Clinical trial NCT02416908
Conditions: Acute Myeloid Leukemia
Sponsor: Washington University School of Medicine
Start date: 2015-06-16; Completion date: 2019-06-21
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Selinexor has shown single-agent activity in a current phase I study enrolling patients with relapsed/refractory AML with durable complete remissions (CR), complete remissions with incomplete hematologic recovery (CRi), partial remissions (PR), and stable disease (SD) observed. Furthermore, common toxicities included nausea, fatigue, and anorexia and were manageable with supportive care agents. Additionally, CLAG chemotherapy has proven activity in relapsed and refractory AML, and has been shown to be a relatively well tolerated regimen without significant non-hematologic toxicity. Given the established role of CLAG chemotherapy, the single agent activity of selinexor, and their non-overlapping toxicities, the investigators propose a phase I/II open label study of selinexor in combination with CLAG for the treatment of patients with relapsed/refractory AML.

Detailed description:

Arms: arm 1: * Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO.
* Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
* Cladribine will be given 5 mg/m\^2/day IV once daily on Days 4-8.
* G-CSF will be given 300 mcg SC once daily on Days 3-8.
* Cytarabine will be given 2000 mg/m\^2/day IV once daily on Days 4-8.
* Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. arm 2: * Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO.
* Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
* Cladribine will be given 5 mg/m\^2/day IV once daily on Days 4-8.
* G-CSF will be given 300 mcg SC once daily on Days 3-8.
* Cytarabine will be given 2000 mg/m\^2/day IV once daily on Days 4-8.
* Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. arm 3: * Selinexor will be given at the schedule as determined in Phase 1.
* Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
* Cladribine will be given 5 mg/m\^2/day IV once daily on Days 4-8.
* G-CSF will be given 300 mcg SC once daily on Days 3-8.
* Cytarabine will be given 2000 mg/m\^2/day IV once daily on Days 4-8.
* Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.
Interventions: intervention 1: Selinexor intervention 2: Cladribine intervention 3: G-CSF intervention 4: Cytarabine intervention 5: Bone marrow biopsy
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version 08/22/17 
 
Page 1 of 61 
 
 
 
An Investigator Sponsored Phase I/II Study of CLAG + Selinexor in Relapsed or 
Refractory Acute Myeloid Leukemia 
 
 
Protocol#: 201505084 
 
Version Date: 08/22/17 
 
 
Sponsor and Principal Investigator: 
Geoffrey Uy, MD 
Phone: (314) 747-8439 
Email: guy@wustl.edu  
 
 
Sub-Investigators 
 
 
Modality 
 
John DiPersio, M.D., Ph.D.  
Medical Oncology  
Michael Rettig, Ph.D.  
 
Medical Oncology 
Kathryn Trinkaus, Ph.D. 
 
Biostatistics 
 
 
 
Study Drug:  
 
Selinexor (KPT-330) 
 
 
 
 
 
 
IND #: 
126367 
ClinicalTrials.gov#: 
NCT02416908 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 


Protocol Version 08/22/17 
 
Page 2 of 61 
An Investigator Sponsored Phase I/II Study of CLAG + Selinexor in Relapsed or 
Refractory Acute Myeloid Leukemia 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
05/15/2015 
Amendment #1 Version 
 
 
 
 
 
 
08/07/2015 
Amendment #2 Version  
 
 
 
 
 
 
12/20/2016 
Amendment #3 Version 
 
 
 
 
 
 
08/22/2017


Protocol Version 08/22/17 
 
Page 3 of 61 
An Investigator Sponsored Phase I/II Study of CLAG + Selinexor in Relapsed or 
Refractory Acute Myeloid Leukemia 
 
SCHEMA 
 
Design Overview:   This phase I/II investigator sponsored study will consist of a phase I 
portion (N= maximum of 24 patients) that evaluates an initial dosing 
schedule (Schedule A) followed by a more intense dosing schedule 
(Schedule B) at the same dose of selinexor.  Once the optimal schedule is 
determined, the phase II study will evaluate the efficacy of this schedule in 
40 patients (inclusive of 12 phase I patients), for a maximum total study 
population of 52 patients.  Optional maintenance phase of single-agent 
selinexor is also allowed.  All dosing cycles are 28 days long and the DLT 
evaluation period for phase I is during Cycle 1 of Schedules A and B.  
Prolonged myelosuppression, i.e., marrow cellularity < 5% on Day 42 or 
later (6 weeks) from start of Cycle 1 without any evidence of leukemia, 
will also be considered a DLT. 
 
The phase I study uses a Bayesian design and allows for a 6 patient 
schedule de-escalation cohort in addition to the dosing of 6 patients on 
each schedule. The phase II portion was designed to compare the primary 
endpoint of complete remission rate (CR + CRi) with an historical rate of 
33%.  With a sample size of 40, it will have 80% power (0.05 significance 
level) to detect a difference from the historical rate if the study observes a 
CR/CRi rate ≥ 0.55. 
 
Phase I Schedule A:  Selinexor will be dosed on Days 1, 5, 10, and 12 of 
the 28-day cycle.  All doses will be 60 mg each. 
 
Phase I Schedule B:  Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 
19 of the 28-day cycle.  All doses will be 60 mg each. 
 
Phase II:  Selinexor will be given at the schedule as determined in phase I.   
 
Selinexor (S): 
Selinexor will be administered at 60 mg PO 
Cladribine (CL): 
5 mg/m2/day IV once daily on Days 4-8 
G-CSF (G): 
300 mcg SC once daily on Days 3-8 
Cytarabine (A): 
2000 mg/m2/day IV once daily on Days 4-8 
Bone marrow 
biopsy/aspirate 
(BM): 
 
Will be performed at baseline/screening, on Day 3, at the time of 
hematopoietic recovery, and as clinically indicated to assess treatment 
response. Additionally, samples will be banked for genomic studies 
indicated to document presence of persistent disease. 
Peripheral blood 
(PB):
Will be performed at baseline/screening, on Day 3, on Day 5, on Day 
7, and at the time of hematopoietic recovery.


Protocol Version 08/22/17 
 
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The initial cohort of patients (N=6) will be dosed according to Schedule A.  If dose limiting 
toxicities (DLTs) are not experienced with the initial cohort of patients, then dosing will be 
intensified whereby a further cohort of patients (N=6) will be treated with Schedule B dosing. 
The phase II dosing schedule will be the most intense schedule in which ≤3 DLTs are observed 
in 12 patients treated using that schedule. Patients in the phase I portion of the study treated at 
the MTD will count towards the phase II accrual goal for evaluation of the primary endpoint.   
Phase II will include a sample size of 40 patients. 
 
Schedule A dosing: 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
S 
 
 
 
S 
 
 
 
 
S 
 
S 
 
 
 
G 
G 
G 
G 
G 
G 
 
 
 
 
 
 
 
 
A 
A 
A 
A 
A 
 
 
 
 
 
 
 
 
CL 
CL 
CL 
CL 
CL 
 
 
 
 
BM 
 
 
BM 
 
 
 
 
 
 
 
PB 
 
 
PB 
 
PB 
 
PB 
 
 
 
 
 
 
Schedule B dosing: 
Day
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
17 
19 
 
S 
 
 
 
S 
 
 
 
 
S 
 
S 
S 
S 
 
 
 
G 
G 
G 
G 
G 
G 
 
 
 
 
 
 
 
 
 
 
A 
A 
A 
A 
A 
 
 
 
 
 
 
 
 
 
 
CL 
CL 
CL 
CL 
CL 
 
 
 
 
 
 
BM 
 
 
BM 
 
 
 
 
 
 
 
 
 
PB 
 
 
PB 
 
PB 
 
PB 
 
 
 
 
 
 
 
 
In both the phase I and II portions of the study, patients are candidates for selinexor single agent 
maintenance therapy if they have achieved a CR or CRi based on post-treatment bone marrow 
assessment at the time of hematopoietic recovery and are either (1) transplant ineligible (defined 
in Section 5.6) or (2) do not have a stem cell transplant donor available.  Prior to initiating 
maintenance therapy with selinexor, a bone marrow biopsy must confirm the presence of the CR 
or CRi. Maintenance therapy consists of 60mg selinexor on Days 1, 8, 15, and 22 of a 28 day 
cycle (4 doses per cycle), continuously until disease relapse, unacceptable toxicity, death, or the 
institution of additional antileukemic therapy including stem cell transplantation or donor 
leukocyte infusion.  
 
Maintenance dosing: 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
S 
 
 
 
 
 
 
S 
 
 
 
 
 
 
Day
15 
16
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
 
S 
 
 
 
 
 
 
S 
 
 
 
 
 
 


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Table of Contents 
SCHEMA ........................................................................................................................................ 3 
 
BACKGROUND AND RATIONALE ............................................................................ 7 
 
Acute Myeloid Leukemia ................................................................................... 7 
 
Nuclear Export .................................................................................................... 8 
 
Selinexor (KPT-330), a Selective Inhibitor of Nuclear Export / SINETM 
Compound 
…………………………………………………………………………………..9 
 
Study Rationale ................................................................................................. 13 
 
Rationale for Doses and Dosing Regimen ........................................................ 14 
 
Planned Correlative Studies .............................................................................. 15 
 
OBJECTIVES ................................................................................................................ 16 
 
Primary Objectives............................................................................................ 16 
 
Secondary Objectives........................................................................................ 16 
 
Exploratory Objectives ..................................................................................... 16 
 
PATIENT SELECTION ................................................................................................ 17 
 
Inclusion Criteria .............................................................................................. 17 
 
Exclusion Criteria ............................................................................................. 18 
 
Inclusion of Women and Minorities ................................................................. 19 
 
REGISTRATION PROCEDURES ............................................................................... 19 
 
Confirmation of Patient Eligibility ................................................................... 19 
 
Patient Registration in the Siteman Cancer Center OnCore Database ............. 19 
 
Assignment of UPN .......................................................................................... 20 
 
TREATMENT PLAN .................................................................................................... 20 
 
Screen Failures .................................................................................................. 20 
 
General Considerations ..................................................................................... 20 
 
Ophthalmic Assessment .................................................................................... 20 
 
Overall Treatment Plan ..................................................................................... 21 
 
Definition of  MTD, DLT, Dose Escalation Criteria, and Patient Evaluability 22 
 
Selinexor Maintenance Therapy for Patients who Achieve CR/CRi ................ 24 
 
Assessment of Ineligibility for Stem Cell Transplant ....................................... 24 
 
Supportive Care Guidelines .............................................................................. 25 
 
Prevention of Pregnancy ................................................................................... 26 
 
Duration of Therapy .......................................................................................... 26 
 
Removal from Study ......................................................................................... 27 
 
Patient Replacement.......................................................................................... 27 
 
Duration of Follow-up ...................................................................................... 27 
 
DOSE DELAYS/DOSE MODIFICATIONS ................................................................ 28 
 
Conditions not Requiring Selinexor Dose Reduction ....................................... 32 
 
Missed or Vomited Doses ................................................................................. 32 
 
REGULATORY AND REPORTING REQUIREMENTS ........................................... 33 
 
Definitions......................................................................................................... 33 
 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
…………………………………………………………………………………35 
 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University ........................................................................................ 36 
 
Reporting to the FDA........................................................................................ 36 


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Reporting to Karyopharm ................................................................................. 36 
 
Classification of Adverse Events by Causality ................................................. 37 
 
Other Safety Reporting ..................................................................................... 37 
 
Timeframe for Reporting Required Events....................................................... 38 
 
PHARMACEUTICAL INFORMATION ...................................................................... 38 
 
Selinexor (KPT-330) ......................................................................................... 38 
 
Cytosine Arabinoside (AraC, Cytarabine) ........................................................ 39 
 
Cladribine (Leustatin) ....................................................................................... 41 
 
Filgrastim (G-CSF, Neupogen) ......................................................................... 42 
 
CORRELATIVE STUDIES .......................................................................................... 43 
 
Sample Collection ............................................................................................. 43 
 
Sample Handling ............................................................................................... 44 
 
STUDY CALENDAR ................................................................................................... 45 
 
DATA SUBMISSION SCHEDULE ............................................................................. 46 
 
MEASUREMENT OF EFFECT.................................................................................... 46 
 
Disease Parameters ........................................................................................... 46 
 
Response Criteria .............................................................................................. 46 
 
DATA AND SAFETY MONITORING ........................................................................ 48 
 
STATISTICAL CONSIDERATIONS........................................................................... 49 
 
Statistical and Analytical Plans ......................................................................... 49 
 
REFERENCES .............................................................................................................. 51 
Appendix 1: ECOG Performance Status Scale ............................................................................. 54 
Appendix 2: NCCN Clinical Practice Guidelines in Oncology: Anorexia/Cachexia ................... 55 
Appendix 3: NCCN Clinical Practice Guidelines in Oncology: Antiemesis ................................ 56 
Appendix 4: glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-acetylcysteine (NAC)-
containing products (representative List)...................................................................................... 59 
Appendix 5: Cataract Clinical Grading Scale ............................................................................... 61 
 
 


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BACKGROUND AND RATIONALE 
 
 
Acute Myeloid Leukemia 
 
Acute myeloid leukemia (AML) represents a heterogeneous group of diseases 
characterized by infiltration of the bone marrow, blood, and other tissues by neoplastic 
hematopoietic cells.  It represents the most common form of acute leukemia in adults, 
with an estimated 11,930 new cases in the United States each year.1  The median age at 
presentation is 65, with a male:female ratio of approximately 5:3.2  Without treatment, 
the disease ultimately progresses and is rapidly fatal within months.3 
 
AML can be further classified based on molecular genetic and chromosomal 
abnormalities.  Additionally other factors like age, performance status, presence of de-
novo versus secondary AML, and laboratory parameters influence prognosis.3,4   
 
Standard induction chemotherapy in AML consists of the “7+3” regimen with 7 days of 
continuous infusion cytarabine and 3 days of daunorubicin or idarubicin.  This approach 
is followed by consolidation therapy including a hematopoietic stem cell transplant 
(HSCT) in those with high-risk disease.  Intensive treatment regimens lead to complete 
remission (CR) in 60-80% of younger patients with de novo AML.5  Unfortunately, for 
elderly patients (defined as those over age 60) CR rates are generally 40-50% with such 
therapy.6  The median overall survival for those not attaining a CR is less than one year, 
with patients often succumbing to fatal complications related to bone marrow aplasia and 
impaired hematopoietic recovery.7    
 
For those that do attain a CR, the majority will recur within three years of diagnosis.8  
The prognosis for those with relapsed or refractory AML remains poor.  Aside from 
patients with specific AML subtypes (core-binding factor positive AML and acute 
promyelocytic leukemia), those with relapsed or primary refractory AML are unlikely to 
be cured without an allogeneic stem cell transplant.  While select patients may move on 
to allogeneic stem cell transplant in first relapse, the majority will require reinduction 
chemotherapy prior to transplantation in order to attain disease control. In general, factors 
such as the duration of first remission, FLT3 mutational status, and the presence of high-
risk cytogenetics have borne out as major prognostic markers in determining who is 
likely to respond to salvage chemotherapy.9  Specifically, patients relapsing within one 
year of achieving a first remission and those patients who have unsuccessfully received a 
prior salvage regimen are unlikely to experience a second complete remission (CR rates 
0-20%).10,11   
 
Commonly utilized salvage regimens include high dose cytarabine alone; fludarabine, 
cytarabine, and G-CSF (FLAG); mitoxantrone, cytarabine, and etoposide (MEC); 
cladribine, cytarabine, and G-CSF (CLAG); and, for those who attained a long disease 
remission, initial induction therapy may be used as a salvage regimen.12-15  Despite 
advances in supportive care and chemotherapy, 2 year overall survival is still poor in this 
population (12-58%); thus novel treatment approaches are needed for remission 
induction.9 


Protocol Version 08/22/17 
 
Page 8 of 61 
 
In a single-center retrospective study of salvage chemotherapy in relapsed/refractory 
AML, the CLAG regimen showed a CR rate of 38% with an approximately 10% 30-day 
death rate.16  
 
 
Nuclear Export 
 
It has been shown that neoplasms must inactivate most or all of the major tumor 
suppressor proteins (TSP) and growth regulatory proteins (GRP) in order to perpetuate 
their phenotypes.17 The vast majority of TSP and GRP require nuclear localization in 
order to carry out their antineoplastic and regulatory activities and therefore nuclear 
export leads to their functional inactivation. Nuclear import and export is a tightly 
regulated process facilitated by shuttle proteins in eukaryotic cells. There are over 15 
nuclear import proteins, or importins, but only seven nuclear export proteins, or exportins 
(Exportins 1-7). The protein Exportin 1 (XPO1, also called CMR1) is known to be 
largely responsible for the export of major TSP and other growth modulators.  
Furthermore, XPO1 levels have been shown to be elevated in both solid and hematologic 
malignancies and higher levels generally correlate with poorer prognosis.18-23   It appears 
that tumor cells have co-opted XPO1 to move TSP and GRP out of the nucleus, thereby 
neutralizing their anti-neoplastic functions.   
 
XPO1 inhibitors block the nuclear export of key TSP, thereby leading to accumulation of 
these proteins in the nucleus, as nuclear import appears to proceed unimpeded. It has 
been shown that nuclear retention appears to prevent proteasome-mediated degradation 
(which is typically cytoplasmic). Forced nuclear retention of TSP and GRP can 
counteract a number of oncogenic (and inflammatory) pathways that perpetuate the 
neoplastic phenotype (Table 1.1). Moreover, certain proteins, specifically survivin and 
p21CIP1 can be anti-apoptotic when localized to the cytoplasm and therefore forcing their 
nuclear retention with XPO1 inhibition can prevent their anti-apoptotic functions, and in 
the case of p21, expose its antitumor activities.24,25 
 
Table 1.1 
Effect of XPO1 Inhibition on Oncogenic and Inflammatory Pathways 
Pathway Affected
Effect of XPO1 Inhibition
Reference
p53 mutation
p73 activation, p21 activation
26
MDM2 activation
Nuclear p53 retention and activation
23
NPM1 mutation
Restoration of nuclear NPM1
33
CEBPA down-regulation
Nuclear retention and activation
26
XPO1 overexpression
XPO1 reduction
34
FLT3 activation
FLT3 reduction
26
KIT activation
KIT reduction
26
NF-B activation
IB nuclear retention and activation
21 
PIK3 or AKT activation
FOXO1, -3, -4 activation
21
Survivin – cytoplasmic
Survivin nuclear retention
35
Bcr-Abl activation
PP2A activation
34
 
 
 


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Selinexor (KPT-330), a Selective Inhibitor of Nuclear Export / SINETM Compound 
 
Selinexor is an oral, first in class, slowly-reversible, potent and Selective Inhibitor of 
Nuclear Export / SINETM compound that specifically blocks the protein Exportin 1 
(XPO1), also known as chromosomal region maintenance 1 (CRM1).  To date, other than 
XPO1, no targets of selinexor have been identified and XPO1 is overexpressed 2-4 fold 
in all cancers studies to date. 
 
Selinexor restores many of the TSP and GRPs to the nucleus where they can carry out 
their normal regulatory and anti-tumor functions. Selinexor has shown to be selectively 
cytotoxic for cells with genomic damage, i.e., for tumor cells, both in vitro and in vivo. 
The nuclear export of eIF4E, a protein that binds to the mRNAs of many oncogenic and 
growth-promoting mediators, requires XPO1 for transport to cytoplasmic ribosomes.  
Selinexor blocks the XPO1-mediated nuclear export of eIF4E, preventing translation of 
the eIF4E-bound mRNAs on ribosomes, with a reduction in levels of the cognate 
oncogenic and growth-promoting proteins.   
 
All cell types exposed to SINETM in vitro undergo G1/S ± G2/M cell cycle arrest, 
followed by a ‘genomic fidelity’ review, and cells with damaged genomes are induced to 
undergo apoptosis. Normal cells, with an intact genome, remain in transient, reversible 
cell cycle arrest until the export block is relieved. Selinexor and other SINETM 
compounds are not directly cytotoxic to cells; rather, they can restore the highly effective 
tumor suppressing pathways that lead to selective elimination of genetically damaged 
(i.e., neoplastic) cells. Hematopoietic tumors are particularly susceptible to induction of 
apoptosis by XPO1 inhibition whereas normal hematopoietic cells and their functions are 
largely spared. 
 
 Preclinical Information 
 
AML cells overexpress the nuclear exporter, Exportin 1 (XPO1/CRM1) and 
higher XPO1 levels generally correlate with poor outcome.23  The novel Selective 
Inhibitor of Nuclear Transport / SINETM, selinexor, antagonizes XPO1 and shows 
potent cytotoxicity for AML and ALL cells in vitro, independent of genotype.  
 
Selinexor shows potent antiproliferative effect and induced apoptosis, cell cycle 
arrest and myeloid differentiation in AML cell lines and patient blasts, including 
those from patients with NPM1 and FLT3-ITD mutations.26  
 
Mechanistic studies show that SINETM compounds induce nuclear localization and 
activation of multiple TSPs, leading to rapid apoptosis of AML cells.  In addition, 
a strong down-regulation of the oncogenes FLT3 and c-KIT were observed after 
SINETM treatment in both FLT3-ITD and wild-type cell lines.26 Selinexor 
treatment also restored the localization of cytoplasmic mutant NPM1 into the 
nucleus.  
 


Protocol Version 08/22/17 
 
Page 10 of 61 
In murine AML and acute lymphoblastic leukemia (ALL) models, selinexor 
showed potent antileukemic activity without toxicity to normal hematopoietic 
cells.26,27  
 
In vitro experiments with continuous (~72 hour) exposure to selinexor 
demonstrated potent proapoptotic activity across a broad panel of tumor-derived 
cell lines and patient samples in culture including multiply-resistant cancers, with 
the majority of inhibitory concentrations, 50% (IC50s) for cytotoxicity < 800 nM 
and most hematologic tumor lines having IC50s of 20-400 nM for selinexor. 
Moreover, selinexor demonstrated cytotoxicity in multiple myeloma (MM) and 
chronic lymphocytic leukemia (CLL) cells in the absence or presence of bone 
marrow stroma cells (BMSC). In contrast, normal cells typically underwent (or 
remained in) cell cycle arrest but were resistant to apoptosis-induction; 
cytotoxicity IC50s were typically > 5 μM. As noted above, selinexor had little 
effect on normal (nonmalignant) lymphocytes or other nontransformed cells, 
which correlated with the low incidence in animals of the typical side effects seen 
with most anti-cancer therapies such as significant myelosuppression, alopecia, 
mucositis and other gastrointestinal (GI) dysfunction. 
 
Selinexor, as well as other SINE™ compounds, was administered in efficacy 
studies to mice and dogs and in toxicology studies to rats and monkeys.  The 
dosing regimen was every other day x 3 each week (QoD x3/wk); anti-tumor 
activity has also been shown with twice weekly (BIW, Days 1 and 4 of each 
week) dosing.  Efficacy was demonstrated at doses of 5-20 mg/kg (15-60 mg/m2) 
in mouse models of myeloma, mantle cell lymphoma (MCL), and T-cell acute 
lymphocytic leukemia (T-ALL) xenografts.  
  
Selinexor demonstrated efficacy in numerous preclinical models of hematological 
and solid tumors (Azmi et al., 2013a; Azmi et al., 2013b; Cheng et al., 2014; 
Etchin et al., 2013a; Fragomeni et al., 2013; Tai et al., 2014; Walker et al., 2013).  
Selinexor treatment resulted in significant survival advantages in models of MM, 
NHL, CLL, AML and ALL.  Selinexor also demonstrated robust single agent 
efficacy in solid tumor xenografts including: prostate, breast, melanoma, colon, 
ovarian, neuroblastoma and several sarcomas.  In addition, marked synergy was 
observed when selinexor was used with a variety of chemotherapies and targeted 
therapies including platinums, taxanes, topoisomerase I and II inhibitors, 
dexamethasone, cytarabine, proteasome inhibitors and various tyrosine kinase 
inhibitors (TKIs).  
 
Preclinical parameters were assessed in three species: mouse (CD1), rat (Sprague-
Dawley), and monkey (cynomolgus). While pharmacokinetic (PK) studies were 
limited to male animals for all three species, toxicokinetic (TK) evaluations were 
conducted in both sexes for rats and monkeys as part of the selinexor toxicology 
studies, and no consistent sex-related differences were observed in either species. 
No accumulation was observed in any of the multi-dose toxicology studies with 
an every other day dosing regimen for selinexor. Overall, systemic exposure was 


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Page 11 of 61 
generally dose-proportional in all TK studies that involved multiple dose levels. 
Higher maximum concentration (Cmax) and earlier time to maximum 
concentration (Tmax) values were observed in monkeys that were fasted versus fed 
prior to dosing. Systemic exposure (area under the curve from first to last plasma 
measurement, AUClast) to selinexor achieved with gelatin capsules was 
comparable to that achieved with oral suspension dosing, with lower Cmax and 
later Tmax values observed with capsules, and was not affected by the feeding 
status in monkeys. Oral bioavailability (F%) of selinexor was remarkably 
consistent among the three species, with average values of 66.5%, 61.2%, and 
67.5% in mice, rats, and monkeys, respectively. See the Selinexor Investigator’s 
Brochure for more information. 
 
Nonclinical toxicology studies indicated that the major side effects (dose limiting 
toxicities, DLTs) across all species are reduced appetite with anorexia-induced 
weight loss partially consistent with satiety induction.  High calorie foods and 
glucocorticoids can mitigate weight loss in animals taking SINETM compounds.  
 
 Clinical Experience 
 
Study KCP-330-001 is a Phase 1, open-label, dose-escalation study to evaluate 
the safety and tolerability of oral selinexor and determine the recommended phase 
II dose in patients with advanced hematological malignancies. Arm 1 of this study 
includes patients with “chronic” hematological malignancies including multiple 
myeloma (MM), Waldenström’s Macroglobulinemia (WM), Non-Hodgkin’s 
Lymphoma (NHL) and chronic lymphocytic leukemia (CLL). 2 patients were 
enrolled in cohort 1 with dose escalation of 100% increase from cohort 1 to 2. 
Cohort 2 enrolled at least 3 patients with dose escalation of 100% increase from 
cohort 2 to 3. For cohorts 3 and beyond, a standard 3+3 design was used with 
dose escalation increase of 30-40% from the previous cohort.   
 
Arm 2 includes patients with acute myeloid leukemia (AML) except M3 subtype. 
Due to the rapidly progressive nature of AML, Arm 2 began dosing at 16.8 mg/m2 
after dose limiting toxicity (DLT) clearance of 12 mg/m2 in cohort 3 and after 
dosing at 16.8 mg/m2 was employed in cohort 4 of the Chronic hematological 
malignancies portion of the study. A standard 3+3 design was used with a dose 
escalation increase of 30-40% from previous cohort. Arm 3 includes up to 12 
patients with relapsed/refractory Peripheral T-cell lymphoma (PTCL) or 
Cutaneous T-cell lymphoma (CTCL) treated at a dose of 30 mg/m2 twice weekly. 
 
As of 10 June 2014, a total of 186 patients have been enrolled in this study, with 
65 patients on Arm 2 (AML) enrolled at ten clinical centers in the USA, Canada, 
and Denmark, and treated at doses ranging from 3 mg/m2 to 70 mg/m2 on 
Schedule 2 or Schedule 3 (10 or 8 doses/cycle).  As of 10 June 2014, 6 AML 
patients remain on study treatment. 
   


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Overview of Clinical Efficacy in AML. In Arm 2 (AML), 32 of the 48 patients 
(67%) evaluated as of 10 June 2014 have experienced a complete remission (CR), 
complete remission without platelet recovery (CRi), partial response, morphologic 
leukemia free state or stable disease (SD).  Seven patients experienced a CR or 
CR(i).  Five of these patients experienced a CR, while the other two patients 
experienced a CR(i).  As of 10 June 2014, 1 patient has experienced a partial 
response, two of these patients showed a morphologic leukemia free state, 22 
patients are showing SD.  Seventeen patients were non evaluable as of 10 June 
2014. Responses for the 48 patients who had been evaluated as of 10 June 2014, 
each of whom received a dose between 16.8 mg/m2 to 70 mg/m2 per cycle, are 
shown in Table 1.2. 
 
Table 1.2 
Responses in Arm 2 (AML) [16.8 mg/m2 to 70 mg/m2] as of 10 June 2014 (Study 
KCP-330-001) 
Number of 
Patients 
Evaluated 
Total CRs, 
CR(i)s, PR 
and SD (%) 
CR (%) 
CR(i) (%) 
PR /MLFS 
(%) 
SD (%) 
PD (%) 
WC (%) 
48 
32 (67%) 
5 (10%) 
2 (4%) 
3 (6%) 
22 (46%) 
16 (33%) 
2 (4%) 
Abbreviations: N=number of patients, CR=complete remission, CRi=complete remission without platelet recovery, 
PR/MLFS= partial response / morphologic leukemia free state, SD=stable disease, PD=progressive disease, 
WC=withdrew consent.   
 
Overview of Clinical Safety in AML. Gastrointestinal adverse events and fatigue 
are the most common types of AEs seen in Arm 2 (AML) patients.  As of 2 May 
2014, Karyopharm has reports of AEs in 54 of the 65 patients enrolled in this arm 
and the AE prevalence percentages below are based upon 65 patients.  As of 2 
May 2014, the gastrointestinal adverse events typically consist of nausea in 27 
patients (42%), anorexia in 26 patients (42%), diarrhea in 23 patients (35%), 
vomiting in 17 patients (26%), and weight loss in 11 patients (17%). The 
gastrointestinal events are primarily Grade 1 or Grade 2 events that are generally 
responsive to standard supportive care.  Fatigue was observed in 31 patients in 
this arm (48%) as of 2 May 2014, including Grade 3 fatigue in five patients (8%) 
and Grade 1 or Grade 2 fatigue in 26 patients (40%).  Karyopharm observed 
Grade 4 thrombocytopenia in four patients (6%) in this arm as of 2 May 2014.  
Karyopharm expects that the thrombocytopenia is primarily a result of patients 
entering this arm with marked bone marrow suppression due to both disease and 
prior therapies.  Karyopharm also observed Grade 4 neutropenia in four patients 
(6%) and Grade 4 anemia in one patient (>2%). 
 
It is anticipated that fewer and more mild gastrointestinal events and reduced 
fatigue will be observed in the future as a result of the initiation of supportive care 
and medications prior to beginning selinexor therapy. 
 
 Potential Risks 
 
Selinexor is currently in clinical development and has not been approved by the 
Food and Drug Administration (FDA) for commercial use. Human experience 


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with Selinexor is currently limited and the entire safety profile is not known at 
this time. Measures will be taken to ensure the safety of the patients participating 
in this trial, including the use of stringent inclusion and exclusion criteria and 
close monitoring. Toxicity grading will be performed in accordance with National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) 4.03. If more than one different type of toxicity occurs concurrently, 
the most severe grade will determine the modification. 
 
If toxicities are encountered, adjustments will be made to the study treatment as 
detailed in the sections below. All adverse events (AEs) and serious adverse 
events (SAEs) will be recorded during the trial and for up to 30 days after the last 
dose of study treatment or until the initiation of another anti-cancer therapy, 
whichever occurs first. 
 
Please refer the Investigator’s Brochure for the most up-to-date information. 
 
Reproductive risks 
Patients should not become pregnant or father a baby while on this study because 
the drugs in this study can affect an unborn baby. Women should not breastfeed a 
baby while on this study. It is important patients understand the need to use birth 
control while on this study. It is not anticipated that female patients enrolling in 
this study will be able to conceive. However, in the rare event that this is possible, 
female patients of child-bearing potential must agree to use dual methods of 
contraception and have a negative serum pregnancy test at screening, and male 
patients must use an effective barrier method of contraception if sexually active 
with a female of child-bearing potential. Acceptable methods of contraception are 
condoms with contraceptive foam, oral, implantable or injectable contraceptives, 
contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a 
sexual partner who is surgically sterilized or post-menopausal. For both male and 
female patients, effective methods of contraception must be used throughout the 
study and for three months following the last dose. 
 
 
Study Rationale 
 
Selinexor has shown single-agent activity in a current phase I study enrolling patients 
with relapsed/refractory AML with durable complete remissions (CR), complete 
remissions with incomplete hematologic recovery (CRi), partial remissions (PR), and 
stable disease (SD) observed.  Furthermore, common toxicities included nausea, fatigue, 
and anorexia and were manageable with supportive care agents.  Additionally, CLAG 
chemotherapy has proven activity in relapsed and refractory AML, and has been shown 
to be a relatively well tolerated regimen without significant non-hematologic 
toxicity.16,28,29 Given the established role of CLAG chemotherapy, the single agent 
activity of selinexor, and their non-overlapping toxicities, we propose a phase I/II open 
label study of selinexor in combination with CLAG for the treatment of patients with 
relapsed/refractory AML.     
 


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Rationale for Doses and Dosing Regimen 
 
Greater than 450 patients with advanced cancers have been treated with oral selinexor in 
three Phase I studies.  KCP-330-001 is a dose escalation study in patients with advanced 
hematologic malignancies including AML.  KCP-330-002 is a dose escalation study in 
patients with advanced solid tumors. KCP-330-003 is a food effect study in patients with 
advanced sarcomas.  Ten doses per 4-week cycle of selinexor were initially evaluated in 
studies. With this dosing regimen, the DLTs were anorexia, nausea, and fatigue at 40 
mg/m2 in KCP-330-002 and the maximum tolerated dose (MTD) was 30 mg/m2 using 
this regimen. However, pharmacodynamics analyses suggest that at doses > 12 mg/m2, 
selinexor inhibits XPO1 activity for > 48 hrs. Therefore, reduced intensity dosing at twice 
weekly was evaluated and subsequently showed improved tolerability with observed anti-
cancer activity.  
 
Selinexor therapy will be dosed based on a fixed oral dose of 60mg of selinexor, roughly 
equivalent to 35 mg/m2.  To ensure that no patient will be dosed at a dose >70mg/m2, the 
study will be limited to patients with a body surface area (BSA) (calculated by Dubois 
method) >1.43 m2. This dosing regimen is supported by the accumulated PK data to date 
(Figure 1.1) and summarized below.  
The 5th and 95th percentile for BSA values encountered to date in Phase 1 trials KCP-
330-001 and KCP-330-002 are 1.5 and 2.3 m2, respectively (N=331).  For this range, flat 
doses of 60 mg and 100 mg of selinexor translate to BSA normalized dose ranges of 27-
40 mg/m2 and 43-70 mg/m2, respectively.  To evaluate PK for flat doses of 60 mg and 
100 mg of selinexor, Cmax and AUC(0-∞) values were compared for the equivalent, 
typical BSA-normalized dose ranges (Figure 1.1).  Both Cmax and AUC(0-∞) were 
found to be significantly different (p<0.0001) for 60 mg and 100 mg of selinexor.  
Therefore, we conclude that 60 mg and 100 mg selinexor doses are expected to provide 
significantly different PK results. 


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Figure 1.1 
Pharmacokinetic Results for 60 mg and 100 mg selinexor Doses 
 
 
Comparison of Cmax and AUC(0-∞) for 60 mg and 100 mg selinexor doses based upon data from BSA-
normalized doses for the typical range of BSA encountered in Phase 1 trials KCP-330-001 and KCP-330-
002.  Lines on plots represent mean and standard deviation P values are based upon unpaired t-test without 
assuming equal standard deviation. 
 
 
Planned Correlative Studies 
 
These summaries are not meant to be comprehensive but rather provide a high level 
overview of the correlative research undertaken here. 
 
As selinexor induces cell cycle arrest and rapid apoptosis, we will quantify the bone 
marrow blast percentage, annexin V/7AAD, and cell cycle status in these samples by 
flow cytometry approximately 48 hours after selinexor administration through bone 
marrow aspirate and peripheral blood studies on Day 3. 
 
To evaluate XPO1 expression, we will perform western blot and qRT-PCR assays for 
XPO1 using flow sorted AML blasts (CD45dimSSClo). 
 
In order to further evaluate nuclear transport inhibition, we will examine if selinexor 
induces nuclear accumulation of some targets (p53, NPM, Fox03a, IκB, others) in AML 
blasts. 
 
Pharmacokinetic analysis will be analyzed for the concentration of selinexor using a 
validated HPLC/MS-MS method through bone marrow aspirate and peripheral blood 
28-40 mg/m2
45-70 mg/m2
0
200
400
600
800
1000
1200
2100
2300
selinexor dose
Cmax (ng/mL)
60 mg (N=80)
100 mg (N=40)
p<0.0001
28-40 mg/m2
45-70 mg/m2
0
3000
6000
9000
12000
15000
selinexor dose
AUC0-¥ (h*ng/mL)
p<0.0001
60 mg (N=76)
100 mg (N=35)


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studies on Day 3. Potential covariates include, but are not limited to: age, body weight, 
gender, disease state, baseline hepatic or renal function, and concomitant medications. 
Pharmacodynamic biomarkers, including XPO1 inhibition may be added as covariates in 
the PK analysis in order to investigate potential pharmacokinetic/pharmacodynamics 
relationships. 
 
 
OBJECTIVES 
 
 
Primary Objectives 
 
Phase I: To determine the safety and tolerability of selinexor + CLAG in patients with 
relapsed or refractory AML that requires treatment. 
 
Phase II: To determine the complete remission rate (CR + CRi) for selinexor + CLAG in 
patients with relapsed or refractory AML that requires treatment. 
 
 
Secondary Objectives 
 
1. To determine the time to hematologic recovery (neutrophils and platelets) of patients 
with relapsed or refractory AML treated with selinexor + CLAG. 
 
2. To determine the event-free survival of patients with relapsed or refractory AML 
treated with selinexor + CLAG. 
 
3. To determine the duration of remission of patients with relapsed or refractory AML 
treated with selinexor + CLAG. 
 
4. To determine the relapse-free survival of patients with relapsed or refractory AML 
treated with selinexor + CLAG. 
 
5. To determine the overall survival of patients with relapsed or refractory AML treated 
with selinexor + CLAG. 
 
6. To determine the number of patients with relapsed or refractory AML treated with 
selinexor + CLAG who were able to undergo hematopoietic stem cell transplantation  
 
 
Exploratory Objectives 
 
1. To characterize the effects of selinexor on nuclear transport inhibition and changes in 
XPO1 expression of patients with relapsed or refractory AML treated with selinexor 
+ CLAG. 
 
2. To evaluate the effects of selinexor on cell cycle arrest and apoptosis in patients with 
relapsed or refractory AML treated with KPT-330. 
 
3. To determine the pharmacokinetics and pharmacodynamics of selinexor. 


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PATIENT SELECTION 
 
 
Inclusion Criteria 
 
1. Histologically confirmed AML (defined using WHO criteria) with one of the 
following: 
a. Primary refractory disease following ≤ 2 cycles of induction chemotherapy, or  
b. First relapse with no prior unsuccessful salvage chemotherapy, or 
c. Relapsed or refractory to hypomethylating agent, defined as a lack of 
response, disease progression, loss of response, or intolerance as deemed by 
the study investigator 
 
2. Age between 18 and 70 years old. 
 
3. ECOG performance status ≤ 3 (see Appendix 1). 
 
4. Adequate organ function as defined below: 
a. AST(SGOT), ALT(SGPT), total bilirubin ≤ 2 x IULN except when in the 
opinion of treating physician is due to direct involvement of leukemia (eg. 
hepatic infiltration or biliary obstruction due to leukemia) or Gilbert’s disease 
b. Creatinine clearance >50 ml/min, calculated using the formula of Cockroft 
and Gault: (140-Age) x Mass (kg) / (72 x Creatinine mg/dL); multiply by 0.85 
if female.  
c. Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram 
 
5. To ensure that no patient will receive a dose of selinexor >70mg/m2, body surface 
area (BSA) calculated by Dubois method must be >1.43 m2 
 
6. Patients should not become pregnant or father a baby while on this study because the 
drugs in this study can affect an unborn baby. Women should not breastfeed a baby 
while on this study. It is important patients understand the need to use birth control 
while on this study. It is not anticipated that female patients enrolling in this study 
will be able to conceive. However, in the rare event that this is possible, female 
patients of child-bearing potential must agree to use dual methods of contraception 
and have a negative serum pregnancy test at screening, and male patients must use an 
effective barrier method of contraception if sexually active with a female of child-
bearing potential. Acceptable methods of contraception are condoms with 
contraceptive foam, oral, implantable or injectable contraceptives, contraceptive 
patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is 
surgically sterilized or post-menopausal. For both male and female patients, effective 
methods of contraception must be used throughout the study and for three months 
following the last dose. 
 
7. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
 


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Exclusion Criteria 
 
1. Acute promyelocytic leukemia (AML with t(15;17)(q22;q11) and variants). 
 
2. Previous treatment with CLAG or other chemotherapy regimen containing both 
cladribine and cytarabine. 
 
3. Colony stimulating factors within 2 weeks of study. 
 
4. Active graft versus host disease (GVHD) after allogeneic stem cell transplantation. At 
least 2 months must have elapsed since completion of an allogeneic stem cell 
transplantation. 
 
5. Less than 7 days from the completion of any previous cytotoxic chemotherapy (with 
the exception of hydroxyurea). 
 
6. Concurrent active malignancy under treatment except prostate or breast cancer 
undergoing treatment with hormonal therapy. 
 
7. Treatment with any investigational agent within three weeks prior to first dose in this 
study. 
 
8. Active CNS involvement with leukemia.   
 
9. Unstable cardiovascular function: 
a. symptomatic ischemia, or 
b. uncontrolled clinically significant conduction abnormalities (i.e. ventricular 
tachycardia on antiarrhythmics are excluded and 1st degree AV block or 
asymptomatic LAFB/RBBB will not be excluded), or 
c. congestive heart failure (CHF) of NYHA class ≥3, or 
d. myocardial infarction (MI) within 3 months 
 
10. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to KPT-330 or other agents used in the study. 
 
11. Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals 
within one week prior to first dose. Infections controlled on concurrent anti-microbial 
agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is 
acceptable. 
 
12. Any medical condition which, in the investigator's opinion, could compromise the 
patient's safety.  
 
13. Pregnant and/or breastfeeding.  Patient must have a negative urine pregnancy test 
within 5 days of study entry. 
 


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14. Unable to swallow tablets, or diagnosed malabsorption syndrome, or any other 
disease significantly affecting gastrointestinal function. 
 
15. Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be 
positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen). 
 
16. Known human immunodeficiency virus (HIV) infection. 
 
17. Serious psychiatric or medical conditions that could interfere with treatment. 
 
 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
    
 
 
 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility  
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below  
 
1. Registering physician’s name 
2. Patient’s race, sex, and date of birth 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form  
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
 
 
 
 


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Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All 
data will be recorded with this identification number on the appropriate CRFs. 
 
 
TREATMENT PLAN 
 
 
Screen Failures 
 
Patients who sign an informed consent form but do not undergo treatment are defined as 
screen failures. Screen failures are to be replaced. 
 
 
General Considerations 
 
Supportive care for prevention of tumor lysis syndrome (hydration, monitoring, etc.) 
must be performed per local institutional guidelines. Additional supportive care (e.g. 
transfusions, prophylactic antibiotics, antifungals and/or antivirals, growth factor support) 
is also allowed per institutional guidelines.  
 
Co-administration of corticosteroids and corticosteroid-containing eye drops (or 
equivalent) is recommended for patients receiving cytarabine containing regimens. Eye 
drops should continue for at least 2 days following the last dose of cytarabine. 
  
Antiemetic prophylaxis given per institutional guidelines is recommended.  
 
Treatment for fatigue and anorexia is recommended for patients receiving selinexor (see 
guideline Section 5.7) 
 
 
 
Ophthalmic Assessment 
 
A complete ophthalmologic assessment will be conducted on all patients by an 
ophthalmologist or optometrist. The full ophthalmic assessment includes: 
 Prior to dilation: best corrected visual acuity and slit lamp examination 
including tonometry 
 Following dilation: Fundoscopy and a slit lamp examination to document 
lens clarity.  If a cataract/lens opacity is seen during the examination, the 
cataract/lens opacity will be graded according to a Grade 1-4 system 
(Error! Reference source not found.). 
A complete ophthalmic assessment should be performed as clinically indicated during the 
course of the study to monitor ophthalmic adverse events.  
 
 
 
 
  
 


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Overall Treatment Plan 
 
Patients treated with selinexor on Schedule A will receive doses on Days 1, 5, 10 and 12 
of a 28 day cycle.  Patients treated on Schedule B will be administered selinexor doses on 
Days 1, 5, 10, 12, 17 and 19 of a 28 day cycle.  For patients being treated with selinexor 
maintenance therapy, selinexor will be administered on Days 1, 8, 15, and 22 of a 28 day 
cycle.  For doses on non-clinic days, patients will be provided doses to take home, one 
dose per container. Compliance to study medication will be recorded by study personnel 
after discussion with the patient and drug accountability.  
 
 Phase I Dosing 
 
For the Phase I portion, patients will be treated with the following: 
 
Selinexor (S): 
Oral doses of 60 mg will be administered
Cladribine (CL): 
5 mg/m2/day IV once daily on Days 4-8
G-CSF (G): 
300 mcg SC once daily on Days 3-8
Cytarabine (A): 
2000 mg/m2/day IV once daily on Days 4-8  
Dosing of cladribine and cytarabine should be performed according to actual body 
weight ± 5% to allow for rounding. Patients will be dosed based on body surface 
area (BSA) (calculated by Dubois method).  Selinexor is dosed on a flat-dosing 
basis.  To ensure that no patient will receive a dose of selinexor >70mg/m2, body 
surface area (BSA) calculated by Dubois method must be >1.43 m2 
 
 
Schedule A dosing: 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9
10 
11 
12 
 
S 
 
 
 
S 
 
 
 
 
S 
 
S 
 
 
 
G 
G 
G 
G 
G 
G 
 
 
 
 
 
 
 
 
A 
A 
A 
A 
A 
 
 
 
 
 
 
 
 
CL
CL 
CL
CL 
CL
 
 
 
 
BM 
 
 
BM 
 
 
 
 
 
 
 
PB 
 
 
PB 
 
PB 
 
PB 
 
 
 
 
 
 
Schedule B dosing: 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
17 
19 
 
S 
 
 
 
S 
 
 
 
 
S 
 
S 
S 
S 
 
 
 
G 
G 
G 
G 
G 
G 
 
 
 
 
 
 
 
 
 
 
A 
A 
A 
A 
A 
 
 
 
 
 
 
 
 
 
 
CL 
CL 
CL 
CL 
CL 
 
 
 
 
 
 
BM 
 
 
BM
 
 
 
 
 
 
 
 
 
PB 
 
 
PB 
 
PB 
 
PB 
 
 
 
 
 
 
 
 
 


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 Phase II Dosing 
 
The phase II dosing schedule is the most intense schedule in which ≤3 DLTs are 
observed in 12 patients treated using that schedule.  If no DLTs are experienced in 
Schedule B, then Schedule B will be considered the Phase II dose.  The phase I 
safety analysis together with the conclusion on the recommended dose for Phase 
II will be distributed to all participating investigators prior to starting the Phase II 
enrollment. 
 
 
Definition of  MTD, DLT, Dose Escalation Criteria, and Patient Evaluability 
 
 Dose Escalation Criteria 
 
The initial cohort of 6 patients will be dosed according to Schedule A.  If no dose 
limiting toxicities (DLTs) are experienced with the initial cohort of 6 patients 
treated according to Schedule A, then dosing will be intensified whereby a further 
cohort of 6 patients will be treated with Schedule B dosing. Six patients will be 
enrolled in each of two cohorts and an additional cohort of 6 may be added if 
schedule reduction is indicated.  No intracohort dosing schedule intensification is 
permitted.  
 
Patients who do not receive at least 5 doses of selinexor (either on Schedule A or 
B) and all doses of CLAG for reasons other than an adverse event at least possibly 
related to the study treatment will not be considered to have adequate date to 
support dose schedule escalation and may be replaced at the same dose schedule 
in the phase I portion of the study. 
 
 
The decision rule is: 
Schedule A
Number of patients treated
6
Intensify schedule if # of DLT =
0 in 6
Repeat schedule if # of DLT = 
1 in 6 
Stop if # of DLT =
2 in 6
Schedule A and B
Accept schedule if # DLTs ≤ 
3 in 12
De-intensify schedule if # of DLT =
4 in 12 *†
Stop if # of DLT = 
5 in 12 
 
* There is no de-escalation below the starting schedule. If 1 DLT is observed in 
the initial cohort with Schedule A dosing and the Schedule A dosing is repeated in 
the second cohort, the study will be stopped if 3 DLTs are observed in the second 
cohort, a total of 4 DLTs in cohorts 1 and 2 together. 
 
† If the schedule is intensified after Schedule A dosing and de-intensification is 
indicated after schedule B dosing, 6 additional patients will be treated using the 


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schedule A. Schedule A dosing will be accepted if no more than 2 DLTs are 
observed in a maximum of 18 patients treated using that schedule. 
 
 Dose Limiting Toxicities (DLTs) 
 
DLTs will be defined as any of the following that occur during treatment on 
Schedule A or B during Cycle 1 that are attributed as possibly, probably, or 
definitely related to selinexor treatment: 
 Grade ≥ 3 nausea/vomiting, dehydration or diarrhea while taking optimal 
supportive medications 
 Grade ≥ 3 fatigue lasting for ≥5 days while taking optimal supportive care 
and with correction of dehydration, anorexia, anemia, endocrine, or 
electrolyte abnormalities (See Section 5.5). 
 Any other Grade ≥3 non-hematological toxicity except electrolyte 
abnormalities correctable with supportive therapy 
 Grade ≥ 3 AST or ALT elevation lasting longer than 7 days OR Grade ≥ 3 
AST or ALT elevation in the setting of bilirubin elevation > 2x ULN (>2X 
baseline for patients with Gilbert’s syndrome) 
 
Patients who have failed to attain hematopoietic recovery by 42 days after the 
start of therapy should undergo a bone marrow biopsy/aspiration in order to 
evaluate for prolonged bone marrow aplasia or to document the persistence of 
leukemia.  Prolonged myelosuppression, i.e. marrow cellularity < 5% on Day 42 
or later (6 weeks) from start of cycle 1 without any evidence of leukemia, will 
also be considered in defining DLT. 
 
The following will specifically not be considered DLTs: 
 Grade 4 neutropenia [absolute neutrophil count (ANC) < 500/mm3] 
lasting ≥7 days; 
 Febrile neutropenia (ANC < 1000/mm3 with a single temperature ≥ 
38.3ºC or sustained temperature of >38°C for over 1 hour) or 
 Grade ≥3 thrombocytopenia with or without associated bleeding 
 
Infection and infection related complications will not be considered DLTs.  
 
Persistent grade 3 or higher neutropenia ≥ 42 days after the start of therapy in the 
absence of leukemia will be considered a DLT.  
 
In rare instances, an event may fall within the definition of a DLT as defined 
above but the event may be considered not a DLT (ie: not clinically 
meaningful/significant). If this occurs, a meeting with all investigators, PI, and 
possibly the drug manufacturer will take place to thoroughly review the event and 
supporting data and the reasons for not considering the event a DLT will be 
clearly documented with supporting rationale. In addition other events may occur 
which do not meet the definition of a DLT but are concerning to the investigators 
and sponsor and may be then considered to be DLTs. 


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 Toxicity, Response, and DLT Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients 
are evaluated from first receiving study treatment until a 30-day follow up after 
the conclusion of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment 
due to treatment related adverse events(s) and have not had any disease 
assessment. 
 
A patient is evaluable for DLT assessment only during Cycle 1 treatment on 
schedule A and/or B.  
 
 
Selinexor Maintenance Therapy for Patients who Achieve CR/CRi 
 
In both the phase I and II portions of the study, patients are candidates for selinexor 
maintenance therapy if they have achieved a CR or CRi based on post-treatment bone 
marrow assessment at the time of hematopoietic recovery and are either (1) transplant 
ineligible (defined in Section 5.6) or (2) do not have a stem cell transplant donor 
available. Prior to initiating maintenance therapy with selinexor, a bone marrow biopsy 
must confirm the presence of the CR or CRi. Maintenance therapy should be initiated no 
sooner than 30 days, but no more than 90 days following the administration of the last 
dose of selinexor therapy.  Maintenance therapy consists of 60mg selinexor on Days 1, 8, 
15, and 22 of a 28 day cycle, continuously until disease relapse, unacceptable toxicity, 
death, or the institution of additional antileukemic therapy including stem cell 
transplantation or donor leukocyte infusion.  
 
  
 
Assessment of Ineligibility for Stem Cell Transplant 
 
The investigator will perform a comprehensive review of patient characteristics (e.g. age, 
performance score, organ dysfunctions, co-morbidities) to assess a patient's eligibility for 
allogeneic stem cell transplant. A detailed description of the reasons for considering a 
patient ineligible for stem cell transplant will be documented in the source records. If co-
morbidities and organ dysfunctions are relevant for considering the patient ineligible for 
stem cell transplant, the documentation will include the details on organ system, type and 
stage/grade of dysfunction (e.g. NYHA for heart failure, Child-Pugh for liver cirrhosis, 
etc.). 
 
 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
S 
 
 
 
 
 
 
S 
 
 
 
 
 
 
Day
15 
16
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
 
S 
 
 
 
 
 
 
S 
 
 
 
 
 
 


Protocol Version 08/22/17 
 
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Supportive Care Guidelines 
 
 Required Supportive Care Medication 
 
5-HT3 Antagonists 
In order to minimize nausea, unless contraindicated, all patients must receive 
5-HT3 antagonists (ondansetron 8 mg or equivalent) starting before the first dose 
of selinexor and continued twice daily (bid) – three times a day (tid) as needed 
(prn). 
 
 Supportive Care Recommendations for Selinexor-Related Adverse 
Events 
 
Supportive measures for optimal medical care should be provided during 
participation in this clinical trial.  Based on clinical observations in over 450 adult 
patients treated with selinexor as of 01 October 2014, the main side effects are 
primarily related to anorexia with poor caloric and fluid intake, fatigue, and 
nausea.  Thrombocytopenia also occurs, although it is rarely associated with 
bleeding.   
 
Besides the required dexamethasone and 5-HT3, supportive care including anti-
nausea / anti-emetic therapy, acid suppression (proton pump inhibitors and/or H2-
blockers) and other treatments may be administered as described below: 
1. Glucocorticoids: In addition to the required dexamethasone supportive care, 
an additional 4-8 mg dexamethasone (or equivalent glucocorticoid) may be 
given on the days after selinexor dosing; a maximum of 40 mg dexamethasone 
or equivalent may be given per week. 
2. Appetite stimulants: megestrol acetate at a dose of 80-400 mg daily. 
3. Centrally acting agents: per National Comprehensive Cancer Network® 
[NCCN] Clinical Practice Guidelines® for anorexia/cachexia and antiemesis 
[palliative care]) see Appendix 2 (anorexia/cachexia) and Appendix 3 
(antiemesis), respectively. 
4. NK1R antagonist:  aprepitant or equivalent should be considered and will be 
covered for selected patients who have severe nausea and vomiting. 
Additional information on supportive care and dose modifications for specific 
adverse events can be found in Supportive Care and Dose Adjustment Guidelines 
for Non-Hematologic Selinexor-Related Toxicities below 
 
 Concomitant Medication and Treatment 
 
Concomitant medication is defined as any prescription or over-the-counter 
preparation, including vitamins and supplements. Patients may continue their 
baseline medication(s). Any diagnostic, therapeutic or surgical procedure 
performed during the study period should be recorded, including the dates, 
description of the procedure(s) and any clinical findings.  
 


Protocol Version 08/22/17 
 
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 Prohibited Medication and Concurrent Therapies 
 
Therapy 
Concurrent therapy with any other approved or investigative anticancer 
therapeutic is not allowed. Other investigational agents should not be used during 
the study.   Use of any immunosuppressive agents during the study must be 
confirmed by the Medical Monitor.  
  
Alcohol 
Ethanol should be avoided on selinexor dosing days as it may compete for 
glutathione (GSH)-mediated metabolism. 
 
Medications 
Although not prohibited, acetaminophen or acetaminophen-containing products 
must not exceed a total daily dose of 1 gram on days of selinexor dosing. 
 
Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-acetylcysteine (NAC)-
containing products should not be taken during participation in this study as these 
products may enhance the metabolism of selinexor.  Please see Appendix 4 for a 
list of representative products. Patients must report all prescription and non-
prescription medicines to their physicians during this study. 
 
 
Prevention of Pregnancy 
 
It is not anticipated that female patients enrolling in this study will be able to conceive.  
However, in the rare event that this is possible, female patients of childbearing potential 
must agree to use dual methods of contraception and have a negative serum pregnancy 
test at screening, and male patients must use an effective barrier method of contraception 
if sexually active with a female of child-bearing potential. Acceptable methods of 
contraception are condoms with contraceptive foam, oral, implantable or injectable 
contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, 
or a sexual partner who is surgically sterilized or post-menopausal. For both male and 
female patients, effective methods of contraception must be used throughout the study 
and for three months following the last dose. If a patient is suspected to be pregnant, 
selinexor should be immediately discontinued.  In addition a positive urine test must be 
confirmed by a serum pregnancy test.  If it is confirmed that the patient is not pregnant, 
the patient may resume dosing. If a female patient or female partner of a male patient 
becomes pregnant during therapy or within 3 months after the last dose of selinexor, the 
investigator must be notified in order to facilitate outcome follow-up. 
 
 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 


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protocol therapy should be discontinued and the reason(s) for discontinuation 
documented in the case report forms. 
 
Patients will be considered to have completed treatment upon achieving CR, 
documentation of persistent leukemia, or upon administration of additional antileukemic 
therapy including stem cell transplantation or donor leukocyte infusion.   As documented 
in Section 5.6, patients who achieve a CR or CRi based on post-treatment bone marrow 
assessment at the time of hematopoietic recovery and are either transplant ineligible or do 
not have a stem cell transplant donor available are candidates for selinexor maintenance 
therapy. Maintenance therapy continues until disease relapse, unacceptable toxicity, 
death, or the institution of additional antileukemic therapy including stem cell 
transplantation or donor leukocyte infusion. 
 
 
Removal from Study 
 
Patients may be removed from the study for any of the following reasons: 
 Death 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious non-compliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
 
Patient Replacement 
 
Patients withdrawn in cycle 1 because of noncompliance not related to study drug related 
toxicity will be replaced. Patients in the Phase II portion of the trial will not be replaced 
for any reason 
 
 
Duration of Follow-up 
 
Patients removed from treatment for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  Patients will be followed for a minimum 
of 30 days post treatment for adverse events. Patients achieving a CR or CRi will be 
followed for disease progression and/or death every 3 months following completion of 
treatment until removal from the study, for at least 12 months and up to a maximum of 2 
years.  For patients being treated with selinexor maintenance therapy, assessments should 
be performed at least every 2 weeks until removal from study. 


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DOSE DELAYS/DOSE MODIFICATIONS 
 
Toxicity will be graded according to National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03; the therapy modifications described below 
are applied according to this severity grading. 
If more than one different type of toxicity occurs concurrently, the most severe grade will 
determine the modification. 
Each dose modification or treatment delay has to be documented, including the respective 
reason. 
Based on observations from the ongoing Phase 1 studies in patients with advanced hematological 
and solid tumors, selinexor shows a reasonably wide therapeutic range, with activities from ~10 
mg/m2 to ≥ 60 mg/m2.  Therefore, in order to optimize specific anti-tumor activity and the 
patient’s tolerability, we will allow for dose and/or schedule modifications as described below. 
Patients should also be treated aggressively with supportive care to reduce toxicities. 
Dose modification pertains to selinexor maintenance therapy only. No dose modification will be 
permitted in cycle 1 for selinexor or CLAG chemotherapy. 
 
 
 
Supportive Care and Dose Adjustment Guidelines for Non-Hematologic Selinexor-Related 
Toxicities   
 
Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Fatigue (common) 
Grade 1 
Rule out other causes of fatigue. 
Insure adequate caloric intake and 
assess volume status. 
Consider addition of 4-12 mg 
dexamethasone or equivalent with 
each dose of selinexor +/- the day 
after selinexor. 
Maintain dose.  
Dose Level 
Dose of KPT-330 
Dose level 0
60 mg and maintain same schedule
Dose level -1
40 mg and maintain same schedule
Dose level -2
20 mg and maintain same schedule
Dose level -3
Discontinue dosing


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 2 
Rule out other causes of fatigue. 
Insure adequate caloric intake and 
assess volume status. 
Consider addition 4-12 mg 
dexamethasone or equivalent with 
each dose of selinexor +/- the day 
after selinexor.  
For additional support see NCCN 
guidelines36. 
Maintain dose. 
Consult medical monitor for 
additional option such as 
temporary dose reduction or short 
dose interruptions. 
Grade 3 
See guidelines for Grade 2 fatigue. 
Interrupt selinexor dosing until 
resolved to Grade ≤ 2, For first 
occurrence of Grade 3, if 
adequate supportive care resulted 
in fatigue improving to Grade ≤1 
within 7 days, restart selinexor at 
current dose.  
Otherwise, restart selinexor at one 
dose level below ( 
. 
 
Anorexia or Weight loss 
Grade 1 
Rule out other causes of anorexia. 
Assess dietary options (e.g., try a 
variety of other foods).  
Add high-calorie supplements 
(e.g., Ensure®).  
Consider addition of 4-12 mg 
dexamethasone or equivalent with 
each dose of selinexor +/- the day 
after selinexor. 
Maintain dose. 
Grade 2 
Rule out other causes of anorexia. 
Assess dietary options (e.g., try a 
variety of other foods).  
Add high-calorie supplements 
(e.g., Ensure®).  
Consider addition of 4-12 mg 
dexamethasone or equivalent with 
each dose of selinexor +/- the day 
after selinexor.  
Consider megesterol acetate 80-
400 mg daily. 
Consider anabolic steroids such as 
oxandrolone, or dronabinol 
(Marinol®) or other cannabinoid, 
mainly for patients who can’t 
tolerate steroids or at high risk to 
progress. 
For additional supportive care see 
NCCN guidelines37 (Appendix 2). 
Selinexor may be skipped 
intermittently while supportive 
medications are instituted, usually 
for <1 week.  
 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3  
See guidelines for Grade 2 
anorexia. 
Interrupt dosing with selinexor.   
Restart selinexor at 1 dose level 
reduction ( 
 once anorexia resolves to Grade 
≤ 2 and patient is clinically 
stable.   
Grade 4 (anorexia only) 
See guidelines for Grade 2 
anorexia. 
Stop dosing of selinexor.   
Restart selinexor at 1 dose level 
reduction ( 
 only if anorexia resolves to 
Grade ≤ 2, patient is clinically 
stable other contributing factors 
have been addressed.   
Nausea/ - acute  (common) 
Grade 1 
Insure adequate caloric intake and 
assess volume status. 
Consider alternate 5-HT3 
antagonists and/or D2 antagonists 
as needed. Consider addition of 
NK1 antagonists. 
 
Consider addition of 4-12 mg 
dexamethasone or equivalent with 
each dose of selinexor +/- the day 
after selinexor.  
Maintain dose. 
Grade 2 
See guidelines for Grade 1 nausea. 
 
For additional options see NCCN 
guidelines for antiemesis38  
(Appendix 3). 
Selinexor may be skipped 
intermittently while supportive 
medications are instituted, usually 
for <1 week.  
 
Grade 3 
See guidelines for Grade 1 nausea. 
 
For additional options see NCCN 
guidelines for antiemesis38  
(Appendix 3).  
Interrupt selinexor dosing until 
resolved to Grade ≤ 2, For first 
occurrence of Grade 3, if 
adequate supportive care resulted 
in nausea improving to Grade ≤1 
within 3 days, restart selinexor at 
current dose.  
Otherwise, restart selinexor at one 
dose level below ( 
.  
If nausea stabilizes for at least 4 
weeks at Grade ≤1, then original 
dose of selinexor may be 
resumed. 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Hyponatremia (common) 
Grade 1 (sodium levels <Normal 
to 130 nM) 
  
Be certain sodium level is 
corrected for hyperglycemia 
(serum glucose >150mmol/L).   
Rule out other causes of low 
sodium (e.g., cardiac, hepatic, 
adrenal, renal and thyroid diseases, 
SIADH, Fanconi Syndrome, 
hyperglycemia, diuretic use). 
Consider salt supplementation one 
– two times per day. 
Maintain dose. 
 
Grade 3 (sodium levels 126-
129nM) without Symptoms  
Be certain sodium level is 
corrected for hyperglycemia 
(serum glucose >150mmol/L).   
Rule out other causes of low 
sodium (e.g., cardiac, hepatic, 
adrenal, renal and thyroid diseases, 
SIADH, Fanconi Syndrome, 
hyperglycemia, diuretic use). 
Initiate salt supplementation two-
three times per day. 
Hold selinexor until Grade ≤1 
(≥130 nM), restart on the same 
dose level.  
Grade 3 (120-125 nM) or Grade 4 
or any Grade 3 with Symptoms 
Correct sodium as per institutional 
guideline. 
Initiate salt supplementation two-
three times per day. 
Hold selinexor until resolved to 
Grade ≤ 1 (≥130nM) then reduce 
selinexor dose by 1 level ( 
. 
For Grade 3 hyponatremia, if 
serum sodium stabilizes to grade 
≤1 for at least 4 weeks, then 
original dose of selinexor may be 
resumed. 
Diarrhea (common) 
Grade 1+2  
  
Diet recommendation as per 
Benson39 guidelines.  
Institute standard anti-diarrheal 
therapy. 
After the first occurrence of 
diarrhea, loperamide 2 mg should 
be considered prophylactically 
approximately 1-2 hours before 
the administration of selinexor and 
repeated every 4 hours for the first 
12 hours. 
For Grade 2 only, reduce 
selinexor one dose level ( 
 until resolved to ≤ Grade 1, then 
re-start at the current dose level. 
 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3   
  
Institute IV fluids  
Diet recommendation as per 
Benson39 guidelines. 
 
Institute standard anti-diarrheal 
therapy. 
 
Once the symptoms resolve to ≤ 
Grade 1, loperamide 2 mg should 
be considered prophylactically 
approximately 1-2 hours before 
the administration of selinexor and 
repeated every 4 hours for the first 
12 hours. 
Delay selinexor until resolved to 
≤ Grade 1, then reduce selinexor 
dose by one dose level ( 
. 
If diarrhea stabilizes for at least 4 
weeks at Grade ≤1, then original 
dose of selinexor may be 
resumed. 
Grade 4 
Rule out other causes of diarrhea, 
including infectious agents. In 
case of opportunistic infection, 
withdraw all steroids (with 
tapering if medically appropriate) 
until culture is negative. Follow 
institutional guidelines for Grade 4 
diarrhea.
Delay selinexor until resolved to 
≤ Grade 1, then reduce selinexor 
dose by one dose level ( 
. 
 
Other selinexor-related adverse events 
Grade 1 or 2 
Initiate standard supportive care 
and follow institutional guidelines. 
Maintain dose. 
Grade 3 
Initiate standard supportive care 
and follow institutional guidelines. 
Delay dose until resolved to 
Grade ≤  1 or baseline, then 
reduce by one dose level ( 
. 
Grade 4 
Initiate standard supportive care 
and follow institutional guidelines. 
Delay dose until resolved to 
Grade ≤  1 or baseline, then 
reduce by two dose levels ( 
. 
All dose modifications should be based on the worst preceding toxicity. 
* Isolated values of ≥ Grade 3 alkaline phosphatase values will NOT require dose 
interruption.  Determination of liver vs. bone etiology should be made, and evaluation of gamma-glutamyl 
transferase (GGT), 5'-nucleotidase (5’NT), or other liver enzymes should be performed. 
 
 
Conditions not Requiring Selinexor Dose Reduction 
 
The following conditions are exceptions to the above guidelines.  Selinexor does not need 
to be held in the case of electrolyte or serum analyte (e.g., urate) abnormalities that are 
reversible with standard interventions. 
 
 
Missed or Vomited Doses 
 
 Missed Doses 
 
If the dose was missed for more than 24 hours, the dose will be skipped and the 


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next dose will be taken as per schedule.  If the dose was missed within 24 hours, 
then it will be replaced.   
 
Doses should not be administered in less than 36 hours apart and all missed doses 
should be documented.  
 
 Vomited Doses 
 
If a dose is vomited within one hour of ingestion, it will be replaced. If vomiting 
occurs more than 1 hour after dosing, it will still be considered a complete dose. 
 
If a patient missed a full week of dosing for non-study drug related events (e.g., a 
required medical procedure or an unanticipated personal emergency), the days 
missed will not be replaced.   
 
 
 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as 
outlined in Section 7.2. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in 
Section 7.4.  In addition, any fatal or life-threatening adverse experiences where there is a 
reasonable possibility of relationship to study intervention must be reported. 
 
Karyopharm requires that all events be reported as outlined in Section 7.5. 
 
 
 
Definitions 
 
 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for all toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for 
the terms listed that should be used are those provided by the Department of 


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Health and Human Services’ Office for Human Research Protections (OHRP).  A 
copy of this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
 
 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is 
not consistent with the current investigator brochure (or risk information, if an IB 
is not required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
 
 Life-Threatening Adverse Experience 
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that, had it occurred in a more severe form, might have 
caused death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
 Unanticipated Problems 
 
Definition: 
 unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 


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 related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
 suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
 
 
 
 
 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
 Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH institution, or that impacts participants or the conduct of the 
study. 
 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 


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These events must be reported to the IRB within 10 working days of the occurrence of 
the event or notification to the PI of the event.  The death of a research participant that 
qualifies as a reportable event should be reported within 1 working day of the occurrence 
of the event or notification to the PI of the event. 
 
 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU 
or any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the investigator to report any unanticipated problem to the FDA as 
follows: 
 
 Report any unexpected fatal or life-threatening adverse experiences (Section 
7.1.4) associated with use of the drug by telephone or fax no later than 7 calendar 
days after initial receipt of the information.   
 Report any serious, unexpected adverse experiences (Section 7.1.3), as well as 
results from animal studies that suggest significant clinical risk within 15 
calendar days after initial receipt of this information.   
 
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
 
Reporting to Karyopharm 
 


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In addition to the regulatory and sponsor reporting requirements, the Sponsor (Dr. 
Geoffrey Uy)  will notify Karyopharm in accordance with the Protocol about any and all 
adverse events (AE), including all non-serious and unexpected AEs every six (6) months 
in the form of line listing in a format as requested by Company. The Principal 
Investigator will assess the causal relationship of all AEs to Study Drug and other drugs 
in the Study in accordance with Section 1.9.2. In addition, any SAE, regardless of the 
causal relationship to Study Drug occurring after the Subject has signed the Informed 
Consent Form (as defined below) until thirty (30) days after the Subject has stopped 
study treatment must be reported to Company within twenty-four (24) hours of Institution 
and Principal Investigator’s awareness on Company’s SAE Report Form (a template is 
provided for this purpose and is attached hereto as Exhibit C). The SAE Report Form will 
be signed by the Principal Investigator.  Any SAE observed after the above-referenced 
30-day period should only be reported to Karyopharm if the Principal Investigator 
suspects that the SAE has causal relationship to the Study Drug.   
 
All notices of adverse events and serious adverse events shall be sent to Karyopharm by 
email on the appropriate form to the following address: 
pharmacovigilance@karyopharm.com 
 
Karyopharm will cross-report applicable suspected unexpected serious adverse reactions 
(SUSARs) to other investigators and competent authorities and relevant ethics 
committees in accordance with the FDA’s ‘Safety Reporting Requirements for 
Investigational New Drugs and Bioanalytical/Bioequivalence Studies’ or as per national 
regulatory requirements in participating countries. 
 
 
 
Classification of Adverse Events by Causality 
 
The Principal Investigator will classify any AE as either Not Related or Related to Study 
Drug and other drugs in the Study in accordance with the following criteria: 
 
Not related 
The lack of a temporal relationship of the event to the study 
treatment makes a causal relationship not reasonably possible, or 
other drugs, therapeutic interventions, or underlying conditions 
provide a sufficient explanation
Related 
The temporal relationship of the event to the study treatment 
makes a definitive relationship, and the event is more likely 
explained by exposure to the study treatment than by any other 
drugs, therapeutic interventions, or underlying conditions. 
 
 
Other Safety Reporting 
 
The Principal Investigator shall also report all incidences of abuse, misuse, medication 
errors, overdose, and occupational exposure to Karyopharm on an SAE Report Form, 
regardless of whether or not there is an associated AE or SAE as soon as possible.  In the 
event the abuse, misuse, medication errors, overdose, and occupational exposure is 
associated with an SAE, the SAE report form must be submitted within twenty-four (24) 


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hours of first knowledge of its occurrence. If there is no AE or SAE, the report must be 
submitted as soon as possible, but in no event later than five (5) business days from the 
first knowledge of its occurrence.  All notices under this section shall be sent to 
Karyopharm by email to the following address:   pharmacovigilance@karyopharm.com. 
 
A new cancer diagnosed during the study (histopathologically different from the cancer 
under study) is considered and SAE and should be reported to Karyopharm. 
 
Hospitalizations for elective surgery or other medical procedures that are not due to an 
AE are not considered SAEs. A hospitalization meeting the regulatory definition for 
‘serious’ is any inpatient hospital admission that includes a minimum of an overnight stay 
in a health care facility. An emergency room visit is not considered a hospitalization 
unless it results in an official admission to the hospital. 
 
Progression of the malignancy (including fatal outcomes) should not be reported as an 
SAE during the study or within the safety reporting period. Sudden and unexplained 
death should be reported as an SAE. If there is any uncertainty about a finding being due 
solely to progression of malignancy, the finding should be reported as an AE or SAE, as 
appropriate. 
 
Pregnancies must be reported to Karyopharm Pharmacovigilance, regardless of whether 
the patient withdraws from the study or the study is completed, for 3 months after the 
patient receives his/her last dose of study treatment. Patients should be instructed to 
inform the investigator regarding any pregnancies. 
 
 
Timeframe for Reporting Required Events  
 
Reportable adverse events will be tracked for 30 days following the last day of study 
treatment or until the start of a subsequent treatment for AML, whichever comes first.  
 
 
 
PHARMACEUTICAL INFORMATION 
 
 
Selinexor (KPT-330) 
 
 Supplier 
 
Selinexor tablets will be provided by Karyopharm Therapeutics, Inc at no cost for 
this study, and will be provided in 20 mg tablets in wallet-sized blister packs (12 
tablets per blister pack). Each wallet-size blister package of selinexor tablets will 
be labeled in accordance with current International Conference on Harmonization 
(ICH), Good Clinical Practice (GCP), and specific regulatory requirements, e.g., 
FDA, Health Canada, EMA, etc.  Blister packages for take-home use may require 
additional in-pharmacy labeling with take-home and patient-specific instructions 
(such as exact dose) depending on country-specific regulations or laws. 
 


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The Investigational medicinal product should not be used for any purpose outside 
the scope of this protocol, nor can Investigational medicinal product be 
transferred or licensed to any party not participating in the clinical study. 
Karyopharm’s data for Investigational medicinal product are confidential and 
proprietary and shall be maintained as such by the Investigators. 
 
 Dosage Form and Preparation 
 
Selinexor tablets are manufactured for Karyopharm, Therapeutics (Newton, MA) 
using methods in accordance with Food and Drug Administration (FDA) 
guidelines for the manufacture and testing of antineoplastic agents for human use.  
The tablets are prepared from a common blend of excipients and all tablet 
excipients are GRAS (generally regarded as safe) listed and suitable for use in 
pharmaceuticals.   
 
 
 Storage and Stability 
 
Selinexor tablets will be stored at room or refrigerated temperatures between 
5-30°C (41-86°F) in a locked and secured area with restricted access. Room 
temperature storage is recommended.  The tablets should not be stored at freezer 
temperatures or allowed to freeze. All medication must be stored in a secure area 
under the proper storage requirements with access restricted to the site staff 
pharmacist or designee(s). 
 
 
 Administration 
 
Selinexor will be administered on schedule A on Days 1, 3, 5, 10 and 12.  Patients 
treated on schedule B will be administered doses on Days 1, 3, 5, 10, 12, 17 and 
19.  For patients being treated with maintenance selinexor therapy, doses will be 
administered on Days 1, 8, 15, and 22 of a 28 day cycle. 
 
Each dose will consist of selinexor for oral administration on a fixed dose basis in 
20 mg increments.  To ensure that no patient will be dosed at a dose >70mg/m2, 
the study will be limited to patients with a body surface area (BSA) (calculated by 
Dubois method) >1.43 m2.  
 
Selinexor will be administered orally at 60mg. Selinexor tablets are to be taken 
within 30-minutes of solid food consumption together with at least 120 mL (4 
ounces) of fluids (water, milk, etc.).  Selinexor tablets should not be crushed 
because of increased risk of dermatologic toxicity if the powder comes in contact 
with skin. 
 
 
Cytosine Arabinoside (AraC, Cytarabine)  
 


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 Cytosine Arabinoside Description 
 
Chemical Name: 4-amino-1-S-D-arabino-furanosyl-2(1H)-primidinone 
Molecular formula: C9H13N3O5 
Molecular weight: 243.217g/mol 
Pharmacologic class: Antimetabolite 
 
 Clinical Pharmacology 
 
Cytarabine is metabolized to its active form, cytarabine triphosphate (AraCTP) by 
deoxycytidine kinase and related kinases. AraCTP serves as an inhibitor of DNA 
polymerase. AraC also is incorporated into cellular RNA and DNA. It exhibits 
cell phase specificity, and is active against cells in the S-phase and may also block 
cells from progressing to S phase from G1.  
 
 
 Pharmacokinetics and Drug Metabolism 
 
After intravenous administration, the disappearance of Cytarabine from plasma is 
biphasic. There is an initial distributive phase with a half-life of approximately 10 
minutes, followed by a second elimination phase with a half-life of approximately 
1 to 3 hours. Within 24 hours about 80 percent of the administered drug can be 
recovered in the urine as the inactive metabolite, AraI.  After a single IV 
administration of Cytarabine, levels in CSF are low. There is little conversion to 
AraU because of low CSF levels of diaminase.    
 
 Supplier 
 
Cytarabine is commercially available and not provided as a study drug and must 
be supplied by the treating institution. 
 
 Dosage Form and Preparation 
 
Cytarabine is supplied as a sterile powder in 100 mg, 500 mg, 1 gram, and 2 gram 
vials for injection. Cytarabine should be reconstituted with sterile water for 
injection. 
 
 Storage and Stability 
 
Sterile powder should be stored at room temperature 15° -30°C (59°- 86°F). 
Solutions reconstituted with sterile water without preservative should be used 
immediately; solutions reconstituted with Bacteriostatic of Water are stable up to 
48 hours at room temperature 15° -30°C (59°- 86°F). Solutions with a slight haze 
should be discarded. 
 
 Administration 


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Cytarabine 2000 mg/m2/day intravenous infusion once daily over 4 hours on Days 
4-8. Dosing should be performed according to actual body weight ± 5% to allow 
for rounding. 
 
 
Cladribine (Leustatin) 
 
 Cladribine Description 
 
Chemical Name: 5-(6-amino-2-chloro-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol 
Molecular formula: C10H12CIN5O3 
Molecular weight: 285.687 g/mol 
Pharmacologic class: Antimetabolite 
 
 Clinical Pharmacology 
 
Cladribine is phosphorylated by deoxycytidine kinase to 2-chloro-2΄-deoxy-β-D-
adenosine 
monophosphate 
(2-CdAMP). 
2-CdAMP 
then 
accumulates 
intracellularly and is subsequently converted into the active triphosphate 
deoxynucleotide, 2-chloro-2΄-deoxy-β-D-adenosine triphosphate (2-CdATP). 
Cells containing high concentrations of deoxynucleotides are unable to properly 
repair single-strand DNA breaks. The broken ends of DNA activate the enzyme 
poly(ADP-ribose) polymerase resulting in NAD and ATP depletion and 
disruption of cellular metabolism. There is also evidence that 2-CdATP is 
incorporated into the DNA of dividing cells, resulting in impairment of DNA 
synthesis.  
 
 Pharmacokinetics and Drug Metabolism 
 
Cladribine plasma concentration after intravenous infusion has been shown to 
decline multi-exponentially and displays an average half-life of 6.7 +/- 2.5 hours. 
The volume of distribution is approximately 9L/kg.  Cladribine penetrates into 
CSF, with concentrations reaching approximately 25% of plasma levels.  
Cladribine is approximately 20% bound to plasma proteins.  Little is known 
regarding the metabolism in human subjects.  Limited data has shown that 18% of 
the administered dose is excreted in the urine of patients treated with a 5-day 
continuous intravenous infusion. Treatment of patients with renal and hepatic 
impairment has not been extensively investigated in human subjects.  
 
 Supplier 
 
Cladribine is commercially available and not provided as a study drug and must 
be supplied by the treating institution. 
 
 Dosage Form and Preparation 
 


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Cladribine is supplied as a sterile, preservative-free, isotonic solution containing 
10 mg (1 mg/mL) of cladribine as 10 mL filled into a single-use clear flint glass 
20 mL vial. Cladribine is supplied in 10 mL (1 mg/mL) single-use vials available 
in a treatment set (case) of seven vials. Cladribine must be diluted with the 
designated diluent prior to administration. Since the drug product does not contain 
any anti-microbial preservative or bacteriostatic agent, aseptic technique and 
proper environmental precautions must be observed in preparation of the 
intravenous infusion. The use of 5% dextrose as a diluent is not recommended 
because of increased degradation of cladribine. 
 
 
 Storage and Stability 
 
When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) protected 
from light, unopened vials of cladribine injection are stable until the expiration 
date indicated on the package. Freezing does not adversely affect the solution. If 
freezing occurs, thaw naturally to room temperature. DO NOT heat or microwave. 
Once thawed, the vial of cladribine injection is stable until expiry if refrigerated. 
DO NOT refreeze. Once diluted, solutions containing cladribine injection should 
be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 
8 hours prior to administration. 
 
 Administration 
 
Cladribine 5 mg/m2/day intravenous infusion once daily over 2 hours on Days 4-
8. Dosing should be performed according to actual body weight ± 5% to allow for 
rounding. 
 
 
 
Filgrastim (G-CSF, Neupogen)  
 
 Filgrastim Description 
 
Molecular formula: C845H1339N223O243S9 
Molecular weight: 18,800 daltons 
Pharmacologic class: Leukocyte growth factor 
 
 Clinical Pharmacology 
 
Colony stimulating factors are endogenous lineage specific glycoproteins that acts 
on hematopoietic cells through binding to a specific cell surface receptor and lead 
to proliferation‚ differentiation‚ and some end-cell functional activation.   
 
G-CSF helps to regulate the production of neutrophils in the bone marrow, and 
also effects the differentiation and proliferation of neutrophil progenitor cells.  G-
CSF also plays a role in regulating some end-cell functional activation including 


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priming cellular metabolism associated with respiratory burst, antibody dependent 
killing, and enhanced phagocytic ability. 
 
 Pharmacokinetics and Drug Metabolism 
 
Absorption and clearance of subcutaneous injection of filgrastim follows first-
order pharmacokinetics. The volume of distribution averaged 150ml/kg and the 
elimination half-life is approximately 3.5 hours.  
 
 
 
 Supplier 
 
Filgrastim is commercially available and not provided as a study drug and must 
be supplied by the treating institution. 
 
 Dosage Form and Preparation 
 
Filgrastim is commercially available in 1.0 and 1.6 mL vials containing 300 μg 
and 480 μg G-CSF, respectively. 
 
 Storage and Stability 
 
Filgrastim should be stored in the refrigerator at 2° to 8°C (36° to 46°F). DO NOT 
ALLOW THE DRUG TO FREEZE. Avoid shaking. Prior to injection‚ filgrastim 
may be allowed to reach room temperature for a maximum of 24 hours. Any vial 
or prefilled syringe left at room temperature for greater than 24 hours should be 
discarded.  
 
 Administration 
 
Each vial should be entered only once, and the remainder of the vial discarded 
and not re-entered a second time. 300 mcg once daily on Days 3-8 should be 
injected subcutaneously in one or two sites.  
 
 
 
CORRELATIVE STUDIES 
 
 
Sample Collection 
 
Ten ml of bone marrow in EDTA tube(s) will be collected at the following time points: 
 Screening 
 Day 3, prior to the administration of G-CSF 
 At the time of hematopoietic recovery 
 


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Ten ml of peripheral blood in EDTA tube(s) will be collected at the following time 
points: 
 Screening 
 Day 3, prior to the administration of G-CSF 
 Day 5, prior to the administration of Selinexor and CLAG chemotherapy 
 Day 7, prior to the administration of CLAG chemotherapy 
 At the time of hematopoietic recovery 
 
 
 
Sample Handling 
 
All correlative studies will be performed by the DiPersio Lab.  Specimens will be 
transported at room temperature immediately to the DiPersio Lab, Monday through 
Friday 8AM-5PM. Please notify the lab and/or Dr. DiPersio prior to submission. Sample 
collections that are outside those hours should be directly discussed with Dr. DiPersio at 
least 72 hours in advance. 
Attention: DiPersio Lab/ Julie Ritchey 
WU-Oncology 6th floor, Southwest Tower Building, Room 626 
4940 Parkview Place 
St Louis, MO, 63110 
Lab: (314) 362-9335 
jdipersi@DOM.wustl.edu, jritchey@dom.wustl.edu 
 


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STUDY CALENDAR 
 
Tests & Observations 
Baseline Examinations1 
Treatment Phase2 
Post-treatment/Maintenance Phase3 
History
X
C
X
Physical Examination
X
C
X
Performance status
X
Toxicity assessment
X
A
X
Laboratory Studies 
CBC with differential
X
B
X
BUN, creatinine, electrolytes
X
B
X
Hepatic  function tests
X
D
X
LDH, uric acid
X
MUGA or echocardiogram
X
Pregnancy test for women of child 
bearing potential
X
Bone marrow biopsy/aspiration
X
E
Ophthalmological exam
G
Research Studies 
Bone marrow aspirate/biopsy and 
peripheral blood
F
F
 
Notes: 
1. All baseline examination are to be performed within 14 days of the start of therapy 
2. Treatment phase begins with first dose of selinexor (Day 1) and ends at the time of documentation of CR/CRi or 
persistent leukemia but no less than 30 days after the start of treatment 
3. Assessment for remission status and survival every 3 months until removal from study, for at least 12 months 
and up to a maximum of 2 years.  For patient’s being treated with maintenance selinexor therapy, laboratory 
assessments should be performed at least every 2 weeks with history and physical examination every 4 weeks 
until removal from study. 
A. Performed at least weekly until count recovery 
B. Performed daily while inpatient but no less than 15 days and then at least twice a week following discharge 
until count recovery 
C. A symptom directed history and physical should be performed daily while inpatient but no less than 15 days and 
then weekly after hospital discharge until count recovery 
D. Performed at least twice a week while inpatient but no less than 15 days and then at least weekly after discharge 
until count recovery  
E. Performed at the time of hematopoietic recovery to document remission status and/or as clinically indicated to 
document persistent leukemia. If hematopoietic recovery does not occur prior to Day 42 (6 weeks) then a bone 
marrow aspirate/biopsy should be attained to evaluate for prolonged bone marrow aplasia. Prior to initiating 
maintenance therapy with selinexor, a bone marrow biopsy must confirm the presence of the CR or Cri 
F. 10 ml of bone marrow aspirate collected in an EDTA containing tube performed at the time of baseline 
screening marrow, on Day 3 prior to the administration of G-CSF, and at the time of hematopoietic recovery 
and/or as clinically indicated to document persistent leukemia. 10 ml of peripheral blood collected in an EDTA 
containing tube performed at baseline, on Day 3 prior to the administration of G-CSF, on Day 5 prior to the 
administration of Selinexor and CLAG chemotherapy, on Day 7 prior to the administration of CLAG 
chemotherapy, and at the time of hematopoietic recovery. 
G. Full ophthalmological exam will be conducted on all patients by an ophthalmologist or optometrist at baseline 
visit during Induction phase only, and if clinically indicated during the rest of the study (e.g., monitoring of pre-
existing cataracts, visual disturbances). Prior to dilation: assessment of best corrected visual acuity, and slit 


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lamp examination including tonometry.  Following dilation, patients will undergo fundoscopy and a slit lamp 
examination to document lens clarity.  If a cataract/lens opacity is seen during the examination, the cataract/lens 
opacity will be graded according to a Grade 1-4 system (Appendix 5: Cataract Clinical Grading Scale). 
 
 
 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form
Prior to registration
Registration Form 
Eligibility Form 
On-Study Form 
On-Study Labs Form 
On-Study Correlative Studies Form 
Cytogenetics and FISH Form 
Bone Marrow Biopsy Form 
Molecular Diagnostics Form
Prior to starting treatment 
Treatment Form
During treatment
Toxicity Form
Continuous
Treatment Summary Form
Completion of treatment
Bone Marrow Biopsy Form 
Cytogenetics and FISH Form 
Response Assessment Form
At time of bone marrow biopsies 
Adverse Event Form
Baseline, and at the time of any toxicity
Follow Up Form
Every 3 months
MedWatch Form 
See Section 7.0 for reporting 
requirements 
 
 
 
MEASUREMENT OF EFFECT 
 
 
Disease Parameters 
 
Disease status will be measured by bone marrow aspirate (or biopsy if aspirate is not 
adequate) at baseline screening and at the time of hematopoietic recovery, and as 
clinically indicated to assess treatment response. 
 
 
Response Criteria 
 
Response to treatment will be assessed according to the Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 


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Leukemia.30  All patients who receive at least one dose of selinexor are considered 
evaluable for response. 
 
Morphologic complete remission (CR): neutrophil count > 1.0 x 109 /L, platelet count ≥ 
100 x 109/L, < 5% bone marrow blasts by morphologic review, no Auer rods, no 
evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin 
concentration). 
 
Cytogenetic complete remission (CRc): only patients with an identified cytogenetic 
abnormality may receive this designation. Defined as a morphologic complete remission 
plus reversion to a normal karyotype (no clonal abnormalities detected in a minimum of 
20 mitotic cells). 
 
Morphologic complete remission with incomplete blood count recovery (CRi): same as 
CR but ANC may be <1000/mcl or platelet count <100,000/mcl 
 
Treatment failure (TF): Treatment failure includes those patients for whom treatment has 
failed to achieve a CR or CRi and will be classified as below:  
 
a) Treatment failure due to resistant disease includes patients who survive at least 7 days 
after completion of the final dose of the initial course of treatment but whose last 
posttreatment peripheral blood smear and/or bone marrow sample showed persistent 
AML 
b) Treatment failure due to complications from aplasia includes patients who survive at 
least 7 days after the final dose of the initial course of treatment and die while 
cytopenic, but whose last posttreatment bone marrow was aplastic or hypoplastic, as 
determined by the institutional morphologist or pathologist, without evidence of 
leukemia, provided that marrow was obtained within 7 days of death.  
c) Treatment failure of indeterminate cause includes three categories of patients:  
i) those who die less than 7 days after conclusion of the initial course of treatment, 
and  
ii) patients who die 7 or more days after the conclusion of treatment whose most 
recent peripheral blood smear did not show persistent leukemia and who did not 
have a bone marrow examination subsequent to therapy 
iii) patients who die without completing the first course of therapy.  
 
Recurrence/morphologic relapse:  Defined as reappearance of blasts in the blood or the 
finding of > 5% blasts in the BM, not attributable to any other cause.  New dysplastic 
changes are considered a relapse.  If there are no blasts in the peripheral blood and 5-19% 
blasts in the BM, the BM biopsy and aspirate should be repeated in > 1 week to confirm 
relapse. 
 
Response rate (RR): Defined as patients obtaining any response as described above. 
 
Time to neutrophil recovery: Defined as the date of the first dose of study drug to the date 
that the absolute neutrophil count is >1,000/mm3 


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Time to platelet recovery: Defined as the date of the first dose of study drug to the date 
that the platelet count is >100,000/mm3 in the absence of platelet transfusions. 
 
Overall survival (OS): Defined as the date of first dose of study drug to the date of death 
from any cause. OS will be evaluated at 3 month intervals for at least 12 months and up 
to a maximum of 2 years. . 
 
Event-free survival (EFS): Defined as the interval from the date of first dose of study 
drug to date of treatment failure including progressive disease, recurrence, or 
discontinuation for any reason (including toxicity, patient preference, initiation of new 
treatment without documented progression, or death due to any cause). 
 
Duration of remission (DOR): Defined as the interval from the date complete remission is 
documented to the date of recurrence. 
 
Relapse-free survival (RFS): For patients achieving a complete remission, defined as the 
interval from the date of first documentation of a leukemia free state to date of recurrence 
or death due to any cause. 
 
Allogeneic stem cell transplant utilization: the number of patients proceeding to 
allogeneic transplant within 2 months following end of study without any additional 
salvage therapy following study treatment. 
 
 
 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, 
the Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the 
Washington University Quality Assurance and Safety Monitoring Committee (QASMC) semi-
annually beginning six months after accrual has opened (if at least five patients have been 
enrolled) or one year after accrual has opened (if fewer than five patients have been enrolled at 
the six-month mark). 
 
This report will include: 
 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of 
study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual  
 Protocol activation date  


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 Average rate of accrual observed in year 1, year 2, and subsequent years  
 Expected accrual end date 
 Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
 Measures of efficacy  
 Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 
 Summary of toxicities  
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study 
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC 
according to institutional guidelines. 
 
 
 
STATISTICAL CONSIDERATIONS 
 
 
Statistical and Analytical Plans 
 
This is a phase I/II, open label study of selinexor given in combination with CLAG in 
patients with relapsed/refractory AML.  
 
The phase I portion will use a Bayesian optimal interval design to identify a schedule 
with grade 3-4 non-hematologic toxicity that does not exceed 20%. Six patients will be 
enrolled in each of two cohorts and an additional cohort of 6 may be added if schedule 
reduction is indicated, for a maximum of 24 patients in the Phase I portion. The 
probability of seeing at least one grade 3-4 non-hematologic toxicity, given a true rate of 
20%, is .73 with 6 patients, .93 with 12 patients and .98 with 18 patients. The decision 
rule is: 
 
Schedule A
Number of patients treated
6
Intensify schedule if # of DLT =
0 in 6
Repeat schedule if # of DLT =
1 in 6
Stop if # of DLT = 
2 in 6 
Schedule A and B
Accept schedule if # DLTs ≤ 
3 in 12
De-intensify schedule if # of DLT = 
4 in 12 *† 
Stop if # of DLT =
5 in 12
 
* There is no de-escalation below the starting schedule. If 1 DLT is observed in the initial 
cohort with Schedule A dosing and the Schedule A dosing is repeated in the second 
cohort, the study will be stopped if 3 DLTs are observed in the second cohort, a total of 4 
DLTs in cohorts 1 and 2 together. 


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† If the schedule is intensified after Schedule A dosing and de-intensification is indicated 
after Schedule B dosing, 6 additional patients will be treated using the Schedule A. 
Schedule A dosing will be accepted if no more than 2 DLTs are observed in a maximum 
of 18 patients treated using that schedule. 
 
The phase II portion was designed to compare the primary endpoint of complete 
remission rate (CR + CRi) with an historical 33%.  Patients in the phase I portion of the 
study, treated at the MTD will count towards the phase II accrual goal for evaluation of 
the primary endpoint.  With a sample size of 40, it will have power of 0.80 at a 0.05 
significance level for a two-sided, one-sample test for difference of a proportion from a 
historical value if the study observes a CR/CRi rate ≥ 0.55.  A continuous toxicity 
monitoring rule based on 40 patients will be employed whereby the expected rate of early 
death or hematologic toxicity is 5% and the maximum allowable rate is 20%.  The 
stopping rule will allow a maximum of 6 cases of excess toxicity in 40 patients (12.5%), 
and it has at least a 0.88 probability of stopping if the true rate is 20%. The study would 
be suspended for review if it observed 2 cases in the first 4 patients, or 3 in the first 12 
patients, or 4 in the first 21 patients, or 5 in the first 32 patients, or if the 6th case is 
observed before the 40th patient has completed the study.    
 
Phase I data will be tabulated by patient, type and grade of toxicity. In the phase II 
portion descriptive statistics will be used to summarize baseline patient characteristics 
and adverse events by patient, type and severity.  Complete remission rate and complete 
cytogenetic remission rate will be calculated with 95% confidence intervals, as will the 
proportion of patients able to undergo hematopoietic stem cell transplant. Comparisons 
with historical rates may be made; if so, one sample tests for difference of proportion will 
be used. Kaplan Meier estimates will be used to describe the median time to hematologic 
recovery (neutrophils and platelets), duration of remission, event-free survival, relapse-
free survival and overall survival using 95% confidence intervals. The Cox proportional 
hazard model and logistic regression model will be used to evaluate the association of 
clinical and laboratory characteristics to survival and response respectively.  We will use 
a P <= 0.05 threshold for significance.  Drug-related AEs will be recorded and followed 
to the end of the study or until resolution.  All AEs will be classified using the 
descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) v4.0 and summarized. Exploratory linear and nonlinear 
mixed models will be used to evaluate correlative endpoints such as bone marrow blast 
percentage, annexin V/7AAD, and cell cycle status, XPO1 expression, nuclear 
accumulation of targets such as p53, NPM, Fox03a, IκB in AML blasts, and selinexor 
concentration. Potential covariates include, but are not limited to: age, body weight, 
gender, disease state, baseline hepatic or renal function, and concomitant medications.     
 
We anticipate completion of the study in 18-24 months. 


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Appendix 1: ECOG Performance Status Scale 
 
 
Grade 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 


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Appendix 2: NCCN Clinical Practice Guidelines in Oncology: Anorexia/Cachexia 
 
 
 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Palliative Care V.1.2014. 
©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be 
reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version 
of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN 
GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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Appendix 3: NCCN Clinical Practice Guidelines in Oncology: Antiemesis 
 
 
 
 
 
 
 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014. © 
2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be 
reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version 
of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN 
GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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


Protocol Version 08/22/17 
 
Page 58 of 61 
 
 
 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014. © 
2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be 
reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version 
of the NCCN Guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN 
GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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Appendix 4: glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-acetylcysteine 
(NAC)-containing products (representative List) 
 
Product Name 
Ingredient 
Manufacturer/Brand 
Strength 
Dose Form 
Other key 
ingredients 
Glutathione 
Glutathione 
glutathione 
NOW Foods 
500 mg 
Vcaps 
milk thistle, 
alpha lipoic acid
Glutathione
L-glutathione
NOW Foods
250 mg
Vcaps
Glutathione 
reduced
glutathione 
Jarrow Formulas 
500 mg 
capsules 
 
Reduced 
glutathione 
sublingual 
complex
glutathione 
Source Naturals 
50 mg 
sublingual 
 
Glutathione 
reduced 
glutathione 
Bulk Supplements 
10, 25, 50, 100, 
250, 500, 1000 
g
powder 
 
Reduced 
glutathione with 
alpha lipoic acid
Setria L-glutathione 
Viva Labs 
500 mg 
capsules 
alpha lipoic acid 
Glutathione, 
Cysteine & C 
glutathione, 50 mg 
L-cysteine, 200 mg 
vitamin C, 500 mg
Life Extension 
750 mg 
capsules 
L-cysteine, 
vitamin C 
Liposomal 
Glutathione
glutathione 
Empirical Labs 
4 mL 
liquid 
 
Lypospheric GSH 
glutathione 
LivOn Laboratories 
450 mg 
packet 
essential 
phospholipids 
from soy 
lecithin
Ivory Caps  
Skin 
Enhancement 
Formula
glutathione 
Princeton Nutritional 
Systems 
1500 mg 
capsules 
 
Glutathione 
GOLD
S-acetyl glutathione 
Health Naturally 
200 mg 
capsules 
 
Mega-Liposomal 
Glutathione
glutathione 
Aurora NutraScience 
750 mg 
liquid 
 
L-Glutathione 500
L-glutathione
GNC
500 mg
capsules
N-acetylcysteine (NAC) 
Acetadote 
 
for acetaminophen 
overdose
acetylecysteine  
Cumberland 
Pharmaceutcals 
IV 
sterile 
solution, 200 
mg/mL 
 
CerefolinNAC 
 
medical food for 
age-related 
memory loss
L-methylfolate 
vitamin B12 
N-acetyl cysteine 
PAMLAB, LLC 
600 mg NAC 
caplets 
L-methylfolate 
vitamin B12 
 
NAC 
N-acetyl cysteine 
NOW Foods 
600 mg 
capsules 
selenium, 
molybdenum
N-A-C Sustain
N-acetyl L-cysteine
Jarrow Formulas
600 mg
capsules
Best NAC Detox 
Regulators 
N-acetyl cysteine 
Doctor’s Best 
600 mg 
capsules 
selenium, 50 mg 
molybdenum, 50 
mg
S-adenosylmethionine (SAM) 
SAM-e Complete
S-adenosylmethionine
Nature Made
400 mg
tablets


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SAMe 
S-adenosyl-L-
methionine
NOW Foods 
400 mg 
tablets 
 
Double Strength 
SAMe 400
S-adenosylmethionine 
Doctor’s Best 
400 mg 
tablets 
 
SAM-e 200
S-adenosylmethionine
Jarrow Formulas
200 mg
tablets
SAMe 
S-adenosyl-l-
methionine
Source Naturals 
400 mg 
tablets 
 
SAMe 
S-adenosyl-l-
methionine
Source Naturals 
200 mg 
tablets 
 
SAMe 
S-adenosylmethionine 
Natrol 
400 mg 
enteric coated 
tablets
 
SAMe 
S-adenosyl-
methionine  
NOW Foods 
200 mg 
tablets 
vitamin B-6, 
folic acid, 
vitamin B-12
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 5: Cataract Clinical Grading Scale 
 
Grading of Cataracts* 
Cataract Type 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nuclear 
Yellowing and 
sclerosis of the lens 
nucleus
Mild 
Moderate 
Pronounced
Severe 
Cortical 
Measured as 
aggregate percentage 
of the intrapupillary 
space occupied by the 
opacity
Obscures 
10% of 
intrapupillary 
space 
Obscures 
10% -50% 
of intra-
pupillary 
space 
Obscures 
50% -90% 
of intra-
pupillary 
space 
Obscures 
>90% of 
intrapupillary 
space 
Posterior subcapsular
Measured as the 
aggregate percentage 
of the posterior 
capsular area 
occupied by the 
opacitiy
Obscures 
10% of the 
area of the 
posterior 
capsule 
Obscures 
30% of the 
area of the 
posterior 
capsule 
Obscures 
50% of the 
area of the 
posterior 
capsule 
Obscures 
>50% of the 
area of the 
posterior 
capsule 
*Designation of cataract severity that falls between grade levels can be made by addition of a + 
sign (e.g., 1+, 2+). Grading of cataracts is usually done when pupil is dilated. 
 
Modified from Optometric Clinical Practice Guideline:  Care of the Adult Patient with Cataracts: 
available on the American Optometric Association website:  www.aoa.org