Phase I/II, Study of Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) + Sorafenib in Acute Myeloid Leukemia
Phase: PHASE1
Conditions: Leukemia, Acute Myeloid Leukemia
Sponsor: M.D. Anderson Cancer Center

2014-0975
July 14, 2016
Page 1
Protocol Page
Phase I/II, Study of Selective Inhibitor of Nuclear Export (SINE) Selinexor 
(KPT-330) + Sorafenib in Acute Myeloid Leukemia
2014-0975
Core Protocol Information
Short Title 
Phase I/II, Study of Selective Inhibitor of Nuclear Export
Study Chair: 
Naval Daver
Additional Contact:
Dana E. Brown
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-794-4392
Unit:
428
Full Title: 
Phase I/II, Study of Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) + 
Sorafenib in Acute Myeloid Leukemia
Protocol Type:
Standard Protocol
Protocol Phase:
Phase I/Phase II
Version Status:
Activated 02/09/2018
Version:
14
Submitted by:
Dana E. Brown--2/2/2018 3:12:37 PM
OPR Action:
Accepted by:  Margaret Okoloise -- 2/8/2018 8:35:17 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

2014-0975
July 14, 2016
Page 2
Protocol Body
 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
1
 
 
 
Phase I/II Investigator Sponsored Study of Selinexor (KPT-330), a 
Selective Inhibitor of Nuclear Export / SINE™ Compound + Sorafenib 
in Acute Myeloid Leukemia 
 
 
Principal Investigator: Naval Daver, M.D. and Michael Andreeff, M.D. 
 
 
Sponsor: University of Texas, MD Anderson Cancer Center 
 
 
IND number: 127,302 
 
 
University of Texas  
 
MD Anderson Cancer Center  
 
Leukemia Department, Unit 428, 
 
Houston, Texas, 77030.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 Selinexor and sorafenib in AML - 2014-0975 
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Contents 
1.0 OBJECTIVES……………………………………………………………………….2 
2.0 BACKGROUND…………………………………………………………………….3 
3.0 STUDY DESIGN…………………………………………………………………...11 
4.0 PATIENT SELECTION…………………………………………………………...15 
5.0 TREATMENT PLAN……………………………………………………………...19 
6.0 CORRELATIVE/SPECIAL STUDIES…………………………………………...37 
7.0 PATIENT EVALUATION………………………………………………………...38 
8.0 CRITERIA FOR RESPONSE…………………………………………………….42 
9.0 DISCONTINUATION OF TREATMENT……………………………………….44 
10.0 ADVERSE EVENT REPORTING………………………………………………45 
11.0 STATISTICAL CONSIDERATIONS…………………………………………...50 
12.0 REFERENCES…………………………………………………………………….55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 OBJECTIVES 
 
1.1 Primary Objectives  
       
Phase I     
1. To determine the maximum tolerated dose (MTD) and the recommended 
phase 2 dose (RP2D) and dose limiting toxicity (DLT) of the combination of 
selinexor with sorafenib in FLT3-ITD and –D835 mutated patients with 
relapsed/refractory acute myeloid leukemia (AML). 
 
Phase II 
1. To determine the composite CR (CRc) rate including CR (complete 
remission) + CRp (complete remission with incomplete platelet recovery) + 
CRi (complete remission with incomplete count recovery) within 3 months of 
treatment initiation in FLT3-ITD and –D835 mutated patients with 
relapsed/refractory AML. 
  
1.2 Secondary Objectives 
 
         Phase I 
1. To determine the composite CRc rate including CR + CRp + CRi within 3 
months of treatment initiation in FLT3-ITD and –D835 mutated patients with 
relapsed/ refractory AML. 
2. To determine the partial response (PR), marrow clearance rate, bone marrow 
blast reduction ≥ 50% within 3 months of treatment initiation in FLT3-ITD 
and –D835 mutated patients with relapsed/ refractory AML.  
3. To determine the duration of response (DOR), event-free survival (EFS), 
overall survival (OS), and number of patients bridged to hematopoetic stem 
cell transplant (HSCT) and median duration to HSCT from the initiation of the 
combination of selinexor with sorafenib in FLT3-ITD and –D835 mutated 
patients with relapsed/ refractory AML. 
4. To determine the safety of the combination of selinexor with sorafenib in 
FLT3-ITD and –D835 mutated patients with relapsed/ refractory AML. 
 
Phase II 
1. To determine the PR, marrow clearance rate, bone marrow blast reduction ≥ 
50% within 3 months of treatment initiation in FLT3-ITD and –D835 mutated 
patients with relapsed/ refractory AML. 
2. To determine the DOR, EFS, OS, and number of patients bridged to HSCT 
and median duration to HSCT from the initiation of the combination of 
selinexor with sorafenib in FLT3-ITD and –D835 mutated patients with 
relapsed/ refractory AML. 
3. To determine the safety of the combination of selinexor with sorafenib in 
FLT3-ITD and –D835 mutated patients with relapsed/ refractory AML. 
 
1.3 Exploratory Objectives 

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1. To evaluate the response rate, EFS and OS in FLT3 mutated/NPM1 wild-type 
patients versus FLT3 mutated/NPM1 mutated versus FLT3 wild-type/NPM1 
mutated patients treated with the combination of selinexor and sorafenib. 
2. Quantitative changes of FLT3-ITD and –D835 allelic burden with time in 
patients treated with the combination of selinexor and sorafenib. 
3. To evaluate the extent of pharmacodynamics biomarker (such as p-FLT3, p-
p70S6K, pERK) inhibition and the induction of apoptosis in the bone marrow 
and peripheral blasts following treatment with the combination of selinexor 
and sorafenib. 
4. To investigate possible relationships between selinexor and other baseline 
gene expression signatures and clinical response. 
5. To store and/or analyze surplus blood or tissue including bone marrow, if 
available, for potential future exploratory research into factors that may 
influence development of AML and/or response to selinexor (where response 
is defined broadly to include efficacy, tolerability or safety). 
6. To evaluate the pharmacodynamic effects of treatment on induction/inhibition 
of XPO1 using qRT-PCR and on plasma protein/cytokine levels. 
 
2. BACKGROUND 
 
2.1 FLT3-mutated AML 
 
FLT3 (FMS-like tyrosine kinase III) belongs to the Class III family of receptor 
tyrosine kinases (RTKs; other members of this family include receptors for KIT, FMS, 
and PDGF) 1. Signaling via RTKs is frequently deregulated in hematological 
malignancies 2. FLT3 is expressed on the leukemic cells of 70–100% of patients with 
AML 3. Additionally, activating mutations in FLT3 are observed in 30% of adult AML 
patients 4. The two FLT3 mutations found in AML include internal tandem 
duplications in the juxta-membrane domain (ITD, 17–34%) and mutations in the 
tyrosine kinase domain (TKD) activation loop (7%) 5. FLT3 stimulates survival and 
proliferation of leukemic blasts 6. FLT3-ITD mutations are associated with adverse 
prognosis. Patients with FLT3-ITD have significantly elevated peripheral blood white 
cell counts, increased bone marrow blasts, increased relapse risk, inferior event-free 
survival (EFS), and decreased overall survival (OS) 7-9. The FLT3-TKD mutations 
have unknown prognostic significance in AML 9.  
 
Several small-molecule FLT3 targeted tyrosine kinase inhibitors (TKIs) that are 
undergoing evaluation in phase I, II, and III trials have shown promising activity as 
single agents and in combination with hypomethylating agents or chemotherapy. 
These include quizartinib (AC220), sorafenib, midostaurin (PKC412), lestaurtinib, and 
crenolanib10-16. These TKIs act as direct inhibitors of FLT3 via competitive inhibition 
of ATP-binding sites in the FLT3 receptor KD17, 18.   
 
FLT3 inhibitors demonstrate potent anti-leukemic activity and improve outcomes in 
patients with relapsed/refractory AML and FLT3-ITD mutations19. About 40-50% of 

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such patients achieve marrow responses to FLT3 inhibitors, with 20-30% bridged to 
allogeneic stem cell transplant. Responses to FLT3 inhibitors last 3-6 months and are 
invariably transient (except among patients who undergo transplantation) due to the 
emergence of resistance20, 21. The primary cause of resistance is the acquisition of 
point mutations in the FLT3 kinase domain (KD). Heidel et al first to identified point 
mutations in the FLT3-ITD KD as a mediator of resistance to the FLT3 inhibitor 
midostaurin. They reported a single amino acid substitution at position 676 (N676K) 
within the FLT3 KD as the sole cause of resistance to midostaurin in a patient with 
AML22. Acquired point mutations in the KD may be preexisting or acquired after 
exposure to the FLT3 inhibitors as has been shown with midostaurin22. Homology 
modeling has identified two main types of FLT3 mutations, namely TKD1 mutations 
involving the ATP-binding (hinge regions) and the TKD2 mutations involving the 
activation loop23.  Non-mutational mechanisms of resistance include up-regulation of 
compensatory pathways including the MAPK/ERK, PI3K/Akt/mTOR, FOXO3A, SYK, 
and STAT5/PIM pathways, up-regulation of the FLT3 ligand or receptor, mutations in 
other kinases (e.g. CBL), activation of anti-apoptotic proteins BCL2, MCL1 and BCL-
x(L), and tumor microenvironment mediated resistance23, 25 24, 25. 
 
Sorafenib is an orally active multikinase inhibitor with potent activity against FLT3 
and the Raf/ERK/mitogen-activated protein kinase pathway 26. Sorafenib is 1000-fold 
more active against ITD mutant FLT3 than wild-type FLT3 in cell based assays 27. In 
phase I studies, sorafenib potently inhibited FLT3-ITD leukemic blasts. Melzelder et 
al reported clinical activity as a single agent in relapsed FLT3-ITD AML 28. We 
performed a phase I/II study of idarubicin, high-dose cytarabine and sorafenib in AML 
patients (median age = 53 years) 29. In this study 15 FLT3-ITD patients were enrolled. 
Fourteen patients achieved a CR and 1 patient achieved complete remission with 
incomplete platelet recovery (CRp). Mutant FLT3 was suppressed in all 10 patients 
evaluated, with fivefold greater suppression of mutant FLT3 as compared to wild-type 
FLT3 on plasma inhibitory assays 29. We recently reported the feasibility and efficacy 
of combining hypomethylator therapy (5-azacytidine) with sorafenib in patients with 
relapsed/refractory FLT3-ITD AML 11. A total of 43 patients were treated (93% were 
FLT3-ITD mutated). Patients had received a median of 2 prior therapies. The response 
rate was 46% including CR, CRp and CRi (complete remission with incomplete 
recovery of counts). This response rate compares favorably with expected response 
rates in multiply relapsed AML. 64% of the patients achieved >85% FLT3 inhibition 
during their first cycle of therapy. The combination was reasonably well tolerated. 
Although hepatotoxicity was seen, most instances were grade 1 or 2. 
 
Over 10 major tumor suppressor pathways have evolved in order to prevent the 
development and progression of neoplasia. The majority of the tumor suppressor 
(TSP) and growth regulatory (GRP) proteins mediating these pathways act in the cell 
nucleus downstream of signaling pathways. Accumulating data suggest that in order to 
maintain their malignant behavior, neoplastic cells must inactivate most or all of the 
known TSP and GRP pathways30. Active nuclear export of TSP/GRP is one very 
efficient and rapid means of overcoming the normal cell cycle and genomic instability 
checkpoints mediated by these proteins. Essentially all known TSP/GRP utilize a 

 Selinexor and sorafenib in AML - 2014-0975 
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single nonredundant nuclear export protein complex in order to exit the nucleus. 
Exportin 1 (XPO1), also called chromosomal region maintenance protein 1 (CRM1), is 
the primary component of this export complex, and is overexpressed in many types of 
cancer31. 
 
 
 
Selinexor is a Selective Inhibitor of Nuclear Export / SINE™ compound that slowly 
reversibly binds and inactivates XPO1, thereby forcing the nuclear retention of key 
TSP/GRP. Transient retention of TSP/GRP in the nucleus at high levels via XPO1 
blockade activates their cell cycle checkpoint and genome surveying actions. This 
leads to the death of nearly all types of malignant cells, whereas normal cells undergo 
transient cell cycle arrest and recovery when the export block is released. Garzon et al 
identified a strong down-regulation of total FLT3 protein expression in primary AML 
samples after XPO-1 inhibition. This inhibition seems to occur at the post-
transcriptional level32. Based on these findings, we propose Phase I combination trial 
of FLT3-ITD inhibitor sorafenib (Nexavar) and SINE™ compound (selinexor) in 
relapsed/refractory AML patients. 
 
2.2 Selinexor, a Selective Inhibitor of Nuclear Export / SINE™ Compound 
 
Selinexor is an oral, first in class, slowly reversible, potent and Selective Inhibitor of 
Nuclear Export / SINE™ compound that specifically blocks exportin 1 (XPO1). To 
date, other than XPO1, no targets of selinexor have been identified. Selinexor restores 
many of the tumor suppressor (TSP) and growth regulatory (GRP) proteins to the 
nucleus where they can carry out their normal functions. Selinexor is 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 a 
SINE™ compound 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 

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apoptosis. Normal cells, with an intact genome, remain in transient, reversible cell 
cycle arrest until the export block is relieved. Selinexor and other SINE™ compounds 
are not intrinsically cytotoxic; rather, they can restore the highly effective tumor 
suppressing pathways that lead to selective elimination of genomically damaged (i.e., 
neoplastic) cells.  Tumors of hematopoietic lineage are particularly susceptible to 
induction of apoptosis by XPO1 inhibition; normal hematopoietic cells and their 
functions are largely spared. 
 
2.2.1 Preclinical Data 
 
In this section a short summary of preclinical data is provided.  More detailed 
information is presented in the selinexor Investigator’s Brochure (Appendix C). 
2.2.1.1 Pharmacology, Pharmacokinetc and Toxicology Summary: 
 
Selinexor has shown potent apoptosis induction with a median IC50 of 90 nM 
across a panel of 46 tumor cell lines representing a broad spectrum of tumor types.  
As noted above, selinexor had little effect on normal lymphocytes or other non-
transformed 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 dysfunction.  
Selinexor has shown substantial efficacy, with dosing regimens that match those 
currently under investigation in humans, in a variety of mouse models of 
hematological and solid tumors and, including AML, CLL, DLBCL, MCL, 
multiple myeloma, T-cell acute lymphoblastic leukemia (T-ALL), neuroblastoma, 
melanoma and prostate, breast, lung and ovarian cancer. 
AML cells overexpress the nuclear exporter, Exportin 1 (XPO1/CRM1) and higher 
XPO1 levels correlate with poor outcome (Kojima 2013).  The novel selective 
inhibitor of nuclear transport / SINE compound, selinexor, antagonizes XPO1 and 
shows potent cytotoxicity for AML and ALL cells in vitro, independent of 
genotype.  
Selinexor shows potent antiproliferative effect and induced apoptosis, cell cycle 
arrest and myeloid differentiation in AML cell lines and patient blasts, including 
those from patients with NPM1 and FLT3-ITD mutations (Ranganathan 2012).  
Mechanistic studies show that SINE compounds induce nuclear localization and 
activation of multiple tumor suppressor proteins (TSPs), leading to rapid apoptosis 
of AML cells.  In addition, a strong down-regulation of the oncogenes FLT3 and c-
KIT were observed after SINE treatment in both FLT3-ITD and wild-type cell 
lines (Ranganathan 2012). Selinexor treatment also restored the localization of 
cytoplasmic mutant NPM1 into the nucleus.  
In murine AML and ALL models, selinexor showed potent antileukemic activity 
without toxicity to normal hematopoietic cells (Etchin 2013a, b; Ranganathan 
2012).  

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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 (non-malignant) lymphocytes or other nontransformed cells, 
which correlated with the low incidence in animals of the typical side effects seen 
with most anti-cancer therapies such as significant myelosuppression, alopecia, 
mucositis and other gastrointestinal (GI) dysfunction. 
Preclinical parameters were assessed in three species: mouse (CD1), rat (Sprague-
Dawley), and monkey (cynomolgus).  While pharmacokinetic (PK) studies were 
limited to male animals for all three species, toxicokinetic (TK) evaluations were 
conducted in both sexes for rats and monkeys as part of the 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 
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.   
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 SINE XPO1 inhibitors.  
See the selinexor Investigator’s Brochure for more information (Appendix C). 
2.2.2. Clinical Experience 
 
KCP-330-001: A Phase I Study of the Safety, Pharmacokinetics and 
Pharmacodynamics of Escalating Doses of the Selective Inhibitor of Nuclear 
Export (SINE) KPT-330 in Patients with Advanced Hematological Malignancies  
Study Design: This is a Phase-1, open-label, parallel-group study, with dose 
escalation and expansion phases, to determine the MTD, preliminary safety, 

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9
preliminary response, and PK of various selinexor dose schedules (3 to 85 mg/m2 
dosed 1-3 times weekly) in patients with RR hematologic malignancies, including:  
• _Chronic hematological malignancies (B-cell) – Multiple myeloma (MM), 
Waldenström’s Macroglobulinemia (WM), Non-Hodgkin’s Lymphoma (NHL), 
chronic lymphocytic leukemia (CLL)  
• _Acute Myeloid Leukemia (AML) - Any subtype except M4 (Acute 
Promyelocytic Leukemia [APL])  
• _Peripheral (PTCL) and Cutaneous (CTCL) T-Cell Lymphoma  
• _Acute Lymphoblastic Leukemia (ALL) - B- or T-cell  
• _Chronic Myelocytic Leukemia (CML)  
 
This study is registered on ClinTrials.gov at NCT01607892.  
 
Preliminary, unaudited response data (as of 04 Dec 2014) and safety reports (as of 
01 Feb 2015) for AML patients are included in the attached IB v4.0_03 April 2015 
(Appendix C).  
Study Design: Sixty-five heavily pretreated patients with progressive RR AML, 
most with ≥ _3 prior lines of treatment, were enrolled in the KCP-330-001 AML 
treatment arm and received selinexor 16.8-70 mg/m2 in four-week cycles.  
Preliminary Response Results: Among 63 evaluable patients, the CR rate, with or 
without full hematologic recovery, was 11%, ORR was 16%, and DCR was 49%. 
(Note: 16 patients [25%] were non-evaluable but were included in the AML 
response rate calculation, based on the ITT approach.) Best response results in 
AML patients as of 13 May 2014 are shown in Table 11. Patients could be deemed 
non evaluable due to either lack of post-dosing bone marrow assessments, failure 
to take the required number of doses of study medication, withdrawal of consent, 
or death during Cycle 1 prior to response determination. During this study, sixteen 
patients died during Cycle 1, including patients who were evaluable due to PD 
prior to death. 
Table 1 Best responses in AML patients as of May 13. 2014 
N 
DCR 
ORR 
CR 
CR(i/p) 
PR 
MLFS 
SD 
PD 
NE 
63 
31 
10 
5 
2 
1 
2 
21 
16 
16 
(100%) (49%) 
(16%) 
(8%) 
(3%) 
(2%) 
(3%) 
(33%) 
(25%) 
(25%) 
 
Preliminary Safety Results: Grade 3/4 TEAEs that were reported in > 3 patients 
include: fatigue (18%), and nausea (8%). Grade 3/4 thrombocytopenia (15%) and 
neutropenia (11%) were observed, however a majority of patients enrolled with 
baseline high-grade thrombocytopenia and neutropenia as part of progressive 
disease (which is associated with reduced hematopoietic function). The most 

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common Grade 1/2 TEAEs were diarrhea (82%), anorexia (78%), nausea (74%), 
and fatigue (65%). No DLTs were reported during the dose escalation phase, 
however due to SAEs that were seen at 85 mg/m2 in study KCP-330-002, a 
maximum allowable dose of 70 mg/m2 twice weekly was assigned for this and 
future studies. The anticipated selinexor dose for patients in future AML studies 
will be 80-100 mg (35-60 mg/m2) twice weekly. For details of overall safety 
results in the AML patients and in all hematologic clinical studies please see the 
attached IB (Appendix C) 
Potential Risks 
 
Selinexor is currently in clinical development and has not been approved by the 
Food and Drug Administration (FDA) for commercial use.  Human experience 
with selinexor is currently limited and the entire safety profile is not known at this 
time.  Measures will be taken to ensure the safety of the patients participating in 
this trial, including the use of stringent inclusion and exclusion criteria and close 
monitoring.  Toxicity grading will be performed in accordance with National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) V4.03.  If more than one different type of toxicity occurs concurrently, 
the most severe grade will determine the modification. 
If toxicities are encountered, adjustments will be made to the study treatment as 
detailed in the sections below. All AEs and serious adverse events (SAEs) will be 
recorded during the trial and for up to 30 days after the last dose of study treatment 
or until the initiation of another anti-cancer therapy, whichever occurs first. 
Side effects observed to date in patients are shown below. Please see Selinexor for 
Oral Administration Investigator’s Brochure (Appendix C) for most up-to-date 
information. 
Most common side effects:  
x 
nausea  
x 
loss of appetite  
x 
fatigue  
x 
vomiting 
x 
weight loss  
x 
diarrhea 
Less common: 
x 
change in taste   
x 
changes in vision including blurred vision 
x 
low platelets  
x 
decrease in red blood cells 
x 
low sodium without symptoms 
Rare (< 5%): 

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x 
worsening of pre-existing cataracts   
x 
elevated levels of bilirubin 
x 
elevated levels liver enzymes (ALT and AST)  
One patient, heavily pre-treated for recurrent pancreatic cancer, developed, ‘acute 
cerebellar syndrome’ following 4 doses of selinexor at 85 mg/m2 twice weekly. 
The patient experienced abnormal speech, loss of coordination, and was unable to 
walk. No other patients have reported such symptoms to date. 
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. 
2.2.3  For further details of selinexor and sorafenib preclinical studies, clinical studies, 
toxicities, pharmacokinetics, and adverse events please see the selinexor 
Investigator Brochure (Appendix C) and sorafenib drug label (Appendix D). 
 
2.3 Rationale for study: 
FLT3 inhibitors demonstrate potent anti-leukemic activity and improve outcomes in 
patients with relapsed/refractory AML and FLT3-ITD mutations19. About 40-50% of such 
patients achieve marrow responses to FLT3 inhibitors, with 20-30% bridged to allogeneic 
stem cell transplant. Responses to FLT3 inhibitors are usually maintained for 3-6 months 
but invariably these responses are transient (except among patients who undergo 
transplantation) due to the emergence of resistance20, 21. The causes of resistance include 
the acquisition of point mutations in the FLT3 KD and non-mutational mechanisms of 
resistance include up-regulation of compensatory pathways including the 
PI3K/Akt/mTOR, FOXO3A, SYK, RAS and STAT5/PIM pathways, up-regulation of the 
FLT3 ligand or receptor, mutations in other kinases (e.g. CBL), activation of ant-
apoptotic proteins BCL2, MCL1 and BCL-x(L), and tumor microenvironment mediated 
resistance23, 25 24. 
 
Selinexor is a first in class Selective Inhibitor of Nuclear Export / SINE™ compound 
that specifically binds and inactivates XPO1, thereby forcing the nuclear retention of key 
TSP/GRP implicated in non-mutational resistance to FLT3-inhibitors including AKT, 

 Selinexor and sorafenib in AML - 2014-0975 
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12
PI3K, mTOR, FOXO, STAT5, BCL2, BCL-x(L). Nuclear retention of these known 
mediators of non-mutational resistance may improve the efficacy and duration of 
response to FLT3 inhibitor sorafenib. Furthermore, Garzon et al identified a direct 
inhibition of FLT3 protein expression in AML samples after XPO1 inhibition. The 
indirect and direct impact of XPO1 inhibition on the FLT3 pathway support combining a 
XPO1 inhibitor (selinexor) with a FLT3 inhibitor (sorafenib).  We have preclinical data 
recently generated showing activity of the KPT330+sorafenib combination in patients 
with D835 alone, double mutant D835+ITD and D842+ITD (Zhang et al., ASH poster, 
December 2015 – attached as appendix K). Based on this data we will evaluate in 
addition to FLT3-ITD also double mutant ITD+D835 as well as D835 alone FLT3 
mutated patients. We do not have active therapies for D835 alone or double mutant AML 
patients and the preclinical data suggests this therapy may be active. In this initial trial, 
we propose to investigate whether selinexor in combination with sorafenib improves the 
response rates in patients with FLT3-ITD and –D835 mutated relapsed/refractory AML. 
If the combination proves to be well tolerated and results in improved response rates, we 
would expand the use of this approach in the frontline setting for FLT3-ITD and –D835 
mutated AML. 
 
3.0 STUDY DESIGN: 
 
3.1 General 
The study will be a phase I/II, single-institution, open-label, non-randomized, 
parallel group clinical trial. The phase II will include two separate cohorts to be 
enrolled simultaneously. All patients will be registered through CORe/PDMS.  
 
x Phase I  
o This will include FLT3-ITD and –D835 mutated patients with 
relapsed/refractory AML, including patients who may have been 
previously exposed to one or more FLT3-inhibitors. Relapsed/ 
refractory status defined by the failure of at least one prior cycle of 
chemotherapy (including but not limited to cytotoxic 
chemotherapy, hypomethylator therapy, immune-based therapy, 
stem cell transplant or stem cell therapy, FLT3-inhibitor therapy, 
investigational therapy, and others). 
o The DLT assessment period will be performed only during Cycle 1 
of Phase I. 
 
x Phase II in two cohorts 
1. Cohort 1 (FLT3 inhibitor failure cohort) in FLT3-ITD and –D835 
mutated relapsed/refractory AML who have failed therapy with up to 
two prior salvage regimens (HSCT or stem cell therapy for patients 
who previously underwent HSCT/stem cell therapy in remission will 
not be considered a salvage regimen) and have previously been 
exposed to at least one prior FLT3 inhibitor. 
 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
13
2. Cohort 2 (FLT3 inhibitor naive cohort) in FLT3-ITD and –D835 
mutated relapsed/refractory AML who have failed therapy with up to 
two prior salvage regimens (HSCT or stem cell therapy for patients 
who previously underwent HSCT/stem cell therapy in remission will 
not be considered a salvage regimen) with no prior exposure to any 
FLT3 inhibitor. 
 
3.2 Study Design 
x The phase I portion is aimed at finding the MTD and RP2D of the 
combination drugs. We will use the standard “3+3” design. The target 
dose is dose level +1, and the starting dose will be dose level 0. The first 3 
patients on study will receive dose level 0.  
 
x Other dose levels will be used for dose adjustments for toxicity during 
therapy (Table 3). 
 
x Prior to advancing/changing dose levels, a cohort summary will be completed 
and submitted to the IND Office Medical Monitor for review and approval. A 
copy of the cohort summary should be placed in the Investigator’s 
Regulatory Binder under “sponsor correspondence”.  
 
x The dosing schema is shown in Table 3 below.  
 
Table 3: Dosing schema  
Dose level 
Sorafenib (in mg) 
Selinexor (in mg) on days 1 and 3 of 
weeks 1-3 of each 4 week cycle 
+1 (Target dose) 
400 twice daily 
100 mg* twice weekly 
0 (Starting dose) 
400 twice daily 
80 mg twice weekly 
-1  
400 twice daily 
60 mg twice weekly 
-2 
400 twice daily 
40 mg twice weekly 
                     *not to exceed 70 mg/m2 based on BSA 
 
3.3  3+3 algorithm   
  The 3+3 algorithm that we will follow in the phase I is described below. 
x Enroll 3 patients at the dose level 0 
x Proceed to the next higher dose level with a cohort of 3 patients until at 
least 1 patient experiences the dose-limiting toxicity (DLT) 
x If only 1 of 3 patients experiences the DLT at a given dose level, enter 3 
additional patients at the current dose level 
x If only 1 of 6 patients experiences the DLT at a given dose level, proceed 
to the next higher dose level with a cohort of 3 patients or open broadly for 
phase II if at maximum escalation dose 
x If at least 2 of 3 or 2 of 6 patients experience the DLT at a given dose level, 
then the MTD has been exceeded 
x Once the MTD has been exceeded, treat another 3 patients at the previous 
dose level if there were only 3 patients treated at that dose level 

 Selinexor and sorafenib in AML - 2014-0975 
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14
x The MTD is the highest dose level in which we have treated 6 patients with 
at most 1 experiencing the DLT 
x If ≥2/6 patients experience DLT at dose level -2, the study will be revised 
to consider additional lower dose levels. 
 
*With up to 2 potential dose de-escalation level (-1 and -2) to be studied and 
up to 6 patients to be treated at a given dose, the target maximum number of 
patients enrolled in the phase I part of the trial will be 12.  
 
3.4  Definition of dose-limiting toxicity (DLT) 
DLT is defined as clinically significant non-hematologic adverse event or 
abnormal laboratory value assessed as unrelated to disease progression, 
intercurrent illness, or concomitant medications and occurring during the first 
cycle on study and at least possibly related to the study drugs that meets any of 
the following criteria:  
 
¾ CTCAE Grade 3 AST (SGOT) or ALT (SGPT) for > 7 days 
 
¾ CTCAE Grade 4 AST (SGOT) or ALT (SGPT) of any duration 
 
¾ Grade 3 nausea/vomiting, dehydration or diarrhea lasting more 
than 3 days in the setting of optimal supportive medications 
 
¾ Grade 3 fatigue lasting more than 5 days in the setting of optimal 
supportive medications 
 
¾ Grade 3 biochemical abnormalities (e.g., lipase or bilirubin 
elevation) will only be considered DLT if accompanied by 
clinical consequences. Grade 3 electrolyte abnormalities will 
only be considered DLT if possibly related to study drug and not 
corrected by optimal replacement therapy or if the Grade 3 
electrolyte abnormalities persist after 7 days of optimal 
replacement therapy  
 
¾ All Grade 4 non-hematologic toxicities of any duration 
 
¾ For the purposes of DLT assessment, asymptomatic 
hyponatremia will be “graded” not by the NCI CTCAE version 
4.03 but rather by clinically meaningful criterion of 
<125mmol/L. Sodium <125mmol/L will be graded as DLT with 
the exception of asymptomatic translational hyponatremia due to 
hyperglycemia (see footnote below for calculation).   
*In marked hyperglycemia, ECF osmolality rises and exceeds that of 
ICF, since glucose penetrates cell membranes slowly in the absence of 
insulin, resulting in movement of water out of cells into the ECF. 
Serum Na concentration falls in proportion to the dilution of the ECF, 
declining 1.6 mEq/ L for every 100 mg/dL (5.55 mmol/L) increment in 

 Selinexor and sorafenib in AML - 2014-0975 
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15
the plasma glucose level above normal. This condition has been called 
translational hyponatremia because no net change in total body water 
(TBW) has occurred. No specific therapy is indicated, because Na 
concentration will return to normal once the plasma glucose 
concentration is lowered. Corrected Sodium (Hillier, 1999) = 
Measured sodium + 0.024 * (Serum glucose - 100)33.  
 
¾ All other clinically significant non-hematological adverse event 
that is Grade 3 according to the NCI CTCAE version 4.03.   
 
¾ Myelosuppression and cytopenias are expected outcomes of 
leukemia treatment and per se will not constitute DLT. Only 
prolonged myelosuppression, as defined by the NCI criteria 
specific for leukemia, i.e. marrow cellularity < 5% on Day 42 or 
later (6 weeks) from start of therapy without any evidence of 
leukemia, will be considered in defining DLT. In case of a 
normocellular bone marrow with <5% blasts, 8 weeks with 
pancytopenia will be considered DLT. Anemia will not be 
considered for the definition of DLT. 
 
Any patients who stop treatment prior to completing evaluation for the 
DLT observation period (first 28 days) due to disease progression or 
refusal for further participation for reasons other than toxicity during the 
DLT defining phase I portion of the study will be replaced at that dose 
level for a full evaluation of that dose level before a decision regarding 
dose escalation can be made. 
 
3.5 Phase II expansion 
Once MTD is defined, the RP2D will be selected based on efficacy and safety 
result from the phase I in discussion with the PI, the sponsor and the supporting 
company (Karyopharm). The Investigator is responsible for completing the 
cohort summary template prior to advancing subjects to the phase II portion. The 
phase II portion will start in two cohorts as defined previously with 20 patients 
per cohort. Any patients still on study from the phase I portion at a dose lower 
than RP2D can be dose escalated up to RP2D in accordance with the dose 
escalation guidelines in section 5.2.3. 
However, the dose for any patient may never exceed the RP2D.  
 
4.0 PATIENT SELECTION 
 
Patients must have baseline evaluations performed prior to the first dose of study 
drug and must meet all inclusion and exclusion criteria. Results of all baseline 
evaluations, which assure that all inclusion and exclusion criteria have been 
satisfied, must be reviewed by the Principal Investigator or his/her designee prior 
to enrollment of that patient. In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent. The written 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
16
informed consent must be obtained from the patient prior to initiating treatment or 
any study-specific procedures. The following criteria apply to all patients enrolled 
onto the study unless otherwise specified. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
 Phase I  
FLT3-ITD and/or FLT3-D835 mutated patients 18 years of age or 
older with relapsed/ refractory AML (any number of relapses) 
including patients who may have been previously exposed to one 
or more FLT3-inhibitor therapies will be eligible for the phase I 
portion of this study. 
 
4.1.2 
Phase II 
FLT3-ITD and/or FLT3-D835 mutated relapsed/refractory 
patients: Patients should have a diagnosis of AML (de novo or 
transformed from hematologic malignancies). Patients with high-
risk myelodysplastic syndrome (MDS) (defined as having >/= 10% 
blasts in the bone marrow) or patients with Chronic 
Myelomonocytic Leukemia (CMML) (having >/= 10% blasts in 
the bone marrow) may also be eligible after discussion with 
Principal Investigator (PI).  
 
           The patients should have one of the following features:  
 
1. Patients with AML should have failed any prior 
induction therapy or have relapsed after prior therapy. 
 
2. Patients with high-risk MDS or high-risk CMML should 
have failed any prior therapy for the MDS or CMML.  
 
3. Patients with MDS or CMML who received therapy for 
the MDS or CMML and progress to AML are eligible at 
the time of diagnosis of AML regardless any prior therapy 
for AML. The WHO classification will be used for AML. 
 
4.1.3 
Patients must be eligible for one of two cohorts:  
 
Cohort 1 (FLT3 inhibitor failure cohort) in FLT3-ITD 
and/or FLT3-D835 mutated relapsed/refractory AML who 
have failed therapy with up to two prior salvage regimens 
(SCT or stem cell therapy for patients who previously 
underwent SCT/stem cell therapy in remission will not be 
considered a salvage regimen) and have previously been 
exposed at least one prior FLT3 inhibitor. 
 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
17
Cohort 2 (FLT3 inhibitor naive cohort) in FLT3-ITD 
and/or FLT3-D835 mutated relapsed/refractory who have 
failed therapy with up to two prior salvage regimens (SCT 
or stem cell therapy for patients who previously underwent 
SCT/stem cell therapy in remission will not be considered a 
salvage regimen) with no prior exposure to any FLT3 
inhibitor.  
 
4.1.4 
Age t18 years. 
 
4.1.5 
ECOG Performance Status d2. 
 
4.1.6 
Patients should have estimated life expectancy of >3 months at 
study entry. 
 
4.1.7 
Adequate hepatic (serum direct bilirubin </= 2.0 x upper limit 
normal (ULN) (or </= 3.0 x ULN if deemed to be elevated due to 
leukemia), alanine aminotransferase and/or aspartate transaminase 
</= 3.0 x ULN (or </= 5.0 x ULN if deemed to be elevated due to 
leukemia), and renal function (creatinine </= 2.0 mg/dL). 
 
4.1.8 
Patients must provide written informed consent. 
 
4.1.9 
In the absence of rapidly progressing disease, the interval from 
prior treatment to time of initiation of selinexor and sorafenib 
administration will be at least 2 weeks for cytotoxic agents or at 
least 5 half-lives for cytotoxic/noncytotoxic agents. The half-life 
for the therapy in question will be based on published 
pharmacokinetic literature (abstracts, manuscripts, investigator 
brochure’s, or drug-administration manuals) and will be 
documented in the protocol eligibility document. The use of 
chemotherapeutic or anti-leukemic agents is not permitted during 
the study with the following exceptions: (1) intrathecal (IT) 
therapy for patients with controlled CNS leukemia at the discretion 
of the PI and with the agreement of the Sponsor. Controlled CNS 
leukemia is defined by the absence of active clinical signs of CNS 
disease and no evidence of CNS leukemia on the most recent 2 
simultaneous CSF evaluations. (2) Use of one dose of cytarabine 
(up to 2 g/m2) or hydroxyurea for patients with rapidly 
proliferative disease is allowed before the start of study therapy 
and for the first four weeks on therapy. These medications will be 
recorded in the case-report form. 
 
4.1.10 
Baseline ejection fraction must be ≥ 40%. 
 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
18
4.1.11 
Females must be surgically or biologically sterile or 
postmenopausal (amenorrheic for at least 12 months) or if of 
childbearing potential, must have a negative serum or urine 
pregnancy test within 72 hours before the start of the treatment.  
 
4.1.12 
Women of childbearing potential must agree to use an adequate 
method of contraception during the study and until 3 months after 
the last treatment. Males must be surgically or biologically sterile 
or agree to use an adequate method of contraception during the 
study until 3 months after the last treatment. 
 
Adequate methods of contraception include: 
x 
Total abstinence when this is in line with the preferred and 
usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
x 
Female 
sterilization 
(have 
had 
surgical 
bilateral 
oophorectomy with or without hysterectomy) or tubal ligation at 
least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level 
assessment 
x 
Male sterilization (at least 6 months prior to screening). For 
female patients on the study, the vasectomized male partner should 
be the sole partner for that patient 
x 
Combination of any of the two following (a+b or a+c or 
b+c) 
a. 
Use of oral, injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have 
comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception 
b. 
Placement of an intrauterine device (IUD) or intrauterine 
system (IUS) 
c. 
Barrier methods of contraception: Condom or Occlusive 
cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/ vaginal suppository 
       In case of use of oral contraception, women should have been 
stable on the same pill before taking study treatment. 
Note: Oral contraceptives are allowed but should be used in 
conjunction with a barrier method of contraception due to 
unknown effect of drug-drug interaction. 
        Women are considered post-menopausal and not of child 
bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
19
age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks ago. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Patients with known allergy or hypersensitivity to selinexor, 
sorafenib or any of its components. 
 
 
4.2.2 
Subject has concurrent, uncontrolled medical condition, laboratory 
abnormality, or psychiatric illness, which could place him/her at 
unacceptable risk. 
 
4.2.3 
Patients who have had any major surgical procedure within 14 
days of Day 1. 
 
4.2.4 
Patients currently receiving any other standard or investigational 
therapy for the treatment of AML. 
 
4.2.5 
Patients unwilling or unable to comply with the protocol. 
 
4.2.6 
Patients receiving concomitant treatment with strong CYP3A4 
inhibitors, unless such drugs are considered critical for the well 
being of the patient and not adequate alternatives are available. 
Strong CYP3A4 inhibitors include the following medications: 
itraconazole, ketoconazole, miconazole, voriconazole; amprenavir, 
atazanavir, 
fosamprenavir, 
indinavir, 
nelfinavir, 
ritonavir; 
ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, 
isoniazid, ketamine, nefazodone, nicardipine, propofol, quinidine, 
telithromycin. 
 
4.2.7 
Patients with any severe gastrointestinal or metabolic condition 
that could interfere with absorption of oral medications. 
 
4.2.8 
Patients who are in blast transformation of chronic myeloid 
leukemia (CML). Prior MDS or CMML is acceptable. 
 
4.2.9 
Patient has a concurrent active malignancy under treatment. 
 
4.2.10 
Unstable cardiovascular function: 
x Symptomatic ischemia, or  
x Uncontrolled 
clinically 
significant 
conduction 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
20
abnormalities 
(i.e., 
ventricular 
tachycardia 
on 
antiarrhythmic 
agents 
are 
excluded; 
1st 
degree 
atrioventricular (AV) block or asymptomatic left anterior 
fascicular block/right bundle branch block (LAFB/RBBB) 
will not be excluded), or 
x Congestive heart failure (CHF) NYHA Class ≥ 3, or 
x Myocardial infarction (MI) within 3 months.  
x Left ventricular ejection fraction < 40 %. 
x Hypertension > 140 mm Hg systolic or > 90 mm Hg 
diastolic with or without antihypertensive therapy. 
 
4.2.11 
Uncontrolled infection at the time of enrollment. Infections 
controlled on concurrent anti-microbial agents are acceptable, and 
anti-microbial 
prophylaxis 
per 
institutional 
guidelines 
is 
acceptable. 
 
4.2.12 
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). 
 
4.2.13 
Known human immunodeficiency virus (HIV) infection. 
 
4.2.14 
Female subjects who are pregnant or breastfeeding. 
 
4.2.15 
Acute promyelocytic leukemia. 
 
4.2.16 
Any medical condition, which in the investigator's opinion, could 
compromise the patient's safety. 
 
 
5.0 
TREATMENT PLAN: 
 
5.1 
Schedule 
 
All patients will be registered through CORe/PDMS. 
 
5.1.1 Selinexor will be administered orally twice a week (e.g. 
Monday/Wednesday or Tuesday/Thursday or Wednesday/Friday) 
for 3 weeks of a 28-day cycle.  Selinexor will not be dosed the last 
week of the cycle (week 4). After initiation of sorafenib on cycle 1 
day 1, sorafenib will be administered orally daily twice 
continuously for the duration of the study with no interruptions 
unless there are adverse events as described in Section 5.2 below. 
Sorafenib doses will be separated by intervals of approximately 12 
hours (+/- 2 hours). Sorafenib will be administered without food, at 
least 1 hour before or 2 hours after eating. If a dose is missed, the 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
21
next dose will not be increased to account for missing a dose. The 
patient will take the next regular dose at the scheduled time. 
Patients will receive one cycle of therapy every 28 days (+/- 7 
days).   
 
On the day when both drugs, Selinexor and Sorafenib, will be 
administered: 
- 
Selinexor needs to be taken with food. 
- Sorafenib should not be taken with food.  Therefore, patient 
should take Sorafenib at least 1 hour before eating or 2 hours after 
eating. 
 
5.1.1.1 Cycles may be started early (but not earlier than day 21) for 
patients with active disease if judged in the best interest of 
the patient.  
*For the phase I, DLT defining period is 28 days. As such, 
cycle 2 should not be started before 28 days for the patients 
being treated on the phase I cohort to allow for adequate 
evaluation of DLTs. 
 
5.1.1.2 Subsequent cycles may be delayed for recovery of toxicity 
or other medical conditions.  Delays in start of subsequent 
cycles greater than 8 weeks will be acceptable only for 
patients who are deriving clinical benefit and after 
discussion with the principal investigator and the sponsor 
of potential risk/benefit ratio and complete documentation 
of the degree of clinical benefit and reason for continuation 
on this regimen.   
 
5.1.1.3 In instances where one drug has to be discontinued 
transiently because of safety, the administration of the other 
drug may continue as scheduled. If the drug that is held can 
resume at a later time, no doses will be made up and the 
administration will follow the originally defined schedule 
calendar according to the drug that was continued.   
 
5.1.1.4 For patients who discontinue therapy, the reason for 
treatment discontinuation will be documented.   
 
5.1.1.5 Patients must receive at least 4 doses of selinexor and at 
least 44 doses of sorafenib during the first 28 days on trial 
(i.e. during cycle 1) to be evaluated for DLT. Patients who 
receive less than 4 doses of selinexor and/or less than 44 
doses of sorafenib during the first 28 days on trial will not 
be evaluable for DLT. Patients not evaluable for DLT will 
be replaced. These patients may continue therapy on trial 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
22
after discussion with the PI if they are having clinical 
benefit and the reasons for continuation and potential 
benefit/risk profile for the patient must be clearly 
documented in the medical records.   
 
5.2 Dose Adjustments 
 
5.2.1  Selinexor and sorafenib dose adjustments for drug-related 
hematological adverse events (AEs): 
            Dose reduction/interruption/discontinuation decisions should be 
based on the CTCAE version 4.03 (Appendix E) of the toxicity and 
the guidelines provided below. 
 
x Patients with acute leukemia’s usually present with abnormal 
peripheral blood counts at the time therapy is started and 
myelosuppression is an expected event during the course of 
therapy for acute leukemia’s. Thus, no dose adjustments or 
treatment interruptions for myelosuppression will be planned for 
the first 4 cycles and/or in the presence of residual leukemia. 
After that, treatment interruptions and dose adjustments may be 
considered according to the following guidelines only when there 
is no evidence of residual leukemia.  
 
¾ Patients with a response (e.g., no evidence of residual 
leukemia or cytopenias not considered to be related to 
leukemia) and pre-cycle counts of neutrophils >1.0 x 
109/L and platelets >50 x 109/L who have sustained low 
counts of neutrophils <0.5 x 109/L or a platelet count 
<20 x 109/L for more than 2 consecutive weeks in the 
current cycle, may have the treatment with selinexor 
and sorafenib interrupted at the discretion of the 
treating physician after discussing with the PI until 
neutrophils recover to ≥0.5 x109/L and platelets to ≥30 
x 109/L. If prolonged myelosuppression defined as 
ANC < 0.5 x 109/L and platelets < 20 x109/L (more 
than 8 weeks) with evidence of a hypocellular marrow 
(marrow cellularity less than 5% without evidence of 
leukemia) is observed in these patients, both selinexor 
and sorafenib will be discontinued. Delays in start of 
subsequent cycles greater than 8 weeks will be 
acceptable only for patients who are deriving clinical 
benefit and after discussion with the principal 
investigator of potential risk/benefit ratio and complete 
documentation of the degree of clinical benefit and 
reason for continuation on this regimen.   
 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
23
¾ If there are persistent peripheral blood blasts, or the 
bone marrow shows >5% blasts or evidence of 
leukemia, treatment may be continued regardless of 
neutrophil and platelet count with supportive care as 
needed. Dose-interruptions of selinexor and sorafenib 
in these patients should be considered on an individual 
case and discussed with the PI and the sponsor.  
 
¾ Patients with a response (no marrow evidence of 
leukemia) and pre-cycle counts of neutrophils <1x109/L 
and platelets <50 x109/L may be continued regardless 
of neutrophil and platelet count with supportive care as 
needed. Dose-interruptions in these patients should be 
considered on an individual case and discussed with the 
PI and the sponsor. 
 
¾ Investigators should, whenever possible, determine 
which medication is causing the toxicity and interrupt 
or dose reduce selinexor and/or sorafenib, as applicable. 
 
           5.2.2    Selinexor and sorafenib dose adjustments for non-hematologic    
drug-related AEs 
Investigators should, whenever possible, determine which 
medication is causing the toxicity and interrupt or dose reduce 
selinexor and/or interrupt sorafenib, as applicable. Thus, if dose 
level 0 is established as the MTD, one and two dose level 
reductions of selinexor will be selinexor 60 mg twice weekly and 
selinxor 40 mg twice weekly, respectively. If the MTD is below 
dose level 0 further dose reduction levels of selinexor will be 
defined before moving to the phase II portion of the study. Dose 
reductions of sorafenib will be as follows: Starting dose = 
sorafenib 400 mg BID, -1 dose level = 400 mg in the AM and 
200 mg in the PM, -2 dose level = 200 mg BID, -3 dose level = 
200 mg Qday. The sorafenib dose will not be reduced beyond 
200 mg Qday.  
 
Table 4 Dose adjustments for non-hematologic drug-related AEs, clinically 
significant in the opinion of the investigator 
 
Grade 
Occurrence 
Dose modification 
1 or 2 
Any time 
No dose reduction. 
3 
 
(Persistent 
grade 2: 
Consider 
1st and 
2nd time 
Hold selinexor and/or sorafenib. 
Resume selinexor and/or sorafenib at prior dose if recovery to ≤ 
Grade 1 or baseline occurs within 14 days. 
If toxicity persists for 15-28 days, hold therapy and resume at 
ONE dose level below current dose for selinexor OR sorafenib 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
24
similar dose 
adjustments if 
persistent and 
not 
responding to 
optimal 
management 
in the opinion 
of PI and 
treating 
physician) 
OR both based on which medication is likely causing the 
toxicity ONLY after recovery of toxicity to ≤ Grade 2. 
Dose re-escalation to prior dose of selinexor OR sorafenib OR 
both is permitted if tolerated and no recurrent Grade 3 or 4 
toxicities occur over 4 weeks while on the lower dose level. 
3rd and 4th 
time 
Hold selinexor and/or sorafenib. 
Follow until toxicity ≤ Grade 2.  
Resume at TWO dose level below current dose for selinexor 
OR sorafenib OR both based on which medication is likely 
causing the toxicity ONLY after recovery of toxicity to ≤ Grade 
2.  
Dose re-escalation by one dose level every 4 weeks of selinexor 
OR sorafenib OR both is permitted if tolerated and no recurrent 
Grade 3 or 4 toxicities occur over the 4 weeks while on the 
lower dose level.  
5th time 
Stop selinexor and sorafenib and discontinue patient. 
(For patients with clinical benefit/response from the 
combination we will consider continuation if toxicities resolve 
to ≤ grade 1 and with proper dose adjustments after 
consultation with the PI and the sponsor) 
4 
Any time 
Stop selinexor and sorafenib and discontinue patient. 
(For patients with clinical benefit/response from the 
combination we will consider continuation if toxicities resolve 
to ≤ grade 1 and with proper dose adjustments after 
consultation with the PI and the sponsor)  
 
x If the criteria to resume treatment are met, the subject should 
restart treatment at the next scheduled time point per protocol. 
However, if the treatment is delayed past the next scheduled time 
point per protocol, the next scheduled time point will be delayed 
until dosing resumes.  
 
x Patients in whom the toxicity occurs or persists beyond the planned 
completion of drug administration for the cycle will have the dose 
reductions for either selinexor or sorafenib or both agents (based 
on attribution of the specific toxicity to selinexor or sorafenib or 
both) implemented in subsequent cycles provided the toxicity has 
resolved as specified in table 4 above.  
 
x These general guidelines constitute guidance to the Investigator 
and may be supplemented by discussions with the Medical 
Monitor representing the Sponsor in specific cases. 
 
x Guidelines for dose adjustment for toxicities that are likely related 
to selinexor are given below: 
 
Table 5 – Specific supportive Care and Dose Adjustment Guidelines for Selinexor-
Related Toxicities 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
25
 
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose 
Modification 
 
Fatigue (common) 
Grade 1 
Rule out other causes of 
fatigue. 
Consider addition of 4-8 
mg dexamethasone or 
equivalent on the day 
after selinexor.  
Insure adequate caloric 
intake and assess 
volume status.  
Maintain dose.  
 
Grade 2 
Rule out other causes of 
fatigue. 
Consider addition of 4-8 
mg dexamethasone or 
equivalent on the day 
after selinexor.  
Insure adequate caloric 
intake and assess 
volume status. 
For additional support 
see NCCN guidelines. 
Maintain dose. 
Consult medical 
monitor for additional 
option such as 
temporary dose 
reduction or short dose 
interruptions. 
 
Grade 3 
See guidelines for Grade 
2 fatigue 
Interrupt selinexor 
dosing until resolved to 
Grade ≤ 2, For first 
occurrence of Grade 3, 
if adequate supportive 
care resulted in fatigue 
improving to Grade ≤1 
within 7 days, restart 
selinexor at current 
dose.  
Otherwise, restart 
selinexor at one dose 
level below (Table 3). 
 
 
Anorexia or Weight loss 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
26
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose 
Modification 
 
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 4-8 
mg dexamethasone or 
equivalent on 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 4-8 
mg dexamethasone or 
equivalent on the day 
after selinexor.  
Consider megesterol 
acetate 80-400 mg daily. 
Consider anabolic 
steroids such as 
oxandrolone, or 
dronabinol (Marinol®) 
or other cannabinoid, 
mainly for patients who 
can’t tolerate steroids or 
at high risk to progress. 
For additional 
supportive care see 
NCCN guidelinesb  
Selinexor may be 
skipped intermittently 
while supportive 
medications are 
instituted, usually for 
<1 week.  
 
 
Grade 3  
See guidelines for Grade 
2 anorexia. 
Interrupt dosing with 
selinexor.   
Restart selinexor at 1 
dose level reduction 
(Table 3) once anorexia 
resolves to Grade ≤ 2 
and patient is clinically 
stable.   
 

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July 12, 2016 
 
27
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose 
Modification 
 
Grade 4 (anorexia 
only) 
See guidelines for Grade 
2 anorexia. 
Stop dosing of 
selinexor.   
Restart selinexor at 1 
dose level reduction 
(Table 3) 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 4-8 
mg dexamethasone or 
equivalent on the day 
after selinexor.  
Maintain dose. 
 
Grade 2 
See guidelines for Grade 
1 nausea. 
 
For additional options 
see NCCN guidelines 
for antiemesisc  
Selinexor may be 
skipped intermittently 
while supportive 
medications are 
instituted, usually for 
<1 week.  
 
 

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July 12, 2016 
 
28
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose 
Modification 
 
Grade 3 
See guidelines for Grade 
1 nausea 
 
For additional options 
see NCCN guidelines 
for antiemesisc  
Interrupt selinexor 
dosing until resolved to 
Grade ≤ 2, For first 
occurrence of Grade 3, 
if adequate supportive 
care resulted in nausea 
improving to Grade ≤1 
within 3 days, restart 
selinexor at current 
dose.  
Otherwise, restart 
selinexor at one dose 
level below (Table 3).  
If nausea stabilizes for 
at least 4 weeks at 
Grade ≤1, then original 
dose of selinexor may 
be resumed. 
 
Hyponatremia (common) 
Grade 1 (sodium 
levels <Normal to 
130 nM) 
  
Be certain sodium level 
is corrected for 
hyperglycemia (serum 
glucose >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. 
 
 

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July 12, 2016 
 
29
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose 
Modification 
 
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 (Table 3). 
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 guidelines (Benson, 
2004)d.  
Institute standard anti-
diarrheal therapy. 
After the first 
occurrence of diarrhea, 
loperamide 2 mg should 
be considered 
prophylactically 
approximately 1-2 hours 
before the 
administration of 
selinexor and repeated 
every 4 hours for the 
first 12 hours. 
For Grade 2 only, 
reduce selinexor one 
dose level (Table 3) 
until resolved to 
≤ Grade 1, then re-start 
at the current dose 
level. 
 
 

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July 12, 2016 
 
30
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose 
Modification 
 
Grade 3   
  
Institute IV fluids  
Diet recommendation as 
per guidelines (Benson, 
2004)d.  
 
Institute standard anti-
diarrheal therapy. 
 
Once the symptoms 
resolve to ≤Grade 1, 
loperamide 2 mg should 
be considered 
prophylactically 
approximately 1-2 hours 
before the 
administration of 
selinexor and repeated 
every 4 hours for the 
first 12 hours. 
Delay selinexor until 
resolved to ≤ Grade 1, 
then reduce selinexor 
dose by one dose level 
(Table 3). 
If diarrhea stabilizes for 
at least 4 weeks at 
Grade ≤1, then original 
dose of selinexor may 
be resumed. 
 
Grade 4 
Rule out other causes of 
diarrhea, including 
infectious agents. In 
case of opportunistic 
infection, withdraw all 
steroids (with tapering if 
medically appropriate) 
until culture is negative. 
Follow institutional 
guidelines for Grade 4 
diarrhea. 
Delay selinexor until 
resolved to ≤ Grade 1, 
then reduce selinexor 
dose by one dose level 
(Table 3). 
 
 
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 
(Table 3). 
 
Grade 4 
Initiate standard 
supportive care and 
follow institutional 
guidelines. 
Delay dose until 
resolved to Grade ≤1 or 
baseline, then reduce 
by two dose levels 
(Table 3). 
 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
31
Toxicity and 
Intensity 
Supportive treatment 
Selinexor Dose 
Modification 
 
All dose modifications should be based on the worst preceding toxicity. 
* Isolated values of ≥ Grade 3 alkaline phosphatase values will NOT require dose 
interruption.  Determination of liver vs. bone etiology should be made, and evaluation of gamma-
glutamyl transferase (GGT), 5'-nucleotidase (5’NT), or other liver enzymes should be performed. 
aNational Comprehensive Cancer Network®.  NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines®): Fatigue. Available at 
http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf 
bNational Comprehensive Cancer Network®.  NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines®): Palliative Care, version 1.2014. Fort Washington, NY.  April 2014.  
Available 
at: 
http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/p
df/facts.pdf. 
cNational Comprehensive Cancer Network®.  NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines®): Antiemesis, version 2.2014. Fort Washington, NY.  April 2014.  Available 
at: http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. 
dBenson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer 
treatment-induced diarrhea. J Clin Onc 2004; 22:2918. 
 
5.2.3     Intra-patient dose escalation  
  Intra-patient dose escalation of selinexor and sorafenib (in 
accordance with the dosing schema in table 3) will be permitted 
provided: 
 
Patient has completed ≥1 cycle at their current dose level  
 
Patient has not experienced any grade 3 or higher non-
hematologic drug-related toxicity, and 
 
Patient has not experienced hematologic DLT, and 
 
At least 3 patients have been treated at the next higher dose 
level and followed for at least 28 days without experiencing 
DLT.  
 
The dose may be escalated by one dose level per cycle (per 
table 3) provided such dose level does not exceed RP2D. 
 
Dose escalation of only one of the two agents is allowed if 
judged in the best interest of the patient (e.g., in patients 
with anorexia this would be likely secondary to selinexor, 
in patients with skin rash this would be likely secondary to 
sorafenib). However, the dose of any agent cannot be 
escalated beyond the established RP2D for that agent. 
 

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32
5.2.4     Modifications of dose schedules other than the above will be allowed 
within the following guidelines: 
 
5.2.4.1 Further dose reductions can be made to keep clinically significant 
toxicities grade < 2.  
 
5.2.4.2 Dose adjustments by more than 1 dose level at a time (e.g., from 
selinexor 80 mg twice weekly to 40 mg twice weekly) can be 
considered when judged in the best interest of the patient (e.g. severe 
myelosuppression) when toxicity has resolved. The reason for this 
reduction will be discussed with the PI or Co-PI and documented in 
the medical record. 
 
5.2.4.3 A patient who has had a dose reduction because of any of the reasons 
mentioned above may have their dose escalated provided the patient 
has remained free of toxicity requiring dose adjustments as defined 
above for at least 1 month. Escalation will be made by 1 dose-level 
increment only, and not more frequent than every month.  
 
5.2.4.4 Treatment interruptions and dose modifications other than the ones 
mentioned above can be considered after discussion with the PI, 
sponsor 
and 
proper 
documentation 
of 
the 
rationale. 
Dose 
adjustment/delay of only one of the agents is permissible if the toxicity 
is most likely judged to be related to one of the agents by the 
investigator (e.g., in patients with anorexia this would be likely 
secondary to selinexor, in patients with skin rash this would be likely 
secondary to sorafenib). 
 
5.3 Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may 
continue until one of the following criteria applies: 
 
1. Clinically significant progressive disease, or 
 
2. Intercurrent illness that prevents further administration of treatment, or 
 
3. Patient request, or 
 
4. General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator, or 
 
5. Unacceptable toxicity that in the opinion of the investigator makes it 
unsafe to continue therapy. 
 
5.3.1     It is planned that up to a total of 24 cycles of therapy will be 
administered for patients deriving benefit from this regimen. 

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33
Continuation of therapy for patients completing 24 cycles of 
therapy may be considered on a case-by-case basis after 
discussion with the principal investigator.  
 
5.3.2.       All patients receiving at least one dose of any of the two drugs 
will be considered evaluable for toxicity. 
 
5.4 Drug administration 
 
(A) Selinexor administration 
 
5.4.1 Dosage form 
Selinexor tablets are manufactured by KABS Laboratories 
(Montreal, ON) 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.  
Selinexor is an investigational agent supplied to investigators of 
this study by Karyopharm Therapeutics at no cost. 
 
Selinexor will be supplied as clear-coated white to off-white 
tablets for oral administration in two (2) dose strengths: 10 and 25 
mg of active ingredient per tablet, with transition to the 20 mg 
tablets as these supplies become available. The tablets are 
distinguishable by size and debossing (K10 and K25 respectively). 
Bulk bottles of 50 tablets per bottle will be supplied for each of the 
two strengths. The 20 mg tablets will be supplied in blister packs.  
Tablets of selinexor should not be crushed because of increased 
risk of dermatologic toxicity if powder comes in contact with skin. 
20 mg Tablets in Blister Packs 
o Selinexor tablets (20 mg) are currently in ongoing stability 
studies. The expiry will be based on concurrent stability 
studies and extended during the course of the study as 
further stability data becomes available. 
o All selinexor tablets must be kept in an appropriate, limited 
access, secure place until dispensed, destroyed or returned 
to Karyopharm Therapeutics, Inc. or designee for 
destruction. 
o Selinexor tablets can be stored at room temperature or 
refrigerated, at or below 86 ˚F or 30 ˚C, do not freeze. 
Room temperature storage is recommended. The study site 

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34
will be required to maintain a log of the temperature where 
the study medication is stored. 
Each bottle of selinexor tablets will be labelled in accordance with 
current International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP), FDA and specific national requirements. 
Sites must request study drug by submitting an order form directly 
to the drug depot in order for the study drug to be shipped to the 
site pharmacy. The Investigator (or designee) will verify and 
acknowledge receipt of all study drug shipments by signing and 
returning all required forms. 
 
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. 
 
5.4.2    Drug Storage 
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. Tablets will be supplied in white 
high-density polyethylene (HDPE) bottles.  All medication must be 
stored in a secure area under the proper storage requirements with 
access restricted to the site staff pharmacist or designee(s). 
5.4.3 Accountability and Destruction of Investigational Medicinal 
Product  
The Principal Investigator (or an authorized designee) at each 
participating institution must maintain a careful record of the 
inventory of the Investigational medicinal product received using 
the Drug Accountability Form. The study drug will be destroyed as 
per the institutions destruction policies and documentation of study 
drug destruction will be provided to Karyopharm. Both used and 
unused study drug may be returned to Karyopahrm if requested. 
 
5.4.4 Drug Administration 
 
Each dose will consist of selinexor for oral administration on a 
fixed dose basis. Patients should not receive more than a 70 mg/m2 
dose, so the dose given is subject to a BSA limit (example for 100 
mg, a BSA is limited to > 1.43 m2). 

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35
Selinexor doses planned for this study are 80 mg twice weekly and 
100 mg twice weekly.  Potential de-escalation doses are 60 mg 
twice weekly and 40 mg twice weekly. 
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. 
   (B) Sorafenib administration 
Sorafenib is supplied as an immediate-release film-coated, round, 
and salmon color tablet containing 200 mg of the free base, 
Sorafenib, and the excipient croscarmellose sodium, 
microcrystalline cellulose, hydroxypropyl methylcellulose, sodium 
lauryl sulfate, and magnesium stearate. The film-coat consists of 
hydroxypropyl methylcellulose, polyethylene glycol, titanium 
dioxide and red iron oxide. The film coating has no effect on the 
rate of release of the active sorafenib.   
 
If sorafenib is administered on a BID schedule, sorafnib drug doses 
must be separated by intervals of approximately 12 hours (+/-3 
hours).  
 
If a dose is missed, the next dose should not be increased to 
account for missing a dose. The subject should take the next 
regular dose at the regularly scheduled time. If a dose is vomited, 
do not take another dose of medication.  Wait until the next dose is 
due.  Take the next regular dose and do not increase it to account 
for missing a dose. 
 
Modifications to the schedule and/or dose of both/either drugs that 
are thought to be in the best interest of the patient are allowed after 
discussion with and approval by the PI. 
 
5.5 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 400 
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.   
Required Supportive Care Medication 
 
5-HT3 Antagonists 

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36
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). 
 
Besides the required 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: 
 
x Glucocorticoids: dexamethasone (4-12 mg) or equivalent glucocorticoid 
(e.g., prednisone 10-20 mg) on days of, and 1 day after, selinexor dosing 
may improve appetite, reduce nausea or vomiting, and minimize fatigue.  
A maximum of 40 mg dexamethasone or equivalent may be given per 
week. 
x Appetite stimulants: megesterol acetate at a dose of 80-400 mg daily. 
 
x Centrally acting agents: per National Comprehensive Cancer Network® 
[NCCN] Clinical Practice Guidelines® for antiemesis and 
anorexia/cachexia [palliative care]). 
 
x NK1R antagonist:  aprepitant or equivalent should be considered and will 
be covered for selected patients who have severe nausea and vomiting. 
 
5.6 
Concomitant medications 
 
5.6.1 Required Concomitant/Supportive Care Medications  
 
x Oral dexamethasone (4 mg) will be given to all patients with each dose of 
selinexor (±1 day after) to improve tolerability.  Co-administration was 
found to improve appetite, reduce nausea/vomiting, and minimize fatigue 
in patients treated with selinexor.  Higher doses of dexamethasone (or an 
equivalent corticosteroids) may be appropriate for short periods of time.  
For all patients, maximum of 40 mg dexamethasone or equivalent per 
week is permitted. 
 
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). 
 
5.6.2 In general, the use of any concomitant medication/therapies 
deemed necessary for patient supportive care and safety are permitted. 
Since the effect of both selinexor and sorafenib may be delayed for up to 
4 weeks, patients with high WBC counts may receive hydroxyurea prior 
to study entry. Hydroxyurea is allowed before the start of study therapy 

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37
and for the first four weeks on therapy. Hydroxyurea is allowed after 
completion of first cycle of treatment to control high WBC with PI 
approval. Concurrent therapy for CNS prophylaxis or continuation of 
therapy for controlled CNS disease is permitted as defined in inclusion 
criteria 4.1.8. With the exception of these agents, concomitant systemic 
chemotherapy is not permitted.  
 
Concomitant medications are recommended as prophylaxis for nausea, 
vomiting, and infections, and are allowed for managing 
myelosuppression as shown in Table 5.   
 
Table 5: Instructions for the use of concomitant medications and therapies 
Category of Use 
Medication 
Comment on Use 
Restriction on Use 
Recommended 
Prophylactic antibiotics, 
antifungal agents, and 
antiviral agents 
Strongly encouraged 
None 
 
Antiemetic agents 
According to standard 
of care at MDACC 
None 
Allowed 
Oral allopurinol or 
rasburicase 
At investigators 
discretion 
 
None 
 
Leukapheresis 
According to standard 
of care at MDACC 
 
Before induction 1 day 
1 only 
 
Red blood cell 
transfusion 
None 
 
 
None 
 
Platelet transfusion 
None 
 
 
None 
 
White blood cell 
transfusion 
At investigators 
discretion according to 
standard of care at 
MDACC 
 
None 
 
Myeloid growth factors 
or platelet growth factor 
At investigators 
discretion according to 
standard of care at 
MDACC 
 
None 
 
Erythropoietin or 
darbepoetin 
 
At investigators 
discretion according to 
standard of care at 
MDACC 
 
None 
 
Any other medication 
for supportive care 
At investigators 
discretion according to 
standard of care at 
MDACC  
None 
 
 

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38
5.6.3 Use of Blood Products 
During the administration of selinexor, patients may receive red blood 
cell (RBC) or platelet transfusions, if clinically indicated, per institutional 
guidelines.  
 
Myelosuppression is expected in patients with AML due to underlying 
disease, as well as due to therapies (such as selinexor and sorafenib), or 
both. Most patients have neutropenia, thrombocytopenia, or both at study 
entry. Significant or life-threatening myelosuppression may be managed 
with growth factor support including G-CSF, GM-CSF and platelet 
growth factors and erythropoeitn/darbopoetin/blood transfusion 
according to institutional standard of care, American Society of Clinical 
Oncology (ASCO) Practice Guidelines, and/or NCCN Practice 
Guidelines.  
 
5.6.4 Radiation Treatment 
If clinically indicated, palliative radiation therapy to non-target lesions is 
permitted but interruption of study drug is not required based on 
preclinical data and limited clinical observations. Treatment with 
selinexor shall not be discontinued solely due to palliative radiation. 
 
5.6.5 Prohibited Concomitant medications 
Erythropoietin and growth factors are not permitted to be used 
prophylactically in cycle 1 but allowed if needed in cycle 2 and onwards. 
However, these can be used therapeutically throughout the study (see 
section 5.6.3 above). 
 
5.6.6 Drugs undergoing Glutathione conjugation 
The primary metabolism of selinexor in vitro and in vivo appears to 
inactivation by glutathione conjugation. In vitro studies using human 
liver microsomes confirm in vivo findings that selinexor undergoes 
minimal CYP450 metabolism. Therefore, administration of selinexor 
with drugs that undergo substantial glutathione conjugation should be 
minimized. These drugs include acetaminophen (paracetamol), which 
should be avoided 2 hours before and four hours after selinexor dosing. 
Studies of selinexor in combination with acetaminophen are ongoing in 
separate protocols. It should also be noted that ethanol ingestion is 
associated with glutathione depletion, therefore use of products 
containing ethanol should be minimized or avoided on selinexor dosing 
days. 
 
5.6.7 Strong CYP3A4 inducers 
Avoid the concomitant use of strong CYP3A4 inducers (e.g., 
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentine, phenobarbital) as they make decrease the systemic exposure 
to sorafenib. 

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39
 
x Other restrictions and precautions: 
o Alcohol:  Ethanol should be avoided on selinexor dosing days as it may 
compete for glutathione-mediated metabolism. 
o Fasting:  Patients on the selinexor arm should maintain an adequate diet. 
o Medications:  Acetaminophen (paracetamol, Tylenol) and products 
containing acetaminophen (paracetamol) should be avoided 2 hours before 
and 2 hours after dosing with selinexor as it may compete with glutathione 
mediated metabolism. 
o Diet:  There are no dietary restrictions on this study.  Patients on the 
selinexor arm should maintain adequate caloric and fluid intake. 
 
6.0 CORRELATIVE/SPECIAL STUDIES (Optional) 
 
     6.1     Effect of MAPK, AKT signaling and apoptosis induction 
The timetable for collection of peripheral blood will be as defined in section 7.2 
below.  
 
Vectra testing will be done for p53, survivin, FLT3, pPI3K, pAKT, pERK. 
Reverse phase protein assay (RPPA) will be utilized to assess activation of 
FLT3, MAPK, AKT (via detection of phosphorylated FLT3, ERK, pS6, 
p4EBP1 and pAKT). We will analyze induction of apoptosis in AML stem cells 
by 3ಣcolor flow cytometry assay (CD34/annexin V/CMXRos) established in Dr 
Andreeffs laboratory. RT-PCR analysis on selected markers will be done only 
on bone marrow samples.  
 
Peripheral blood for these studies (Vectra, 3-color flow, RPPA) will be 
collected prior to the first dose of selinexor (baseline: day 1) in cycle 1, 24 (+/- 
4) hours post the first dose of selinexor in cycle 1, cycle 1 day 28 (+/- 7 days), 
and at progression/relapse (if available). Bone marrow samples for studies 
(Vectra, 3-color flow, RPPA, PCR) will be collected at baseline (within the last 
7 days preceding the first dose of selinexor), cycle 1 day 28 (+/- 7 days), and at 
progression/relapse (if available). Correlative studies and biomarker evaluation 
will be performed by Dr Andreeff’s lab.  
 
6.2 XPO1 induction/inhibition  
Whole blood (2 tubes X 2.5 mL) will be obtained to assess XPO1 
induction/inhibition in leukocytes prior to the first dose of selinexor and 4 hours 
(+/- 1) hours post the first dose of selinexor on cycle 1 day 1 only, by quantitative 
real time polymerase chain reaction (qRT-CR). Karyopharm Therapeutics will be 
responsible for this testing.  Karyopharm will also analyze a panel of additional 
genes as well as microRNA expression on the blood samples from these time 
points. 
A Karyopharm Therapeutics laboratory manual (Appendix F) and supplies has be 
provided to facilitate testing.  Sample collection and shipment details will be 
included in the laboratory manual. 

 Selinexor and sorafenib in AML - 2014-0975 
July 12, 2016 
 
40
 
6.3 Plasma protein/cytokine analysis 
Plasma samples (2 ml) will be collected prior to the first dose of selinexor and 4 
hours (+/-1) hours post the first dose of selinexor on cycle 1 day 1 only, and will 
be analyzed for plasma proteins/cytokine concentrations. Karyopharm 
Therapeutics will be responsible for this testing. A Karyopharm Therapeutics 
laboratory manual and supplies has been provided to the site in order to facilitate 
testing.  Sample collection and shipment details will be included in the lab 
manual. 
 
7.0 
PATIENT EVALUATION 
 
Every effort will be made to adhere to the schedule of events and all protocol 
requirements. Variations in schedule of events and other protocol requirements that 
do not affect the rights and safety of the patient will not be considered as 
deviations. Such variations may include laboratory assessments completed outside of 
schedule, occasional missed required research samples such correlative assays. 
 
7.1 Pre-Treatment Evaluation 
 
           All pretreatment studies should be obtained within 14 days from time of first 
dose of the study drug administration, unless otherwise specified: 
 
7.1.1 A complete history and physical, concomitant medications and 
performance status. 
 
7.1.2 CBC, platelet count, hemoglobin, differential (differential can be 
omitted if WBC is ≤0.5 x109/L). 
 
7.1.3 Creatinine, BUN, direct bilirubin, total bilirubin, AST, ALT.  
 
7.1.4 Serum or urine pregnancy test in females of childbearing potential, 
should be performed within 72 hours before the initiation of therapy. 
 
7.1.5 Bone marrow aspirate within the last 7 days preceding study initiation.  
 
7.1.6 Evaluation of FLT3-ITD and –D835, NPM1, IDH1 & 2 should have 
been done within 60 days preceding study initiation.   
 
7.1.7 12-lead EKG and ECHO and/or MUGA.  
 
7.1.8 A baseline neurological examination will be documented for all 
patients within the last 7 days preceding study initiation. MRI Brain 
will be performed at the discretion of the treating physician and/or the 
PI if clinically indicated.  
 

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July 12, 2016 
 
41
7.1.9 A baseline full Ophthalmological and Visual Acuity Examination, 
including slit lamp examination and anterior segment photographs for 
cataracts or other abnormalities must be performed at screening and 
must be document for all patients. Follow-up ophthalmologic 
evaluations will be performed if clinically indicated during the study. 
 
7.1.10 Pretreatment optional correlative studies (see section 6.0) 
 
Peripheral blood (up to 35 cc) – (1) Flow cytometry for 
CD34/annexinV/CMXRos, (2) Vectra, (3) RPPA, (4) RT-PCR for 
selected genes, and (5) XPO1 induction/inhibition in leukocytes and 
plasma protein/cytokine analysis in the blood prior to first dose of 
selinexor at baseline (Cycle 1 Day 1) 
 
Bone marrow samples (up to 10 cc): (1) Flow cytometry for 
CD34/annexinV/CMXRos, (2) Vectra, (3) RPPA in the bone marrow 
at baseline, and (4) RT-PCR for selected genes (within the last 7 days 
preceding study initiation) 
 
7.2 Evaluation During Treatment 
 
7.2.1 Physical exam on day 1 of each cycle (± 1 days) for the first 4 cycles, 
then every 1-2 cycles.  
 
7.2.2 CBC, platelet count, hemoglobin, differential at least once weekly for 
the first 3 cycles, then every 2-4 weeks (differential can be omitted if 
WBC is ≤0.5 x109/L).  Outside labs may be used, but the PI/Treating 
physician must review all protocol specific outside lab results and 
determine the clinical significance of abnormal values then sign/date 
the results or dictate this process in the medical record. 
 
7.2.3 Creatinine, BUN, total bilirubin, ALT, AST weekly (r4 days) for the 
first 3 cycles, then every 2-4 weeks. 
 
7.2.4 Laboratory tests can be ordered more frequently if mandated by 
development of peripheral blast/blood counts or electrolyte/liver 
function test abnormalities. 
 
7.2.5 Bone marrow aspiration for differential and PCR for FLT3 on day 28 
(±7 days) of cycle 1, day 28 of cycle 3 (±7 days), then every 1-3 
cycles. Bone marrow tests can be ordered more frequently if mandated 
by development of peripheral blood counts. No repeat bone marrow is 
necessary if nonresponse or progressive disease can be unequivocally 
diagnosed from peripheral blood tests or, in patients with a WBC < 0.3 
if the bone marrow test is considered noncontributory by the 
investigator at any time point. 

 Selinexor and sorafenib in AML - 2014-0975 
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42
 
7.2.6 Concomitant medication data will not be collected or entered into the 
case report form (PDMS is the case report form for this study). 
Concomitant medication data will not be collected or entered into the 
case report form except for concomitant hydroxyurea if administered 
during the first cycle; however, the subject’s medication record will 
contain a list of concomitant medications. 
 
7.2.7 12-lead EKG will be performed on day 1 (±1 day) of each cycle for the 
first 4 cycles, then every 1-3 cycles 
 
7.2.8 Peripheral blood (up to 35 cc each time) and bone marrow (up to 10 cc 
each time) for pharmacodynamic studies (Optional) as defined in 
section 6.2 on  
 
x 
Peripheral blood: 
x 
Prior to first dose of selinexor at baseline (Cycle 1 Day 1) as 
per section 7.1.10. 
x 
Cycle 1 Day 1: 4 (+/- 1) hours after the first dose of selinexor 
to evaluate (1) XPO1 induction/inhibition in leukocytes and (2) 
plasma protein/cytokine analysis 
x 
Cycle 1 Day 2: 24 (+/-4) hours after first dose of selinexor for 
evaluation of (1) Flow cytometry for CD34/annexin 
V/CMXRos, (2) Vectra, (3) RPPA, and (4) RT-PCR for 
selected genes 
x 
Cycle 1 Day 28 (+/- 7 days): for evaluation of (1) Flow 
cytometry for CD34/annexinV/CMXRos, (2) Vectra, (3) 
RPPA, and (4) RT-PCR for selected genes 
x 
At progression/relapse (if sample available): for evaluation of 
(1) Flow cytometry for CD34/annexinV/CMXRos, (2) Vectra, 
(3) RPPA, and (4) RT-PCR for selected genes 
 
x 
Bone marrow samples: 
x 
At screening (within the last 7 days preceding study initiation) 
as per section 7.1.10.  
x 
At the time of disease assessment on day 28 (+/- 7 days): for 
evaluation of (1) Flow cytometry for 
CD34/annexinV/CMXRos, (2) Vectra, (3) RPPA, and (4) RT-
PCR for selected genes 
x 
At progression/relapse (if sample available): for evaluation of 
(1) Flow cytometry for CD34/annexinV/CMXRos, (2) Vectra, 
(3) RPPA, and (4) RT-PCR for selected genes 
 
x 
Missed samples for correlative studies will not constitute 
protocol deviations. These studies are optional on this protocol. 
 

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43
7.2.9 All treatment prescriptions for sorafenib and selinexor must be 
written by the patient’s attending physician at MDACC or the PI of 
the study. We do not intend for the subjects to receive prescriptions for 
sorafenib or selinexor at an outside physician’s office. During the first 
cycle all the protocol required laboratory evaluations will be done at 
MDACC. Subsequently, the patient may have the laboratory work 
done at a local clinic and the results reported to the research nurse 
for the study. The laboratory work done at the local clinic will be 
forwarded to the patient’s attending physician at MDACC or PI of 
the study, who will sign off on the labs to verify that the results have 
been reviewed. 
 
      Outside Physician Participation During Treatment 
 
1. MDACC Physician communications with the outside physician 
is required prior to the patient returning to the local physician.  
This will be documented in the patient record. 
 
2. A letter to the local physician outlining the patient's participation 
in a clinical trial will request local physician agreement to 
supervise the patient's care (Appendix G). 
 
3. Protocol required evaluations outside MDACC will be 
documented by telephone, fax or e-mail. The PI/treating physician 
must review the labs, determine clinical significance and sign and 
date the report.  
 
4. A copy of the informed consent, protocol abstract, treatment 
schema and evaluation during treatment will be provided to the 
local physician. 
 
5. Documentation to be provided by the local physician will 
include progress notes, reports of protocol required laboratory and 
diagnostic studies and documentation of any hospitalizations. 
 
6. The home physician will be requested to report to the MDACC 
physician investigator all life threatening events within 24 hours of 
documented occurrence. 
 
           7. All follow-up visits will be performed at MDACC. 
 
           8. Changes in drug dose and/or schedule must be discussed with 
and approved by the MDACC physician investigator, or their 
representative prior to initiation, and will be documented in the 
patient record. 
 

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44
7.2.10 For patients that remain on study with no significant toxicity for 
more than 6 months, subsequent evaluations during study may be 
modified after discussion with the PI. These include a decrease in 
frequency of bone marrow aspirations to every 6-12 months (or as 
clinically indicated) and other laboratory tests to once every cycle.  
 
7.2.11 Pregnancy test (urine or serum) in females of childbearing potential 
every 3 months (±2 weeks).  
 
7.2.12 Patients with an objective response will be followed for survival at 
MD Anderson Cancer Center (MDACC) every 3 to 6 months after 
the end of treatment visit for up to 5 years after completion of 
active treatment. If the patient is unable to return to MDACC the 
follow-up visits may be conducted via telephone. 
 
8.0 CRITERIA FOR RESPONSE 
Response criteria will be modified from the International Working Group for AML34.  
Responders are patients who obtain a Composite Complete Remission Rate (CRc) with or 
without cytogenetic response, hematologic improvements, and morphologic leukemia-
free state. CRc rate is defined as the confirmed remission rate of all complete and 
incomplete CRs (i.e., CR+ CRp + CRi). 
 
8.1 Complete Remission (CR) 
For patients to be classified as being in CR, they must have bone marrow 
regenerating normal hematopoietic cells and achieve a morphologic leukemia-free 
state and must have an ANC > 1 × 109/L and platelet count ≥ 100 × 109/L, and normal 
marrow differential with < 5% blasts, and patients will be red blood cell (RBC) and 
platelet transfusion independent (defined as 4 weeks without RBC transfusion and 1 
week without platelet transfusion). There should be no evidence of extramedullary 
leukemia. 
 
8.2 Complete Remission with Incomplete Platelet Recovery (CRp) 
For patients to be classified as being in CRp, they must achieve CR except for 
incomplete platelet recovery (< 100 × 109/L). 
 
8.3 Complete Remission with Incomplete Hematological Recovery (CRi) 
For patients to be classified as being in CRi, they must fulfill the criteria for CR 
except for incomplete hematological recovery with residual neutropenia (ANC ≤ 1 × 
109/L) with or without thrombocytopenia (platelet count < 100 × 109/L). In addition, 
patients do not need to be RBC or platelet transfusion independent (modification to 
Cheson criteria). 
 
8.4 Partial Remission (PR) 
For patients to be classified as being in PR, they must have bone marrow regenerating 
normal hematopoietic cells with evidence of peripheral recovery with no (or only a 
few regenerating) circulating blasts and with a decrease of at least 50% in the 

 Selinexor and sorafenib in AML - 2014-0975 
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45
percentage of blasts in the bone marrow aspirate with the total marrow blasts between 
5% and 25%. 
 
8.5 Morphologic leukemia-free state:  
        Bone marrow: 5% myeloblasts   
 
8.6 Hematologic Improvement (HI): Hematologic response must be described by 
the number of positively affected cell lines. 
 
i Erythroid response (E) (pretreatment Hgb <11 g/dL) 
 
Hgb increase by 1.5 g/dL 
 
i Platelet response (P) (pretreatment platelets <100 x109/L) 
 
Absolute increase of 30 x 109/L for patients starting with > 20 x 109/L platelets 
          Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 
 
i Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
 
At least 100% increase and an absolute increase > 0.5 x 109/L 
 
i Blast response (B) 
          ≥50% reduction in peripheral blood or bone marrow blasts but still >5% 
 
8.7 Recurrence of Disease 
Relapse after CR is defined as a reappearance of leukemic blasts in the peripheral 
blood or ≥ 5% blasts in the bone marrow aspirate not attributable to any other cause 
or reappearance or new appearance of extramedullary leukemia. Relapse after PR is 
similarly defined with reappearance of significant numbers of peripheral blasts and an 
increase in the percentage of blasts in the bone marrow aspirate to > 25% not 
attributable to any other cause or reappearance or new appearance 
of extramedullary leukemia. 
 
8.8 Best Response measurement 
Response will be measured and defined for primary endpoints as the best response 
achieved during the first 3 cycles of therapy, or at time off study, for those patients 
discontinuing treatment before the completion of 3 cycles of therapy. Best response is 
defined to be the best-measured response (CRc=CR+CRp+CRi, PR, or marrow 
clearance) post-treatment up to that time. Best response will also be evaluated for the 
full treatment period using all assessments up to and including treatment 
discontinuation. 
 
9.0 DISCONTINUATION OF TREATMENT: 
 
9.1 Discontinuation Criteria for Individual Patients 
 
9.1.1 Patient Withdrawal 

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46
Patients may voluntarily withdraw consent to participate in the clinical study at any 
time and without giving any reason. Their withdrawal will not jeopardize their 
relationship with their healthcare providers or affect their future care. Patients may 
also choose to withdraw from study treatment, but agree to remain in the study for 
follow-up procedures.  
 
9.1.2 Investigator Discontinuation of Patient 
The investigator may exercise medical judgment to discontinue study treatment if 
clinically significant changes in clinical status or laboratory values are noted. 
 
9.1.3 Criteria for Protocol-Defined Required Discontinuation of Treatment 
The protocol requires discontinuation of study treatment for the following reasons: 
1.  Patient requests discontinuation. 
2.  Unacceptable toxicity that in the opinion of the investigator makes it unsafe to     
continue therapy.  
3. Clinically significant progressive disease.  
4. Investigator discretion.  
 
9.1.4 Follow-Up at Treatment Discontinuation or Early Withdrawal 
Patients who discontinue treatment for any reason should complete end-of-treatment 
procedures when possible. End of treatment procedures will include a physical 
examination, CBC with differential and platelets and a limited chemistry profile (total 
bilirubin, serum creatinine, SGPT or SGOT). A bone marrow aspiration may be 
recommended only if non-response or progressive disease cannot be unequivocally 
diagnosed from peripheral blood. Although treatment will be discontinued at that 
time, all patients who do not withdraw consent for follow-up, die, or become lost to 
follow-up, will remain on study for follow-up evaluations. Subject will be followed 
for toxicity for at least 30 days after the last protocol treatment. The 30-day (+/-7 
days) follow-up visit will be scheduled as a clinic visits for clinical evaluation and 
physical examinations. If the patient cannot make it to the MDACC clinic for this 
visit, the required follow up treatment procedures may be done with a local physician 
and the records forwarded to MDACC. The research nurse will contact the patient by 
telephone and get a verbal assessment of the patient’s condition. The phone 
conversation will then be documented in the patient’s charts.  
 
9.2 Study Stopping Rules 
The principal investigator and MDACC IND office have the right to terminate this 
clinical study at any time. The principal investigator and MDACC IND office, as 
appropriate, will be involved in any decisions regarding terminating the study, 
temporarily suspending enrollment, or stopping ongoing treatment with study 
treatment. 
Reasons for terminating the clinical study or a study site’s participation include, but 
are not limited to, the following: 
x The incidence or severity of an adverse reaction related to treatment in this study 
or other studies indicates a potential health hazard to patients 
x Data recording is significantly inaccurate or incomplete 

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47
x Study site personnel are noncompliant with study procedures 
x Pattern of noncompliance is observed 
 
9.3 Protocol Violations and Deviations 
Protocol violations are defined as significant departures from protocol-required 
processes or procedures that affect patient safety or benefit potential, or confound 
assessments of safety or clinical activity. A protocol deviation is a departure from the 
protocol that does not meet the above criteria. Protocol violations or deviations may 
be grouped into the following classes: 
x Enrollment criteria 
x Study activities (missed evaluations or visits) except for those allowed per 
protocol 
x Noncompliance with dose or schedule, including dose calculation, administration, 
interruption, reduction, or delay; or discontinuation criteria 
x Investigational product handling, including storage and accountability 
x Informed consent and ethical issues 
 
10.0 ADVERSE EVENT REPORTING 
 
10.1     Adverse event is any untoward medical occurrence that may present during 
treatment with a pharmaceutical product but which does not necessarily have a 
causal relationship with this treatment.  
 
 
Adverse drug reaction is a response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for the modification of physiologic function.  
 
 
Assessing causal connections between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a 
contributory cause of an adverse event if, had the drug not been administered, 1) 
the event would not have happened at all, 2) the event would have occurred later 
than it actually did, or 3) the event would have been less severe. 
 
 
The Investigator or physician designee is responsible for providing source 
documentation and assigning attribution for all AEs.  
 
10.2     Adverse Events (AEs) will be evaluated against the most current version of the 
selinexor and sorafenib Investigator Brochure (Appendix C and D) for 
expectedness. Adverse Events (AEs) will be evaluated according to the latest 
CTCAE version 4.03 (Appendix E) and documented in medical record.  AEs will 
be recorded in the Case Report Form (CRF) as per appendix I.  Expected events 
during leukemia therapy are: 
  
10.2.1 Myelosuppression related events (due to disease or leukemia 
therapy) 
 

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48
10.2.1.1 febrile or infection episodes not requiring management in 
the intensive care unit 
 
10.2.1.2 epistaxis or bleeding except for catastrophic CNS or 
pulmonary hemorrhage 
 
10.2.1.3 anemia, neutropenia, lymphopenia, thrombocytopenia, 
leukopenia 
 
10.2.2 Disease related events 
 
10.2.2.1 symptoms associated with anemia 
 
-fatigue 
 
-weakness 
 
-shortness of breath 
 
10.2.2.2 electrolyte abnormalities (sodium, potassium, bicarbonate, 
CO2, magnesium) 
 
10.2.2.3 chemistry abnormalities (LDH, phosphorus, calcium, 
BUN, protein, albumin, uric acid, alkaline phosphatase, glucose) 
 
10.2.2.4 coagulation abnormalities 
 
10.2.2.5 disease specific therapy (induction, maintenance, salvage, 
or stem cell therapy) 
 
10.2.2.6 alopecia 
 
10.2.2.7 bone, joint, or muscle pain 
 
10.2.2.8 liver function test abnormalities associated with infection 
or disease progression 
 
10.2.2.9 disease progression 
 
10.2.2.10 abnormal hematologic values  
 
10.2.3 General therapy related events 
 
10.2.3.1 catheter related events 
 

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49
10.2.3.2 renal failure related to tumor lysis syndrome or antibiotic/ 
antifungal therapy 
 
10.2.3.3 rash related to antibiotic use 
 
10.3 Abnormal hematologic values will not be recorded on the case report 
form. For abnormal chemical values, the apogee or nadir (whichever is 
appropriate) will be reported per course on the case report form, unless 
the event is considered a DLT as listed in section 3.4.  
 
10.4 Serious Adverse Event Reporting (SAE) 
An adverse event (AE) or suspected adverse event is considered “serious” if, 
in the view of either the investigator or the sponsor, it results in any of the 
following outcomes:  
 
x Death 
x A life-threatening adverse drug experience – any adverse experience 
that places the patient, in the view of the initial reporter, at immediate 
risk of death from the adverse experience as it occurred. It does not 
include an adverse experience that might have caused death if it had 
occurred in a more severe form,. 
x Inpatient hospitalization or prolongation of existing hospitalization 
x A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
x A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug 
abuse (21 CFR 312.32). 
 
x Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should 
be reported as an SAE if deemed appropriate by the Principal 
Investigator or the IND Sponsor, IND Office.     
 
x 
All events occurring during the conduct of a protocol that meet the 
definition of a SAE must be reported to the IRB in accordance with 
the timeframes and procedures outlined in “University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs 

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50
and Devices.” Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the 
event). 
 
x 
All life-threatening or fatal events, that are unexpected, and related 
to the study drug, must have a written report submitted within 24 
hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office.   
 
x 
Unless otherwise noted, the electronic SAE application (eSAE) will 
be utilized for safety reporting to the IND Office and MDACC IRB.  
 
x 
Serious adverse events will be captured from the time of the first 
protocol-specific intervention, until 30 days after the last dose of 
drug, unless the participant withdraws consent. Serious adverse 
events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event 
has stabilized, or there has been acceptable resolution of the event. 
 
x 
Additionally, any serious adverse events that occur after the 30-day 
time period that is related to the study treatment must be reported to 
the IND Office and Karyopharm Therapeutics, Inc. This may include 
the development of a secondary malignancy.  
 
x 
All cases of selinexor or sorfenib overdose (defined as accidental or 
intentional ingestion of any dose of the product that is considered 
excessive and medically important) must be reported as an SAE to the 
Sponsor (MDACC IND office) and to the supporting company on the 
SAE Form.  
 
x 
Pregnancy alone is not considered an AE. However, if a patient 
becomes pregnant or causes a pregnancy during treatment or within 4 
weeks of ending treatment, even if the subject is withdrawn from the 
study, the pregnancy must be reported immediately to the sponsor 
(MDACC IND office) on the MD Anderson SAE Form and to the 
supporting company within 1 days of the Investigator’s knowledge of 
the pregnancy. The investigator should abide by necessary regulation 
for medical release from a female partner of a male subject prior to 
obtaining follow up. The investigator will follow the pregnancy to 
term or termination, will collect data on both the maternal and fetal 
outcome and will report all outcomes as a follow-up report to the 
initial pregnancy notification to the supporting company, Karyopharm 
Inc.. 
Notwithstanding, all pregnancy outcomes that meet the regulatory 
definition of serious (i.e. spontaneous abortion, neonatal death, 

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51
congenital anomaly in an aborted fetus or neonate) will be reported 
on the MD Anderson SAE Form to the sponsor (MDACC IND office) 
and the supporting companies within 24 hours of Investigator 
knowledge of the outcome.   
 
10.5 Reporting to FDA 
Serious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI, and the research team, to ensure 
serious adverse events are reported according to the Code of Federal 
Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
 
            10.6 Serious Adverse event Reporting to Karyopharm Inc. 
All SAEs, whether related or unrelated to selinexor, pregnancies and 
reports of overdose regardless of suspected causality and expectedness 
will be reported immediately but not later than 24 hours of the PI 
becoming aware of the SAE to Karyopharm’s SAE Management team 
who will ensure data is captured in Karyopharm’s Pharmacovigilance 
system.  The PI will forward completed SAE and pregnancy forms by 
email to pvg@karyopharm.com.  
 
 
Information not available at the time of the initial report (e.g., an end date 
for the adverse event or laboratory values received after the report) must 
be documented on a follow-up report. A final report to document 
resolution of the SAE is required. 
 
11.0 STATISTICAL CONSIDERATIONS 
 
The primary objectives of the study are to evaluate safety and efficacy of selinexor in 
combination with sorafenib in patients with FLT3-ITD and –D835 mutated AML. The 
total accrual is 52 patients (Phase I: up to 12 patients and Phase II: 20 patients per 
cohort). 
 
11.1 Phase I  
In order to determine the MTD of selinexor in combination with sorafenib, we will use 
the standard 3+3 design for dose finding. The MTD is defined as the highest dose level 
with </= 1 out of 6 patients experience a DLT during the first 28 days of treatment. DLT 
is defined in section 3.4 (page 13). The 3+3-dosing algorithm is presented in section 3.3 
and the dosing schema for the combination treatment is shown in Table 3. The RP2D will 
be selected at the end of the phase I portion based on safety and efficacy of selinexor and 
sorafenib after discussion with the sponsor and the supporting company (Karyopahrm). 
The Investigator is responsible for completing the cohort summary template prior to 
advancing subjects to the phase II part. Once RP2D has been established, any patients 

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52
still on study at a dose lower than RP2D can be dose escalated up to RP2D in accordance 
with the dose-escalation guidelines in section 5.2.3. 
 
11.2 Phase II 
The primary objective of the phase II is to evaluate the efficacy of the combination. The 
study has two cohorts (maximum of 20 patients for each cohort): (1) FLT3-ITD and –
D835 mutated relapsed/refractory AML previously exposed to any FLT3 inhibitor, and 
(2) FLT3-ITD and –D835 mutated relapsed/refractory AML with no prior exposure to 
any FLT3 inhibitor.  
For all the cohorts, the primary endpoint is the achievement of CRc (CRc=CR/CRp/CRi) 
at any time during the first three cycles of therapy and toxicity assessed at the end of one 
cycle of therapy. CRc and toxicity will be monitored simultaneously using the Bayesian 
approach of Thall, Simon, Estey (1995, 1996) and the extension by Thall and Sung 
(1998) separately for each cohort. Multc Lean Desktop (version 2.1) was used to generate 
the stopping boundaries and the OC tables for futility and toxicity monitoring.  
 
x Cohort #1: Patients with relapse FLT3-ITD and –D835 mutant AML 
(FLT3 inhibitor naïve cohort):  
 
The historical data suggested a CRc rate of 20% for this population and 
the target CRc with selinexor and sorafenib combination is 35%. The 
treatment will be considered worthy of further investigation if it elicits an 
increase in CRc to 35% with acceptable toxicity. A >30% therapy related 
non-hematological grade 3/4 toxicity rate is considered unacceptable. 
Given this, we will stop enrollment into this cohort if the observed 
patients’ data suggest that: 
 
1) Pr (CRcE> CRcH +0.15|data) < 0.025 or 
2) Pr (TOXE> 0.30|data) > 0.90 
 
Here CRcE and CRcH are the CRc rate for selinexor in combination with 
sorafenib and the historical treatment, respectively. TOXE is the toxicity 
rate for selinexor in combination with sorafenib. That is, if at any time 
during the study we determine that there is a less than 2.5% chance that 
the average CRc rate improves over historical CRc rate by more than 15% 
we will stop enrollment to this cohort. The second condition will stop the 
study early if excessive therapy-related non-hematological grade 3/4 
toxicity (>30%) is highly probable (i.e., probability >90.0%) for the CRcE 
and CRcH are assumed to follow a prior of Beta (0.4, 1.6) and a constant 
of 20%, respectively. The stopping boundaries for CRc, based on these 
assumptions and monitoring conditions are found in Table 6. We will 
apply these stopping boundaries continuously starting from the fifth 
patient in a cohort size of 5 patients.  For example, accrual will cease if 0 
patients experiences CRc among the first 10 patients treated.  
Table 6. Stopping boundaries for CRc rate 
Stop accrual if the number with overall response is less than or equal to indicated (i.e., # 

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53
patients with overall response) among the number of patients evaluated 
Number of patients evaluated for 
CRc 
5 
10 
15 
20 
Number of patients with CRc  
(i.e., CR, CRp, or CRi)  
is less than or equal to 
0 
0-1 
0-2 
Always stop with 
this many patients 
 
The monitoring rule for the toxicity rate, based on these assumptions and 
monitoring conditions above is found in Table 7. For example, accrual 
will cease if 4 or more patients experience toxicities among the first 5 
patients. 
Table 7. Stopping boundaries for Toxicity 
Stop accrual if the number of drug-related non-hematological grade 3/4 toxicities is 
greater than or equal to indicated (i.e., # patients with toxicities) among the number of 
patients evaluated 
# patients evaluated  
5 
10 
15 
20 
# patients with toxicities 
4-5 
6-10 
8-15 
Always stop with this many 
patients 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and 
futility stopping boundaries and the OC table (Table 8). In order to utilize 
the software for the design, a 20.0% ORR and beta (0.4, 1.6) priors were 
assumed for the standard treatment response distribution and experimental 
treatment response prior distribution, respectively. In addition, a 30% 
toxicity constant rate and beta (0.6, 1.4) priors were assumed for the 
standard treatment toxicity constant rate and experimental treatment 
toxicity prior distribution, respectively. 
 
The probability of stopping the study early if the true ORR of the 
combination treatment was 35% and the true toxicity rate was 30% was 
23.8%.  Probabilities of stopping early for high true toxicity rates (i.e., 
50%) were 63.3% when the true ORR was 35% and 57.5% when true 
ORR rate was 50%. 
 
Table 8.  Operating characteristics for simultaneous monitoring response and toxicity 
rates for patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.20 
0.5391 
 
0.25 
0.3835 
 
0.35 
0.1686 
 
0.45 
0.0642 
 
0.50 
0.0378 
0.20 
0.20 
0.5450 
 
0.25 
0.3913 
 
0.35 
0.1791 

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54
Table 8.  Operating characteristics for simultaneous monitoring response and toxicity 
rates for patients treated with combination treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
 
0.45 
0.0760 
 
0.50 
0.0499 
0.30 
0.20 
0.5778 
 
0.25 
0.4352 
 
0.35 
0.2384 
 
0.45 
0.1427 
 
0.50 
0.1185 
0.40 
0.20 
0.6650 
 
0.25 
0.5519 
 
0.35 
0.3957 
 
0.45 
0.3198 
 
0.50 
0.3006 
0.50 
0.20 
0.7965 
 
0.25 
0.7278 
 
0.35 
0.6330 
 
0.45 
0.5869 
 
0.50 
0.5752 
 
 
 
x Cohort #2: Patients with relapsed FLT3-ITD and –D835 mutant AML 
(FLT3 inhibitor failure cohort)   
 
The historical data suggested a CRc rate of 10% for this population and 
the target CRc rate with selinexor ad sorafenib combination is 20%. Given 
this, we will stop enrollment into this cohort if the observed patients’ data 
suggest that: 
 
1) Pr (CRcE> CRcH +0.10|data) < 0.025 
2) Pr (TOXE> 0.30|data) > 0.875 
 
Here CRcE and CRcH are the CRc rate for selinexor in combination with 
sorafenib and historical treatment, respectively. TOXE is the toxicity rate 
for selinexor in combination with sorafenib. That is, if at any time during 
the study we determine that there is a less than 2.5% chance that the 
average CRc rate improves over historical rate by more than 10% we will 
stop enrollment to this cohort. CRcE and CRcH are assumed to follow a 
prior of Beta (0.2, 1.8) and constant of 10%, respectively. The second 
condition will stop the study early if excessive therapy-related non-
hematological grade 3/4 toxicity (>30%) is highly probable (i.e., 
probability >95.0%). The stopping boundaries for CRc rate, based on 
these assumptions and monitoring conditions are found in Table 9. We 

 Selinexor and sorafenib in AML - 2014-0975 
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55
will apply these stopping boundaries continuously starting from the fifth 
patient and in cohort size of 5 patients. For example, accrual will cease if 
no patient experiences CRc among the first 10 patients treated.  
 
Table 9. Stopping boundaries for CRc rate 
Stop accrual if the number with overall response is less than or equal to indicated (i.e., # 
patients with overall response) among the number of patients evaluated 
Number of patients evaluated for CRc 
5 
10-15 
20 
Number of patients with CRc  
(i.e., CR, CRp, or CRi)  
is less than or equal to 
Never stop 
with this 
many patients 
0 
Always stop with 
this many patients 
 
The monitoring rule for the toxicity rate, based on these assumptions and 
monitoring conditions above is found in Table 10. For example, accrual 
will cease if 4 or more patients experience toxicities among the first 5 
patients. 
Table 10. Stopping boundaries for Toxicity 
Stop accrual if the number of drug-related non-hematological grade 3/4 toxicities is 
greater than or equal to indicated (i.e., # patients with toxicities) among the number of 
patients evaluated 
# patients evaluated  
5 
10 
15 
20 
# patients with toxicities 
4-5 
5-10 
7-15 
Always stop with this many 
patients 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and 
futility stopping boundaries and the OC table (Table 11). In order to utilize 
the software for the design, a 10.0% ORR and beta (0.2, 1.8) priors were 
assumed for the standard treatment response distribution and experimental 
treatment response prior distribution, respectively. In addition, a 30% 
toxicity constant rate and beta (0.6, 1.4) priors were assumed for the 
standard treatment toxicity constant rate and experimental treatment 
toxicity prior distribution, respectively. 
 
The probability of stopping the study early if the true ORR of the 
combination treatment was 30% and the true toxicity rate was 20% was 
28.2%.  Probabilities of stopping early for high true toxicity rates (i.e., 
50%) were 77.8% when the true ORR was 20% and 75.8% when true 
ORR rate was 30%. 
 
 
Table 11.  Operating characteristics for simultaneous monitoring response and toxicity 
rates for patients treated with combination treatment  
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 

 Selinexor and sorafenib in AML - 2014-0975 
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56
Table 11.  Operating characteristics for simultaneous monitoring response and toxicity 
rates for patients treated with combination treatment  
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.10 
0.3500 
 
0.15 
0.1985 
 
0.20 
0.1092 
 
0.25 
0.0582 
 
0.30 
0.0302 
0.20 
0.10 
0.3756 
 
0.15 
0.2301 
 
0.20 
0.1443 
 
0.25 
0.0953 
 
0.30 
0.0684 
0.30 
0.10 
0.4761 
 
0.15 
0.3540 
 
0.20 
0.2820 
 
0.25 
0.2410 
 
0.30 
0.2184 
0.40 
0.10 
0.6552 
 
0.15 
0.5748 
 
0.20 
0.5274 
 
0.25 
0.5004 
 
0.30 
0.4855 
0.50 
0.10 
0.8381 
 
0.15 
0.8003 
 
0.20 
0.7781 
 
0.25 
0.7654 
 
0.30 
0.7584 
 
 
11.3 Statistical Analysis Plan 
All patients who received any dose of the study agent will be included in the analysis for 
efficacy and safety.  Demographic/clinical characteristics (including duration of 
response) and safety data of the patients will be summarized using descriptive statistics 
such as mean, standard deviation, median and range. For the primary efficacy analysis, 
we will estimate the ORR for the combination treatment, along with the 95% confidence 
interval.  In addition, we will estimate composite CRc rate, partial response and marrow 
clearance rate within 3 months by FLT3 mutation. Patients who drop out of the study 
before completing all the cycles will be treated as “failures” for the primary analysis. 
ORR during the study period will also be presented with the 95% confidence interval. 
The association between ORR and patient’s clinical characteristics will be examined by 
Wilcoxon’s rank sum test or Fisher’s exact test, as appropriate. Toxicity type, severity 
and attribution will be summarized for each patient using frequency tables.  

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57
The distribution of time-to-event endpoints (DFS and OS) including overall survival and 
progression free survival will be estimated using the method of Kaplan and Meier. 
Comparisons of time-to-event endpoints by important subgroups will be made using the 
log-rank tests. Paired t-tests will be used to determine the immunological and molecular 
changes in the peripheral blood and bone marrow from baseline to the time of response, 
and to the time of disease progression.  
 
 
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