Clinical trial NCT03071276
Conditions: Acute Myeloid Leukemia (AML)
Sponsor: St. Jude Children's Research Hospital
Start date: 2016-01-14; Completion date: 2019-04-30
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will be done in two parts: Phase I (NCT02212561) has been completed and published. The goal of the Phase I portion of this study was to find the highest tolerable dose of selinexor (KPT-330) that can be given to patients with leukemia or myelodysplastic syndrome (MDS), when it is combined with fludarabine and cytarabine.

The Phase II portion of the protocol is reflected in this registration.

The goal of the Phase II portion of this protocol is to give the highest dose of selinexor (KPT-330) in combination with fludarabine/cytarabine that was found in Phase I to be safe for children with acute myeloid leukemia (AML). The investigators will examine the effect of this combination treatment.

Detailed description:
After the recommended Phase II dose was determined, additional patients began enrolling to receive selinexor at the recommended dose level for further evaluation of tolerability and response.

PRIMARY OBJECTIVE:

* To estimate the overall response rate, as defined by complete response or complete response with incomplete count recovery, of selinexor in combination with fludarabine and cytarabine for patients with relapsed or refractory AML in the phase II portion of the study.

Arms: arm 1: Interventions: Selinexor, Fludarabine, and Cytarabine. Methotrexate/hydrocortisone/cytarabine (intrathecal triples) will be given prior to cycle 1.
Interventions: intervention 1: Selinexor intervention 2: Fludarabine intervention 3: Cytarabine intervention 4: methotrexate/hydrocortisone/cytarabine
Intervention descriptions: intervention 1: Given orally on days 1,3,8,10,22 and 24 of each cycle intervention 2: Will be given intravenously (IV) over 30 minutes daily on days 16 through 20. Fludarabine may be given prior to day 16 if it is determined to be in the participant's best interest based on disease progression. Chemotherapy may be delayed by 1-3 days if clinically indicated. intervention 3: Will be given IV over 4 hours daily on days 16 through 20. Cytarabine may be given prior to day 16 if it is determined to be in the participant's best interest based on disease progression. Chemotherapy may be delayed by 1-3 days if clinically indicated. intervention 4: Intrathecal (IT) triples will be given prior to cycle 1: IT cytarabine, IT methotrexate, and IT methotrexate/hydrocortisone/cytarabine (MHA) are acceptable. Patients without evidence of central nervous system (CNS) leukemia will receive no further IT therapy during cycle 1. Patients with CNS disease will receive weekly ITMHA until the cerebrospinal fluid becomes free of leukemia (minimum of 4 doses).

Protocol documents:
Prot_SAP_000.pdf: 
SELHEM 
Amendment 6.0, dated: 03-24-2017 
Protocol document dated: 03-24-2017 
IRB Approval date: 05-02-2017 
 
 
 
St. Jude 
SELHEM CTG# - NCT03071276 
Initial version, dated: 03-27-2014. Resubmitted to CT-SRC 05-07-2014. Resubmitted to IRB 
07-02-2014. Resubmitted to IRB 07-24-2014 (IRB approved: 07-28-2014) 
Activation date: 08-06-2014 
Amendment 1.0, dated 11-10-2014. Resubmitted to CT-SRC 12-23-2014. Resubmitted to IRB 
01-29-2015 (IRB approved:02-02-2015) 
Activation date: 02-18-2015 
Amendment 2.0, dated 10-16-2015. Resubmitted to IRB 11-11-2015 (IRB approved:  11-17-2015). 
Activation date: 01-04-2016 
Amendment 3.0, dated 05-23-2016. Resubitted to IRB 07-20-2016 (IRB approved: 08-18-2016) 
Activation date: 08-19-2016 
Amendment 4.0, dated 11-22-2016. (IRB approved: 01/10/2017) Activated: 02-14-2017 
Amendment 5.0, dated 03-07-2017. (IRB approved: 03-21-2017) Activated: 03-31-2017 
Amendment 6.0, dated 03-24-2017. (IRB approved: 05-02-2017) Activated: 05-05-2017 
 
 
A PHASE I/II STUDY OF THE SELECTIVE INHIBITOR OF NUCLEAR 
EXPORT SELINEXOR (KPT-330) IN COMBINATION WITH FLUDARABINE 
AND CYTARABINE IN PEDIATRIC PATIENTS WITH REFRACTORY OR 
RELAPSED LEUKEMIA OR MYELODYSPLASTIC SYNDROME 
 
IND# 122,979 
 
Principal Investigator 
Jeffrey E. Rubnitz, MD, PhD1 
 
Co-Investigators 
Thomas Alexander, MD, MPH1 
John Choi, MD, PhD2 
Hiroto Inaba, MD, PhD1 
Sima Jeha, MD1 
Jeffery Klco, MD, PhD2 
Stanley Pounds, PhD3 
Raul Ribeiro, MD1 
 
 
Departments of 1Oncology and Leukemia/Lymphoma Division, 2Pathology, 3Biostatistics 
St. Jude Children's Research Hospital 
262 Danny Thomas Place 
Memphis, Tennessee 38105-3678 
Telephone:  (901) 595-3300 
 
 
Additional contact information for PI 
 
 
 
 
Contents of this document may not be extracted without permission from the Principal Investigator. 


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List of Collaborating Investigators/Institutions 
Contact Information 
 
 
Pediatric Hematology/Oncology 
University of Chicago Comer Children's 
Hospital 
5841 S Maryland Ave, MC 4060 
Chicago, IL 60637 
 
PI: Jennifer McNeer, MD 
 
Division of Hematology/Oncology 
Children's Hospital of Michigan 
3901 Beaubien Blvd. 
Detroit, MI 48201 
 
PI: Jeffrey W. Taub, M.D. 
 
 
Cook Children’s Medical Center 
Hematology/Oncology 
1500 Cooper St. 
Fort Worth, TX 76104 
 
PI: Kenneth Heym, MD 
 
Phoenix Children’s Hospital 
Hematology/Oncology 
10415 N. 22nd St. 
Phoenix, AZ 85028 
 
PI: Jessica L. Boklan, MD 
 
 
Bass Cancer Center – Lucille Packard 
Children’s Hospital 
Stanford Children’s Health 
725 Welch Road, MC5913 
Palo Alto, CA 94304 
 
PI: Norman J. Lacayo, MD 
 
Pediatric Hematology/Oncology 
Duke University Medical Center 
397 Hanes House 
DUMC Box 102382 
Durham, NC 27710 
 
PI: Daniel S. Wechsler, MD, PhD 
 


SELHEM 
Amendment 6.0, dated: 03-24-2017 
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SELHEM: A PHASE I/II STUDY OF THE SELECTIVE INHIBITOR OF NUCLEAR EXPORT 
SELINEXOR (KPT-330) IN COMBINATION WITH FLUDARABINE AND CYTARABINE IN 
PEDIATRIC PATIENTS WITH REFRACTORY LEUKEMIA OR MYELODYSPLASTIC 
SYNDROME 
Principal Investigator: Jeffrey E. Rubnitz, MD, PhD 
Institution/Sponsor-IND holder: St. Jude Children’s Research Hospital.  IND# 122,979 
Brief overview: Phase I/II study to characterize the toxicity profile and to determine the maximum 
tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor when given with 
fludarabine and cytarabine in pediatric patients with relapsed or refractory hematologic malignancies 
including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), mixed phenotype acute 
leukemia (MPAL) and myelodysplastic syndrome (MDS). 
Intervention: Interventional, primary therapeutic. 
Drug: Selinexor 
Drug: Fludarabine 
Drug:  Cytarabine 
Procedure:  LP with administration of ITHMA or cytarabine 
Brief outline of treatment plan: 
Selinexor will be given orally on days 1, 3, 8, 10, 22, and 24. The starting dose of Selinexor is 30 
mg/m2/dose po given twice weekly and escalated or de-escalated based on tolerability. 
Fludarabine (30 mg/m2/dose IV over 30 minutes daily for 5 days) and cytarabine (2 gram/m2/dose IV 
over 4 hours daily for 5 days) will be given on days 16 through 20. Fludarabine and cytarabine may be 
given before day 15 if the treating physician, after consulting with the principal investigator (PI), 
believes it is in the patient’s best interest based on disease progression. 
Diagnostic lumbar puncture and intrathecal (IT) chemotherapy will be given prior to cycle 1. Patients 
without evidence of central nervous system (CNS) leukemia will receive no further IT therapy during 
cycle 1. Patients with CNS disease will receive weekly IT therapy (age-adjusted methotrexate, 
hydrocortisone, and cytarabine) until the cerebrospinal fluid (CSF) becomes free of leukemia (minimum 
of 4 doses). Bone marrow aspiration (BMA) and biopsy (if indicated) to assess response will be 
performed on days 15 and 29 of cycle 1. One cycle of therapy will be 42-56 days. Participants may 
receive one subsequent course of selinexor + fludarabine and cytarabine if there is no disease 
progression or unacceptable toxicity (maximum 2 courses). In addition, patients who demonstrated 
response to selinexor may receive selinexor alone in subsequent courses at the discretion of the treating 
physician, after consultation with the study PI; the selinexor may be continued indefinitely. 
Dose level 
Selinexor 
(mg/m2/dose on days 
1, 3, 8, 10, 22, 24) 
Fludarabine 
(mg/m2/dose on days 
16-20) 
Cytarabine (g/m2/dose 
on days 16-20) 
-1 
20 
30 
2 
1 
30 
30 
2 
2 
40 
30 
2 
3 
55 
30 
2 
4 
70 
30 
2 


SELHEM 
Amendment 6.0, dated: 03-24-2017 
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SELHEM: A PHASE I/II STUDY OF THE SELECTIVE INHIBITOR OF NUCLEAR EXPORT 
SELINEXOR (KPT-330) IN COMBINATION WITH FLUDARABINE AND CYTARABINE IN 
PEDIATRIC PATIENTS WITH REFRACTORY LEUKEMIA OR MYELODYSPLASTIC 
SYNDROME 
Study design: Phase I/II study with include two phases. The dose-escalation phase will characterize the 
dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) and recommended 
phase 2 dose (RP2D) of selinexor when given in combination with fludarabine and cytarabine. The 
RP2D will be chosen based on the MTD and totality of the data (clinical, PK, and PD data from this and 
other trials). The Phase II cohort will further assess the safety and will explore the efficacy of this 
combination. 
Sample size: The sample size is determined by the number of DLTs observed at each dose level in each 
stratum. The minimum sample size is 6 and the maximum sample size is 24 evaluable patients for the 
dose escalation phase. Additionally, the phase II portion of the study will include a minimum of 28 and 
maximum of 39 evaluable patients. 
Data management: Data management and statistical analysis will be provided locally by the 
Comprehensive Cancer Center Hematological Malignancies Program and the Biostatistics Department 
at St. Jude Children’s Research Hospital. 
Human subjects: The main risk to research participants will be the potential toxicities associated with 
the use of chemotherapy and the investigational agent, selinexor. The research participants will be 
informed of the toxicities that have been associated with the study drugs and potential side effects of 
procedures recommended in this study. Adverse events will be monitored, treated, and reported 
following institutional and federal guidelines and regulations. 


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Table of Contents 
1.0 
OBJECTIVES ...................................................................................................................... 1 
1.1 
Primary Objective ...................................................................................................... 1 
1.2 
Secondary Objectives ................................................................................................. 1 
1.3 
Exploratory Objectives .............................................................................................. 1 
2.0 
BACKGROUND AND RATIONALE ................................................................................ 1 
2.1 
Background ................................................................................................................ 1 
2.2 
Rationale for this Study ............................................................................................. 6 
3.0 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT ............................................... 6 
3.1 
Inclusion Criteria ....................................................................................................... 6 
3.2 
Exclusion Criteria ...................................................................................................... 8 
3.3 
Enrollment on Study at St. Jude ................................................................................. 9 
3.4 
Enrollment on Study at Collaborating Sites ............................................................... 9 
4.0 
TREATMENT PLAN .......................................................................................................... 9 
4.1 
Overview .................................................................................................................... 9 
4.2 
Intrathecal Chemotherapy ........................................................................................ 11 
4.3 
Dose-Escalation Cohort (completed) ....................................................................... 11 
4.4 
Phase II Cohort ........................................................................................................ 12 
4.5 
Response Evaluations .............................................................................................. 12 
4.6 
Definitions of Dose-Limiting Toxicities (DLT) ...................................................... 13 
4.7 
Cycle 2 and Subsequent Courses ............................................................................. 14 
4.8 
Supportive Care and Concomitant Therapy ............................................................. 15 
5.0 
DRUG INFORMATION .................................................................................................... 17 
5.1 
SELINEXOR (KPT-330) ......................................................................................... 17 
5.2 
Fludarabine (Fludara®, fludarabine phosphate, 2-fluoro-ara-AMP) ........................ 19 
5.3 
Cytarabine (Cytosine arabinoside, Ara-C, Cytosar®) .............................................. 20 
5.4 
Intrathecal Triples .................................................................................................... 20 
6.0 
REQUIRED EVALUATIONS, TESTS, OBSERVATIONS ............................................ 21 
6.1 
Pre-Treatment Clinical Evaluations ......................................................................... 21 
6.2 
Evaluations During Therapy .................................................................................... 22 
6.3 
Response Evaluations .............................................................................................. 22 
6.4 
Evaluations After Completion of Therapy ............................................................... 23 
7.0 
OPTIONAL CORRELATIVE RESEARCH STUDIES .................................................... 23 
7.1 
Optional Pharmacokinetic (PK) Studies - Plasma (completed) ............................... 23 
7.2 
Optional Pharmacodynamic (PD) Studies (completed) ........................................... 23 
7.3 
Optional Correlative Biological Studies (Phase II) .................................................. 24 
8.0 
EVALUATION CRITERIA ............................................................................................... 24 
8.1 
Response Criteria ..................................................................................................... 24 
8.2 
Toxicity Evaluation Criteria..................................................................................... 25 
9.0 
OFF-TREATMENT AND OFF-STUDY CRITERIA ....................................................... 25 
9.1 
Off-Treatment Criteria ............................................................................................. 25 
9.2 
Off-Study Criteria .................................................................................................... 26 
10.0 SAFETY AND ADVERSE EVENT REPORTING .......................................................... 26 
10.1 
Reporting Adverse Experiences and Deaths ............................................................ 26 
10.2 
Recording and Reporting AEs and SAEs ................................................................ 27 
10.3 
Process for Reporting Adverse Events From and To Collaborating Sites ............... 28 
11.0 DATA COLLECTION, MONITORING AND CONFIDENTIALITY ............................ 30 
11.1 
Data Collection ........................................................................................................ 30 


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11.2 
Study Monitoring ..................................................................................................... 30 
11.3 
Confidentiality ......................................................................................................... 31 
12.0 STATISTICAL CONSIDERATIONS ............................................................................... 31 
12.1 
Dose Escalation Phase ............................................................................................. 32 
12.2 
Phase I Sample Size/Accrual Rate ........................................................................... 33 
12.3 
Phase II Sample Size/Accrual Rate .......................................................................... 33 
12.4 
Analysis of Secondary Objectives ........................................................................... 33 
12.5 
Analysis of Exploratory Objectives ......................................................................... 34 
12.6 
Anticipated Completion Dates ................................................................................. 34 
13.0 OBTAINING INFORMED CONSENT............................................................................. 34 
13.1 
Consent Prior to Research Interventions .................................................................. 34 
13.2 
Consent at Enrollment .............................................................................................. 35 
13.3 
Consent at Age of Majority ...................................................................................... 35 
13.4 
Consent When English is Not the Primary Language .............................................. 35 
14.0 REFERENCES ................................................................................................................... 36 
 
APPENDICES 
 
Appendix I: 
Selinexor Dose Rounding Chart 
Appendix II: Performance Status Criteria 
Appendix III:  Tests Performed for Routine Care and for Research 
Appendix IV: Selinexor Dose Modification Guidelines for AEs Associated with Selinexor 
Appendix V:   Specimen Submission Guidelines 


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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
1.1.1 To determine a tolerable combination of selinexor, fludarabine, and cytarabine in 
pediatric patients with relapsed or refractory hematologic malignancies including 
acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), mixed 
phenotype acute leukemia (MPAL) and myelodysplastic syndrome (MDS) in the 
phase I portion of the study. 
 
1.1.2 To estimate the overall response rate, as defined by complete response or 
complete response with incomplete count recovery, of selinexor in combination 
with fludarabine and cytarabine for patients with relapsed or refractory AML in 
the phase II portion of the study. 
 
1.2 
Secondary Objectives 
 
1.2.1 To characterize the pharmacokinetics of selinexor, when administered in tablet 
form, after the first dose and at steady-state, as well as in combination with 
fludarabine and cytarabine. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To characterize the pharmacodynamic and biological effects of selinexor and to 
search for biological predictors of response. 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Background 
 
The outcome for children with relapsed or refractory leukemia is very poor, necessitating 
the development of novel agents and effective salvage regimens. An attractive target is 
Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), a nuclear 
protein exporter that is a member of the karyopherin β family of transporters and is the 
primary nuclear exporter of key tumor suppressor and regulatory proteins, including p53, 
p21, p27, NPM1, eIF4e and I-κB.1,2 
 
Neoplasms must inactivate most major tumor suppressor pathways in order to perpetuate 
their phenotypes. Since the vast majority of tumor suppressor proteins and other growth 
modulators require nuclear localization in order to carry out their antineoplastic activities, 
enhancing their nuclear export leads to their functional inactivation. The control of 
nuclear import and export is tightly regulated by shuttle proteins in eukaryotic cells. 
Although there are 15 nuclear import proteins (importins) and 7 nuclear export proteins 
(Exportins 1-7), nearly all tumor suppressor proteins and growth regulatory proteins are 
exported exclusively by XPO1. All malignancies studied to date, including AML, show 
elevated XPO1 levels, and increasing levels often correlate with poorer prognosis.3-8 In 


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these malignancies, elevated XPO1 levels lead to cytoplasmic mislocalization and 
functional inactivation of tumor suppressor and growth regulatory proteins. 
 
XPO1 inhibitors have been shown to block the nuclear export of key tumor suppressor 
proteins, leading to accumulation of these proteins in the nucleus, as nuclear import 
appears to proceed unimpeded. Moreover, nuclear retention appears to prevent 
proteasome-mediated degradation. Forced nuclear retention of various proteins can 
counteract a multitude of oncogenic and inflammatory pathways that perpetuate the 
neoplastic phenotype (Table 1). 
 
In addition, eIF4e, which is one of the cargoes of XPO1, mediates the nuclear export of 
certain messenger RNAs (mRNAs) which codes for growth stimulatory proteins with 
short half-lives. These mRNAs include FLT3, c-KIT, and c-MYC. Therefore, XPO1 
inhibition leads to nuclear retention of these mRNAs, leading to the down regulation of 
multiple oncogenic proteins including, further providing anti-neoplastic activity (Table 1). 
 
Table 1. Effects of XPO1 Inhibition on Oncogenic and Inflammatory Pathways 
Pathway/protein affected Effect of XPO1 Inhibition 
Reference 
TP53 mutation 
p73 activation, p21 activation 
9 
MDM2 activation 
Nuclear p53 retention and activation 
6 
NPM1 mutation 
Restoration of nuclear NPM1 
10 
CEBPA down-regulation 
Nuclear retention and activation 
9 
XPO1 overexpression 
XPO1 reduction 
11 
FLT3 activation 
FLT3 reduction 
9 
KIT activation 
KIT reduction 
9 
NF-КB activation 
I-κB nuclear retention and activation 
8 
PIK3 or AKT activation 
FOXO1, -3, -4 activation 
8 
 
Karyopharm Therapeutics has recently developed novel, small molecule selective 
inhibitors of nuclear export (SINEs) that inhibit XPO1 by covalently binding to the 
Cys528 residue and thereby blocking XPO1-mediated efflux of proteins.6,7,9,11-13 Selinexor 
is an oral, first in class, slowly reversible, potent SINE that specifically blocks XPO1. 
Selinexor restores many of the tumor suppressor and growth regulatory proteins to the 
nucleus where they can carry out their normal functions. It is selectively cytotoxic for cells 
with genomic damage, i.e., for tumor cells, both in vitro and in vivo. All cell types 
exposed to selinexor in vitro undergo G1 ± G2 cell cycle arrest, followed by a ‘genomic 
fidelity’ review. Cells with damaged genomes are induced to undergo apoptosis. Normal 
cells, with an intact genome, remain in transient, reversible cell cycle arrest until the 
export block is relieved. Selinexor and other 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. 


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2.1.1 Preclinical Data 
 
A summary of the preclinical data package is included here. Please refer to the selinexor 
Investigator’s Brochure for additional information. 
 
Pharmacology 
 
Selinexor has shown potent pro-apoptotic activity 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 solid tumors hematological malignancies and, including lung, melanoma, 
prostate, breast, and ovarian cancers as well as hematological malignancies including 
NHL, multiple myeloma and leukemia. 
 
Pharmacokinetics and toxicology 
 
The preclinical properties of selinexor were assessed in three species: mouse (CD1), rat 
(Sprague-Dawley), and monkey (cynomolgus). While 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. Results were 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. 
 
2.1.2 Clinical Summary 
 
Selinexor is currently under clinical investigation for the treatment of patients with 
advanced hematologic and advanced solid malignancies. Three Phase 1 studies (KCP- 
330-001 in hematologic malignancies, KCP-330-002 in solid tumor malignancies, KCP- 


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330-00: food effect in sarcoma) are in progress. In addition, a Phase 1 study of selinexor 
in pediatric patients with AML and ALL (NCT02091245) as well as several Phase 2 
studies in multiple hematologic and solid tumor indications are currently ongoing or in 
process of being initiated (protocol submitted to FDA). These studies and current safety 
and efficacy results are described in detail in the Investigator’s Brochure. The first 
clinical trial of selinexor in an adult population was recently reported.14 
As of 1 May 2014, broad anti-tumor activity has been reported during the dose-escalation 
phase with single agent selinexor in over 300 adult patients with heavily pretreated, 
relapsed/refractory, progressive solid tumor and hematologic malignancies. The most 
common adverse effects (AEs) have been similar to those reported in nonclinical studies 
and include anorexia, weight loss, nausea and fatigue. These AEs can be prevented or 
mitigated with dietary counselling and prophylactic supportive medications. No major 
organ toxicities have been observed to date, and no clinically significant cumulative 
toxicities have been observed in >10 months of dosing. Overall, oral selinexor 
pharmacokinetics was predictable, reasonably dose-proportional, and exhibited moderate 
to moderately high inter-patient variability across a wide dose range in male and female 
patients with advanced solid tumor or hematological malignancies. 
 
Cerebellar syndrome has been seen in one adult patient who had been heavily pre-treated 
for recurrent pancreatic cancer. This adult patient experienced abnormal speech, loss of 
coordination, and was unable to walk after receiving 4 doses of selinexor at 85 mg/m2 
twice weekly. In this study, we have seen 2 children with similar symptoms after 
receiving 4 doses of selinexor at 70 mg/m2 twice weekly. In both pediatric cases, the 
symptoms of cerebellar syndrome happened within 2 weeks of receiving selinexor. The 
symptoms improved after the drug was stopped. 
 
Although data from a phase I trial of selinexor in adults with advanced solid tumors 
indicate that anorexia, weight loss and fatigue are common, these side effects were rarely 
observed in the phase one portion of this study.14 Hyponatremia was common, but was 
asymptomatic and easily corrected in all cases. 
 
The phase I study in advanced hematologic malignancies (KCP-330-001) is ongoing at 
multiple institutions, with 168 patients enrolled as of 24 April 2014. Of the 37 patients 
assessed for efficacy in Arm 2 (AML) as of 28 February 2014, 5 (14%) patients had 
complete response, and an additional 4 patients (11%) achieved either CR(i), PR or 
MLFS. Thirteen patients achieved stable disease (35%) and while 15 (41%) had 
progressive disease (See Table 2 below). 
 
Table 2. Best Responses in Patients with AML in KCP-330-001 as of 28 February 2014 
No. of Pts. 
Evaluated 
CR (%) 
CR(i) (%) 
PR (%) 
MLFS (%) 
SD (%) 
PD (%) 
37 
5 (14%) 
1 (3%) 
2 (5%) 
1 (3%) 
13 (35%) 
15 (41%) 
Abbreviations: CR=complete response, CR(i)=complete response without hematological 
recovery, PR=partial response, MLFS=morphological leukemia free state, SD=stable 
disease, PD=progressive disease. 


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In the recently completed phase I portion of this study, 7 of 15 evaluable patients (47%) 
achieved complete response or complete response with incomplete count recovery. The 
complete responses observed in this study suggest activity of the combined therapeutic 
regimen of selinexor, fludarabine, and cytarabine. Two recent large trials evaluating 
regimens for refractory or first relapse of pediatric AML showed complete response rates 
of 48% and 64%.15,16 The higher risk nature of our patient population and the small 
number of patients in the phase I portion of this study preclude direct comparisons with 
the response rates reported from these studies. The characteristics of our patient cohort 
more closely resemble those of patients enrolled on other early phase trials for children 
with relapsed AML, such as a phase I trial of gemtuzumab ozogamicin and a phase II 
trial of clofarabine, in which response rates of 28% and 26%, respectively, were 
reported.17,18 Notably, two patients in the present study became MRD negative after 
receiving only selinexor, indicating that there is a patient population who might benefit 
from single-agent selinexor therapy. In addition, three of the seven patients who attained 
CR or CRi were in second relapse, suggesting that this therapy may be beneficial for 
patients at more advanced stage of relapse. 
 
In summary, early results from ongoing studies demonstrated tolerability and responses 
across a variety of hematologic malignancies.19 Constitutional symptoms of weight loss, 
fatigue, and anorexia were common in adults but can be successfully prevented or 
mitigated using aggressive prophylactic supportive measures. 
 
Potential Risks 
 
The most common side effects (≥ 20%) are nausea, loss of appetite, fatigue, vomiting, 
weight loss, thrombocytopenia and anemia. Asymptomatic hyponatremia (median sodium 
nadir, 128.5 meq/L, range 123-132 meq/L), was common in the phase I portion of this 
study, but was easily corrected by oral or intravenous supplementation in all cases. 
 
Less common side effects (<20%) are diarrhea, change in taste, dizziness, dehydration, 
constipation, dry mouth, changes in vision including blurred vision (without objective 
findings on ophthalmological exam), decrease in neutrophils, decrease in white blood 
cells, and low sodium. 
 
Side effects that are rarely (< 5%) observed include: worsening of pre-existing cataracts, 
infection, sepsis – a potentially life-threatening complication of infection and pneumonia. 
 
Cerebellar syndrome has been seen in one adult patient who had been heavily pre-treated 
for recurrent pancreatic cancer. This adult patient experienced abnormal speech, loss of 
coordination, and was unable to walk after receiving 4 doses of selinexor at 85 
mg/m2 twice weekly. In this study, we have seen 2 children with similar symptoms after 
receiving 4 doses of selinexor at 70 mg/m2 twice weekly. In both pediatric cases, the 
symptoms of cerebellar syndrome happened within 2 weeks of receiving selinexor. The 
symptoms improved after the drug was stopped. 


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2.1.3 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. Female patients of child-bearing potential who are sexually active must agree 
to use dual methods of contraception and have a negative serum pregnancy test at 
screening (≤ 3 days prior to first dose), 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 who are sexually active, effective 
methods of contraception must be used throughout the study and for three months 
following the last dose. 
 
2.2 
Rationale for this Study 
 
The present proposal is a pilot study of selinexor in combination with fludarabine and 
cytarabine in pediatric patients with refractory or relapsed hematologic malignancies. The 
starting dose will be 30 mg/m2/dose, which is well below the maximum adult Phase I 
dose of 70 mg/m2 (trial KCP-330-001) and 2 dose levels below the adult Phase II AML 
dose of 55 mg/m2 (trial KCP-330-008). The chemotherapy backbone will be 
fludarabine/cytarabine, an active combination that has been used to treat patients with 
relapsed AML for over 20 years (given alone, with G-CSF in the FLAG regimen, or with 
idarubicin in the ida-FLAG regimen). In addition, these agents are also active in ALL. 
 
We found that six doses of selinexor, given at 55 mg/m2/dose, are well tolerated in 
combination with fludarabine and cytarabine in children with relapsed and refractory 
acute leukemia. The dose-limiting reversible cerebellar toxicity was only observed at a 
dose level of 70 mg/m2. Complete responses observed in this high risk population, after 
single agent and combination therapy, suggests that selinexor may have a role in the 
treatment of pediatric acute leukemia. Taken together, this phase I study of selinexor, 
along with promising preclinical studies demonstrating efficacy in high-risk leukemia and 
on leukemia-initiating cells, justify further studies to evaluate the safety and efficacy of 
selinexor-based therapy in children with relapsed and refractory acute leukemia. Based 
upon PK/PD data from the phase 1 portion of the study, along with PK/PD and selected 
phase II data from unpublished adult trials, we have chosen to proceed with phase II dose 
of 40 mg/m2/dose. 
 
3.0 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT 
 
3.1 
Inclusion Criteria 
 
According to institutional and NIH policy, the study will accession research participants 
regardless of gender and ethnic background. Institutional experience confirms broad 
representation in this regard. 


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3.1.1 Phase I (completed): Participants must have a diagnosis of AML, MDS, ALL or 
MPAL and must have disease that has relapsed or is refractory to chemotherapy, 
or that has relapsed after hematopoietic stem cell transplantation (HSCT) 
a) Refractory disease is defined as persistent disease after at least two 
courses of induction chemotherapy. 
b) Patients with AML, MPAL or MDS are eligible at first or subsequent 
relapse, whereas patients with ALL are eligible at second or subsequent 
relapse or any relapse that is refractory to salvage chemotherapy. 
c) Patients with AML or ALL must have ≥ 5% leukemic blasts in the bone 
marrow or increasing levels of MRD in the bone marrow as assessed by 
flow cytometry. If an adequate bone marrow sample cannot be obtained, 
patients may be enrolled if there is unequivocal evidence of leukemia in 
the peripheral blood. 
 
3.1.2 Phase II: Participants must have a diagnosis of AML and must have disease that 
has relapsed or is refractory to chemotherapy, or that has relapsed after 
hematopoietic stem cell transplantation (HSCT) 
• Refractory disease is defined as persistent disease after at least two 
courses of induction chemotherapy. 
• Patients are eligible at first or subsequent relapse or any relapse that is 
refractory to salvage chemotherapy. 
 
3.1.3 Patients must have ≥ 5% leukemic blasts in the bone marrow and/or increasing 
levels of MRD in the bone marrow as assessed by flow cytometry. If an adequate 
bone marrow sample cannot be obtained, patients may be enrolled if there is 
unequivocal evidence of leukemia in the peripheral blood. 
 
3.1.4 Adequate organ function defined as the following: 
 
• Direct bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) 
• AST (SGOT)/ALT (SGPT) < 3 x IULN 
• Creatinine within normal institutional limits for age 
 
3.1.5 Prothrombin time (PT) and partial thromboplastin (PTT) ≤ 1.5 x IULN. 
 
3.1.6 Age criteria: Patients treated at collaborating sites and current St. Jude patients 
who are on therapy or within 3 years of completion of therapy must be ≤ 24 years 
old. All other St. Jude patients must be < 21 years old. 
 
3.1.7 Patients must be able to swallow tablets. 
 
3.1.8 Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and 
Karnofsky ≥ 50% for patients who are > 16 years old. 


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3.1.9 Patients must have fully recovered from the acute effects of all prior therapy. For 
patients who have received prior HSCT, there can be no evidence of GVHD and 
greater than 60 days must have elapsed since the HSCT. 
 
3.2 
Exclusion Criteria 
 
3.2.1 History of cerebellar toxicity or cerebellar neurological findings on exam. 
 
3.2.2 Must not be pregnant or breastfeeding. Female patients who are sexually active 
and 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 
who are sexually active, effective methods of contraception must be used 
throughout the study and for three months following the last dose. Abstinence is 
an acceptable form of contraception. 
 
3.2.3 Patients with Down syndrome, acute promyelocytic leukemia, juvenile 
myelomonocytic leukemia, Fanconi anemia, Kostmann syndrome, Shwachman 
syndrome, or other bone marrow failure syndromes are not eligible. 
 
3.2.4 Use of investigational agents, with the exception of gemtuzumab ozogamicin, 
within 30 days. 
 
3.2.5 Any significant concurrent disease, illness, or psychiatric disorder that would 
compromise patient safety or compliance, study participation, follow up, or 
interpretation of study research. 
 
3.2.6 Unstable cardiovascular function: 
• symptomatic ischemia 
• congestive heart failure NYHA Class > 3 
• myocardial infarction (MI) within 3 months 
 
3.2.7 Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals 
within one week prior to first dose. Infections controlled on concurrent anti- 
microbial agents are acceptable, and anti-microbial prophylaxis per institutional 
guidelines are acceptable. 
 
3.2.8 Known human immunodeficiency virus (HIV) infection (pre-study testing not 
required). 
 
3.2.9 Patients with malabsorption syndrome, or any other disease significantly affecting 
gastrointestinal function. 
 
3.2.10 Prior treatment with selinexor. 


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3.3 
Enrollment on Study at St. Jude 
 
A member of the study team will confirm potential participant eligibility as defined in 
Section 3.1-3.2, complete and sign the ‘Participant Eligibility Checklist.’ The study team 
will enter the eligibility checklist information into the Patient Protocol Manager (PPM) 
system. Eligibility will be reviewed, and a research participant-specific consent form and 
assent document (where applicable) will be generated. The complete signed consent/assent 
form(s) must be faxed or emailed to the CPDMO at 
 to complete the enrollment 
process. The CPDMO is staffed 7:30 am-5:00 pm CST, Monday through Friday. A staff 
member is on call Saturday, Sunday, and holidays from 8:00 am to 5:00 pm. Enrollments 
may be requested during weekends or holidays by calling the CPDMO “On Call” cell 
phone 
 or referencing the “On Call Schedule” on the intranet. 
 
3.4 
Enrollment on Study at Collaborating Sites 
 
Collaborating Site research participants should be registered at St. Jude within 24 hours of 
enrollment at the site. The completed Eligibility Checklist and entire signed Informed 
Consent should be faxed to 
. Please call 
 if confirmation of the 
enrollment information is needed. The Protocol Eligibility Coordinator will then register 
the research participant in the Patient Protocol Manager (PPM) system. 
 
4.0 
TREATMENT PLAN 
 
4.1 
Overview 
 
Patients must have fully recovered from the acute effects of all prior therapy before 
starting selinexor. In addition, at least 14 days must have elapsed since the completion of 
myelosuppressive therapy or gemtuzumab ozogamicin and the first dose of selinexor. At 
least 24 hours must have elapsed since the completion of low-dose or non- 
myelosuppressive therapy, such as hydroxyurea, vincristine, steroids, or low-dose 
cytarabine (up to 100 mg/m2/day), and the first dose of selinexor. For patients who have 
received prior HSCT, there can be no evidence of GVHD and greater than 60 days must 
have elapsed since the HSCT. 
 
This study will include two phases. The dose-escalation phase will characterize the dose- 
limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) and 
recommended phase 2 dose (RP2D) of selinexor when given in combination with 
fludarabine and cytarabine. The RP2D will be chosen based on the MTD and totality of 
the data (clinical, PK, and PD data from this and other trials). The phase II cohort will 
further assess the safety and will explore the efficacy of this combination. 


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Selinexor will be given orally on days 1, 3, 8, 10, 22 and 24 of each cycle. 
 
Fludarabine (30 mg/m2/dose IV over 30 minutes daily) and cytarabine (2 gram/m2/dose 
IV over 4 hours daily) will be given on days 16 (± 2 days) through 20 (± 2 days). 
Chemotherapy may be delayed if clinically indicated. 
 
For patients who achieve CR or CRi with negative MRD or with MRD that has decreased at 
Day 15, the treating physician may continue single agent selinexor without fludarabine and 
cytarabine. In this case, selinexor should be given on days 1, 3, 8, 10, 15, 17, 22 and 24. 
 
Patients who achieve CR or CRi status (as defined in Section 8.1) at day 15 (regardless of 
MRD status) may proceed directly to HSCT at the discretion of the treating physician. 
 
Fludarabine and cytarabine may be given before Day 16 if the treating physician, after 
consulting with the principal investigator (PI), believes it is in the patient’s best interest 
based on disease progression. In general, the fludarabine/cytarabine combination should 
begin prior to day 16 if the leukocyte count is greater than 50,000/µl and increases by 
>50%. For example, if the leukocyte count is 30,000/µl and increases to 46,000/µl, 
fludarabine and cytarabine will start on day 16 as planned. However, if the leukocyte count 
is 60,000/µl and increases to 91,000/µl, fludarabine and cytarabine may be started early. 
 
Note that these are guidelines that should be used in the context of each patient’s clinical 
condition. 
 
If fludarabine and cytarabine are given prior to Day 16, the administration of selinexor 
should be held at start of fludarabine and cytarabine administration and resumed 3 days 
after completion of fludarabine and cytarabine to complete total of three weeks of selinexor 
during course one. 
 
Diagnostic lumbar puncture and intrathecal (IT) chemotherapy should be given prior to 
cycle 1, but may be delayed if clinically indicated. IT cytarabine, IT methotrexate, and IT 
methotrexate/ hydrocortisone/cytarabine (MHA) are all acceptable. Note that the first dose 
of IT chemotherapy may be given prior to or after enrollment on SELHEM. 
 
Patients without evidence of central nervous system (CNS) leukemia will receive no further 
IT therapy during cycle 1. Patients with CNS disease (defined as the presence of any blasts 
in the CSF) will receive weekly ITMHA until the cerebrospinal fluid becomes free of 
leukemia. 
 
For patients who require IT therapy on day 15, administration of IT therapy should be 
separated from administration of IV fludarabine and cytarabine by at least one day. 


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4.2 
Intrathecal Chemotherapy 
 
Patient Age 
Methotrexate 
Hydrocortisone 
Cytarabine 
Volume 
< 1 year 
6 mg 
12 mg 
18 mg 
6 ml 
1-2 years 
8 mg 
16 mg 
24 mg 
8 ml 
2-3 years 
10 mg 
20 mg 
30 mg 
10 ml 
> 3 years 
12 mg 
24 mg 
36 mg 
12 ml 
 
Leucovorin rescue (5 mg/m2/dose, max 5 mg) PO will be given at 24 and 30 hours after 
each triple intrathecal treatment. Follow plasma methotrexate levels (starting 24 hours after 
intrathecal therapy and until level becomes undetectable) in patients with renal dysfunction 
or extra fluid in third space, and rescue with leucovorin as clinically indicated. 
 
4.3 
Dose-Escalation Cohort (completed) 
 
As described above, the starting dose of selinexor will be 30 mg/m2/dose, which is well 
below the current adult Phase I dose (trial KCP-330-001) of 70 mg/m2 which has cleared 
DLT and below the adult Phase II dose of 55 mg/m2 (trial KCP-330-008). 
 
Selinexor, initially at 30 mg/m2/dose, will be given twice weekly (on days 1 and 3) and 
escalated or de-escalated based on tolerability (Dose level -1, 1, 2, and 4 are shown in 
Table 3 below). The rolling-6 design will be used for the conduct of this study. 
 
A full safety evaluation will be conducted when participants have completed 28 days of 
therapy. Only cycle 1 of therapy will be used to evaluate the DLT. 
 
Two to 6 participants can be concurrently enrolled onto a dose level, dependent on: 
 
1) the number of participants enrolled at the current dose level, and 
2) the number of participants who have experienced DLT at the current dose level, and 
3) the number of participants entered but with tolerability data pending at the current 
dose level. 
 
Accrual is suspended when a cohort of 6 has enrolled or when the study endpoints have 
been met. 
 
The decision as to which dose level to enroll a participant is based on the number of 
participants currently enrolled and evaluable, the number of participants experiencing 
DLT, and the number of participants still at risk of developing a DLT at the time of new 
participant entry. For example, when 3 participants are enrolled onto a dose level, if 
toxicity data is available for all 3 participants and no DLTs are observed when the 4th 
participants enter, the dose is escalated and the 4th participants is enrolled to the next 
higher dose level; if toxicity data is not yet available for 1 or more of the three 
participants and no DLT has been observed, or if 1 DLT has been observed, the new 
participant is entered at the same dose level; if 2 or more DLTs have been observed from 
the 3 participants, the dose level is de-escalated. This process is repeated for the 5th and 
6th participants. 


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Table 3. Dose-escalation plan 
Dose 
level 
Selinexor 
(mg/m2/dose on days 1, 3, 8, 
10, 22 and 24) 
Fludarabine 
(mg/m2/dose on days 16-20) 
Cytarabine 
(g/m2/dose on days 16-20) 
-1 
20 
30 
2 
1 
30 
30 
2 
2 
40 
30 
2 
3 
55 
30 
2 
4 
70 
30 
2 
 
4.4 
Phase II Cohort 
 
The Phase II portion of the study will enroll patients at a selinexor dose of 40 mg/m2/dose 
on the same administration schedule as the dose escalation cohort. 
 
Evaluation of response to single agent selinexor: unless there is evidence of progressive 
disease by examination of the blood, participants should undergo bone marrow evaluation 
on day 15 (± 2 days). This evaluation must be performed prior to administration of 
fludarabine and cytarabine. 
 
Evaluation of response to Cycle 1: participants should undergo response evaluation 
between days 42 and 56 of Cycle 1 (with the exception of any patient who obtains 
complete response at Day15 and elects to continue single agent selinexor and forego 
fludarabine and cytarabine therapy). Patients may be evaluated earlier if there is evidence 
of hematopoietic recovery or at discretion of treating physician. In cases with 
hypocellular marrows (<10% cellularity), repeat bone marrow examinations should be 
considered when there is evidence of hematopoietic recovery. 
 
Table 4. Treatment administration 
Drug 
Dose 
Route 
Schedule 
Selinexor 
40 mg/m2 
PO 
Days 1, 3, 8, 10, 22 and 24 
Fludarabine 30 mg/m2/dose 
IV over 30 minutes Days 16-20a 
Cytarabine 
2 gram/m2/dose IV over 4 hoursb 
Days 16-20a 
a May be given earlier or later, as clinically indicated 
b Cytarabine should start at least 3.5 hours after completion of fludarabine 
 
Selinexor should be administered with food or within 30 minutes after a meal. The dose 
will be determined according to Appendix I and rounded to the nearest 10 mg. 
 
4.5 
Response Evaluations 
 
Bone Marrow Evaluation of single agent selinexor during Cycle 1: unless there is 
evidence of progressive disease by examination of the blood, participants should undergo 
bone marrow evaluation on day 15 (± 2 days). This evaluation must be performed prior to 
administration of day 15 therapy. 


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Evaluation of response to Cycle 1: participants should undergo response evaluation 
between days 42 and 56 of Cycle 1 (with the exception of patients who obtain complete 
response at Day15 and elect to continue single agent selinexor and forego fludarabine and 
cytarabine therapy). Patients may be evaluated earlier if there is evidence of 
hematopoietic recovery or at discretion of treating physician. In cases with hypocellular 
marrows (<10% cellularity), repeat bone marrow examinations should be considered 
when there is evidence of hematopoietic recovery. 
 
4.6 
Definitions of Dose-Limiting Toxicities (DLT) 
 
Toxicities will be graded according the CTEP Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. DLT is based on non-hematologic toxicities that 
occur during Cycle 1 and that are deemed to be possibly attributable to selinexor. 
 
4.6.2.1 Non-hematologic DLT (phase I only) 
 
• Any Grade 5 event 
• Any Grade 4 event that is at least possibly related to selinexor, unless event is 
clearly and incontrovertibly due to extraneous causes or disease progression 
 
4.6.2.2 Hematologic toxicity (phase I only) 
 
Grade 3 or 4 hematologic toxicities will be monitored, but will not be considered dose- 
limiting toxicities. 
 
4.6.2.3 Dose modifications (See Appendix IV) 
 
During Cycle 1 patients should receive 5 of the 6 intended doses of selinexor; failure to 
receive 5 doses by Day 35 because of toxicity will be considered a DLT (phase I only). 
 
Note that at least 48 hours must pass between doses. Doses should be delayed, rather than 
omitted, for the following non-hematologic toxicities. Patients should also be treated 
aggressively with supportive care to reduce toxicities. 
 
Weight loss: if a participant develops Grade 3 weight loss, the next dose of selinexor 
should be delayed until the weight loss resolves to Grade ≤ 2. If weight loss does not 
improve to Grade ≤ 2 within 7 days, this participant will have experienced a DLT (phase 
I only). 
 
Electrolyte abnormalities: if a participant develops Grade ≥ 3 uncorrectable electrolyte 
abnormalities, the next dose of selinexor should be delayed until the abnormalities resolve to 
Grade ≤ 2. If abnormalities do not improve to Grade ≤ 2 within 7 days despite attempts to 
correct, this participant will have experienced a DLT (phase I only). 
 
Infection: the occurrence of Grade 4 infection will not be considered a DLT (phase I 
only). Selinexor should be delayed in any participant with Grade 4 infection or clinical 
sepsis until condition has clinically stabilized. If during Cycle 1, selinexor is suspended 


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due to Grade 4 infection or clinical sepsis and participant misses ≥ 3 doses of study drug, 
the participant will be deemed not evaluable and removed from study. These patients will 
be replaced during the DLT period, but will be included in the evaluation of the safety 
profile of the regimen and determining the recommended phase 2 dose (phase I only). 
Selinexor dosing (at the same dose level) can be re-initiated once the patient’s condition 
has stabilized clinically, even when the patient is taking antimicrobial or other agents. 
 
Other DLTs: in the event of a DLT in Cycle 1 (phase I only), or other toxicity that 
warrants discontinuation in the opinion of the investigator, selinexor should be 
discontinued and the  participant removed from study. 
 
The following adverse events will not be considered DLTs (phase I only): 
 
• Grade 3 nausea, vomiting or diarrhea (unless persisting > 3 days with appropriate 
treatment of anti-emetics or anti-diarrheals) 
• Alopecia of any grade 
• Weight loss of less than 20% 
• Electrolyte or serum analyte (e.g., urate) abnormalities that are reversible with 
standard interventions 
 
4.7 
Cycle 2 and Subsequent Courses 
 
Participants who have acceptable toxicity (Grade 3 non-hematologic toxicity that has 
resolved, or stable Grade 1-2 non-hematologic toxicity) and have PR or better response 
are eligible to receive a second course of therapy. Intrathecal therapy may be given prior 
to Cycle 2 at the discretion of the treating physician. 
 
4.7.1 Cycle 2 combination therapy 
 
Participants may begin Cycle 2 combination therapy when the absolute neutrophil count 
(ANC) is ≥ 300/μl and rising and the platelet count ≥ 30,000/μl and rising. 
 
• Selinexor (40 mg/m2/dose) will be given orally on days 1, 3, 8, 10, 22 and 24 at 
the same dose that was given in Cycle 1. 
• Fludarabine (30 mg/m2/dose IV over 30 minutes daily) on days 15-19 
• Cytarabine (2 gram/m2/dose IV over 4 hours daily) will be given on days 15-19 
Combination therapy will be limited to a maximum of 2 cycles. 
4.7.2 Cycle 2 selinexor single agent therapy 
 
Patients who had at least partial response on Day 15 of Cycle 1 may receive selinexor 
alone during Cycle 2 after consultation with the Principal Investigator. 
Participants may begin Cycle 2 (and subsequent) single agent therapy when the absolute 
neutrophil count (ANC) is ≥ 500/μl and rising and the platelet count ≥ 50,000/μl and rising. 


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Patients may continue to receive single agent selinexor as long as there is clinical benefit 
and no disease progression or unacceptable toxicities. 
 
For patients who achieve complete remission, protocol therapy will be discontinued when a 
suitable donor has been identified and the patient is ready to proceed to HSCT, or two 
cycles beyond achieving remission. In general, therapy with selinexor should be 
discontinued approximately 2 weeks prior to HSCT. 
 
4.8 
Supportive Care and Concomitant Therapy 
 
Anorexia and weight loss: Selinexor frequently causes anorexia and weight loss. Thus, 
participants should be weighed daily while inpatient and at every outpatient visit. High 
caloric supplements and appetite stimulating agents should be considered in all participants. 
 
Prophylactic treatment to prevent anorexia and nausea during is strongly recommended. 
An example regimen is outlined below, but exact regimen is at the discretion of the 
treating institution or physician. 
 
• Ondansetron 0.15 mg/kg/dose TID, starting prior to the first dose of selinexor and 
continuing for at least 24 hours after the dose (may be continued throughout 
therapy as needed). Granisetron or other appropriate 5-HT3 antagonist may be 
substituted for ondansetron. 
 
• Dexamethasone 5 mg/m2/day x 3 days (given on the day prior to, the day of, and 
the day after selinexor). 
 
• Olanzapine 1.25 to 2.5 mg daily (may be divided BID), starting one day prior to 
selinexor. If olanzapine is tolerated, the dose may be increased to 5 mg daily as 
needed. 
 
Missed doses: a maximum of two doses may be given per week. If the dose was missed 
for more than 24 hours, the dose will be skipped and the next dose will be taken as per 
schedule. If the dose was missed within 24 hrs, then it will be replaced. Doses should not 
be administered in less than 48 hours apart and all missed doses should be documented. 
 
Vomited doses: if a dose is vomited within one hour of ingestion, it will be replaced. If 
vomiting occurs more than 1 hour after dosing, it will still be considered a complete dose. 
If a patient missed a full week of dosing for non-study drug related events (e.g., a 
required medical procedure or an unanticipated personal emergency), the days missed 
will not be replaced. 
 
Compliance to study medication: will be recorded by study personnel after discussion 
with the patient and drug accountability. Compliance to study medication will be done by 
the investigator or delegate and recorded in source documents. The date will be recorded 
as per study drug schedule. The principal investigator or the designee will account for the 
number of tablets dispensed against those returned by the patient. Any deviations and 
missed doses will be recorded in the CRF and drug accountability logs for verification 


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with the reasons. The investigator/designee will try to ensure complete compliance with 
the dosing schedule by providing timely instructions to the patients 
 
Antineoplastic therapy: Concurrent cancer therapy, including chemotherapy (other than 
protocol drugs fludarabine, cytarabine and ITHMA), immunotherapy, or biologic therapy 
cannot be administered to patients while receiving selinexor. 
 
Radiation therapy: Concurrent radiotherapy is prohibited. 
 
Investigational agents: No other investigational agents may be given while the patient is 
on protocol therapy. 
 
Growth factors: The routine use of filgrastim (G-CSF, Neupogen®) or other growth 
factors is discouraged, but may be used in cases of documented infection or sepsis during 
periods of neutropenia, according to institutional practice. 
 
Conjunctivitis prophylaxis: Dexamethasone or prednisolone ophthalmic solution or 
artificial tears (e.g., hydroxymethylcellulose, hypromellose, polyvinyl alcohol), 2 drops 
in each eye every 4 hours while awake, should be used during cytarabine administration 
and for 24 hours after completion to prevent conjunctival irritation. 
 
Drugs undergoing glutathione conjugation: The primary metabolism of selinexor is 
inactivation by glucuronidation; conjugation with glutathione is a secondary mode of 
metabolism. Because acetaminophen is associated with glutathione depletion, patients 
should not take acetaminophen on days of selinexor administration. 
 
Prophylaxis and treatment of metabolic derangement: Care should be taken to prevent 
hyperuricemia and hyperphosphatemia in participants with large tumor burdens. Such 
participants should receive IV hydration at 1500-3000 mL/m2/day before the initiation of 
therapy, oral phosphate binders, and recombinant urate oxidase or allopurinol as needed. 
 
Prophylaxis for Pneumocystis jiroveci pneumonia: All participants should receive 
prophylaxis for Pneumocystis jiroveci pneumonia according to institutional guidelines. 
 
Prophylaxis for fungal infections: Because patients with relapsed leukemia are at high risk 
for fungal infections, all participants should receive antifungal prophylaxis according to 
institutional guidelines. Prophylaxis with voriconazole or posaconazole are strongly 
recommended. 
 
Prophylaxis for bacterial infections: Because patients with relapsed leukemia are also at 
high risk for bacterial infections, all participants should receive antibiotic prophylaxis 
according to institutional guidelines. We recommend starting prophylactic antibiotics 
when the ANC ≤ 1000 and falling or predicted to fall and continued until the ANC ≥ 100 
and rising. 


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Management of febrile neutropenia: All patients with fever ≥ 38.3°C on a single occasion 
or ≥ 38°C on two occasions within 12 hours should be hospitalized and treated 
immediately with broad spectrum antibiotics according to institutional guidelines. 
 
Prophylactic antiemetic: treatment is recommended prior to the first dose of selinexor, 
although selinexor does not usually cause high grade nausea or vomiting. 5-HT3 receptor 
antagonists, with or without glucocorticoids, appear to be effective at preventing nausea 
associate with selinexor. Olanzapine or mirtazpine are also effective at reducing nausea. 
Neurokinin-1 receptor antagonists (e.g., aprepitant) should be considered in case of 
uncontrolled emesis with standard treatments as described above. Neurokinin-1 receptor 
antagonists can be given with dexamethasone and 5-HT3 receptor antagonists. 
Metoclopramide hydrochloride given prior to meals and dronabinol may be used as well. 
 
Selinexor is infrequently associated with delayed, resistant emesis. Many of the regimens 
associated with delayed emesis are classified as high-emetic risk, and guidelines 
recommend the use of an NK1 receptor antagonist (either NK-1 blockers (e.g., aprepitant 
on days 1 to 3 or fosaprepitant on day 1 only), plus a glucocorticoids on days 1 to 4, 
along with a 5-HT3 receptor antagonist (particularly second generation agents) on day 1. 
This regimen is effective against both acute and delayed emesis. 
 
Conventional antiemetics are more successful at preventing emesis than in preventing 
nausea, particularly delayed nausea. In adult studies, olanzapine once daily (typically 
given at night to mitigate sedative effects) was proven effective in both antiemetic and 
nausea control. It may also be useful for management of breakthrough emesis, and to 
improve food intake in patients with anorexia. Olanzapine is typically used in children 
greater than 10 years of age. 
 
Restrictions and precautions: 
 
Alcohol: 
Ethanol should be avoided on selinexor dosing days as it may compete for 
glutathione mediated metabolism. 
Fasting: 
Patients on selinexor should maintain an adequate diet. 
Medications: Acetaminophen (paracetamol, Tylenol®) and products containing 
acetaminophen should be avoided on days of selinexor administration as it 
may compete with glutathione mediated metabolism. 
Diet: 
There are no dietary restrictions on this study. Patients should maintain 
adequate caloric and fluid intake. 
 
5.0 
DRUG INFORMATION 
 
5.1 
SELINEXOR (KPT-330) 
 
Description: Selinexor is a selective inhibitor of nuclear export (SINE). Selinexor 
specifically blocks XPO1-mediated nuclear export by forming a slowly reversible 
covalent bond with the nuclear export protein XPO1. 


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Selinexor is 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. Selinexor is an investigational agent supplied to investigators by 
Karyopharm Therapeutics. 
 
Selinexor will be supplied as clear-coated tablets for oral use in two (2) dose strengths: 
10 and 25 mg of active ingredient per tablet. Bulk bottles of 50 tablets per bottle will be 
supplied for each of the two strengths. Tablets of selinexor should not be crushed because 
of increased risk of dermatologic toxicity if powder comes in contact with skin. Selinexor 
will be available in 20 mg strength tablets, provided in blister packs, as an additional 
option for patients in the future. 
 
Storage and stability: Tablets of selinexor drug product will be stored at ambient 
temperature in white HDPE bottles, in a locked and secured area with restricted access. 
Selinexor tablets can be stored long term between 5 and 30 ˚C, but should not be stored 
frozen or at freezer temperatures. Room temperature storage is recommended. 
 
Stability of tablets: Selinexor tablets are currently in on-going stability studies. The 
current expiry is 30 months for the 10 mg and 25 mg bottled samples and 21 months for 
the blister-packed 20 mg tablets, and will be extended when further stability data 
becomes available. 
 
Handling: Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
 
Supplier: Selinexor is an investigational agent and will be supplied free-of-charge from 
Karyopharm Therapeutics, Inc. 
Administration: Selinexor tablets for oral administration should be taken within 30- 
minutes of food consumption. 
Each dose will consist of selinexor for oral administration based on mg/m2 basis, and 
should be based on the patient’s actual body surface area (BSA) calculated at baseline 
(Cycle 1) and at the start of each subsequent cycle. See Appendix I for Dosing Guidelines 
 
Toxicity: Please see Investigator’s brochure and safety updates for full information. 
 
Ordering: Karyopharm Therapeutics will supply the drug in the form of 10 mg and 25 mg 
coated tablets in 50 count bottles and 20 mg blister packed tablets. Drug order forms with 
all the needed contact information will be provided at the start of the trial, along with 
recommended initial and resupply stock orders. Orders submitted via e-mail will be filled 
within 5 business days of receipt. 
 
Accountability: The investigator, or a responsible party designated by the investigator at 
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(investigational or free of charge) using the NCI Drug Accountability Record Form 
(DARF) or another comparable drug accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the drug 
accountability form). 
 
Destruction and return: At the end of the study, unused supplies of selinexor should be 
destroyed according to institutional policies at the request of Karyopharm Therapeutics. 
Destruction will be documented in the DARF. 
 
5.2 
Fludarabine (Fludara®, fludarabine phosphate, 2-fluoro-ara-AMP) 
 
Source and pharmacology: Fludarabine phosphate is a synthetic purine nucleoside 
analog. It acts by inhibiting DNA polymerase, ribonucleotide reductase and DNA 
primase by competing with the physiologic substrate, deoxyadenosine triphosphate, 
resulting in inhibition of DNA synthesis. In addition, fludarabine can be incorporated into 
growing DNA chains as a false base, thus interfering with chain elongation and halting 
DNA synthesis. Fludarabine is rapidly dephosphorylated in the blood and transported 
intracellularly via a carrier mediated process. It is then phosphorylated intracellularly by 
deoxycytidine kinase to the active triphosphate form. Approximately 23% of the dose is 
excreted as the active metabolite in the urine (with dosages of 18-25 mg/m2/day for 5 
days). Renal clearance appears to become more important at higher doses, with 
approximately 41-60% of the dose being excreted as the active metabolite in the urine 
with dosages of 80-260mg/m2. 
 
Formulation and stability: Fludarabine is supplied in single-dose vials containing 50 mg 
fludarabine as a white lyophilized powder and 50 mg of mannitol. The intact vials should 
be stored under refrigeration. Each vial can be reconstituted by adding 2 ml of sterile 
water for injection resulting in a final concentration of 25 mg/ml. Because the 
reconstituted solution contains no antimicrobial preservative, the manufacturer 
recommends that it should be used within 8 hours of preparation. The solution should be 
further diluted in 5% dextrose or 0.9% NaCl prior to administration. 
 
Supplier: Commercially available. 
 
Toxicity: The major dose-limiting toxicity of fludarabine is myelosuppression. Nausea 
and vomiting are usually mild. Side effects reported commonly include, anorexia, fever 
and chills, alopecia and rash. Neurotoxicity can be manifested by somnolence, fatigue, 
peripheral neuropathy, mental status changes, cortical blindness and coma and is more 
common at high doses. Neurotoxicity is usually delayed, occurring 21-60 days after the 
completion of a course of therapy and may be irreversible. Side effects reported less 
commonly include diarrhea, stomatitis, increased liver function tests, liver failure, chest 
pain, arrhythmias and seizures. Pulmonary toxicity includes allergic pneumonitis 
characterized by cough, dyspnea, hypoxia and pulmonary infiltrates. Drug induced 
pneumonitis is a delayed effect, occurring 3-28 days after the administration of the third 
or later course of therapy. Administration of corticosteroids usually results in resolution 
of these symptoms. 


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Guidelines for administration: IV infusion over 30 minutes.  See treatment plan section. 
 
5.3 
Cytarabine (Cytosine arabinoside, Ara-C, Cytosar®) 
 
Source and pharmacology: Cytarabine is a deoxycytidine analogue. It must be tri- 
phosphorylated to its active form, ARA-CTP, by deoxycytidine kinase and other nucleotide 
kinases. Ara-CTP inhibits DNA polymerase. In addition, ara-CTP is incorporated into 
DNA as a false base, causing inhibition of DNA synthesis. It is cell cycle, S phase specific. 
Cytarabine does penetrate the blood brain barrier. It is converted to its inactive form, uracil 
arabinoside, by pyrimidine nucleoside deaminase. Approximately 80% of the dose is 
recovered in the urine, mostly as uracil arabinoside (ara-U). 
 
Formulation and stability: Cytarabine is available in multi-dose vials containing 100, 500, 
1000 and 2000mg of lyophilized drug. Intact vials can be stored at room temperature. For 
IV use, either sterile water for injection or bacteriostatic water for injection can be used 
to reconstitute the lyophilized drug. For intrathecal use, only sterile water for injection 
should be used for reconstitution. The 100 and 500 mg vials are reconstituted with 2 and 
10 ml respectively resulting in a final concentration of 50 mg/ml. The 1000 and 2000 mg 
vials are reconstituted with 20 ml and 40 ml respectively resulting in a final concentration 
of 50 mg/ml. After reconstitution, the drug is stable for 8 days at room temperature. 
 
Supplier: Commercially available. 
 
Toxicity: Myelosuppression is the dose limiting adverse effect, with leukopenia and 
thrombocytopenia being predominant. Other adverse effects reported commonly include 
nausea and vomiting (may be severe at high doses), diarrhea, mucositis, anorexia, 
alopecia, skin rash and liver dysfunction. A flu-like syndrome characterized by fever, 
muscle and bone aches is common. Less common side effects include allergic reactions 
and cellulitis at the injection site. High doses of cytarabine can cause conjunctivitis, 
hepatitis, and a group of CNS symptoms including somnolence, peripheral neuropathy, 
ataxia, and personality changes. CNS symptoms are usually reversible and are more 
common in patients who have received previous cranial irradiation. In addition, a 
syndrome of sudden respiratory distress progressing to pulmonary edema has occurred. 
 
Guidelines for administration: Intrathecal and intravenous. See treatment plan section of 
protocol. 
 
5.4 
Intrathecal Triples 
(ITMHA, methotrexate/hydrocortisone/cytarabine) 
 
Source and pharmacology: The intrathecal route of administration of a drug produces 
more consistent CSF drug concentrations at relatively smaller doses because of the 
volume difference between the CSF and blood compartments (140 mL vs. 3500 mL in an 
adult). (The CSF volume of children after the first 3 years is equivalent to that of an 
adult). Drug half-lives are longer as well because clearance is related to flow rather than 
metabolism or protein binding. Intrathecal methotrexate has a biphasic elimination curve 
from the CSF with a t½ of 4.5 and 14 hours respectively. Following IT injection of 


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cytarabine the elimination of the drug from the CSF is biphasic with a t½ of 1 and 3.4 
hours respectively which is 8-fold longer than the clearance from plasma. The 
elimination of hydrocortisone is similarly prolonged. 
 
Formulation and stability: Methotrexate 25 mg/mL preservative free 2 mL vial or 
methotrexate 20 mg preservative free sterile powder for injection vial. Cytarabine 100 mg 
preservative free sterile powder for injection. Hydrocortisone sodium succinate100 mg 
vial sterile powder for injection. 
 
Toxicity:  Nausea, vomiting, fever, headache. 
 
Guidelines for administration:  See treatment plan, Section 4.2. 
 
6.0 
REQUIRED EVALUATIONS, TESTS, OBSERVATIONS 
 
6.1 
Pre-Treatment Clinical Evaluations 
 
• Complete medical history 
• Physical exam with vital signs 
• Height, weight, BSA 
• Complete blood count with differential* 
• Chemistry profile: glucose, electrolytes, BUN, creatinine, LDH, uric acid, bilirubin, SGOT, 
SGPT, calcium, phosphorous, magnesium, total protein and albumin* 
• Coagulation screen* 
• HLA typing, if not done previously 
• Chest x-ray* 
• EKG, echocardiogram* 
• Lumbar puncture with CSF cell count and cytology. 
• Ophthalmic exam (preferably prior to first dose of selinexor, but may be obtained within one 
week of dose #1). 
• Serum pregnancy test of females of childbearing potential 
• Bone marrow evaluation for morphology, immunophenotyping, cytogenetics, molecular 
diagnosis, minimal residual disease (MRD), and tissue banking*. Morphologic examination 
and MRD are required for all patients. Immunophenotyping, cytogenetic analysis, and 
molecular analysis should be performed as clinically indicated (e.g., if not done at the time 
of relapse). For patients with elevated leukocyte counts and high blast percentages, and 
patients too ill to undergo bone marrow aspirate, all diagnostic studies may be performed on 
blood rather than bone marrow. MRD studies must be performed centrally at St. Jude, 
whereas other diagnostic studies may be performed locally as desired by the treating 
physician. 
 
* Complete blood count and chemistry profile should be performed within 48 hours of 
first dose of selinexor. Chest x-ray, EKG, and echocardiogram should be performed with 
2 weeks of first dose of selinexor. Tissue banking applies to participants who have signed 
St. Jude TBANK consent only. TBANK is an optional protocol for collaborating sites. 


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6.2 
Evaluations During Therapy 
During Cycle 1-2 
(combination therapy) 
Cycles 2-5 selinexor single agent 
Clinical studies 
Physical exam, BSA, vital signs, 
performance status 
Weekly 
Prior to each cycle and then every 2 
weeks 
CBC with diff 
Weekly and as clinically 
indicated 
Prior to each cycle and then every 2 
weeks 
Serum chemistries1 
Weekly, and as 
clinically indicated 
Prior to each cycle and then every 2 
weeks 
Ophthalmic examination2 
Prior to cycle2 
As clinically indicated 
Bone marrow aspirate and/or biopsy 
for morphology, MRD 
Prior to Cycle 1 and 2 
Every other cycle 
Bone marrow aspiration for MRD and 
correlative biological studies – see 
Section 7.3 and Appendix V 
Prior to Cycle 1, at day 
15, and at the end of 
Cycle 1 
--- 
EKG and echocardiogram 
Prior to each cycle 
Prior to each cycle 
Correlative research studies 
Pharmacokinetics – see Section 7.1 
Cycle 1, dose escalation 
cohort (phase I) only 
--- 
Pharmacodynamics (XPO1 expression 
levels and cytokine analysis) – see 
Sections 7.2.1 and 7.2.2 
Cycle 1, dose escalation 
cohort (phase I) only 
--- 
1Serum chemistries include: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
calcium, phosphate, magnesium, uric acid, ALT, AST, alkaline phosphatase, total bilirubin and LDH 
2Full ophthalmic examination will be conducted on all patients by an ophthalmologist or optometrist 
at screening and as clinically indicated during thereafter. Ideally, the initial exam should be 
conducted prior to the first dose of selinexor, but may be conducted within one week of the first dose. 
 
6.3 
Response Evaluations 
 
6.3.1 Evaluation of response to Cycle 1 combination therapy 
 
All participants should undergo response evaluation between days 42 and 56 of Cycle 1. 
In addition to bone marrow aspiration, bone marrow biopsy should be considered to 
evaluate cellularity. In cases with hypocellular marrows (<10 % cellularity), repeat bone 
marrow examination should be considered when there is evidence of hematopoietic 
recovery. If multiple bone marrow examinations are performed after a course of therapy, 
the last examination will be used to classify the response to that course. 
 
6.3.2 Evaluation of response to single agent selinexor (during cycle 1) 
 
Unless there is evidence of progressive disease by examination of the blood, participants 
should undergo bone marrow aspiration on day 15 (± 2 days). This evaluation must be 
performed prior to administration of day 15 therapy. 


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6.4 
Evaluations After Completion of Therapy 
 
When a participant discontinues the study, a final visit will be conducted. Following 
discontinuation of the study treatment, the participant will be treated according to the 
investigator’s discretion. If a participant discontinues from the study due to an adverse 
event considered related to study treatment, a follow-up visit should be conducted no later 
than 30 days after the last dose of protocol therapy. Safety assessments are recommended 
at least every 30 days, until all toxicities resolve, return to baseline or become clinically 
satisfactory, stable, or are considered irreversible. 
 
7.0 
OPTIONAL CORRELATIVE RESEARCH STUDIES 
 
Summary information is provided below. Detailed information will be included in the 
laboratory manual to be provided by Karyopharm. Materials for collection and processing 
will also be provided by Karyopharm. 
 
7.1 
Optional Pharmacokinetic (PK) Studies - Plasma (completed) 
 
Samples for pharmacokinetic (PK) analysis will be collected during Cycle 1 of the dose 
escalation portion of the trial. 
 
7.1.1 Timing of PK samples 
 
Day 1 dose of selinexor (single agent): prior to day 1 dose, and at 30 minutes, 1 hour, 2 
hours, 4 hours, 8 hours, 24 hours, and 48 hours after day 1 dose. 
 
Day 22 dose of selinexor (to support combination kinetics): prior to day 22 dose and at 1 
hour, 2 hours, 4 hours, and 8 hours after day 22 dose. 
 
2 mL samples will be collected for each sampling point. 
 
7.2 
Optional Pharmacodynamic (PD) Studies (completed) 
 
Samples for pharmacodynamic (PD) analysis will be collected during Cycle 1 of the dose 
escalation portion of the trial. 
 
7.2.1 XPO1 expression levels 
 
Measurement of XPO1 mRNA will be performed by Karyopharm as described in the lab 
manual. Whole blood will be collected from patients (2x2 ml), collected pre- and post- 
dosing (≥ 4hr) and total RNA will be isolated to study changes in gene expression before 
and after exposure to selinexor. Inhibition of XPO1 (selinexor target) will be assessed by 
qRT-PCR of XPO1 and other genes, which are upregulated once XPO1 is inactivated 
(e.g., ARRDC3, NGFR, SLC family, PCLO) will also be analyzed. Please refer to Lab 
Manual for detailed instructions. 


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Timing of XPO1 expression samples 
 
Whole blood samples (2x2.5 ml per time point) for leukocyte XPO1 analysis will be 
collected prior to the first dose of selinexor and at 4 hours, 8 hours, 24 hours, and 48 
hours after the first dose. 
 
7.2.2 Cytokine analysis 
 
Blood samples (2 ml) will be collected pre- and post-dosing and analyzed for plasma 
cytokine concentrations. Cytokines include: IL1α, TNFα, IL-6, MCP1, IFNγ, VEGFα, 
IL-8, IFNα, IL-10. 
 
Timing of cytokine samples 
 
Blood samples (2 ml per time point) for cytokine analysis will be collected prior to first 
dose of selinexor (within 10 minutes before administration) and 4 hours (± 20 min), 8 
hours (± 30 min), 24 hours (± 2 hours), and 48 hours (± 2 hours) after the dose. 
 
7.3 
Optional Correlative Biological Studies (Phase II) 
 
Preclinical studies have suggested that XPO1 expression is associated with disease 
outcome, p53 status may correlated with response, and subcellular protein localization 
may be predictive of response.6,20 Notably, two patients the phase I portion of this study 
became MRD negative after receiving only selinexor, indicating that there is a patient 
population who might benefit from single-agent selinexor therapy and would benefit 
from development of predictive tools. 
 
Bone marrow aspiration (5 ml in EDTA) will be collected for research purposes at the 
planned disease evaluations prior to the start of therapy (but after consent), at the day 15 
evaluation, and at the end of cycle 1 evaluation. Genomics studies prior to therapy will 
include whole-genome sequencing, whole-exome sequencing, and RNA-seq to fully 
characterize the leukemic cells. At subsequent time points, these studies will include 
whole-exome sequencing (or other targeted sequencing approaches) and RNA-seq to 
investigate how the leukemia cells are responding to therapy. In cases with a blast 
percentage of <50% at any time point, the blasts may need to be sorted by flow cytometry 
to enrich for the leukemic cell population to provide enough cells for analysis. Additional 
biologic studies may include chemical screens with assessment of apoptosis, assessment 
of subcellular protein localization, and the development of xenograft models to further 
characterize the leukemia response to selinexor. 
 
8.0 
EVALUATION CRITERIA 
 
8.1 
Response Criteria 
 
Because morphologic examination of the bone marrow during periods of hematopoietic 
recovery after intensive chemotherapy may be unreliable, response will be based on blast 


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percentage by flow cytometry. Blast percentages determined by morphology will be used 
in cases that are not evaluable by flow cytometry. 
 
8.1.1 Complete remission (CR) 
 
• Bone marrow with < 5% blasts confirmed by flow cytometry 
• ANC ≥ 500/μL and platelets ≥ 75,000/μL without transfusions 
• No evidence of extramedullary disease 
 
8.1.2 Complete remission with incomplete blood count recovery (CRi) 
 
• Bone marrow with < 5% blasts confirmed by flow cytometry 
• ANC < 500/μL or platelets < 75,000/μL without transfusions 
• No evidence of extramedullary disease 
 
8.1.3 Partial response (PR) 
 
• Bone marrow with 5% to 25% blasts by flow cytometry and a decrease of at 
least 50% in blast percentage 
• No evidence of extramedullary disease 
 
8.1.4 No response (NR) 
 
Participant fails to qualify for any of the categories listed above 
 
8.1.5 Relapse 
 
Subsequent appearance, after achievement of CR, of ≥ 5% blasts in the bone 
marrow with confirmation by flow cytometry or the development of 
extramedullary disease after achievement of CR 
 
8.2 
Toxicity Evaluation Criteria 
 
Common Terminology Criteria for Adverse Events v4 (CTCAE): This study will utilize 
the CTCAE of the National Cancer Institute (NCI) for toxicity and performance 
reporting. A copy of the current version of the CTCAE can be downloaded from the 
Cancer Therapy Evaluation Program (CTEP) home page (http://ctep.info.nih.gov). 
Additionally, toxicities will be reported on the appropriate data collection screens. 
 
9.0 
OFF-TREATMENT AND OFF-STUDY CRITERIA 
 
9.1 
Off-Treatment Criteria 
 
• Development of a DLT 
• No response to therapy 
• Relapse 


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• Second malignancy 
• Treatment with other antineoplastic therapy or hematopoietic stem cell 
transplantation 
• Development of unacceptable toxicity during treatment 
• Refusal of further protocol therapy by participant, parent, or guardian 
• Completion of protocol therapy 
 
9.2 
Off-Study Criteria 
 
• Death 
• Lost to follow up 
• Withdrawal of consent 
 
10.0 
SAFETY AND ADVERSE EVENT REPORTING 
 
10.1 
REPORTING ADVERSE EXPERIENCES AND DEATHS 
 
Principal investigators are responsible for promptly reporting to the IRB any adverse 
events that are unanticipated, serious, and that may represent potential harm or increased 
risk to research participants. When an unanticipated death occurs, the PI should report it 
to the Director of the Office of Human Subjects’ Protection immediately, by phone: 
 
, Cell: 
, fax: 
, or e-mail: 
). 
 
A reportable event entry into TRACKS should follow within 48 hours. Serious, 
unanticipated, and related or possibly related events will be reported within 10 working days. 
 
The principal investigator is responsible for reviewing the aggregate toxicity reports and 
reporting to the IRB if the frequency or severity of serious toxicities exceed those 
expected as defined in the protocol or based on clinical experience or the published 
literature. Any proposed changes in the consent form or research procedures resulting 
from the report are to be prepared by the study team and submitted with the report to the 
IRB for approval. 
 
The following definitions apply: 
 
A serious event refers to any event in which the outcome is fatal or life-threatening, 
results in permanent disability, causes inpatient hospitalization or prolongs existing 
inpatient hospitalization, or is a congenital anomaly, cancer, or overdose. 
 
An unanticipated adverse event refers to those not identified in their nature, severity, or 
frequency in the current risk documents (e.g., investigator’s brochure), or consistent with 
the investigational plan. 
 
The following are considered reportable: Any injuries, serious event or other 
unanticipated adverse events involving risk to participants or others which occur at a 
frequency above that considered acceptable by the investigators and the IRB. (FDA) As 


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described in 4.3 above, the OHSP Director or designee performs the initial review of 
unanticipated problems or serious adverse event reports. Internal reports of events that 
are unanticipated, serious, and related or possibly related to study interventions or 
procedures are then forwarded to the IRB Chair or designee and if necessary, referred to 
the full IRB. Based on the frequency and seriousness of adverse events, the IRB Chair or 
Committee may deem it necessary to suspend or terminate a research study or studies. 
 
10.1.1  Reporting to Karyopharm 
 
In addition to reporting to the FDA, St. Jude will forward completed SAE form to 
representatives of the Karyopharm Team: 
 
 
 
It is the responsibility of St. Jude, the sponsor, to collect and document required 
information regarding Adverse Events (AEs) in accordance with all applicable laws and 
regulations. 
 
St. Jude shall be responsible for ensuring that reports of Serious Unexpected Suspected 
Adverse Reactions (SUSARs) are prepared and submitted to the appropriate Regulatory 
Authorities, Competent Authorities, Institutional Review Boards (IRBs) and Ethics 
Committees (ECs) in accordance with applicable regulations and legislation. 
 
For all SUSARS, St. Jude is responsible for providing a copy of the regulatory report (to 
include a MedWatch or CIOMS forms) to Karyopharm Therapeutics at 
 promptly - to mean as soon as is possible, and not more than 15 
days from becoming aware of the event. 
 
In addition to SUSAR reporting to Karyopharm, St. Jude is responsible for providing 6- 
month Adverse Reaction Reports ( all AEs assessed as causality related to Karyopharm 
investigational product) to Karyopharm Therapeutics at 
 
throughout the duration of the study. These reports are to contain listings of non-serious 
(expected or unexpected) adverse reactions and serious or non-serious expected adverse 
reactions which were collected during the 6-month report cycle. 
 
St. Jude is responsible for obtaining any additional follow-up information regarding 
safety reports, upon request from Karyopharm. 
 
KARYOPHARM THERAPEUTICS will inform St. Jude regarding any SUSAR detected 
in other clinical studies, ISTs, or compassionate use as promptly as is possible upon 
becoming aware of same. 
 
10.2 
Recording and Reporting AEs and SAEs 
 
Adverse events (AEs) will be evaluated and documented by the clinical staff and 
investigators throughout inpatient hospitalizations and each outpatient visit. CRAs are 
responsible for reviewing documentation related to AEs and entering directly into CRIS 


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protocol-specific database. The data to be recorded are 1) the event description, 2) the 
NCI CTCAE v4.0 code and grade, 3) the onset date, 4) the resolution date (or ongoing), 
4) action taken for event, 5) patient outcome 6) relationship of AE to protocol 
treatment/interventions, 7) if AE was expected or unexpected, and 8) comments, if 
applicable. 
 
AEs that are classified as serious, unexpected, and at least possibly related will be notated 
as such in the database as “SAEs”. 
 
Attribution of an Adverse Event 
 
Not related- The lack of a temporal relationship of the event to study treatment makes a 
causal relationship not reasonably possible, or other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation. 
 
Unlikely related- The temporal relationship of the event to study treatment makes a causal 
relationship reasonably unlikely, and other drugs, therapeutic interventions or underlying 
conditions may not provide sufficient explanation for the observed event. 
 
Possibly related- The temporal relationship of the event to study treatment makes a causal 
relationship reasonably possible, and the event is more likely explained by exposure to the 
study treatment than by other drugs, therapeutic interventions or underlying conditions. 
 
For the purpose of safety analyses, all AE’s that are classified as unlikely or possible will 
be considered treatment-related events. 
 
These events will be reported expeditiously to the St. Jude IRB within the timeframes as 
described above. Cumulative summary of Grades 2-5 events will be reported as part of 
the progress reports to IRB at the time of continuing review. Specific data entry 
instructions for AEs and other protocol-related data will be documented in protocol- 
specific data entry guidelines, which will be developed and maintained by study team and 
clinical research informatics. 
 
Patients with abnormal blood counts due to bone marrow involvement by disease (i.e. all 
leukemia patients and lymphoma patients with bone marrow involvement) will be 
considered non-evaluable for hematological toxicities. 
 
The study team will meet regularly to discuss AEs (and other study progress as required 
by institutional DSMP). The PI will review Adverse Event reports generated from the 
research database, and corrections will be made if applicable. Once the information is 
final the PI will sign and date reports, to acknowledge his/her review and approval of the 
AE as entered in the research database. 
 
10.3 
Process for Reporting Adverse Events From and To Collaborating Sites 
 
Adverse events from collaborating sites will also be reviewed by the PI and discussed in 
study team meetings as described above. SAE reports from collaborating sites for AEs 


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that are serious, unexpected, and at least possibly related to protocol treatment or 
interventions will be reported to site IRB and the St. Jude IRB within the reporting 
requirements described above. The PI will determine if this is an event that will need to 
be reported expeditiously to all participating sites, considering the following criteria: 
• Is the AE serious, unexpected, and related or possibly related to participation in 
the research? 
• Is the AE expected, but occurring at a significantly higher frequency or severity 
than expected? 
• Is this an AE that is unexpected (regardless of severity that may alter the IRB’s 
analysis of the risk versus potential benefit of the research and, as a result, 
warrant consideration of substantive changes in the research protocol or informed 
consent process/document? 
 
With the submission of the “Reportable Event” in St. Jude TRACKS application, the PI 
will indicate if all sites should be notified to report to their IRBs, and if the protocol 
and/or consent should be amended (consent will be amended if event is information that 
should be communicated to currently enrolled subjects). 
 
Generally, only events that warrant an amendment to the protocol and/or consent will be 
reported expeditiously to all sites. However, any event may be reported expeditiously to 
all sites at the discretion of the PI. 
 
A cumulative summary of Grade 2-5 AEs and expected/unrelated deaths that occur more 
than 30 days after protocol treatment will be reported to all sites with study progress 
report at the time of continuing review. 
 
For collaborating sites: Serious AND unexpected events are to be reported to the St. Jude 
PI (Dr. Jeffrey Rubnitz) within 48-72 hours via fax or email. 
 
Unexpected deaths must be reported to the St. Jude PI via phone call or email within 24 
hours of the event.  A written report must follow. 
 
All correspondence and reports must also be sent by email to the SELHEM study team. 
 
Jeffery E. Rubnitz, MD, PhD 
Department of Oncology 
Leukemia/Lymphoma Division 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Phone: 
 
FAX: 
 
 
Email: 
 
Email: 
 


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11.0 
DATA COLLECTION, MONITORING AND CONFIDENTIALITY 
 
11.1 
Data Collection 
 
Electronic case report forms (e-CRFs) will be completed by the clinical trials staff from 
the Cancer Center Comprehensive Center, Hematological Malignancies Program. Data 
will be entered from record directly into a secure CRIS database, developed and 
maintained by St. Jude Clinical Research Informatics. 
 
Data Management will be supervised by the Director of Clinical Trials Management, and 
Manager of Clinical Research Operations for the Hematological Malignancies Program, 
working with Dr. Rubnitz or his designee. All protocol-specific data and all grade 2-5 
adverse events will be recorded by the clinical research associates into the CRIS 
database, ideally within 2-4 weeks of completion of study phase. All questions will be 
directed to the attending physician and/or PI and reviewed at regularly-scheduled 
working meetings. Data collection for adverse events will be captured for 30 days after 
participant is removed from treatment, or until the participant receives other anti- 
leukemia therapy. 
 
The attending physicians (or their designees) are responsible for keeping up-to-date 
roadmaps in the patient’s primary SJCRH medical chart. Regular (at least monthly) 
summaries of toxicity and protocol events will be generated for the PI and the department 
of Biostatistics to review. 
 
11.2 
Study Monitoring 
 
The Clinical Research Monitor will track accrual continuously and verify 100% of all 
data points on all study participants quarterly to assess overall study conduct, Human 
Subjects Protections, and the accuracy of database entries. Essential regulatory 
documents and all study documents including medical records, electronic media, database 
entries, study worksheets, and case report forms will be reviewed for recording and 
reporting of Adverse Events/Serious Adverse Events (SAEs) to include type, grade, 
attribution, duration, timeliness and appropriateness. Study documents are also reviewed 
for participant status, eligibility, the informed consent process, demographics, staging, 
study objectives, subgroup assignment, treatments, evaluations, responses, participant 
protocol status, off-study and off-therapy criteria, and for all other specifics as detailed in 
the protocol. The Monitor will generate a formal report which is shared with the Principal 
Investigator (PI), study team and the Internal Monitoring Committee (IMC). 
 
Monitoring may be conducted more frequently if deemed necessary by the CPDMO 
and/or the IMC. 
 
Continuing reviews by the IRB and CT-SRC will occur at least annually. In addition, 
SAE reports in TRACKS (Total Research and Knowledge System) are reviewed in a 
timely manner by the IRB/ OHSP. 


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Source document verification of eligibility for all SJCRH cases will be performed within 
two weeks of completion of enrollment. This will include verification of appropriate 
documentation of consent. Monitoring of timeliness of serious adverse event reporting 
will be done as events are reported in TRACKS. 
 
Monitoring of this protocol is considered to be in the high-risk 2 category (HR-2). The 
Monitoring Plan is outlined in a separate document from this protocol, but has been 
submitted for review and approval by the Clinical Trials Scientific Review Committee 
and the Institutional Review Board. 
 
St. Jude affiliates and domestic collaborating study sites will be monitored on-site by a 
representative of St. Jude at intervals specified in the Data and Safety Monitoring Plan. 
International collaborators will be monitored by a Contract Research Organization 
(CRO), or other mechanisms according to the study-specific monitoring plan. 
 
11.3 
Confidentiality 
 
Study numbers will be used in place of an identifier such as a medical record number. No 
research participant names will be recorded on the data collection forms. The list 
containing the study number and the medical record number will be maintained in a 
locked file and will be destroyed after all data have been analyzed. 
 
The medical records of study participants may be reviewed by the St. Jude IRB, FDA, 
and clinical research monitors. 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
The primary objective of the phase I portion of this study is to determine a tolerable 
combination of selinexor, fludarabine, and cytarabine in patients with relapsed or 
refractory hematologic malignancies including acute myeloid leukemia (AML), acute 
lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). Although disease 
response to treatment will be explored, this phase I portion of the study is not designed to 
yield a formal evaluation of the efficacy of this regimen. 
 
The primary objective of the phase II portion of the study is to estimate the overall 
response rate, as defined by complete response or complete response with incomplete 
count recovery, of selinexor in combination with fludarabine and cytarabine for patients 
with relapsed or refractory AML. This will be assess be assessing the null hypothesis that 
overall response rate is < 30%, as specifically described below. 
 
Responsible investigator: Jeffrey Rubnitz, MD, PhD 
Responsible statistician:  Stanley Pounds, PhD 


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12.1 
Dose Escalation Phase 
 
Evaluable for toxicity 
 
Any participant who experiences dose-limiting toxicities (DLT) at any time during the 
first 35 days after taking the initial dose of selinexor and before receiving non-protocol 
therapy (such as transplant) is considered evaluable for toxicity. Participants without 
DLT who receive at least 5 of the 6 prescribed cycle I doses of selinexor and can be 
followed for 35 days following their initial dose of selinexor are also considered 
evaluable for toxicity. The evaluation period for purposes of determining whether a 
participant has a DLT will be the first 35 days following the initial dose of selinexor. 
Participants who are not evaluable for toxicity (such as those removed early from therapy 
to start alternate therapy) at a given dose level will be replaced. 
 
Maximum tolerated dose (MTD) 
 
The MTD is empirically defined as the highest dose level at which six participants have 
been treated with at most one participant experiencing a DLT and the next higher dose 
has been determined to be too toxic. If the lowest dose level studied is too toxic or the 
highest dose level studied is considered safe, the MTD will not have been considered 
estimated. 
 
Dose escalation/de-escalation rules 
 
The rolling-6 design21 will be used to determine dose escalation and reduction within 
each stratum separately. The rolling-6 design is described in greater detail below. 
 
Two to six participants can be concurrently enrolled onto a dose level, dependent on 1) 
the number of participants enrolled at the current dose level, 2) the number of participants 
who have experienced DLT at the current dose level, and 3) the number of participants 
entered but with tolerability data pending at the current dose level. Accrual is suspended 
when a cohort of six has enrolled or when the study endpoints have been met. 
 
Decision as to which dose level to enroll a participant is based on the number of 
participants currently enrolled and evaluable, the number of participants experiencing 
DLT, and the number of participants still at risk of developing a DLT at the time of new 
participant entry. For example, when three participants are enrolled onto a dose level, if 
toxicity data is available for all three participants and no DLTs are observed when the 4th 
participants enter, the dose is escalated and the 4th participants is enrolled to the next 
higher dose level; if toxicity data is not yet available for one or more of the three 
participants and no DLT has been observed, or if one DLT has been observed, the new 
participant is entered at the same dose level; if two or more DLTs have been observed 
from the three participants, the dose level is de-escalated. This process is repeated for the 
5th and 6th participants. Accrual is only suspended when a cohort of six is filled. The 
starting dose of selinexor will be 30 mg/m2/dose. Table 3 of section 4.3 lists the dose 
levels to be explored in this study. Section 4.3.2 defines the dose limiting toxicity for this 
study. 


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12.2 
Phase I Sample Size/Accrual Rate 
 
As previously stated, the rolling-6 design will be applied. The minimum sample size of 
four occurs in the case that the first two patients on dose level 1 have a DLT, the dose is 
reduced and then the first two patients on dose level -1 have a DLT. The maximum 
sample size of 24 patients occurs if 6 patients are treated at each of the 4 dose levels. 
Thus, the total sample size may be as small as 4 and as large as 24 evaluable participants. 
The principal investigator estimates an annual accrual of 10 to 12 patients per year. 
 
12.3 
Phase II Sample Size/Accrual Rate 
 
For purposes of this Phase II evaluation, we define a success as complete remission, 
complete remission with incomplete count recovery, or, for patients who are enrolled 
with <5% blasts, the achievement of MRD negativity, by the end of one course of 
therapy. Patients who die before reaching this milestone will be counted as failures for 
purposes of this Phase II design. We will use Simon’s minimax two-stage design for the 
Phase II component.22  In the first stage, we will enroll 28 patients. Patients who have 
been enrolled on the dose expansion cohort and who meet the eligibity criteria for the 
Phase II portion of the study, will be included in the analysis. The study will stop at any 
point it becomes impossible to obtain 8 or more successes (CR or CRi or MRD 
negativity) among the first 28 patients. If 8 or more successes are observed among the 
first 28 patients, the study will continue to enroll an additional 11 patients for a total of 39 
patients. For the phase I portion of the trial, we enrolled 18 patients in 15 months, for an 
accrual rate of 1.2 patients/month. Conservatively assuming each of the four additional 
participating sites enroll one patient per year, the accrual will increase to 1.5 
patients/month. At this rate the study will be open for as little at 19 months or up to as 
long as 26 months. 
 
12.4 
Analysis of Secondary Objectives 
 
Pharmacokinetic studies 
 
Plasma samples will be analyzed via a validated high performance liquid 
chromatography/tandem mass spectrometry (HPLC/MS-MS) method for plasma 
selinexor concentration. Selinexor concentration data will be analyzed in a non-linear 
mixed effects population PK model with potential covariates including, but not limited 
to: age, body weight, gender, disease state, baseline hepatic or renal function, 
concomitant medications, and treatment. Details of the population PK analysis, including 
software, post-processing and statistical analysis, will be outlined in a separate Data 
Analysis Plan, to be completed prior to database lock. Interim analysis may be conducted 
on draft plasma selinexor concentration data throughout the study. Summary statistics, 
including mean, median, standard deviation, coefficient of variation and group size may 
be compiled and reported during the study. Interim analysis of key selinexor PK 
parameters and key biomarker analyses may be performed in order to provide a 
pharmacokinetic-pharmacodynamic assessment throughout the study. 


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Efficacy 
 
The efficacy of the combination of selinexor, fludarabine, and cytarabine, as measured by 
the complete response (CR) rate and the overall response (OR) rate (CR + CRi + PR) will 
be assessed for the patients enrolled at the RP2D. The rates of CR and OR will be 
presented as a point estimate with a 95% exact binomial confidence interval. 
 
The therapy offered in the phase II portion of this protocol will be considered worthy of 
further study if success, as defined in section 12.3, is achieved for 16 or more of the 39 
patients. This design has a 10% probability of declaring the therapy worthy of further 
study under the null hypothesis that the true success rate is 30%. This design has a 90% 
probability of declaring the therapy worthy of further study under the alternative 
hypothesis that the true success rate is 50%. This design was obtained by the R command 
ph2simon(pu = 0.3, pa = 0.5, ep1=0.1, ep2=0.1) defined in version 1.0.11 of the R 
package clinfun. The method of Koyama and Chen as implemented in the twostage 
inference procedure of the clinfun R package will be used to compute the confidence 
interval for the success rate.22 
 
Responsible investigator: Jeffrey Rubnitz, MD, PhD 
Responsible statistician:  Stanley Pounds, PhD 
 
12.5 
Analysis of Exploratory Objectives 
 
Pharmacodynamic and correlative biological studies 
 
Analysis of the pharmacodynamic and correlative biological studies will be descriptive. 
 
Responsible investigator: Jeffrey Rubnitz, MD, PhD 
Responsible statistician:  Stanley Pounds, PhD 
 
12.6 
Anticipated Completion Dates 
 
Anticipated primary completion date: December, 2018 
Anticipated study completion date:  January, 2020 
 
13.0 
OBTAINING INFORMED CONSENT 
 
13.1 
Consent Prior to Research Interventions 
 
Initially, informed consent will be sought for the institutional banking protocol (TBANK 
research study), PGEN5, and for other procedures as necessary for standard medical care. 
During the screening process for eligibility, informed consent for SCREEN protocol OR 
for SELHEM is required before any research tests are performed. 


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13.2 
Consent at Enrollment 
 
The process of informed consent for SELHEM will follow institutional policy. The 
informed consent process is an ongoing one that begins at the time of diagnosis and ends 
after the completion of therapy. Informed consent should be obtained by the attending 
physician or his/her designee, in the presence of at least one non-physician witness. 
Initially, informed consent will be sought for the institutional banking protocol (research 
study), blood transfusion and other procedures as necessary. After the diagnosis of 
relapsed or refractory leukemia is established, we will invite the patient to participate in 
the SELHEM protocol. 
 
Throughout the entire treatment period, participants and their parents receive constant 
education from health professionals at SJCRH and collaborating sites, and are encouraged 
to ask questions regarding alternatives and therapy. All families have ready access to 
chaplains, psychologists, social workers, and the St. Jude ombudsperson for support, in 
addition to that provided by the primary physician and other clinicians involved in their 
care. We will also obtain verbal assent from children 7 to 14 years old and written assent 
for all participants >14 years of age. 
 
13.3 
Consent at Age of Majority 
 
Participants who reach the age of majority while on study will be re-consented for 
continued participation on SELHEM at the time of their next clinic visit after turning 18 
year according to Cancer Center and institutional policy. 
 
13.4 
Consent When English is Not the Primary Language 
 
When English is not the participant, parent, or legally authorized representative’s primary 
language, the Social Work department will determine the need for an interpreter. This 
information will be documented in the participant’s medical record. Either a certified 
interpreter or the telephone interpreter’s service will be used to translate the consent 
information. The process for obtaining an interpreter and for the appropriate use of an 
interpreter is outlined on the Interpreter Services, OHSP, and CPDMO websites. 


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14.0 
REFERENCES 
 
1. Fukuda M, Asano S, Nakamura T, et al. CRM1 is responsible for intracellular transport 
mediated by the nuclear export signal. Nature 1997;390:308-11. 
2. Ossareh-Nazari B, Bachelerie F, Dargemont C. Evidence for a role of CRM1 in signal- 
mediated nuclear protein export. Science 1997;278:141-4. 
3. Huang WY, Yue L, Qiu WS, Wang LW, Zhou XH, Sun YJ. Prognostic value of CRM1 in 
pancreas cancer. Clinical and investigative medicine Medecine clinique et experimentale 
2009;32:E315. 
4. Yao Y, Dong Y, Lin F, et al. The expression of CRM1 is associated with prognosis in 
human osteosarcoma. Oncology reports 2009;21:229-35. 
5. van der Watt PJ, Maske CP, Hendricks DT, et al. The Karyopherin proteins, Crm1 and 
Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell 
survival and proliferation. International journal of cancer 2009;124:1829-40. 
6. Kojima K, Kornblau SM, Ruvolo V, et al. Prognostic impact and targeting of CRM1 in 
acute myeloid leukemia. Blood 2013;121:4166-74. 
7. Tai YT, Landesman Y, Acharya C, et al. CRM1 inhibition induces tumor cell cytotoxicity 
and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and 
therapeutic implications. Leukemia 2014;28:155-65. 
8. Lapalombella R, Sun Q, Williams K, et al. Selective inhibitors of nuclear export show that 
CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood 2012;120:4621-34. 
9. Ranganathan P, Yu X, Na C, et al. Preclinical activity of a novel CRM1 inhibitor in acute 
myeloid leukemia. Blood 2012;120:1765-73. 
10. Falini B, Nicoletti I, Martelli MF, Mecucci C. Acute myeloid leukemia carrying 
cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood 
2007;109:874-85. 
11. Walker CJ, Oaks JJ, Santhanam R, et al. Preclinical and clinical efficacy of XPO1/CRM1 
inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias. Blood 2013;122:3034- 
44. 
12. Etchin J, Sanda T, Mansour MR, et al. KPT-330 inhibitor of CRM1 (XPO1)-mediated 
nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute 
lymphoblastic leukaemia and acute myeloid leukaemia. British journal of haematology 
2013;161:117-27. 
13. Etchin J, Sun Q, Kentsis A, et al. Antileukemic activity of nuclear export inhibitors that 
spare normal hematopoietic cells. Leukemia 2013;27:66-74. 
14. Abdul Razak AR, Mau-Soerensen M, Gabrail NY, et al. First-in-Class, First-in-Human 
Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With 
Advanced Solid Tumors. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2016. 
15. Kaspers GJ, Zimmermann M, Reinhardt D, et al. Improved outcome in pediatric relapsed 
acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the 
International BFM Study Group. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2013;31:599-607. 
16. Cooper TM, Franklin J, Gerbing RB, et al. AAML03P1, a pilot study of the safety of 
gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed 
childhood acute myeloid leukemia: a report from the Children's Oncology Group. Cancer 
2012;118:761-9. 


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17. Arceci RJ, Sande J, Lange B, et al. Safety and efficacy of gemtuzumab ozogamicin in 
pediatric patients with advanced CD33+ acute myeloid leukemia. Blood 2005;106:1183-8. 
18. Jeha S, Razzouk B, Rytting M, et al. Phase II study of clofarabine in pediatric patients with 
refractory or relapsed acute myeloid leukemia. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2009;27:4392-7. 
19. Savona M, Garzon, R., Brown, P., Yee, K., Lancet, J.E., Gutierrez, M., Gabrail, N., Mau- 
Sorensen, M., Baz, R., Byrd, J.C., Kuruvilla, J., Siegel, D.S., Shacham, S., Rashal T., Yau, 
C.Y.F., McCauley, D., Saint-Martin, J.R., McCartney, J., Landesman, Y., Klebanov, B., 
Pond, G., Oza, A.M., Kauffman, M., Mirza, M.R., Stone, R.M. Phase I trial of selinexor 
(KPT-330), a first-in-class oral selective inhibitor of nuclear export (SINE) in patients with 
advanced acute myelogenous leukemia.  ASH; 2013. 
20. Attiyeh EF, Maris JM, Lock R, et al. Pharmacodynamic and genomic markers associated 
with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the 
pediatric preclinical testing program. Pediatric blood & cancer 2016;63:276-86. 
21. Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of 
pediatric phase I trials: the rolling six design. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology 2008;26:190-5. 
22. Koyama T, Chen H. Proper inference from Simon's two-stage designs. Statistics in 
medicine 2008;27:3145-54. 


Amendment 6.0, dated: 03-24-2017 
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SELHEM 
Appendix I 
 
 
APPENDIX I:  SELINEXOR Dosing Guidelines 
 
Phase II Cohort: Dose Level 2 (40 mg/m2) 
BSA range 
Total mg dose 
0.45 – 0.55 
20 
0.56 – 0.68 
25 
0.69 – 0.81 
30 
0.82 – 0.93 
35 
0.94 – 1.06 
40 
1.07 – 1.18 
45 
1.19 – 1.31 
50 
1.32 – 1.43 
55 
1.44 – 1.56 
60 
1.57 – 1.68 
65 
1.69 – 1.81 
70 
1.82 – 1.93 
75 
1.94 – 2.06 
80 
2.07 – 2.18 
85 
2.19 – 2.31 
90 
2.32 – 2.43 
95 
2.44 and greater 
100 


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SELHEM 
Appendix II 
 
 
 
APPENDIX II: PERFORMANCE STATUS CRITERIA 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky 
Score Description 
Score Description 
Score Description 
0 
Fully active, able to carry 
on all pre-disease 
performance without 
restriction 
100 
Normal, no complaints, no 
evidence of disease 
100 
Fully active, normal 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease 
90 
Minor restrictions in 
physically strenuous 
activity 
1 
Restricted in physically 
strenuous activity by 
ambulatory and able to 
carry out work of a light 
or sedentary nature, e.g., 
light housework, office 
work 
80 
Normal activity with effort; 
some signs or symptoms of 
disease 
80 
Active, but tires more 
quickly 
70 
Cares for self; unable to carry 
on normal activity or do 
active work 
70 
Both greater restriction of 
and less time spent in 
play activity 
2 
Ambulatory and capable 
of self-care but unable to 
carry out any work 
activities; up and about 
more than 50% of 
waking hours 
60 
Requires occasional 
assistance, but is able to care 
for most of his/her needs 
60 
Up and around, but 
minimal active play; 
keeps busy with quieter 
activities 
50 
Requires considerable 
assistance and frequent 
medical care 
50 
Gets dressed, but lies 
around much of the day; 
no active play, able to 
participate in all quiet 
play and activities 
3 
Capable of only limited 
self-care, confined to bed 
or chair more than 50% 
of waking hours 
40 
Disabled, requires special 
care and assistance 
40 
Mostly in bed; 
participates in quiet 
activities 
30 
Severely disabled, 
hospitalization indicated; 
death not imminent 
30 
In bed; needs assistance 
even for quiet play 
4 
Completely disabled; 
cannot carry on any self- 
care; totally confined to 
bed or chair 
20 
Very sick, hospitalization 
indicated. Death not 
imminent 
20 
Often sleeping; play 
entirely limited to very 
passive activities 
10 
Moribund, fatal processes 
progressing rapidly 
10 
No play; does not get out 
of bed 


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SELHEM 
Appendix III 
 
 
 
APPENDIX III:  TESTS PERFORMED FOR ROUTINE CARE AND FOR RESEARCH 
 
Routine care 
 
History & physical (including vital signs, BSA, PS) 
CBC, differential, platelets 
Serum chemistries 
Amylase/lipase 
Creatinine kinase, urate 
TSH 
Coagulation studies 
GFR or creatinine clearance 
Ophthalmologic exam 
Pregnancy testing 
EKG 
Chest x-ray 
Pulse oximetry 
Lumbar puncture for IT chemotherapy, CSF cell count and differential 
Bone marrow procedure for morphology, response assessment, MRD 
Peripheral blood for MRD, if done 
Commercially available agents – fludarabine, cytarabine, ITHMA 
Research 
Investigational agent – Selinexor 
Pharmacokinetic studies (phase I only) 
Pharmacodynamic studies (phase I only) 
Correlative biological samples (phase II only) 


Amendment 6.0, dated: 03-24-2017 
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SELHEM 
Appendix IV 
 
 
 
APPENDIX IV: SELINEXOR DOSE MODIFICATION GUIDELINES FOR ADVERSE 
EVENTS ASSOCIATED WITH SELINEXOR 
 
Toxicity and 
Intensity 
Dose Modification 
Fatigue (common) 
Grade 1 
Insure adequate caloric intake and assess volume status. Adjust other medications. Consider 
addition of low dose corticosteroids (dexamethasone 5-10 mg/m2/day with each dose of 
selinexor). Rule out other causes of fatigue such as adrenal insufficiency. 
Grade 2 
Insure adequate caloric and fluid intake and assess volume status. Add corticosteroids on day of 
selinexor (e.g., dexamethasone 5-10 mg/m2/day). If fatigue dose not resolve to Grade 1, give 
dexamethasone on the day of and the day after selinexor dosing. If this does not improve fatigue, 
add a stimulant or bupropion q am, or reduce the dose of selinexor by one level (Table A2.1). 
Grade 3 
Insure adequate caloric and fluid intake and assess volume status. Initiate glucocorticoids as 
described for Grade 2. Interrupt selinexor dosing until resolved to Grade ≤ 2, reduce dose of 
selinexor by 1 level (Table A2.1), and add corticosteroids on day of and day after selinexor dosing. 
Anorexia (common) 
Grade 1 
Assess dietary options (e.g., try a variety of other foods). Add high-calorie supplements (e.g., 
Ensure®). If fatigue or nausea also present, consider low doses of corticosteroids (as for fatigue) on 
day of ± day after selinexor dosing. 
Grade 2 
Add high-calorie supplements (e.g., Ensure®). Consider olanzapine 1.25 to 5 mg po qhs or 
mirtazapine 7.5-15mg po qhs (especially if nausea or sleep disturbance present). Consider 
megesterol acetate, 10 to 15 mg/kg/day; 800 mg/day maximum dose. Consider low dose 
corticosteroids (see fatigue), anabolic steroids such as oxandrolone, or dronabinol (Marinol®) or 
other cannabinoid. Selinexor may be skipped intermittently while supportive medications are 
instituted, usually for <1 week. If Grade 2 anorexia does not resolve after institution of supportive 
medications, reduce selinexor dose by 1 level (Table A2.1). 
Grade 3 
Interrupt dosing with selinexor.  Add high calorie supplements.  Use supportive medications alone 
or in combinations. Restart selinexor at 1 dose level reduction (Table A2.1) once anorexia resolves 
to Grade ≤ 2. If Grade 2 anorexia persists with supportive medications, reduce dose of selinexor 
another level (Table A2.1). 
Nausea - acute (common) 
Grade 1 
5-HT3 antagonists, D2 antagonists, olanzapine 1.25 to 5mg daily, corticosteroids (e.g., 
dexamethasone 5-10 mg/m2/day with each dose of selinexor ± the day after dosing), NK1 
antagonists, or dronabinol (Marinol) or combinations can prevent nausea in the majority of 
patients. 
Grade 2 
Implement one or more combinations of anti-nausea medications. If nausea does not resolve to 
Grade ≤ 1, reduce dose of selinexor by one dose level (Table A2.1). 
Grade 3 
Implement one or more combinations of anti-nausea medications and interrupt dosing of selinexor. 
selinexor may be restarted with one dose level reduction (Table A2.1) when nausea is Grade ≤ 2 
and adequate caloric and fluid intake have been achieved. 


Amendment 6.0, dated: 03-24-2017 
Protocol document dated: 03-24-2017 
IRB Approval date: 05-02-2017 
SELHEM 
Appendix IV 
 
 
 
Hyponatremia (common) 
Grade 1 (Lower Limit of 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). 
Maintain selinexor dose level, assure adequate fluid, electrolyte and caloric intake, 
adjust other medications, consider salt supplementation one – two times per day. 
Hyponatremia 126-129nM 
without Symptoms (Grade 3) 
Be certain sodium level is corrected for hyperglycemia. Rule out other causes of 
low sodium (e.g., cardiac, hepatic, adrenal, renal and thyroid diseases, SIADH), 
Fanconi Syndrome, hyperglycemia, diuretic use). 
Hold selinexor until Grade ≤1 (≥130 nM) and initiate aggressive salt 
supplementation two-three times per day. 
Grade 3 (120-125 nM) or any 
Grade 3 with Symptoms 
Be certain sodium level is corrected for hyperglycemia. Rule out other causes of 
low sodium (e.g., cardiac, hepatic, adrenal, renal and thyroid diseases, SIADH), 
Fanconi Syndrome, hyperglycemia, diuretic use). 
Hold selinexor until resolved to Grade ≤ 1 (≥130nM) then reduce selinexor dose by 
1 level. Initiate aggressive salt supplementation two-three times per day. If serum 
sodium stabilizes for at least 4 weeks, then original dose of selinexor may be 
resumed. 
Diarrhea (common) 
Grade 1 (despite maximal anti- 
diarrheal medication) 
At the first sign of abdominal cramping, loose stools, or onset of diarrhea, it is 
recommended that the patient be treated according to institutional standard of care, 
e.g., loperamide (Immodium®). Maintain dose level of selinexor. 
Grade 2 (despite maximal anti- 
diarrheal medication) 
Reduce to selinexor to one weekly until resolved to ≤ Grade 1, then re-start twice 
weekly at the current dose level. 
If diarrhea returns as ≥ Grade 2, then reduce selinexor dose by one dose level and 
dose once weekly until resolved to ≤ Grade 1, then re-start twice weekly at reduced 
dose level 
Grade 3/4 (despite maximal anti- 
diarrheal medication) 
Delay selinexor until resolved to ≤ Grade 2, then follow guidelines above. 
Thrombocytopenia 
Grade 3 Thrombocytopenia 
Without bleeding 
Implement platelet growth factors or transfusions. Begin (or maintain) once weekly 
dosing at the same dose level until resolved to Grade ≤2. 
Grade 4 Thrombocytopenia 
Without bleeding 
Implement platelet growth factors or transfusions. Hold dosing until Grade ≤3 and 
follow above guidelines if Grade 3. 
≥ Grade 3 Thrombocytopenia 
associated with petechiae or 
purpura 
Implement platelet growth factors and/or transfusions. 
Hold selinexor for 5 days after last bleeding. Restart dosing one dose level below. 
Neutropenia 
Grade 3 neutropenia without fever 
Implement growth factors. 
Grade 4 neutropenia without fever 
Implement growth factors. If appropriate, initiate prophylactic anti- microbial 
agents. 
Grade ≥3 febrile neutropenia 
Implement growth factors. Initiate appropriate broad spectrum anti- microbial 
agents. 
Hold selinexor until fever resolves and patient is clinically stable. 
Restart dosing one dose level below. 


Amendment 6.0, dated: 03-24-2017 
Protocol document dated: 03-24-2017 
IRB Approval date: 05-02-2017 
SELHEM 
Appendix IV 
 
 
 
Other selinexor-related adverse events 
Grade 1 or 2 
Maintain dose level and initiate standard supportive care. 
Grade 3 
Delay dose until resolved to ≤ Grade 1, then reduce by 1 dose level (Table A2.1). 
Grade 4 
Discontinue selinexor and rule out other causes. If other causes of Grade 4 adverse 
event are uncovered, selinexor may be re-initiated at 1 dose level reduction (Table 
A2.1). 
All dose modifications should be based on the worst preceding toxicity. 
Isolated values of ≥ Grade 3 alkaline phosphatase values will NOT require dose interruption. Determination of liver vs. 
bone etiology should be made, and evaluation of gamma-glutamyl transferase (GGT), 5'-nucleotidase (5’NT), or other 
liver enzymes should be performed. 
Patients are allowed dose reductions to a minimum dose of 15 mg/m2 as described in Table A2.1. 
a. Common Terminology Criteria for Adverse Events (CTCAE Version 4.03 ) otherwise specified values. 


Amendment 6.0, dated: 03-24-2017 
Protocol document dated: 03-24-2017 
IRB Approval date: 05-02-2017 
SELHEM 
Appendix IV 
 
 
 
APPENDIX V – SPECIMEN SUBMISSION GUIDELINES 
 
Diagnostic studies 
 
Morphology review 
 
Central review of morphology is not required. However, Dr. John Choi 
 is available for review or assistance if requested by any 
collaborating site. 
 
Cytogenetic review 
 
Conventional karyotyping will be performed at local institutions as needed and the results 
will be reviewed by Dr. Susana Raimondi at St. Jude. Please submit two karyotypes of 
each abnormal line (this can be done electronically) and a final report to the following: 
 
Dr. Susana Raimondi 
Department of Pathology 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Phone: 
 
FAX: 
 
Email: 
 
 
Immunophenotyping and molecular studies 
 
Immunophenotyping for diagnostic purposes may be performed at local institutions or 
centrally, as desired by the treating physician. If the local institution prefers 
immunophenotyping to be done at St. Jude, please indicate this at the time the diagnostic 
bone marrow is shipped. Immunophenotyping to determine a leukemic-specific phenotype 
for future MRD studies will be performed at St. Jude. 
 
Molecular studies may be performed at local institutions or centrally, as desired by the treating 
physician. The Molecular Pathology laboratory at St. Jude (Dr. Sheila Shurtleff, technical 
director) will carry out molecular studies as needed. AML cases may be tested for the presence 
of the CBF-beta/MYH11, RUNX1/RUNX1T1 (AML-1/ETO), MLL/MLLT3 (MLL/AF-9) and 
MLL/MLLT4 (MLL/AF-6) fusion transcripts, FLT3-ITD, and mutations in the FLT3, NPM1, 
and CEPBA genes. Selected cases will also be screened for the presence of MLL gene 
rearrangements by FISH and for the MLL-ENL, MLL-ELL, MLL-AF10, or RBM15/MKL1 
fusions as needed. 
 
At diagnosis, please collect a minimum of 10 mL of anticoagulated bone marrow 
(preservative free heparin). Place in a 15 mL sterile conical centrifuge tube and add 5 mL 
of sterile RPMI-1640 with 20% fetal calf serum (bovine serum albumin). Label the 
tube(s) with patient name, date of birth, and date sample obtained. Seal centrifuge tube 
with parafilm or equivalent. Complete the SELHEM Specimen Submission Form and 


Amendment 6.0, dated: 03-24-2017 
Protocol document dated: 03-24-2017 
IRB Approval date: 05-02-2017 
SELHEM 
Appendix IV 
 
 
 
include with specimen(s) for shipping. Clinical specimens with a low probability of 
containing an infectious agent must be “triple packaged” in accordance with Dangerous 
Goods Regulations (DRG), International Air Transport Association (IATA) and OSHA 
guidelines (see http://www.iata.org, http://osha.gov, and AML08 Submission Form for 
additional information). Specimens should be shipped at ambient temperature. 
 
Note: If bone marrow is unattainable (dry tap) or is less than 5 mL, peripheral blood 
containing leukemic blasts should submitted along with any bone marrow obtained. 5 to 
10 mL of peripheral blood collected in preservative free heparin should be added to 
RPMI 1640 with 20% FCS or BSA, processed and packaged for shipment as described 
for bone marrow specimens. 
Ship by Federal Express for next day delivery to: 
Tissue Resources 
Department of Pathology, Room C5013B 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Phone: 
 
Email: 
 
*Please include FedEx tracking number 
 
Please notify the Tissue Resources lab (Matthew Lear, technical director, 
) and Dr. John Choi 
 via email 
when shipping MRD samples. 
 
Minimal Residual Disease studies (required) 
 
At Day 15 and all subsequent time points, please send 5 ml of bone marrow for MRD 
studies. Samples for MRD should be sent to the Tissue Resources Lab in preservative- 
free heparin stored at ambient temperature. In addition, for patients with leukemia- 
specific fusion transcripts, all bone marrow aspirates should be sent for RT-PCR 
analysis. 
 
Note that MRD studies are not performed on weekends. Hence, samples for MRD should 
be drawn Monday through Thursday and sent by overnight delivery. MRD samples that 
arrive on weekends are processed on Monday, but such delay may affect the quality of 
the assay. Only diagnostic specimens will be accepted on weekends and holidays with 
prior notice. 
 
Please notify the Tissue Resources lab and Dr. John Choi 
 via email when shipping MRD samples. 


Amendment 6.0, dated: 03-24-2017 
Protocol document dated: 03-24-2017 
IRB Approval date: 05-02-2017 
SELHEM 
Appendix IV 
 
 
 
Correlative Biological Studies (optional) 
 
Bone marrow aspiration (5 ml in EDTA) will be collected for research purposes at the planned 
disease evaluations prior to the start of therapy (but after consent), at the day 15 evaluation, 
and at the end of cycle 1 evaluation. 
Ship by Federal Express for next day delivery to: 
Tissue Resources 
Department of Pathology, Room C5013B 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Phone: 
 
Email: 
 
*Please include FedEx tracking number 
 
Please notify the Tissue Resources lab (Matthew Lear, technical director, 
) and Dr. Thomas Alexander 
 
via email when shipping correlative biological samples.