A Phase 1 Open-label Study of KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia
Phase: PHASE1
Conditions: Acute Myeloid Leukemia, Acute Myeloid Leukemia, in Relapse, Acute Myeloid Leukemia Refractory
Sponsor: University of Colorado, Denver

  
 
HCTU-1091-B 
 
Page 1 of 1 
 
 
 
Protocol Administrative Letter 
Date:  29AUG2025 
Sponsor – Investigator:  Daniel Pollyea, MD  
Protocol #:  20-2350 
Protocol Title:  A Phase 1 Open-Label Study Of KPT-9274 In Patients With Relapsed or Refractory Acute 
Myeloid Leukemia 
 
This letter is to communication termination of this study by the funding sponsor. 
On 28AUG2025, the sponsor-investigator received a notice of termination letter for IST-347 from the 
funding sponsor, Karyopharm Therapeutics. This letter directs that in accordance with Section 10.3 of the 
contract agreement, the site is to cease enrollment of subjects into the study and, as quickly as medically 
permissible, terminate the study with respect to enrolled subjects including completing all study wind-
down activities. Effectively, upon approval of this letter, the final subject in follow up at the site will be 
discontinued from trial. 
 
This letter must receive IRB approval prior to implementation at the site.  Any questions should be 
directed to the Sponsor-Investigator, Dr Pollyea, at 720-848-8084. 
 
 
Approval of Sponsor-Investigator:   
 
 
 
 
 
Date:   
 
 
 
Docusign Envelope ID: 3D72BD5F-A676-452E-8D28-AA10A2A48173
September 2, 2025 | 5:47:19 PM MDT

 
Hematology Clinical 
Trials Unit 
Division of Hematology 
 
Document: HCTU-1214 
Version: A 
Effective Date: DEC2021 
 
DLT Determination Memo  
 
 
HCTU-1214-A 
 
Page 1 of 1 
 
To: 
Investigative Sites, TMF 
From: 
Daniel Pollyea, MD 
Protocol # 
20-2350 
Date 
29APR2025 
SC meeting Date 
Not applicable 
SI  
Daniel Pollyea, MD 
The SI reviewed data for subject in the following cohort: 
 
• 
Cohort 1, 30 mg dose 
• 
Subject 1-08 
 
Summary of Findings: 
☐ Yes   ☒ No 
 
Did subject 1-08 experience a DLT? 
 
After reviewing the data, the following decision(s) have been made: 
☒ Yes   ☐ No 
 
Study will proceed with enrolling up to 1 more subject in Cohort 1, 30 mg.  
 
 
I am approving this document. 
Date 
Sponsor Investigator Signature 
 
 
 
 
Sponsor Investigator Name  
 
Docusign Envelope ID: EAECFB91-9BAC-485B-99D0-60255CE870E7
April 29, 2025 | 3:46:29 PM MDT
Daniel Pollyea, MD

Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 1 of 58 
 
A PHASE 1 OPEN-LABEL STUDY OF KPT-9274  
IN PATIENTS WITH RELAPSED OR REFRACTORY  
ACUTE MYELOID LEUKEMIA  
 
Study Phase: 
1 
Investigational Product: 
KPT-9274 
Protocol Number: 
20-2350 
IND Number: 
156351 
Indication: 
Relapsed or refractory acute myeloid leukemia 
Sponsor: 
University of Colorado, Anschutz Medical Campus 
Sponsor Contact: 
Daniel A. Pollyea, MD, MS 
 
Protocol Version and Date: 
 
V7, 31JAN2025 
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Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 2 of 58 
 
INVESTIGATORS' AGREEMENT 
STATEMENT OF COMPLIANCE 
This is an investigator-initiated study.  The principal investigator (PI), Daniel Pollyea, MD, is 
conducting the study and the University of Colorado is acting as the sponsor.  As the sponsor-
investigator, both the legal/ethical obligations of a PI and those of a sponsor will be followed. 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by 
applicable United States (US) laws and applications, including but not limited to United States 
(US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR 
Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
In accordance with 21 CFR 25.30/25.31, this protocol qualifies for a categorical exclusion from 
the requirement for an environmental assessment for the manufacture and formulation for use in 
human clinical trials. All waste from the investigational drug(s) will be properly controlled. The 
amount of waste expected to enter the environment may reasonably be expected to be nontoxic. 
To the Sponsor-Investigator’s knowledge, no extraordinary circumstances exist. 
The PI will assure that no changes to the protocol will take place without documented approval 
from the Institutional Review Board (IRB). All personnel involved in the conduct of this study 
have completed Human Subjects Protection Training.  
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
Investigator’s Name: 
Daniel Pollyea, MD, MS 
Institution: 
University of Colorado 
Date: 
 
 
Sponsor-Investigator Signature: 
 
 
 
 
 
 
 
 
 
 
 
Docusign Envelope ID: 0D99C498-8D2C-4C6C-954C-4BC685BF3FDB
March 14, 2025 | 10:48:32 AM MDT

Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 3 of 58 
 
PROTOCOL SYNOPSIS 
Sponsor: 
CU-AMC, Daniel Pollyea, MD 
Investigational Product: 
KPT-9274 
Study Phase: 
Phase 1 
Title of Study:  A Phase 1 Open-Label Study Of KPT-9274 In Patients With Relapsed or Refractory 
Acute Myeloid Leukemia  
Name of Active Ingredient:  (E)-3-(6-aminopyridin-3-yl)-N-((5-(4-(4,4-difluoropiperidine-1-
carbonyl)phenyl)-7-(4-fluorophenyl)benzofuran-2-yl)methyl)acrylamide 
Protocol Number: 20-2350 
Study Center: University of Colorado, Anschutz Medical Campus 
Patient Population: Patients with relapsed/refractory acute myeloid leukemia (AML)  
Objectives and Endpoints: 
This study will evaluate the safety and tolerability of oral KPT-9274 for the treatment of patients with 
relapsed or refractory acute myeloid leukemia 
 
Objectives 
Endpoints 
• Primary Objective: To assess the 
maximum tolerated dose (MTD)  
• Secondary Objective: To establish a 
recommended phase 2 dose (RP2D) 
 
Dose Expansion (if conducted) 
• Primary Objective: Determine preliminary 
evidence of efficacy of KPT-9274 at the 
RP2D  
 
• The occurrence of dose limiting toxicities 
(DLTs) and the occurrence, nature and 
severity of adverse events (AEs) 
 
 
Dose Expansion (if conducted) 
• Primary Endpoint: Overall response rate 
(ORR)  
• Secondary Endpoint: Duration of response 
(DOR), progression-free survival (PFS), 
overall survival (OS) 
 
Rationale for the Study: 
KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 
protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase 
/PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway 
that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic 
cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, 
NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem 
cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with 
relapsed or refractory AML. 
 
 
Docusign Envelope ID: 0D99C498-8D2C-4C6C-954C-4BC685BF3FDB

Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 4 of 58 
 
Methodology:  
This is a first-in-disease, single-center, open-label dose-finding clinical study to determine safety and 
tolerability of KPT-9274, a dual inhibitor of PAK4 and NAMPT, in patients with relapsed or refractory 
acute myeloid leukemia (AML).  
In the first-in-human solid tumor Phase 1 study, patients received oral KPT-9274 three times a week 
every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28-day cycle. A starting 
dose of 10 mg KPT-9274 was selected and escalated to 40 mg.  The MTD was not reached, and there 
was only one DLT in a patient who received KPT-9274 (anemia).  
Based on this experience, in the current study patients will receive oral KPT-9274 three times a week 
every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28-day cycle, and the 
first dose cohort will use 30 mg. Subsequent dose escalation cohorts, as well as a de-escalation cohort, 
will be administered per the table below. Dose escalation/de-escalation will continue until the MTD is 
determined. The MTD is defined as the highest dose at which ≤1 patient experiences a DLT in Cycle 1. 
A RP2D equal to or less than the MTD will be declared and used for the Dose Expansion Phase, if 
conducted.  
Patients must complete a minimum of 1 cycle of treatment, defined as receiving ≥ 75% of KPT-9274 
doses during Cycle 1 (e.g., ≥ 9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first 
cycle of treatment to be evaluable for dose escalation decisions. The cycle length is 28 days; the DLT 
period is the first 28 days. Dose escalation decisions will occur when a cohort of patients has met these 
criteria. 
 
KPT-9274 Dose Escalation Levels  
Cohort 
KPT-9274 
Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 in a 28-day cycle 
0 
(de-escalation, if needed) 
20 mg 
1 
(starting cohort) 
30 mg 
2 
40 mg 
3 
60 mg 
4 
80 mg 
5 
100 mg 
*after the MTD has been established, subjects at lower dose cohorts may have the option to change dose to the MTD, per 
investigator discretion 
Three patients will be enrolled in each cohort; if 1 of the first 3 patients in a cohort experiences a DLT, 
the number of patients in that cohort will be expanded to 6 patients. A maximum of 6 patients will be 
enrolled per cohort.  The MTD is defined as the highest dose at which ≤1 patient out of a maximum 
potential cohort of 6 experiences a DLT. 
A DLT will be defined as an AE or abnormal laboratory value that occurs within the first 28 days of 
treatment with KPT-9274, except for those that are clearly and incontrovertibly due to underlying 
disease, disease progression, or extraneous causes, and meets any of the criteria for defining dose-
limiting toxicities as described in the table below. CTCAE, Version 5.0 will be used for grading. In 
addition, > 3 missed (consecutive or nonconsecutive) doses of KPT-9274 in the first 28 days due to a 
drug related toxicity will be considered a DLT. 
Other events may occur which do not meet the definition of a DLT but are of concern to the 
Investigators may be considered DLTs. 
 
 
 
Docusign Envelope ID: 0D99C498-8D2C-4C6C-954C-4BC685BF3FDB

Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 5 of 58 
 
Criteria for Defining Dose-Limiting Toxicities 
Toxicity 
Any of the following criteria (based on CTCAE [Version 5.0]) , with the 
exception of events that are clearly and incontrovertibly due to underlying 
disease, disease progression or extraneous causes: 
Non-
Hematologic 
Grade 3 AST (SGOT) or ALT (SGPT) for ≥7 days or grade 3 direct 
hyperbilirubinemia for >7 days 
Grade 2 AST (SGOT) or ALT (SGPT) accompanied by grade 2 direct 
hyperbilirubinemia 
All other clinically significant non-hematological ≥ grade 3 AEs with the 
following exceptions: 
• Grade 3 nausea, vomiting or diarrhea will be considered DLT only if not 
controlled with optimal therapy after 72 hours; however, if these AEs 
require hospitalization, total parenteral nutrition or tube feeding, they will 
be considered DLTs regardless of the time required for recovery.  
• ≥ Grade 4 nausea, vomiting or diarrhea will be considered a DLT 
regardless of duration. 
• < Grade 4 neutropenic fever 
• Grade 3 biochemical or electrolyte abnormalities may be considered 
exceptions to the DLT criteria only if they have no clinical consequences 
and resolve with appropriate management within 72 hours 
Any grade AE that is related to KPT-9274 that results in permanent 
discontinuation of therapy 
Any death related to KPT-9274 
Hematologic 
≥Grade 3 anemia, neutropenia and/or thrombocytopenia lasting for ≥28 days 
from cycle 1 day 1 in the absence of residual AML (<5% blasts by morphology 
or detectable disease by immunohistochemistry and/or flow cytometry or other 
methods) 
CTCAE Version 5.0 will be used for grading AEs and laboratory abnormalities. Patients may receive 
supportive care as per local institutional guidelines. 
 
DOSE EXPANSION PHASE 
After completion of the Dose Escalation, Dose Expansion in up to 10 additional patients may be 
conducted to further explore safety, tolerability and preliminary evidence of anti-tumor activity of the 
RP2D of KPT-9274.  
 
After the MTD has been established, subjects at lower dose cohorts may have the option to change dose 
to the MTD, per investigator discretion. 
 
Number of Patients (planned): 
As many as 40 patients may be enrolled, a maximum of 30 in the dose escalation and 10 in the 
expansion. However, the number of patients required for completion of study enrollment cannot be 
defined a priori since this depends on the MTD.  
 
Investigational product, dosage and mode of administration:  
Docusign Envelope ID: 0D99C498-8D2C-4C6C-954C-4BC685BF3FDB

Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 6 of 58 
 
KPT-9274 is an orally bioavailable small molecule and a tablet solid dosage form for oral administration 
is being used for clinical studies.  
KPT-9274 tablets are designed for immediate-release oral administration and will be supplied in high-
density polyethylene (HDPE) bottles with induction seals. KPT-9274 tablets will be film coated for ease 
of handling and provided in tablet strengths of 5 mg and 20 mg. KPT-9274 will be supplied by 
Karyopharm. Additional details on KPT-9274 are provided in the Investigator’s Brochure. The 
investigational treatments will be administered as a flat dose and not by body weight or body surface 
area. 
 
Permitted Concomitant Medications: 
No significant inhibition of any of the CYP450 enzymes were observed after KPT-9274 treatment. 
Weak induction of CYPs 1A2, 2B6, and 3A4 were observed in an exploratory pre-clinical study after 
KPT-9274 treatment. There were no drug-drug interactions (DDIs) noted in the first 50 patients treated 
in Parts A and B. Therefore, the use of any concomitant medication/therapy (except for the medications 
listed in the prohibited concomitant medication section), including over-the-counter (OTC) medications 
(excluding herbal supplements, dietary supplements), deemed necessary for the care of the patient is 
permitted during the study. Medications required to treat AEs, manage cancer symptoms, concurrent 
stable diseases and supportive care agents (e.g., blood product transfusions, antibiotics with [if 
appropriate] granulocyte-colony stimulating factors [G-CSF] for neutropenic infection), pain 
medications, anti-emetics, and anti-diarrheals are allowed. Concurrent therapy with growth factors is 
allowed.  
Hormonal contraceptives are permitted in women of child-bearing potential. Hormonal contraceptives 
include any marketed contraceptive agent that includes an estrogen and/or a progestational agent. 
 
Supportive Care:   
Supportive care including anti-nausea/anti-emetic therapy, acid suppression (e.g., proton pump 
inhibitors [PPIs] ± H2-blockers), anti-diarrheal therapy, and other standard treatments may be 
administered as per institutional guidelines for symptomatic patients. For additional options, see NCCN 
Supportive Care Clinical Practice Guidelines in Oncology.  
 
Prohibited Concomitant Medications: 
The use of niacin or niacin-containing supplements (e.g., multivitamins and energy drinks) is not 
allowed. Investigational or commercial anticancer agents other than KPT-9274 are not allowed during 
the study.  
 
Treatment Duration: 
Treatment cycles are 28 days long. A patient may continue to receive KPT-9274 until the patient 
experiences progressive disease, withdraws consent or decides to withdraw from further treatment, is 
lost to follow-up, experiences intolerable toxicity which precludes further treatment with KPT-9274, or 
treatment is discontinued at the discretion of the Investigator. 
 
Criteria for Evaluation: 
Safety Endpoints: 
The safety and tolerability of KPT-9274 will be evaluated by means of DLTs, AE reports, physical 
examination results, electrocardiogram results and laboratory safety evaluations. The National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, will be used 
for grading of AEs. 
Docusign Envelope ID: 0D99C498-8D2C-4C6C-954C-4BC685BF3FDB

Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 7 of 58 
 
A DLT is defined as a pre-specified AE or abnormal laboratory value that occurs within the first 28 days 
of treatment with KPT-9274, except for those that are clearly and incontrovertibly due to underlying 
disease, disease progression, or extraneous causes, and meets any of the criteria for defining dose-
limiting toxicities.  
 
Efficacy Endpoints: 
Efficacy is an endpoint of the dose expansion portion of the study, if conducted. Bone marrow biopsies 
will occur for efficacy assessment purposes at the conclusion of each cycle until the subject has 
achieved a MLFS, CRi or CR, or per investigator discretion. Efficacy will be assessed per the European 
Leukemia Network guidelines1.  
• 
Overall response rate (ORR): complete remission (CR), complete remission with 
incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial 
remission (PR). 
• 
Duration of response (DOR): the duration of time from first meeting CR, PR, MLFS, CRi, 
measurement criteria (whichever occurs first) until the first date that progressive disease 
(PD) is objectively documented.  
• 
Progression-free survival (PFS): the duration of time from date of first study treatment 
until the first date that disease progression is objectively documented or death due to any 
cause.  
• 
Overall survival (OS): the duration of time from date of first study treatment until death 
from any cause.  
Statistical Methods:  
Sample size justification 
The sample size for the Dose Escalation Phase is based on a standard 3+3 design for the purpose of 
determining the RP2D and MTD. For the Dose Expansion Phase, up to 10 additional patients may be 
enrolled at the RP2D for KPT-9274.  
 
Docusign Envelope ID: 0D99C498-8D2C-4C6C-954C-4BC685BF3FDB

Pollyea          
 
KPT-9274                                                                                                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 8 of 58 
 
Table 1 
Schedule of Assessments: Screening and Cycle 1   
 
 
Screening 
Cycle 1 
Week 1 
Week 2 
Week 3 
Week 4 
Day -30  
to Day -1 
Day -14 
to Day -1 
Day 1 
Day 2 
 
Dosing  
Days 3 & 5  
 
Day 8 
Dosing  
Days 10 & 12 
Day 15 
Dosing  
Days 17 & 
19 
Day 22 
Dosing  
Days 24 & 
26 
Day 28 
Window for Assessments (days) 
- 
- 
+/- 1 
 
- 
+/- 1 
- 
+/- 1 
- 
+/- 1 
 
+/- 3 
Visit Type 
Clinic 
Clinic 
Clinic 
 
 
Clinic 
 
Clinic 
 
Clinic 
 
Clinic 
Activity/Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Patient History 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history2 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Patient height  
X 
 
 
 
 
 
 
 
 
 
 
 
Patient weight 
X 
 
X 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, pulse, temp)3 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
Complete physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed physical exam 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
12-lead ECG4 
X4 
 
X4 
 
 
 
 
 
 
 
 
 
ECOG6 
X 
 
X 
 
 
 
 
 
 
 
 
 
TLS Monitoring10 
 
 
X 
X 
 
 
 
 
 
 
 
 
Clinical Labs 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential6 
 
X 
X 
 
 
X 
 
X 
 
X 
 
 
Complete metabolic panel 5,6 
 
X 
X 
 
 
X 
 
X 
 
X 
 
 
Serum hCG pregnancy test7 
 
X 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate and biopsy8,9 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Dosing of KPT 9274 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Serious Adverse Events 
Continuous (during screening, only SAEs related to study procedures) 
Adverse Events 
 
 
Continuous 
Concomitant Medications 
Continuous 
 
Abbreviations: AE = adverse event; CBC = complete blood count; D = Day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EoT = End of Treatment 
 
Historical records related to screening procedures are permitted per Investigator discretion.  Sites should adhere to the 28-day cycle.   
Docusign Envelope ID: 0D99C498-8D2C-4C6C-954C-4BC685BF3FDB

Pollyea          
 
KPT-9274                                                                                                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 9 of 58 
 
 
1 
Prior to any study-specific measure.  
2 
A complete medical history will be obtained from each patient. Medical history will include baseline symptoms of the disease under study as well as a detailed history of prior 
therapies for the patient’s AML. 
3 
Vital signs: blood pressure, pulse and body temperature; see Section 6.4.1.2 for a detailed description of vital sign assessments. 
4 
12-Lead ECG to be completed at Screening (Day -30 to Day -1) and C1D1 (pre-dose and 4 hours post-dose (+/- 30 minutes)). 
5 
Complete metabolic panel (CMP) consists of sodium, potassium, chloride, carbon dioxide, glucose, blood urea nitrogen, creatinine, magnesium, phosphorous, uric acid, 
alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, protein, albumin and lactate dehydrogenase 
6 
The following procedures must be performed at Screening and pre-dose on C1D1 (and as shown in Table 1, 2, and 3): ECOG performance assessment (Day -30 to Day -1), 
CBC with differential (Day -14 to Day -1), Complete Metabolic Panel (Day -14 to Day -1). 
7 
For females of childbearing potential, negative serum hCG pregnancy test must be performed ≤ 3 days of C1D1 and the EoT Visit. Repeat testing during the study as 
clinically appropriate.  
8 
Bone marrow biopsies and aspirates will be taken within 30 days prior to first dose (baseline).  
9 
BM - day 28 +/- 3 days; at conclusion of each cycle until the subject has achieved a MLFS, CRi or CR, or per investigator discretion 
10 
TLS Monitoring is defined as “Tumor lysis syndrome monitoring,” and occurs on day 1, 8 hours (+/- 2 hours) after the first dose, and on day 2, 24 hours (+/- 4 hours) after the 
first dose.  Labs include potassium, uric acid, phosphorus, calcium, and serum creatinine. TLS labs must be collected at CU Anschutz. 
 
 
 
 
 
 
 
 
Docusign Envelope ID: 0D99C498-8D2C-4C6C-954C-4BC685BF3FDB

Pollyea          
 
KPT-9274                                                                                                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 10 of 58 
 
Table 2 
Schedule of Assessments: Cycles 2 and Beyond  
 
Cycle 2 
Cycle 3 and Beyond 
Week 1-2 
Week 3-4 
Week 1-2 
Week 3-4 
Day 1 
 
Dosing 
 Days 
3,5,8,10,12  
 
Day 15 
Dosing 
 Days 
17,19,22, 
24,26 
Day 28 
 
Day 1 
Dosing 
Days 
3,5,8,10,12 
Day 15 
Dosing  
Days 
17,19,22, 
24,26 
Day 28 
 
Window for Assessments 
(days) 
+/- 1 
 
+/- 1 
 
+/- 3 
+/- 1 
 
 
 
+/- 3 
Visit Type 
Clinic 
 
Clinic 
 
Clinic 
Clinic 
 
 
 
Clinic 
Activity/Assessment 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
Patient weight 
X 
 
X 
 
 
X 
 
 
 
 
Vital Signs (BP, pulse, 
temp)1 
X 
 
X 
 
 
X 
 
 
 
 
Symptom-directed 
physical exam 
X 
 
X 
 
 
X 
 
 
 
 
ECOG 
X 
 
 
 
 
X 
 
 
 
 
Clinical Labs 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
 
X 
 
 
X 
 
 
 
 
Complete metabolic 
panel 2 
X 
 
X 
 
 
X 
 
 
 
 
Bone marrow biopsy 
 
 
 
 
X3 
 
 
 
 
X3 
Dosing of KPT 9274 at 
Home 
 
X 
 
X 
 
 
X 
X 
X 
 
Adverse events 
Continuous 
Continuous 
Concomitant medications 
Continuous 
Continuous 
 
Abbreviations: AE = adverse event; CBC = complete blood count; D = Day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EoT = End of Treatment 
 
Sites should adhere to the 28-day cycle.  
 
1 
Vital signs: blood pressure, pulse and body temperature; see Section 6.4.1.2 for a detailed description of vital sign assessments. 
2 
Complete metabolic panel (CMP) equals: sodium, potassium, chloride, carbon dioxide, glucose, blood urea nitrogen, creatinine, magnesium, phosphorous, uric acid, alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, protein, albumin and lactate dehydrogenase  
3 
BM - day 28 +/- 3 days; conclusion of each cycle until the subject has achieved a MLFS, CRi or CR, or per investigator discretion 
 
Docusign Envelope ID: 0D99C498-8D2C-4C6C-954C-4BC685BF3FDB

Pollyea          
 
KPT-9274                                                                                                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 11 of 58 
 
Table 3 
Schedule of Assessments: End-of-Treatment and Beyond 
  
Activity/Assessment 
End-of-Treatment (EoT) Visit 
Safety Follow-up3 
Durability of Response and 
Survival  
Follow-up 
≤ 14 Days Post Last Dose 
30 Days Post-Last Dose 
Every 3 months for 1 year after 
the safety follow-up call 
+ 7 days 
± 7 days 
Clinical Assessments 
Patient weight 
X 
 
 
Vital Signs (BP, pulse, temp)1 
X 
 
 
Complete physical exam  
X 
 
 
ECOG 
X 
 
 
Bone marrow biopsy, if not performed <30 days prior to EoT 
X 
 
 
Clinical Labs 
CBC with differential 
X 
 
 
Complete metabolic panel2  
X 
 
 
Serum hCG pregnancy test 
X 
 
 
Adverse events 
X 
X 
 
Concomitant medications 
X 
X 
 
Survival and Response Status 
 
 
X 
 
Abbreviations: AE = adverse event; CBC = complete blood count; D = Day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EoT = End of Treatment 
Sites should adhere to the 28-day cycle.    
1 
Vital signs: blood pressure, pulse and body temperature; see Section 6.4.1.2 for a detailed description of vital sign assessments. 
2 
Complete metabolic panel (CMP) equals: sodium, potassium, chloride, carbon dioxide, glucose, blood urea nitrogen, creatinine, magnesium, phosphorous, uric acid, alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, protein, albumin and lactate dehydrogenase  
3 
Safety follow-up with patient after 30 days post-last dose (+ 7 days) of their last dose of study treatment to record concomitant medications, AEs, including follow-up on any AEs that were not 
resolved at the EoT Visit, and collection of information on any antineoplastic therapies used after discontinuation of study treatment.  This safety follow may occur via phone or in-person, by 
delegated staff. 
 
Table 4 
Dosing Schedule of KPT-9274 
KPT-9274 
Week 1 
Week 2 
Week 3 
Week 4 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15 
D16 
D17 
D18 
D19 
D20 
D21 
D22 
D23 
D24 
D25 
D26 
D27 
D28 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
Docusign Envelope ID: 0D99C498-8D2C-4C6C-954C-4BC685BF3FDB

Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 
 
PROTOCOL SYNOPSIS.................................................................................................................3 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ..................................12 
LIST OF TABLES .........................................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Indication ....................................................................................................................18 
1.2. 
KPT-9274 ...................................................................................................................18 
1.3. 
Study Rationale ...........................................................................................................20 
1.4. 
Objectives ...................................................................................................................20 
1.5. 
Endpoints ....................................................................................................................21 
2. 
INVESTIGATIONAL PLAN .....................................................................................22 
2.1. 
Overall Study Design and Plan ...................................................................................22 
2.2. 
Replacement Policy ....................................................................................................23 
2.3. 
Treatment Duration .....................................................................................................23 
3. 
STUDY POPULATION SELECTION ......................................................................24 
3.1. 
Study Population .........................................................................................................24 
3.2. 
Eligibility ....................................................................................................................24 
3.3. 
Screening and Registration .........................................................................................25 
4. 
DISCONTINUATION CRITERIA ............................................................................26 
4.1. 
Early Termination of the Study ..................................................................................26 
4.2. 
Discontinuation of Study Treatment and/or Withdrawal of Patients from the 
Study ...........................................................................................................................26 
5. 
STUDY TREATMENTS ............................................................................................27 
5.1. 
Treatments Administered ............................................................................................27 
5.2. 
Study Treatment Dose Schedules and Administration ...............................................27 
5.3. 
Study Treatment Storage ............................................................................................33 
5.4. 
Study Treatment Accountability .................................................................................33 
5.5. 
Selection and Timing of Dose for Each Patient ..........................................................33 
5.6. 
Compliance .................................................................................................................33 
5.7. 
Supportive Care, Contraception Requirements, and Concomitant 
Medications .................................................................................................................34 
6. 
ASSESSMENTS .........................................................................................................37 
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6.1. 
Informed Consent .......................................................................................................37 
6.2. 
Demographic and Baseline Characteristics Assessments ...........................................37 
6.3. 
Efficacy Assessments .................................................................................................37 
6.4. 
Safety Assessments .....................................................................................................37 
7. 
SAFETY DEFINITIONS, RECORDING, AND REPORTING ................................40 
7.1. 
Adverse Events ...........................................................................................................40 
7.2. 
Serious Adverse Events ..............................................................................................42 
7.3. 
Procedures for Handling Special Situations ...............................................................44 
8. 
STATISTICAL METHODS .......................................................................................46 
8.1. 
General Considerations ...............................................................................................46 
8.2. 
Determination of Sample Size ....................................................................................46 
8.3. 
Analysis Populations ..................................................................................................46 
8.4. 
Data Analysis and Presentation ..................................................................................46 
8.5. 
Efficacy Analysis ........................................................................................................47 
8.6. 
Safety Analysis ...........................................................................................................47 
9. 
ADMINISTRATIVE MATTERS ..............................................................................49 
9.1. 
Regulatory and Ethical Compliance ...........................................................................49 
9.2. 
Ethics Committees ......................................................................................................49 
9.3. 
Regulatory Authority Approval ..................................................................................49 
9.4. 
Protocol Adherence ....................................................................................................49 
9.5. 
Amendments to the Protocol ......................................................................................49 
9.6. 
Informed Consent .......................................................................................................49 
9.7. 
Patient Confidentiality and Disclosure .......................................................................50 
9.8. 
Collection, Auditing Study Documentation, and Data Storage ..................................50 
9.9. 
Termination of the Study ............................................................................................52 
10. 
REFERENCES ...........................................................................................................53 
APPENDIX 1. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS CRITERIA ...................................................................54 
APPENDIX 2. EUROPEAN LEUKEMIA NETWORK RESPONSE CRITIERA FOR 
AML (DOHNER ET AL, 2017) .................................................................................55 
APPENDIX 3. SAMPLE SERIOUS ADVERSE EVENT REPORT FORM ............................56 
APPENDIX 4. TEMPLATE FOR LINE LISTING OF ADVERSE EVENTS ..........................57 
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LIST OF TABLES 
Table 1 
Schedule of Assessments: Screening and Cycle 1 ........................................................8 
Table 2 
Schedule of Assessments: Cycles 2 and Beyond ........................................................10 
Table 3 
Schedule of Assessments: End-of-Treatment and Beyond .........................................11 
Table 4 
Dosing Schedule of KPT-9274 ...................................................................................11 
Table 8  
KPT-9274 Dose Escalation Levels .............................................................................28 
Table 9  
Criteria for Defining Dose-Limiting Toxicities in AML Patients ..............................30 
Table 10 
KPT-9274 Dose Modification and Supportive Care Guidelines ................................32 
Table 11 
Clinical Laboratory Tests ...........................................................................................39 
Table 12 
Classification of Adverse Events by Causality ...........................................................42 
Table 13 
ECOG Performance Status Scale ................................................................................54 
Table 14 
European leukemia network response critiera for AML ............................................55 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or Specialist Term 
Explanation 
°C 
degrees Celsius 
°F 
degrees Fahrenheit 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
B-ALL 
B-cell acute lymphoblastic leukemia 
BP 
blood pressure 
BSA 
body surface area 
CBC 
complete blood count 
CBR 
clinical benefit rate 
 
CI 
confidence interval 
CL/F 
plasma clearance rate 
Cmax  
maximum plasma concentration 
cm 
centimeter 
CNS 
central nervous system 
COX-2 
cyclooxygenase-2 
CR 
complete response 
CrCl 
creatinine clearance 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXDX (e.g., C1D1) 
Cycle X Day X (e.g., Cycle 1 Day 1) 
DAP 
Data Analysis Plan 
DCR 
disease control rate 
DDA 
deoxyribonucleic acid damaging agent 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC QLQ 
European Organization for Research and Treatment of Cancer 
EoT 
end of treatment 
ER 
extended release 
FACT-G 
Functional Assessment of Cancer Therapy 
FACT-Lym 
Functional Assessment of Cancer Therapy-Lymphoma 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
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Abbreviation or Specialist Term 
Explanation 
FLC 
free light chain 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
HAT 
hormone ablation therapy 
Hb 
hemoglobin 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
HPLC/MS-MS 
high performance liquid chromatography/tandem mass 
hr 
hour 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDH1 
isocitrate dehydrogenase 1 (NADP+), soluble 
IHC 
immunohistochemistry 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
intent-to-treat  
IV 
intravenous 
Karyopharm 
Karyopharm Therapeutics Inc. 
kg 
kilogram 
LLN 
lower limit of normal 
LVEF 
left ventricular ejection fraction 
MDR 
multiple drug resistance 
mIU 
milli-international units 
mL 
milliliter  
MM 
multiple myeloma 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition 
N 
number of patients 
NAD 
nicotinamide adenine dinucleotide 
NAMPT 
nicotinamide phosphoribosyltransferase/PBEF/visfatin 
NAPRT1 
nicotinate phosphoribosyltransferase 
NCI 
National Cancer Institute 
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Abbreviation or Specialist Term 
Explanation 
NHL 
non-Hodgkin’s lymphoma 
Niacin 
vitamin B3/nicotinic acid 
NSAID 
non-steroidal anti-inflammatory drug 
ORR 
overall response rate 
OS 
overall survival 
OTC 
over the counter 
PAK4 
p21 protein (Cdc42/Rac)-activated kinase 4 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PDn 
pharmacodynamic(s) 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PPI 
proton pump inhibitor 
PR 
partial response 
QMSP 
quantitative methylation specific 
QOD 
every other day 
QoL 
quality of life 
qRT 
quantitative real time 
RAS 
rat sarcoma viral oncogene homolog 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
Recommended Phase 2 Dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SUSAR 
suspected unexpected serious adverse reaction 
t½  
terminal plasma half-life 
TEAE 
treatment-emergent adverse event 
tmax  
time to peak plasma concentration 
TLS 
tumor lysis syndrome 
TNM 
tumor nodes metastasis 
TOI 
trial outcomes index 
TSH 
thyroid stimulating hormone 
TTP 
time to progression 
ULN 
upper limit of normal 
Vd/F 
volume of distribution 
WBC 
white blood cell 
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1. 
INTRODUCTION 
1.1. 
Indication  
This study will enroll patients with relapsed or refractory acute myeloid leukemia (AML) for 
whom all standard therapeutic options considered useful by the investigator have been exhausted. 
1.2. 
KPT-9274 
KPT-9274 is a first-in-class orally bioavailable small molecule that is a non-competitive dual 
modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide 
phosphoribosyltransferase/PBEF/visfatin (NAMPT). Co-inhibition of these targets leads to 
synergistic anti-tumor effects through energy depletion, inhibition of deoxyribonucleic acid 
(DNA) repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis. Normal cells 
are more resistant to inhibition by KPT-9274 due in part to their relative genomic stability and 
lower metabolic rates. 
KPT-9274 demonstrated potent anti-proliferative activity against cancer cell lines (solid tumor 
cells MTT median IC50: 135 nM, range 0.007 to >10 µM; hematological cancer cells MTT median 
IC50: 40 nM, range 0.003 to >10 µM) with minimal toxicity to normal cells (median MTT IC50: 
~0.9 µM, range 0.033 to >10 µM). In mouse xenograft studies, KPT-9274 (oral 50-200 mg/kg 
twice daily for 5 days/week) was well tolerated and resulted in a marked reduction in tumor size 
across a variety of tumors, including colon, pancreatic, lung, multiple myeloma, leukemia, and 
lymphoma. In approximately half of the tumor types studied, complete elimination of tumors in as 
short as 3 weeks was observed with no regrowth after cessation of treatment (up to 3 weeks). In 
other cell types tumor growth inhibition was observed. KPT-9274 was able to control systemic 
acute B lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML) tumor growth and 
significantly extended overall survival. Moreover, KPT-9274 has shown preliminary efficacy in 
companion dogs with spontaneous advanced lymphomas and multiple myeloma (MM).  
Unlike the Pan-PAK inhibitor (PF-3758309), or the NAMPT inhibitors (APO866 and 
GMX1777/GMX1778) that advanced to human clinical trials, the dual NAMPT/PAK inhibitor 
KPT-9274 demonstrates consistent pharmacokinetic (PK) properties (e.g., oral absorption), 
exhibits minimal brain penetration, and does not inhibit any of the cytochrome P450 (CYP450) 
enzymes. The nonclinical toxicity profile of KPT-9274 recapitulates the expected class level 
gastrointestinal (GI) and hematopoietic toxicities but not the retinal and cardiac effects observed 
preclinically with some NAMPT inhibitors. The lack of retinal and cardiac effects of KPT-9274 
may be attributed to its minimal permeability and decreased potency compared to other NAMPT 
inhibitors. Furthermore, no orally available PAK4 selective inhibitors have been developed to date. 
Thus, KPT-9274 captures many of the favorable therapeutic aspects of targeting both NAMPT and 
PAK4 with the potential for reduced adverse effects.  
Preliminary two-week non-good laboratory practices (GLP) toxicology studies in rats and dogs 
suggest that KPT-9274 has an acceptable tolerability profile. The dog has been identified as the 
most sensitive species for KPT-9274 GI toxicity, with rats also showing GI toxicity at significantly 
higher doses. The primary KPT-9274 toxicity that has been observed in dogs is gastrointestinal 
hemorrhages in the small intestine, colon, and rectum. Other target organ effects include 
hypocellularity in the bone marrow and lymphoid depletion in the lymphoid tissues.  
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Nicotinamide adenine dinucleotide (NAD) regeneration pathways can bypass NAMPT inhibition 
by utilizing niacin (vitamin B3/nicotinic acid) through nicotinate phosphoribosyltransferase 
(NAPRT1). Supplemented niacin can alleviate adverse events due to NAMPT inhibition when 
tissues express NAPRT1. However, NAPRT1 is frequently repressed in tumors (through 
epigenetic modulation or isocitrate dehydrogenase 1 (NADP+), soluble [IDH1] mutation) while 
remaining intact in surrounding normal tissue potentially increasing therapeutic index in the 
presence of niacin. Additional exploratory studies and data from 4-week GLP studies indicate that 
co-administration of niacin can increase tolerability of KPT-9274 in dogs. These data demonstrate 
that a dose of KPT-9274 previously shown to have an adverse toxicologic profile was tolerable 
and had minimal GI macroscopic findings. For this reason, co-administration of KPT-9274 with 
niacin in patients with or without NAPRT1 or IDH1 mutation in their tumors is planned. 
KPT-9274 demonstrated anti-tumor activity in dogs with spontaneous advanced lymphomas and 
multiple myeloma. Patient dog #1 was given 4 doses of 2 mg/kg KPT-9274 and had progressive 
disease after 1 week. This patient dog was given 25 mg/kg doxorubicin (Adriamycin) on Day 8 
(~24 hours post-final KPT-9274 dose). The bulk disease responded shortly thereafter with a partial 
response (PR) at the end of week 2 that transitioned into a complete response (CR). As of October 
2015, the patient dog remains in complete remission for >4 months off all therapy with no AEs 
reported to date. A T-cell lymphoma dog experienced a ~1 week PR at 2 mg/kg of KPT-9274 
every other day (QOD) × 3 but subsequently progressed. A patient dog with refractory multiple 
myeloma (4 lines of previous therapy) treated with 3 mg/kg of KPT-9274 QOD x 3 plus prednisone 
had a PR with decreases in globulins and resolution of anemia and thrombocytopenia for ~5 weeks, 
but progressed during Week 6. Two additional B-cell lymphoma dogs did not respond to 2 mg/kg 
or 3 mg/kg of KPT-9274 QOD × 3 in which one dog (2 mg/kg dose) had low drug levels in the 
plasma. These preliminary results suggest that KPT-9274 show anti-tumor activity both as a single 
agent and in combination with DNA damaging agents (DDA) with minimal or no side effects 
observed. Dose escalation evaluation in patient dogs with lymphoma and solid tumors is on-going. 
KPT-9274 has clear preclinical anti-tumor activity (in vitro and in vivo) as well as an encouraging 
safety profile (compared to previously described Pan-PAK and NAMPT inhibitors) making it an 
attractive novel drug candidate. Since both solid tumor and hematologic malignancies were seen 
to be susceptible to single-agent cytotoxicity with KPT-9274, development is planned in both 
areas. 
1.2.1. 
Potential Risks 
In the completed study, KCP-9274-901, 50 patients had received KPT-9274 alone or with niacin 
ER, and an additional 10 patients received KPT-9274 in combination with nivolumab. The most 
common AEs occurring across all patients include the following: anemia (81.7%, 49/60), fatigue 
(45.0%, 27/60), arthralgia (40.0%, 24/60), nausea (40%, 24/60), dyspnea (33.3%, 20/60), diarrhea 
(31.7%, 19/60), vomiting (26.7%, 16/60), myalgia (23.3%, 14/60), decreased appetite (21.7%, 
13/60), flushing (21.7%, 13/60), and abdominal pain (20.0%, 12/60). The following events were 
identified as potential risks of KPT-9274: anemia, fatigue, arthralgia and myalgia, and nausea. . 
AEs were largely dose dependent and increased with higher doses of KPT-9274. A total of 3 DLTs 
were reported during the study, one at the 40 mg QODx3 dose and two at the 80 mg + niacin 
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QODx3 dose. Maximum tolerable dose was not reached in either Part A (KPT-9274 monotherapy) 
or B (KPT-9274 with niacin ER).  
1.2.2. 
Reproductive Risks of KPT-9274 
It is unknown whether KPT-9274 might have reproductive toxicity in humans; therefore, all 
patients in this study must agree to use effective contraception (see Prevention of Pregnancy, 
Section 5.7.2.2) during the study, and for 3 months after their last dose of KPT-9274. 
1.3. 
Study Rationale 
KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator 
of PAK4 and NAMPT. NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway 
that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential 
metabolic cofactor and second messenger. 
Hematologic and solid tumor cells are susceptible to single-agent cytotoxicity by KPT-9274 as 
they become dependent on both the PAK4 and NAMPT pathways. KPT-9274 demonstrated potent 
anti-proliferative activity against cancer cell lines with minimal toxicity to normal cells. In mouse 
xenograft studies, KPT-9274 was well tolerated and resulted in a marked reduction/elimination of 
tumors, tumor growth inhibition or disease control across a variety of tumors, including colon, 
pancreatic, lung, sarcoma, multiple myeloma, leukemia, and lymphoma. In approximately half of 
the tumor types studied, complete elimination of tumors in as short as 3 weeks was observed with 
no regrowth after cessation of treatment (for up to 3 additional weeks). Moreover, KPT-9274 has 
shown preliminary efficacy in companion dogs with spontaneous advanced lymphomas and 
multiple myeloma.  
In AML, pre-clinical studies have shown increased dependency of AML cells on NAMPT2, and 
in the clinical setting, higher NAMPT expression is associated with decreased overall survival3. In 
an AML model, KPT-9274 depleted NAD+, resulting in loss of mitochondrial respiration and 
glycolysis and apoptosis, regardless of mutational/genomic profiles4. Furthermore, emerging data 
suggests that targeting NAMPT can specifically eradicate the relapsed/refractory leukemia stem 
cell population, which has previously not had any promising therapeutic opportunities (Jones et al, 
Cell Stem Cell 2020 Nov 5;27(5):748-764).  
1.3.1. 
Rationale for the Starting KPT-9274 Dose 
In the first-in-human solid tumor Phase 1 study, patients received oral KPT-9274 three times a 
week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28-day cycle. 
A starting dose of 10 mg KPT-9274 was selected and escalated to 40 mg. The study was stopped 
but the MTD was not reached, and there was only one DLT in a patient who received KPT-9274 
alone (anemia). Based on this experience, in the current study patients will receive oral KPT-9274 
three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 
28-day cycle, and the first dose cohort will be 30 mg.  
1.4. 
Objectives 
1.4.1. 
Primary Objective 
• To assess the maximum tolerated dose (MTD) 
1.4.2.  
Secondary Objective 
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• To establish a recommended phase 2 dose (RP2D) 
Dose Expansion (if conducted) 
• To determine preliminary evidence of efficacy of KPT-9274 at the RP2D 
1.5. 
Endpoints 
1.5.1. 
Safety Endpoints 
• The occurrence of dose limiting toxicities (DLTs) and the occurrence, nature and 
severity of adverse events (AEs) 
2.2.2.   
Efficacy Endpoints (if dose expansion is conducted) 
• Primary Endpoint: Overall response rate (ORR)  
• Secondary Endpoint: Duration of response (DOR), progression-free survival (PFS), 
overall survival (OS) 
Disease response will be evaluated according to the European Leukemia Network (AML) 
(Appendix 2)1 and will include the following:  
• Overall response rate (ORR): complete remission (CR), complete remission with 
incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), 
partial remission (PR). 
• Duration of response (DOR): the duration of time from first meeting CR, PR, MLFS, 
CRi, measurement criteria (whichever occurs first) until the first date that progressive 
disease (PD) is objectively documented.  
• Progression-free survival (PFS): the duration of time from date of first study 
treatment until the first date that disease progression is objectively documented or death 
due to any cause.  
• Overall survival (OS): the duration of time from date of first study treatment until 
death from any cause.  
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2. 
INVESTIGATIONAL PLAN 
2.1. 
Overall Study Design and Plan 
This is a first-in-disease, single-center, open-label dose escalation clinical study to assess 
preliminary safety, tolerability, and efficacy of KPT-9274, a dual inhibitor of PAK4 and NAMPT, 
in patients with relapsed or refractory AML for whom all standard therapeutic options considered 
useful by the investigator have been exhausted. 
During dose escalation, patients will receive oral KPT-9274 three times a week every other day 
(Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28-day cycle, and the first dose 
cohort will be 30 mg. Subsequent dose escalation cohorts, as well as a de-escalation cohort, will 
be administered per the table below. Dose escalation will continue until the MTD is determined. 
The MTD is defined as the highest dose at which ≤1 patient experiences a DLT in Cycle 1. A 
RP2D equal to or less than the MTD will be declared and used for the Dose Expansion Phase, if 
conducted.  
Patients must complete a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-
9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT 
within the first cycle of treatment to be evaluable for dose escalation decisions. The cycle length 
is 28 days the DLT period is the first 28 days of cycle 1. Dose escalation decisions will occur when 
a cohort of patients has met these criteria. 
After the RP2D is determined, a dose expansion phase, of up to 10 additional patients, might be 
conducted, in which a preliminary determination of efficacy will be conducted, using the ELN 
criteria1 (Appendix 2).  After the RP2D has been established, subjects at lower dose Cohorts may 
have the option to change dose to the RP2D, per investigator discretion. 
Screening will be performed within 30 or 14 days prior to the start of therapy (i.e., Day -30 to Day 
-1, or Day -14 to Day -1), as summarized in Table 1.  The Follow-up period includes the EOT 
visit, the Safety Follow-up visit, and Durability of Response and Survival Follow-up; see Table 3 
for assessments to be completed during the Follow-up period. 
The number of patients required for completion of study enrollment cannot be defined a priori 
since this depends on the number of patients needed for the dose escalation; but the maximum 
number of patients from the escalation and expansion cohorts will be 40.  
 
KPT-9274 Dose Escalation Levels  
Cohort 
KPT-9274 
Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 in a 28-day cycle 
0 
(de-escalation, if needed) 
20 mg 
1 
(starting cohort) 
30 mg 
2 
40 mg 
3 
60 mg 
4 
80 mg 
5 
100 mg 
 
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2.2. 
Replacement Policy 
Patients who complete the first cycle of therapy will not be replaced during the Escalation Phase 
of the study. However, if a patient is considered as non-evaluable for DLT (i.e., did not complete 
the first cycle of therapy or the minimum number of doses of KPT-9274 and did not experience a 
DLT), enrollment of a new patient to the current cohort will be considered if there is less than the 
required number of evaluable patients. 
During the Dose Expansion Phase, patients who have not completed 1 cycle will be replaced unless 
they were discontinued from the study due to a drug-related toxicity, PD, or death. 
2.3. 
Treatment Duration 
Treatment cycles are 28 days long. A patient may continue to receive KPT-9274 until that patient 
experiences PD, withdraws consent, is lost to follow-up, experiences intolerable toxicity which 
precludes further treatment with KPT-9274, or treatment is discontinued at the discretion of the 
Investigator. 
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3. 
STUDY POPULATION SELECTION 
3.1. 
Study Population 
This study will enroll adult patients with relapsed or refractory AML for whom standard 
therapeutic options considered useful by the investigator have been exhausted, and meet all of the 
inclusion criteria and none of the exclusion criteria. 
3.2. 
Eligibility 
3.2.1. 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible to enroll in this study. 
1. Written informed consent obtained prior to any screening procedures  
2. Age ≥18 years. 
3. Patients with WHO-confirmed non-APL AML who have not responded to or relapsed after 
at least one prior therapy and for whom no standard therapy that may provide clinical 
benefit is available.  
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
5. Adequate hepatic function: 
• Total bilirubin < 1.5 times the upper limit of normal (ULN) (except patients with 
Gilbert’s syndrome [hereditary indirect hyperbilirubinemia], subjects with 
Gilbert’s syndrome, total bilirubin needs to be ≤ 4 x ULN). 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times 
ULN (except patients with known liver involvement of their AML who must have 
AST and ALT ≤ 5.0 times ULN). 
6. Adequate renal function: estimated creatinine clearance of ≥ 60 mL/min, calculated using 
CKD-EPI Creatinine Equation (2021). https://www.kidney.org/content/ckd-epi-creatinine-
equation-2021. 
7. Female patients of child-bearing potential must agree to use dual methods of contraception 
(including one highly effective and one effective method of contraception) and have a 
negative serum pregnancy test at Screening.   For both male and female patients, effective 
methods of contraception must be used throughout the study and for 3 months following 
the last dose. 
a. Fertile female patients must agree to refrain from egg donation from first dose until 
at least 3 months following the last dose of KPT-9724. 
b. Women should not breastfeed during treatment with KPT-9724 and for 2 weeks 
after the last dose. 
c. Male patients must use 2 highly effective methods of contraception if sexually active with 
a female of child-bearing potential, during treatment with KPT-9724, during a period of 2 
weeks (5 half-lives) after the last dose of KPT-9724 plus a period of 3 months. (for 3.5 
months after their last dose of KPT-9724). Fertile male patients must agree to refrain from 
sperm donation from first dose until at least 3.5 months following the last dose of KPT-
9724. 
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3.2.2. 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not eligible to enroll in this study. 
1. Female patients who are pregnant or lactating. 
2. Radiation, chemotherapy, immunotherapy or any other anticancer therapy, including 
investigational anti-cancer therapy ≤ 2 weeks prior to C1D1. Hydroxyurea is not 
considered an anti-cancer therapy.  
3. Patients who have not recovered or stabilized (Grade 1 or to their baseline for non-hematologic 
toxicities) from toxicities related to their previous treatment, except for alopecia.  
4. White blood cell count ≥25x109/L (hydroxyurea or leukapheresis permitted to reduce to 
below the exclusion criteria threshold and allow eligibility) 
5. Patients with known active central nervous system (CNS) disease  
6. Clinically significant severe heart disease  
7. Active clinically significant infection. Use of prophylactic antibiotics, antivirals or 
antifungals are permitted. 
8. Known, active hepatitis A, B, or C infection; or known to be positive for HCV RNA or 
HBsAg (HBV surface antigen). Testing is not required. 
9. Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled 
vomiting or diarrhea that could interfere with the absorption of KPT-9274.  
10. Serious psychiatric or medical conditions that, in the opinion of the Investigator, could 
interfere with treatment, compliance, or the ability to give consent. 
3.3. 
Screening and Registration 
The Screening period starts once a patient has provided written informed consent to participate in 
the study and ends on the day of study entry (C1D1). 
Patient eligibility (inclusion/exclusion criteria) will be reviewed for each patient participating in 
the study by the investigator before the patient receives study treatment on C1D1.  
Upon signing consent, each patient will be assigned a unique patient number and will keep this 
number for the duration of the study.  
3.3.1. 
Screen Failures 
Patients who sign an informed consent but fail to start on treatment for any reason will be 
considered a screen failure. Date of consent and reason for ineligibility will be entered into the 
clinical database. No other data will be entered into the clinical database for patients who are screen 
failures, unless those patients experience serious adverse event (SAE) related to study procedures 
during the Screening Phase. 
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4. 
DISCONTINUATION CRITERIA 
4.1. 
Early Termination of the Study 
This study may be discontinued at the discretion of the Sponsor for any reason. This could occur 
due to concerns related to safety, tolerability or efficacy of KPT-9274. 
4.2. 
Discontinuation of Study Treatment and/or Withdrawal of Patients 
from the Study 
The Investigator may remove a patient from study treatment for any of the following reasons: 
• Unacceptable AEs or toxicity that cannot be managed by supportive care 
• Any medically appropriate reason (e.g., clinical progression) or significant protocol 
violation, in the opinion of the Investigator 
The Investigator must remove a patient from study treatment for any of the following reasons: 
• Disease progression per response criteria 
• Patient withdraws consent to continue study treatment 
• Pregnancy 
Patients who are removed from study treatment by the Investigator are not permitted to restart 
study treatment. 
Patients may discontinue study treatment for any reason. Patients who choose to discontinue study 
treatment will be encouraged to continue in the study so that follow-up information on disease 
progression and survival status may be obtained. Patients may elect to withdraw consent and 
decline further participation in the study at any time.  
The reason for the patient’s discontinuation of study treatment/withdrawal from the study must be 
recorded on the eCRF. 
All patients will be followed until PD, withdrawal of consent, occurrence of any withdrawal 
criteria, intolerable toxicity precluding further treatment with study treatment, death or lost to 
follow up. 
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KPT-9274                                
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5. 
STUDY TREATMENTS 
5.1. 
Treatments Administered 
5.1.1. 
Study Treatments 
KPT-9274 is an orally bioavailable small molecule prepared in a tablet solid dosage form for oral 
administration. 
KPT-9274 tablets are designed for immediate-release oral administration and will be supplied in 
high-density polyethylene (HDPE) bottles with induction seals and polypropylene caps. KPT-9274 
tablets will be film coated for ease of handling and provided in tablet strengths of 5 mg and 20 mg. 
KPT-9274 will be supplied by Karyopharm. Additional details on KPT-9274 are provided in the 
IB. The investigational treatments will be administered as a flat dose and not by body weight or 
body surface area. 
5.2. 
Study Treatment Dose Schedules and Administration 
5.2.1. 
Labeling 
All labels will include conditions for storage, lot number, and other information required by the 
Food and Drug Administration (FDA), International Council for Harmonisation (ICH), and/or 
Annex 13, and all local regulations for investigational medications. 
5.2.2. 
Dispensing Directions 
The Investigator or responsible site personnel must instruct the patient or caregiver to take the 
study treatment(s) as per protocol. Study treatment(s) will be dispensed to the patient by authorized 
site personnel only.  
5.2.3. 
Dosing Information 
Patients will receive oral KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 
15, 17, 19, 22, 24, and 26) during each 28-day cycle. 
5.2.4. 
Dosing Instructions for Patients 
Study medications will be dosed according to the schedules provided in Table 4. Patients will be 
provided with a take home diary to complete; the patient diary will be reviewed prior to the next 
cycle.  
Oral KPT-9274 should be given with food, or within 30 minutes after the patient has eaten, together 
with 240-355 mL (8-12 ounces) of fluids.  
KPT-9274 tablets should be swallowed whole (not crushed). 
5.2.5. 
Dose Schedules for Evaluation During the Dose Escalation Phase 
The dose schedule for evaluation during the Dose Escalation Phase is presented in Table 8.  
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KPT-9274                                
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Table 5  
KPT-9274 Dose Escalation Levels 
KPT-9274 Dose Escalation Levels  
Cohort 
KPT-9274 
Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 in a 28-day cycle 
0 
(de-escalation, if needed) 
20 mg 
1 
(starting cohort) 
30 mg 
2 
40 mg 
3 
60 mg 
4 
80 mg 
5 
100 mg 
 
Three patients will be enrolled in each cohort, if 1 of 3 patients in a cohort experiences a DLT, the 
number of patients in that cohort will be expanded to 6 patients. A maximum of 6 patients will be 
enrolled per cohort. The MTD is defined as the highest dose at which ≤1 patients out of a maximum 
potential cohort of 6 experiences a DLT.  
5.2.6. 
Dose Escalation Guidelines 
5.2.6.1. 
Dose Escalation Procedures 
For the purposes of dose escalation decisions, a standard 3+3 dose escalation design will be used.  
The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. If 
these patients do not experience a DLT during Cycle 1, the KPT-9274 dose will be escalated to 40 
mg for another group of 3 patients (Cohort 2). If the MTD is exceeded at cohort 1, de-escalation 
to cohort 0 (20 mg) will occur. If the MTD is not exceeded in cohort 1, dose escalation will 
continue based on a standard 3+3 design at the dose levels specified in  
Table 8. 
A RP2D equal to or less than the MTD will be declared at the conclusion of the dose escalation, 
and potentially used for the Dose Expansion Phase. The RP2D will be based on an evaluation of 
any and all pharmacokinetic, pharmacodynamic and safety data, including an evaluation of SAEs 
that occur after the end of the DLT window to ensure the tolerability of the RP2D. The MTD is 
defined as the highest dose at which ≤ 1 patient experiences a DLT in Cycle 1. 
Patients must complete a minimum of 1 cycle of treatment, defined as receiving ≥ 75% of 
KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a 
DLT within the first cycle of treatment to be evaluable for dose escalation decisions. Dose 
escalation decisions will occur when the cohort of patients has met these criteria. 
Dose escalation will be conducted as follows: 
• If 0 of 3 patients experiences a DLT, escalate to next higher dose cohort. 
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• If 1 of 3 patients experiences a DLT, that cohort will be expanded to 6 patients. If 1 of 6 
patients experiences a DLT, escalate to the next higher dose cohort; 
• If ≥ 2 of 3 or ≥ 2 of 6 patients experience a DLT, MTD is exceeded. If the MTD is exceeded, 
the patients will be de-escalated to the next lower dose level (the MTD). 
5.2.6.2. 
Dose-Limiting Toxicity 
A DLT will be defined as an AE or abnormal laboratory value that occurs within the first 28 days 
of treatment with KPT-9274, except for those that are clearly and incontrovertibly due to 
underlying disease, disease progression, or extraneous causes, and meets any of the criteria for 
defining dose-limiting toxicities as described in the table below. The CTCAE, Version 5.0 will be 
used for grading. In addition, > 3 missed (consecutive or nonconsecutive) doses of KPT-9274 in 
the first 28 days due to a drug related toxicity will be considered to be a DLT. 
Other events may occur which do not meet the definition of a DLT but are of concern to the 
Investigators may be considered to be DLTs. 
 
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Table 6  
Criteria for Defining Dose-Limiting Toxicities in AML Patients 
Toxicity 
Any of the following criteria (based on CTCAE [Version 5.0]), with the 
exception of events that are clearly and incontrovertibly due to underlying 
disease, disease progression or extraneous causes: 
Non-
Hematologic 
Grade 3 AST (SGOT) or ALT (SGPT) for ≥7 days or grade 3 direct 
hyperbilirubinemia for >7 days 
Grade 2 AST (SGOT) or ALT (SGPT) accompanied by grade 2 direct 
hyperbilirubinemia 
All other clinically significant non-hematological ≥grade 3 AEs with the following 
exceptions: 
• Grade 3 nausea, vomiting or diarrhea will be considered DLT only if not 
controlled with optimal therapy after 72 hours; however, if these AEs require 
hospitalization, total parenteral nutrition or tube feeding, they will be 
considered DLTs regardless of the time required for recovery.  
• ≥ Grade 4 nausea, vomiting or diarrhea will be considered a DLT 
regardless of duration. 
• Grade<4 neutropenic fever 
• Grade 3 biochemical or electrolyte abnormalities may be considered 
exceptions to the DLT criteria only if they have no clinical consequences and 
resolve with appropriate management within 72 hours 
Any grade AE that is related to KPT-9274 that results in permanent 
discontinuation of therapy 
Any death related to KPT-9274 
Hematologic 
≥Grade 3 anemia, neutropenia and/or thrombocytopenia lasting for ≥28 days from 
cycle 1 day 1 in the absence of residual AML (<5% blasts by morphology or 
detectable disease by immunohistochemistry and/or flow cytometry or other 
methods) 
CTCAE Version 5.0 will be used for grading AEs and laboratory abnormalities. Patients may receive 
supportive care as per local institutional guidelines. 
 
5.2.7. 
Dose Schedule for Evaluation During the Dose Expansion Phase 
After completion of the Dose Escalation, Dose Expansion in up to 10 additional patients who meet 
the inclusion/exclusion criteria may be conducted to further explore safety, tolerability and 
preliminary evidence of anti-tumor activity of the RP2D of KPT-9274.  
5.2.8. 
KPT-9274 Dose Reduction Guidelines for Toxicity 
Prior to achieving a morphologic remission, KPT-9274 will not be held for any toxicities that are 
not attributable to KPT-9274. 
After patients have achieved a morphologic remission, dose adjustments of KPT-9274 are 
permitted for those who do not tolerate the protocol-specified dosing schedule. The criteria for 
dose modifications of KPT-9274 for toxicities are outlined in Table 10.  
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If, after the DLT period, interruption of treatment is required and this results in the resolution of 
the event, treatment will be resumed at the same dose. If after re-introduction the same toxicity 
reoccurs with the same severity, treatment re-initiation can resume at 25% of the current dose if 
the AE recovers to ≤grade 1 or baseline within 28 days. Patients who do not recover (i.e., ≤ Grade 
1 or baseline) within 28 days of discontinuation of study treatment will not be permitted to re-start 
study treatment and will be discontinued from the study. 
In the event of a DLT (Cycle 1) during the Dose Escalation Phase the patient must discontinue 
KPT-9274. 
In the event of any other possibly related, likely related or related  toxicity (≥ Grade 3) during the 
Dose Escalation Phase after a patient has achieved a morphologic remission, one of the following 
actions may be taken at the Investigator’s discretion: 
• Patients can continue treatment with KPT-9274 without a dose delay or reduction. 
• If the decision is made to hold KPT-9274: 
o Patients may be re-started on KPT-9274 either at the original dose OR at 25% of 
the dose upon recovery to Grade ≤ 1 or baseline (see Table 9 for pre-specified dose 
modifications for AEs and Table 10 for dose modification guidelines for KPT-
9274). 
5.2.8.1. 
 Conditions Not Requiring KPT-9274 Dose Reduction 
The following conditions are exceptions to the dose-modification guidelines. KPT-9274 does 
not need to be held in the following cases: 
• Alopecia of any grade 
• Electrolyte or serum analyte (e.g., urate) abnormalities that are reversible with standard 
interventions 
• Anemia  
 
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Table 7 
KPT-9274 Dose Modification and Supportive Care Guidelines 
Toxicity and 
Intensity 
Dose Modification 
Non-hematologic Toxicity 
Grade 1 
Maintain dose. 
Consider instituting supportive care medications per institutional guidelines.  
Grade 2 
Institute supportive care medications per institutional guidelines.  
If modifications are desired, guidelines for AEs ≥ Grade 3 should be followed. At 
the Investigator’s discretion, patients may continue on KPT-9274 uninterrupted 
at their current dose. 
≥ Grade 3 
Optimal supportive care medications according to institutional guidelines should 
be instituted.  
Hold KPT-9274 until the event resolves to ≤ Grade1 or baseline (as appropriate): 
• 
First occurrence of ≥ Grade 3: 
o If supportive care results in the AE improving to Grade ≤1 or 
baseline within 3 days, restart KPT-9274 at the current dose. 
o If the improvement to Grade ≤1 or baseline takes longer than 3 
days, KPT-9274 should be resumed at 25% of the dose. 
• 
Second or greater occurrence of ≥ Grade 3, restart KPT-9274 at 50% of 
the dose upon improvement to Grade ≤ 1 or baseline irrespective of 
duration. 
**If the toxicity does not resolve to ≤ Grade 1 or baseline within 28 days, study 
treatment will be discontinued permanently. 
 
Hematological Toxicity for AML Patients 
AML patients typically have abnormal peripheral blood counts at diagnosis; myelosuppression is an 
expected event during the course of any therapy. Therefore, no dose adjustments or treatment interruption 
for hematological toxicity will occur during the first cycle or at any cycle in the presence of residual 
AML. Dose adjustments and/or treatment interruptions for hematological toxicity will be considered 
after the first cycle, in the absence of residual disease,  according to the following guidelines: 
• 
Patients in morphological remission (<5% blasts in the bone marrow by morphology, 
immunohistochemistry or flow cytometry) with pre-cycle ANC>1x109/L, platelets >50x109/L 
and hemoglobin ≥9.0 g/dL who have sustained neutropenia (ANC <0.5x109/L), anemia 
hemoglobin ≤7.0 g/dL) or thrombocytopenia (platelets <20 x109/L) for more than two 
consecutive weeks in the current cycle may hold KPT-9274, with growth factors per institutional 
policies, until the ANC recovers to ≥1 x109/L, hemoglobin recovers to ≥9.0 g/dL and platelets 
recover to ≥50 x109/L. 
• 
Patients in morphological remission (<5% blasts in the bone marrow by morphology, and no 
detectable disease by immunohistochemistry and/or flow cytometry or other methods) with pre-
cycle ANC<1x109/L, hemoglobin ≤7.0 g/dL and platelets <50x109/L may continue KPT-9274 
regardless of neutrophil, red blood cell or platelet count, with supportive care as needed.  
• 
Patients with active or residual disease (>5% blasts in the bone marrow by morphology, 
immunohistochemistry and/or flow cytometry or other methods) may continue treatment 
regardless of neutrophil, red blood cell or platelet counts with supportive care as needed.  
 
 
 
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5.2.9. 
Missed or Vomited Doses   
5.2.9.1. 
Missed Doses of Study Treatments 
If a dose must be skipped (e.g., due to recommendation of Investigator), the next dose will be taken 
as per schedule; all missed doses should be documented. 
5.2.9.2. 
Vomited Doses of Study Treatments 
If a dose is vomited within 1 hour of ingestion, it will be replaced. If vomiting occurs more than 1 
hour after dosing, it will be considered a complete dose. 
 
5.3. 
Study Treatment Storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, KPT-9274 should be stored according to the instructions 
specified on the drug labels and in the IB for KPT-9274. 
Reference the Pharmacy Manual: KPT-9274 Investigator Sponsored Trials for more information. 
 
5.4. 
Study Treatment Accountability 
The Investigator or designee must maintain an accurate record of the shipment and dispensing of 
study treatment in a drug accountability log. Study treatment accountability will be noted by the 
clinical research monitor during site visits and at the completion of the study. Patients will be asked 
to return all unused study treatment and packaging on a regular basis, at the end of the study or at 
the time of study treatment discontinuation. 
KPT-9274 should not be used for any purpose outside the scope of this protocol, nor may 
KPT-9274 be transferred or licensed to any party not participating in the clinical study. 
 
5.5. 
Selection and Timing of Dose for Each Patient 
The rationale for the dose to be used is provided in Section 1.3.1. Guidelines for modifying the 
dose of KPT-9274, if needed due to AEs, are given in Table 10. 
 
5.6. 
Compliance 
The Investigator or other study staff will instruct the patient on study medication self-
administration, as appropriate. Patients will be provided with a take home diary to complete; the 
patient diary will be reviewed prior to the next cycle. 
Patients will be asked to bring their study medication containers with them at the conclusion of 
each cycle and compliance with protocol-defined study treatment intake will be checked by tablet 
count.  
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Compliance to study medication will be assessed by the clinical trials team at the completion of 
each cycle and recorded in source documents after discussion with the patient and performing drug 
accountability. Dates will be recorded as per study treatment schedule. The Investigational 
Pharmacy will account for the number of tablets dispensed against those returned by the patient. 
Any dosing deviations and missed doses will be recorded in the eCRF.  
5.7. 
Supportive Care, Contraception Requirements, and Concomitant 
Medications 
5.7.1. 
Supportive Care 
Patients are expected to be aggressively treated to minimize the likelihood and/or severity of side 
effects at the discretion of the Investigator, including hematologic and musculoskeletal (arthralgias 
and myalgias) symptoms. 
Supportive care including anti-nausea/anti-emetic therapy, acid suppression (e.g., PPIs ± H2 
blockers), anti-diarrheal therapy, and other standard treatments may be administered as per 
institutional guidelines for symptomatic patients. For additional options, please see NCCN 
Supportive Care Clinical Practice Guidelines in Oncology.  
5.7.2. 
Non-study Related Concomitant Medication and Treatment 
No significant inhibition of any of the CYP450 enzymes were observed after KPT-9274 treatment. 
Weak induction of CYPs 1A2, 2B6, and 3A4 were observed in an exploratory pre-clinical study 
after KPT-9274 treatment; however, it is unlikely that a potential drug-drug interaction will occur 
in a clinical setting. Therefore, the use of any concomitant medication/therapy (except medications 
listed in the prohibited medications section, see Section 5.7.3), including over-the-counter (OTC) 
medications (excluding herbal supplements, dietary supplements), deemed necessary for the care 
of the patient is permitted during the study.  
5.7.2.1. 
Permitted Concomitant Medication 
Medications required to treat AEs, manage cancer symptoms, concurrent stable diseases and 
supportive care agents (e.g., blood product transfusions [see Section 5.7.2.4], antibiotics with [if 
appropriate] granulocyte-colony stimulating factors [G-CSF] for neutropenic infection), pain 
medications, anti-emetics, and anti-diarrheals are allowed. Concurrent therapy with growth factors 
is allowed.  
Hormonal contraceptives are permitted in women of child-bearing potential. Hormonal 
contraceptives include any marketed contraceptive agent that includes an estrogen and/or a 
progestational agent. Since the effect of KPT-9274 on oral contraceptives is unknown at this time, 
it is required that patients use at least 2 forms of contraceptives while on study. 
5.7.2.2. 
Prevention of Pregnancy 
Patients should not become pregnant or father a child while on this study because it is unknown 
whether KPT-9274 can affect an unborn baby. Women should not breastfeed a baby while on this 
study. Fertile female patients must agree to refrain from egg donation from first dose until at least 
3 months following the last dose of KPT-9274. Women should not breastfeed during treatment 
with KPT-9274 and for 2weeks after the last dose. 
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Female patients of child-bearing potential must agree to use dual methods of contraception and 
have a negative serum pregnancy test at Screening; male patients must use two highly effective 
barrier method of contraception if sexually active with a female of child bearing potential, during 
treatment with KPT-9274, during a period of 2 weeks (5 half-lives) after the last dose of KPT-
9274 plus a period of 3 months. (for 3.5 months after their last dose of KPT-9274). Fertile male 
patients must agree to refrain from sperm donation from first dose until at least 3.5 months 
following the last dose of  KPT-9274. 
The use of two forms of contraception are required, including one highly effective and one 
effective method of contraception, from the following lists. 
• Highly effective methods include:  
− Hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, 
injectables, and implants)  
− Intrauterine device (IUD) or intrauterine system (IUS)  
− Vasectomy and tubal ligation 
• Effective methods include:  
− Barrier methods of contraception (e.g., male condom, female condom, cervical cap, 
diaphragm, contraceptive sponge)  
Notes: 
o No barrier method by itself achieves a highly effective standard of 
contraception 
o The proper use of diaphragm or cervical cap includes use of spermicide and is 
considered one barrier method. 
o The cervical cap and contraceptive sponge are less effective in parous women. 
o The use of spermicide alone is not considered a suitable barrier method for 
contraception. 
o When used consistently and correctly, “double barrier” methods of 
contraception (e.g., male condom with diaphragm, male condom with cervical 
cap) can be used as an effective alternative to the highly effective contraception 
methods described above. 
o Male and female condoms should not be used together as they can tear or 
become damaged. 
Acceptable methods of contraception also include: 
• A sexual partner who is surgically sterilized or post-menopausal.  
• Total (true) abstinence (when this is in line with the preferred and usual lifestyle of the 
patient), is an acceptable method of contraception. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  
For both male and female patients, effective methods of contraception must be used throughout 
the study and for 3 months following the last dose. 
See Section 1.2.2 for additional safety information related to pregnancy. 
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5.7.2.3. 
Glucocorticoid Therapy 
Glucocorticoids ≥10 mg oral prednisone (or equivalent) per day are not permitted at baseline; 
however physiological doses ≤10 mg oral or inhaled prednisone (or equivalent) for non-malignant 
conditions (e.g., asthma, IBD, etc.) are permitted as needed.  
As part of supportive care (e.g., for nausea or anorexia), oral dexamethasone, up to 40 mg/week, 
may be given to patients. 
5.7.2.4. 
Use of Blood Products 
During treatment, patients may receive RBC or platelet transfusions per institutional guidelines.  
Appropriate anti-coagulation is allowed during the study (e.g., low molecular weight heparin, 
direct factor Xa inhibitors, etc.). 
Patients may receive supportive care with erythropoietin, darbepoetin, G-CSF or granulocyte 
macrophage-colony stimulating factor (GM-CSF), pegylated growth factors, and platelet 
stimulatory factors, in accordance with clinical practice or institutional guidelines prior to entry 
and throughout the study. 
5.7.3. 
Prohibited Concomitant Medications 
The use of niacin or niacin-containing supplements (e.g., multivitamins and energy drinks) is not 
allowed. Investigational or commercial anticancer agents other than KPT-9274 are not allowed 
during the study. The initiation of any non-protocol specific anti-tumor treatment is considered an 
indication of disease relapse/progression and should be recorded appropriately in the eCRFs. 
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6. 
ASSESSMENTS 
6.1. 
Informed Consent 
Study-specific assessments may not be performed until the patient provides written informed 
consent (see Section 9.4). 
6.2. 
Demographic and Baseline Characteristics Assessments 
6.2.1. 
Demographics 
Patient demographics (including date of birth, sex, race, ethnicity, and age at time of consent) will 
be collected at study entry. 
6.2.2. 
Medical History 
A complete medical history will be obtained from each patient. Medical history will include 
baseline symptoms of the disease under study as well as a detailed history of prior therapies. 
6.2.3. 
Baseline Characteristics and Determination of Eligibility 
Baseline characteristics will include ECOG performance status, duration from initial diagnosis, 
response to previous therapy, types of prior therapy, and height/weight. 
Inclusion/exclusion criteria will be reviewed to determine eligibility. 
Patients with known active HAV, HBV, HBC, or HIV infection will be excluded from this study. 
However, testing for these viruses is not required as part of this study. 
6.3. 
Efficacy Assessments 
6.3.1. 
Bone Marrow Aspirate and Biopsy 
Bone marrow biopsy and aspirate will be taken within 30 days prior to first dose (baseline) for all 
AML patients. This will be repeated on cycle 1 day 8. It will again be repeated, for efficacy 
purposes according to the ELN criteria1, at the conclusion of each cycle until the subject has 
achieved a MLFS, CRi or CR, or per investigator discretion.  . It will also be performed as an end 
of treatment assessment if this occurs >30 days from another scheduled or unscheduled bone 
marrow biopsy. Bone marrow biopsies will also be performed at any time at the discretion of the 
investigator in accordance with standard of care (i.e. at the time of suspected progression, etc). 
6.3.2. 
Response Assessments 
Response assessments will occur at each bone marrow biopsy starting with cycle 1 day 28. 
Responses will be assessed per the ELN criteria1 (Appendix 2).  
 
 
6.4. 
Safety Assessments 
Safety evaluations will be conducted as described below. Refer to Table 1, Table 2, and Table 3 
for the timing of all safety assessments. 
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KPT-9274                                
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6.4.1. 
Clinical Safety Assessments 
6.4.1.1. 
Weight and Height  
Height in centimeters (cm), at screening,  and weight in kilograms (kg) will be measured.  
6.4.1.2. 
Physical Examination, Vital Signs, and ECOG Performance Status 
These examinations will be performed according to the institution’s standards.  Vital signs include 
systolic and diastolic BP, pulse measurements, and body temperature (°C or °F). ECOG 
performance status assessments will be performed at the timepoints in the schedule of assessments.  
Reference the ECOG grading table in  (Appendix 1). 
6.4.1.3. 
Electrocardiography 
A single standard 12-lead ECG will be performed at Screening (Day -30 to Day -1) and C1D1 
(pre-dose and 4 hours post-dose (+/- 30 minutes) and institutional standards as needed.  
6.4.1.4. 
Tumor Lysis System Monitoring 
TLS Monitoring is defined as “Tumor lysis syndrome monitoring,” and occurs on day 1, 8 hours 
(+/- 2 hours) after the first dose, and on day 2, 24 hours (+/- 4 hours) after the first dose.  Labs 
include potassium, uric acid, phosphorus, calcium, and serum creatinine. 
6.4.1.5. 
Concomitant Medications 
Concomitant medications will be documented for each patient at the completion of each cycle. A 
detailed history of medications will be documented during Screening and C1D1. All concomitant 
medications including dietary supplements, over-the-counter medications, and oral herbal 
preparations, as well as changes in medication, will be recorded on the eCRFs. 
Necessary supportive care such as appetite stimulants, anti-emetics, and anti-diarrheals, etc., are 
allowed (see Section 5.7.1). 
6.4.1.6. 
Adverse Events 
Information regarding AEs and SAEs will be collected. See Section 7.  It is the responsibility of 
the Investigator to record and document all SAEs (occurring from the signing of the informed 
consent form [ICF]) and all AEs (occurring from the first dose of study treatment on C1D1) 
throughout the study and for 30 days after the last dose of study treatment.   
Each AE will be graded according to the CTCAE v5.0 at every visit (Section 7.1.3).  
6.4.2. 
Laboratory Safety Assessments 
6.4.2.1. 
Clinical Laboratory Tests 
Table 11 presents the clinical laboratory tests that will be performed during the study. 
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Table 8 
Clinical Laboratory Tests 
Complete Blood Count with Differential  
Complete metabolic panel 
The Investigator or designee will review the laboratory results and assess the clinical significance 
of all abnormal values. Appropriate action will be taken for any clinically significant abnormal 
values.  
In addition, laboratory safety assessments will be collected and analyzed on the scheduled day, 
even if study treatment is being withheld. More frequent assessments may be performed if 
clinically indicated, or at the Investigator’s discretion. 
Any laboratory value that remains abnormal at the EoT Visit and that is considered clinically 
meaningful will be followed according to accepted medical standards for up to 30 days or until 
resolution of the abnormality or return to baseline. Toxicity will be graded using CTCAE Version 
5.0. 
6.4.2.2. 
Pregnancy Testing 
For females of childbearing potential, a negative serum human chorionic gonadotropin (hCG) 
pregnancy test must be obtained < 3 days prior to Cycle 1 Day 1 and at the EoT Visit. Pregnancy 
testing is to be performed as clinically indicated at the discretion of the Investigator during the 
study. 
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KPT-9274                                
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7. 
SAFETY DEFINITIONS, RECORDING, AND REPORTING 
7.1. 
Adverse Events 
7.1.1. 
Definitions 
• Adverse event (AE): Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of study treatment, 
whether or not considered related to the study treatment.  
• Treatment-emergent adverse event (TEAE): Any event that was not present prior to the 
initiation of study treatment or any event already present that worsens in either intensity 
or frequency following exposure to study treatment.  
• Serious adverse event (SAE): Any untoward medical occurrence that, at any dose, 
results in death; is life threatening (i.e., an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe); requires inpatient hospitalization or 
prolongation of existing hospitalization; results in persistent or significant 
disability/incapacity; or is a congenital anomaly/birth defect. (See Section 7.2.2 for 
additional information about SAE reporting.)  
7.1.2. 
Recording of Adverse Events 
Adverse Events will be reported and recorded in the eCRF from the time of the first dose of study 
drug through 30 days after the last dose of study drug or until the start of subsequent antineoplastic 
therapy, whichever occurs first. That is, if a patient begins a new antineoplastic therapy, the AE 
reporting period for nonserious AEs ends at the time the new treatment is started.  SAEs during 
screening will only be reported if related to study procedure. 
AE monitoring should be continued for at least 30 days following the last dose of study treatment 
(ie, through 30 days following last dose or until resolution or through the end of the study for 
events considered related to study treatment by the Investigator). 
Adverse events (including laboratory abnormalities that constitute AEs) should be described using 
a diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be recorded as a separate AE. 
The Investigator should ask the patient non-leading questions to determine if any AEs have 
occurred during the study, since the last study visit. Adverse events may also be recorded when 
they are volunteered by the patient, or through physical examination, laboratory tests, or other 
clinical assessments. 
An AE should be followed, and an assessment should be made at each visit (or more frequently, if 
necessary) for any changes in severity of the event, the suspected relationship to the study 
treatment, the interventions required to treat the event, and the outcome.  
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7.1.2.1. 
Laboratory Test Abnormalities 
Laboratory abnormalities and changes in vital signs are AE only if they result in study 
discontinuation, necessitate medical intervention, meet protocol specific criteria, and/or are 
considered by the investigator to be clinically significant or AEs.  Whenever possible, a diagnosis, 
rather than a symptom should be provided (e.g., anemia instead of low hemoglobin). 
Laboratory abnormalities that meet the criteria for an AE should be followed until they have 
returned to baseline levels (as measured during the Screening Visit) or an adequate explanation of 
the abnormality is identified. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported AE, it is not necessary to separately record the laboratory/test 
result as an additional event. 
A laboratory abnormality that does not meet the definition of an AE should not be reported as an 
AE. A Grade 3 or 4 event (severe per NCI CTCAE v5.0) does not automatically indicate an SAE 
unless it meets the definition of serious as defined in Section 7.1.1 and/or as per Investigator’s 
discretion. A laboratory abnormality that results in a dose being held or modified would, by 
definition, be an AE and must be recorded as such in the eCRFs. 
7.1.3. 
Adverse Event Severity 
The term “severe” is used to describe the intensity of an AE; the event itself could be of relatively 
minor clinical significance (eg, ‘severe’ headache). This is not the same as a “serious” AE. 
The severity of the AE will be graded by the Investigator according to the NCI CTCAE Grading 
Scale, v. 5.0 (the NCI CTCAE files can be accessed online at the following URL: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
If NCI CTCAE grading does not exist for an AE, the severity will be characterized as “mild,” 
“moderate,” “severe,” or “life-threatening (corresponding to Grades 1 to 4) according to the 
following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily activities. 
• Moderate events introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities. 
• Severe events interrupt the patient’s usual daily activities. 
• Life-threatening. 
The term “severe” is used to describe the intensity of an AE; the event itself could be of relatively 
minor clinical significance (e.g., ‘severe’ headache). This is not the same as a “serious” AE. 
7.1.4. 
Adverse Event Causality 
The Investigator will make a judgment regarding the relationship of the AE to study treatment, as 
outlined in Table 12  
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Table 9 
Classification of Adverse Events by Causality 
Not related 
These events will lack a temporal relationship of the event to the study 
treatment, making a causal relationship not reasonably possible. Exposure to 
other drugs, therapeutic interventions, or underlying conditions may provide a 
sufficient explanation for the event. 
Possibly Related 
Some evidence to suggest a causal relationship (e.g. occurrence within a 
reasonable time after administration of the trial medication), but other factors 
may have contributed to the event (e.g. another clinical condition or other 
concomitant treatment). 
Likely Related 
Evidence to suggest a causal relationship; the influence of other factors is 
unlikely. 
Related 
There is a temporal relationship of the event to the study treatment making a 
definitive relationship, and the event is more likely explained by exposure to 
the study treatment than by any other drugs, therapeutic interventions, or 
underlying conditions. 
 
7.2. 
Serious Adverse Events 
See Section 7.1.1 for the definition of an SAE. Please note that SAEs related to study procedures 
that occur at any time between the signing of the ICF up to the first dose of study treatment, must 
be reported (in addition to SAEs that occur after the first dose of study treatment). 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in in-patient hospitalization, or the development of drug dependency or drug 
abuse. 
7.2.1. 
Events that Do Not Meet the Definition of a Serious Adverse Event 
Elective hospitalizations to administer, or to simplify study treatment or study procedures (ie, an 
overnight stay to facilitate 24-hour urine collection) or other medical procedures are not considered 
SAEs. A ‘serious’ hospitalization is defined as any inpatient hospital admission that includes a 
minimum of an overnight stay in a health care facility. An emergency room visit is not considered 
a hospitalization unless it results in an official admission as in inpatient to the hospital (eg, 
undesirable effects of any administered treatment) and must be documented as an SAE. 
Progression of the AML (including fatal outcomes) should not be reported as an SAE during the 
study or within the safety reporting period (see Section 7.2.2). Sudden and unexplained death 
should be reported as an SAE. If there is any uncertainty about a finding being due solely to 
progression of malignancy, the finding should be reported as an AE or SAE, as appropriate.  
7.2.2. 
Recording of Serious Adverse Events 
It is the responsibility of the Sponsor-Investigator to record and document all SAEs occurring from 
the signing of the ICF, during screening only those related to study procedures, until at least 30 
days after the patient has stopped study treatment. All SAEs must be reported on Karyopharm’s 
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SAE Report Form in addition to being recorded in the sponsor-investigator’s database. The 
original SAE Report Form must be retained in the Investigator’s site file. 
All applicable sections of the form must be completed in order to provide a clinically thorough 
report. The Investigator must assess and record the relationship of each SAE to study treatment 
and complete the SAE Report Form (in English). 
See ICH E2A (Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Attachment 1) for key data elements that are required for expedited reporting. 
7.2.3. 
Reporting of Serious Adverse Events 
Every SAE, regardless of the causal relationship to the study treatment, occurring after the patient 
has signed informed consent, until at least 30 days after the patient has stopped study treatment, 
must be reported to the HCTU Quality Team and Karyopharm Pharmacovigilance Department 
within 24 hours of learning of its occurrence. The investigational site personnel must use the SAE 
Report Form provided by Karyopharm for reporting any SAE to the Karyopharm 
Pharmacovigilance Department (Appendix 1).  
Upon completion, the SAE Report Form must be immediately emailed or faxed to: 
Pharmacovigilance Department 
Karyopharm Therapeutics Inc. 
Email: pharmacovigilance@karyopharm.com and HCTU.quality@ucdenver.edu   
Fax: 
+1-617-334-7617 (USA) 
Any SAE observed after the 30-day follow-up period should only be reported to HCTU Quality 
Team and Karyopharm if the Investigator suspects that the SAE has causal relationship to the 
Karyopharm study drug. Recurrent episodes, complications, or progression of the initial SAE must 
be reported as follow-up to the original episode within 24 hours of the Investigator receiving the 
follow-up information. 
An SAE should be followed until its resolution or until it is judged to be permanent, and assessment 
should be made at each visit (or more frequently, if necessary) of any changes in severity of the 
event, the suspected relationship to the study treatment, the interventions required to treat the 
event, and the outcome. 
Sponsor-Investigator is responsible as applicable for notifying their appropriate Health 
Authorities, Institutional Review Board, Local and Central Ethics Committees (EC) and Food and 
Drug Administration of all SAEs in accordance with regulations.  
7.2.4. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected (per the 
current version of the IB) and judged by the Sponsor-Investigator or Karyopharm to be related to 
the Karyopharm study drug administered. All SUSARs will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with the FDA’s “Safety 
Reporting Requirements for Investigational New Drugs and Bioanalytical/Bioequivalence 
Studies” (FDA 2012). 
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7.2.5. 
Adverse Event Reporting 
The Investigator will report all AEs (including all non-serious AEs) to Karyopharm 
Pharmacovigilance twice per year in the form of line-listings in an excel spreadsheet.  
Karyopharm, the drug supplier, will supply the cut-off dates of each requested line listing.  The 
line listings will contain the following information: study ID, unique subject ID, adverse event 
term, serious event (yes or no), onset date (complete or partial), end date (complete or partial), 
action taken with KPT-9274, causality to KPT-9274, event ongoing (yes or no), outcome of AE, 
severity CTCAE Grade (1-5), subject dosed with KPT-9274 (yes or no), date of first dose of KPT-
9274, preferred term, system organ class (optional) 
See the excel spreadsheet template in Appendix 4. 
 
7.3. 
Procedures for Handling Special Situations 
7.3.1. 
Pregnancy 
Note: Pregnancy per se is not considered to be an AE; however, it is discussed here because of the 
importance of reporting pregnancies that occur during studies and because a medical occurrence 
observed in the mother or fetus/newborn would be classified as an AE. 
Female patients of childbearing potential and fertile male patients will be informed as to the 
potential risk of conception while participating in this study and will be advised that they must use 
highly effective contraception listed below (ie, results in a low failure rate when used consistently 
and correctly) during the dosing period and for a period of at least 3 months after the end of 
treatment. 
A list of highly effective methods of contraception is provided in Section 5.7. 
A pregnancy test will be performed on each premenopausal female patient of childbearing 
potential prior to the first dose of study drug, on Day 1 of Cycles ≥2 while on treatment, and again 
at treatment discontinuation during the End-of-Treatment visit. A negative pregnancy test must be 
documented prior to administration of study drug. 
If a patient is confirmed pregnant during the study, study drug administration must be discontinued 
immediately. The Investigator must immediately notify the Sponsor investigator of this event and 
record the Pregnancy on the Pregnancy Form. The initial information regarding a pregnancy must 
be forwarded to Karyopharm’s Pharmacovigilance Department by email or fax within 24 hours of 
first knowledge of its occurrence. A pregnancy report form is provided by Karyopharm 
Pharmacovigilance. 
The pregnancy should be followed up to determine the outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.  
All pregnancies occurring within 3 months after the patient’s last dose of study drug must be 
reported to Karyopharm, regardless of whether the patient received the Karyopharm study drug or 
other study drugs, withdraws from the study, or the study is completed. Patients should be 
instructed to inform the Investigator regarding any pregnancies.  
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Any SAE that occurs during pregnancy must be recorded on the SAE report form (eg, maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, or birth defect) and reported within 24 hours in accordance with the procedure 
for reporting SAEs (described in Section7.2. 
A pregnancy in a female partner of a male patient must be reported to Karyopharm 
Pharmacovigilance within 24 hours of learning of its occurrence. Pregnancies in female partners 
should only be followed if the male patient is being treated with a KPT-9274-containing regimen. 
Consent to report information regarding these pregnancy outcomes should be obtained from the 
female partner. 
It is not known whether KPT-9274 passes into the breast milk. Mothers should not breastfeed 
while being treated with a KPT-9274-containing regimen and for 2 weeks after the last dose.  
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8. 
STATISTICAL METHODS 
8.1. 
General Considerations 
Tabulations will be produced for appropriate disposition, demographic, baseline, efficacy, and 
safety parameters. For categorical variables, summary tabulations of the number and percentage 
of patients within each category (with a category for missing data) of the parameter will be 
presented. For continuous variables, the number of patients, mean, median, standard deviation, 
minimum, and maximum values will be presented. Time-to-event data will be summarized using 
Kaplan-Meier methodology with median event time and associated 2 sided 95% confidence 
intervals, as well as number and percentage of patients with events and censored patients. 
Patients who are in the Dose Escalation Phase being treated at the RP2D chosen for expansion will 
be included in the efficacy and safety assessment of the Dose Expansion Phase. 
8.2. 
Determination of Sample Size 
8.2.1. 
Sample size  
The sample size for the Dose Escalation Phase is based on a standard 3+3 design for the purpose 
of determining the RP2D and MTD. Each cohort will consist of 3 or 6 patients per cohort. 
For the Dose Expansion Phase, up to 10 additional patients may be enrolled at the RP2D for KPT-
9274  
Assuming that 4 dose levels of KPT-9274 are evaluated during the Dose Escalation Phase and up 
to 10 additional patients are enrolled in the Dose Expansion Phase, the total combined enrollment 
is estimated to be at most 34 patients. 
8.3. 
Analysis Populations 
8.3.1. 
Intent-to-Treat Population 
The intent to treat (ITT) population for will consist of all patients who receive at least one dose of 
the RP2D chosen for expansion.   
ITT population will be used for analyses of efficacy. 
8.3.2. 
Safety Population 
All patients who receive any amount of the study treatment will be included in the safety 
population for analysis. All safety analyses will be performed on the safety population.  
8.3.3. 
DLT Evaluable Population 
All patients who complete a minimum of 1 cycle of treatment, defined as having received ≥ 75% 
of KPT-9274 doses during Cycle 1 (e.g., ≥ 9 of 12 doses in the 3 doses/week schedule), or who 
have a DLT within the first cycle of treatment, will be included in the DLT evaluable population. 
8.4. 
Data Analysis and Presentation 
Summary tabulations will be provided for disposition, demographic, baseline, efficacy and safety 
data as noted in the following sections. All data collected on the eCRF will be provided in by-
patient data listings.  
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8.4.1. 
Disposition of Patients 
A tabulation of patient disposition will be presented including the number in each analysis 
population, the number lost to follow-up, the number that withdrew, and reason(s) for withdrawal. 
8.4.2. 
Demographic Characteristics 
Demographic characteristics will be summarized by dose cohort, as well as overall, and will 
include date of birth, sex, race, ethnicity, and age at time of consent. For sex, race, and ethnicity, 
the summary statistics will be the number and percentage of patients within each category. The 
categories for race will be those recorded in the database. For age at time of consent, the mean, 
median, minimum, maximum, and standard deviation will be provided for each arm and the total 
sample. No formal hypothesis testing of differences among dose cohorts will be performed. 
8.4.3. 
Baseline Characteristics and Medical History 
Baseline characteristics include ECOG performance status, duration from initial diagnosis, 
response to previous therapy, types of prior therapy, and height/weight. Baseline data will be 
tabulated for the same categories as used for demographics, using summary statistics; no formal 
hypothesis testing of dose cohort differences will be performed. Medical history and physical 
examination results at baseline will be tabulated by treatment cohort. 
8.5. 
Efficacy Analysis 
• Overall response rate (AML): complete remission (CR), complete remission with 
incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), 
partial remission (PR). 
• Duration of response (DOR): the duration of time from first meeting CR, PR, MLFS, 
CRi, measurement criteria (whichever occurs first) until the first date that PD 
recurrence is objectively documented.  
• Progression-free survival (PFS): the duration of time from date of first study 
treatment until the first date that PD is objectively documented or death due to any 
cause.  
• Overall survival (OS): the duration of time from date of first study treatment until 
death from any cause.  
• Time to Progression (TTP): The duration of time from date of first study treatment 
until the first date that PD is objectively documented or death due to PD. Patients 
without documented PD will be censored on the date of last disease assessment.  
 
8.6. 
Safety Analysis  
All safety analyses will be made on the Safety Population.  
The safety and tolerability of KPT-9274 will be evaluated by means of DLTs, AE reports, physical 
examination results, electrocardiogram results and laboratory safety evaluations. NCI CTCAE, 
Version 5.0 will be used for grading of AEs. 
The MTD will be based on the assessment of DLTs during the first cycle of therapy and will be 
defined as the highest dose at which ≤1 patient experiences DLTs within Cycle 1.  
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Interim safety data will be examined on an ongoing basis to ensure patient safety. 
8.6.1. 
Adverse Events 
Analyses of AEs will be performed for those events that are considered to be treatment-emergent 
AEs (TEAEs), defined as any AE with onset or worsening of a pre-existing condition on or after 
the first administration of study medication through 30 days following last dose or any event 
considered drug-related by the Investigator through the end of the study. Adverse events with 
partial dates will be assessed using the available date information to determine if treatment-
emergent; AEs with completely missing dates will be assumed to be treatment-emergent. 
Adverse events will be summarized by frequency counts at patient level. Tabulations will be 
provided for all TEAEs, for TEAEs assessed by the Investigator as at least possibly related to 
treatment, for ≥ Grade 3 TEAEs, and for serious AEs (SAEs).  
No formal hypothesis-testing analysis of AE incidence rates will be performed. 
All AEs (treatment-emergent and post-treatment) will be listed in patient data listings. Separate 
by-patient listings will be provided for the following: patient deaths, SAEs, and AEs leading to 
withdrawal. 
8.6.2. 
Clinical Laboratory Data 
Clinical laboratory values will be expressed using conventional SI units. 
The actual value and change from Baseline for each on study evaluation will be summarized for 
each clinical laboratory parameter, including hematology and clinical chemistry. 
Severity of select clinical lab measures will be determined using CTCAE criteria (i.e., those 
measures that have a corresponding CTCAE grade classification). Shift tables that present changes 
from baseline to worst on-study and baseline to last on-study values relative to CTCAE 
classification ranges will be produced. 
8.6.3. 
Vital Signs and Examinations 
The actual value and change from baseline to each on-study evaluation will be summarized. 
Physical examination results at Screening will be summarized; all other abnormal physical 
examination data are to be recorded on the AE eCRF. All examination findings will be presented 
in a data listing.  ECOG performance status scores, and 12-lead ECG results will be summarized. 
8.6.4. 
Concomitant Medications 
Concomitant medications will be tabulated based on the current version of the World Health 
Organization (WHO) Drug Dictionary.  
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9. 
ADMINISTRATIVE MATTERS 
9.1. 
Regulatory and Ethical Compliance  
This clinical study was designed and will be implemented and reported in accordance with the ICH 
Harmonised Tripartite Guidelines for Good Clinical Practice (GCP). Applicable local regulations, 
including European Directive 2001/20/EC and United States Code of Federal Regulations Title 
21, and the ethical principles outlined in the Declaration of Helsinki will be followed. 
9.2. 
Ethics Committees 
The protocol, the proposed ICF, and any other relevant records must be reviewed and approved by 
a properly constituted ethics committee (eg, IRB) before study start.  
9.3. 
Regulatory Authority Approval 
Before implementing this study, the protocol must be approved by relevant, competent regulatory 
authorities. 
9.4. 
Protocol Adherence  
Prior to study start, the Investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with the instructions and procedures found in this 
protocol and to give access to all relevant data and records to the drug supplier, Quality Assurance 
representatives, designated agents of the Sponsor-Investigator, ethics committees, and regulatory 
authorities as required. Investigators attest they will apply due diligence to avoid protocol 
deviations. All significant protocol deviations will be recorded and reported in the clinical study 
report (CSR). A significant protocol deviation is defined as any change to the execution of the 
protocol, that affects the scientific integrity or design of the study, or the rights, safety or welfare 
of study patients. 
9.5. 
Amendments to the Protocol  
Any significant change or addition to the protocol by the Sponsor-Investigator can only be made 
in a written protocol amendment that must be provided by the Sponsor-Investigator, 
reviewed/approved by the drug supplier, and approved by Health Authorities where required, and 
the ethics committee (eg, IRB). Only amendments that are required for clarification or patient 
safety, by the Sponsor-Investigator, may be implemented prior to ethics committee (eg, IRB) 
approval. Notwithstanding the need for approval of formal protocol amendments, the Investigator 
is expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the Sponsor-
Investigator should be notified of this action and the ethics committee (eg, IRB) at the study site 
should be informed according to local regulations but not later than 10 working days. 
9.6. 
Informed Consent 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law, ethics committee [eg, IRB], or regulation), ethics committee (eg, IRB)-approved 
informed consent. 
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IRB # 20-2350 
 
Version:  7, 31JAN2025 
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Informed consent must be obtained before conducting any study-specific procedures. Procedures 
that are part of the clinical routine evaluations during the initial diagnostic work-up of the patient 
may be performed before the ICF is signed and dated (ie, procedures that are not specific to the 
conduct of the study). 
Informed consent must also be obtained for patients before conducting any study-specific 
procedures for treatment. 
The process of obtaining informed consent should be documented in the patient source documents. 
A copy of the ICF must be given to the patient or to the person signing the form on behalf of the 
patient. The Investigator or designee must record the date when the study ICF was signed in the 
medical records of the patient. The name and role of the witness, if required, should also be 
documented. 
The Sponsor-Investigator will provide to the drug supplier, in a separate document, a proposed 
ICF that is appropriate for this study and complies with the ICH GCP guideline and regulatory 
requirements.  
9.7. 
Patient Confidentiality and Disclosure 
The Investigator must ensure anonymity of all patients; patients must not be identified by names 
in any documents submitted to the drug supplier or its designee. Signed ICFs and patient 
enrollment logs must be kept strictly confidential. 
9.8. 
Collection, Auditing Study Documentation, and Data Storage 
9.8.1. 
Study Documentations, Record Keeping and Retention of Documents 
Each participating site will maintain appropriate medical and research records for this study, in 
compliance with Section 4.9 of ICH E6 GCP, and according to the regulatory and institutional 
requirements.  
Source data include all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study.  
Data collection is the responsibility of the clinical study staff at the site under the supervision of 
the site Investigator. The study database is the primary data collection instrument for the study. 
The Investigator is responsible for the accuracy, completeness, and timeliness of the data reported 
in the database and all other required reports. Data reported in the database, which are derived 
from source documents, should be consistent with the source documents or the discrepancies 
should be explained. All data requested on the source documents must be recorded. Any missing 
data must be explained. If electronic records are used, an audit trail will be maintained by the 
system, in compliance with 21 CFR Part 11. 
The Investigator/institution should maintain study documents as specified in Essential Documents 
for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable regulations 
and/or guidelines. The Investigator/institution should take measures to prevent accidental or 
premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
15 years from the completion of the clinical study unless the Sponsor provides written permission 
to dispose of them or, requires their retention for an additional period of time because of applicable 
laws, regulations, and/or guidelines. 
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KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
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9.8.2. 
Monitoring and Oversight 
The sponsor investigator will be responsible for monitoring the trial per the trial monitoring plan, 
in addition to overseeing the safety and efficacy of the trial including any specimens collected, 
executing the data and safety monitoring (DSM) plan, and complying with all reporting 
requirements to local and federal authorities. This oversight will be accomplished through 
additional oversight from the Data and Safety Monitoring Committee (DSMC) at the University 
of Colorado Cancer Center (CU Cancer Center). The DSMC is responsible for ensuring data 
quality and study participant safety for all clinical studies at the CU Cancer Center, which is the 
coordinating institution of this trial.  
 
A summary of the DSMC’s activities is as follows:  
• Conduct of internal audits  
• Ongoing review of all serious adverse events (SAEs) and unanticipated problems (UAPs)  
• May submit recommendations for corrective actions to the CU Cancer Center’s Executive 
Committee  
 
Per the CU Cancer Center Institutional DSM Plan, SAEs and UAPs are reported to the DSMC, 
IRB and the sponsor investigator per protocol. All SAEs and UAPs are to be reported to the DSMC 
within 7 (for fatal or life-threatening events) or 15 (non-life-threatening events) calendar days of 
the sponsor investigator receiving notification of the occurrence. 
 
Each subject’s treatment outcomes will be discussed by the site PI and appropriate staff at regularly 
scheduled meetings. Data regarding number of subjects, significant toxicities, dose modifications, 
and treatment responses will be discussed and documented in the meeting’s minutes.  
 
The sponsor investigator will provide a DSM progress report to the CU Cancer Center DSMC on 
a recurring basis (either every six or twelve months based on DSMC vote). The DSM report will 
include a protocol summary, current enrollment numbers, summary of toxicity data to include 
specific SAEs, UAPs and AEs, any dose modifications, all protocol deviations, and protocol 
amendments. The DSM progress report submitted to the DSMC will also include, if applicable, 
the results of any efficacy data analysis conducted. Results and recommendations from the review 
of this progress report by the DSMC will then be provided to the sponsor investigator in a DSMC 
review letter. The sponsor investigator is then responsible for ensuring this letter is submitted to 
the site’s IRB of record at the time of IRB continuing review. 
9.8.3. 
Clinical Monitoring, Audit Procedures 
Clinical site monitoring will be conducted to ensure that the rights and well-being of human 
participants are protected, that the reported trial data are accurate, , legible, attributable, complete, 
and verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/ amendment(s), with GCP, and with applicable regulatory requirement(s).  
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time.  They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies of transcriptions that are certified after 
verification as being accurate and complete, microfiche, photographic negatives, microfilm or 
magnetic media, X-rays, patient files, and records kept at pharmacies, laboratories, and medico 
technical departments involved in a clinical trial. 
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KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
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Monitoring for this study will be performed by a qualified research monitor in accordance with 
the clinical monitoring plan (CMP).  The CMP describes in detail who will conduct the monitoring, 
at what frequency monitoring will be done, at what level of detail monitoring will be performed, 
and the distribution of the monitoring reports. 
Source documents that are required to verify the validity and completeness of data entered into the 
eCRFs must not be obliterated or destroyed and must be retained per the policy for retention of 
records.  
To facilitate source data verification, the investigators and institutions must provide the study 
monitor(s) direct access to applicable source documents and reports for trial-related monitoring, 
Sponsor audits, and IRB/EC review.  The study site must also allow inspection by applicable health 
authorities. 
9.9. 
Termination of the Study 
It is agreed that, for reasonable cause, either the Sponsor-Investigator or drug provider, may 
terminate the Investigator’s participation in this study after submission of a written notice. The 
drug provider may terminate the study at any time upon immediate notice for any reason including 
the drug provider’s belief that discontinuation of the study is necessary for patient safety. 
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KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
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10. 
REFERENCES 
1. 
Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 
ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. 
2. 
Nahimana A, Attinger A, Aubry D, et al. The NAD biosynthesis inhibitor APO866 has 
potent antitumor activity against hematologic malignancies. Blood. 2009;113(14):3276-
3286. 
3. 
Cagnetta A, Caffa I, Acharya C, et al. APO866 Increases Antitumor Activity of 
Cyclosporin-A by Inducing Mitochondrial and Endoplasmic Reticulum Stress in Leukemia 
Cells. Clin Cancer Res. 2015;21(17):3934-3945. 
4. 
Mitchell SR, Larkin K, Grieselhuber NR, et al. Selective targeting of NAMPT by KPT-
9274 in acute myeloid leukemia. Blood Adv. 2019;3(3):242-255. 
 
 
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Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 54 of 58 
 
APPENDIX 1. EASTERN 
COOPERATIVE 
ONCOLOGY 
GROUP 
PERFORMANCE STATUS CRITERIA 
Table 10 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair. 
5 
Dead. 
 
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Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 55 of 58 
 
APPENDIX 2. EUROPEAN 
LEUKEMIA 
NETWORK 
RESPONSE 
CRITIERA FOR AML (DOHNER ET AL, 2017) 
Table 11 
European leukemia network response criteria for AML 
Response  
Definition 
Comment 
Complete remission 
(CR) 
Bone marrow blasts <5%, absence of circulating blast and blasts 
with 
Auer 
rods; 
absence 
of 
extramedullary 
disease; 
ANC≥1.0x109/L; platelet count ≥100x109/L 
MRD status to be 
reported if known 
CR with incomplete 
hematologic recovery 
(CRi) 
All CR criteria except for residual neutropenia (<1.0 x 109/L) or 
thrombocytopenia (<100x109/L) 
 
Morphologic 
leukemia-free 
state 
(MLFS) 
Bone marrow blasts <5%, absence of blasts with Auer rods; absence 
of extramedullary disease; no hematologic recovery required 
Marrow 
should 
not 
merely 
be 
“aplastic”; at least 
200 cells should 
be enumerated or 
cellularity should 
be at least 10% 
Partial 
remission 
(PR) 
All hematologic criteria of CR; decrease of bone marrow blast 
percentage to 5% to 25%, and decrease of pretreatment bone 
marrow blasts percentage by at least 50% 
 
 
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Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 56 of 58 
 
APPENDIX 3.  SAMPLE SERIOUS ADVERSE EVENT REPORT FORM  
 
 
 
 
 
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Pollyea          
 
KPT-9274                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 57 of 58 
 
APPENDIX 4.  TEMPLATE FOR LINE LISTING OF ADVERSE EVENTS  
 
Template is a guide.  Sponsor-Investigator may provide equivalent information in a differing format
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Pollyea          
 
KPT-9274                                                                                                                
IRB # 20-2350 
 
Version:  7, 31JAN2025 
Page 58 of 58 
 
 
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