% of the subjects with MDS and are mutually exclusive.(14, 
15) They are most commonly present in MDS subjects when compared to the patients with other 
malignancies. In the third phase, clonal predominance of the mutant clone is established with 
further acquisitions of additional mutations (median of 3).(16, 17) The fourth phase is initiated 
with the selection of a clone that usually harbors AML-driving mutations (i.e., FLT3, PTPN11, 
WT1, IDH1, NPM1, IDH2 and NRAS) leading to progression into secondary AML (s-AML) with 
≥20% blasts in the bone marrow.
According to the World Health Organization (WHO) 2016 classification of myeloid neoplasms 
and acute leukemia,(1) several different MDS-related entities can be discriminated with defined 
diagnostic criteria such as the number of lineages affected by dysplastic changes, the percentage 
of blasts in bone marrow, the existence of ring sideroblasts and genetic changes. MDS precursor 
conditions, such as CHIP and CCUS, are defined by expert panels through a consensus 
process.(18-21)
The prognosis of MDS depends on disease- and patient-related characteristics. The disease-
specific factors with major influence on the prognosis of participants with MDS are the number 
and depth of cytopenias, the percentage of bone marrow blasts and the cytogenetic aberrations. 
These factors are incorporated in Revised International Prognostic Scoring System (IPSS-R), 
currently the most commonly used prognostic index that stratifies MDS patients into 5 prognostic 
groups predicting overall survival (OS) and time-to-progression to AML.(22) For the purposes of 
clinical practice, an IPSS-R score of 3.5 is generally accepted as a cutoff for stratifying patients 
into “higher-risk” MDS (HR-MDS) versus “lower-risk” MDS (LR-MDS) with corresponding 
median OS of 1.5 versus 5.9 years, respectively.(23) Using this stratification system, about 1/3 of 
patients with MDS are classified as having HR-MDS and about 2/3 are classified as having LR-
MDS.

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1.2.2
Current treatment options for patients with HR-MDS
Currently, the only curative treatment modality for patients with MDS is allogeneic hematopoietic 
stem cell transplantation (HSCT). Since HSCT is associated with high incidence of mortality and 
morbidity, only a small portion of fit patients are eligible to undergo a transplant.(24, 25) There is 
an estimate that only 6 of 100 MDS patients will receive HSCT (2 will be cured, 3 will relapse and 
1 will die from the HSCT-related complications).(3)
Hypomethylating agents (HMAs), such as 5-azacitidine (AZA) and decitabine (DAC), are the 
standard of care therapies for HR-MDS. Inqovi is an oral formulation of decitabine, in combination 
with the cytidine deaminase inhibitor cedazuridine, which was recently FDA approved in July 
2020 based on clinical trial results which showed similar drug concentrations between intravenous 
decitabine and oral decitabine-cedazuridine, with comparable efficacy. In the Phase 3 
registrational trial for oral decitabine-cedazuridine, CR rate was 21%; additionally, 53% of patients 
who were RBC and/or platelet transfusion dependent at baseline achieved transfusion 
independence during any 56-day post-baseline period.(26)
Unfortunately, less than a half of patients respond to HMAs, and even the best responses are 
transient, non-durable, and non-curative.(27) Although the benefit on OS was significant in the 
AZA registrational trial, (27) in real-life practice the impact on OS is not reproducible and prolongs 
OS for just a few months.(28, 29)
Numerous combination therapies with HMAs have been explored in treatment of MDS and AML. 
The BCL-2-inhibitor, venetoclax, in combination with HMA has emerged as a promising 
therapeutic combination with good safety and efficacy in AML,(30) though remains under clinical 
investigation in MDS.(31-33) Two presentations on early data from ongoing clinical trials of 
venetoclax in combination with HMA were presented at the 2020 American Society of 
Hematology conference: (a) a Phase 1b trial by Garcia et al. that explored use of venetoclax plus 
azacitidine in 57 high-risk MDS participants, and reported an ORR of 77% with a 13 month median 
follow-up, and high rates of grade 3 AEs in 97% of participants, including febrile neutropenia in 
46% and neutropenia and thrombocytopenia in 51% and 30%, respectively;(32) and (b) a Phase 
1b trial of venetoclax plus azacitidine by Zeidan et al. for treatment of MDS in the 
relapsed/refractory setting. Of the 38 participants enrolled, with a median follow up of 6.8 months, 
there was a clinical response of CR + mCR in 40%, and HI in 25%. Common grade 3-4 AEs 
included neutropenia and thrombocytopenia in 50% and 42% of participants, respectively.(33) 
While reported efficacy is promising for this combination, the side effect profile and complications 
due to cytopenias appear significant based on these preliminarily data and this regimen may require 
further optimization in the MDS setting.
1.2.3
KPT-8602 (eltanexor)
1.2.3.1
Selective Inhibitors of Nuclear Export (SINE)
Selective inhibitors of nuclear export (SINE) compounds directly bind and block the nucler export 
protein exportin 1 (XPO1). XPO1 mediates the nuclear export of cargo proteins including tumor 
suppressor proteins (TSPs) such as p53, p21, and IB, as well as eIF4E bound messenger 
ribonucleic acids (mRNAs) encoding oncogenic proteins such as c-MYC, Bcl-2, Bcl-SL, MDM2, 
and cyclin D1. As a result, XPO1 inhibition leads to nuclear retention and activation of TSPs, a 
reduction in the level of oncogenic proteins, and down-regulation of drug resistance and pro-
inflammatory pathways. The inhibition of XPO1 by SINE compounds and subsequent nuclear 

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accumulation of TSPs results in selective cytotoxicity to cells with genomic damage (such as tumor 
cells) both in vitro and in vivo. All cell types exposed to SINE compounds in vitro undergo G1 
and/or G2 cell cycle arrest, followed by a “genomic fidelity” review. Cancer cells with damanged 
genomes fail the review and undergo apoptosis. Normal cells remain in a transient, reversible cell 
cycle arrest until the export block is relieved. Additionally, through retention of eIF4E-bound 
oncogenic mRNAs in the nucleus, SINE compounds reduce oncogenic protein expression, 
contributing to selective induction of apoptosis in malignancies driven by these pathways.
There are 2 SINE compounds currently under clinical development for oncology indications: 
selinexor and eltanexor.
Selinexor (KPT-330; XPOVIO®) (34) is a first-in-class SINE compound that, in combination with 
dexamethasone, has regular approval from the US Food and Drug Administration (FDA) for the 
treatment of adult patients with relaped or refractory multiple myeloma (MM) who have received 
at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 
2 immunomodulatory agents, and an anti-CD38 monoclonal antibody. Selinexor, in combination 
with bortezomib and dexamethasone, also has regular FDA approval for the treatment of adult 
pateints with multiple myeloma who have received at least 1 prior therapy. Additionally, selinexor 
has accelerated approval from the FDA for the treatment of adult patients with relapsed or 
refractory diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), including 
DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Selinexor is 
also currently under investigation for the treatment of various other hematologic and solid tumor 
indications, including further evaluation in MM, DLBCL, endometrial cancer and other 
gynecological malignancies, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and 
advanced unresectable dedifferentiated liposarcoma (DDLS), glioblastoma multiforme (GBM), 
and recently for patients with COVID-19. Notably, selinexor has also been investigated for the 
treatment of acute myeloid leukemia (AML) in 2 separate phase I trials and shown some 
preliminary efficacy in this setting, particularly when given in combination with decitabine.(35, 
36) However, toxicity has been an issue. Selinexor can cross the blood-brain barrier (BBB). 
Neurotoxicity is therefore a common side effect, occurring in 25-30% of patients with MM and 
DLBCL in clinical trials, with severe (Grade 3-4) events occurring in 3-6%. Other common TEAEs 
(occurring in  35%) reported with selinexor have included nausea (66%), fatigue (57%), anorexia 
(51%), thrombocytopenia (51%), anemia (44%), vomiting (39%), and diarrhea (37%). 
Eltanexor (KPT-8602) is a second-generation, slowly reversible, orally bioavailable SINE 
compound, currently in Phase 1/2 development. It has similar potency to selinexor in vitro against 
XPO1-mediated transport and in cancer cell lines. However, it has a distinct pharmacology related 
to its unique chemical structure resulting in substantially lower brain penetration when compared 
with selinexor: ~30-fold lower in monkey studies. In animal models, this resulted in lower levels 
of anorexia and weight loss and permitted eltanexor once daily dosing for 5 consecutive days each 
week. It also exhibited superior anti-leukemic activity in in vitro studies of AML cell lines, and 
was associated with improved survival in a human xenograft model of AML. Preclinical studies 
also showed that eltanexor is minimally toxic to normal hematopoietic stem and progenitor cells, 
and eltanexor did not accumulate in plasma after repetitive dosing. The improved tolerability of 
eltanexor may be due to its reduced brain penetration and improved therapeutic window. The 
safety, tolerability, and preliminary efficacy of eltanexor is currently under investigation in Study 
KCP-8602-801 (hereafter referred to as Study 801, NCT02649790) which is an ongoing first-in-
human, open-label dose-escalation study in patients with relapsed/refractory multiple myeloma 

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(R/R MM) followed by a dose-expansion phase in patients with select advanced malignancies, 
including mCRC, mCRPC, and HR-MDS.
1.2.3.2
Dosing
As of 18 November 2023, a total of 153 patients (39 patients with R/R MM, 30 patients with with 
RR CRC, 30 patients with mCRPC, and 50 patients with HR-MDS, and 4 with ND MDS) have 
received eltanexor on Study 801 and have safety data available. In addition, 3 patients have been 
dosed in Part F Phase 2 (HR-MDS) and 2 patients in Part G (newly diagnosed intermediate or high 
risk MDS in combination with Inqovi); however, no safety data is available as of the cut-off date 
in these 5 patients.
In the dose escalation phase, which is now complete, patients with R/R MM were dosed with 5-40 
mg eltanexor daily x 5 days (5 days on, 2 days off) per week or 60 mg eltanexor every other day 
x 3 doses (every other day for 5 days, 2 days off), alone or in combination with dexamethasone. 
There were 2 DLTs observed (>4 missed doses and Grade 4 thromobcytopenia) in different dose 
cohorts, however, the protocol-defined MTD was not reached.(37) Therefore, both 20 mg and 30 
mg eltanexor daily x 5 + 20 mg dexamethasone twice weekly were selected for further evaluation 
to clearly define the recommended phase 2 dose (RP2D). 
In the dose-expansion phase, patients with mCRC were dosed at 20 or 30 mg eltanexor daily x 5, 
mCRPC patients were dosed at 20 or 30 mg eltanexor daily x 5 alone or in combination with 
abiraterone, and HR-MDS patients were dosed at 10 or 20 mg eltanexor x 5 (5 days on, 2 days off, 
in 28-day cycles).
In patients with HMA-refactory HR-MDS (n = 35) treated with single-agent eltanexor, the median 
duration of eltanexor (10 mg) was 19.1 weeks (range 2 to 85); however 10 patients treated for  
24 weeks. In 10 mg cohort (n = 5), 3 patients (60%) had  marrow complete response (mCR) and 2 
patients (40%) had stable disease (SD). In the 20 mg cohort (n = 10), 4 patients (40%) had mCR 
and 3 (30%) had SD. The overall survival (OS) for all patients was 9.9 months, and 11.9 months 
for those achieving mCR vs 8.7 months for those who did not achieve mCR (hazard ratio = 0.27, 
p=0.05). (38)
In the entire safety population, the most frequently occurring TEAEs of any grade were nausea 
(56.9%), fatigue (64.1%), diarrhea (54.9%), decreased appetite (43.8%), thrombocytopenia 
(45.8%), weight decreased (42%), neutropenia (42.5%), anemia (38.6%), vomiting (38.6%), and 
constipation (30.7%). The most frequently occurring  Grade 3 TEAEs were thrombocytopenia 
(31.4%), anemia (25.5%), and neutropenia (32.7%). However, no clinically significant cumulative 
toxicities were identified, major organ dysfunction was not observed, and no grade 5 TRAEs were 
reported. Adverse events leading to discontinuation of eltanexor that occurred in  3 patients were 
fatigue (5%), nausea and acute kidney injury (3.4% each), sepsis and weight decreased (2.5% 
each). There was one patient that did not have a TEAE.
In the MDS cohort (n = 20), the most frequently occurring TEAEs of any grade were diarrhea 
(70%), nausea (60%), dyspnea (50%), abdominal pain (45%), fatigue (45%), anemia (40%), 
constipation (40%), dizziness (40%), weight decreased (35%), neutropenia (35%), leukopenia 
(30%), and thrombocytopenia (30%). The most frequently occurring  Grade 3 TEAEs were 
anemia (40%), neutropenia (30%), and thrombocytopenia (30%). However, all AEs were 
reversible and manageable by supportive care and dose modification, and no grade 5 TRAEs were 
reported. (39) See the Eltanexor Investigator’s Brochure (IB) for more information.

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Clinicians typically underestimate the symptoms of the toxic effects or adverse events experienced 
by patients.(40, 41) Patient-centered outcomes assessment starts with an understanding of the 
impact of a disease and its treatment on patients, and what patients value from a treatment 
perspective. In cancer-related clinical trials, regulatory agencies and advocacy groups increasingly 
encourage using patient-reported outcomes (PROs) to describe the clinical benefit of a therapeutic 
regimen. This includes using information on disease-associated symptoms or functions to help 
determine treatment efficacy and understand treatment-associated side effects.  These measures, 
which collect information directly from the patient, without interpretation by somebody else, 
improve researchers’ understanding of the patient perspective on the treatment’s impact. 
Standardizing and incorporating PROs into earlier phase trials such as this dose finding in re-
irradiation would allow them to be optimized, improve study design and allow more rigorous and 
systematic assessment of PROs in later-phase trials. 
Tolerability and efficacy for KPT-8602 in HR-MDS are being further studied in the Phase 2 
portion of Study 801 along with a Phase 1b study in AML. Additional studies in both solid tumors 
and hematological malignancies are planned. Phase 1 evaluation is also ongoing in newly 
diagnosed intermediate or high risk MDS.
Additionally, preclinical studies have expored various dosing strategies for KPT-8601 including 5 
days/week and continuous daily dosing, and have suggested that either strategy is feasible (42, 43).
1.2.3.3
Pharmacokinetic (PK) and pharmacodynamic (PD) data
In Study 801, the PK profile of KPT-8602 (eltanexor) after oral administration was predictable, 
dose-proportional, and exhibited moderate inter-patient variability across doses of 5-20 mg in male 
and female patients with R/R MM, mCRC, mCRPC, and HR-MDS. Following single doses of 5-
60 mg at C1D1, the eltanexor PK profile was characterized by rapid absorption (median Tmax 1-3 
hours) and moderate clearance (21-35 L/h), volume of distribution 170-264 L, and terminal half-
life 4-6 hours. Interindividual variablility was moderate as evidenced by geometric mean percent 
coefficient of variation (%CV) values (range) for AUC 0– 24-44% and Cmax 15-53% (Eltanexor 
IB, version 4.0).
Based on nonclinical and exploratory clinical data from SINE compounds, the change in XPO1 
mRNA expression after treatment is an appropriate PD marker and was used to evaluate target 
engagement across the first 6 R/R MM cohorts treated with single-agent eltanexor on Study 801. 
Target engagement was assessed from whole blood collected on C1D1 at 2, 4, 8, and 24 hours post 
dose of eltanexor and was compared to the relative level (i.e., set to 1 at 0 hrs) at pre-dose. The 
plasma concentration of eltanexor was also calculated and plotted. For all cohorts evaluated, the 
fold-change maximum (Fmax) of XPO1 mRNA expression was achieved 4 to 8 hours post-dose. 
The Fmax and AUC24 for XPO1 mRNA was roughly dose proportional to the Cmax and AUC24 of 
eltanexor in plasma samples from these patients. The plateau for Fmax and AUC24 of XPO1 
mRNA in treated patients was 5-fold change and 100-fold change (baseline*hr), respectively, 
when compared with pre-dose levels. Based on these preliminary data, the maximum dose for 
these XPO1 changes occurs in patients treated with 60 mg of eltanexor. Although the RP2D of 20-
30 mg eltanexor (depending on the indication) does not maximize the Fmax at C1D1, this reduced 
response of XPO1 mRNA may correlate with the improved tolerability of eltanexor. Of note, there 
is currently not enough data for a clinically reliable marker of maximal pharmacologic activity for 
eltanexor. We will use the MTD to make our RP2D determination and use the totality of data from 

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this early phase trial, including PK, PD, safety and MTD interpretation to best determine optimal 
dosing in later trials.
1.2.3.4
Rationale for combining KPT-8602 (eltanexor) and Inqovi
DNMT3B is one protein responsible for de novo DNA methylation and fast rebound methylation 
after HMA cessation in MDS. The proto-oncogene c-MYC directly binds the DNMT3B promoter, 
causing increased expression of DNMT3B. By interfering with c-MYC translation, KPT-8602 may 
diminish rebound methylation after decitabine cessation and improve treatment responses in 
patients with MDS (Figure 1). Preliminary reports from Study 801 show anti-tumor activity and 
an acceptable toxicity profile for KPT-8602 in patients with HR-MDS who have failed HMAs. 
Additionally, preclinical studies have shown that decitabine priming increases antileukemic effects 
of selective inhibitors of nuclear transport (SINEs) in AML in vitro and in vivo. (44) Therefore, 
sequential addition of KPT-8602 to Inqovi may further improve treatment responses in participants 
with myeloid malignancies by acting synergistically to inhibit further DNA methylation.
Figure 1: Synergy between eltanexor (KPT-8602) and decitabine
Abbreviations: DAC, decitabine; Elta, eltanexor; TSP, tumor suppressor protein
Figure provided by Dr. Alen Ostojic, NCI
1.2.3.5
Rationale for Myeloid Malignancy Program Investigation
In general, long term treatment outcomes for MDS patients are dismal. It is estimated that of every 
100 MDS patients, 4 will be long-time survivors, with the rest of succumbing to either MDS- or 
treatment-related complications (67) or MDS-unrelated complications (29).(3) There has been no 
progress in populations based studies in survival of MDS patients during last 2 decades.(29) Novel 
approaches are needed which do not rely exclusively on cytotoxic therapy and/or intervene earlier 
in the course of the disease. Current clinical trials for participants with MDS enroll less than 5% 

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of MDS patients.(28) With better understanding of complex MDS pathophysiology, trials using 
combination treatments are emerging, especially for those ineligible for HSCT.(11)  
A new Clinical and Translational Correlates Facility was recently funded by the FY20 Directors 
Challenge Innovation Award and is physically housed initially within NHLBI space (PI 
Christopher Hourigan et al). This facility will create the ability to perform standardized research 
correlates proposed on this study and across the growing NIH Myeloid Malignancies Clinical 
Trials portfolio. Work from intramural investigators has recently demonstrated that high-
sensitivity genomic measurements outperform conventional clinical assessments for myeloid 
malignancy participants in predicting relapse and survival following HSCT and suggest that 
additional intervention on high-risk subjects can improve clinical outcomes.(45) This sets the stage 
for a “precision medicine” approach where personalized assessments of clonal disease burden can 
be used not only to judge the success of therapy, but also as a target for intervention.
In this trial, we hypothesize that sequential addition of KPT-8602 (eltanexor) to Inqovi is safe in 
treatment of adult MDS participants. For the phase 2 trial, we hypothesize that eltanexor enhances 
the efficacy of Inqovi in adult MDS participants.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Participants must have histologically or cytologically confirmed MDS  by the Laboratory 
of Pathology, NCI- according to 2016 WHO criteria(1)
AND:
•
Cohort 1 (Phase 1) & 2 (Phase 2): have HR-MDS (IPSS-R > 3.5) with inadequate 
response to hypomethylating agent (HMA) therapy [(received  4 cycles of the 
standard dose (35 mg decitabine and 100 mg cedazuridine) without prior dose-
reductions, with failure to achieve at least a PR or experienced disease 
progression prior to completing 4 cycles)
2.1.1.2
Age >18 years
2.1.1.3
ECOG performance status  2 (Karnofsky  60%, see Appendix A)
2.1.1.4
Participants must have adequate organ and marrow function as defined below: 
•
total bilirubin
 1.5 X institutional upper limit of normal
OR
≤ 3 X institutional upper limit of normal in 
participants with Gilbert’s syndrome (except 
for participants with increased bilirubin 
levels attributed to intramedullary hemolysis, 
which will be allowable)
•
AST(SGOT)/ALT(SGPT)
 3 X institutional upper limit of normal
OR

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≤ 5 X institutional upper limit of normal if 
related to MDS-specific cause
•
creatinine clearance
 60 mL/min/1.73 m2
     (by Cockcroft-Gault)
•
QTc(F)
≤ 470 ms
2.1.1.5
Individuals of child-bearing potential (IOCBP) must have a negative serum test at 
screening. IOCBP is defined as the following:
•
Has not undergone a hysterectomy, tubal ligation, or bilateral oophorectomy
•
Has not been naturally postmenopausal for at least 24 consecutive months (i.e., 
has had menses at any time in the preceding 24 consecutive months).
2.1.1.6
Individuals of childbearing potential (IOCBP) as well as those able to father a child with 
an individual able to become pregnant must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) unless they have had a prior 
vasectomy, hysterectomy, or bilateral oophorectomy, prior to study entry, for the 
duration of study participation, and for at least 6 months after last dose of HMA.
2.1.1.7
Breastfeeding participants must be willing to discontinue breastfeeding from study 
treatment initiation through 30 days after the last administration of study drug
2.1.1.8
Any prior therapy must have been completed >4 weeks or, if known,  5 half-lives of the 
prior agent (whichever is shorter) prior to treatment (with a minimum of 1 week between 
prior therapy and study treatment). Note: This does not apply to prior HMA therapy if 
that therapy is Inqovi per Section 2.1.1.1.
2.1.1.9
Ability to understand and the willingness to sign a written informed consent document.
2.1.2
Exclusion Criteria
2.1.2.1
Participants with platelet transfusion-refractory thrombocytopenia, with inability to keep 
platelet threshold above 10K/mcL with transfusions or those with ongoing or 
uncontrolled hemorrhagic complications.
2.1.2.2
Participants with clinically significant neutropenia, defined as ANC <100 cells/mcL with 
frequent hospitalizations for infection (average > 1 hospitalization per month in the past 
6 months).
2.1.2.3
Participants on treatment with a myeloid growth factor (e.g., G-CSF) within 14 days prior 
to initiation of study treatment.
2.1.2.4
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to HMAs or other agents used in study.
2.1.2.5
Uncontrolled intercurrent illness evaluated by history, physical exam, and chemistries or 
situations that would limit compliance with study requirements, interpretation of results 
or that could increase risk to the participant 
2.1.2.6
Participants with the following cardiac conditions:  symptomatic congestive heart failure, 
unstable angina pectoris, or uncontrolled cardiac arrhythmia as assessed by 
electrocardiogram (ECG).

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2.1.2.7
Pregnancy (confirmed with β-HCG serum or urine pregnancy test performed in 
individuals of childbearing potential at screening)
2.1.2.8
Presence of any other malignancy (except basal and squamous cell carcinoma of the skin, 
or stable chronic cancers on hormone or targeted therapy) for which participant received 
systemic anticancer treatment (except maintenance therapy) within 24 months prior to 
treatment.
2.1.2.9
Participants with active/uncontrolled Hepatitis B
2.1.2.10 Participants with active/uncontrolled Hepatitis C
2.1.2.11 Participants with active/uncontrolled HIV infection or AIDS.
2.1.2.12  Participants currently taking contraindicated medications for HIV, Hepatitis B, or 
Hepatitis C disease control (Appendix L)
2.1.3
Recruitment Strategies
This protocol will be advertised on NIH websites (clinicaltrials.gov, future Myeloid Malignancy 
Program Web Site) and social media platforms, as well as through professional MDS associations.
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
•
Email, written, in person or telephone communications with prospective subjects 
•
Review of existing medical records to include H&P, laboratory studies, etc.  
•
Review of existing MRI, x-ray, or CT images
•
Review of existing photographs or videos
•
Review of existing pathology reports from a specimen obtained for diagnostic purposes
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the participant has signed the consent for this 
study for screening. Assessments performed at outside facilities or on another NIH protocol within 
the timeframes listed below may be used to determine eligibility once a participant has signed the 
consent for this study. 
Assessments and procedures to confirm study eligibility should be completed within 30 days prior 
to the start of treatment, unless otherwise indicated. See also Section 3.5, Study Calendar.
Any time prior (no time limit):
•
Histologic confirmation: All participants are required to have histologically confirmed 
MDS. If pathology reports are from outside institutions, outside slides pathologic review 
of diagnosis by Laboratory of Pathology of NCI is required to determine study eligibility 
at screening.
Within 30 days:

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•
History and physical examination: Complete history and physical examination (including 
height, weight, vital signs, and performance status) 
•
Laboratory Evaluation: 
o
Hematological Profile: CBC with differential, reticulocyte count
o
Biochemical Profile: total bilirubin, BUN, albumin, calcium, creatinine, SGOT 
[AST], SGPT [ALT], phosphorous, magnesium, potassium, sodium, LDH, uric 
acid, ferritin, endogenous erythropoietin
o
Vitamin B12, folate, copper, zinc, TSH, free T4- to assess alternative/reversible 
causes of cytopenias that may confound MDS diagnosis
o
Infectious serologies including HIV, HBV, HCV
o
Urine and/or serum pregnancy test for individuals of childbearing potential (must 
be performed within 24 hours prior to initating study treatment)
•
Cardiac Evaluation: Electrocardiogram (ECG)
•
Next Generation Sequencing (as needed): panel of myeloid genes from bone marrow. May 
be performed during screening evaluation if the MDS diagnosis is in question based on 
histology alone.
•
Bone marrow aspirate and biopsy (as needed): if no prior sample is available for pathology 
review, a fresh bone marrow aspirate and will be taken at screening to determine diagnosis.
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration 
& 
Status 
Updates 
found 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
any specific inclusion/exclusion criteria by discretion of PI may be rescreened.
Circumstances when a participant may be re-screened:
1. If a participant consented to participate and met the eligibility criteria, but there was a delay 
in starting due to a change in situation (e.g., family issues, individual request for attending 
a private matter, etc.)
2. If a participant previously failed screening due to an acute event that has now 
resolved/reversed.

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3. If a participant failed screening due to being on a prohibited medication, which has been 
discontinued.
4. If reversible causes of screen failure have been adequately treated.
2.3.2
Treatment Assignment (for Phase I and II)
Cohorts
Number
Name
Description
1
Phase I- “Higher-risk” MDS
Participants with confirmed MDS and IPSS-R score > 3.5 (high 
and higher intermediate-risk) 
2
Phase II- “Higher-risk” 
MDS
Participants with confirmed MDS and IPSS-R score > 3.5 (high 
and higher intermediate-risk) for phase II dose expansion
Arms
Number
Name
Description
1
Phase I- Dose escalation of 
KPT-8602 for HR-MDS
Inqovi for 5 days, followed by escalating doses of KPT-8602
2
Phase II- Dose expansion for 
HR-MDS
Inqovi for 5 days, followed by Phase II dose of KPT-8602
Arm Assignment
Participants in Cohort 1 will be directly assigned to Arm 1; Cohort 2 will be directly assigned to 
Arm 2; 
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
The study consists of two phases:
•
Phase I: Safety evaluation with determination of the recommended phase 2 dose (RP2D) 
of KPT-8602 in combination with Inqovi, and
•
Phase II: Efficacy evaluation of KPT-8602 in combination with Inqovi
Participants will be enrolled into one of two cohorts, depending on the phase of study as follows:
•
Phase I:
o
Cohort 1: Participants with higher-risk MDS that will be treated with Inqovi for 5 
days, followed by KPT-8602 at escalating doses.
•
Phase II:
o
Cohort 2: Participants with higher-risk MDS that will be treated with Inqovi for 5 
days, followed by KPT-8602 at the RP2D.
In Phase I, participants enrolled in Cohort 1 will be treated with Inqovi 35 mg/100 mg daily on 
Days 1-5 of each 28-day cycle, plus KPT-8602 at the corresponding dose level and schedule.. 

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Dose-escalation will follow a standard 3+3 design (see Section 3.1.2), with DLT assessment during 
the first 28 days of treatment. 
In Phase II, participants enrolled in Cohort 2 will be treated with Inqovi 35 mg/100 mg daily on 
Days 1-5 of each 28-day cycle, plus KPT-8602 at the RP2D identified in Phase I. 
The study drugs will be self-adminstered by the patient, except on days of PK blood draws.
Participants in Cohorts 1 and 2 are eligible to participate in the study if they have received a 
minimum of 4 cycles of HMA therapy with inadequate response (failure to achieve at least a PR, 
or experienced disease progression prior to completing 4 cycles). For participants on HMA therapy 
with Inqovi prior to enrollment, descriptions of initiation of study therapy refer to initiation of 
KPT-8602 only. Of note, participants receiving Inqovi prior to enrollment must be on the standard 
dose (35 mg decitabine and 100 mg cedazuridine) without prior dose-reductions.
In both Phase I and Phase II, participants will continue treatment until disease progression, death, 
unacceptable toxicities as listed in Section 3.3.2, or another off-treatment criterion is met (see 
Section 3.7.1) as long as no other contraindications to further treatment. Participants that do not 
achieve at least partial remission following cycle 6 will not receive additional treatment.
Blood samples for correlative research will be collected (Section 5.1). Participants may be 
admitted on day 8 of cycle 1 for pharmacokinetics (PK) studies to be performed, and on other days 
if necessary or for convenience.
Upon discontinuation of study treatment, participants will be followed for safety for at least 30 
days after the last dose of treatment, and for event-free survival (EFS), progression-free survival 
(PFS), and overall survival (OS) until study follow-up requirements have been completed. The 
study will be closed to follow-up when all enrolled participants have been followed for up to 8 
years or have died.

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Phase I/II Study Schema
3.1.1
Dose Limiting Toxicity (DLT)
The DLT evaluation window will be the first 28 days of study treatment. No dose reductions or 
interruptions are allowed during the DLT observation period. 
A DLT is defined as any of the following treatment-related toxicities (based on CTCAE Version 
5.0):
•
Any Grade 5 toxicity, unless due to underyling disease, disease progression, or accidental 
injury.
•
Any Grade ≥ 3 non-hematologic toxicity, except:
o
Grade 3 or 4 isolated electrolyte abnormalities that resolve, with or without 
intervention, to Grade  2 within 72 hours
o
Grade 3 nausea, vomiting, or diarrhea that does not require/prolong hospitalization, 
does not require TPN or NGT feeding, and resolves to Grade  2 within 72 hours
o
Grade 3 fatigue, fever, flu-like symptoms, or headache lasting ≤ 72 hours
o
Grade 3 laboratory abnormalities that are not associated with organ pathology
o
Direct complications of cytopenia(s) due to active myeloid malignancy, such as:
Grade 3 or 4 febrile neutropenia 
Grade 3 or 4 infection
Grade 3 or 4 hypotension explained by sepsis 
Grade 3 or 4 hemorrhage/bleeding 
•
Confirmed Hy’s law cases, defined as: 
o
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN), AND
o
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase), AND

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o
No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic. 
•
In the absence of active MDS, hematologic DLTs for each arm include:
o
any Grade ≥4 decrease ANC or PLTs lasting more than 28 days.
•
Any adverse reaction that leads to dose reduction or withdrawal of KPT-8602.
3.1.2
Dose Escalation
In a phase I/II study (NCT 02649790) that evaluated single agent eltanexor in higher-risk MDS, 2 
doses were evaluated: 5 patients received 10 mg and 15 patients received 20 mg, every day for 5 
days per week of a 28-day cycle. The majority of patients were aged ≥75 and all were treated and 
refractory to hypomethylating agents. None of the patients experienced dose-limiting toxicities 
(DLTs) and the RP2D for eltanexor was selected as 10 mg given on days 1-5 of each week of a 
28-day cycle in HR-MDS (20/28 days). Given the overlap in toxicities, particularly hematologic, 
between hypomethylating agents and eltanexor, our starting dose was set at 10 mg PO daily on 
Days 8-12 and Days 15-19 (total of 10 days per 28-day cycle as opposed to 20 days per 28-day 
cycle in NCT 02649790).
In Phase I, dose escalation will proceed in cohorts of 3-6 participants. The MTD is the dose level 
at which no more than 1 of up to 6 participants experience DLT during the first cycle (28 days) of 
treatment, and the dose below that at which at least 2 (of ≤6) participants have DLT as a result of 
the drug. 
Participants in Cohort 1 will be eligible for the DLT evaluation if 90% (9 out of 10 doses) of 
KPT-8602 and 80% (4 out of 5 doses) of Inqovi were taken within the DLT period. Participants 
not evaluable for toxicity, will be replaced in the dose level.
Dose Escalation Schedule
Dose Level
Dose of KPT-8602 
Level -2
5 mg PO daily on Days 8-12 and Days 15-19
Level -1
5 mg PO daily on Days 8-21
Level 1 (starting dose)
10 mg PO daily on Days 8-12 and Days 15-19
Level 2
10 mg PO daily on Days 8-21

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Dose escalation will start at dose level 1 and follow the rules outlined in the Table below.
Number of Participants 
with DLT
at a Given Dose Level
Escalation Decision Rule
0 out of 3
Enter up to 3 participants at the next dose level
> 2
Dose escalation will be stopped. This dose level will be 
declared the maximally administered dose (highest dose 
administered). Up to three (3) additional participants will 
be entered at the next lowest dose level if only 3 
participants were treated previously at that dose.
1 out of 3
Enter up to 3 more participants at this dose level.
•
If 0 of these 3 participants experience DLT, proceed 
to the next dose level.
•
If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose. Up to three (3) 
additional participants will be entered at the next 
lowest dose level if only 3 participants were treated 
previously at that dose.
<1 out of 6 at highest dose 
level below the maximally 
administered dose
This is the MTD and is generally the recommended phase 
2 dose. At least 6 participants must be entered at the 
recommended phase 2 dose.
No new participants will initiate study treatment at the current or next higher (or lower) dose level 
until the required number of participants have completed DLT evaluation. Each dose-escalation or 
de-escalation decision will be documented in the study file. The report including the supporting 
safety data and delineation of each criteria met, with the dose-escalation decisions will be provided 
to the Sponsor (OSROSafety@nih.gov) before additional participants will be enrolled into the 
study. 
The 
Dose 
Escalation 
Determination 
form 
on 
the 
sponsor 
website: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions  may be used for 
this purpose.
3.1.3
Dose Expansion
If no DLTs are observed at the highest planned dose level for evaluation (dose level 2), dose 
escalation will stop and this will be considered the recommended phase 2 dose (RP2D) of KPT-
8602. Phase II may begin once the RP2D has been identified.
3.1.4
Protocol Stopping Rules
This study will incorporate stopping rules related to safety and response.
For safety stopping rules, see Section 10.4.4. 
For response stopping rules, see Section 10.2. 

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3.2
DRUG ADMINISTRATION
Drugs will be self-administered at home except for the days that participants are being seen in 
clinic for pharmacokinetic blood draws. On those days, participants should be instructed to bring 
in their medication supply from home, without taking the medication, as they will be instructed 
when to do so as the blood draws must be timed with drug administration.
3.2.1
KPT-8602
KPT-8602 will be dosed per participant assignment and as outlined in Section 3.1.2. KPT-8602 
tablets are film coated for ease in handling and should be swallowed whole (not crushed). Do not 
break, crush, or divide the tablets to prevent an increased risk of dermatologic toxicity if the 
powder comes in contact with skin. Oral KPT-8602 should be taken with or within 30 minutes of 
eating.
Medication bottles and leftover pills will be collected at the end of each cycle to monitor participant 
adherence.
Participants will be asked to complete a medication diary (Appendix K). If a dose is missed within 
12 hours of the time it is usually administered, administer the missed dose as soon as possible and 
then resume the normal daily dosing schedule. Extend the dosing period by 1 day for every missed 
dose to complete the total number of daily doses for each cycle. If a dose is vomited, do not 
administer an additional dose (continue with the next scheduled dose).
3.2.2
Decitabine and Cedazuridine (Inqovi)
In both Phase I and Phase II, the study drug of KPT-8602 will be given in combination with 
standard-of-care (SOC) FDA-approved PO decitabine and cedazuridine (Inqovi).
•
Inqovi will be administered via oral route once daily on Days 1-5 of each treatment cycle, 
according to guidelines outlined in the FDA product label.
The tablet should be taken on an empty stomach, 2 hours before or 2 hours after meals, and at the 
same time each day.
Tablet should be swallowed whole, and may not be crushed, cut, or chewed. 
Participants will be asked to complete a medication diary. If a dose is missed within 12 hours of 
the time it is usually administered, administer the missed dose as soon as possible and then resume 
the normal daily dosing schedule. Extend the dosing period by 1 day for every missed dose to 
complete 5 daily doses for each cycle. If a dose is vomited, do not administer an additional dose 
(continue with the next scheduled dose).
3.3
DOSE MODIFICATIONS
Participants may continue study treatment if toxicity can be managed by interruption of the dose 
of study treatment or dose reductions as explained below. The following outlines dose 
modifications for study-drug related toxicities.
If toxicity is considered to be due solely to one of the study drugs as defined below, the participant 
may be taken off this drug and after consulting with a Sponsor may continue treatment with the 
other drug only if the participant is deriving benefit from treatment in the form of stabilization of 
disease or response.

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When, at the beginning of a treatment cycle, treatment delay related to one drug is indicated, 
treatment with the other drug will be continued. For the purpose of restaging, cycle number will 
continue to be defined on the basis of a time of 28 days (+/- 7 days), i.e., cycle number will not 
change due to one drug being held.
Overlapping toxicities may be attributed solely to KPT-8602 if a participant who was already on 
Inqovi prior to starting on study treatment develops the toxicity upon addition of KPT-8602. In 
addition, overlapping toxicities may be attributed solely to one of the drugs if dose modification 
or delay of one drug (while the other is continued at the same dose) results in resolution of the 
toxicity. 
3.3.1
Dose Levels for Toxicity Management
Dose levels for KPT-8602 (eltanexor) are as follows, for the purposes of toxicity management.
•
Dose level
KPT-8602 dosage
2
10 mg orally once daily on Days 8-21
1
10 mg orally once daily on Days 8-12 and Days 15-19
-1
5 mg orally once daily on Days 8-21
-2
5 mg orally once daily on Days 8-12 and Days 15-19
Dose levels for Inqovi are as follows, for the purposes of toxicity management.
•
Dose level
Inqovi dosage
1
1 tablet orally once daily on Days 1 through 5
-1
1 tablet orally once daily on Days 1 through 4
-2
1 tablet orally once daily on Days 1 through 3
-3
1 tablet orally once daily on Days 1, 3, and 5
3.3.2
Dose Modification Guidelines
3.3.2.1
Criteria for initiation of subsequent cycles
The next cycle of therapy may proceed if the following criteria are met:
Non-hematologic criteria to start the next cycle:
•
Serum Cr < 2 mg/dL
•
Serum bilirubin < 2 x ULN
•
AST or ALT < 2 x ULN
•
No active or uncontrolled infection
Participants who do not meet these non-hematologic criteria should have the next cycle delayed 
and labs monitored at least weekly. Once resolved, study treatment may resume at the same dose 
for the next cycle. If not resolved within 4 weeks, dose-reduce when participant meets criteria (as 

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noted above) to start the next cycle as noted below (if not resolved within 8 weeks participant will 
be taken off treatment):
Dose 
reduction
Inqovi dosage*
KPT-8602 dosage*
First
Continue same dose
Reduce by one dose level
Second
Reduce by one dose level
Reduce by one dose level
Third
Reduce by one dose level
Reduce by one dose level
Fourth
Reduce by one dose level
Permanently discontinue
Hematologic criteria to start the next cycle (applies only to participants without active 
disease by bone marrow):
•
ANC  1000/mcL
•
PLT  50,000/mcL
Participants who do not meet these hematologic criteria (and without active disease by bone 
marrow) should have the next cycle delayed and CBC monitored at least weekly until ANC is  
1000/mcL and PLT  50,000/mcL.
•
If hematologic recovery (ANC  1000/mcL and PLT  50,000/mcL) occurs within 2 weeks 
of achieving remission by bone marrow, continue Inqovi and KPT-8602 at the same dose 
for the next cycle.
•
If hematologic recovery does not occur within 2 weeks of achieving remission by bone 
marrow, delay Inqovi and KPT-8602 for up to 2 additional weeks and dose-reduce for the 
next cycle as noted below:
Dose 
reduction
Inqovi dosage*
KPT-8602 dosage*
First
Continue same dose
Reduce by one dose level
Second
Reduce by one dose level
Reduce by one dose level
Third
Reduce by one dose level
Reduce by one dose level
Fourth
Reduce by one dose level
Permanently discontinue
*Once the lowest dose level has been reached for a given drug, if myelosuppression 
persists, discontinue drug.
If not resolved within 8 weeks participant will be taken off treatment.
3.3.2.2
Toxicity Guidelines
In addition, the tables below show general supportive care and dose modification guidelines for 
toxicities noted at any point during study treatment (other than the scenarios described above). 
Dose levels of KPT-8602 and Inqovi for the purposes of toxicity management are as noted in 
Section 3.3.1.

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3.3.2.2.1 Hematologic toxicities
Toxicity 
Recommended Action*
Thrombocytopenia
Grade 2 (PLT  
75,000/mcL)
•
Maintain dose of KPT-8602 and Inqovi.
•
Consider dose reduction of any anti-platelet agents.
•
Start PPI.
Grade 3 or 4 
thrombocytopenia 
(PLT  50,000/mcL) 
without bleeding
•
In cases where there is still significant disease involvement in the bone marrow:
o
The treating physician, in consultation with the PI, may continue KPT-8602 
and Inqovi at the same dose level
•
Otherwise, the following guidelines should be followed:
o
Hold KPT-8602 and Inqovi until improves to  Grade 2 or baseline.
▪
If improves to  Grade 2 or baseline within 72 hours:
•
Resume KPT-8602 and Inqovi at the same dose
▪
If does not improve to  Grade 2 or baseline within 72 hours:
•
Hold KPT-8602 and Inqovi for the remainder of the current 
cycle.
•
Reduce KPT-8602 by one dose level with the next cycle
•
Resume Inqovi at the same dose for the next cycle (first 
occurrence) or reduce Inqovi by one dose level for the next 
cycle (second or later occurences)
•
Note: Toxicity must resolve to  Grade 2 or baseline before 
drugs can be resumed
•
In addition, the following steps should be taken for all cases:
o
Consider initiating a platelet growth factor per institutional guidelines.
o
Monitor platelet counts at least twice weekly and closely monitor for any 
bleeding signs/symptoms.
o
Transfuse as per institutional guidelines.
o
Consider dose reduction of any anti-platelet agents.
o
Start PPI.
Grade 3-4 
thrombocytopenia 
(PLT  50,000/mcL) 
with bleeding
•
Consider initiating a platelet growth factor per institutional guidelines.
•
Transfuse as per institutional guidelines.
•
Start PPI.
•
Hold KPT-8602 and Inqovi for the remainder of the cycle and until bleeding resolves 
and platelet count improves to  Grade 2 or baseline, then:
o
Reduce KPT-8602 by one dose level with the next cycle.
o
Resume Inqovi at the same dose for the next cycle (first occurrence) or 
reduce Inqovi by one dose level with the next cycle (second or later 
occurences).
Neutropenia
Grade 3 neutropenia 
(ANC  1000/mcL) 
without fever
•
Maintain dose of KPT-8602 and Inqovi.
•
Consider use of growth factors per institutional guidelines.
Grade 4 neutropenia 
(ANC  500/mcL) 
without fever
•
In cases where there is still significant disease involvement in the bone marrow:
o
The treating physician, in consultation with the PI, may continue KPT-8602 
and Inqovi at the same dose level
•
Otherwise, the following guidelines should be followed:
o
Hold KPT-8602 and Inqovi until improves to  Grade 3 or baseline.

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Toxicity 
Recommended Action*
▪
If improves to  Grade 3 or baseline within 72 hours:
•
Resume KPT-8602 and Inqovi at the same dose.
▪
If does not improve to  Grade 3 or baseline within 72 hours:
•
Hold KPT-8602 and Inqovi for the remainder of the current 
cycle.
•
Reduce KPT-8602 by one dose level with the next cycle.
•
Resume Inqovi at the same dose for the next cycle (first 
occurrence) or reduce Inqovi by one dose level for the next 
cycle (second or later occurences).
•
Note: Toxicity must resolve to  Grade 3 or baseline before 
drugs can be resumed
•
Consider use of growth factors.
•
If growth factors are implemented, for participants who achieve neutrophil levels 
>1000/mcL for >4 weeks, KPT-8602 may be re-escalated with the next cycle of 
therapy, with frequent monitoring implemented.
Grade 3 or 4 
neutropenia with 
fever
•
Implement broad-spectrum anti-microbial agents per institutional guidelines.
•
Consider use of growth factors.
•
Hold KPT-8602 and Inqovi for the remainder of the cycle and until fever resolves 
and the participant is clinically stable, then:
o
Reduce KPT-8602 by one dose level with the next cycle.
o
Resume Inqovi at the same dose for the next cycle (first occurrence) or 
reduce Inqovi by one dose level with the next cycle (second or later 
occurences).
•
If growth factors are implemented, for participants who achieve neutrophil levels 
>1000/mcL for >4 weeks, KPT-8602 may be re-escalated with the next cycle of 
therapy, with frequent monitoring.
*Once the lowest dose level has been reached, if toxicity persists, discontinue drug.
3.3.2.2.2 Non-hematologic toxicities
Toxicity
Recommended Action*
Fatigue
Grade 3
•
Interrupt KPT-8602 dosing until fatigue improves to Grade  2 or baseline. 
Maintain dose of Inqovi.
•
If fatigue does not improve to Grade  2 or baseline within 7 days despite holding 
KPT-8602, interrupt Inqovi dosing.
•
Once improved to Grade  2 or baseline:
o
If first occurrence: restart KPT-8602 and Inqovi at the same dose.
o
If second occurrence: restart KPT-8602 one dose level below and Inqovi at 
same dose.
o
If third or later occurrence: restart both KPT-8602 and Inqovi one dose 
level below.
Unintentional weight loss and anorexia
Grade 3
•
Interrupt KPT-8602 dosing until weight loss/anorexia resolves to Grade  2 or 
baseline. Maintain dose of Inqovi.

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Toxicity
Recommended Action*
•
If weight loss/anorexia does not improve to Grade  2 or baseline within 7 days 
despite holding KPT-8602, interrupt Inqovi dosing. 
•
Once improved to Grade  2 or baseline and participant is clinically stable:
o
If first occurrence: restart KPT-8602 one dose level below and Inqovi at the 
same dose.
o
If second or later occurrence: restart both KPT-8602 and Inqovi one dose 
level below.
•
Provide supportive care, including high-calorie supplements, as needed.
Grade 4 (anorexia 
only)
•
Interrupt KPT-8602 and Inqovi dosing until anorexia resolves to Grade  2 or 
baseline.
•
Once improved to Grade  2 or baseline, participant is clinically stable, and any 
other contributing factors have been addressed: restart both KPT-8602 and Inqovi 
one dose level below.
•
If anorexia does not improve to Grade  2 or baseline within 7 days, permanently 
discontinue treatment.
Nausea or vomiting, acute
Grade 3
•
Interrupt KPT-8602 and Inqovi dosing until resolved to Grade  2 or baseline.
•
Once improved to Grade  2 or baseline and participant is clinically stable:
o
If first occurrence and adequate supportive care resulted in improvement to 
Grade  1 within 3 days: restart KPT-8602 and Inqovi at the current dose
o
If second occurrence or first occurrence not meeting criteria above: restart 
KPT-8602 one dose level below and Inqovi at same dose. 
o
If third occurrence: restart both KPT-8602 and Inqovi one dose level below.
Diarrhea
Grade 2
•
Rule out infectious causes and institute standard anti-diarrheal therapy
•
After the first occurrence, consider instituting loperamide 2 mg prophylactically 
approximately 1-2 hours before the administration of KPT-8602 and repeated every 
4 hours for the first 12 hours
•
Reduce KPT-8602 by one dose level until resolved to Grade  1 or baseline, then 
restart at the current dose level. Maintain Inqovi dose.
Grade 3
•
Rule out infectious causes and institute standard anti-diarrheal therapy
•
Institute prophylactic loperamide, as above
•
Interrupt KPT-8602 and Inqovi until resolved to Grade  1 or baseline.
•
Once resolved to Grade  1 or baseline:
o
If first occurrence: restart KPT-8602 one dose level below and Inqovi at 
same dose.
o
If second or later occurrence: restart both KPT-8602 and Inqovi one dose 
level below.
o
If diarrhea stabilizes for at least 4 weeks at Grade  1 or baseline, then the 
prior dose of KPT-8602 and Inqovi may be resumed at PI discretion.
Grade 4
•
Rule out infectious causes and institute standard anti-diarrheal therapy
•
Institute prophylactic loperamide, as above
•
Interrupt KPT-8602 and Inqovi until resolved to Grade  1 or baseline.
•
Once resolved to Grade  1 or baseline: restart both KPT-8602 and Inqovi one dose 
level below.
Hyponatremia

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Toxicity
Recommended Action*
Grade 3 (sodium 
level 125-129 
mmol/L 
symptomatic; 120-
124 mmol/L 
regardless of 
symptoms)
•
Consider administration of appropriate saline solution and re-measure serum sodium 
levels. If (corrected) sodium is Grade ≤1 or baseline, then participant may receive 
standard dose of KPT-8602.
•
If immediate sodium correction is not successful, skip 1 dose of KPT-8602 and 
reassess sodium within 48 hours. Resume KPT-8602 dosing when sodium is Grade 
≤1 (≥129 mmol/L) at the same dose level.
•
Institute salt supplementation 2-3 times per day.
Grade 4 (<120 
mmol/L; life-
threatening 
consequences)
•
Correct sodium as per institutional guidelines.
•
Institute salt supplementation 2-3 times per day.
•
Hold KPT-8602 until sodium resolved to Grade ≤1 (≥129 mmol/L) then reduce 
KPT-8602 dose by 1 level. Sodium should be reassessed after 1 dose of KPT-8602 
is skipped (i.e., within 48 hours) and corrective measures implemented.
•
If serum sodium stabilizes to Grade ≤1 for at least 4 weeks, original dose of KPT-
8602 may be resumed.
Other non-hematologic toxicities at least possibly related to study treatmenta
aFollow standard dose-modifications for Inqovi as noted in the USPI for Inqovi
Grade 1 or 2
•
Maintain dose of KPT-8602.
•
Initiate standard supportive care per institutional guidelines.
Grade 3
•
Interrupt KPT-8602 dosing until resolved to  2 or baseline, then reduce by one 
dose level.
•
Initiate standard supportive care per institutional guidelines.
Grade 4
•
Interrupt KPT-8602 dosing until resolved to  2 or baseline, then reduce by two 
dose levels.
•
Initiate standard supportive care per institutional guidelines.
*Once the lowest dose level has been reached, if toxicity persists, discontinue drug.Exceptions can be made (i.e., dose 
reduction not required with the next cycle) for the following adverse events which are not considered clinically 
significant by the PI: isolated values of  Grade 3 alkaline phosphatase elevation, alopecia
3.4
ON STUDY ASSESSMENTS/EVALUATIONS
The following describes all tests and procedures to be conducted on the study and during treatment. 
Assessments will be performed according to the Study Calendar (Section 3.5).
3.4.1
Timing of Procedures
For each time period, consider the following order of assessments:
•
Screening: Refer to Section 2.2.
•
Baseline: Baseline assessments to be performed within 7 days prior to initiating study 
treatment. Tests performed as part of screening do not need to be repeated if they were 
performed within the specified window prior to initiating treatment.
•
Assessment Windows: All evaluation days, for flexibility around participant schedules, 
can be performed within -3 days for a new cycle (day 1, cycle 2-beyond); mid-cycle 
assessments can be performed with a window of +/- 3 days for cycles 2-beyond.  The 
maximum number of days permitted between the last day of the previous cycle and the 
start of the next cycle is 28 days.

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•
Unscheduled Visits: In the event of an unscheduled/unplanned visit (e.g., additional 
clinical assessment(s) due to toxicity), the investigator should use the best clinical 
judgment as to the necessary assessments. In the event that the decision is made to continue 
treatment, all tests/assessments as required by the next visit on the Study Calendar (Section 
3.5) should still be conducted (or repeated) within the applicable windows. If a decision is 
made to discontinue treatment, the participant should have a post-therapy follow-up with 
tests/assessments completed (or repeated) within the applicable windows.
•
Disease Progression: When a participant has disease progression on treatment while being 
evaluated at the NIH, evaluations should be done within +10 days after diagnosis of 
progression.
•
End of Treatment Visit: To be done 30 days (+10 day window) after the last dose of study 
therapy. If participants are not able to come to the Clinical Center for this visit, they will 
be contacted by a member of the study team for adverse events and further cancer therapy. 
In these cases, the physical exam will not be required, and laboratory tests performed 
outside of the Clinical Center may be collected.
•
Post-therapy Follow-up: Follow up will occur via phone call every 3 months (+/-2 weeks)  
for first 24 months, then every 6 months (+/-4 weeks) for 3 years, then annually until the 
end of study. Outside medical records will be requested along with the phone call for the 
first follow-up visit only and if clinically indicated at a later point.
•
End of Study: To occur when all participants have been followed for up to 8 years or 
have died.
•
Telehealth/Remote Visits: In instances when participant is not able to come, participant 
may be contact by phone, email or other NIH approved remote platform used in compliance 
with local policy, including HRPP Policy 303. Only unscheduled/unplanned visits may be 
conducted by telehealth. Scheduled timepoint visits must be conducted in-person, therefore 
collection datapoints will not be affected.
3.4.2
Description of Procedures
•
Medical history: a review of treatment history, any ongoing medical conditions, and 
medical history pertaining to eligibility on study and involvement during the study. 
•
Physical exam: review of organ systems, weight, and vital signs (i.e., temperature, pulse, 
respirations, blood pressure, and oxygen saturation). After initiation of study drug, 
symptom-directed physical examinations will be performed as clinically indicated in the 
investigator’s judgment. Note: Height will only be required prior to treatment no later than 
Cycle 1 Day 1.
•
Performance status (ECOG and Karnofsky):  an assessment of activities of daily living; see 
Appendix A.
•
Laboratory assessments:  the following comprises the required tests/analytes. These 
assessments may be performed at Clinical Laboratory Improvement Amendments (CLIA) 
(or equivalent) certified laboratories outside the enrolling site and results forwarded to the 
study team for review and management. Given that the methodologies utilized are similar 

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across all laboratories, no significant variability is expected and there is no anticipation that 
study data will be affected.
However, as different laboratories use slightly different kinds of equipment, each 
laboratory must determine/validate its own reference ranges. Therefore, on this protocol, 
normal ranges from each lab will be used in reference to terms such as ULN, except in 
cases where absolute values are appropriate and are specified as such. Note: Panels 
containing the tests below may be ordered in lieu of individual tests.
o
CBC with differential: includes Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils, WBC, RBC, Hemoglobin, Hematocrit, RBC Indices, 
MCV, RDW, Platelet. 
o
Blood chemistries: includes Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin, Total Protein will be performed to 
assess organ function for safety
o
HIV, HBV, HCV – infectious disease serologies as per section 2.2.2
o
Vitamin B12, Folate, copper, zinc, TSH, free T4- to assess alternative/reversible 
causes of cytopenias that may confound MDS diagnosis at screening
o
Reticulocyte count
o
Urinalysis: for safety
o
Serum or urine pregnancy test: performed prior to administration of study therapy 
in individuals of childbearing potential (see Section 2.1.1.5)
•
Electrocardiogram: 12-lead ECGs will be performed to assess cardiac activity
•
Bone marrow biopsy and aspiration:  to assess response to therapy
•
Concomitant medications: a record of all medications including herbal supplements but not 
including study therapy that a participant has taken during the study will be recorded in 
order to assess confounding factors in safety and efficacy assessments
•
Adverse events: participant reported adverse events will be collected throughout the study 
in order to assess safety.
•
TBNK: for immunologic phenotyping
•
Study drug administration, including dispensing and adherence review:  Study drug will be 
dispensed at each cycle and instructed to be self-administered by participants, unless 
otherwise described, per schedule – see Section 3.1.4. Participants will be given a dosing 
diary (see Appendix K) to be reviewed at each noted visit for drug 
dherence/accountability.
3.4.3
Correlative/Exploratory Assessments
•
Research blood and tissue samples:  refer to Section 5. 
•
Clinician tools:

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o
Rockwood Frailty Index (Appendix E): The Rockwood Clinical Frailty Score 
(CFS) was developed as a deployable tool to be used by clinicians to assess level 
of vulnerability. It uses clinical descriptors and pictographs to divide participants 
into 9 levels of vulnerability ranging from 1 (very fit) to 9 (terminally ill). (46) This 
9-point scale uses a visual chart to assess frailty classifications; someone with a 
score of ≥5 is classified as frail. The CFS was validated in a sample of 2305 older 
Canadian participants who remained alive 5 years after the Canadian Study of 
Health and Aging (CSHA-2). (47) CFS will be completed in a clinical setting. A 
member of the study team will observe the participants physical activity and ability 
and score them. 
o
MDS-CI (Appendix F): MDS-specific comorbidity index (MDS-CI) is a scoring 
system for MDS participants to be used by clinicians using a time-dependent index 
to predict the effects of comorbidities on treatment outcomes. (48) Five 
comorbidities independently predictive for non-leukemic death (cardiac, hepatic, 
pulmonary, renal, solid tumor) were assigned a score proportional to the regression 
coefficient of the multivariable Cox’s proportional hazards model, the MDS-CI 
score was calculated as the sum of these weighted scores, and grouped into three 
risk groups – low, intermediate, and high risk. The MDS-CI was validated in a 
sample of 840 MDS participants from Pavia, Italy and a validation cohort of 504 
participants in Dusseldorf, Germany. (49) A member of the study team will assess 
clinical information and score by completing the standard form.
•
Patient-reported outcomes (PROs):  The following PROs will be administered on this study 
(electronically via a CCR-approved system – Scribe;which is not yet 21 CFR 11 validated, 
however certification is currently being pursued).  Participant questionnaires are only 
offered in English and are therefore are not required in non-English speaking participants 
that may be enrolled on the protocol
o
European Organization for Research and Treatment of Cancer (EORTC) 
quality of life questionnaire = EORTC QLQC30 score (see Study Instrument 
packet and Appendix G): The European Organization for Research and Treatment 
of Cancer (EORTC) Quality of Life Questionnaire is a participant self-report 
questionnaire used to assess participants’ health-related quality of life in the 
oncology field. (50) This questionnaire incorporates nine multi-item scales, three 
symptom scales, a global health scale, and a quality-of-life scale. This questionnaire 
was validated across three language-cultural groups as well as against different 
questionnaires. (51) EORTC QLQ‐C30 has been the most frequently used 
participant-reported outcome (PRO)/quality of life questionnaire in published MDS 
studies to-date and has commonly been a contributory measure of PRO to drug-
approval processes for MDS. (52) This questionnaire takes approximately 15 
minutes to complete. This will be completed at baseline, at response evaluation, at 
disease progression, at the end of treatment and post therapy follow-up.
o
NIH MDS Adult Psychosocial Assessment  (see Study Instrument packet/ 
Appendix H): The psychosocial assessment is a self-report form that was originally 
developed for the NIH gastrointestinal stromal tumor (GIST) Clinic(53) in order to 
identify specific psychosocial areas of concern and symptoms not covered in the 
Patient-Reported Outcomes Measurement Information System (PROMIS) and 

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other standardized measures. It contains items covering demographic factors, 
perceived general health, psychosocial concerns, psychiatric history, self-identified 
needs, and interest in a range of possible psychosocial services. It has now been 
adapted and is being used with participants at the NIH participating in the 
Medullary Thyroid Cancer (MTC) and RUNX1 natural history studies. This 
questionnaires takes approximately 10 minutes to complete.
o
PRO-CTCAE  (see Study Instrument packet/Appendix H): The PRO-CTCAE is 
a participant-reported outcome measurement system developed by the NIH to 
capture the symptomatic adverse events in participants on cancer clinical trials [1]. 
It was designed as a companion to the Common Terminology Criteria for Adverse 
Event (CTCAE), which is often used per medical professionals’ evaluation. This 
instrument will allow us to select, but not be limited to the symptoms that are 
anticipated based on the previous experiences. It can be a flexible tool for 
descriptive reporting system, which participants can complete at their own 
convenience. It also can be used in conjunction with the CTCAE to provide a better 
understanding of the toxicities of the clinical trial treatments. The PRO-CTCAE 
predetermined symptoms will consist of 15 symptoms and additional five open text 
boxes for participants to also add additional symptoms they may be experiencing. 
Completion of this instrument will take 3-4 minutes on average to complete. This 
will be completed at baseline, weekly for the first two cycles, at response 
evaluation, at disease progression, at the end of treatment and post therapy follow-
up.
o
PROMIS Physical Function Short Form 10B (see Study Instrument 
packet/Appendix H): A PROMIS Physical Function (PROMIS-PF) item bank was 
developed with the goal of measuring a person’s ability to carry out various 
activities that require physical capabilities, ranging from self-care to more vigorous 
activities that require mobility, strength or endurance [5,6]. The PROMIS Physical 
Function 10b, a 10-item tool is scored from 1 ‘unable to do’ to 5 ‘without any 
difficulty’.  Time frame is not provided but current status is inferred.  Completion 
of this instrument will take on average 2-3 minutes. This will be completed at 
baseline, weekly for the first two cycles, at response evaluation, at disease 
progression, at the end of treatment and post therapy follow-up.
o
Overall Side Effect Bother (see Study Instrument packet/Appendix H): FACIT 
Measurement System Item GP5 ‘I am bothered by the side effects of treatment’, is 
a single item summary index of bother that has demonstrated association with 
clinician-reported adverse events and with participants’ ability to enjoy their lives 
that can help to adjudicate the variability in adverse effects across treatments being 
compared with each other [7]. Completion of this item will take less than a minute. 
This will be completed weekly for the first two cycles, at response evaluation, at 
disease progression, at the end of treatment and post therapy follow-up.
o
Patient  Global Impression of Severity (PGI-S) (see Study Instrument 
packet/Appendix H): The Patient Global Impression of Severity (PGI-S) is a 
global index that may be used to rate the severity of a specific condition (a 
single-state scale).  It is a simple, direct, easy to use scale that is intuitively 
understandable to clinicians. It has been validated in studies of incontinence [8] 

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and insomnia[9]. For this study, we will ask participants to rate the severity of 
their symptoms using a 5-point scale (0-none, 1-mild, 2-moderate, 3-severe, 4-
very severe) that will take less than a minute on average to complete. This will be 
completed at baseline, weekly for the first two cycles, at response evaluation, at 
disease progression, at the end of treatment and post therapy follow-up.
o
Patient Global Impression of Change (PGI-C) (see Study Instrument 
packet/Appendix H): Patient Global Impression of Change (PGI-C) aims to 
quantify disease activity relative to an anchor point. Specifically, participants are 
asked to calculate the difference between their current and previous health state 
based on a Likert scale. Although PGI-C scales typically comprise between 7 and 
11 points which show optimal participant preference, discriminative ability and 
test–retest ability, they can be tailored to specific conditions and disease parameters 
as per the clinicians’ needs [10]. For this study, we will ask participants to rate their 
global impression of change in their symptoms since their last visit using a 5-point 
scale (1-much improved, 2-improved, 3-no change, 4-worse, 5-much worse). 
Completion of this item will take less than a minute on average. This will be 
completed weekly for the first two cycles, at response evaluation, at disease 
progression, at the end of treatment and post therapy follow-up.

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3.5
STUDY CALENDAR
3.5.1
Phase I and II – Screening & Cycle 1
Cycle 1
Procedure
Screening
Baseline
Day 
1
Days 
2-3
Days 
4-5
Day 
8
Days 
9-12
Days 
13-14
Day 
15
Days 
16-19
Day 
20
Day 
21
Day 
22
Day 
23
Day 
28
Window(s):
≤30 days
≤7 days
≤7 days
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Histologic confirmation1
X
Medical history
X
X
X
Physical exam
X
X
X
X
X
X
Vital signs2
X
X
X
X
X
X
Height 
X
Weight
X
X
X
X
X
X
Performance score
X
X
X
CBC/differential
X
X
X
X
X
X
Reticulocyte count
X
X
X
Chemistries3
X
X
X
X
X
X
Folate, copper, zinc, TSH, free 
T4, Vitamin B12
X
Ferritin, erythropoietin
X
X
HIV HBV and HBC serologies
X
Pregnancy test
X
X
X4
Urinalysis
X
X
ECG
X
X
X5
X5
Bone marrow biopsy and 
aspirate6
X7
X8
X9
TBNK panel10
X
X
Next gen seq- myeloid panel
X11
X12
Correlative research studies 
(see Section 5.1)
X
X13
PK/PD (see Section 5.1)
X14
X15
X
X16
X
X
Inqovi administration17
X
X
X
KPT-8602 administration
X
X
X18
X
X
X19
X20

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Cycle 1
Procedure
Screening
Baseline
Day 
1
Days 
2-3
Days 
4-5
Day 
8
Days 
9-12
Days 
13-14
Day 
15
Days 
16-19
Day 
20
Day 
21
Day 
22
Day 
23
Day 
28
Window(s):
≤30 days
≤7 days
≤7 days
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Transfusion dependency 
assessment
X
X
Adverse event assessment
X
X 
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
Response Assessment
X
Rockwood/CFS and MDS-CI 
Questionnaires
X
PRO: NIH MDS Adult 
Psychosocial Assesment
X
PRO: EORTC-QLQC3021 
X
X
X
PRO: PRO-CTCAE21
X
X
X
X
X
X
PRO:Overall Side Effect 
Bother21
X
X
X
X
PRO:PROMIS Physical 
Function21
X
X
X
X
X
X
PRO: PGI-S21
X
X
X
X
X
X
PRO: PGI-C21
X
X
X
X
1Any time prior to enrollment.
2Includes temperature, blood pressure, heart rate, respiratory rate, oxygen saturation
3Includes sodium, chloride, potassium, CO2, BUN, creatinine, glucose, AST/ALT, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, total protein, 
magnesium, phosphorous, calcium, LDH, uric acid
4To be performed within 24 hrs prior to initating study treatment, for individuals of childbearing potential.
5ECG on C1D1 and C1D15 will be done 2 hours post-dose that day (+/- 20 minutes) for QTc monitoring.
6Bone marrow core biopsy will be sent for pathologic evaluation. Bone marrow aspirate will be sent for flow cytometry and additional studies per Section 5.1.
7May be performed during screening evaluation if no prior sample is available to pathology review to determine diagnosis; must be done within 30 days prior to 
treatment initiation. 
8Must be done within 30 days prior to treatment initiation. If a fresh sample was taken at screening to determine eligibility, and 30 days have not elapsed, then 
bone marrow biopsy and aspirate will not be repeated at baseline.
9Phase I only. Bone marrow biopsy and aspirate and flow cytometry may be done on C1D28 +/- 3 days.
10CD3, CD4, CD8, CD19, CD4:CD8 ratio, NK markers clinical panel.
11May be performed during screening evaluation or baseline; must be done within 30 days prior to treatment initiation.

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12May be performed during screening evaluation or baseline; must be done within 30 days prior to treatment initiation.
13Phase I only, on day of bone marrow biopsy (which may be done on C1D28 +/- 3 days).
14See Section 5.1 for detailed PK/PD sampling schedule.
15On C1D12, blood samples for PK will be collected for participants receiving KPT-8602 at dose level 1 or dose level -2 only (see Section 5.1 for detailed 
PK/PD sampling schedule). 
16On C1D21, blood samples for PK will be collected for participants receiving KPT-8602 at dose level 2 or dose level -1 only (see Section 5.1 for detailed 
PK/PD sampling schedule).
17HR-MDS cohorts (Cohorts 1 & 2): administer Inqovi orally once daily on Days 1-5 of each 28-day cycle. 
18Participants receiving KPT-8602 at dose level 2 or dose level -1 only. 
19Participants receiving KPT-8602 at dose level 2 or dose level -1 only. 
20Participants receiving KPT-8602 at dose level 2 or dose level -1 only.
21PROs administered at baseline need not be repeasted at C1D1 if within 7 days.

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3.5.2
Phase I and II – Cycle 2 – beyond
Cycles 2-3
Cycles  4
Procedure
Day
1
Day
8
Day
15
Day
22
Day
28
Day
1
Day
8
Day
28
At Disease 
Progression
End of 
Treatment 
Post-therapy 
follow-up1
End of 
Study
Window(s):
-3 days ±3 days ±3 days ±3 days ±3 days -3 days ±3 days ±3 days
±3 days
30+7 days
See note.
Physical exam
X
X
X
X
Vital signs2
X
X
X
X
Height
Weight
X
X
X
X
Performance score
Chemistries3
X
X
X
X
X
CBC/differential
X
X
X
X
X
Reticulocyte count
X
X
X
X
Pregnancy test
X
X
Urinalysis
X
X
X
Bone marrow biopsy and aspirate 4
X5
X6
X
TBNK panel7
X
X
X
X
Peripheral blood flow cytometry
X8
Next gen seq- myeloid panel
X9
X10
X
Correlative research studies (see 
Section 5.1)
X
X11
X12
X
X13
X
X
Inqovi administration14
X
X
KPT-8602 administration15
X
X
X
Response evaluation16
X
X
Transfusion dependency assessment
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
X
X
Concomittant-medications
X
X
X
X
PRO: NIH MDS Adult Psychosocial 
assessment17
X
X
X
PRO: EORTC-QLQC3018
X
X
X
X
X
X
X
PRO: PRO-CTCAE19
X
X
X
X
X
X
X
X
X
X
PRO: Overall Side Effect Bother20
X
X
X
X
X
X
PRO: PROMIS Physical Function19
X
X
X
X
X
X
X
X
X
X
PRO: PGI-S19
X
X
X
X
X
X
X
X
X
X

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Cycles 2-3
Cycles  4
Procedure
Day
1
Day
8
Day
15
Day
22
Day
28
Day
1
Day
8
Day
28
At Disease 
Progression
End of 
Treatment 
Post-therapy 
follow-up1
End of 
Study
Window(s):
-3 days ±3 days ±3 days ±3 days ±3 days -3 days ±3 days ±3 days
±3 days
30+7 days
See note.
PRO: PGI-C20
X
X
X
X
X
X
Survival
X
X
1Follow-up will occur via phone call every 3 months (+/-2 weeks) for the first 24 months, then every 6 months (+/- 4 weeks) for 3 years, then annually for up to 8 
years. Overall survival, event-free survival, progression-free survival, and treatment status will be assessed at all timepoints.
2Includes temperature, blood pressure, heart rate, respiratory rate, oxygen saturation
3Includes sodium, chloride, potassium, CO2, BUN, creatinine, glucose, AST/ALT, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, total protein, 
magnesium, phosphorous, calcium, LDH, uric acid for all timepoints beyond screening and baseline
4Bone marrow core biopsy will be sent for pathologic evaluation. Bone marrow aspirate will be sent for flow cytometry and additional studies per Section 5.1.
5Required for Phase II, C2D28 +/- 3 days. Additional timepoints as clinically indicated 
6Required for Phase II, C6D28 +/- 3 days. Additional timepoints as clinically indicated 
7CD3, CD4, CD8, C19 clinical panel.
8If evidence of peripheral blood blasts
9Required for Phase II, C2D28 +/- 3 days. Additional timepoints as clinically indicated 
10Required for Phase II, C6D28 +/- 3 days. Additional timepoints as clinically indicated 
11Sparse PK sampling for all participants on C2D15 and C3D15 to be drawn prior to taking dose (trough).
12On day of bone marrow biopsy, if being performed. 
13On day of bone marrow biopsy, if being performed. 
14HR-MDS cohorts (Cohorts 1 & 2): administer Inqovi orally once daily on Days 1-5 of each 28-day cycle. 
15Administer KPT-8602 according to dose level assigned to each participant (see Section 3.3)
16Assessment of response to therapy, based on peripheral blood counts +/- bone marrow results (if done).
17NIH MDS Adult Psychosocial Assesment to be completed at C12D28 (+/- 1 day), C24D28 (+/- 1 day) and end of treatment.
18EORTC-QLQC30 to be completed by participants at C3D28 (+/- 1 day), C6D28 (+/- 1 day), C9D28 (+/- 1 day), C12D28 (+/- 1 day), C24D28 (+/-1 day) and 
end of treatment. See Section 3.4.3
19PRO_CTCAE, PROMIS PF 10b, and PGI-S will be completed at baseline, weekly for cycles 1 through 3 on D8 (+/- 7 days), D15 (+/- 7 days), D22 (+/- 7 days) 
and D28 (+/- 7 days), C6D28 (+/- 7 days), C9D28 (+/- 7 days), C12D28 (+/- 7 days), C24D28 (+/- 7 days), at disease progression, and end of treatment. See 
Section 3.4.3.
20FACIT Bother and PGI-C done weekly for cycles 1 through 3 on D28 (+/- 7 days), D15 (+/- 7 days), D22 (+/- 7 days), D28 (+/- 7 days), C6D28 (+/- 7 days), 
C9D28 (+/- 7 days), C12D28 (+/- 7 days), C24D28 (+/- 7 days), at disease progression, and end of treatment. See Section 3.4.3.

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3.6
COST AND COMPENSATION 
3.6.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs.
3.6.2
Compensation
Participants will not be compensated on this study.
3.6.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.   
3.7
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from protocol therapy, effort must be made to have all participants complete a 
safety visit approximately 30 days after the last dose of study therapy (i.e., End of Treatment Visit 
– see Study Calendar [Section 3.5]).
3.7.1
Criteria for removal from protocol therapy
•
Progressive disease
•
Participant requests to be withdrawn from active therapy
•
Toxicities (see Section 3.3.2)
•
Lack of, at least partial remission, after 6 cycles of therapy
•
Investigator discretion
•
Positive pregnancy test
3.7.2
Off-Study Criteria
•
Off treatment and completed follow-up on study (i.e., all participants will be followed for 
8 years, or until death, whichever comes first)
•
Participant requests to be withdrawn from study
•
Death
•
Screen failure
•
Lost to follow-up
•
Study is cancelled for any reason

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3.7.3
Lost to Follow-up
A participant will be considered lost to follow-up if they fail to return for 3 scheduled visits or 
respond to follow-up hpone calls/is unable to be reached by the study site staff.
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
•
The site will attempt to contact the participant and reschedule the missed visit within 30 
days and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, an IRB-approved certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file.
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
ALLOWED CONCOMITANT MEDICATIONS/SUPPORTIVE MEASURES
4.1.1
Antimicrobial Prophylaxis
•
Per standard of care supportive measures for participants with MDS, standard antimicrobial 
prophylaxis will be considered for neutropenic participants who exhibit ANC <1000 
cells/mcL for ≥7 days prior to study enrollment, either initiation of continuation of prior 
supportive therapy, including but not limited to:
o
antibacterial prophylaxis with levofloxacin 750 mg daily 
o
antiviral prophylaxis with acyclovir 800 mg twice daily
•
For participants with clinical indication administration of anti-Pneumocystis jiroveci 
pneumonia prophylactic therapy is allowed. 
•
For participants with history of fungal infection, or other clinical indication, continuation 
of antifungal prophylaxis will be allowed.
4.1.2
Hematologic Support
•
Due to the hematologic abnormalities associated with MDS, management of hematologic 
toxicity in MDS participants will be at the discretion of the PI/treating investigator. 
•
Transfusions of red blood cells and platelets will be allowed per the appropriate participant-
specific hematologic parameters. 
•
G-CSF may be administered for participants with ANC < 500/mcL per the discretion of 
the treating physician.
•
Thrombopoietin agonists may be administered for participants with PLT < 50 x 109/L per 
the discrestion of the treating physician.

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•
Participants receiving a stable dose of erythropoiesis-stimulating agent (ESA) for at least 
1 month at the time of study entry may continue to receive ESA, but changes in dosing of 
ESA or new start of ESA within <30 days are not permitted.
4.1.3
Other Supportive Care
•
In order to minimize nausea, unless contraindicated, all participants will receive a serotonin 
receptor subtype 3 (5-HT3) antagonist (ondansetron or equivalent) before KPT-8602 
dosing. This may be tapered after 1-2 cycles of treatment, per Investigator discretion. 
o
5-HT3 receptor antagonists (ondansetron 8 mg or equivalent) should be started 
before study treatment dosing and continued for 3 consecutive days.
4.2
DRUG INTERACTIONS
The risk of drug-drug interactions with KPT-8602 is low. However, administration of eltanexor 
with drugs that undergo substantial GSH conjugation (e.g., acetaminophen) should be minimized. 
See Section 14.1.7.
4.3
CONTRAINDICATED AGENTS
•
No other antineoplastic, immunomodulatory, or immunosuppressive therapies, including 
corticosteroids (barring adrenal insufficiency supplementation dosing), should be given 
concomitantly while on study treatment. 
5
CORRELATIVE STUDIES FOR RESEARCH
Participants may submit none, all, or a portion of research specific biospecimens to stay on study. 
Providing all research biospecimens is not a criterion for study inclusion and all samples are 
optional with the exception of pharmacokinetic (PK) samples. Any unused biological sample or 
derivative that is obtained from a participant during a clinical procedure on this study may be used 
for research and/or stored for future research purposes. 
Every effort will be made to collect all research samples, including bone marrow aspirates and 
peripheral blood draws, at the time of a scheduled diagnostic bone marrow aspirate or blood draw 
for clinical purposes  as listed in the study calendar and table below.
If additional tests are done for clinical purposes, additional samples will be collected also at that 
time(s), if feasible, and used for research.   
5.1
BIOSPECIMEN COLLECTION
Test/assay
Volume 
(approx.)
Type of sample/ 
tube(s)^
Collection point 
Location of 
specimen 
analysis
Pharmacokinetics 
(PK)
4 mL
Blood, 
SST vacutainer 
tubes
-Serum samples 
should then be 
Dose levels -2 and 1:
C1D8 (1)Pre-dose, (2) 1 hr 
(± 10 min) post-dose, (3) 2 
hr (± 10 min) post-dose, (4) 
3 hr (± 10 min) post-dose, 
Clinical 
Pharmacology 
Program (CPP) ; 
Figg laboratory

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Test/assay
Volume 
(approx.)
Type of sample/ 
tube(s)^
Collection point 
Location of 
specimen 
analysis
transferred to 
micronic tubes 
for shipping to 
bioanalytical lab.
(5) 4 hr (± 20 min) post-
dose, (6) 8 hr (± 20 min) 
post-dose, (7) 24 hr (± 1 hr) 
post-dose (8) 24 hr (± 1 hr) 
post-dose-i.e, C1D9 pre-
dose
C1D12 (9) Pre-dose, (10) 2 
hr (± 10 min) post-dose, 
(11) 3 hr (± 10 min) post-
dose, (12) 8 hr (± 20 min) 
post-dose, (13) 24 hr (± 1 
hr) post-dose-i.e, C1D13 
pre-dose, (14) 48 hrs (± 
2hr) post-dose- i.e, C1D14 
pre-dose
Dose levels -1 and 2:
C1D8 (1)Pre-dose, (2) 1 hr 
(± 10 min) post-dose, (3) 2 
hr (± 10 min) post-dose, (4) 
3 hr (± 10 min) post-dose, 
(5) 4 hr (± 20 min) post-
dose, (6) 8 hr (± 20 min)
post-dose, (7) 24 hr (± 1 hr) 
post-dose i.e, C1D9 pre-
dose
C1D21 (9) Pre-dose, (10) 1 
hr (± 10 min) post-dose, 
(11) 3 hr (± 10 min) post-
dose, (12) 4 hr (± 20 min) 
post-dose, (13) 8 hr (± 20 
min) post-dose, (14) 24 hr 
(± 1 hr) post-dose-i.e, 
C1D22 pre-dose, (15) 48 
hrs (± 2hr) post-dose- i.e, 
C1D23 pre-dose
Sparse PK sampling for 
all participants:
C2D15, C3D15 trough 
dosing to be drawn prior to 
taking dose that day.
Pharmacodynamics 
(PD):
2.5 mL
Blood, 
Paxgene RNA 
tube
Phase I: C1D8 (1)Pre-
dose, (2) 1 hr (± 10 min) 
post-dose, (3) 2 hr (± 10 
Clinical 
Pharmacology 

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Test/assay
Volume 
(approx.)
Type of sample/ 
tube(s)^
Collection point 
Location of 
specimen 
analysis
XPO1 mRNA 
expression (RT-
PCR)
min) post-dose, (4) 3 hr (± 
10 min) post-dose, (5) 4 hr 
(± 20 min) post-dose, (6) 8 
hr (± 20 min) post-dose, (7) 
24 hr (± 1 hr) post-dose
Program (CPP) ; 
Figg laboratory
Larson laboratory
Next generation 
sequencing/ 
Myeloid molecular 
mutation panel:
TSO-500 Panel
Methylation studies 
per Section 5.2 
2 mL per 
tube
Bone marrow, 
EDTA (lavender 
top) or ACD 
(yellow top)
 
(1) Baseline 
(2) Phase I: C1D28 (+/-3 
days)
(3) Phase II: C2D28 (+/-3 
days)
(4) Phase II:C6D28 (+/-3 
days)
(5) Any additional 
timepoints when bone 
marrow biopsy is done
(6) Disease progression
NCI Laboratory 
of Pathology
Clinical MDS 
FISH*
*only needed if 
cytogenetic 
analysis not 
possible or 
unrevealing
 
3 mL per 
tube if 
bone 
marrow
 
5 mL per 
tube if 
whole 
blood
 
Blood or bone 
marrow aspirate, 
Sodium Heparin 
green top
 
(1) Baseline 
(2) Phase I: C1D28 (+/-3 
days)
(3) Phase II: C2D28 (+/-3 
days)
(4) Phase II:C6D28 (+/-3 
days)
(5) Any additional 
timepoints when bone 
marrow biopsy is done
(6) Disease progression
Mayo send out 
test
 
Clinical 
Cytogenetics
 
3 mL
 
Bone marrow, 
Sodium Heparin 
green top
 
(1) Baseline 
(2) Phase I: C1D28 (+/-3 
days)
(3) Phase II: C2D28 (+/-3 
days)
(4) Phase II:C6D28 (+/-3 
days)
(5) Any additional 
timepoints when bone 
marrow biopsy is done
(6) Disease progression
Mayo send out 
test
 
Additional samples 
(e.g., proteomics, 
cytokines); Section 
5.2
5 mL x 2 
tubes
Blood, 
EDTA tube
(1) Baseline 
(2) Phase I: C1D28 (+/-3 
days)
(3) Phase II: C2D28 (+/-3 
days)
(4) Phase II:C6D28 (+/-3 
days)
CPP; Figg 
laboratory 

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Test/assay
Volume 
(approx.)
Type of sample/ 
tube(s)^
Collection point 
Location of 
specimen 
analysis
(5) Any additional 
timepoints when bone 
marrow biopsy is done
(6) Disease progression
Additional samples 
(e.g., proteomics, 
cytokines); Section 
5.2 
5 mL x 2 
tubes
Bone marrow 
aspirate, 
EDTA tube
(1) Baseline 
(2) Phase I: C1D28 (+/-3 
days)
(3) Phase II: C2D28 (+/-3 
days)
(4) Phase II:C6D28 (+/-3 
days)
(5) Any additional 
timepoints when bone 
marrow biopsy is done
(6) Disease progression
CPP; Figg 
laboratory
Research: 
Ribosome 
footprinting; 
Quantitative mass 
spectrometry
10 mL
Bone marrow 
aspirate, 
EDTA tube
(1) Baseline 
(2) Phase I: C1D28 (+/-3 
days)
(3) Phase II: C2D28 (+/-3 
days)
(4) Phase II:C6D28 (+/-3 
days)
(5) Any additional 
timepoints when bone 
marrow biopsy is done
(6) Disease progression
Larson laboratory
^ Tubes may be substituted based on availability with the permission of the PI or laboratory investigator.
5.1.1
Peripheral Blood
Blood samples for research will be collected at time points indicated in the table above and initially 
processed in Blood Processing Core (BPC) prior to sharing with the research labs for analyses, as 
indicated below (Section  5.2). 
5.1.2
Bone Marrow Samples
Bone marrow for research will be collected at the same time as clinical procedures whenever 
possible.  Samples will be collected distributed per the biospecimen table (Section 5.1), including 
the Blood Processing Core (BPC) and Larson laboratory.  Additional samples than those that 
would be routinely sent to LP will include aspirate to be tested per TSO 500 and research 
methylation studies as well as sent to Mayo as a send-out test for Clinical Cytogenetics with reflex 
to Clinical MDS FISH analyses if cytogenetic analysis is not possible or unrevealing.  The results 
of CLIA approved clinical testing will be made available in the participant’s medical record.   
5.2
CORRELATIVE ANALYSES
We hypothesize that aberrancies in methylation, molecular shuttling, and ribosome biogenesis in 
MDS may be corrected by the combination of Inqovi and XPO1 inhibition. As such we propose 
the following assays to study these phenomena. Not all assays may be performed in each 

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participant specimen and additional assays not outlined here may be performed to address 
particular research questions or as technology develops and improved assays are implemented. 
Analyses may be performed on banked or fresh tissue dictated by the specifics of the particular 
assay. In general, correlative assays will be performed using standard techniques on cells or plasma 
isolated using the Ficoll-PaqueTM method. Commercial kits will be used for DNA and RNA 
isolations, as well as specific assays such as ELISA, LDH assay, and others. Standard procedures 
will be used for qPCR, mass spectrophotometry, western blotting, flow cytometry, and 
immunofluorescence. Assays will be performed by an assigned investigator(s) with extensive 
expertise and supervised by Dr. Larson laboratory with collaboration from NIH cores and field 
experts. 
5.2.1
PK Studies
PK studies of KPT-8602 will be done by Dr. Figg’s Clinical Pharmacology Program (CPP). For 
processing details see Appendix J.  
Blood draws for PK analysis will be performed relative to in-clinic KPT-8602 dose. The actual 
date and time (24-hour clock time) of each sample collection and each dose of KPT-8602 will be 
recorded.
5.2.1.1
Phase I
In Phase I, PK sampling will be done in all participants receiving KPT-8602. The timing of blood 
sample collection for PK studies are specified  in the table in Section 5.1. 
5.2.1.2
Phase II
In Phase II, PK sampling schedules at the RP2D of KPT-8602 will be the same as planned in Phase 
I.
5.2.2
PD Studies
5.2.2.1
Phase I only
Changes in XPO1 mRNA expression will be assessed by reverse transcription polymerase chain 
reaction (RT-PCR) in peripheral blood samples from participants treated with KPT-8602. Samples 
will be collected at the timepoints specified in the table in Section 5.1.
5.2.3
Methylation Studies
Epigenetic studies including whole methylome analysis using next generation sequencing may be 
performed on bone marrow mononuclear cells. In general, MDS participants display increased 
methylation signatures, the foundation for which hypomethylating agents such as AZA and DAC 
have been used as the standard of care for HR-MDS. However, significant changes in methylation 
status post-HMA treatment has been inconclusive. Further, the effect of combined HMA and 
Eltanexor has yet to be studied and will be evaluated here. These studies will be performed by Dr. 
Aldape.   
5.2.4
Proteomics Studies
Bone marrow cells may be used for global mass spectroscopy (MS)-based protein and phospho –
protein proteomic analysis. Cells may also be fractioned prior to proteomic and MS analysis. We 
may also perform quantitative MS and surface MS to determine mechanisms of protein transport 

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and contribution of XPO1 inhibition to ribosome biogenesis, disease state, and response. These 
studies will be performed by Dr. Larson.
5.2.5
Cytokine Studies
Peripheral blood and bone marrow plasma will be frozen for chemokine and cytokine analysis.  
These studies will be performed by Dr. Larson.
5.2.6
Gene Editing
Gene editing may be performed to study specific biological disease processing. Editing may be 
performed using siRNA, shRNA, and/or CRIPSR editing methods. These may be performed using 
electroporation or viral transduction. Any cell line created by gene editing will not contain any 
participant identifying information. As pathways affected specifically by the combination of Inqovi 
and KPT-8602 are uncovered, specific pathway components may be modulated for validation. 
These studies will be performed by Dr. Larson.
5.2.7
Microarrays/Immunohistochemistry
Bone marrow aspirates may also be fixed in formalin and embedded in paraffin blocks for later 
use in tissue microarrays and/or immunohistochemistry. 
5.2.8
DNA Damage
Both decitabine and XPO1 inhibition have been shown to increase DNA damage in cells; therefore, 
we will monitor DNA damage in participants bone marrow cells by evaluating expression of 
γH2AX before and after treatment via immunofluorescence and flow cytometry. Further, DNA 
damage repair pathways may also be evaluated by western blotting, immunofluorescence, and flow 
cytometry.
5.2.9
Additional Studies
In addition to assessing XPO-1 mRNA by RT-PCR, we may also investigate other potential PD 
markers including decreased expression of oncogenes (i.e., c-Myc), increased expression of tumor 
suppressor genes (i.e., ARRDC3) and decreased expression of DNA damage repair genes 
(phenomena that have been observed after XPO1 inhibition by eltanexor). In addition, we may 
examine protein marker levels including increased XPO1 protein degradation, increased NFkB 
signaling, nuclear accumulation of tumor suppressors such as p53, as well as plasma levels of 
proinflammatory cytokines such as IL-6 or IL-8.
Additional assays not described here may be used to validate findings from any of the proposed 
correlative assays. For example, western blotting, flow cytometry, and/or immunoflorescence may 
be used to quantitate protein expression or ribosome biogenesis in whole or fractionated cells. 
Further, validation assays not described here may be used to assess changes in specific cellular 
pathways (i.e., translation, secretion, and inflammatory pathways). 
5.3
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if required. 
All samples will be barcoded, with data entered and stored in the secure databases. These databases 
create a unique barcode ID for every sample and sample box, which cannot be traced back to 

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participants without database access. The data recorded for each sample includes the participant 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well 
as box and freezer location. Participant demographics associated with the clinical center participant 
number are provided in the system. For each sample, there are notes associated with the processing 
method (delay in sample processing, storage conditions on the ward, etc.).
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in database. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned. It is the responsibility of the NCI Principal Investigator to ensure that the samples 
requested are being used in a manner consistent with IRB approval.
Note: The tracking system for the Blood Processing Core (BPC; Figg lab) is described below. All 
other CCR lab systems/databases at which samples will be stored/analyzed will follow required 
CCR requirements for tracking.
5.3.1
Dr. Figg’s Blood Processing Core (BPC)
5.3.1.1
Blood and Bone Marrow Collection
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov
See Appendix J for processing instructions.
5.3.1.2
Sample Data Collection
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix limited 
to defined Figg lab personnel, who are issued individual user accounts. Installation of Labmatrix 
is limited to computers specified by Dr. Figg. These computers all have a password restricted login 
screen. 
5.3.1.3
Sample Storage 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C according 
to stability requirements.  These freezers are located onsite in the BPC and offsite at NCI Frederick 
Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be 
accompanied by laboratory staff at all times. 
5.3.2
Protocol Completion/Sample Destruction 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material.

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If, at any time, a participant withdraws from the study and does not wish for their existing samples 
to be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the participant, if so requested). The PI will record any 
loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements 
of section 7.2.
Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to participant information such as race, age, 
dates of diagnosis and death, and histological information. 
5.4
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.4.1
Description of the scope of genetic/genomic analysis
Genetic analysis will be performed as outlined in section  5.2.2, 5.2.6, 5.2.8 and 5.2.9. Briefly, 
DNA or RNA may be sequenced on any tissue or derivative and will include analysis of both 
somatic and germline mutations. 
5.4.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Initially the samples of each participant will be barcoded. At no time will participant’s names be 
used on the blood and tissue samples. In some instances  a subject’s genetic data will be deposited 
into a public database such as dbGaP, however. Although there is controlled access to such a 
database, such a submission carries theoretical risks of revealing the identity of the subject. This 
is discussed in the consent.
5.4.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the American 
College of Medical Genetics and Genomics recommendations for the return of incidental findings 
that is current at the time of primary analysis. (A list of current guidelines is maintained on the 
CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 
Subjects will be contacted at this time with a request to provide a blood sample to be sent to a 
CLIA certified laboratory. If the research findings are verified in the CLIA certified lab, the subject 
will be offered the opportunity to come to NIH (at our expense) to have genetic education and 
counseling to explain this result. If the subject does not want to come to NIH, a referral to a local 
genetic healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
5.4.4
Genetic counseling
Genetic counseling will be offered in the case of finding a clinically actionable gene variant.

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6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. 
Data entry may also be achieved via other systems as permitted by CCR requirements (e.g., 
Labmatrix, PROs directly via Scribe). The principal investigator, associate investigators/research 
nurses and/or a contracted data manager will assist with the data management efforts.  Primary 
and final analyzed data will have identifiers so that research data can be attributed to an individual 
human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until resolution or stabilization of event. 
Document AEs from the first study intervention, study day 1, through 30 days after the last dose of 
any study drug. Beyond 30 days, only adverse events which are serious and related to the study 
investigational agent need to be recorded.
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization. 
•
Is judged by the Investigator to be of significant clinical impact
•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the 
participant’s outcome.
The PI (or designee) evaluation of each AE not captured in the clinical database determining that 
it meets the criteria above will be documented in the source documents. Note: The investigator 
performing the assessment must be a licensed provider listed on the 1572.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
_x_ Coded, linked data in an NIH-funded or approved public repository.
_x_ Coded, linked data in another public repository.
_x_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)

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_x_ Coded, linked or identified data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:
_x_ An NIH-funded or approved public repository. Insert name or names: ClinicalTrials.gov, 
dbGaP
_x_ BTRIS (automatic for activities in the Clinical Center)
_x_ Approved outside collaborators under appropriate individual agreements.
_x_ Publication and/or public presentations.
When will the data be shared? 
_x_ Before publication.
_x_ At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
Participants will be assessed for response by standard response criteria for MDS.(54) For the 
purposes of this study, participants will be re-evaluated for response after each cycle by CBC with 
differential to assess for improvement in cytopenias and by protocol-defined time points for bone 
marrow evaluation. If results from bone marrow assessment and/or CBC demonstrate progression 
of disease (as defined by an increase in the number of malignant cells or blasts when compared to 
pre-treatment bone marrow examination or worsening cytopenias by amounts as defined below in 
section 6.3.1), the participant will be taken off treatment. However, the participant will continue 
to be followed on study for other survival endpoints.
6.3.1
Response Criteria
The table below shows the 2006 International Working Group response criteria for altering the 
natural history of MDS,(55) with modified definitions for HI-E, HI-P, and HI-N in the suggested 
2018 International Working Group response criteria.(54)
 
Category
Response criteria
(responses must last at least 4 weeks)
Complete remission
•      Bone marrow: ≤5% myeloblasts with normal maturation of 
all cell lines*
•      Persistent dysplasia will be noted*
•      Peripheral blood†
•
 Hgb ≥11 g/dL
•
Platelets ≥100 X 109/L
•
Neutrophils ≥1.0 X 109/L
•
Blasts 0%

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Category
Response criteria
(responses must last at least 4 weeks)
Partial remission
All CR criteria if abnormal before treatment except:
•      Bone marrow blasts decreased by >50% over pretreatment 
but still >5%
•      Cellularity and morphology not relevant
Marrow CR
•      Bone marrow: ≤5% myeloblasts and decrease by ≥50% 
over pretreatment
•      Peripheral blood: if HI responses, they will be noted in 
addition to marrow CR
Stable disease
Failure to achieve at least PR, but no evidence of progression 
for >8 wks
Failure
Death during treatment or disease progression characterized 
by worsening of cytopenias, increase in percentage of bone 
marrow blasts, or progression to more advanced MDS FAB 
subtype than pre-treatment
Relapse after CR or PR
At least 1 of the following:
•      Return to pre-treatment bone marrow blast percentage
•      Decrement of >50% from maximum remission/response 
levels in granulocytes or platelets
•      Reduction in Hgb concentration by >1.5 g/dL or 
transfusion dependence
Cytogenetic response
Complete
•      Disappearance of the chromosomal abnormality without 
appearance of new ones
Partial
•      At least 50% reduction of the chromosomal abnormality
Disease progression
For participants with:
•      Less than 5% blasts: ≥50% increase in blasts to >5% blasts
•      5%-10% blasts: ≥50% increase to 10% blasts
•      10%-20% blasts: ≥50% increase to >20% blasts
•      20%-30% blasts: ≥50% increase to >30% blasts
Any of the following:
•      At least 50% decrement from maximum 
remission/response in granulocytes or platelets
•      Reduction in Hgb by ≥2 g/dL
•      Transfusion dependence
Survival
Endpoints:
•      Overall: death from any cause
•      Event free: failure or death from any cause
•      PFS: disease progression or death from MDS
•      DFS: time to relapse
•      Cause-specific death: death related to MDS
MDS, myelodysplastic syndromes; Hgb, hemoglobin; CR, complete remission; HI, hematologic improvement; PR, partial
remission; FAB, French-American-British; AML, acute myeloid leukemia; PFS, progression-free survival; DFS, disease-free

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survival.
To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
*Dysplastic changes should consider the normal range of dysplastic changes.
†In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, maintenance) before
the 4-week period. Such participants can be included in the response category into which they fit at the time the 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 previous course.
 
Hematologic Improvement
Category
Participant pre-trial 
baseline
Response criteria
 
No Transfusion 
Dependence at 
baseline (0 RBC 
transfusions in 16 
weeks)
At least 2 consecutive Hgb measurements 
>1.5 g/dL for a period of minimum 8 weeks in 
an observation period of 16 to 24 weeks 
compared with the lowest mean of 2 Hgb 
measurements (apart from any transfusion) 
within 16 weeks before treatment onset; only 
a response duration of at least 16 weeks, 
however, is considered clinically meaningful
Low Transfusion 
Dependence at 
baseline (3-7 RBC 
transfusions in 16 
weeks in at least 2 
transfusion episodes, 
maximum 3 in 8 
weeks)
Transfusion independence, defined by the 
absence of any transfusions for at least 8 
weeks in an observation period of 16-24 
weeks with the same transfusion policy 
compared with 16 weeks prior to treatment; 
only a response duration of at least 16 weeks, 
however, is considered clinically meaningful
Major 
response
Transfusion independence, 
defined by the absence of any 
transfusions over a period of 
minimum 8 weeks in an 
observation period of 16-24 
weeks with the same transfusion 
policy compared with 16 weeks 
prior to treatment; only a response 
duration of at least 16 weeks, 
however, is considered clinically 
meaningful
Erythroid response 
(HI-E)
High Transfusion 
Dependence at 
baseline (>8 RBC 
transfusions in 16 
weeks, > 4 
transfusion episodes 
in 8 weeks)
Minor 
response
A reduction by at least 50% of 
RBCs over a minimum of 16 
weeks with the same transfusion 
policy, compared with 16 weeks 
prior to treatment
Platelet response 
(HI-P)
Pre-treatment PLT 
<100 x 109/L
•      Absolute increase of 30 x 109/L for 
participants starting with >20 x 109/L 
PLTs

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Category
Participant pre-trial 
baseline
Response criteria
or
•      Increase from <20 x 109/L to >20 x 109/L 
and by at least 100%
In addition:
•      In addition, evolution of bleeding 
symptoms is to be taken into account
•      Increments of platelets also for participants 
with a pre-treatment PLT count of >100 x 
109 are to be reported
Neutrophil response 
(HI-N)
 
Pre-treatment ANC 
<1.0 x 109/L
•      At least 100% increase and an absolute 
increase >0.5 x 109/L
•      Increments of neutrophils also for 
participants with a pre-treatment ANC of 
>1.0 x 109/L are to be reported
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 
Non-Compliance 
Human 
Subjects 
Research 
found 
at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety Reports 
that meet the definition of an unanticipated problem will need to be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.

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7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to the 
Clinical Director/designee at NCICCRQA@mail.nih.gov within one business day of learning of 
the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular weekly basis when participants are being actively 
treated on the trial to discuss each participant. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior participants. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in section 
7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The principal investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a participant or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (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 related to the medicinal (investigational) 
product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death,
•
A life-threatening adverse event (see section 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 

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condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions
•
A congenital anomaly/birth defect
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate 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.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  
•
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.1.6
Adverse Events of Special Interest (AESI)
Neurological toxicity is considered an AESI and should be reported following SAE reporting 
procedures in Section 8.3 irrespective of temporal relationship to study drug administration and 
regardless of causality.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution (or stabilization) of the event, seriousness and outcome. The assessment of severity and 
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a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
AEs occurring during the collection and reporting period will be documented appropriately 
regardless of relationship.  AEs will be followed through resolution.
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to Section 6.1. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form.  Any exceptions to the expedited 
reporting requirements are found in section 8.5 
All SAE reporting must include the elements described in section 8.2. All serious adverse events 
recorded from the time of first investigational product administration to 30 days after last 
investigational product administration must be reported to the sponsor with the exception of any 
listed in Section 8.4.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form and 
instructions 
can 
be 
found 
at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR
As death due to disease progression is part of the study objectives (PFS), and captured as an 
endpoint in this study, they will not be reported in expedited manner to the sponsor. However, if 
there is evidence suggesting a causal relationship between the study drug and the event, the 
event will be reported in an expedited manner according to Section 8.3.
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement. 
8.6
REPORTING PREGNANCY 
All 
required 
pregnancy 
reports/follow-up 
to 
OSRO 
will 
be 
submitted 
to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions can 
be found here: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 

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8.6.1
Maternal exposure
If a participant becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known.
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (Section 8.1.2) should be reported as SAEs. 
The outcome of all pregnancies should be followed up and documented until 6 months after last 
dose of study drug.
8.6.2
Paternal exposure
Male participants should refrain from fathering a child or donating sperm during the study and for 
6 months after the last dose of KPT-8602 or Inqovi.
Pregnancy of the participant’s partner is not considered to be an AE. However, the outcome of all 
pregnancies occurring from the date of the first dose until 6 months after the last dose should, if 
possible, be followed up and documented. Pregnant partners may be offered the opportunity to 
participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry 
study) to provide data about the outcome of the pregnancy for safety reporting purposes.
8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected in expedited manner to the FDA in accordance 
to 21 CFR 31.2.32.  CCR will report an AE as a suspected adverse reaction only if there is evidence 
to suggest a causal relationship between the study product and the adverse event.  CCR will notify 
FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing 
drug under its INDs or under any investigator’s IND) in an IND safety report of potential serious 
risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 
312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.8
SPONSOR PROTOCOL DEVIATION REPORTING
Protocol deviation is defined as any noncompliance with the clinical trial protocol, Manual of 
Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the Staff 
or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. 
The entries into the PDTS online application should be timely, complete, and maintained per CCR 
PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source records 
and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation 
reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance 
with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations.

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9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure:
•
that the rights of the participants are protected, 
•
that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and
•
that the quality and integrity of study data and data collection methods are maintained.
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Monitoring and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory 
requirements. 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring will be based on several factors, including study type, phase, risk, 
complexity, expected enrollment rate, and any unique attributes of the study and the site. The 
Sponsor will conduct a periodic review of the CMP to confirm the plan's continued 
appropriateness. A change to the protocol, significant or pervasive non-compliance with GCP, or 
the protocol may trigger CMP updates.
OSRO-SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts, to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will take place at the study 
site(s).  Monitoring visit reports will describe visit activities, observations, findings of protocol 
non-adherence and associated action items or follow-up required for resolution of findings.  
Monitoring reports will be distributed to the study PI, NCI CCR QA, coordinating center (if 
applicable) and the OSRO regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.

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10 STATISTICAL CONSIDERATIONS  
10.1 OBJECTIVES AND ENDPOINTS 
OBJECTIVES
ENDPOINTS
JUSTIFICATION 
FOR ENDPOINTS
Primary
Phase I: To determine the 
recommended phase 2 dose (RP2D) 
of KPT-8602 in combination with 
Inqovi in adult participants with 
with higher-MDS
Phase II: To determine the overall 
response rate (ORR) of KPT-8602 
in combination with Inqovi in adult 
participants with with higher-MDS
- Recommended phase 2 dose 
(RP2D), as determined by the number 
of participants with DLTs reported at 
each dose level studied (Section 
3.1.1) 
-Any toxicitites identified from Day 1 
of study drug through 28 days after 
the first dose. AEs are reported by 
type and grade.
-ORR (defined as CR+PR+mCR with 
HI) per each cohort
Responses will be assessed after 
every cyle with CBC and at the end of 
Cycles 2 and 6 with bone marrow 
assessment during treatment and 
every 3-6 months after that until time 
of disease relapse, disease 
progression, or death, or 8 years, 
whichever occurs first. 
Standard endpoint for 
Phase I protocol
Efficacy evaluation, 
standard for Phase II 
protocol
Secondary
Phase I: To characterize the PK 
properties of KPT-8602 in 
combination with Inqovi in MDS 
participants
-AUC, half-life, and steady state 
concentration, measured by the KPT-
8602 blood concentration 1, 2, 3, 4, 8, 
24 and 48 hours after the product 
administration on days 8 and 21 of 
cycle one
PK studies to evaluate 
for adequate absorption 
of therapy and further 
define half-life/AUC 
and other properties of 
the study drug, when 
given in combination 
with Inqovi
Phase II: To further evaluate the PK 
properties and safety of KPT-8602 
in combination with Inqovi in MDS 
participants
-Safety, as measured by: Incidence of 
AEs, SAEs; and AEs leading to 
discontinuation, death, and laboratory 
abnormalities, assessed at least 
weekly through cycle 3 and then at 
the start and and every cycle after that
Confirm safety of the 
study drug at the RP2D
Exploratory 
To evaluate the relationship 
between KPT-8602 exposure (PK) 
and response
Each of these will be evaluated using 
descriptive methods and reported as 
exploratory results. If any statistical 
Evaluate mechanism of 
the study drug, target 
engagement, 

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OBJECTIVES
ENDPOINTS
JUSTIFICATION 
FOR ENDPOINTS
To evaluate changes in XPO1 
mRNA expression and other 
potential PD markers with 
treatment
To assess changes in DNA damage 
repair by evaluation of 
gammaH2AX levels
To evaluate compliance and 
feasibility of administering PRO in 
this patient population
To evaluate tolerability of treatment 
by assessing symptomatic adverse 
events, physical function and side 
effect bother 
To longitudinally describe and 
evaluate disease and treatment-
related symptom severity and 
functional well-being
To determine meaningful change in 
disease and treatment related 
symptoms and functional well-
being by using anchors
To evaluate changes in DNA 
methylation status pre- and post-
treatment
To evaluate changes in cell 
composition in the bone marrow 
and peripheral blood 
microenvironment pre- and post-
treatment
To evaluate changes in genetic 
clonal diversity during treatment
To evaluate changes in gene 
expression patterns of tumor 
suppressor genes and oncogenes 
(including DNMT3B expression)
To evaluate the influence of 
splicing factor mutations (U2AF1, 
SRSF2, SF3B1, ZRSR2) on nuclear 
shuttling
To evaluate the degree of disruption 
of ribosome biogenesis after XPO1 
inhibition
To evaluate changes in nuclear and 
cytoplasmic protein composition by  
mass spectometry
tests are performed in these analyses, 
the results will be presented without 
adjustment for multiple comparisons 
but reported in the context of the 
number of tests performed. See 
Section 5 for collection timepoints.
relationship between 
exposures and 
response, and treatment 
impact on quality of 
life.

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OBJECTIVES
ENDPOINTS
JUSTIFICATION 
FOR ENDPOINTS
To evaluate other clinical outcomes 
-Secondary clinical outcomes, 
including: overall improvement rate 
(OIR), transfusion-independence (TI), 
cytogenetic response rate, time to best 
response (CR, PR, marrow CR + HI, 
HI), DFS, PFS, LFS, and OS; 
assessed every 3-6 months
Common set of 
outcomes reported in 
MDS therapy studies  
10.2 STATISTICAL HYPOTHESIS AND SAMPLE SIZE DETERMINATION
The trial will begin with a phase I dose-escalation phase using a standard 3+3 design which will 
enroll participants with relapsed/refractory HR-MDS, Up to 18 participants may be enrolled based 
on the 3+3 design.
Participants will be eligible for the DLT evaluation if 90% (9 out of 10 doses) of KPT-8602 and 
80% (4 out of 5 doses) of Inqovi were taken within the DLT period. Participants not evaluable for 
toxicity, will be replaced in the dose level.
Phase II will use a Simon’s minimal two-stage design, applied separately as noted below:
•
Trial will be conducted using a Simon minimax two-stage phase II trial design to rule out 
an unacceptably low response rate of 25% (p0=0.25) in favor of an improved response rate 
of 45% (p1=0.45) in order to determine if the combination of  KPT-8602 with Inqovi will 
be able to improve upon an expected 30-40% response rate in participants who have 
received other agents. With two-sided alpha=0.05 and beta=0.20, the first stage will enroll 
21 evaluable participants, and if 0 to 5 of the 21 have a response, then no further 
participants will be accrued. If 6 or more of the first 21 participants have a response, then 
accrual would continue until a total of 43 evaluable participants have been treated . If there 
are only 6-16 participants with a response out of 43 participants, this would be an 
uninterestingly low response rate. If there were 17 or more of 43 (39.5%) who experienced 
a response, treatment would be sufficiently interesting to warrant further study in later 
trials. The probability of early termination under the null (25%) response rate is 56.7%.
It is expected that up to 12-15 participants with MDS may be accrued per year. Thus, in order to 
accrue up to 18 +43=61 participants (which may be reduced by up to 6 if up to 6 participants in 
phase I may be included in phase II), and to allow for a small number of inevaluable participants 
(12), it is expected that 3-4 years may be required to accrue the required 73 participants. Note: To 
allow for screen failures (7), the accrual ceiling will be set at 80 participants for the purposes of 
the NIH accrual ceiling.
10.3 POPULATIONS FOR ANALYSES
10.3.1 Evaluable for toxicity 
All participants will be evaluable for toxicity from the time of their first treatment with KPT-8602.

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10.3.2 Evaluable for objective response 
Only those participants who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These participants will have their response classified according to the definitions stated 
below.  (Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
•
Participants in phase I will be evaluated for safety, reporting the toxicities noted per dose 
level. 
•
Participants in phase II will have their response rate reported along with a confidence 
interval.
10.4.2 Analysis of the Primary Endpoints
•
Participants enrolled in phase I will have the grades and types of toxicity reported at each 
dose level. The overall estimate of the fraction of participants who have a DLT at the RP2D 
will be reported.
•
Participants evaluated in phase II will have the fraction with clinical responses reported, 
with a 95% confidence interval.
10.4.3 Analysis of the Secondary Endpoints
•
The secondary objectives for phase I are to describe pharmacokinetic properties of KPT-
8602 in MDS participants and to evaluate safety and tolerability of KPT-8602 in 
combination with Inqovi in MDS participants. The AUC, half-life, and Css of KPT-8602 
will be evaluated in participants, by dose level using descriptive statistics.
•
The secondary objectives for phase II are to evaluate the safety and tolerability of the agent 
as measured by the grades and types of toxicity noted for the agent at each dose level and 
reported descriptively.
10.4.4 Safety Analyses
The safety and tolerability of the agent will be evaluated by reporting the grades and types of 
toxicity noted for the agent at each dose level.
10.4.4.1 Safety stopping rules
Phase I will follow a 3+3 dose-escalation design, paused for review when the toxicity reaches the 
criteria in Section 3.1.1.
For phase II, our goal toxicity rate is less than 20%.
Phase II toxicity assessment will use Bayesian toxicity monitoring with maximum probability of 
DLT of 0.2, prior distribution (1,1), maximum participants 43, minimum number of participants 
before stopping 9, cohort size 1, and posterior probability > 80%. Using this approach, the study 
would be paused for review for toxicities that meet the definition of DLT in 3/9, 4/11, 5/15, 6/20, 
7/24, 8/28, and 9/32 participants.

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10.4.5 Baseline Descriptive Statistics
Standard sample statistics will be provided for each cohort and overall.
10.4.6 Planned Interim Analyses
As indicated above in Section 10.2, participants in phase II will be evaluated after 21 participants 
have been treated, an evaluation will be performed of the responses at that point to determine 
suitability to enroll the remaining participants. Specifically, the trial will proceed to the second 
stage if there are least 6 responses out of 21 participants with HR-MDS with a safety follow-up 
through day 28 required for the interim analysis, enrollment to the cohort will be halted to allow 
for an analysis by the study investigator. A brief memo will be created by the study investigator to 
document the number of responses in the first stage and will be reviewed by the PI and study team. 
The memo will be provided to study sponsor prior to continuation of accrual. Also, if the required 
number of responses is observed before that time, the memo will be generated, reviewed and 
provided to the study sponsor at that point without a pause in accrual. Response rates will be 
calculated using the revised International Working Group (IWG) 2006 response criteria for all 
responses, except hematologic improvement (HI) responses which will use the IWG 2018 response 
criteria, as described in the protocol.
10.4.7 Sub-Group Analyses
Results from phase II will be presented according to MDS-subgroup, disease risk category and 
genomic features.
10.4.8 Tabulation of individual Participant Data
None will be provided.
10.4.9 Exploratory Analyses
All exploratory analyses will be performed with descriptive intent, largely done separately by 
cohort. In the cases in which a statistical test is performed, the tests will be done without formal 
adjustment for multiple comparisons, but in the context of the number of tests performed.
10.4.9.1 Anslyses of Patient-Reported Outcomes
Evaluating Compliance and Feasibility of Administering PRO: Received PRO forms will be 
checked versus the timing schedule and considered as valid if they fall within the specified days 
of the scheduled assessment window. Compliance rates will be calculated as the number of 
received valid forms over the number of expected forms. Compliance rates will be described using 
summary statistics. 
We will collectively refer to the symptom scales and functional well-being subscales from the 
EORTC QLQ C30, individual symptom items from the PRO-CTCAE items, PROMIS physical 
function T-scores, and the single item overall side effect bother as PRO outcomes. These PRO 
outcomes will be summarized by descriptive statistics, such as mean, percentages, frequency, 
standard deviation, and 95% confidence interval. The change in PRO outcomes over time will be 
evaluated using paired-t test or Wilcoxon signed rank test depending on the distributional 
assumptions. When appropriate, a linear or generalized linear mixed model will be used to make 
inferences on the trajectory of PRO outcomes. Error bar graphs for each of the PRO outcomes will 
be constructed at each time point. Because the PRO-CTCAE complements the CTCAE, we will 
use the same analysis approach for the PRO-CTCAE. The traditional method of reporting AEs 

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over the course of a clinical trial is by taking the maximum value. This single value is then reported 
descriptively. Because many participants enter clinical trials with symptoms at baseline, it is 
desirable to perform baseline adjustment in the analysis of symptomatic adverse events.(56) The 
baseline adjustment method consists of two steps. First, determine the maximum AE score for a 
participant over the study period post baseline. Second, if the maximum AE score is worse than 
baseline, then use the maximum AE score. However, if the maximum AE score is the same or 
better than baseline, then assign a value of zero.
Longitudinally describing and evaluating disease and treatment-related symptom severity and 
functional well-being: We will use two graphical approaches to address this objective. First, 
Locally weighted regression (LOWESS) curves showing symptom trajectories over time for each 
symptom scales and functional well-being subscales from the EORTC-QLQ C30 will be 
constructed. Second, we will also construct individual participant profiles for each of the EORTC 
QLQ C30 symptom scales and functional well-being subscales to describe the individual 
participants’ patterns of change over time. Effect sizes that standardize the difference in symptom 
improvement or worsening between two preselected time points will be calculated. 
Determining meaningful change in disease and treatment related symptoms and functional well-
being by using anchors: In order to determine meaningful change in the EORTC QLQ C30 
symptom scales and functional well-being subscales, we will use both clinician-rated (Karnofsky) 
and patient-rated (PGI-Severity, PGI-Change) anchors. We will stratify patients into 3 change 
groups (improved, no change, declining) between pre-selected time points (e.g. baseline and end 
of first disease evaluation). The difference in the EORTC QLQ C30 symptom scale scores and 
functional well-being subscale scores between the pre-selected time points within each of the 
change groups provide an estimate of meaningful change.  
11 COLLABORATIVE AGREEMENTS
11.1 AGREEMENT TYPE
This study will be conducted under an Umbrella Collaborative Research and Development 
Agreement (CRADA) with Karyopharm Therapeutics, Inc (#03377).
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR PARTICIPANT SELECTION
No participants will be excluded from participation based on gender, race or ethnicity. The study 
will be open to all participants who satisfy the inclusion criteria and provide an informed consent 
to the protocol.
Participants with active HIV, HCV, or HBV are excluded because study treatment can pose more 
risks for these participants.
Due to the unknown effects of KPT-8602 on the fetus and infants, and known teratogenicity of 
Inqovi, women of reproductive age will only be allowed to enroll if they commit to following a 
strict manner of contraception; Females who are breast-feeding will not be eligible for the trial. 
Men who are sexually active with women of childbearing age will also have to commit to strict 
contraceptive practices while on study. 

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12.2 PARTICIPATION OF CHILDREN
Children will not be eligible for participation in this study due to lack of adequate safety data in 
children. Biologic rationale and preclinical work were validated in adult population and would 
need reanalysis in children, where MDS may arise more so from inherited bone marrow failure 
syndromes than in adults and have a different pathophysiology. 
12.3 RISK/BENEFIT ASSESSMENT
12.3.1 Known Potential Risks
All known potential risks associated with KPT-8602 from prior experience in humans has been 
discussed in Section 14. In the first-in-human study of KPT-8602 monotherapy, the most 
frequently occurring AEs were gastrointestinal effects (nausea, fatigue, diarrhea, decreased 
appetite, weight decreased) and cytopenias (thrombocytopenia, anemia). The potential risks of 
Inqovi are noted in the USPI for INQOVI and includes myelosuppression and embryo-fetal 
toxicity. However, there is an unknown element here which is why this is a phase I safety study 
and participants will be closely monitored for all AEs.
Other risks involved in the study include that of standard MDS procedures, including regular blood 
draws and bone marrow evaluations. These are invasive procedures that carry with them the risk 
of infection, bleeding and damage to surrounding tissues/organs. Phlebotomy and bone marrow 
evaluations will be conducted by well-trained personnel who follow sterile techniques to minimize 
complications.
12.3.1.1 Risks related to study procedures
12.3.1.1.1 Blood samples 
Minor complications including bleeding, pain, and hematoma formation at the site of blood 
draws, or infections may rarely occur. Up to 82 mL of blood may be collected at one time, no 
more than 250 mL will be collected over an 8-week period.
12.3.1.1.2 Bone marrow aspiration/biopsy
The bone marrow aspiration and biopsy may cause pain, bruising, bleeding and infection.  Soreness 
near the site may last for a couple of days after the procedure. The subject may have more pain, 
risk of bleeding and bruising if he/she complete both aspiration and biopsy rather than just the 
aspiration.  The subject should contact the study team immediately if pain is severe or fever 
develops. 
12.3.1.1.3 Electrocardiogram
Other than possibly experiencing some minor skin irritation from the electrodes there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram.
12.3.1.1.4 Intravenous catheter
The risks of IV insertion include temporary pain and bleeding or bruising at the site where the IV 
enters the skin.  In placing the IV, there is a small chance of fluid leaking into the tissue surrounding 
the IV and infection, which may cause some swelling and discomfort. Rarely, the IV site may 
become infected, which might require treatment with antibiotics. 

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12.3.1.1.5 Questionnaires
Some of the questions in the questionnaire may be upsetting or make subjects feel uncomfortable. 
Subjects can skip any of the questions he/she does not want to answer, and can stop at any time.
12.3.1.1.6 Urine collection
No physical risks are associated with urine collection.
12.3.1.1.7 Losing data 
This includes the risk that data obtained during this study can be released to members of the public, 
insurers, employers, or law enforcement agencies. Although there are no plans to release results to 
the participants, family members, or health care providers, this risk will be included in the informed 
consent document.
12.3.2 Known Potential Benefits
Due to the significant preclinical and prior clinical experience with KPT-8602, this study 
hypothesis has strong evidence that KPT-8602 may have disease-modifying beneficial therapeutic 
activity in MDS. If this is confirmed via this trial, participants have the potential for immediate-
benefits that include, improved cytopenias, less transfusion- and growth factor-dependence, less 
complications of cytopenias such as infections and hemorrhagic complications. Transfusion 
independence also leads to improved quality of life. Long-range potential benefits, should our 
investigational agent confirm efficacy, include stability of MDS disease with improved quality of 
life and potential for less progression into AML, which is associated with significant morbidity 
and mortality. 
12.3.3 Assessment of Potential Risks and Benefits
Risks to participants have been minimized in the study and involve no more than that expected 
from standard of care monitoring of MDS, which includes regular peripheral blood draws and bone 
marrow evaluations. The potential disease modifying/therapeutic benefit of KPT-8602 as an 
investigative agent outweighs the risks discussed, which are otherwise mostly standard procedures 
for participants with MDS. 
12.4 CONSENT AND ASSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting.  A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will be 
given, including an opportunity to discuss it with friends, family members and/or other advisors, 
and to ask questions of any designated study investigator. A signed informed consent document 
will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy of 
the subject will be maintained. Consenting investigators (and participant/consent designee, when 
in person) will be located in a private area (e.g., clinic consult room). When consent is conducted 

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remotely, the participant/consent designee will be informed of the private nature of the discussion 
and will be encouraged to relocate to a more private setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or on the electronic document.  
Signatures on electronic documents are described below. 
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will the following to obtain the required signatures:
•
Adobe platform (which is not 21 CFR Part 11 compliant); or,  
•
iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location, but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigators, funding agency, the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional 
Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension.  
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility

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Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council on Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the National Cancer Institute has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a secure 

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location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by the clinical site(s) and by NCI CCR research staff will be secured and password protected. At 
the end of the study, all study databases will be archived at the NCI CCR.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.
14 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION  
14.1 KPT-8602 (IND # 163958)
14.1.1 Description
Current formulations
Dosage form
Tablet
Route of administration
Oral
Strength(s)a
5 mg, 10 mg
Manufacturing process
Roller compaction dry granulation:
API and inactive excipients are blended before roller compaction to 
make granules. Granules are further blended with additional 
excipients and subsequently compressed, then film coated.
Componentsb
eltanexor (KPT-8602)
~6.25% by weight for 5 mg and 10 mg
microcrystalline cellulose
mannitol
providone
croscarmellose sodium
colloidal silicon dioxide
sodium lauryl sulfate
magnesium stearate
Coating
Opadry 200 Clear (sub-coat) and Opadry II Orange (top-coat)
Color
Orange to peach
Packaging
HDPE bottles with desiccant
Shipping
2-25C
Storage
Store at or below 25C. Do not freeze.
aTablet strengths are distinguished by tablet size and debossing (5 mg tablets are scored, 10 mg 
tablets have no debossing)

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bThese tablet components/excipients are common to oral pharmaceuticals and/or compendial.
Chemical structure: 
5-Pyrimidineacetamide, α-[[3-[3,5-bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl]methylene]-, 
(αE)-(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide
•
Molecular weight: 428.30 g/mol
•
Mechanism of action: selective inhibitor of nuclear export (SINE)
14.1.2 Source/Acquisition and Accountability 
KPT-8602 (eltanexor) is manufactured and supplied for by the trial by Karyopharm Therapeutics, 
Inc.
KPT-8602 will be provided to the clinical trial site by the manufacturer. The investigator or 
designee (e.g., pharmacist) will maintain an ongoing inventory of the investigational product 
supply according to standard site procedures. The investigational product will be dispensed at the 
direction of an investigator for administration to a study participant enrolled on the clinical trial. 
Disposal of expired or unused product will be returned to the manufacturer or disposed of 
according to standard site procedures based on agreement between the manufacturer and the site
14.1.3 Toxicity 
The key preclinical safety findings in rats and monkeys are as follows:
•
In general, the major effects across the toxicology studies was non-adverse, reversible 
weight loss, some of which also observed for other SINE compounds (selinexor, 
verdinexor, etc). The effects on body weight were typically associated with lower food 
consumption, were fully reversible, and considered non-adverse.
•
Eltanexor-related effects in male rat reproductive tissues were dependent on dosing 
frequency and duration, consistent with other SINE compounds. In the 4-week rat GLP 
study (QDx5/week), non-adverse microscopic findings were reported for thetestes. In rats 
given 20 doses at ≥4 mg/kg (24 mg/m2), minimal-mild germ cell degeneration in the testes 
was accompanied by minimal-mild cellular debris in the epididymis; these findings were 
non-adverse and fully reversible after a 28-day recovery period. In monkeys, there were no 
adverse effects observed.
•
In the GLP, 4-week study in monkeys (QD×5/week), serum chemistry measures indicated 
significantly higher serum amylase and lipase. These correlated to microscopic findings in 
the pancreas including acinar atrophy, acinar hyperplasia (males), individual cell 

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degeneration/necrosis, interstitial fibrosis, and ductal hypertrophy/hyperplasia (males). 
Following a 28-day recovery period, effects on the pancreas were fully reversible, except 
for minimal pancreatic acinar atrophy, interstitial fibrosis, ductal hypertrophy/hyperplasia, 
and minimally decreased zymogen granules. Based on these results, eltanexor is not 
considered to pose a risk for pancreatitis.
•
Eltanexor was not genotoxic in a GLP in vitro bacterial reverse mutation (Ames assay).
The safety, tolerability, and preliminary efficacy of eltanexor in humans is currently under 
investigation in Study KCP-8602-801 (Study 801) which is an ongoing first-in-human, open-label 
dose-escalation study in patients with relapsed/refractory multiple myeloma (R/R MM) followed 
by a dose-expansion phase in patients with select advanced malignancies. As of 18 November 
2021, a total of 124 patients have received eltanexor in Study 801, of which 119 patients (39 
patients with R/R MM, 30 patients with mCRPC, and 20 patients with HR-MDS) have safety data 
available. In the entire safety population, the most frequently occurring TEAEs of any grade were 
nausea (63%), fatigue (63%), diarrhea (58%), decreased appetite (49%), thrombocytopenia (49%), 
weight decreased (48%), anemia (45%), vomiting (45%). The most frequently occurring  Grade 
3 TEAEs were thrombocytopenia (31%), anemia (29%), and neutropenia (25%). However, no 
clinically significant cumulative toxicities were identified, major organ dysfunction was not 
observed, and no grade 5 TRAEs were reported. Adverse events leading to discontinuation of 
eltanexor that occurred in  3 patients were fatigue (6.7%), nausea (4.2%), sepsis (3.4%), as well 
as vomiting, acute kidney injury, decreased appetite, and weight decreased (2.5% each). See the 
Eltanexor Investigator’s Brochure (IB) for more information.
14.1.4 Formulation and preparation 
Eltanexor is an immediate-release tablet for oral administration. Initial supplies came in 2 
strengths: 5 mg and 20 mg of the active pharmaceutical ingredient per tablet. The 20 mg tablet is 
no longer being used. Current supplies for the clinic are 5 mg and 10 mg tablets, where the 10- mg 
tablet is weight proportional (2×) with respect to the 5-mg tablet. All inactive ingredients used in 
the tablets are either compendia or generally recognized as safe. Tablets are film coated for ease 
of handling. Detailed information related to the manufacturing, components/excipients, packaging, 
and storage of the drug formulations is provided in the Eltanexor IB.
14.1.5 Stability and Storage 
Eltanexor tablets are packaged in white high-density polyethylene bottles with induction seals with 
polypropylene caps. The eltanexor-containing bottles should be stored at/or below 25°C but not 
frozen.
14.1.6 Administration Procedures
See Section 3.2.1.
14.1.7 Incompatibilities
The primary metabolism of eltanexor based on nonclinical studies in vitro and in vivo appears to 
involve inactivation by GSH conjugation. This process can be mediated in the absence of proteins, 
indicating that it is thermodynamically favorable. In vitro studies using human liver microsomes 
indicate that eltanexor undergoes minimal CYP450 mediated metabolism. There was also minimal 
to no induction of CYP450 activity observed for CYP1A2, CYP2B6, or CYP3A4.

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Therefore, the risk of drug-drug interactions with eltanexor is low; however, administration of 
eltanexor with drugs that undergo substantial GSH conjugation should be minimized. These drugs 
include acetaminophen (paracetamol). In the event that GSH depletion is believed to be 
contributing to patients’ symptoms, signs or laboratory findings, replenishment with SAM (S-
adenosyl-L-methionine) oral (e.g., 400 mg) or N-acetylcysteine (e.g., up to 140 mg/kg loading 
dose followed by 70 mg/kg Q4 hours) until symptoms resolve. It should be noted that no studies 
of eltanexor in combination with acetaminophen have been performed to date and that these 
recommendations are empirical. 
Eltanexor is also a substrate for BCRP and a marginal substrate of P-gp, therefore concomitatnt 
administration of inhibitors of BCRP and P-gp should be avoided. (Examples can be found at the 
following 
link: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-
drug-interactions-table-substrates-inhibitors-and-inducers#table5-2)
The effect of concomitant administration of gastric acid reducing agents on eltanexor PK cannot 
be ruled out at this time, therefore concomitant administration of acid-reducing agents, e.g. proton 
pump inhibitors or H2-receptor antagonists, with eltanexor during the dose finding portion of the 
study will be avoided.
There are no other known drug interactions.
14.2 INQOVI® (DECITABINE AND CEDAZURIDINE)
INQOVI is a combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a 
cytidine deaminase inhibitor, indicated for treatment of adult patients with myelodysplastic 
syndromes (MDS).
14.2.1 Source/Acquisition and Accountability 
For participant administration, decitabine and cedazuridine will be purchased by the NIH Clinical 
Center Pharmacy Department from commercial sources.
14.2.2 Toxicity 
Fatal and serious myelosuppression and infectious complications can occur. Can cause fetal harm. 
Most common adverse reactions (incidence ≥ 20%) are fatigue, constipation, hemorrhage, 
myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, 
edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and 
transaminase increased. The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were 
leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin 
decreased. (57-59)
14.2.3 Formulation and preparation 
INQOVI (decitabine and cedazuridine) tablets, for oral use contain 35 mg decitabine and 100 mg 
cedazuridine. The tablets are biconvex, oval-shaped, film-coated, red and debossed with “H35” on 
one side. Each film-coated tablet contains the following inactive ingredients: lactose monohydrate, 
hypromellose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The film 
coating material contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron 
oxide red.

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14.2.4 Stability and Storage 
Each tablet should be stored at 20°C to 25°C. Excursions of the tablet are permitted to 15°C to 
30°C. Any unused portion of the tablet should be discarded using special handling and disposal 
procedures.
14.2.5 Administration Procedures
See Section 3.2.2 for details.
14.2.6 Incompatibilities
Avoid coadministration of INQOVI with drugs that are metabolized by cytidine deaminase (CDA) 
enzymes, such as gemcitabine, cytarabine, and capecitabine.

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Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 
2010;362(10):865-9.
41.
Basch E, Bennett A, Pietanza MC. Use of patient-reported outcomes to improve the 
predictive accuracy of clinician-reported adverse events. J Natl Cancer Inst. 2011;103(24):1808-
10.

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42.
Etchin J, Berezovskaya A, Conway AS, Galinsky IA, Stone RM, Baloglu E, et al. KPT-
8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and 
highly active against AML blasts and leukemia-initiating cells. Leukemia. 2017;31(1):143-50.
43.
Hing ZA, Fung HY, Ranganathan P, Mitchell S, El-Gamal D, Woyach JA, et al. Next-
generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological 
malignancies. Leukemia. 2016;30(12):2364-72.
44.
Ranganathan P, Yu X, Santhanam R, Hofstetter J, Walker A, Walsh K, et al. Decitabine 
priming enhances the antileukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in 
acute myeloid leukemia. Blood. 2015;125(17):2689-92.
45.
Hourigan CS, Dillon LW, Gui G, Logan BR, Fei M, Ghannam J, et al. Impact of 
Conditioning Intensity of Allogeneic Transplantation for Acute Myeloid Leukemia With 
Genomic Evidence of Residual Disease. J Clin Oncol. 2020;38(12):1273-83.
46.
Buckstein RJ. Integrating patient-centered factors in the risk assessment of MDS. 
Hematology Am Soc Hematol Educ Program. 2019;2019(1):373-80.
47.
Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I, Mitnitski A. 
A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173(5):489-95.
48.
Breccia M, Salaroli A, Loglisci G, Finsinger P, Serrao A, Alimena G. MDS-specific 
comorbidity index is useful to identify myelodysplastic patients who can have better outcome 
with 5-azacitidine. Haematologica. 2012;97(2):e2.
49.
Della Porta MG, Malcovati L, Strupp C, Ambaglio I, Kuendgen A, Zipperer E, et al. Risk 
stratification based on both disease status and extra-hematologic comorbidities in patients with 
myelodysplastic syndrome. Haematologica. 2011;96(3):441-9.
50.
Fayers P, Bottomley A, Group EQoL, Quality of Life U. Quality of life research within 
the EORTC-the EORTC QLQ-C30. European Organisation for Research and Treatment of 
Cancer. Eur J Cancer. 2002;38 Suppl 4:S125-33.
51.
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life 
instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-
76.
52.
Stauder R, Lambert J, Desruol-Allardin S, Savre I, Gaugler L, Stojkov I, et al. Patient-
reported outcome measures in studies of myelodysplastic syndromes and acute myeloid 
leukemia: Literature review and landscape analysis. Eur J Haematol. 2020;104(5):476-87.
53.
Wiener L, Battles H, Zadeh S, Smith CJ, Helman LJ, Kim SY. Gastrointestinal stromal 
tumor: psychosocial characteristics and considerations. Support Care Cancer. 2012;20(6):1343-9.
54.
Platzbecker U, Fenaux P, Ades L, Giagounidis A, Santini V, van de Loosdrecht AA, et al. 
Proposals for revised IWG 2018 hematological response criteria in patients with MDS included 
in clinical trials. Blood. 2019;133(10):1020-30.
55.
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. 
Clinical application and proposal for modification of the International Working Group (IWG) 
response criteria in myelodysplasia. Blood. 2006;108(2):419-25.

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56.
Dueck AC, Scher HI, Bennett AV, Mazza GL, Thanarajasingam G, Schwab G, et al. 
Assessment of Adverse Events From the Patient Perspective in a Phase 3 Metastatic Castration-
Resistant Prostate Cancer Clinical Trial. JAMA Oncol. 2020;6(2):e193332.
57.
Garcia-Manero G, Griffiths EA, Roboz GJ, Busque L, Wells RA, Odenike O, et al. A 
Phase 2 Dose-Confirmation Study of Oral ASTX727, a Combination of Oral Decitabine with a 
Cytidine Deaminase Inhibitor (CDAi) Cedazuridine (E7727), in Subjects with Myelodysplastic 
Syndromes (MDS). Blood. 2017;130.
58.
Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, et al. An 
oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a 
multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematology. 2019;6(4):E194-
E203.
59.
Savona MR, McCloskey JK, Griffiths EA, Yee KWL, Al-Kali A, Zeidan AM, et al. 
Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with 
Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML). Blood. 
2020;136.

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16 LIST OF ABBREVIATIONS
Abbreviation
Term
ACAT
Ability to Consent Assessment Team
AE
Adverse Event/Adverse Experience
AESI
Adverse Event/Experience of Special Interest
ANC
Absolute neutrophil count
BTRIS
Biomedical Translational Research Information System
CCR
Center for Cancer Research
CDA
Confidential Disclosure Agreement
CFR
Code of Federal Regulations
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COV
Close-out Visit
CR
Complete Response
CSR 
Clinical Study Report
CRADA
Cooperative Research and Development Agreement
CT
Computed Tomography
CTA
Clinical Trials Agreement
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose-limiting toxicity
DTA
Data Transfer Agreement
EC
Ethics Committee
eCRF
Electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EFS
Event-free survival
EKG
Electrocardiogram
FDA
Food and Drug Administration
FWA
Federal-Wide Assurance
GCP
Good Clinical Practice
GDS
Genomic Data Sharing
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HHS
Health and Human Services
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
IBC
Institutional Biosafety Committee
ICD/ICF
Informed Consent Document/Form
ICH
International Council on Harmonisation
IMV
Interim Monitoring Visit
IND
Investigational New Drug 
IOCBP
Individuals of childbearing potential

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Abbreviation
Term
IRB
Institutional Review Board
IRBO
Institutional Review Board Office
IV
Intravenous
LAR
Legally Authorized Representative
MRI
Magnetic Resonance Imaging
MTA
Material Transfer Agreement
MTD
Maximal tolerated dose
N
Number (typically refers to subjects)
NCT
National Clinical Trial (number)
NDA
New Drug Application
NIH
National Institutes of Health
NOS
Not otherwise specified
OHSRP
Office for Human Subjects Research Protections
OHRP
Office for Human Research Protections
OS
Overall survival
OSRO
Office of Sponsor and Regulatory Oversight
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression-free survival
PI
Principal Investigator
PR
Partial Response
PS
Performance Status
QA
Quality Assurance
QC
Quality Control
rCR
Revised Common Rule
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase II dose
SAE
Serious Adverse Event/Serious Adverse Experience
SAV
Site Assessment Visit
SIV
Site Initiation Visit
SD
Stable Disease
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
ULN
Upper limit of normal
US
United States
WHO
World Health Organization

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17 APPENDICES
17.1 APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory. 
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).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated. Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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17.2 APPENDIX B:  2016 WHO CLASSIFICATION FOR MYELODYSPLASTIC SYNDROME 
Reference:  Arber, DA, et al.(1)
Myelodysplastic syndromes (MDS)
•
MDS with single lineage dysplasia (MDS-SLD)
•
MDS with ring sideroblasts (MDS-RS)
o
MDS-RS and single lineage dysplasia
o
MDS-RS and multilineage dysplasia
•
MDS with multilineage dysplasia (MDS-MLD)
•
MDS with excess blasts
•
MDS with isolated del(5q)
•
MDS, unclassifiable
•
Provisional entity: Refractory cytopenia of childhood

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17.3 APPENDIX C:  REVISED INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS-R) FOR 
MYELODYSPLASTIC SYNDROMES
Score
Prognostic variable
0
0.5
1.0
1.5
2.0
3.0
4.0
Cytogenetics*
Very 
good
 
Good
 
Intermediate
Poor
Very 
poor
Bone marrow blast (percent)
≤2
 
>2 to 
<5
 
5 to 10
>10
 
Hemoglobin (g/dL)
≥10
 
8 to <10
<8
 
 
 
Platelets (cells/microL)
≥100
50 to 
100
<50
 
 
 
 
Absolute neutrophil count 
(cells/microL)
≥0.8
<0.8
 
 
 
 
 
Risk group
IPSS-R score
Median overall 
survival (years)
Median time to 
25 percent AML 
evolution (years)
Very low
≤1.5
8.8
>14.5
Low
>1.5 to 3.0
5.3
10.8
Intermediate
>3 to 4.5
3.0
3.2
High
>4.5 to 6
1.6
1.4
Very high
>6
0.8
0.7
AML: acute myeloid leukemia; MDS: myelodysplastic syndromes.
* Cytogenetic definitions:
Very good: –Y, del(11q)
Good: Normal, del(5q), del(12p), del(20q), double including del(5q)
Intermediate: del(7q), +8, +19, i(17q), any other single, double not including del(5q) or –7/del(7q), or independent clones
Poor: –7, inv(3)/t(3q)/del(3q), double including –7/del(7q), complex: 3 abnormalities.
Very poor: Complex: >3 abnormalities
This research was originally published in Blood. Greenberg PL, Tuechler H, Schanz J, et al. Revised International Prognostic 
Scoring System (IPSS-R) for myelodysplastic syndromes. Blood 2012. Copyright © 2012 the American Society of Hematology.

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17.4 APPENDIX D: THE 2006 INTERNATIONAL WORKING GROUP RESPONSE CRITERIA WITH 
MODIFIED DEFINITIONS FOR HEMATOLOGIC IMPROVEMENT BY THE 2018 
INTERNATIONAL WORKING GROUP RESPONSE CRITERIA
Reference: Platzbecker, U, et al.(54)
Category
Response criteria
(responses must last at least 4 weeks)
Complete remission
•      Bone marrow: ≤5% myeloblasts with normal maturation of 
all cell lines*
•      Persistent dysplasia will be noted*
•      Peripheral blood†
•
 Hgb ≥11 g/dL
•
Platelets ≥100 X 109/L
•
Neutrophils ≥1.0 X 109/L
•
Blasts 0%
Partial remission
All CR criteria if abnormal before treatment except:
•      Bone marrow blasts decreased by >50% over pretreatment 
but still >5%
•      Cellularity and morphology not relevant
Marrow CR
•      Bone marrow: ≤5% myeloblasts and decrease by ≥50% 
over pretreatment
•      Peripheral blood: if HI responses, they will be noted in 
addition to marrow CR
Stable disease
Failure to achieve at least PR, but no evidence of progression 
for >8 weeks
Failure
Death during treatment or disease progression characterized 
by worsening of cytopenias, increase in percentage of bone 
marrow blasts, or progression to more advanced MDS FAB 
subtype than pre-treatment
Relapse after CR or PR
At least 1 of the following:
•      Return to pre-treatment bone marrow blast percentage
•      Decrement of >50% from maximum remission/response 
levels in granulocytes or platelets
•      Reduction in Hgb concentration by >1.5 g/dL or 
transfusion dependence
Cytogenetic response
Complete
•      Disappearance of the chromosomal abnormality without 
appearance of new ones
Partial
•      At least 50% reduction of the chromosomal abnormality
Disease progression
For patients with:
•      Less than 5% blasts: ≥50% increase in blasts to >5% blasts
•      5%-10% blasts: ≥50% increase to 10% blasts

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•      10%-20% blasts: ≥50% increase to >20% blasts
•      20%-30% blasts: ≥50% increase to >30% blasts
Any of the following:
•      At least 50% decrement from maximum 
remission/response in granulocytes or platelets
•      Reduction in Hgb by ≥2 g/dL
•      Transfusion dependence
Survival
Endpoints:
•      Overall: death from any cause
•      Event free: failure or death from any cause
•      PFS: disease progression or death from MDS
•      DFS: time to relapse
•      Cause-specific death: death related to MDS
MDS, myelodysplastic syndromes; Hgb, hemoglobin; CR, complete remission; HI, hematologic improvement; PR, partial
remission; FAB, French-American-British; AML, acute myeloid leukemia; PFS, progression-free survival; DFS, disease-free
survival.
To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.
*Dysplastic changes should consider the normal range of dysplastic changes.
†In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, maintenance) before
the 4-week period. Such patients can be included in the response category into which they fit at the time the 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 previous course.
 
Hematologic Improvement
Category
Patient pre-trial 
baseline
Response criteria
 
No Transfusion 
Dependence at 
baseline (0 RBC 
transfusions in 16 
weeks)
At least 2 consecutive Hgb measurements 
>1.5 g/dL for a period of minimum 8 weeks in 
an observation period of 16 to 24 weeks 
compared with the lowest mean of 2 Hgb 
measurements (apart from any transfusion) 
within 16 weeks before treatment onset; only 
a response duration of at least 16 weeks, 
however, is considered clinically meaningful
Low Transfusion 
Dependence at 
baseline (3-7 RBC 
transfusions in 16 
weeks in at least 2 
transfusion episodes, 
maximum 3 in 8 
weeks)
Transfusion independence, defined by the 
absence of any transfusions for at least 8 
weeks in an observation period of 16-24 
weeks with the same transfusion policy 
compared with 16 weeks prior to treatment; 
only a response duration of at least 16 weeks, 
however, is considered clinically meaningful
Erythroid response 
(HI-E)
High Transfusion 
Dependence at 
baseline (>8 RBC 
transfusions in 16 
Major 
response
Transfusion independence, 
defined by the absence of any 
transfusions over a period of 
minimum 8 weeks in an 

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observation period of 16-24 
weeks with the same transfusion 
policy compared with 16 weeks 
prior to treatment; only a response 
duration of at least 16 weeks, 
however, is considered clinically 
meaningful
weeks, > 4 
transfusion episodes 
in 8 weeks)
Minor 
response
A reduction by at least 50% of 
RBCs over a minimum of 16 
weeks with the same transfusion 
policy, compared with 16 weeks 
prior to treatment
Platelet response 
(HI-P)
Pre-treatment PLT 
<100 x 109/L
•      Absolute increase of 30 x 109/L for 
patients starting with >20 x 109/L PLTs
or
•      Increase from <20 x 109/L to >20 x 109/L 
and by at least 100%
In addition:
•      In addition, evolution of bleeding 
symptoms is to be taken into account
•      Increments of platelets also for patients 
with a pre-treatment PLT count of >100 x 
109 are to be reported
Neutrophil response 
(HI-N)
 
Pre-treatment ANC 
<1.0 x 109/L
•      At least 100% increase and an absolute 
increase >0.5 x 109/L
•      Increments of neutrophils also for patients 
with a pre-treatment ANC of >1.0 x 109/L 
are to be reported

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17.5 APPENDIX E: ROCKWOOD FRAILTY INDEX
Reference: Rockwood, K, et al.  (47)

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17.6 APPENDIX F: MDS-SPECIFIC COMORBIDITY INDEX (MDS-CI)
Comorbidity
Definition
Variable Weighted 
Score (to be considered 
if the specific 
comorbidity is present)
Cardiac disease
Arrhythmia*
Heart valve disease**
Coronary artery disease*** or myocardial 
infarction
Congestive heart failure or ejection 
fraction ≤50%
2
Moderate-to-severe 
hepatic disease****
Cirrhosis, fibrosis, persistent bilirubin > 
1.5 x ULN or AST/ALT > 2.5 x ULN
1
Severe pulmonary disease
DLCO and/or FEV1 ≤65% or dyspnea at 
rest or requires oxygen
1
Renal disease
Persistent creatinine > 2 mg/dL, renal 
dialysis, or renal transplant
1
Solid tumor
Malignancy at any time point in the 
patient’s history, excluding non-
melanoma skin cancer
1
DLCO indicates diffusion capacity of the lung for carbon monoxide; FEV1: forced expiratory volume in 
one second; ULN: upper limit of normal; AST: aspartate aminotransferase; ALT: alanine 
aminotransferase. *Atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmias; **Except 
mitral valve prolapse; ***One or more vessel-coronary artery stenosis requiring medical treatment, stent, 
or bypass graft; ****HCV infection was documented in 7% of patients.
MDS – CI Key
MDS-CI Risk
Sum of Individual Variable 
Scores
Low risk
0
Intermediate risk
1-2
High risk
>2
Della Porta MG, Malcovati L, Strupp C, Ambaglio I, Kuendgen A, Zipperer E, Travaglino E, Invernizzi R, Pascutto 
C, Lazzarino M, Germing U and Cazzola M. Risk stratification based on both disease status and extra-hematologic 
comorbidities in patients with myelodysplastic syndrome. Haematologica 2011;96(3):441-449. 
doi:10.3324/haematol.2010.033506 

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17.7 APPENDIX G: EUROPEAN ORGANIZATION FOR RESEARCH AND TREATMENT OF CANCER 
(EORTC) QUALITY OF LIFE QUESTIONNAIRE = EORTC QLQC30 SCORE 
Reference: Fayers, P, et al.(50)
See Study Instrument Packet.

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17.8 APPENDIX H: PATIENT-REPORTED OUTCOMES (NIH ADULT PSYCHOSOCIAL 
ASSESSMENT FOR MDS, CTCAE, OVERALL SIDE EFFECT BOTHER, PROMIS PHYSICAL 
FUNCTION, PGI-S, AND PGI-C)
See Study Instrument Packet.

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17.9 APPENDIX I: DATA ELEMENTS TO CONSIDER FOR CRF ENTRY IN CLINICAL DATABASE
Participant characteristics at protocol entry
•
Sex (male, female)
•
Age at enrollment (number)
•
Ethnicity (white, black, American Indian/Alaskan native, Asian/Pacific islander, 
Hispanic, other)
•
ECOG and Karnofsky performance status
•
Diagnosis - MDS (high risk and higher intermediate risk)
•
2016 WHO classification of MDS (MDS with single lineage dysplasia [MDS-SLD], 
MDS with ring sideroblasts and single lineage dysplasia [MDS-RS-SLD], MDS with ring 
sideroblasts and multilineage dysplasia [MDS-RS-MLD], MDS with multilineage 
dysplasia [MDS-MLD], MDS with excess blasts [MDS-EB], MDS with isolated del(5q), 
MDS unclassifiable [MDS-U], 
•
Date of MDS diagnosis (month, year)
•
Age at MDS diagnosis 
•
Revised International Prognostic Scoring System (IPSS-R) score at MDS diagnosis 
•
Cytogenetic profile at diagnosis and enrollment, if available (see Appendix C)- only need 
overall score (very good, good, intermediate, poor, very poor) 
•
Bone marrow blasts %, if available (flow/asp and IHC/bx)
•
Hemoglobin, if available (at diagnosis and at enrolment) use counts from day of bone 
marrow for enrollment
•
Platelet count, if available (at diagnosis and at enrolment) day of bone marrow for 
enrollment
•
Absolute neutrophil count (ANC), if available (at diagnosis and at enrolment) day of 
bone marrow for enrollment
•
RBC transfusion dependance (transfusion dependent or independent)
•
Platelet transfusion dependance (transfusion dependent or independent) 
•
Average # of transfusions per month (RBCs units and instances of platelets transfusions) 
in the 3 months leading up to baseline on study
•
Laboratory values will be collected from time of screening for duration of trial
•
TP53 mutation status at enrollment, if available (TP53 mutation positive or negative) 
•
Names and # of cycles of prior Lines of therapy for MDS.
•
Response to most recent line of therapy: CR (complete response), PR (partial response), 
HI (hematologic improvement), mCR with HI (marrow CR with hematologic 
improvement), mCR without HI (marrow CR without hematologic improvement), SD 
(stable disease), PD (disease progression)
•
MDS-CI (low risk, intermediate risk, high risk)
•
Rockwood frailty index (see Clinical Frailty Scale)
•
Disease status at time of enrollment:  CR (complete response), PR (partial response), HI 
(hematologic improvement), mCR with HI (marrow CR with hematologic improvement), 
mCR without HI (marrow CR without hematologic improvement), SD (stable disease), 
PD (disease progression)
•
History of prior allogeneic transplantation (yes/no)
o
If history of prior allogeneic transplantation:

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▪
Date of allogeneic transplant/Day 0
•
Patient Reported Outcome Questionnaires (per section 3.5.3)
Data collection during study/treatment
•
Cycle number & day of treatment
•
Study Drug Administration 
•
Disease response at assessment timepoints: CR (complete response), PR (partial 
response), HI (hematologic improvement), mCR with HI (marrow CR with hematologic 
improvement), mCR without HI (marrow CR without hematologic improvement), SD 
(stable disease), PD (disease progression)
•
Best overall response to study treatment: CR (complete response), PR (partial response), 
HI (hematologic improvement), mCR with HI (marrow CR with hematologic 
improvement), mCR without HI (marrow CR without hematologic improvement), SD 
(stable disease), PD (disease progression)
•
Bone marrow percent blasts
•
RBC transfusion dependence (transfusion dependent or transfusion independent) 
•
Platelet transfusion dependence (transfusion dependent or transfusion independent)
•
# of transfusions per month (RBCs units and instances of platelets transfusions)
•
Adverse events 
•
Patient Reported Outcome Questionnaires: (per section 3.5.3)
Data collection at post-therapy follow-up visits 
•
Alive (yes/no)
•
Adverse events
•
Progression of MDS (if yes, to what and when)
•
Diagnosed with sAML (yes/no)
o
If diagnosed with sAML, date of sAML diagnosis (month, year)
Data collection at time of death
•
Date of death
•
Disease status at time of death: CR or not CR
•
Cause of death: disease progression/relapse vs non-relapse mortality (definition of non-
relapse mortality: subject in clinical remission at time of death)
•
If non-relapse mortality, primary cause of death (per CTCAE)

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17.10 APPENDIX J: BLOOD PROCESSING CORE PROCEDURES
Note: The following processing details and supplies may be adjusted as required during the 
course of the study with approval of the laboratory(ies). 
 
Samples to be Collected:
1. Peripheral Blood: 
a.
2 x 5 mL EDTA tubes (for separation and storage of MNC and plasma, protocol 
below)
b. 4 mL SST (or 2 x 2.5ml)Vacutainer tube (for PK analysis)
c.
1 x 2.5ml Paxgene RNA tube (for storage then pickup by Larson lab)
2. Bone Marrow Aspirate: 2 x 5mL EDTA tubes (for separation and storage of MNC and 
plasma, protocol below)
Processing Protocols:
Bone Marrow and Peripheral Blood Processing from EDTA Tubes:
1. Spin the bone marrow (BM) aspirate or peripheral blood (PB) at 2500 rpm (1500 rcf) for 
5 minutes to isolate neat plasma prior to adding the PBS/Ficoll.
2. Store 5 x 300uL aliquots of plasma at -80deg C.
3. Add 2 volumes of PBS to the PB/BM and be sure to mix well to ensure a good underlay 
of the Ficoll. 
4. Add a 1:1 volume of Ficoll to the diluted BM/PB by carefully dispensing at the bottom of 
the conical tube. The BM/PB should lay on top of the Ficoll layer. Try not to mix the 
Ficoll and BM/PB.
5. Spin the tubes at 3000 rpm (2000 rcf) for 15 minutes.
6. The mononuclear layer interface will lay between the Ficoll and plasma/PBS layers and 
will often appear whitish if there is a larger number of cells. Carefully remove this 
interface taking as little Ficoll as possible. If you cannot see the layer, just remove several 
mL from on top of the Ficoll layer, this will contain all the cell. Dilute the interface 
containing the cells, with 4 volumes of RPMI (supplemented with 10%FBS, and 1% 
Pen/Strep). The remaining Ficoll and RBCs at the bottom of the tube can be discarded. 
7. Spin the mononuclear cells at 1000rpm for 5 min.
8. Resuspend the cell pellet in 10 to 40ml of RBC Lysis Buffer (ie; Qiagen RBC Lysis 
Buffer). The volume of lysis buffer depends on the cell pellet. For very small pellets use 
10mL, for very large pellets, use 40mL RBC lysis .
9. Resuspend the cells in RPMI (supplemented with 10%FBS, and 1% Pen/Strep) and count 
the cells using a hemacytometer.
10. Freeze the cells in 10% DMSO, 20% FBS, and 70% RPMI with no more than 10million 
cells per mL and 1 mL per cryotube. Freeze samples either using a cell freezer container 
in a -80deg C freezer (i.e.; Mr Frosty container) or a controlled rate freezer. Once cells 
have reached -80deg C, transfer cryotubes to a liquid nitrogen cryounit.  

Abbreviated Title: DELTA-MDS
99
Version Date: 10/30/2024
PK Studies, Peripheral Blood Processing from SST Tube
1. Blood samples will be collected by direct venipuncture or through an indwelling catheter. 
If a catheter is used for blood collection, then approximately 1mL of blood should be 
withdrawn initially then discarded. Only saline is permitted to keep catheters patent, 
unless discussed and agreed upon by the Sponsor. If samples are obtained through a 
heparin lock, sufficient blood (~1mL) must be withdrawn to remove the heparin solution. 
2. Immediately after collection, gently invert each tube 5 times and allow blood to clot for 
30-45m at room temperature (tube standing upright).
3. Centrifuge samples at 4deg C for 10min (singing buckets) or 15 minutes (fixed buckets) 
at 100-1300g until clot and serum are well separated. Note: If refrigerated centrifuge is 
not available, prechill centrifuge tube holders at -20deg C for 20m prior to centrifugation.
4. Transfer 1mL aliquots of serum into 4 appropriately labeled screw cap polypropylene 
tubes.
5. Store samples at -80deg C until ready for analysis.
PAXgene Tube Storage for BM 
1. Tubes will be stored upright at -80deg C until ready for pickup by the Larson Lab. 

Abbreviated Title: DELTA-MDS
100
Version Date: 10/30/2024
17.11 APPENDIX K: PARTICIPANT MEDICATION DIARY
Cohort 1 and 2 – Medication Diary 
Cycle: ___________________ Participant’s ID: ___________________
Instructions:
1.
Complete one form for each cycle of treatment.
2.
You will take Inqovi once daily on Days 1-5  or Days 1-4 , Days 1-3 or Day 1, 3 and 5 depending 
on the dose level you are assigned,
3.
The tablet should be taken on an empty stomach, 2 hours before or 2 hours after meals, and at the 
same time each day.
4.
If a dose of Inqovi is missed within 12 hours of the time it was supposed to be taken, it should be 
taken as soon as possible. If it is past 12 hours, the dose should not be made up. Extend the 
dosing period by 1 day for every missed dose to complete the total number of daily doses for each 
cycle.
5.
You will take KPT-8602 once daily on Days 8-12 for all dose levels, and possibly on Days 13-21 
or on Days 15-19 dpending on the dose level you are assigned, during a 28-day cycle.
6.
If a dose of KPT-8602 is missed within 12 hours of the time it was supposed to be taken, it should 
be taken as soon as possible. If it is past 12 hours, the dose should not be made up. Extend the 
dosing period by 1 day for every missed dose to complete the total number of daily doses for each 
cycle.
7.
If you vomit after taking a dose of KPT-8602 and/or Inqovi, do not retake the dose.  Take the 
next dose of KPT-8602 and/or Inqovi at the regular schedule. 
8.
If you miss any doses please contact us. 
9.
Record the date, the number of tablets that you took, and when you took them. If you miss a dose, 
please record this also below. 
10. If you have any comments or notice any side effects, please record them in the ‘comments’ 
column.
11. On the days you are being seen in clinic, you must bring in your medication supply from home; 
however, you should not take your medication until instructed, as the blood draws must be timed 
with when you take your medication.
12. Please bring this form and your bottles (even it is empty) when you come for your clinic visits.
Study Drug
KPT-8602
INQOVI
Day
Date
Time
# of 
Tablets
Time
# of 
Tablets
Comments
1
None
None
2
None
None
3
None
None
4
None
None

Abbreviated Title: DELTA-MDS
101
Version Date: 10/30/2024
Study Drug
KPT-8602
INQOVI
Day
Date
Time
# of 
Tablets
Time
# of 
Tablets
Comments
5
None
None
6
None
None
None
None
7
None
None
None
None
8
None
None
9
None
None
10
None
None
11
None
None
12
None
None
13
None
None
14
None
None
15
None
None
16
None
None
17
None
None
18
None
None
19
None
None
20
None
None
21
None
None
22
None
None
None
None
23
None
None
None
None
24
None
None
None
None
25
None
None
None
None
26
None
None
None
None
27
None
None
None
None
28
None
None

Abbreviated Title: DELTA-MDS
102
Version Date: 10/30/2024
17.12 APPENDIX L: CONTROLLED MEDICATIONS FOR HIV, HEPATITIS B OR HEPATITIS C 
DISEASE CONTROL (CYP SUBSTRATES)
Hepatitis C:
➢Epclusa (sofosbuvir/velpatasvir), Velpatasvir
➢Vosevi (sofosbuvir/velpatasvir/voxilapresvir), Velpatasvir
➢Zepatier (Elbasvir/grazoprevir)
Hepatitis B:
➢N/A
HIV:
➢Efavirenz
➢Nevirapine
➢Rilpivirine
➢Ritonavir
➢Dolutegravir