Clinical trial NCT02178436
Conditions: Acinar Cell Adenocarcinoma of the Pancreas Duct Cell Adenocarcinoma of the Pancreas Stage IV Pancreatic Cancer
Sponsor: Mohammed Najeeb Al Hallak
Start date: 2014-10-31; Completion date: 2023-04-05
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This partially randomized phase Ib/II trial studies the side effects and best dose of selinexor when given together with gemcitabine and nab-paclitaxel, and to see how well they work in treating patients with pancreatic cancer that has spread to other parts of the body (metastatic). Drugs used in chemotherapy, such as selinexor, gemcitabine and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
Primary Objectives:

1. Phase I: To determine the recommended phase 2 dose (RP2D) of gemcitabine, nabpaclitaxel and selinexor for untreated metastatic pancreatic cancer \[COMPLETED\]
2. Phase I: To determine the safety profile of gemcitabine, nab-paclitaxel and selinexor \[COMPLETED\]
3. Phase II: To test whether the combination of gemcitabine and selinexor improves the median overall survival of patients with metastatic pancreatic cancer who have failed frontline non-gemcitabine containing regimens beyond 5.6 months (median overall survival of patient receiving gemcitabine only based on historical data.

Secondary Objectives:

1. To determine objective response rate to the combination of gemcitabine and selinexor using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
2. To assess safety of selinexor in combination with gemcitabine in phase II portion of the study
3. To determine progression free survival (PFS) in patients treated with gemcitabine and selinexor
4. To determine the influence of selinexor and gemcitabine on the nuclear expression and localization of tumor suppressor gene proteins.

Arms: arm 1: Patients receive gemcitabine hydrochloride IV, nab-paclitaxel IV, and selinexor PO on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive gemcitabine hydrochloride IV on days 1, 8, and 15. Patients also receive selinexor PO on days 3, 8, and 15 of cycle 1 and on days 1, 8, and 15 for the subsequent cycles. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity arm 3: Patients receive gemcitabine hydrochloride IV and selinexor PO on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: gemcitabine hydrochloride intervention 2: Selinexor intervention 3: Pharmacological Study intervention 4: Laboratory Biomarker Analysis intervention 5: Nab paclitaxel
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies intervention 4: Correlative studies intervention 5: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
Page 1 of 76                         
Karyopharm IST identifier: IST-25 
 
Initial Protocol:  October 14, 2013                    
Amendment 1:  September 16, 2014                
Amendment 2:  July 28, 2015 
 
         
Amendment 3:  July 07, 2016 
 
 
 
 
 
         
Amendment 4: October 06, 2016  
Amendment 5: January 26, 2017  
Amendment 6: November 25, 2019 
Amendment 7: May 27, 2020 
Amendment 8: August 18, 2022 
 
2013-133:  Phase Ib Study of the Selective Inhibitor of Nuclear Export (SINE) 
Selinexor (KPT-330), Gemcitabine and nab-Paclitaxel and Phase II Study of 
Gemcitabine and Selinexor  in Patients with Metastatic Pancreatic Cancer 
 
Principal Investigator:  
Mohammed Najeeb Al Hallak, MD, MS 
 
 
 
 
Karmanos Cancer Institute 
 
 
 
 
4100 John R – HW04HO 
Detroit, MI  48201 
Tel# 313-576-8718 
Fax# 313-576-8767 
E mail:  alhallakm@karmanos.org  
 
Sponsor:  
 
 
Karmanos Cancer Institute 
 
Co-Investigators:   
Anthony F Shields, MD, PhD 
 
 
Karmanos Cancer Institute  
4100 John R – HW04HO 
Detroit, MI 48201 
Tel# 313-576-8735 
Fax# 313-576-8767 
E mail:  shieldsa@karmanos.org  
 
 
E mail:  minsig.choi@stonybrookmedicine.edu 
 
 
 
 
 
Biostatistician: 
Gregory Dyson, PhD 
Karmanos Cancer Institute  
4100 John R – MMBI03  
Detroit, MI 48201 
Tel# 313-576-8654  
E mail:  dysong@karmanos.org 


 
Page 2 of 76                         
 
Study Coordinators: 
Allison Wolgast 
Karmanos Cancer Institute 
4100 John R-MM03CT 
Detroit, MI 48201 
Office: (313) 576-8994 
Fax: (313) 576-8368 
Email: wolgasta@karmanos.org 
 
  
 
Ms. Taylor Brewer, CCRP 
Karmanos Cancer Institute 
4100 John R  - MM03CT 
Detroit, MI  48201 
Tel# 313-576-8526 
Fax# 313-576-8368 
E mail:  brewert@karmanos.org 
 
Regualtory Coordinator: Angela Powell, MPH, CCRP 
 
 
 
 
Karmanos Cancer Institute 
4100 John R – MM05P1  
Detroit, MI 48201 
Tel# 313-576-9367 
Fax# 313-576-9684 
Email: powellan@karmanos.org 
Lab Correlative Studies: 
Ramzi Mohammad, PhD 
Karmanos Cancer Institute 
4100 John R – HW07A0 
HWCRC - 732 
Detroit MI, 48201 
Tel# 313-576-8329 
E mail:  mohammad@karmanos.org   
 
Asfar S. Azmi, PhD 
Wayne State University School of Medicine 
4100 John R – HW07A0  
HWCRC - 732 
Detroit MI, 48201 
Tel# 313-576-8328 
E mail:  azmia@karmanos.org  
  
Drug Supplier:  
 
Karyopharm Therapeutics Inc  
85 Wells Avenue 
Newton MA 02459 


 
Page 3 of 76                         
 
Karyopharm IST Identifier: IST-25 


 
Page 4 of 76                         
INVESTIGATORS' AGREEMENT 
 
I have read and understand the contents of this clinical protocol for Study No <insert study 
number> dated <DD Month YYYY> and will adhere to the study requirements as presented, 
including all statements regarding confidentiality. In addition, I will conduct the Study in 
accordance with current Good Clinical Practices, ICH E6, and applicable FDA regulatory 
requirements. 
 
 
Principal Investigator’s Signature: 
 
Principal Investigator’s Name: 
 
Institution: 
 
Date: 
 
 
 
Co-Investigator’s Signature: 
 
Co-Investigator’s Name: 
 
Institution: 
 
Date: 
 
 
Co-Investigator’s Signature: 
 
Co-Investigator’s Name: 
 
Institution: 
 
Date: 
 
 
Co-Investigator’s Signature: 
 
Co-Investigator’s Name: 
 
Institution: 
 
Date: 
 
 
Co-Investigator’s Signature: 
 
Co-Investigator’s Name: 
 
Institution: 
 
Date: 
 
 
 


 
Page 5 of 76                         
Title:  Phase Ib Study of the Selective Inhibitor of Nuclear Export (SINE) Selinexor 
(KPT-330), Gemcitabine and nab-Paclitaxel and Phase II Study of Gemcitabine and 
Selinexor  in Patients with Metastatic Pancreatic Cancer 
 
STUDY SYNOPSIS  
Study Title:  
Phase Ib Study of the Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330), 
Gemcitabine and nab-Paclitaxel and Phase II Study of Gemcitabine and Selinexor  in 
Patients with Metastatic Pancreatic Cancer 
 
Primary Objectives:  
1.  
Phase I: To determine the recommended phase 2 dose (RP2D) of gemcitabine, nab-
paclitaxel and selinexor for untreated metastatic pancreatic cancer [COMPLETED] 
2.  
Phase I: To determine the safety profile of gemcitabine, nab-paclitaxel and selinexor 
[COMPLETED]  
3.   
Phase II: To test whether the combination of gemcitabine and selinexor improves 
the median overall survival of patients with metastatic pancreatic cancer who have 
failed frontline non-gemcitabine containing regimens beyond 5.6 months (median 
overall survival of patient receiving gemcitabine only based on historical data; J Clin 
Oncol. 1997 jun;15(6):2403-13) 
 
Secondary Objectives:  
1.  
To determine objective response rate to combination of gemcitabine, nab-paclitaxel 
and selinexor using RECIST criteria 
2.  
To assess safety of selinexor in combination with gemcitabine in phase II portion of 
the study 
3. 
To determine progression free survival (PFS) in patients treated with gemcitabine 
and selinexor 
4. 
To explore the influence of selinexor and gemcitabine on the nuclear expression and 
localization of tumor suppressor gene proteins 
 
Sample Size:  
Phase I:  
Up to 12 patients with metastatic pancreatic cancer [COMPLETED] 
Phase II:  
up to 44 patients.  
 
Study Design:  
This is a multicenter phase Ib study to investigate selinexor when combined with 
gemcitabine and nab-paclitaxel for first line treatment of metastatic pancreatic cancer and 
phase II study of selinexor plus gemcitabine in patients with pancreatic cancer in second 
line setting. Objectives include the determination of the safety profile of selinexor in 
combination with gemcitabine and selinexor and the overall survival of patients who 
receive the gemcitabine-selinexor combination. 
 
The study was a phase Ib study that was designed according to a standard 3+3 design and 
is now completed. The Maximum Tolerated Dose (MTD) was the lowest dose for which less 
than a third of patients experienced a Dose Limiting Toxicity (DLT). To ensure sufficient 


 
Page 6 of 76                         
toxicity data at the MTD, a minimum of 6 patients were to be enrolled at the MTD. We 
anticipated that the RP2D would be the same as the MTD. 
 
Phase Ib had three cohorts as shown in table 1. Only initial cohort was completed because 
of DLT.  
 
At this time, up to 44 patients with metastatic pancreatic adenocarcinoma that were 
previously treated with a non-gemcitabine based regimen will be enrolled onto the phase II 
part of the study. The first fourteen  patients with liver metastases that are accessible for 
image guided percutaneous core biopsies will be randomized into two post-treatment 
biopsy groups, group 1 and 2. The remaining 30 patients enrolled in this trial will be placed 
in group 3 (no biopsy group).The post-treatment biopsy will be done only on C1D3 and the 
tissue obtained will be studied for changes in expression of tumor suppressor proteins 
(TSPs) caused by the combination of drugs compared to either biopsy sample obtained at 
screening or archival tissue obtained at time of diagnosis.  
• 
Group 1 will receive gemcitabine without selinexor on cycle 1 day 1. This will be 
followed by a biopsy of metastatic liver lesion approximately 48 hours after 
administration of the gemcitabine. Following the biopsy (C1D3), patients in group 1 
will receive the first dose of selinexor.  Then on C1D8 and C1D15, selinexor will be 
given with  gemcitabine. In the subsequent cycles, Selinexor will be given 
concurrently with Gemcitabine on days 1, 8, and 15 of each 4-week cycle. 
• 
Group 2 will receive gemcitabine concurrently with selinexor starting on C1D1. A 
biopsy of the liver will be performed approximately 48 hours after administration of 
gemcitabine and selinexor. In Group 2, gemcitabine /selinexor combination will be 
administered once every week for three weeks on days 1, 8 and 15 of each 4-week 
cycle.   
• 
Group 3 will receive gemcitabine concurrently with selinexor starting on C1D1 and 
then weekly for three weeks (days 1, 8 and 15) of each 4-week cycle.   
 
It should be noted that the goal of randomization is to obtain tissue for pharmacodynamics 
assessment and determine the impact of the treatment on target molecules. If any of the 
first 14 patients with liver metastates consented to enroll in the study but refused to 
consider the C1D3 biopsy then those patients will be allocated to Group 3 (no biopsy 
group).    
 
Table 1: Cohorts in phase I [COMPLETED] 
Cohort 
Gemcitabine (mg/m2) 
Days 1, 8, 15 
Nab-paclitaxel (mg/m2) 
Days 1, 8, 15 
Selinexor (mg) 
Days 1, 8, 15* 
Level 2 
1000 
125 
80 
Level 1 (starting) 
1000 
125 
60 
Level -1 
1000 
125 
40 
 
 
 


 
Page 7 of 76                         
Table 2: Phase 2 dose adjustment 
 
Gemcitabine (mg/m2) 
Days 1, 8, 15 
Selinexor (mg) 
Days 1, 8, 15* 
Level 1 (starting) 
1000 
80 
Level -1 
750 
60 
Level -2 
500 
 
*Except for C1 of phase II in Group 1 where selinexor will be given on C1D3. 
 
Dose Schedule and Definition of a Treatment Cycle:  
Phase 1b [COMPLETED]: A treatment cycle will be 4 weeks (+/- 3 days). In each cycle, 
patients will have 3 doses of gemcitabine/ nab-paclitaxel and 3 doses of selinexor. 
Gemcitabine/ nab-paclitaxel combination will be administered IV weekly for 3 weeks with 
one week off. Selinexor will be administered orally once a week on Weeks 1, 2 and 3 of each 
4-week cycle. Once a MTD is determined, it will be the recommended dose of selinexor for 
Phase II and patients will be treated with it until disease progression or undue toxicities. 
 
Phase II: A treatment cycle will be 4 weeks (+/- 3 days). Group 1 will receive IV 
gemcitabine without selinexor on day 1 of cycle 1.  A liver biopsy will be performed on day 
3 of cycle 1 followed by oral administration of the C1 Week1 dose of selinexor.  Then, 
gemcitabine/selinexor will be administered on day 8 and 15 of week 2 and 3. Gemcitabine 
and selinexor will not be administered on week 4. In the subsequent cycles, both drugs will 
be given on days 1, 8, and 15 of 4-week cycle. Group 2 will receive gemcitabine/selinexor 
on day 1, 8, 15 of week 1, 2, 3 of a 4-week cycle.  A biopsy of the liver will be performed 
approximately 48 hours after administration of gemcitabine and selinexor on C1 D1. 
Gemcitabine/selinexor will not be administered in week 4. Group 3 will receive 
gemcitabine/selinexor on day 1, 8, 15 of week 1, 2, 3 of a 4-week cycle. No biopsy is 
planned for this group. Gemcitabine/selinexor will not be administered in week 4 
 
Definition of Dose Limiting Toxicity (DLT): 
DLT is defined as any of the following occurring in the first 28 days (first cycle) of study 
participation that is considered at least possibly related to selinexor administration:   
• 
> 1 missed doses in 28 days due to a toxicity that is possibly selinexor-related   
• 
Discontinuation of a patient due to a toxicity that is at least possibly selinexor-
related prior to completing Day 28 of the first cycle  
 
Non-Hematologic:  
• 
Grade ≥ 3 fatigue, nausea, vomiting or diarrhea despite receiving optimal supportive 
medications   
• 
Any other Grade ≥3 non-hematological toxicity [except for electrolyte abnormalities 
that are reversible and asymptomatic]  
• 
Grade ≥3 AST or ALT elevation lasting longer than 7 days or Grade ≥3 AST or ALT 
elevation in the setting of bilirubin elevation > 2x ULN  
 
 


 
Page 8 of 76                         
Hematologic:  
• 
Grade 4 neutropenia [absolute neutrophil count (ANC) < 500/mm3] lasting ≥7 days   
• 
Febrile neutropenia (ANC<1000/mm3 with a single temperature ≥ 38.3ºC or 
sustained temperature of >38°C for over 1 hour)  
• 
Thrombocytopenia (platelet count <25,000/mm3) that persists for ≥7 days   
• 
Grade ≥3 thrombocytopenia associated with clinically significant bleeding  
 
Discontinuation Criteria:  
The investigator may remove a patient from the study for the following reasons:  
• 
Subjective and/or objective disease progression  
• 
Noncompliance with study procedures  
• 
Need of treatment with medications not permitted by the study protocol  
• 
Patient withdrawing consent to participate in the study  
• 
Intercurrent illness that interferes with study assessments or safe administration of 
study drugs  
• 
Frequency and/or severity of Adverse Events (AEs) in this study that indicate an 
unacceptable health hazard to study participants  
• 
For the third occurrence of the same Grade≥3 non-hematological toxicity  
• 
Investigator discretion   
  
 
Duration of the Study:  
The enrollment period for the study is expected to be approximately 28-32 months with an 
additional 12 months for follow up after the last patient enrolled in the phase II cohort. The 
treatment period for an individual patient is expected to be greater than 2 months and 
without mandated maximum treatment duration or number of cycles. 
 
Study Eligibility Criteria:  
Inclusion Criteria:  
1.  
Written informed consent in accordance with federal, local, and institutional 
guidelines  
2.  
Age >18 years  
3.  
Patients with metastatic pancreatic adenocarcinoma who have failed one  non-
gemcitabine based regimen for metastatic disease.  
4.  
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (see 
Appendix 1)  
5.  
Adequate hematopoietic function: absolute neutrophil count (ANC) ≥1500/mm3 and 
platelet count ≥100,000/mm3  
6.  
Adequate hepatic function: bilirubin <2 times the upper limit of normal (ULN) 
(except patients with Gilbert’s syndrome who must have a total bilirubin of < 3 
times ULN) and ALT or AST <2.5 times ULN  
7.  
Adequate renal function: serum creatinine < 1.5 mg/dL 
8.  
Serum albumin > 3.0 g/dL 
9. 
Effective contraception: Female patients of childbearing potential must agree to use 
highly effective methods of contraception and have a negative serum pregnancy test 
at screening. Male patients must use an effective barrier method of contraception if 


 
Page 9 of 76                         
sexually active with a female of childbearing potential. Acceptable methods of 
contraception are condoms with contraceptive foam, oral, implantable or injectable 
contraceptives, contraceptive patch, intrauterine device, diaphragm with 
spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. 
For both male and female patients, highly effective methods of contraception must 
be used throughout the study and for three months following the last dose.  
10.  Patients with history of previously treated other malignancies who do not have any 
evidence of recurrent disease for the last three years are allowed 
 
Exclusion Criteria:  
Patients meeting any of the following exclusion criteria are not eligible to enroll in this 
study.  
1.  
Patients who are pregnant or breast feeding   
2.  
Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤3 
weeks prior to cycle 1 day 1. Treatment with mitomycin C or radio-immunotherapy 
must be completed within 6 weeks prior to cycle 1 day 1. 
3.  
Major surgery within 3 weeks of cycle 1 day 1 
4.  
Prior therapy with gemcitabine based regimen for metastatic disease or 
gemcitabine based adjuvant therapy completed less than twelve months from 
enrollment 
5.  
Unstable cardiovascular function that includes and may not be limited to:   
o 
symptomatic myocardial ischemia, or  
o 
uncontrolled clinically significant conduction abnormalities (e.g., ventricular 
tachycardia on antiarrhythmics are excluded and 1st degree AV block or 
asymptomatic LAFB/RBBB will not be excluded), or  
o 
congestive heart failure (CHF) of NYHA Class ≥3, or   
o 
myocardial infarction (MI) within 3 months of cycle 1 day 1  
6.  
Uncontrolled active infection requiring parenteral antibiotics, antivirals, or 
antifungals within one week prior to first dose  
7.  
Known to be HIV seropositive who are on anti-HIV drugs because of the unknown 
interactions between these drugs and the study agents 
8.  
Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or 
HBsAg (HBV surface antigen)  
9.  
Patients with active CNS malignancy. Asymptomatic small lesions are not 
considered active. Treated lesions may be considered inactive if they are stable for 
at least 3 months.  
10.  Patients with significantly diseased or obstructed gastrointestinal tract or 
uncontrolled vomiting or diarrhea   
11.  History of seizures, movement disorders, or cerebrovascular accident within the 
past 5 years prior to cycle 1 day 1  
12.  Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased 
visual acuity based on physician’s assessment   
13.  Serious psychiatric illness (e.g., depression, psychosis) or medical conditions that 
could interfere with treatment  
14.  Participation in an investigational anti-cancer study within 3 weeks prior to cycle 1 
day 1  


 
Page 10 of 76                         
15.  Concurrent therapy with approved or investigational anticancer therapeutics other 
that what is stipulated by the protocol 
16. Clinically significant ascites 
 
Pharmacodynamic Assessments:  
The assay is comprised of immunohistochemistry on paraffin embedded tumor samples to 
determine nuclear localization of p27, IκB, FOXO, and PAR4 tumor suppressor proteins.  
 
Efficacy Assessment: 
Objective disease response assessment will be made according to standard, international 
RECIST 1.1 criteria for solid tumors[1]. Anti-tumor activity will be described in terms of 
best overall objective tumor response, duration of response (DOR), progression free 
survival (PFS), and duration of stable disease and overall survival (primary endpoint). The 
reasons for going off study treatment will be described for all patients.  
 
Safety Variables & Analysis:  
The safety and tolerability of selinexor in combination with gemcitabine will be evaluated 
by means of DLTs, AE reports, physical examinations, and laboratory safety evaluations. 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 will be used for grading 
of AEs. Investigators will provide their assessment of attribution as 1) unrelated, 2) 
possible,3) probable, or 4) definite for all AEs.  
 
All patients who receive at least one dose of selinexor will be included in the safety 
population. Interim safety data will be examined on an ongoing basis to ensure patient 
safety and to comply with the clinical trial dose change rules. 
 
Futility monitoring  
A concern with this regimen is that selinexor may impede the activity of gemcitabine, due 
to possible increased toxicity and decreased exposure to gemcitabine, resulting in worse 
survival outcomes. While our final analysis will be able to quantify this hypothesis (as it is a 
two-sided test), it is necessary to continually monitor the patients on trial for futility of 
treatment. As our final sample size is small for our 1-arm study, utilizing a survival 
endpoint for futility monitoring is not feasible. Therefore, we will monitor the proportion 
of patients who survive less than the reported median survival under the null hypothesis 
(5.6 months). We would recommend reconsidering the phase II portion of the study for 
futility reasons if there were greater than half of the registered patients at any time who 
did not survive longer than 5.6 months once at least 10 patients have either had an event or 
survived longer than 5.6 months. Thus, we will compute the [number of patients who 
survived less than 5.6 months]/([number of patients who survived less than 5.6 months] + 
[number of patients will have survived longer than 5.6 months]) and monitor if that 
proportion ever becomes greater than one half once 10 patients had either outcome in the 
denominator. 
 
 


 
Page 11 of 76                         
TABLE OF CONTENTS 
 
STUDY SYNOPSIS ................................................................................................................................... 5 
LIST OF ABBREVIATIONS .................................................................................................................. 15 
1  
INTRODUCTION ................................................................................................................... 17 
1. 1  
OVERVIEW ............................................................................................................................. 17 
1.1.1  
NUCLEAR EXPORT ............................................................................................................... 17 
1.1.2  
INACTIVATION OF TSP/GRP BY NUCLEAR EXPORT ................................................ 18 
1.1.3  
CRM1 IN HUMAN CANCER ................................................................................................ 20 
1.1.4  
SELINEXOR ............................................................................................................................ 20 
1.2  
RATIONALE FOR THE STUDY .......................................................................................... 26 
1.2.1  
RATIONALE FOR STARTING DOSE AND DOSING SCHEDULE ................................ 27 
1.3  
STUDY POPULATION AND SAMPLE SIZE ..................................................................... 28 
1.4  
PHARMACODYNAMIC (PDN) BIOMARKERS ............................................................... 28 
2  
OBJECTIVES ........................................................................................................................... 28 
2.1  
PRIMARY OBJECTIVES ....................................................................................................... 28 
2.2  
SECONDARY OBJECTIVES ................................................................................................. 28 
3  
PATIENT SELECTION .......................................................................................................... 29 
3.1  
INCLUSION CRITERIA ......................................................................................................... 29 
3.2  
EXCLUSION CRITERIA ........................................................................................................ 29 
3.3  
PATIENT REGISTRATION ................................................................................................. 30 
4  
STUDY CALENDARS ............................................................................................................ 32 
5  
TREATMENT PLAN .............................................................................................................. 33 
5.1  
STUDY DESIGN ..................................................................................................................... 33 
5.2  
DOSE SCHEDULE .................................................................................................................. 35 
5.3  
SUGGESTED SUPPORTIVE CARE/PRE-MEDICATION............................................... 35 
5.3.1  
SUPPORTIVE CARE RECOMMENDATIONS FOR SELINEXOR-RELATED 
ADVERSE EVENTS ................................................................................................................ 35 
5.4  
CRITERIA FOR INITIATION OF NEXT CYCLE .............................................................. 35 
5.5  
DEFINITION OF RP2D ........................................................................................................ 36 
5.6  
PHASE II COHORT ............................................................................................................... 36 
5.7  
DEFINITION OF DOSE LIMITING TOXICITY (DLT) ................................................... 36 
5.8  
SAFETY COHORT REVIEW ................................................................................................ 37 


 
Page 12 of 76                         
5.9  
DOSING ADJUSTMENTS ..................................................................................................... 37 
5.9.1  
DOSE MODIFICATIONS FOR SELINEXOR ..................................................................... 37 
5.9.1.1  CONDITIONS NOT REQUIRING SELINEXOR DOSE REDUCTION ........................... 43 
5.9.1.2  DOSE ADJUSTMENTS WITH CHANGES IN BSA ........................................................... 43 
5.9.1.3  SELINEXOR DOSE ADJUSTMENT IN THE SETTING OF INFECTION ...................... 43 
5.9.1.4  MISSED OR VOMITED DOSES ........................................................................................... 43 
5.9.1.5  DELAYS, MODIFICATIONS, AND REINTRODUCTION ............................................... 44 
5.9.2  
DOSE ADJUSTMENT FOR GEMCITABINE ..................................................................... 44 
5.9.2.1  DOSE ADJUSTMENT GUIDELINES FOR NON-HEMATOLOGIC TOXICITIES ........ 44 
5.9.2.2  DOSE ADJUSTMENT GUIDELINES FOR HEMATOLOGIC TOXICITIES .................. 45 
5.10  
PATIENT COMPLIANCE AND REPLACEMENT ............................................................. 45 
5.11  
PREMATURE WITHDRAWAL/ DISCONTINUATION CRITERIA ............................. 45 
6  
CONCOMITANT MEDICATIONS ....................................................................................... 46 
6.1  
PERMITTED CONCOMITANT MEDICATIONS .............................................................. 46 
6.2  
PROHIBITED CONCOMITANT MEDICATIONS ............................................................ 47 
7  
DRUGS ..................................................................................................................................... 48 
7.1  
SELINEXOR ............................................................................................................................ 48 
7.1.1  
DRUG PREPARATION AND ADMINISTRATION .......................................................... 48 
7.1.2  
DRUG STORAGE ................................................................................................................... 48 
7.1.3  
ACCOUNTABILITY AND DESTRUCTION OF INVESTIGATIONAL MEDICINAL 
PRODUCT ............................................................................................................................... 48 
7.1.4  
DRUG ADMINISTRATION .................................................................................................. 48 
7.2 
GEMCITABINE HYDROCHLORIDE (GEMZAR®) ......................................................... 49 
8  
MEASUREMENT OF DRUG EFFECTS .............................................................................. 50 
8.1  
SAFETY ASSESSMENT ......................................................................................................... 50 
8.2  
EFFICACY ASSESSMENTS .................................................................................................. 50 
8.3  
PHARMACODYNAMICS ...................................................................................................... 50 
9  
SAFETY AND REPORTING REQUIREMENTS ................................................................ 51 
9.1  
ADVERSE EVENTS ................................................................................................................ 51 
9.1.1  
ADVERSE EVENT DOCUMENTATION ............................................................................ 52 
9.1.1.1  RECORDING OF ADVERSE EVENTS ................................................................................ 52 
9.1.1.2  ADVERSE EVENT REPORTING: ........................................................................................ 53 


 
Page 13 of 76                         
9.1.1.3  ADVERSE EVENT CAUSALITY .......................................................................................... 53 
9.2  
SERIOUS ADVERSE EVENTS ............................................................................................. 53 
9.2.1  
EVENTS THAT DO NOT MEET THE DEFINITION OF A SERIOUS ADVERSE 
EVENT ...................................................................................................................................... 54 
9.2.2  
RECORDING OF SERIOUS ADVERSE EVENTS .............................................................. 54 
9.3  
REPORTING OF SERIOUS ADVERSE EVENTS .............................................................. 54 
9.3.1  
REPORTING SERIOUS ADVERSE EVENTS TO THE PRINCIPAL INVESTIGATOR 
AND CLINICAL TRIALS OFFICE (CTO) AT KARMANOS ............................................ 54 
9.3.2  
REPORTING SAES TO KARYOPHARM ........................................................................... 55 
9.3.3  
REPORTING SERIOUS ADVERSE EVENTS TO LOCAL ETHICS BOARDS .............. 56 
9.3.4  
REPORTING PERIOD FOR ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
 ................................................................................................................................................... 56 
9.3.5  
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS ................................. 56 
9.4  
PROCEDURES FOR HANDLING SPECIAL SITUATIONS ............................................. 57 
9.4.1  
PREGNANCY AND BREASTFEEDING .............................................................................. 57 
9.4.2  
OVERDOSE, ABUSE, MISUSE, MEDICATION ERRORS, AND OCCUPATIONAL 
EXPOSURE .............................................................................................................................. 58 
9.4.2.1  OVERDOSE ............................................................................................................................. 58 
9.4.2.2.  ABUSE, MISUSE, OR MEDICATION ERROR .................................................................. 58 
9.4.2.3  OCCUPATIONAL EXPOSURE ............................................................................................. 59 
9.5  
RELATIONSHIP TO STUDY DRUG ................................................................................... 59 
10  
STATISTICAL ANALYSES ................................................................................................... 59 
10.1  
STUDY DESIGN/ENDPOINTS............................................................................................ 59 
10.2  
SAMPLE SIZE ......................................................................................................................... 60 
10.3  
ANALYSIS................................................................................................................................ 60 
10.4  
EVALUATION OF TOXICITY .............................................................................................. 61 
10.5  
SPECIFIC TOXIC OUTCOMES ............................................................................................ 61 
10.6  
OTHER TOXIC OUTCOMES ................................................................................................ 61 
10.7  
FUTILITY MONITORING .................................................................................................... 62 
10.8  
EXPECTED ACCRUAL RATE, ACCRUAL DURATION, AND STUDY DURATION .. 62 
11  
ETHICS .................................................................................................................................... 62 
11.1  
PATIENT PROTECTION ..................................................................................................... 62 
11.2  
PATIENT INFORMATION ................................................................................................... 63 


 
Page 14 of 76                         
11.3  
INFORMED CONSENT ......................................................................................................... 63 
11.4  
ETHICS BOARD APPROVAL .............................................................................................. 63 
12  
DOCUMENTATION, RECORD ACCESS, AND MAINTENANCE OF STUDY 
RECORDS ................................................................................................................................ 64 
12.1  
DOCUMENTATION OF PATIENT’S PARTICIPATION ................................................. 64 
12.2  
REGULATORY REQUIREMENTS ...................................................................................... 64 
12.3  
COMPLIANCE WITH LAWS AND REGULATIONS ........................................................ 66 
12.4  
PATIENT CONFIDENTIALITY AND ACCESS TO SOURCE DATA/DOCUMENTS 
PATIENT IDENTIFICATION .............................................................................................. 66 
12.5  
CONFIDENTIALITY OF THE STUDY ............................................................................... 67 
12.6  
REGISTRATION OF CLINICAL TRIAL ............................................................................. 67 
12.7  
DATA REPORTING ............................................................................................................... 67 
12.8  
DATA MONITORING: .......................................................................................................... 67 
12.9  
MAINTENANCE OF STUDY RECORDS ............................................................................ 68 
13  
QUALITY ASSURANCES AND QUALITY CONTROL..................................................... 68 
13.1  
DATA AND SAFETY MONITORING ................................................................................. 68 
14  
ADMINISTRATIVE PROCEDURES ................................................................................... 69 
14.1  
PROTOCOL DEVIATIONS AND VIOLATIONS ............................................................... 69 
14.2  
PREMATURE DISCONTINUATION OF THE STUDY .................................................... 69 
15  
PUBLICATION POLICY ....................................................................................................... 69 
16.  
APPENDICES .......................................................................................................................... 70 
16.1  
APPENDIX 1: EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS CRITERIA ............................................................................................................... 70 
16.2  
APPENDIX 2: ......................................................................................................................... 70 
16.3  
APPENDIX 3: TEMPLATE FOR LINE LISTING OF ADVERSE EVENTS ................... 70 
16.5.  
APPENIX 5: MEMO REGARDING CROSS-REPORTED SUSAR FORM KPT CSTS . 74 
17  
REFERENCES ......................................................................................................................... 75 
 
 
 
 
 
 


 
Page 15 of 76                         
LIST OF ABBREVIATIONS  
Acronym  
Definition  
AE  
 
adverse event  
APC  
 
adenomatous polyposis coli gene/protein  
AST  
 
aspartate aminotransferase  
AUC   
area under the plasma concentration versus time curve  
BSA  
 
body surface area  
BUN   
blood urea nitrogen  
CBR   
clinical benefit rate  
Cmax   
maximum plasma concentration  
CR  
 
complete response  
CRM1   
chromosomal maintenance region 1 gene/protein (XPO1)  
CTCAE  
Common Terminology Criteria for Adverse Events  
CYP450  
cytochrome P450  
Cys  
 
cysteine  
Del  
 
deletion  
DOR   
duration of response  
DLT   
dose-limiting toxicity  
ECG  
 
electrocardiogram  
G-CSF   
granulocyte-colony stimulation factor  
GI  
 
gastrointestinal  
GLP  
 
Good Laboratory Practice  
GRP   
growth regulatory proteins (e.g., p21CIP, p27KIP)  
hERG   
human ether-à-go-go-related gene  
HNSTD  
highest non-severely toxic dose  
IC50   
50% inhibitory concentration  
ICH  
 
International Conference on Harmonization  
IND  
 
Investigational New Drug [Application]  
IFN  
 
interferon  
IκB 
  
Inhibitor of NF-κB  
IL  
 
interleukin  
IV  
 
intravenous  
kD  
 
kilodalton (molecular weight)  
LMB   
leptomycin B  
MAA   
Marketing Authorization Application  
MedDRA  
Medical Dictionary for Regulatory Activities  
MR  
 
minimal response  
MTD   
maximum tolerated dose  
NDA   
New Drug Application  
NEI  
 
nuclear export inhibitor / inhibition  
NES  
 
nuclear export sequence  
NF-κB  
nuclear factor kappa B  
NOAEL  
no observed adverse effect level  
NPC   
nuclear pore complex  
NPM   
nucleophosmin gene/protein  
NS  
 
not specified  


 
Page 16 of 76                         
Acronym  
Definition  
NSCLC  
non-small cell lung cancer  
ORR   
overall response rate  
OS  
 
overall survival  
p21  
 
cyclin dependent kinase (CDK4) inhibitor protein of 21K molecular weight  
p27  
 
cyclin dependent kinase (CDK2) inhibitor protein of 27K molecular weight  
P2RD   
phase 2 recommended dose  
p53  
 
tumor suppressor gene/protein of 53K molecular weight, TP53  
PBMCs  
peripheral blood mononuclear cells  
PD  
 
progressive disease  
PDn   
pharmacodynamics  
PI3K   
phosphoinositol triphosphate kinase  
PK  
 
pharmacokinetics  
PO  
 
per os (oral)  
PR  
 
partial response  
pRB   
retinoblastoma gene/protein  
PTEN   
phosphatase and tensin homolog 
RP2D  
Recommended phase 2 dose  
QOD   
every other day dosing  
QODx3  
every other day dosing for 3 doses (over 5 days)  
QT interval 
the interval between Q and T waves of the electrocardiogram  
QTc interval corrected QT interval  
RBC   
red blood cell  
SAE  
 
serious adverse event  
SD  
 
stable disease  
SINE   
selective inhibitor/inhibition of nuclear export  
STD10  
severely toxic dose to 10% of animals  
t1/2   
half-life  
TEAE   
treatment emergent adverse events  
TIW   
three times weekly  
TK  
 
toxicokinetics  
TSP  
 
tumor suppressor proteins  
topo2   
topoisomerase 2  
TTP  
 
time to progression  
ULN   
upper limit of normal  
Vss  
 
volume of distribution at steady state  
XPO1   
exportin 1 gene/protein (CRM1)  
 
 
 
 
 
 
 
 
 


 
Page 17 of 76                         
1  
INTRODUCTION  
1. 1  
Overview  
Over 10 major tumor suppressor pathways have evolved to prevent the development and 
progression of cancer. The majority of the tumor suppressor (TSP) and growth regulatory 
proteins (GRPs) mediating these pathways act in the cell nucleus downstream of signaling 
pathways. Accumulating data suggest that in order to maintain their malignant behavior, 
neoplastic cells must inactivate most or all of the known TSP and GRP pathways [2]. Active 
nuclear export of TSP/GRP is a very efficient and rapid means of overcoming the normal 
cell cycle and genomic instability checkpoints mediated by these proteins. Essentially, all 
known TSP/GRP utilize a single non-redundant nuclear export protein complex in order to 
exit the nucleus. Exportin 1 (XPO1), more commonly called chromosomal region 
maintenance protein 1 (CRM1), is the primary component of this export complex, and is 
overexpressed in many types of cancer [3].  
 
Selinexor is a Selective Inhibitor of Nuclear Export (SINE) that binds in a reversible manner 
and inactivates CRM1, thereby forcing the nuclear retention of key TSPs/GRPs, such as 
FOXO, p21, p27, PAR4, p53. Transient retention of TSPs/GRPs in the nucleus at high levels 
via CRM1 blockade re-activates their cell cycle checkpoint and genome surveying actions. 
This leads to the death of nearly all types of malignant cells, whereas normal cells undergo 
transient cell cycle arrest and recovery when the export block is released.  
 
1.1.1  Nuclear Export  
The majority of proteins (>40kD) and many RNAs require specific transporters in order to 
enter and exit the nucleus through the nuclear pore complex (NPC), and these transporters 
are known as importins or exportins, depending on their specific activity.  
CRM1, also called exportin 1 (XPO1), is the major nuclear export protein in the cell  
[4]. CRM1/XPO1 controls the nuclear export of key TSPs and GRPs in the cell through the 
NPC. CRM1 forms trimeric transport complexes with RanGTP and a cargo molecule, a 
process that is promoted by the Ran-binding protein RanBP3 (Figure 1). Approximately 
200 different mammalian CRM1 cargo proteins are known [5], including the vast majority 
of known TSPs and GRPs. CRM1 “recognizes” most of these cargo proteins for nuclear 
export through canonical Nuclear Export Sequences (NES), typically leucine-rich repeats in 
the cargo protein. These NES are often buried in the protein cargoes, and only unmasked 
when cells receive specific signals from their environments. CRM1 itself has a very specific 
cargo-binding groove that allows it to accommodate NES-bearing proteins from very 
diverse families without undergoing significant conformational changes [5]. In some cases, 
cargoes require adaptor proteins such as 14-3-3 in order to bind to CRM1 [6]; this binding 
is also usually under post-translational control. In addition, CRM1 mediates the export of a 
small number of RNAs [7]such as COX2 [8], though most RNAs are exported by NXF1/TAP 
[7].  
 
 
 
 
 
 


 
Page 18 of 76                         
Figure 1: CRM1 Nuclear Export Cycle  
 
 
1.1.2  Inactivation of TSP/GRP by Nuclear Export  
The regulation of TSPs and GRPs is normally tightly regulated by the cell in response to 
environmental signals. In order for cells to divide efficiently, ordered activation and 
inactivation of cell cycle control proteins is required. One of the most efficient means of 
altering a protein’s functions is simply to change the protein’s location within the cell. 
Because TSPs and GRPs mediate most of their control functions in the nucleus, the nuclear 
export of these molecules is an effective means of inactivating them. Emerging data suggest 
that tumor cells take advantage of this by increasing CRM1 levels [9, 10]. Most TSPs/GRPs 
are not good substrates for CRM1-mediated export unless they undergo post-translational 
modification. A diverse set of cargo modifications have been linked to nuclear export and 
only a few are mentioned here with specific TSPs.  
 
The tumor suppressor protein p53 is normally activated by stress and damage signals from 
the environment, including chemotherapy and radiation, and is rapidly synthesized and 
imported into the nucleus. It activates a diverse set of downstream proteins leading to cell 
cycle arrest, initiation of a ‘genome survey’, and apoptotic cell death when cell damage is 
severe [11]. Mono-ubiquitination of p53 by MDM2 (hDM2), a protein that is often 
overexpressed in neoplastic cells, renders it an excellent substrate for CRM1, and it is 
exported from the nucleus to be degraded in the cytoplasm by the proteasome [11]. Most 
tumors harboring wild type p53 (p53wt) show overexpression of MDM2, indicating that 
p53 inactivation is probably necessary for the neoplastic phenotype. In cells that are 
defective (deleted or mutant on both p53 alleles), the related TSP p73 can be engaged [12]. 
CRM1 blockade forces p53 and p73 nuclear retention and even in cells with a single p53wt 
allele there will be activation of downstream cell cycle regulatory and apoptotic functions 
[3].  
 


 
Page 19 of 76                         
A commonly activated pathway across human cancers is the PI3K/AKT/mTOR pathway [6, 
13]. Activation is accomplished by a number of mechanisms including loss of the TSP PTEN 
(phosphatase and tensin homolog) or activating mutations in PI3K or AKT. One of the major 
downstream effects of activation of this pathway is the phosphorylation and subsequent 
nuclear export of TSPs known as forkhead-box (FKH) proteins. The O-subfamily of FKH 
proteins, called FOXO, particularly FOXO3, are potent cell cycle regulators with clear TSP 
function [13, 14]. CRM1 blockade forces FOXO and p53 nuclear retention and counteracts 
an activated PI3K/AKT pathway that is independent of the upstream aberration in the 
pathway.  
 
The IκB kinase that is activated in inflammation, stress, and in several metastatic cancers, 
phosphorylates the inhibitor (I-κB) of nuclear factor κB (NF-κB)[15, 16]. IKK also 
phosphorylates FOXO, leading to its nuclear export[17]. Phosphorylated I-κB is a good 
substrate for CRM1, and is rapidly exported from the nucleus and degraded in the 
cytoplasm. Blockade of CRM1 prevents export of I-κB from the nucleus, neutralizes NF-κB 
activity, and reduces inflammation and NF-κB mediated metastasis [16].  
 
CRM1 also regulates the nuclear export of nucleosphosmin (NPM1) which is mutated in up 
to 35% of AML [18]. The mutant forms of NPM1, called NPM1c, create a novel CRM1-
binding site (NES) and lead to the inappropriate nuclear export of NPM1 and localization to 
the cytoplasm. Cytoplasmic localization of NPM1 appears to be sufficient to convert it from 
a tumor suppressor to an oncogene [19]. Blockade of CRM1 leads to nuclear accumulation 
of NPM1 – even in NPM1 mutant AML (YM Chuk, Personal Communication) – and induces 
rapid apoptosis in these cells (DP Lane, Personal Communication, R Garzon, Unpublished 
Data).  
 
CRM1 inhibition upregulates a number of TSPs/GRPs in addition to those discussed here. 
CRM1 appears to stimulate at least one counteracting pathway for major growth and tumor 
stimulating pathways across different cancers. This may explain the broad activity of CRM1 
inhibitors in vitro and in animal in vivo models. By activating a genome survey, TSPs/GRPs 
can ‘distinguish’ between cancerous and normal cells, inducing apoptosis in the former and 
maintaining cell cycle arrest (until the CRM1 export block is released) in the latter (Figure 
2):  


 
Page 20 of 76                         
 
Figure 2: KPT-SINE (CRM1 Inhibitors) Induce Distinct Outcomes in Normal and Malignant 
Cells.  
 
1.1.3 CRM1 in Human Cancer 
As mentioned earlier, human cancers frequently overexpress CRM1 and/or show 
inappropriate cytoplasmic expression of TSPs/GRPs, suggesting a major dysfunctional 
nucleocytoplasmic transport system.  Overexpression of CRM1 has been reported in 
ovarian, pancreatic, hepatocellular, neuroblastoma, cervical, and other tumors, and often 
correlated with poorer prognosis [3]. Studies have similarly demonstrated increased CRM1 
levels in various hematologic malignancies compared with their normal cell counterparts. 
Overexpression of CRM1 will drive TSPs/GRPs out of the nucleus and extinguish their 
growth and survival regulatory properties.  Inhibition of CRM1 forces the nuclear 
expression of TSPs/GRPs and induces cell cycle arrest through activation of multiple 
pathways. Normal cells recover from the arrest, but neoplastic cells initiate apoptosis (or 
necrosis), likely because TSP/GRP induce a genome survey [11, 20, 21]. 
 
1.1.4  Selinexor  
Selinexor is an oral, first in class, slowly reversible, potent and Selective Inhibitor of 
Nuclear Export (SINE) that specifically blocks chromosomal regional maintenance 1 
(CRM1). Selinexor restores many of the tumor suppressor (TSP) and growth regulatory 
(GRP) proteins to the nucleus where they can carry out their normal functions. It is 
selectively cytotoxic for cells with genomic damage seen in tumor cells, both in vitro and in 
vivo. All cell types exposed to SINE in vitro undergo G1/S±G2/M cell cycle arrest, followed 
by a ‘genomic fidelity’ review, and cells with damaged genomes are induced to undergo 
apoptosis. Normal cells, with an intact genome, remain in transient, reversible cell cycle 
arrest until the export block is relieved. Selinexor and other SINE compounds are not 
intrinsically cytotoxic; rather, they can restore the highly effective tumor suppressing 
pathways that lead to selective elimination of genomically damaged (i.e., neoplastic) cells. 
Tumors of hematopoietic lineage are particularly susceptible to induction of apoptosis by 
CRM1 inhibition; normal hematopoietic cells and their functions are largely spared.  
 


 
Page 21 of 76                         
Selinexor is supplied as 20 mg tablets in blister packs for oral administration. Each blister 
pack will contain 12 tablets. All packages will be shipped as open-label stock (i.e., it will not 
be labeled for a specific subject/patient). 
 
In vitro experiments with continuous (~72 hour) exposure to selinexor demonstrated 
potent pro-apoptotic activity across a broad panel of tumor-derived cell lines and patient  
samples in culture, including multiply resistant cancers, with the majority of IC50s for  
cytotoxicity <800 nM and most hematologic tumor lines having IC50s of 20-400 nM for  
selinexor. In contrast, normal cells typically underwent (or remained in) cell cycle arrest 
but were resistant to apoptosis-induction; cytotoxicity IC50s were typically >5 µM. As noted 
above, selinexor had little effect on normal (nonmalignant) lymphocytes or other  
non-transformed cells, which correlated with the low incidence in animals of the typical 
side effects seen with most anti-cancer therapies such as significant myelosuppression,  
alopecia, mucositis, and other gastrointestinal dysfunction.  
 
Selinexor, as well as other SINE compounds, has been tested for efficacy studies in mice and 
dogs and for toxicology in rats and monkeys. The dosing regimen was every other day x 3 
each week (QoDx3/wk); anti-tumor activity has also been shown with twice weekly dosing. 
Efficacy was demonstrated at doses of 15-60 mg/m2 (5-20 mg/kg) in mouse models of 
myeloma, mantle cell lymphoma (MCL), and T-cell acute lymphocytic leukemia (T-ALL) 
xenografts. Moreover, efficacy including significant survival advantages was demonstrated 
in acute myeloid leukemia (AML) [MV4-11 (FLT3-ITD)] and chronic lymphocytic leukemia 
(CLL) (TCL-1) leukemografts. Efficacy was also demonstrated in solid tumor xenografts 
including prostate, breast, liver, glioblastoma, and kidney and colon cancers. In an attempt 
to predict activity and tolerability in larger animals with spontaneous tumors, KPT-276 and 
KPT-335 that are closely related to selinexor, have been given orally to several dogs with 
various cancers in pilot studies. Preliminary evidence of antitumor activity with acceptable 
tolerability has been obtained (e.g., in a De Novo CHOP-resistant diffuse large B cell non-
Hodgkin's lymphoma (DLBCL-NHL) in dogs). Reduced food intake accompanied by weight 
loss was observed; food supplementation can largely overcome this and dosing has been 
maintained for up to 6 months in dogs with cancer.  
 
Projected antitumor doses are in the 15-45 mg/m2 range based on studies in mice and  
dogs; this corresponds to a minimal area under the curve (AUC) value of ~5,000  
ng•hr/mL in mice and lower levels in dogs. Based on pharmacokinetic studies in  
multiple nonclinical species (mice, rats, dogs, monkeys), it is anticipated that an AUC  
value of >5,000 ng•hr/mL will also be achieved at doses of 15-45 mg/m2 in humans.  
These doses were generally well tolerated in rats and monkeys, with the primary adverse 
effects observed being reduced food intake and consequent weight loss. At projected 
antitumor doses of SINE compounds (=45 mg/m2), vomiting is very uncommon in monkeys 
or dogs, and diarrhea quite rare in any species. Thus, the etiology of the reduced food 
intake and weight loss is under further investigation.  
 
Selinexor has been studied at 10 µM in an in vitro selectivity assay including receptors, 
kinases, and cysteine proteases (including caspases and matrix metalloproteinases), with 
none of the targets significantly affected by selinexor except for Monoamine Oxidase B 


 
Page 22 of 76                         
(MAO-B; binding IC50 of >5 µM and minimal functional activity). Minimal inhibition of 
human Ether-à-go-go Related Gene (hERG) tail current density was displayed by selinexor 
(IC50 >25 µM in the absence of serum protein), which is substantially below the expected 
circulating levels of selinexor. In the pivotal, GLP, 4-week monkey study, ECGs were 
recorded on all animals during the pretest period, and on all animals assigned to the study 
during the final dosing cycle (1-2 hours post dose on Day 21) and during the last week of 
the recovery period on Day 39. There was no ECG evidence of a direct or indirect effect of 
selinexor on the morphology and intervals of the ECG at up to 36 mg/m2 (3 mg/kg). Based 
on these results, QT prolongation or other cardiac effect does not appear to be a safety 
concern for selinexor. A GLP, rat neurofunctional study (Irwin test) has also been 
performed at dose levels of 12, 60, or 300 mg/m2 (2, 10, and 50 mg/kg). No behavioral 
changes were observed at all doses tested. In addition, no central nervous system (CNS)-
related adverse side effects were observed in the GLP, rat and monkey 4-cycle toxicity 
studies.  
 
Preclinical PK parameters were assessed in three species: mouse (CD1), rat (Sprague- 
Dawley), and monkey (cynomolgus). While PK studies were limited to male animals for all 
three species, TK evaluations were conducted in both sexes for rats and monkeys as part of 
the selinexor toxicology studies, and no consistent sex-related differences were observed in 
either species. No accumulation was observed in any of the multi-dose toxicology studies 
with an every other day dosing regimen for selinexor. Overall, systemic exposure was 
generally dose-proportional in all TK studies that involved multiple dose levels. Higher 
Cmax and earlier Tmax values were observed in monkeys that were fasted versus fed prior 
to dosing. Systemic exposure (AUClast) was not affected by the feeding status in monkeys. 
PO dosing of selinexor drug product in gelatin capsules was also investigated in monkeys 
and rats. Systemic exposure to selinexor achieved with capsules was comparable to that 
achieved with oral suspension dosing, with lower Cmax and later Tmax values observed 
with capsules. Oral bioavailability (F%) of selinexor was remarkably consistent among the 
three species, with average values of 66.5%, 61.2%, and 67.5% in mice, rats, and monkeys, 
respectively.  
 
Selinexor underwent minimal metabolism in vitro by liver microsomes from humans, mice, 
rats, dogs, or monkeys, as well as minimal metabolism by the human liver S9 fraction. In 
protein binding studies, selinexor demonstrated high protein binding to mouse, rat, 
monkey, and human plasma proteins with 95%, 96.3%, 96.2%, and 94.1% binding, 
respectively and only moderate binding (54.2%) to dog plasma proteins. KPT330 showed 
no significant in vitro interactions with any of the cytochrome P450 (CYP450) enzymes 
(i.e., IC50 >10 µM), except for one substrate of CYP3A4 (testosterone) which displayed an 
IC50 of 4.7 µM (the IC50 for midazolam, the other CYP3A4 substrate, was >10 µM). 
Conjugation of glutathione (GSH) to selinexor is the major product of metabolism both in 
vitro and in vivo, and led to inactive metabolites including N-acetylcysteinyl- and cysteinyl-
derivatives which were found in the urine of monkeys. No induction of CYP450 activity was 
observed for CYP1A2 or CYP3A4.  
 
Sprague-Dawley rats and cynomolgus monkeys were chosen as the toxicology species for 
the selinexor nonclinical safety program. In both species, the primary effects of KPT-330 


 
Page 23 of 76                         
were dose-dependent reductions in food intake and body weight (or reductions in body 
weight gain), with minimal clinical symptoms (no or mild non-bloody diarrhea), associated 
primarily with gastrointestinal atrophy. Similar effects are observed in mice  
and dogs given selinexor and related SINE compounds. Increases in amylase and/or lipase, 
ALT (with less effects on AST), CK, and LDH were observed, but generally were not 
indicative of organ failure across species. Dose-dependent lymphocyte depletion in 
lymphoid organs was observed, with alterations in blood hematology parameters generally 
considered to be clinically insignificant. At high repeated doses of selinexor associated with 
marked weight loss, there were changes in cerebellar granular layer of neurons in both rats 
(=300 mg/m2) and monkeys (=72 mg/m2), but only monkeys showed any CNS symptoms. 
In summary, dose limiting toxicity (DLT)/mortality in both rats and monkeys is related 
primarily to marked weight loss with atrophy of the gastrointestinal (GI) tract and 
noncritical effects on other major organs.  
 
In rats, DLT was related to subacute progressive weight loss and GI tract atrophy across all 
of the studies. There have been no adverse CNS clinical signs observed in any of the rat 
studies. Acute single PO gavage doses of selinexor at up to 3,000 mg/m2 (500 mg/kg) 
showed no mortality at up to 24 hours post-dose. There were dose-dependent reductions 
in food and water intake and body weight, and non-bloody diarrhea was observed. 
Clinically significant changes in serum chemistry (LFTs, CK, LDH) were observed at the 
highest dose tested, with no clinically significant changes in hematological or coagulation 
parameters. Gross necropsy showed thinning of the gastrointestinal wall. In a non-GLP, 2-
week study, selinexor was administered on Days 1, 3, 5, 8, 10, and 12 by PO gavage, similar 
to the proposed clinical regimen. Mortality was observed at the highest dose, 300 mg/m2 
(50 mg/kg), after 3-4 doses, and was characterized by a marked reduction in food intake 
with ~30% weight loss; death was attributed to atrophy, ulceration, and erosion in the GI 
tract (with essentially no diarrhea).  
 
Alterations in clinical pathology included moderate LFT, CK, and LDH increases, with 
moderate reductions in most hematological parameters. Necrosis in the granular layer of 
the cerebellum was observed only at the high dose, 300 mg/m2 (50 mg/kg), and there were 
no clinical signs attributable to this finding; no recovery group was planned in this study so 
reversibility was not assessable. The 60 mg/m2 (10 mg/kg) dose level showed  
~10% body weight loss after two weeks, reduced food consumption, and modest adverse 
effects with mucosal atrophy in the colon and crypt hyperplasia in the duodenum; this was 
considered the MTD. In general, selinexor at 12 mg/m2 (2 mg/kg) was relatively well 
tolerated over 2 weeks.  
 
The rat GLP, 4-cycle study (dosing QoDx3 each week; 12 doses in 28 days) confirmed that 
the DLT in rats was a reduction in food intake and a corresponding reduction in body 
weight gain, as compared to control animals. Mortality was observed in 8 males (1 at 8.5 
mg/kg, 7 at 15 mg/kg) and 4 females (15 mg/kg) with tests with bone marrow, 
gastrointestinal, and lymphoid findings contributing to death. Gastrointestinal, lymphoid, 
and bone marrow microscopic changes were considered adverse in the 5 and 15 mg/kg 
group males and 15 mg/kg group females and contributed to body weight loss and 
debilitation. Intestinal, pancreatic, gland (salivary, lacrimal, Harderian), bone, and bone 


 
Page 24 of 76                         
marrow lesions were not observed at the recovery necropsy. Single cell necrosis was 
observed mainly in the 5 and 15 mg/kg groups in multiple organs (glands, pancreas, 
intestine, urinary bladder, and ureters) and was accompanied by crypt hyperplasia in the 
intestine of males and females and transitional cell hyperplasia in the urinary bladder of 
males. Hyperplasia was considered reactive indicating that normal cells can recover under 
treatment. Minimal to mild cardiomyocyte necrosis and degeneration with interstitial cell 
hypertrophy was found only at the high dose in primary necropsy. Lower testes and 
epididymis weight reductions were noted in males at all dose groups in primary and 
recovery necropsy. Seminiferous tubule degeneration and/or atrophy and epididymal 
hypospermia also occurred during treatment and recovery periods. Lower ovary/oviduct 
and uterus/cervix weight parameters were noted in females at all dose groups at primary 
and recovery necropsy and were associated with decreased ovarian follicles. Based on 
these findings the STD10, was considered to be ≥30 mg/m2.  
 
Monkeys showed similar DLTs as observed in rats, namely dose-dependent weight loss 
associated with reduced food intake that were both rapidly reversible. A pilot non-GLP 
study included two male monkeys administered selinexor at 90 mg/m2 (7.5 mg/kg) on 
Days 1, 3, 5, and 8. Adverse clinical signs were observed in both animals starting on Day 2 
and included non-bloody loose feces and occasional vomiting. There was a marked 
decrease in body weight and food consumption during the treatment period. Starting on 
Day 7, both animals displayed involuntary swinging along with uncoordinated movements. 
One animal was found dead on Day 11 and the cause of death was attributed to marked 
weight loss. In a non-GLP, 2-week study, selinexor was given at doses up to 72 mg/m2 (6 
mg/kg) on Days 1, 3, and 5 each week, with a 2-week recovery period. On Days 9-11, 3 of 4 
males and 3 of 4 females in the high dose (72 mg/m2) group were sacrificed moribund. At 
72 mg/m2, adverse clinical signs included soft feces (without diarrhea), decreased 
defecation, impaired muscle coordination, and intermittent to continuous convulsions 
without loss of consciousness, with weight loss of ~8.5% by Day 7. For the surviving high-
dose animals (1 male/1 female), effects on body weights were fully reversible by the end of 
the 2-week recovery period and there were no abnormal muscle symptoms. In moribund 
animals, clinically significant laboratory changes were not present. In the 72 mg/m2 (6 
mg/kg) group only, test-article related microscopic findings (mild to moderate) were 
observed in the granular cell layer of the cerebellum, the inner nuclear layer of the eye 
(similar morphology to cerebellar granular cells), the pancreatic parenchymal cells, gastric 
and duodenal atrophy and gastric ulceration, bone marrow, mesenteric lymph node, 
salivary glands and thymus, with severity ranging from minimal to moderate. Diffuse 
atrophy throughout the gastrointestinal tract was noted. Death was attributed to reduced 
food intake and weight loss, possibly related to the GI and to a lesser extent, the pancreatic 
findings. At 30 mg/m2 (2.5 mg/kg) after two weeks of dosing, there were no clinically 
significant laboratory changes. Small thyroid glands and male sex organs were noted on 
gross pathology. Mild changes were observed on histopathology and, except for thymic 
atrophy, all were completely reversible. Body weight losses were =5% at 12 mg/m2 (1 
mg/kg) and there were no major pathological findings; reduced sex organ weights were 
completely reversible after 2 weeks. Based on this study, 30 mg/m2 was considered the 
MTD for selinexor administered QoDx3 weekly to monkeys for 2 consecutive weeks.  
 


 
Page 25 of 76                         
In the monkey GLP 4-week study (dosing QoDx3 each week; 12 doses in 28 days), dose 
levels of 9, 18 or 36 mg/m2 (0.75, 1.5, and 3 mg/kg) were tested. One female died at Day  
15 due to acute thoracic cavity inflammation, likely secondary to gavage-related injury, 
unrelated to the test article. One female was euthanized on Day 26, apparently related to 
rapid weight loss. The DLT in monkeys, as in rats, included body weight loss accompanied 
by reduced food intake. There were no adverse CNS clinical signs in this study at any dose 
level. Minimal diarrhea or vomiting was observed. Animals that had >7.5% body weight 
loss were given Ensure® and additional food supplements during the study. The body 
weights of the recovery group animals returned to approximately baseline levels by the 
end of the recovery period (two weeks) and substantial recovery had already occurred by 
4-5 days after dosing. Macroscopic findings following early or scheduled sacrifice and 
recovery necropsy were minimal and included discolored and distended GI tract for both 
sexes, decreased size of spleen, thyroid gland and thymus, adhesion of lungs and decreased 
size of seminal vesicle for males, mainly in the 36 mg/m2 group animals. There were no 
significant alterations in clinical pathology except for lipase elevations (with minimal (<2 
fold) changes in amylase levels) in animals in the high dose group. Selinexor related 
microscopic findings included: thymic atrophy at = 9 mg/m2 (0.75 mg/kg); minimal to mild 
single cell pancreatic necrosis, bone marrow depletion and salivary gland atrophy at = 1.5 
mg/kg/day; and, mild pancreatic acinar atrophy, minimal kidney nephrosis (without 
creatinine increases; not adverse), minimal single cell necrosis of the testes (males), and 
minimal to moderate lymphoid depletion of lymph nodes, spleen, and Peyer’s patches at 3 
mg/kg/day. Thymus atrophy persisted in a dose-related manner following the 2-week 
recovery period, but kidney nephrosis, testicular necrosis, bone marrow depletion, 
pancreatic acinar atrophy, and lymphoid depletion of the spleen, lymph nodes, and Peyer’s 
patches showed complete recovery. In the 36 mg/m2 (3 mg/kg) group, pancreatic necrosis 
and salivary gland atrophy showed partial recovery, being minimal and present in 1 female 
each at the recovery necropsy. Based on these data, the highest non-severely toxic dose 
(HNSTD) in monkeys was 18 mg/m2 (1.5 mg/kg) and the NOAEL was 9 mg/m2.  
 
ICH guidance for starting dose of oncology drugs in humans uses the rat STD10÷10 or the 
monkey (if it is the more appropriate species) HNSTD÷6. In the selinexor GLP studies, the 
rat STD10÷10 is 30mg/m2 ÷10 = 3mg/m2, and the monkey HNSTD÷6 is  
18mg/m2 ÷6 = 3mg/m2. Therefore, human clinical trials were started with 3 mg/m2.  
 
Selinexor is currently under clinical investigation for the treatment of patients with 
advanced hematologic and advanced solid malignancies.  Three Phase 1 studies (KCP-330-
001, KCP-330-002, and KCP-330-003 with NCT numbers of NCT01607905, NCT01607892, 
NCT01896505) and six Phase 2 studies (KCP-330-004, KCP-330-005, KCP-330-007 and 
KCP-330-008) are currently ongoing or in process of being initiated.   In these trials, a dose 
range of 3-85 mg/m2 was explored and 65 mg/m2 was determined to be the recommended 
phase II dose for single agent selinexor.  Weekly selinexor dosing were designed based on 
pharmacodynamic markers showing that the biological effects of selinexor have prolonged 
durations. Multiple clinical trials have employed weekly dosing regimens in hematological 
and solid malignancies and have demonstrated both efficacy and tolerability. Maximum 
selinexor serum levels of 1-2 μM can typically be achieved in cancer patients following 
selinexor oral doses of 40-100 mg (~25-60 mg/m2). An analysis of existing PK data from 


 
Page 26 of 76                         
phase 1 studies KCP-330-001 and KCP-330-002 supports the use of fixed, rather than body 
surface area (BSA) based dosing. In the combination setting, selinexor is typically 
recommended at a starting dose of 40-60 mg weekly across multiple indications and 
responses were observed in combination setting with selinexor doses as low as 20 mg flat.  
Preliminary safety information available for 1175 patients indicated that selinexor is 
generally well tolerated with the most frequent selinexor-related treatment-emergent 
adverse events including low-grade nausea, fatigue, anorexia, thrombocytopenia, and 
vomiting that were manageable with standard supportive care.  
 
1.2  
Rationale for the Study  
Pre-clinical in vitro and in vivo data have shown that both hematologic and solid tumor cells 
are susceptible to single-agent cytotoxicity by selinexor, consistent with its restoration of 
multiple tumor suppressor and growth regulatory pathways leading to the death of cancer 
cells. The major adverse event across all tested species to date (mice, rats, dogs, monkeys) 
is reversible weight reduction accompanied by reduced food intake without significant 
vomiting or diarrhea. Based on these observations, selinexor is currently being developed 
in both hematologic and solid tumor indications. Given the novel mechanism of action, the 
risk benefit assessment favors further development of selinexor. Further information about 
the preclinical pharmacology and toxicology of selinexor is presented in the Investigator’s 
Brochure.  
 
Pancreatic cancer is one of the most fatal malignancies. Gemcitabine alone has been the 
standard of treatment for pancreatic cancer until recently and has been associated with a 
median survival of approximately six months. The addition of nab-paclitaxel to gemcitabine 
improved the survival outcome to 8.5 months as presented in the annual meeting of ASCO 
2013[22]. FOLFIRINOX has prolonged the median overall survival to approximately 11 
months [23], and is the standard first line therapy for patients who are able to tolerate this 
chemotherapy. Significant number of patients who progress on FOLFIRINOX will not 
tolerate the combination of gemcitabine and nab-paclitaxel as a next line of treatment and 
they go on to receive gemcitabine as single agent. This is especially a setback for patients 
with good performance status who do not qualify for the use of nab-paclitaxel due to 
baseline neuropathy or acquired neuropathy post FOLFIRINOX regimen. Gemcitabine as 
single agent in the second line setting would lead to a survival of around 5.6 months[24-
26]. New treatments aiming to improve the effectiveness of treatment in second or third 
line is therefore needed. Our preliminary data show that pancreatic cancer cell lines in vitro 
are susceptible to the cytotoxicity of selinexor. Our collaborators in association with 
Karyopharm Therapeutics have demonstrated synergy between selinexor and gemcitabine 
in pancreatic cancer cell lines and animal xenograft models as well[27]. Mechanistically, 
these studies demonstrated that KPT-330 (selinexor) and gemcitabine promoted apoptosis, 
induced p27, depleted survivin, and inhibited accumulation of DNA repair proteins. The 
Clonogenic assay results from our laboratory demonstrate long term colony suppressing 
effects of selinexor-gemcitabine combination compared to single agent treatment (Fig 
3A&B). Additionally, in agreement with the published findings, we also observe superior 
inhibition of tumor growth in the combination treatment of selinexor (used at sub-optimal 
doses) and gemcitabine (Fig3C)  
 


 
Page 27 of 76                         
 
 
Figure 3. Nuclear export inhibitor KPT-330 (selinexor) enhances the activity of gemcitabine 
in pancreatic ductal adenocarcinoma cellular and xenograft model. Detailed synergy 
analysis between selinexor and gemcitabine in pancreatic cancer models in vitro and in 
vivo has been published by Karyopharm and our collaborator Dr. Amit Mahipal (PMCID: 
PMC4577050 DOI: 10.1158/1535-7163.MCT-15-0104) [A&B] MiaPaCa-2 and L3.6pl cells 
were grown at a density of 50,000 cells per well in six well plates and exposed for 72hrs to 
either vehicle, KPT-330 (300 nM); gemcitabine (90 nM) or the combination of KPT-330 
(300 nM)+Gemcitabine (90 nM). At the end of the treatment period, the cells were 
trypsinized and 1000 cells were re-plated in 100 mm petri dishes for additional three 
weeks. At the end of the 3-week period, the plates were stained with Comassie Blue. The 
stained colonies were photographed under an inverted light microscope. Colonies were 
counted manually under inverted light microscope. [C] AsPC1 PDAC cell line was grown to 
form tumors at the subcutaneous site in ICR-SCID mice. The mice were administered 
selinexor (KPT-330) three times a week for three weeks at 7.5 mg/kg (sub maximum 
tolerated dose) in the absence or presence of gemcitabine (Gemzar) 50 mg/kg twice a week 
for two weeks. 
 
1.2.1  Rationale for Starting Dose and Dosing Schedule  
From the ongoing human studies, selinexor as single agent at the dose of 65 mg/m2 by 
mouth twice a week has been found to be safe and well tolerated. The common adverse 
events at this dose level have been reversible weight loss, anorexia and thrombocytopenia. 
At dose level 1, we kept gemcitabine and nab-paclitaxel at standard doses. For the safety of 
patients, we started selinexor at dose as low as 60 mg flat dose on Mondays and 
Wednesdays every week in combination with weekly standard dose of gemcitabine and 
nab-paclitaxel.  Because of the possible selinexor-related toxicity of mood changes that 
required hospitalization of two patients in cohort 1, we decided to stay at the same dose 
level but give the selinexor on Day 1 only and eliminated the Day 3 dose. We confirmed that 
there was no DLT in this cohort..  
 
Based on review of toxicity profile of the phase I cohort of selinexor, gemcitabine and 
nabpaclitaxel we came to the conclusion that the regimen’s side effects were related to the 
gemcitabine and nab-paclitaxel rather than the selinexor per se. We also had the 
experience of one patient who had an outstanding response to therapy that was prolonged 
to close to three times the expected time to disease progression and who was treated on 


 
Page 28 of 76                         
lower dose of gemcitabine plus selinexor and without nab-paclitaxel for the most of his 
treatment course. Based also on the safety data provided by Karyopharm regarding the 80 
mg dose of selinexor we felt it is appropriate to move forward in the phase II to do single 
agent gemcitabine and selinexor at dose level of 80 mg flat dose given weekly. 
 
1.3  
Study Population and Sample Size  
Phase Ib: Up to 12 patients with untreated metastatic pancreatic cancer will be enrolled 
[COMPLETED]. 
 
Phase II: In this portion of the study, 44 patients will be enrolled. The first 14 patients with 
liver metastases accessible for core biopsies will be randomized into two groups, group 1 
and group 2. The remaining 30 patients will be allocated to group 3 (no biopsy group). If 
any of the first 14 patients with liver metastates consented to enroll in the study but 
refused to refused to consider the C1D3 biopsy then those subjects will be allocated to 
Group 3 (no biopsy group). Altogether, 44 patients will be enrolled in phase II. The study 
will be conducted at multiple sites across the US, including Karmanos Cancer Institute,  
Stony Brook University Cancer Center (Long Island, NY), Froedtert and the Medical College 
of Wisconsin (Milwaukee, WI) and The University of Kansas Medical Center (Westwood, 
KS). 
 
1.4  
Pharmacodynamic (PDn) Biomarkers  
Exposure of mixed white blood cells ex vivo from humans and other species to selinexor 
leads to 2-5 fold induction of CRM1 mRNA using quantitative reverse transcription 
polymerase chain reaction (qRT-PCR). This induction of CRM1 is the expected cellular 
response to increase CRM1 synthesis following inhibition of CRM1 protein function. In 
addition, p53 mRNA and mRNA from the p53-dependent gene monocyte inhibitory 
cytokine 1 (MIC1) also increase following selinexor exposure. In the phase II part of the 
study, patients will have a biopsy of liver lesions pre- (fixed paraffin embedded archival 
tissue) and post treatments. We will study the expression of p27, FOXO, PAR4 and IκB on 
liver tissues before and after treatment.  
 
2  
OBJECTIVES  
2.1  
Primary Objectives  
1. 
Phase I: To determine the recommended phase 2 dose (RP2D) of gemcitabine, nab-
paclitaxel and selinexor for untreated metastatic pancreatic cancer [COMPLETED]. 
2.  
Phase I: To determine the safety profile of gemcitabine, nab-paclitaxel, and selinexor 
[COMPLETED].  
3.  
Phase II:  To test whether the combination of gemcitabine and selinexor improves 
the median overall survival of patients with metastatic pancreatic cancer who have 
failed frontline non-gemcitabine containing regimens, beyond 5.6 months (median 
overall survival of patients receiving gemcitabine only based on historical data; J 
Clin Oncol. 1997 Jun;15(6):2403-13) 
 
2.2  
Secondary Objectives  
1.  
To determine objective response rate to the combination of gemcitabine and 
selinexor using RECIST criteria 


 
Page 29 of 76                         
2.  
To assess safety of selinexor in combination with gemcitabinein phase II portion of 
the study 
3. 
To determine progression free survival (PFS) in patients treated with gemcitabine 
and selinexor 
4. 
To determine the influence of selinexor and gemcitabine on the nuclear expression 
and localization of tumor suppressor gene proteins 
 
 3  
PATIENT SELECTION  
This trial will be conducted in compliance with the protocol, GCP, and applicable 
regulations. Any questions about eligibility criteria must be addressed prior to patient 
registration.  
 
3.1  
Inclusion Criteria  
Patients must meet all of the following inclusion criteria to be eligible to enroll in this 
study.  
1.  
Written informed consent in accordance with federal, local, and institutional 
guidelines  
2.  
Age >18 years  
3.  
Patients with metastatic pancreatic adenocarcinoma who have failed one non-
gemcitabine based regimen for metastatic disease. 
4.  
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (see 
Appendix 1)  
5.  
Adequate hematopoietic function: absolute neutrophil count (ANC) ≥1500/mm3 and 
platelet count ≥100,000/mm3  
6.  
Adequate hepatic function: bilirubin <2 times the upper limit of normal (ULN) 
(except patients with Gilbert’s syndrome who must have a total bilirubin of < 3 
times ULN) and ALT or AST <2.5 times ULN  
7.  
Adequate renal function: serum creatinine < 1.5 mg/dL 
8.  
Serum albumin > 3.0 g/dL 
9. 
Effective contraception: Female patients of childbearing potential must agree to use 
highly effective methods of contraception and have a negative serum pregnancy test 
at screening. Male patients must use an effective barrier method of contraception if 
sexually active with a female of childbearing potential. Acceptable methods of 
contraception are condoms with contraceptive foam, oral, implantable or injectable 
contraceptives, contraceptive patch, intrauterine device, diaphragm with 
spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. 
For both male and female patients, highly effective methods of contraception must 
be used throughout the study and for three months following the last dose.  
10.  Patients with history of previously treated other malignancies who do not have any 
evidence of recurrent disease for the last three years are allowed 
 
3.2  
Exclusion Criteria  
Patients meeting any of the following exclusion criteria are not eligible to enroll in this 
study.  
1.  
Patients who are pregnant or breast feeding  


 
Page 30 of 76                         
2.  
Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤3 
weeks prior to cycle 1 day 1. Treatment with mitomycin C or radio-immunotherapy 
must be completed within 6 weeks prior to cycle 1 day 1. 
3.  
Major surgery within 3 weeks of cycle 1 day 1 
4.  
Prior therapy with gemcitabine based regimen for metastatic disease or 
gemcitabine based adjuvant therapy completed less than twelve months from 
enrollment 
5.  
Unstable cardiovascular function that includes and may not be limited to:   
o 
symptomatic myocardial ischemia, or  
o 
uncontrolled clinically significant conduction abnormalities (e.g., ventricular 
tachycardia on antiarrhythmics are excluded and 1st degree AV block or 
asymptomatic LAFB/RBBB will not be excluded), or  
o 
congestive heart failure (CHF) of NYHA Class ≥3, or   
o 
myocardial infarction (MI) within 3 months of cycle 1 day 1  
6.  
Uncontrolled active infection requiring parenteral antibiotics, antivirals, or 
antifungals within one week prior to first dose  
7.  
Known to be HIV seropositive who are on anti-HIV drugs because of the unknown 
interactions between these drugs and the study agents 
8.  
Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or 
HBsAg (HBV surface antigen)  
9.  
Patients with active CNS malignancy. Asymptomatic small lesions are not 
considered active. Treated lesions may be considered inactive if they are stable for 
at least 3 months.  
10.  Patients with significantly diseased or obstructed gastrointestinal tract or 
uncontrolled vomiting or diarrhea   
11.  History of seizures, movement disorders, or cerebrovascular accident within the 
past 5 years prior to cycle 1 day 1  
12.  Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased 
visual acuity based on physician’s assessment   
13.  Serious psychiatric illness (e.g., depression, psychosis) or medical conditions that 
could interfere with treatment  
14.  Participation in an investigational anti-cancer study within 3 weeks prior to cycle 1 
day 1  
15.  Concurrent therapy with approved or investigational anticancer therapeutics other 
that what is stipulated by the protocol 
16. Clinically significant ascites 
17. Major surgery within 3 weeks of C1D1 
 
3.3  
Patient Registration  
All patients will be screened by the principal investigator or co-investigators prior to entry 
into this study. An explanation of the study, discussion of the expected side effects, 
alternative treatment options, benefits versus risks, and full disclosure of the “informed 
consent” document will take place. Consented and eligible patients will be registered into 
the study.  
 
The contact information for registrations is indicated below:  


 
Page 31 of 76                         
Ms. Taylor Brewer 
Clinical Trials Office  
Study Coordinator  
E mail:  brewert@karmanos.org  
Tel# 313-576-8526 
Fax# 313-576-8368 
 
Allison Wolgast 
Karmanos Cancer Institute 
4100 John R-MM03CT 
Detroit, MI 48201 
Office: (313) 576-8994 
Fax: (313) 576-8368 
Email: wolgasta@karmanos.org 
 
Registration will be done through Karmanos Cancer Institute, Clinical Trial Office utilizing 
OnCore, and the Clinical Trial Management System.   A unique set of patient ID numbers 
will be assigned to each patient, which should be used on all documentation and 
correspondence. Prior to registering a patient, each institution must have submitted all 
necessary regulatory documentation to Karmanos Cancer Institute and received a Local 
Activation Letter. Teleconferences will be held with all participating sites on monthly basis 
during the Phase II part of the study to verify potential patients at each site, accrual status, 
and toxicity reports. Available slots will be announced through email by Karmanos Cancer 
Institute.  
 
No patient can receive protocol treatment until registration has taken place. Registration of 
a patient can only occur if confirmation of a slot has been provided in writing by Karmanos 
Cancer Institute. All eligibility criteria must be met at the time of registration. There will be 
no exceptions or waivers from eligibility.  Any questions should be addressed with 
Karmanos Cancer Institute prior to registration. The eligibility checklist must be 
completed, and signed by the investigator, who must be listed on the FDA 1572, prior to 
registration. Sites will email the signed, completed eligibility checklist and pertinent 
registration documents to Karmanos Cancer Institute’s Study Coordinator, Allison Wolgast 
at wolgasta@karmanos.org.  If email is not possible, the signed, completed eligibility 
documents should be faxed to 313-576-8368 with a follow up phone call to the Study 
Coordinator, Allison Wolgast; 313-576-8994 to alert the Study Coordinator of a registration 
submission. Karmanos Cancer Institute will then review the checklist and confirm 
eligibility.   The site will receive the Confirmation of Registration form indicating the 
unique patient ID number and confirmation of registration into the trial. Only after this 
faxed or emailed Confirmation of Registration sheet has been received from Karmanos 
Cancer Institute can the patient receive study drug(s). Protocol treatment should begin 
within 7 days of patient registration.  
 


 
Page 32 of 76                         
4  
STUDY CALENDARS  
The calendar of events for phase Ib and phase II part of the study is illustrated in table 1 
and 2 below. 
 
Table 1: Calendar of Events for Phase Ib [COMPLETED] 
 
 
Cycle 1 
Cycle 2 and beyond 
 
Phase Ib Calendar 
Screenin
g 
Week 1 
Week 2-3 
Week 4 
Week 1-3 
Week 4 
Off 
Treatment 
Visit 
 
D-28 to 
D-1 
D1 
D2 
 
D8, 
15 
 
D22 
 
D1, 
8,15 
 
D22 
 
 
Written Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History and prior cancer treatments 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
Visual acuity and full eye exam 
x 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
Weight 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
Vitals  
x 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
12 lead EKG 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
CBC with differentials 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
Complete Serum Chemistry 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
Serum CA19-9 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
PT, INR, PTT 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Urinalysis 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
Imaging with tumor measurement (CT or 
MRI)1 
x1 
 
 
 
 
 
 
 
x1 
 
 
 
 
Selinexor in clinic2 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Gemcitabine infusion 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
nab-Paclitaxel infusion 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Archival Tumor tissue 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
Concomitant medications 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
1: CT or MRI of chest, abdomen with and without contrast or PET/CT are allowed. The imaging study needs to be repeated every 8 weeks for 
response assessment (+ / – 5 days). MRI of brain is required if intracranial metastasis is suspected. 
2: Selinexor given in clinic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 33 of 76                         
Table 2: Calendar of Events for Phase II  
 
 
Cycle 1 
Cycle 2 and beyond 
 
 
Phase II Calendar 
Screening 
Week 1 
Week 2-3 
Week 4 
Week 1-3 
Week 4 
Off 
Treatment  
Visit 
Follow up 
 
D -28 to 
D -1 
D1 
D3 
D8, 15 
 
D1, 8, 15 
 
 
 
Written Informed Consent 
x 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
Medical History and prior cancer treatments 
x 
 
 
 
 
 
 
 
 
Complete Physical Examination 
x 
x 
 
x 
 
x 
 
x 
 
Visual acuity and full eye exam 
x 
 
 
 
 
 
 
 
 
ECOG 
x 
x 
 
x 
 
x 
 
x 
 
Weight 
x 
x 
 
x 
 
x 
 
x 
 
Vitals  
x 
x 
 
x 
 
x 
 
x 
 
12 lead EKG 
x 
 
 
 
 
 
 
 
 
CBC with differentials 
x 
x 
 
x 
 
x 
 
x 
 
Complete Serum Chemistry 
x 
x 
 
x 
 
x 
 
x 
 
Serum CA 19-9 
x 
 
 
 
 
x 
 
 
 
Serum pregnancy test 
x 
 
 
 
 
 
 
 
 
Imaging with tumor measurement (CT or 
MRI) 
x 1 
 
 
 
 
 
x 1 
 
 
Selinexor in clinic 
 
x 3,4 
x 2 
x 
 
x 
 
 
 
Gemcitabine infusion  
 
x 
 
x 
 
x 
 
 
 
Tumor biopsy 
x 
 
x 5 
 
 
 
 
 
 
Blood for pharmacodynamics markers5 
x 6 
 
x 6 
 
 
 
 
 
 
Adverse Events 
x 
x 
 
x 
 
x 
 
x 
 
Concomitant medications 
x 
x 
 
x 
 
x 
 
x 
 
Survival 
 
 
 
 
 
 
 
 
x 7 
1: CT or MRI of chest, abdomen with and without contrast is allowed. The imaging study needs to be repeated every 8 weeks for response 
assessment (+/or – 5 days).   Imaging modality must be consistent in serial studies. MRI of brain is required only if intracranial 
metastasis is clinically suspected. 
2: Group 1, selinexor after liver biopsy    
3: Group 2    
4: Group 3 
5: Tumor biopsy or archival tissue at screening.  Group 1 liver biopsy on C1, D3 approximately 48 hours after administration of 
gemcitabine and before taking selinexor.  Group 2 will have a liver biopsy C1, D3 approximately 48 hours after administration of 
gemcitabine and selinexor. 
6: Blood for pharmacodynamics markers at baseline (or prior to C1 D1 treatment) and D3 
7: Follow up every 2 months for one year (12 months)     
 
5  
TREATMENT PLAN  
5.1  
Study Design  
This is a multicenter phase Ib study to investigate selinexor when combined with 
gemcitabine and nab-paclitaxel for first line treatment of metastatic pancreatic cancer and 
phase II study of selinexor plus gemcitabine in patients with pancreatic cancer in second 
line setting. Objectives include the determination of the safety profile of selinexor in 
combination with gemcitabine and selinexor and the overall survival of patients who 
receive the gemcitabine-selinexor combination. 
 
The study was a phase Ib study that was designed according to a standard 3+3 design and 
is now completed. The Maximum Tolerated Dose (MTD) was the lowest dose for which less 
than a third of patients experienced a Dose Limiting Toxicity (DLT). To ensure sufficient 
toxicity data at the MTD, a minimum of 6 patients were to be enrolled at the MTD. We 
anticipated that the RP2D would be the same as the MTD 
 
 
Phase Ib had three cohorts as shown in table 3. Only initial cohort was completed because 
of DLT.  


 
Page 34 of 76                         
At this time, up to 44 patients with metastatic pancreatic adenocarcinoma that were 
previously treated with a non-gemcitabine based regimen will be enrolled onto the phase II 
part of the study. The first fourteen patients with liver metastases that are accessible for 
image guided percutaneous core biopsies will be randomized into two post-treatment 
biopsy groups, group 1 and 2. The remaining 30 patients enrolled in this trial will be placed 
in group 3 (no biopsy group).The post-treatment biopsy will done only on C1D3 and the 
tissue obtained will be studied for changes in expression of tumor suppressor proteins 
(TSPs) caused by the combination of drugs compared to either biopsy sample obtained at 
screening or archival tissue obtained at time of diagnosis. 
• 
Group 1 will receive gemcitabine without selinexor on cycle 1 day 1. This will be 
followed by a biopsy of metastatic liver lesion approximately 48 hours after 
administration of the gemcitabine. Following the biopsy (C1D3), patients in group 1 
will receive the first dose of selinexor. Then on C1D8 and C1D15, selinexor will be 
given with  gemcitabine. In the subsequent cycles, Selinexor will be given 
concurrently with Gemcitabine on days 1, 8, and 15 of each 4-week cycle. 
• 
Group 2 will receive gemcitabine concurrent with selinexor starting on C1D1. A 
biopsy of the liver will be performed approximately 48 hours after administration of 
gemcitabine and selinexor. In Group 2, the gemcitabine/selinexor combination will 
be administered once every week for three weeks on days 1, 8 and 15 of each 4-
week cycle.  
• 
Group 3 will receive gemcitabine concurrently with selinexor starting on C1D1 and 
then weekly for three weeks (days 1, 8 and 15) of each 4-week cycle.   
 
It should be noted that the goal of randomization is to obtain tissue for pharmacodynamics 
assessment and determine the impact of selinexor on target molecules. If any of the first 14 
patients with liver metastates consented to enroll in the study but refused to consider the 
C1D3 biopsy then those patients will be allocated to Group 3 (no biopsy group).    
 
Table 3: Cohorts in phase I [COMPLETED] 
Cohort 
Gemcitabine (mg/m2) 
Days 1, 8, 15 
Nab-paclitaxel (mg/m2) 
Days 1, 8, 15 
Selinexor (mg) 
Days 1, 8, 15* 
Level 2 
1000 
125 
80 
Level 1 (starting) 
1000 
125 
60 
Level -1 
1000 
125 
40 
 
Table 4: Phase 2 dose adjustment 
 
Gemcitabine (mg/m2) 
Days 1, 8, 15 
Selinexor (mg) 
Days 1, 8, 15* 
Level 1 (starting) 
1000 
80 
Level -1 
750 
60 
Level -2 
500 
 
*Except for C1 of phase II in Group 1 where selinexor will be given on C1D3. 


 
Page 35 of 76                         
5.2  
Dose Schedule  
Phase 1b [COMPLETED]: A treatment cycle will be 4 weeks (+/- 3 days). In each cycle, 
patients will have 3 doses of gemcitabine/ nab-paclitaxel and 3 doses of selinexor. 
Gemcitabine/ nab-paclitaxel combination will be administered IV weekly for 3 weeks with 
one week off. Selinexor will be administered orally once a week on Weeks 1, 2 and 3 of each 
4-week cycle. Once a MTD is determined, it will be the recommended dose of selinexor for 
Phase II and patients will be treated with it until disease progression or undue toxicities.  
 
Phase II: A treatment cycle will be 4 weeks (+/- 3 days). Group 1 will receive IV 
gemcitabine without selinexor on day 1 of cycle 1. A liver biopsy will be performed on day 
3 of cycle 1 followed by oral administration of the C1 Week1 dose of selinexor. Then, 
gemcitabine/selinexor will be administered on day 8 and 15 of week 2 and 3. Gemcitabine 
and selinexor will not be administered on week 4. In the subsequent cycles, both drugs will 
be given on days 1, 8, and 15 of 4-week cycle. Group 2 will receive gemcitabine/selinexor 
on day 1, 8, 15 of week 1, 2, 3 of a 4-week cycle.  A biopsy of the liver will be performed 
approximately 48 hours after administration of gemcitabine and selinexor on C1 D1. 
Gemcitabine/selinexor will not be administered in week 4. Group 3 will receive 
gemcitabine/selinexor on day 1, 8, 15 of week 1, 2, 3 of a 4-week cycle. No biopsy is 
planned for this group. Gemcitabine/selinexor will not be administered in week 4 
 
5.3  
Suggested Supportive Care/Pre-medication  
Required 5-HT3 Antagonists  
In order to minimize nausea, all patients should receive 5-hydroxytryptamine (5-HT3) 
antagonists (8 mg or equivalent) unless contraindicated, starting on C1D1 before the first 
dose of study treatment and continued 2 to 3 times daily thereafter, as needed. Alternative 
treatment may be provided if the patient does not tolerate 5-HT3 antagonists.  
 
5.3.1  Supportive Care Recommendations for Selinexor-Related Adverse Events  
Supportive measures for optimal medical care should be provided to all patients during 
participation in this study. In addition to the required prophylactic therapy with 5-HT3 
antagonists (Section 5.3.1), supportive care per institutional guidelines and/or the National 
Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®) should be used as clinically indicated at the discretion of the Investigator.  
Supportive care guidelines for managing AEs are provided in the table 5 in 5.9.1. 
 
5.4  
Criteria for Initiation of Next Cycle  
In order to be eligible to start the next cycle of treatment, patients will be required to have 
adequate hematologic parameters:  
• 
ANC > 1.0 x 109/L  
• 
Platelets > 100 x 109/L 
 
Adequate resolution of non-hematological toxicities (excluding alopecia) from the previous 
cycle to grade 2 or lower is required.  


 
Page 36 of 76                         
5.5  
Definition of RP2D  
MTD is defined as the next lower dose level below the one in which ≥ 2 of 6 patients 
experience DLT. In general, we anticipate that the MTD will be the RP2D. However, based 
on evaluation with participating investigators, sponsor and how patients tolerate long-
term treatment with selinexor, the RP2D dose may be less than the MTD. The RP2D will be 
further evaluated in the Phase II Cohort.  
 
5.6  
Phase II cohort 
Approximately 44 patients will be included in the phase II part of the trial. The first 14 
patients with liver metastases who consent to a second liver biopsy will be randomized 
into two groups, group 1 and group 2. The dose schedule for this cohort will be the same as 
that for the phase I part, except the omission of selinexor on day 1 of cycle 1 in patients 
randomized to group 1 as described in section 5.1. There is no maximum duration of 
participation for any patient enrolled in this study and will be based on tolerance of study 
drugs and the clinical judgment of the treating physician and patient wishes.  
 
5.7  
Definition of Dose Limiting Toxicity (DLT)  
DLT is defined as any of the following occurring in the first 28 days (first cycle) of study 
participation that is considered at least possibly related to selinexor administration:  
• 
> 1 missed doses in 28 days due to a toxicity that is possibly selinexor-related  
• 
Discontinuation of a patient due to a toxicity that is at least possibly selinexor-
related prior to completing Day 28 of the first cycle 
 
Non-Hematologic:  
• 
Grade ≥ 3 fatigue, nausea, vomiting, or diarrhea despite receiving optimal 
supportive medications   
• 
Any other Grade ≥3 non-hematological toxicity (except for electrolytes 
abnormalities that are reversible and asymptomatic)  
• 
Grade ≥3 AST or ALT elevation lasting longer than 7 days OR Grade ≥3 AST or ALT 
elevation in the setting of bilirubin elevation > 2x ULN  
 
Hematologic:  
• 
Grade 4 neutropenia [absolute neutrophil count (ANC) < 500/mm3] lasting ≥7 days   
• 
Febrile neutropenia (ANC<1000/mm3 with a single temperature ≥ 38.3oC or 
sustained temperature of >38°C for over 1 hour)  
• 
Thrombocytopenia (platelet count <25,000/mm3) that persists for ≥7 days   
• 
Grade ≥3 thrombocytopenia associated with clinically significant bleeding  
 
Note the following: patients who missed ≥2 doses during cycle 1 for reasons unrelated to 
study drug are not evaluable for DLT and will be replaced.  
 
An event may not be considered a DLT if it is not clinically meaningful or significant even if 
it falls within the definition of a DLT as defined above. If this occurs, a discussion among all 
investigators, PI, and the Sponsor must take place after thoroughly reviewing the event, 
supporting data and the reasons for not considering the event a DLT. This must also be 


 
Page 37 of 76                         
clearly documented by the study coordinators. Conversely, certain adverse events may 
occur that do not meet the definition of a DLT but are clinically concerning and may 
therefore be considered DLTs after an agreement between investigators, PI, and the 
Sponsor.  
 
5.8  
Safety Cohort Review  
The following sections of the Cycle 1 and Cycle 2 Day 1 case report form (CRF) and source 
documentation for laboratory results data will be reviewed.  
• 
Study Drug Administration  
• 
Adverse Events Log  
• 
Hematology and Biochemistry.  
• 
Laboratory normal ranges page, if applicable  
• 
Concomitant Medications  
 
It is imperative that the CRF data listed above are entered promptly and as soon as a 
patient is removed from the study, if prior to completion of cycle 1, to assess safety at the 
opened dose level and to determine the feasibility of proceeding to a new dose level.  
 
An “Accrual on Hold” notice will be sent out to investigators by electronic mail once the 
study has recruited the required number of patients per cohort. A safety cohort review 
meeting may take place with the PI, investigators, and Karyopharm. After a decision is 
made by the sponsor based on the data submitted for a cohort regarding whether the study 
will be re-opened, a cohort will be expanded, or if there will be escalation, etc., all 
applicable parties will be notified. This process for toxicity review and cohort review will 
continue to be repeated and followed regularly until the RP2D is reached. 
 
5.9  
Dosing Adjustments  
5.9.1  Dose Modifications for Selinexor 
All dose modifications will be captured in the in the site’s internal database. 
Dose reductions and/or schedule modifications are allowed in order to optimize the 
antitumor activity and tolerability of selinexor. For some AEs, dose interruption and/or 
reduction is recommended. See Table 5 for pre-specified dose modifications for AEs related 
to study treatment. 
 
While drug-related major organ toxicities are not prominent, thrombocytopenia and a 
number of constitutional side effects can limit dosing with selinexor. Therefore, patients 
should also be treated with supportive care to reduce toxicities. In addition, it should be 
noted that the constitutional side effects often attenuate over the first 4 to 6 weeks of 
dosing. Finally, some patients with rapid tumor responses experience significant fatigue, 
nausea, malaise and/or asthenia after 1 or more doses of selinexor.  
 
The CTCAE v 4.03 is used for grading the severity of AEs; the therapy modifications 
described in Table 5 are applied according to this severity grading. Toxicity will be 
documented as described in Section 9.1.1. If more than 1 type of toxicity occurs 
concurrently, the most severe grade will determine the modification. 


 
Page 38 of 76                         
 
Each dose modification or treatment delay, as well as the reason, must be documented. 
 
Table 5: Supportive Care and Selinexor Dose Adjustment Guidelines for AEs Related 
to Selinexor 
Toxicity and Intensity 
Supportive Care and Dose Adjustment Guidelinesa,b 
Fatigue 
Grade 1 
• Maintain dose. Rule out other causes. If found to be 
anemic and symptomatic, consider transfusing even 
with hemoglobin >8 g/dL (anemia Grade <3). 
• Patients with significant fatigue after several doses of 
selinexor may have an antitumor response. Consider 
an unscheduled assessment of tumor response as 
part of the patient’s evaluation. 
Grade 2 lasting ≤7 days 
• As per NCCN guidelines, consider stimulants such as 
methylphenidate 5mg QD in the morning only. 
Grade 2 lasting >7 days or 
Grade ≥3 
• Rule out other causes. If found to be anemic and 
symptomatic, consider transfusions for hemoglobin 
>8 g/dL (Grade <3); transfusions usually are 
indicated for hemoglobin <8 g/dL (Grade ≥3). 
Interrupt selinexor dosing until resolved to Grade 1 
or baseline.  
• For first occurrence, restart selinexor at current 
dose.  
• For ≥ second occurrence, reduce selinexor by 1 dose 
level. 
• Patients with significant fatigue after several doses of 
selinexor may have an antitumor response. Consider 
an unscheduled assessment of tumor response as 
part of the patient’s evaluation. 
• As per NCCN guidelines, consider stimulants such as 
methylphenidate 5mg QD in the morning only. 
Anorexia or Weight loss 
Grade 1 anorexia 
• Maintain dose. Rule out other causes. Consider 
nutritional consultation and use nutritional 
supplements (e.g., Ensure®, Boost®). 
• For persistent symptoms, initiate appetite 
stimulants, such as olanzapine (2.5 to 5 mg PO every 
morning) or megesterol acetate (400 mg QD), as per 
NCCN guidelines. 


 
Page 39 of 76                         
Toxicity and Intensity 
Supportive Care and Dose Adjustment Guidelinesa,b 
Grade 1 weight loss 
Grade 2 anorexia 
• Initiate appetite stimulants, such as olanzapine (2.5 
to 5 mg PO every morning) or megesterol acetate 
(400 mg QD), as per NCCN guidelines. 
Grade 2 weight loss 
Grade 3 anorexia 
 
• Interrupt selinexor dosing until improved to Grade 1 
or baseline and weight stabilizes.  
• Reduce selinexor by 1 dose level. 
• Rule out other causes. Consider nutritional 
consultation and use nutritional supplements (e.g, 
Ensure®, Boost®)  
• Initiate appetite stimulants as above 
Nausea, Acute 
Grade 1 or 2 
 
• Maintain dose. Rule out other causes. Use standard 
additional anti-nausea medications to supplement 
the protocol-required 5-HT3 antagonists. 
• If persistent, use additional anti-nausea medications 
to supplement the protocol-required 5-HT3 
antagonist(s). Olanzapine 2.5 to 5 mg PO every 
morning, as per NCCN guidelines, can mitigate 
nausea and anorexia. 
Grade 3 
• Rule out other causes.  Use additional anti-nausea 
medications to supplement the protocol-required 5-
HT3 antagonist(s).  Olanzapine 2.5 to 5 mg PO every 
morning, as per NCCN guidelines, can mitigate 
nausea and anorexia. 
• Interrupt selinexor dosing until resolved to Grade ≤ 2 
or baseline and reduce selinexor by 1 dose level.  
• Patients with significant nausea/vomiting after 
several doses of selinexor may have an antitumor 
response. Consider an unscheduled assessment of 
tumor response as part of the patient’s evaluation. 
Hyponatremia 
Grade 1 (sodium levels 
< Normal to 130 mmol/L) 
• Maintain dose. Rule out other causes including drug 
(e.g., diuretic) effects. 
• Be certain that reported sodium level is corrected for 
concurrent hyperglycemia (serum glucose >150 
mg/dL).  
• Treat hyponatremia per institutional guidelines 
including dietary review. Provide supplemental oral 
and/or intravenous fluids if dehydration is present. 
Consider addition of salt tablets to patient’s diet. 


 
Page 40 of 76                         
Toxicity and Intensity 
Supportive Care and Dose Adjustment Guidelinesa,b 
Grade 3 with sodium levels 
<130-120 mmol/L without 
symptoms 
• Rule out other causes including drug (e.g., diuretic) 
effects. 
• Be certain that reported sodium level is corrected for 
concurrent hyperglycemia (serum glucose >150 
mg/dL).  
• If (corrected) sodium is Grade ≤3 and continues to be 
asymptomatic, then patient may continue current 
dosing without interruption provided that IV saline 
and/or salt tablets are provided and patient is 
followed closely.  
• If Grade 3 is persistent or worsens or does not 
respond to treatment, interrupt selinexor dosing 
until resolved to Grade 1 or baseline and reduce 
selinexor by 1 dose level. 
Grade 3 with sodium levels 
<130-120 mmol/L with 
symptoms or Grade 4 
(<120 mmol/L) 
• Rule out other causes including drug (e.g., diuretic) 
effects. 
• Be certain that reported sodium level is corrected for 
concurrent hyperglycemia (serum glucose > 150 
mg/dL).  
• Interrupt selinexor dosing until resolved to Grade 1 
or baseline and without symptoms. Reduce selinexor 
by 1 dose level. 
Diarrhea 
Grade 1 
• Maintain dose. Rule out other causes including drug 
effects. Treat per institutional guidelines with anti-
diarrheals, such as loperamide. 
Grade 2 
• Rule out other causes including drug effects. Treat 
per institutional guidelines with anti-diarrheals. 
Interrupt selinexor dosing until resolved to Grade 1 
or baseline.  
• For first occurrence, restart selinexor at current 
dose.  
• For ≥ second occurrence, reduce selinexor by 1 dose 
level. 
Grade 3 or 4 
• Interrupt selinexor dosing until resolved to Grade 1 
or baseline and patient is clinically stable. Reduce 
selinexor dose by 1 dose level. 
Thrombocytopenia 
Grade 1 or 2 
• Maintain dose. Rule out other causes including drug 
effects. 


 
Page 41 of 76                         
Toxicity and Intensity 
Supportive Care and Dose Adjustment Guidelinesa,b 
Grade 3 without bleeding 
• Rule out other causes including drug effects.  
• For first occurrence: skip 1 dose and reduce 
selinexor by 1 dose level. 
• If recurrent, unless contraindicated, initiate 
treatment with moderate to high doses of 
thrombopoietin stimulating agents such as 
romiplostim 5 to 10 µg/kg SC weekly (preferred) or 
eltrombopag 100 to 150 mg QD. 
• In cases where there is significant disease 
involvement in the bone marrow or pre-existing 
compromised marrow function (e.g., due to prior 
marrow-toxic therapy), the Investigator in 
consultation with the Sponsor-Investigator  may 
decide to continue selinexor dosing without dose 
reductions and/or interruptions as specified above, 
provided that platelet counts and bleeding 
symptoms/signs are closely monitored. 
Thrombopoietin stimulating agents are 
recommended. 
Grade 4 without bleeding 
• Rule out other causes including drug effects.  
• Interrupt selinexor until patient recovers to Grade 2 
or baseline. Selinexor dosing may be reduced by 1 
dose level (it is recommended to have only 1 dose 
modification per cycle) 
• If recurrent, unless contraindicated, initiate 
treatment with moderate to high doses of 
thrombopoietin stimulating agents as above.  
• In cases where there is significant disease 
involvement in the bone marrow  or pre-existing 
compromised marrow function (e.g., due to prior 
marrow-toxic therapy), the Investigator in 
consultation with the Sponsor-Investigator may 
decide to continue selinexor dosing without dose 
reductions and/or interruptions as specified above, 
provided that platelet counts and bleeding 
symptoms/signs are closely monitored. 
Grade ≥3 with bleeding 
 
• Interrupt selinexor dosing and check platelet counts 
weekly until the bleeding has stopped, patient is 
clinically stable and the platelets have recovered to 
Grade 2 or baseline. When resuming selinexor, 
reduce by 1 dose level. 


 
Page 42 of 76                         
Toxicity and Intensity 
Supportive Care and Dose Adjustment Guidelinesa,b 
• If recurrent, unless contraindicated, initiate 
treatment with moderate to high doses of 
thrombopoietin stimulating agents as above. 
Neutropenia 
Grade 3 or 4 neutropenia 
(afebrile) OR Febrile 
neutropenia 
• If afebrile: Continue Selinexor, may consider using 
colony stimulating factors and prophylactic 
antibiotics as clinically indicated per institutional 
guidelines. 
• If febrile: Interrupt Selinexor and check neutrophils 
at least weekly until recover to Grade 2 or baseline 
and without fever (if febrile) and the patient is 
clinically stable. Reinitiate selinexor therapy at the 
same dose level and may use colony stimulating 
factors per institutional guidelines. 
• If recurrent, may continue colony stimulating factors, 
interrupt selinexor until neutrophil counts improve 
to Grade ≤2 or baseline levels, and reduce the dose of 
Selinexor at reinitiation by 1 dose level. 
Anemia 
• Treat per institutional guidelines including blood transfusions and/or 
erythropoietins. Consider transfusing for symptoms with hemoglobin >8 g/dL 
(Grade <3) or for any Grade 3 (hemoglobin <8 g/dL). If possible, maintain 
selinexor dose as long as patient is clinically stable, but if a dose reduction or 
interruption is desired, consult with the Sponsor-Investigator. 
Other selinexor-related adverse events 
Grade 1 or 2 
• Rule out other causes. Maintain dose. Start treatment 
and/or standard supportive care per institutional 
guidelines. 
Grade 3 or 4 
• Rule out other causes. Interrupt selinexor until 
recovers to Grade 2 or baseline and reduce selinexor 
by 1 dose level. 
• Isolated values of Grade ≥3 alkaline phosphatase do 
NOT require dose interruption. Determination of 
liver versus bone etiology should be made, and 
evaluation of gamma-glutamyl transferase, 5'-
nucleotidase, or other liver enzymes should be 
performed. 
IV: intravenous; NCCN: National Comprehensive Cancer Network; QD: once daily; PO: 
oral; SC: subcutaneous  
 


 
Page 43 of 76                         
Toxicity and Intensity 
Supportive Care and Dose Adjustment Guidelinesa,b 
aFor all  Grade ≥3 hematological or non-hematological AEs that are NOT selinexor 
related, after consultation with the Sponsor-Investigator  and at the discretion of the 
Investigator, selinexor dosing may be maintained. 
 
bFor all selinexor-related AE’s, if the below prescribed dose reductions/interruptions 
result in a stabilization of ≥ 4 weeks, a re-escalation may be considered after approval 
from the Sponsor-Investigator  . 
 
All dose modifications should be based on the worst preceding toxicity. 
 
Note: When toxicities due to selinexor have returned to baseline levels or the patient 
has stabilized, the dose of selinexor may be re-escalated in consultation with the 
Sponsor-Investigator. 
 
5.9.1.1  
Conditions not Requiring Selinexor Dose Reduction  
The following conditions are exceptions to the above guidelines. Selinexor does not need to 
be held in the following cases:  
• 
Alopecia of any grade  
• 
Electrolytes abnormalities that are reversible with standard interventions (see 
special consideration or Grade 3-4 Hyponatremia in table 5) 
• 
Isolated values of Grade ≥3 alkaline phosphatase. Determination of liver versus 
bone etiology should be made, and evaluation of gamma-glutamyl transferase, 5' 
nucleotidase, or other liver enzymes should be performed. 
 
5.9.1.2  
Dose Adjustments with Changes in BSA  
Dose adjustments do not need to be made for weight gains/losses of ≤20%. If weight 
changed by >20% from baseline recorded at the beginning of the study then Gemcitabine 
dose maybe adjusted based on the body surface area (BSA) per investigator discretion. No 
dose adjustment for Selinexor is required based on weight changes.   
 
5.9.1.3  
Selinexor Dose Adjustment in the Setting of Infection 
Patients with active uncontrolled or suspected infections should have treatment withheld 
until the infection has clinically resolved and/or the patient is clinically stable. When ready 
to resume dosing, treatment may continue at the original dose. Missed doses will not be 
replaced. Patients may continue antibiotics for prolonged periods while re-initiating their 
treatment at the discretion of the Investigator. 
 
5.9.1.4  
Missed or Vomited Doses  
Missed doses should be managed as follows:  
• 
If a dose was missed, the schedule of that week should be altered to accommodate 1 
dose in that week with at least 5 days between 2 consecutive doses.  


 
Page 44 of 76                         
• 
If a dose must be skipped (e.g., due to recommendation of treating physician), the 
next dose will be taken as per schedule. All missed and delayed doses should be 
documented. 
 
If a patient missed a full 1- or 2-week period of dosing for non-study treatment-related 
events (e.g., a required medical procedure or an unanticipated personal emergency), the 
days missed will be reported. The schedule however, will be followed as before. As an 
example, if patient missed Cycle 2 Day 8 and Cycle 2 Day 15, schedule will be resumed at 
Cycle 3 Day1 after the break. 
 
Vomited doses should be managed as follows: 
• 
If a dose of selinexor 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. 
 
5.9.1.5  
Delays, Modifications, and Reintroduction  
All delays, modifications, and reintroductions of selinexor dosing will be made in 
consultation with the PI and the Sponsor.  
 
5.9.2  Dose Adjustment for Gemcitabine  
• 
If toxicity is attributed to gemcitabine and it necessitates dose modification in the 
opinion of investigators, following general guidelines are recommended. 
• 
If toxicity is attributed to gemcitabine alone, modifications should be made to 
gemcitabine dose.  
• 
Gemcitabine will be permanently discontinued for any of the following:  
o Unexplained dyspnea or other evidence of severe pulmonary toxicity  
o Severe hepatic toxicity  
o Hemolytic-Uremic Syndrome  
o Capillary Leak Syndrome  
o Posterior reversible encephalopathy syndrome 
• 
If the patient tolerates a reduced dose for two cycles, patient may be dose escalated 
to the dose they received prior to the reduction only after authorization from the 
study PI and sponsor.  
• 
No dose modifications are recommended for alopecia, nausea, or vomiting.  
 
5.9.2.1  
Dose Adjustment Guidelines for Non-hematologic Toxicities  
 
Recommended action  
≥Grade 3  
Non-hematologic 
Gemcitabine 
related toxicities  
*Hold gemcitabine until toxicity resolves to ≤ Grade 1 or baseline 
(maximum 14 days).  
*If the toxicity resolves to ≤Grade 1 or baseline within 14 days, 
restart at 75% of starting dose (dose reduction by 25%)  
 *If toxicity recurs, a 2nd dose reduction to dose level 50% of 
starting dose may be permitted (dose reduction by 50%).  
 
 


 
Page 45 of 76                         
5.9.2.2  
Dose Adjustment Guidelines for Hematologic Toxicities 
Both gemcitabine is myelosuppressive. If ≥grade 3 hematologic toxicities are noted, 
following paradigm will be used.  
 
Recommended action 
≥ Grade 3 
hematologic 
toxicities 
*Hold gemcitabine first until toxicity resolves to ≤ Grade 1 or 
baseline (maximum 14 days).  
*If the toxicity resolves to ≤Grade 1 or baseline within 14 days, 
restart gemcitabine at 75% of starting dose (dose reduction by 
25%)  
*If grade 3-4 toxicity recurs despite a 25% dose reduction in 
gemcitabine it should be permanently discontinued.  
 
5.10  Patient Compliance and Replacement  
To the extent possible, patients must strictly follow the standard dosing schedule. Patients 
will be requested to complete a pill diary or calendar. Patients who miss more than 2 doses 
or more of selinexor in a cycle in the absence of study drug related toxicity will be 
discontinued unless these are consecutively missed doses due to a required medical 
procedure that is unrelated to study drug or an anticipated personal emergency.  
 
Compliance to study medication will be ascertained by use of patient diaries for the days 
where patient receives the study drug. Compliance to study medication will be determined 
by the investigator or a delegate and recorded in source documents. The date, time and 
number of tablets consumed will be recorded as per study drug schedule. The principal 
investigator or the designee will account for the number of tablets dispensed against those 
returned by the patient. Any deviations and missed doses will be recorded in the CRF and 
drug accountability logs for verification with the reasons. The investigator / designee will 
try to ensure complete compliance with the dosing schedule by providing timely 
instructions to the patients.  
 
Patients who miss 1 or more doses of gemcitabine in a cycle in the absence of drug related 
toxicity will be discontinued unless these are consecutively missed doses due to a required 
medical procedure that is unrelated to the study regimen or an anticipated personal 
emergency.  
 
Patients withdrawn in cycle 1 because of non-compliance not related to study drug related 
toxicity will be replaced.  
 
5.11  Premature Withdrawal/ Discontinuation Criteria  
Patients may withdraw from the study at any time. Patients who discontinue from the 
study will be encouraged to return to the study site to undergo the evaluations listed for 
the Off Treatment Visit.  
 
At the discretion of the Investigator, the investigator may remove a patient from the study 
for the following reasons:  
• 
Disease progression based on clinical and/or radiological grounds. 


 
Page 46 of 76                         
• 
Noncompliance with study procedures  
• 
Need of treatment with medications not allowed by the study protocol  
• 
Patient no longer consents to participate in the study  
• 
Intercurrent illness that interferes with study assessments and outcome  
• 
Incidence or severity of AEs in this study indicates a potential health hazard to the 
patient  
• 
For the third occurrence of the same Grade ≥3 non-hematological toxicity  
• 
Investigator discretion  
• 
Other treatments become available  
 
If the reason for withdrawal is the occurrence of an AE or drug related DLT, the patient will 
be followed up by the investigator until such events resolve, stabilize, and according to the 
Investigator’s judgment there is no need of further follow-up. The reason for withdrawal 
from the study will be documented in the case report form.  
 
Sponsor and Karyopharm must be notified within 24 hours of a patient’s discontinuation 
from the study.  
 
6  
Concomitant Medications  
Concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements. All concomitant medications must be recorded on the 
source documents and case report form beginning 14 days prior to Day 1 and through the 
end of the patient’s study participation.  
 
6.1  
Permitted Concomitant Medications  
Prevention of Pregnancy  
Female patients of childbearing potential must agree to use highly effective methods of 
contraception and must have a negative serum pregnancy test at screening. Male patients 
must use an effective barrier method of contraception if sexually active. Acceptable 
methods of contraception are condoms with contraceptive foam, oral, implantable or 
injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with 
spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For 
both male and female patients, highly effective methods of contraception must be used 
throughout the study and for three months following the last dose of study drugs.  
 
Use of Blood Products  
During the administration of study regimen, patients may receive red blood cell (RBC) or 
platelet transfusions, if clinically indicated and per institutional guidelines.  
 
Radiation Treatment  
If clinically indicated, palliative radiation therapy to non-target lesions is permitted. 
Treatment with selinexor shall not be discontinued solely due to palliative radiation. 
However, gemcitabine will be discontinued while getting palliative radiation.  
 
 


 
Page 47 of 76                         
Glucocorticoid Therapy  
As part of supportive care (e.g. for nausea or anorexia), oral dexamethasone, up to 40 
mg/week, can be given to patients based on the investigator discretion. 
 
Supportive Care Guidelines  
Supportive measures for optimal medical care shall be provided during participation in this 
clinical trial.  
• 
Appropriate anti-coagulation is allowed during the study (e.g.: LMW heparin, direct 
factor Xa inhibitors, etc.). Warfarin is allowed during the study provided that 
patients are monitored for INR twice a week in cycles 1 and 2 and anytime the dose 
is adjusted. If the INR is stable after the first two cycles, then monitoring may revert 
to the local practice.  
• 
Erythropoietin and growth factors are not permitted to be used prophylactically in 
cycle 1 but are allowed if needed in cycle 2 and onwards. However, these can be 
used therapeutically to treat hematologic toxicities throughout the study including 
in cycle 1.  
• 
Medications to treat concomitant diseases like diabetes, hypertension, etc. are 
allowed.  
• 
Standard appetite stimulants are allowed.  
• 
Use of any immunosuppressive agents during the study must be confirmed by the 
sponsor. 
 
 6.2  
Prohibited Concomitant Medications  
Erythropoietin and growth factors are not permitted to be used prophylactically in cycle 1 
but allowed if needed in cycle 2 and onwards. However, these can be used therapeutically 
to treat hematologic toxicities throughout the study. 
 
Anticancer Therapy  
Concurrent therapy with an approved or investigative anticancer therapeutic, other than  
glucocorticoids and gemcitabine as specified herein, are not allowed.  
 
Investigational Agents  
Other investigational agents should not be used during the study.  
 
Drugs undergoing Glutathione conjugation  
The primary metabolism of selinexor in vitro and in vivo appears to be inactivated by 
glutathione conjugation. This process can be mediated in the absence of proteins, 
indicating that it is thermodynamically favorable. In vitro studies using human liver 
microsomes confirm in vivo findings that selinexor undergoes minimal CYP450 
metabolism. Therefore, administration of selinexor with drugs which undergo substantial 
glutathione conjugation should be minimized or avoided. These drugs include 
acetaminophen. It should be noted that no studies of selinexor in combination with 
acetaminophen have been performed to date and that these recommendations are 
empirical. It should also be noted that ethanol ingestion is associated with glutathione 


 
Page 48 of 76                         
depletion; therefore, use of products containing ethanol should be minimized or avoided on 
selinexor dosing days.  
 
7  
Drugs 
7.1  
Selinexor 
7.1.1  Drug Preparation and Administration  
Selinexor is an investigational product and will be provided by Karyopharm.  
 
Selinexor will be supplied 20 mg blister packs for oral administration. Each blister pack will 
contain 12 tablets. 
 
Refer to the IST Pharmacy Manual for details of selinexor formulation, preparation, and 
administration. 
 
Selinexor tablets should be taken orally with at least 120 mL (4 ounces) of water at 
approximately the same time each dosing day. It can be taken with or without food.  
 
Selinexor tablets should be swallowed whole (not crushed) to prevent an increased risk of 
dermatologic toxicity if the powder comes in contact with skin. 
 
Each dose will consist of selinexor for oral administration on a flat dose basis starting at 80 
mg once a week for 3 weeks of each 4-week cycle.  Selinexor will not be taken during week 
4 (total three doses per cycle).  
 
All drugs will be prepared, stored and administered as approved by FDA and according to 
the institutional standards.  
 
7.1.2  Drug Storage  
Selinexor tablets will be stored at or_below_86°F_(30°C) in a locked and secured area with 
restricted access to study staff. The tablets should not be stored at freezer temperatures or 
allowed to freeze. All medication must be stored in a secure area under the proper storage 
requirements with access restricted to the site staff pharmacist or designee(s). 
 
7.1.3  Accountability and Destruction of Investigational Medicinal Product  
The Principal Investigator (or an authorized designee) at each participating institution 
must maintain a careful record of the inventory of the Investigational medicinal product 
received using the Drug Accountability Form. The study drug will be destroyed as per site’s 
destruction policies and documentation of study drug destruction will be provided to 
Karyopharm. Both used and unused study drug may be returned to Karyopharm if 
requested by Karyopharm.  
 
7.1.4  Drug Administration  
Study drug is provided by Karyopharm Therapeutics Inc. and will be labeled as per the 
applicable regulations. Sites must request selinexor through  Karyopharm’s  automated 
drug ordering system (Endpoint DRIVE).The sponsor’s research pharmacists are required 
to attend a DRIVE training and to train their respective sites afterwards.  Karyoharm’s 


 
Page 49 of 76                         
Addditional Site Forms must be completed and sent to Karyopharm prior to additional 
sites’ being able to order drug.  The sponsor is required to keep track of all onsite drug 
supply and expiry for all study sites. Drug should be ordered 2-3 weeks in advance of need, 
therefore pre-planning for estimated supply requirements needs to be done regularly. This 
requires regular communication between the sponsor’s clinical team and the research 
pharmacists. 
 
Study drug accountability records will be maintained at the site pharmacy and will be 
available for monitoring and submission to Karyopharm upon request. 
 
Study drug must be stored in a secure area under the proper storage requirements with 
access restricted to the site staff pharmacist or designee(s).  
 
The Investigational Product should not be used for any purpose outside the scope of this 
protocol, nor can the Investigational Product be transferred or licensed to any party not 
participating in the clinical study. Karyopharm’s data for Investigational Products are 
confidential and proprietary and shall be maintained as such by the Investigators.  
 
7.2  
Gemcitabine hydrochloride (Gemzar®)  
For full prescribing information on gemcitabine, please refer to FDA website 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Information regarding 
warning, recommendations for dose reduction and discontinuation, precautions for 
preparation and administration, preparation for iv administration, stability of gemcitabine, 
clinical trial experience, post-marketing experience, drug interactions, use in specific 
patient population (geriatric patient, patients with renal or hepatic impairment, pregnancy, 
nursing mother etc.), overdose, clinical pharmacology and toxicology are available on the 
above webpage.  
 
Briefly, gemcitabine is available from commercial providers. It is provided in single use vial 
containing 200mg/vial or 1 gram/vial of gemcitabine. The vial with 200 mg gemcitabine 
can be reconstituted with 5 ml 0.9% sterile normal saline solution and 1 gram vial with 25 
ml, each reconstitution yielding gemcitabine concentration of 38 mg/ml. Before 
administration to the patient, gemcitabine needs to be diluted with injection of appropriate 
amount of normal saline. The final concentration can be as low as 0.1 mg/ml. Reconstituted 
gemcitabine solution is stable for 24 hours at room temperature 20-25 °C (68-77 °F) and it 
should not be refrigerated to avoid crystallization.   
 
Gemcitabine is approved for treatment of pancreatic cancer. Patients participating in this 
study will treated with 1000 mg/m2 of gemcitabine on day 1, 8, 15 of a 4-week cycle.   
 
Treatment will be continued until disease progression, prohibitive toxicity or start of 
alternative treatment. Patiens with prohibitive toxicitywho have no disease progression 
(achieved PR or SD), necessitating treatment discontinuation, at the discretion of the 
investigator, may continue with weekly selinexor upon recovery to ≤ grade 1 of the toxicity.  
 


 
Page 50 of 76                         
8  
MEASUREMENT OF DRUG EFFECTS  
8.1  
Safety Assessment  
The safety and tolerability of selinexor in combination with gemcitabine will be evaluated 
by means of drug related DLT, AE reports, physical examinations, and clinically significant 
changes in the laboratory safety evaluations. A teleconference will be held every week to 
discuss the safety of all patients enrolled in phase Ib. All the investigators, drug provider or 
their designee must participate in the weekly teleconference. In the case when a 
participating investigator cannot participate in the teleconference discussion, he/she will 
be asked to update the sponsor/principal investigator about safety of the patients via 
email.  
 
Adverse events (AE) will use the descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03.  
 
8.2  
Efficacy Assessments  
All patients who received at least one dose of selinexor in combination with gemcitabine 
shall be included in the efficacy analysis. The clinical activity will be evaluated for its effects 
on disease response criteria in terms of best response, duration of response, progression 
free survival (PFS), duration of stable disease and overall survival.  
Objective disease response assessment will be made according to standard, international 
RECIST 1.1 criteria for solid tumors.  Patients who discontinue treatment for safety related 
reasons and and NOT for progressive disease will continue being followed up with 
scheduled disease assessment until disease progression or start of of alternative therapy.  
 
8.3  
Pharmacodynamics  
As noted earlier, the first fourteen patients participating in the phase II part will be 
randomized to group 1 and 2.  Each group will have liver biopsies on day three . The 
expression of p27, FOXO, PAR4 and IκB on liver tissues before and after treatment will be 
determined by immunohistochemistry. 
 
For immunohistochemistry, the hematoxylin and eosin-stained slides will be reviewed for 
grading and the selection of representative tissue block(s) for immunohistochemical 
analysis. Immunohistochemistry will be performed on liver biopsies from the study 
patients for antibodies against p27, FOXO, PAR-4 and IκB. After deparaffinizing and 
hydrating to phosphate-buffered saline (PBS) buffer (pH 7.4), the sections will be 
pretreated with hydrogen peroxide (3%) for 10 minutes to remove endogenous 
peroxidase, followed by antigen retrieval via stem bath for 20 minutes in EDTA. A primary 
antibody will be applied, followed by washing and incubation with the biotinylated 
secondary antibody for 30 minutes at room temperature. Detection will be performed with 
diaminobenzidine (DAB) and counterstaining with Mayer hematoxylin followed by 
dehydration and mounting.  
 
Immunostaining will be scored semiquantitatively by assessing the localization and 
intensity in tumor cells nucleus. The staining will be then categorized into: 0, none; 1, up to 
10% staining; 2, 11% to 50% staining; and 3, >50% staining. Intensity will be scores as 1 
for low and 2 for high. Final score will be obtained by multiplying the 2 scores.  


 
Page 51 of 76                         
Biopsies will be performed at the participating sites for phase 2 portion of the protocol.  
When available, baseline archival tissue in the Phase 1 portion of the study will be 
submitted. Tissues and blood obtained for pharmacodynamics will be shipped to Karmanos 
Cancer Center for processing.  
 
Dr. Ramzi Mohammad/Dr. Asfar Azmi 
Karmanos Cancer Institute 
HWCRC 732 
4100 John R 
Detroit, MI 
48201 
Tel # 3135768328 
Fax # 3135778389 
Email: mohammad@karmanos.org 
 
9  
SAFETY AND REPORTING REQUIREMENTS  
9.1  
Adverse Events  
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.  
• 
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.  
 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (i.e., are considered to be 
clinically significant, induce clinical signs or symptoms, require concomitant therapy, or 
require changes in study treatment), should be recorded as an AE. Whenever possible, a 
diagnosis rather than a symptom should be recorded (e.g., anemia instead of low 
hemoglobin).  
 
Laboratory abnormalities that meet the criteria for an AE should be followed until they 
have returned to normal 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. 
 


 
Page 52 of 76                         
A laboratory abnormality that does not meet the definition of an AE should not be recorded 
as an AE. A Grade 3 or 4 event (severity per the current version of NCI CTCAE) does not 
automatically indicate an SAE unless it meets the definition of serious as defined under the 
definitions above and/or as per the Investigator’s discretion. A laboratory abnormality that 
results in a dose being held or modified would, by definition, be an AE.  
 
9.1.1  Adverse Event Documentation  
The severity* of the AE should be graded by the Investigator according to the NCI CTCAE 
Grading Scale, utilizing a current version of NCI CTCAE.  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 should be characterized as 
‘mild,’ ‘moderate,’ ‘severe,’ ‘life-threatening’, or ‘fatal’ (corresponding to Grades 1 to 5) 
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  
• 
Fatal event. 
 
*Severity ≠ Seriousness:  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.  Grades do not define seriousness. 
 
9.1.1.1  
Recording of Adverse Events: 
All AEs that begin or worsen after the patient has provided informed consent should be 
recorded by the Investigator, regardless of relationship to study treatment. AE monitoring 
should be continued for at least 30 days following the last dose of study treatment (i.e., 
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). AEs (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 AEs occur 
during the study. AEs 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 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. 
 


 
Page 53 of 76                         
9.1.1.2  
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 selinexor, causality to selinexor, event ongoing (yes or no), 
outcome of AE, severity CTCAE Grade (1-5), subject dosed with selinexor (yes or no), date 
of first dose of selinexor, preferred term, system organ class (optional) 
See the excel spreadsheet template in Appendix 3. 
 
9.1.1.3  
Adverse Event Causality 
The Investigator will make a judgment regarding the relationship of the AE to study 
treatment, as outlined in the following table. 
 
Classification of Adverse Events by Causality 
Not related 
The lack of a temporal relationship of the event to the study treatment 
makes a causal relationship not reasonably possible, or other drugs, 
therapeutic interventions, or underlying conditions provide a sufficient 
explanation. 
Related 
The temporal relationship of the event to the study treatment makes a 
definitive relationship, and the event is more likely explained by exposure 
to the study treatment than by any other drugs, therapeutic interventions, 
or underlying conditions. 
 
9.2  
Serious Adverse Events  
An AE that meets the criteria of any untoward medical occurrence that, at any dose,  
• 
results in death 
• 
is life threatening (ie, 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;  
• 
is a congenital anomaly/birth defect.  
• 
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 
 
Please note that SAEs 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). 


 
Page 54 of 76                         
9.2.1  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 malignancy/disease (including fatal outcomes) should NOT be reported 
as an SAE during the study or within the safety reporting period (see Section 9.2.3). Sudden 
or unexplained death should be reported as an SAE. If there is any uncertainty about a 
finding being due solely to progression of malignancy/disease, the finding should be 
reported as an AE or SAE, as appropriate. 
 
9.2.2  Recording of Serious Adverse Events 
It is the responsibility of the Investigator to record and document all SAEs occurring from the 
time when the ICF is signed until at least 30 days after the patient has stopped study 
treatment. All SAEs must be reported on Karyopharm’s SAE Report Form in addition to 
being recorded in the sponsor’s database. The original SAE Report Form must be retained 
in the Investigator’s site file. 
 
All applicable sections of the SAE Report 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. 
 
9.3  
Reporting of Serious Adverse Events 
9.3.1  Reporting Serious Adverse Events to the Principal Investigator and Clinical 
Trials Office (CTO) at Karmanos 
All serious adverse events (SAE) as defined must be reported immediately.   
 
SAEs that are unexpected and/or related to protocol therapy will have a written report (the 
MedWatch form may be used) sent to the following within 24 hours: 
 
1. Study Principal Investigator - Mohammed Najeeb Al Hallak, MD,MS 
(alhallakm@karmanos.org)    
 
2. Clinical Trials Office:  
Allison Wolgast 
Karmanos Cancer Institute 
4100 John R-MM03CT 
Detroit, MI 48201 
Office: (313) 576-8994 
Fax: (313) 576-8368 
Email: wolgasta@karmanos.org 


 
Page 55 of 76                         
or 
Taylor Brewer 
Study Coordinator 
brewert@karmanos.org 
Tel # 313-576-8526 
Fax # 313-576-8368 
 
The Clinical Trials Office will coordinate the reporting process between the Investigator 
and the IRB, as well as other applicable reporting agencies (FDA).  Investigators, with the 
help of clinical trials office staff, will inform the FDA of any unexpected possibly related 
SAEs that occur in the course of the study within 15 calendar days of when he or she 
becomes aware of the occurrence. Fatal or life threatening SAEs must be reported to the 
FDA no later than 7 calendar days from the time that he or she becomes aware of them.  
 
9.3.2  Reporting SAEs to Karyopharm 
The Clinical Trials Office will coordinate the process of reporting the SAEs to Karyopharm. 
Every SAE, regardless of the causal relationship to the Karyopharm study drug, occurring 
after the patient has signed informed consent until at least 30 days after the patient has 
stopped the Karyopharm study drug must be reported to the 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 4). 
 
Upon completion, the SAE Report Form must be immediately emailed or faxed to: 
Pharmacovigilance Department 
Karyopharm Therapeutics Inc. 
E mail: pharmacovigilance@karyopharm.com 
Fax: +1-617-334-7617 (USA) 
+49-89-9218-5650 (Germany) 
 
Any SAE observed after the 30-day follow-up period should only be reported to 
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 and an assessment should be made at each study 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 of 
the event. 
 
Investigators are responsible as applicable for notifying their appropriate Health 
Authorities, Institutional Review Board or Local and Central Ethics Committees (EC) of all 
SAEs in accordance with local regulations.  
 


 
Page 56 of 76                         
Karyopharm will report applicable SAEs to other applicable regulatory authorities and 
Investigators utilizing selinexor, as may be required. 
 
9.3.3  Reporting Serious Adverse Events to Local Ethics Boards  
The sponsor will notify all Investigators of all Serious Adverse Events that are reportable to 
regulatory authorities in US. This includes all serious events that are unexpected and 
related to protocol treatment. Investigators must notify their Institutional Research Board 
(IRB) or Research Ethics Boards (REBs) or Independent Ethics Committee (IEC) in 
accordance with local regulations and file the report with their Investigator Site File. 
Documentation that serious adverse events (SAEs) have been reported to IRBs/REBs/IEC 
must be forwarded to the sponsor and Karyopharm for filing.  
Documentation can be any of the following:  
• 
Letter from the IRB/REB/IEC acknowledging receipt  
• 
Stamp from the IRB/REB/IEC, signed and dated by IRB/REB/IEC chair, 
acknowledging receipt  
• 
Letter demonstrating the SAE was sent to the board  
 
All expedited local serious adverse events occurring within a center should also be 
reported to local IRBs/REBs/IEC as per the ethics board’s or committee’s guidelines.  
 
9.3.4  Reporting Period for Adverse Events and Serious Adverse Events  
The CRF should capture all AEs occurring from cycle 1 day 1 till the date of scheduled 4 
weeks (+ 1 week) follow-up visit or 30 days after discontinuation of the study drug, 
whichever is later.  
 
In addition, any known untoward event of any severity that occurs subsequent to the AE 
reporting period that the Investigator assesses as at least possibly related to the study 
therapy (i.e., the relationship cannot be ruled out) should also be reported as an AE.  
For the SAEs that have been deemed by the investigator as unrelated to protocol treatment, 
the SAE reporting period begins after patient signs informed consent and ends on the date 
of scheduled 4 weeks (+ 1 week) follow-up visit or 30 days after discontinuation of the 
study drug, whichever is later. For the SAEs that have been deemed by the investigator as 
at least possibly related to protocol treatment, the SAE must be reported even if this occurs 
after the date of scheduled 4 weeks (+ 1 week) follow-up visit or 30 days after 
discontinuation of the study drug.  
 
SAEs that occur prior to dosing will not be reported in an expedited fashion to any health 
authority, and will be summarized and described in the clinical study report. The 
investigator shall provide follow-up information as and when available in a new follow-up 
SAE form. All SAEs must be followed until resolved, become chronic, or stable unless the 
patient is lost to follow up. Resolution status of such an event should be documented on the 
CRF.  
 
9.3.5  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 Investigator or Karyopharm to be related 


 
Page 57 of 76                         
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) or as per national regulatory requirements in participating countries. 
 
Selinexor SUSARs originating from Karyopharm’s CSTs in specific countries do not need to 
be cross-reported to the Competent Authorities. Please see memo in Appendix 5, for more 
information (list of countries). 
 
9.4  
Procedures for Handling Special Situations 
9.4.1  Pregnancy and Breastfeeding 
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 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.  
 
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 Section 9.3). 
 


 
Page 58 of 76                         
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 selinexor-
containing regimen. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
 
It is not known whether selinexor passes into the breast milk. Mothers should not 
breastfeed while being treated with a selinexor-containing regimen.  
 
9.4.2  Overdose, Abuse, Misuse, Medication Errors, and Occupational Exposure 
All incidences of overdose, abuse, misuse, medication errors, and occupational exposure 
are required to be reported to Karyopharm Pharmacovigilance on Karyopharm’s SAE 
report form and emailed to pharmacovigilance@karyopharm.com, regardless of whether 
or not there is an associated AE or SAE. 
 
9.4.2.1  
Overdose 
An overdose is a deliberate or accidental administration of any Karyopharm study drug to a 
study patient, at a dose greater than that which was assigned to that patient per the study 
protocol. If an overdose occurs, Karyopharm Pharmacovigilance should be notified 
immediately, and the patient should be observed closely for AEs. Resulting symptoms 
should be treated, as appropriate, and the incident of overdose and related AEs and/or 
treatment should be recorded. Information regarding the overdose is to be recorded on 
Karyopharm’s SAE report form and sent to Karyopharm Pharmacovigilance regardless of 
whether or not an AE or SAE has occurred due to the overdose. If the overdose is 
associated with an SAE, the SAE report form must be submitted to Karyopharm 
Pharmacovigilance within 24 hours of awareness. If there is no AE or SAE, the report must 
be submitted within 24 hours of awareness. 
 
As selinexor is metabolized by GSH conjugation, it is possible, but not demonstrated, that 
hepatic GSH depletion might occur in case of extreme overdose. Therefore, in overdose 
cases, if patients develop liver function test abnormalities, supportive measures such as 
SAM or other drugs that can replace GSH might be considered as part of the overall 
management plan. 
 
9.4.2.2.   
Abuse, Misuse, or Medication Error 
Abuse is the persistent or sporadic, intentional excessive use of the Karyopharm study drug 
which is accompanied by harmful physical or psychological effects.  
 
A medication error is any preventable incident that may cause or lead to inappropriate 
study treatment use or patient harm while the study treatment is in the control of the 
health care professionals or patients. Such incident may be due to health care professional 
practice, product labeling, packaging and preparation, procedures for administration, and 
systems, including the following: prescribing, order communication, nomenclature, 
compounding, dispensing, distribution, administration, education, monitoring, and use. 
 


 
Page 59 of 76                         
All occurrences of abuse, misuse, or medication error with the Karyopharm study drug are 
to be recorded on Karyopharm’s SAE report form and sent to Karyopharm 
Pharmacovigilance regardless of whether or not an AE or SAE has occurred due to the 
abuse, misuse, or medication error. If the abuse, misuse, or medication error is associated 
with an SAE, the SAE report form must be submitted to Karyopharm Pharmacovigilance 
within 24 hours of awareness. If there is no AE or SAE, the report must be submitted within 
24 hours of awareness. 
 
9.4.2.3  
Occupational Exposure 
Occupational exposure is the exposure to a study treatment as a result of one’s professional 
or non-professional occupation.  
 
All occurrences of occupational exposure with the Karyopharm study drug are to be 
recorded on Karyopharm’s SAE report form and sent to Karyopharm Pharmacovigilance 
regardless of whether or not an AE or SAE has occurred due to the occupational exposure.  
 
If the occupational exposure is associated with an SAE, the SAE report form must be 
submitted to Karyopharm Pharmacovigilance within 24 hours of awareness. If there is no 
AE or SAE, the report must be submitted within 24 hours of awareness. 
 
9.5  
Relationship to Study Drug 
All laboratory findings as defined in the CTCAE v4.03 that have been deemed by the  
Investigator as clinically significant should be recorded as AEs.  
 
For all AEs, relationship to study drug will be reported on the appropriate AE CRF page.  
The investigator must judge whether the study drug caused or contributed to the AE or SAE 
and whether or not the SAE is reportable to regulatory authorities.  
 
The Principal Investigator may delegate duties such as the assessment of causality of the 
AEs/SAEs to Sub-Investigators but must assure that these Sub-Investigators are qualified 
to perform these duties under the supervision of the Principal Investigator and that they 
are listed on the Form FDA 1572.  
 
Causality will be assessed as 1) unrelated 2) possibly related, or 3) probably or definitely 
related for all AEs. In addition, each AE will be categorized as clinically significant (CS) and 
non-clinically significant (NCS). 
 
10  
STATISTICAL ANALYSES  
10.1  Study Design/Endpoints 
The objectives of this combined phase Ib/II clinical trial are to identify the maximum 
tolerated dose of selinexor and gemcitabine combination (phase I component), determine 
the toxicity profile of the drug combination and test whether the combination improves 
overall survival (OS) as compared to an historical standard (phase II component). 
Secondary endpoints are to determine the pharmacodynamics (PDn) of selinexor in 
combination with gemcitabine, to determine response rate of the 2 drug combination, to 
confirm safety of RP2D of selinexor in combination with gemcitabine  in phase II portion of 


 
Page 60 of 76                         
the study, to determine progression free survival (PFS) in phase II cohort treated with the 2 
drug combination, and correlative studies. 
 
To facilitate investigation of correlative objectives; the administration of selinexor will be 
delayed in half of the 14 patients who consent to a second biopsy during the Phase II trial 
until after a second biopsy has occurred (48 hours post first treatment).  This design will 
allow for two separate but clinically relevant comparisons to be made: pre and post 
treatment differences in the molecular profile of combination of gemcitabine and selinexor, 
and the difference in the molecular profile of gemcitabine and selinexor versus gemcitabine 
only. We denote the group initially receiving the 2-drug combination treatment 
(gemcitabine only) as group 1 and the group initially receiving the 2 drug combination 
treatment as group 2. As the selinexor treatment is only delayed 48 hours for group 1, the 
effect on the survival endpoints for patients in group 1 should be negligible, although we 
will test for it to be certain. 
 
Our purpose in creating two different treatment regimens is to obtain biomarker data on a 
group of patients receiving gemcitabine to compare to patients receiving the 2 drug 
combination initially. These patients will still receive the experimental drug, but in a 
delayed fashion to allow us to measure our correlative objective. Since there are 2 groups 
in the treatment schedule (in case there is a survival difference between the groups), a 
permuted block design of random block size will be used to assign patients to groups. The 
Biostatistics Core will produce the randomization and monitor the compliance of the 
treatment assignments. This will help eliminate the impact of known or unknown 
confounding variables.  
 
10.2  Sample Size 
The phase I portion of this trial will employ a modified 3+3 design as detailed in section 5.1. 
At the conclusion of the phase I study there will be 6 patients enrolled at the MTD for the 2 
drug combination. We will include those 6 patients in the phase II efficacy and toxicity 
studies. A previous study indicated that the median survival of advanced/metastatic 
pancreatic cancer patients taking gemcitabine as second line is 5.6 months[24]. The 
hypothesis in this trial is that the addition of selinexor to this treatment regimen will 
increase the median overall survival to 8.4 months (a 50% increase). A sample size of 44 
yields 80% power to detect an increase in median survival of 2.8 months assuming 
exponentially distributed death times, 24 months of accrual and 12 months minimum 
follow up with a two-sided Type I error of 0.10[28].  
 
10.3  Analysis 
Descriptive statistics (point and exact 90% confidence interval estimates from the resultant 
Kaplan-Meier curve) will be generated for the primary endpoint as well for the PFS 
endpoint in the tertiary objectives. If the lower bound of the 90% confidence interval does 
not include 5.6 months, then the study will be deemed a success. The median OS and PFS 
will be estimated on an intention-to-treat basis (using all registered patients), and on a 
response-evaluable basis (using all patients who completed at least one 4-week treatment 
cycle) using the Kaplan-Meier method. Toxicity rates will be estimated using all treated 
patients from the phase II portion of the trial. Point and 90% Wilson’s confidence intervals 


 
Page 61 of 76                         
will be estimated to describe binary endpoints including toxicity rate and response rate. 
Patients who did not have an event 24 months after the last patient was enrolled will be 
censored for the survival endpoints (date of last contact for OS and date of last evaluation 
for progression for PFS). Exploratory Cox regression analyses will be undertaken to 
determine if any of the clinical covariates measured at the beginning of the trial (e.g., age, 
race, group assignment) are associated with OS and/or PFS.  
 
The pilot correlative studies that will be undertaken include the validation of CRM1 
measured through H & E staining and nuclear TSP alterations measured using IHC 
(including FOXO, IkB, p27, Par4 and pSTAT3) as the target of selinexor. We will utilize the 
first 14 patients from the phase II portion of the trial who consent to the required 2 
biopsies. Our study design will ensure that half of these 14 will be group 1 patients and half 
will be group 2 patients.  As our sample size is small, at most these correlative studies will 
be able to estimate mean change in gene expression in the 7 patients in each group. Seven 
patients in each group will yield a two-sided 90% confidence interval with a distance from 
the mean change to the limits of 0.75 standard deviation units. A two-sided alpha of 0.10 
will be used for all analyses. 
 
10.4  Evaluation of Toxicity 
All registered patients will be evaluated for toxicity probably related to the treatment. It is 
anticipated that one-third of the patients will experience a grade 3 or higher toxicity 
probably or definitely due to the treatment (using the toxicity rates reported from prior 
studies of selinexor, Section 1.1.4). Toxicity data will be collected at least weekly during the 
course of treatment.  
 
10.5  Specific Toxic Outcomes 
We will closely monitor the following outcomes: weight loss, loss of appetite, liver function 
tests, including AST, ALT and bilirubin, complete blood count. If 4 or more patients out of 
the first 10 (or fewer) treated in the phase II portion of the study develop a grade III (using 
the CTCAE guidelines) or higher toxicity in any of these categories that are probably or 
definitely related to the treatment received within the 6 months after the completion of 
treatment, we would recommend revisiting the study for safety reasons. We will continue 
to monitor these specific toxic outcomes throughout the course of the trial, in a sliding 
window fashion.  
 
10.6  Other Toxic Outcomes 
Data on other toxic side effects (excluding those detailed in the previous paragraph) that 
patients may experience will also be collected. We have chosen a safety threshold of 0.25 to 
monitor other toxic side effects. We would recommend reconsidering the phase II portion 
of the study for safety reasons if there were X many occurrences of grade 3 or higher 
toxicity (using the CTCAE guidelines) among the first N (or fewer) patients treated, as it 
would result in an upper confidence limit greater than 0.25: 
 
N 
X 
p 
UCL 
8 
1 
0.125 
0.255 


 
Page 62 of 76                         
13 
2 
0.154 
0.256 
18 
3 
0.167 
0.253 
22 
4 
0.181 
0.261 
27 
5 
0.185 
0.256 
32 
6 
0.188 
0.252 
 
In the above table, N = the number of patients treated; X = the cumulative number of 
patients with a grade 3 or higher toxicity currently observed; p = the observed toxicity rate; 
and UCL = the exact 1-sided upper 80% confidence limit for p, using Wilson's method 
without a continuity correction. After treating 32 patients, the potential toxicity risk of this 
regimen should be well defined, and thereafter the possible need for termination of the 
study based on toxicity should be minimal. 
 
10.7  Futility monitoring  
A concern with this regimen is that selinexor may impede the activity of gemcitabine, due 
to possible increased toxicity and decreased exposure to gemcitabine, resulting in worse 
survival outcomes. While our final analysis will be able to quantify this hypothesis (as it is a 
two-sided test), it is necessary to continually monitor the patients on trial for futility of 
treatment. As our final sample size is small for our 1-arm study, utilizing a survival 
endpoint for futility monitoring is not feasible. Therefore, we will monitor the proportion 
of patients who survive less than the reported median survival under the null hypothesis 
(5.6 months). We would recommend reconsidering the phase II portion of the study for 
futility reasons if there were greater than half of the registered patients at any time who 
did not survive longer than 5.6 months once at least 10 patients have either had an event or 
survived longer than 5.6 months. Thus, we will compute the [number of patients who 
survived less than 5.6 months]/([number of patients who survived less than 5.6 months] + 
[number of patients will survived longer than 5.6 months]) and monitor if that proportion 
ever becomes greater than one half once 10 patients had either outcome in the 
denominator. 
 
10.8  Expected Accrual Rate, Accrual Duration, and Study Duration 
Our anticipated accrual rate is 16-20 patients per year, including collaborative centers. We 
anticipate the accrual of ~12 patients per year at Karmanos and ~6 patients per year at 
other participating sites. Thus, it should take approximately 30 months to accrue the 
maximum 44 patients needed for the phase II portion of the trial. Allowing for 12 months of 
follow-up to obtain the primary endpoint on the last patient enrolled and 4 months to 
assemble, analyze and interpret the data the total study duration is projected to be at most 
4 years.  
 
11  
ETHICS  
11.1  Patient Protection 
The study will be conducted in accordance with the ethical principles of the Declaration of 
Helsinki and the ICH-GCP guidelines. The local principal investigators are responsible for 
ensuring that the study will be conducted in accordance with the protocol, the ethical 


 
Page 63 of 76                         
principles of the Declaration of Helsinki, current ICH guidelines on Good Clinical practice 
(GCP) and applicable local regulatory requirements.  
 
11.2  Patient Information  
Before entry into the trial all eligible patients will receive written patient, information 
describing the aim of the study, as well as probable and possible side effects and risks.  
Oral information from one of the investigators or a delegated person at the institution will 
also be given, and the patient must have the opportunity to ask questions, and to consider 
participation together with his/her family members if applicable. It will be emphasized that 
the participation is voluntary and that it is the right of the patient to refuse further 
participation in the study whenever he/she wants and that this will not influence his/her 
subsequent care.  
 
11.3  Informed Consent  
Patient / Legally acceptable representative (LAR) (as applicable) written consent must be 
obtained according to local Institutional and/or University Human Experimentation 
Committee requirements and must conform to the ICH guidelines for Good Clinical 
Practice, prior to any study-specific screening procedures and trial entry. The written 
informed consent form should be signed and personally dated by the patient or by the 
patient’s legally acceptable representative. A copy of the signed informed consent will be 
given to the patient or patient’s legally authorized representative. The original signed 
consent must be maintained by the Investigator at the institution and available for 
inspection regulatory authority at any time.  
 
The sponsor will provide the Investigator with a sample consent form. Local and/or 
institutional requirements may require disclosure of additional information in the 
informed consent. Any changes to the consent form must be submitted to the sponsor for 
approval, prior to submission to the IRB/REB/IEC. The IRB/REB/IEC will review the 
consent form for approval. A copy of the approved form must be submitted to the sponsor 
prior to initiation of the study.  
 
11.4  Ethics Board Approval  
Each site is responsible for submission of this study to the appropriate ethics board for 
approval, i.e. Institutional Review Board (IRB).   
 
Serious Adverse Events, Safety Updates and Investigator Brochure Updates during the 
course of the study may be sent to you for reporting to your IRB/REB/IEC. The investigator 
is responsible for notifying their IRB/REB/IEC of any such updates and documentation of 
ethics submission of this information must be forwarded to the sponsor. 
 
Initial approval: All study sites are required to obtain full board local ethics approval of the 
protocol and consent form by the appropriate REB/IRB/IEC prior to commencement of the 
clinical trial at each site.  
 


 
Page 64 of 76                         
Continuing approval: Annual (or as required by the REB/IRB/IEC) re-approval may be 
required until a closeout visit has been completed. It will be investigator’s responsibility to 
apply for and obtain the re-approval.  
 
Amendment: Modifications of the signed protocol are only possible by approved protocol 
amendments authorized by the Sponsor, who will inform sites in writing of any substantive 
changes to this protocol as a protocol amendment. Sites are responsible for submitting all 
protocol amendments with a revised informed consent form, if applicable, for review by 
their REB/IRB/IEC. Amendments will be reviewed and approved by applicable regulatory 
authorities prior to central implementation of the amendment, and by REB/IRB/IEC prior 
to local implementation, EXCEPT when the amendment eliminates an immediate hazard to 
clinical trial patients or when the change(s) involves only logistical or administrative 
aspects of the trial. The Investigator should not implement any deviation from, or change to 
the protocol, except where it is necessary to eliminate an immediate hazard to trial patient 
or when the change(s) involves only logistical or administrative aspects of the trial.  
 
REB/IRB/IEC Refusals: If an REB/IRB/IEC refuses to approve this protocol (or an 
amendment/revision to this protocol), the sponsor must be notified immediately of the 
date of refusal and the reason(s) for the refusal. Notification will then be made to the 
regulatory authorities.  
 
Upon completion of the trial, the Investigator must provide the IRB/REB/IEC with a 
summary of the trial’s outcome.  
 
Annual Report: The sponsor will submit annual reports to the FDA and may request 
information from the sites to support the completion of this annual report.  
 
12  
DOCUMENTATION, RECORD ACCESS, AND MAINTENANCE OF STUDY RECORDS  
12.1  Documentation of Patient’s Participation  
A statement acknowledging the participation of a patient in this clinical trial must be 
documented in the patient's medical records along with the signed ICF.  
 
Source Documentation  
Source records are original documents, data, and records (e.g., medical records, raw data 
collection forms, pharmacy dispensing records, recorded data from automated 
instruments, laboratory data) that are relevant to the clinical trial. The Investigator will 
prepare and maintain adequate and accurate source documents. These documents are 
designed to record all observations and other pertinent data for each patient enrolled in 
this clinical trial. Source records must be adequate to reconstruct all data transcribed onto 
the Case Report Forms (CRFs).  
 
12.2  Regulatory Requirements  
As this study will be submitted under an IND, the following documents are required for all 
sites:  
• 
All Investigators must complete and sign an FDA Form 1572.  


 
Page 65 of 76                         
• 
All Investigators must complete and submit a Financial Disclosure Statement.  
 
Before the start of the study, the following documents must be forwarded to the sponsor 
• 
An original U.S. Form FDA 1572 for the site, signed by the Principal Investigator.  
• 
Current (within 2 years of study start) Curriculum Vitae (CV) for the Principal  
• 
Investigator and all Sub Investigators  
• 
Original financial disclosure forms for the Principal Investigator and all Sub  
• 
Investigators listed on the U.S. Form FDA 1572  
• 
Current IRB membership list and/or Department of Health and Human Services 
number  
• 
Copies of all appropriate laboratory certifications and laboratory normal ranges  
• 
IRB approval of the protocol: the approval letter must identify the protocol  
• 
Number, title and date of protocol  
• 
IRB approved informed consent: the approval letter must identify the protocol 
number, title of protocol and date of the informed consent. 
• 
IRB approval of any advertising materials to be used for study recruitment, if 
applicable  
• 
IRB approval of any other study materials (e.g. patient diary)  
• 
HIPAA Forms (if applicable)  
• 
Original signed Investigator agreement  
• 
Original signed and dated Investigator Protocol Signature page  
• 
Site delegation list  
 
Study Completion  
The following documents/data must be received by the sponsor before a study site may be 
closed:  
• 
All completed CRFs and corresponding data clarifications  
• 
All laboratory samples (received by sponsor) and data  
• 
Original, final SAE reports and copies of all relevant de-identified supporting 
documentation (i.e., discharge summaries, laboratory results)  
• 
Original, final Pregnancy Information Forms (PIF) and copies of all relevant de-
identified supporting documentation  
• 
Complete and accurate drug accountability records and inventory logs  
• 
Original screening and enrollment log  
• 
Copies of all ethics board correspondence (including, e.g., annual reports, SAE 
notifications, ethics board submissions) and approvals for the protocol, 
amendments, informed consent, and advertising materials (if applicable)  
• 
A copy of the ethics board study summary close letter  
• 
All regulatory documents (i.e., current CV’s for the Principal Investigator and  
• 
Sub-Investigators, updated FDA Form 1572, current laboratory certifications, 
normal ranges, completed delegation log)  
• 
Updated financial disclosure forms for the Principal Investigator and all Sub-
Investigators listed in the FDA Form 1572. All remaining study materials (i.e., 


 
Page 66 of 76                         
unused CRFs, used/unused study drug) must be returned to the sponsor or 
disposed of following notification and approval by Sponsor.  
 
12.3  Compliance with Laws and Regulations  
The study will be conducted in accordance with U.S. FDA and International Conference on 
Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), the ethical principles of 
the Declaration of Helsinki, any applicable local health authority, and Institutional Review 
Board (IRB) or Research Ethics Board (REB) or Institutional Ethics Committee (IEC) 
requirements.  
 
Before the investigational drug is shipped to the Investigator, the Investigator will provide 
the sponsor with a copy of the IRB or REB approval letter stating that the study protocol 
and any subsequent amendments and informed consent form have been reviewed and 
approved.  
 
12.4  Patient Confidentiality and Access to Source Data/Documents Patient 
Identification  
A sequential unique identification number will be attributed to each patient registered in 
the trial. This number will identify the patient and must be included on all case report 
forms. A patient will not be identified by name, only by his/her initials. The patient’s name 
or any identifying information will not appear in any reports published as a result of this 
study. In order to avoid identification errors, patient’s initials and date of birth (as 
permitted by the ethics board) will also be reported on the study forms. Any research 
information obtained about the patient in this study will be kept confidential. However, 
information obtained from individual patient’s participation in the study may be disclosed 
with his/her consent to the health care providers for the purpose of obtaining appropriate 
medical care. The patient’s medical records/charts, tests will be made available to the 
Sponsor, the US FDA and Karyopharm Therapeutics Inc., the REB/IRB/IEC and any other 
regulatory authorities. This is for the purpose of verifying information obtained for this 
study. Confidentiality will be maintained throughout the study within the limits of the law.  
 
A patient’s name will not be given to anyone except the researchers conducting the study, 
who have signed a confidentiality agreement. All identifying information will be kept 
behind locked doors, under the supervision of the study Principal Investigator and will not 
be transferred outside of the hospital.  
 
A patient may take away his/her permission to collect, use and share information about 
him/her at any time. If this situation occurs, the patient will not be able to remain in the 
study. No new information that identifies the patient will be gathered after that date. 
However, the information about the patient that has already been gathered and transferred 
may still be used and given to others as described above in order to preserve the scientific 
integrity and quality of the study.  
 


 
Page 67 of 76                         
12.5  Confidentiality of the Study  
Data generated as a result of this study are to be available for inspection on request by local 
health authority auditors, the Sponsor’s Study Monitors and other personnel and by the 
IRB/REB/IEC. The Investigator shall permit sponsor and Karyopharm, authorized agents of 
the sponsor and Karyopharm and regulatory agency employees to enter and inspect any 
site where the drug or records pertaining to the drug are held, and to inspect all source 
documents. The protocol and other study documents contain confidential information and 
should not be shared or distributed without the prior written permission of sponsor. 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for 
Privacy of Individually Identifiable Health Information, 45 CFR 164.508.  
 
12.6  Registration of Clinical Trial  
Prior to the first patient being registered/enrolled into this study, Karmanos Cancer 
Institute will be responsible for ensuring that the clinical trial is registered appropriately to 
remain eligible for publication in any major peer-reviewed journal, adhering to the 
guidelines put forth by the International Committee of Medical Journal Editors (ICMJE).  
 
12.7  Data Reporting  
Clinical trial data will be collected utilizing OnCore’s electronic data capture system 
electronic CRF’s.   
 
Appropriate personnel at all participating sites will be trained to utilize the Oncore system 
by the Karmanos Informatics department.  
 
Trial data entered in Oncore will be verified by source documentation. CRFs should be 
completed by participating sites within 10 business days of the availability of clinical 
documentation of a study visit. Data clarification and queries should be completed within 7 
working days of notification.  
 
A monitor specialist from KCI CTO will remotely monitor essential clinical trial data. 
Frequency of monitoring will be based on accrual at a site but will occur at least once every 
2 months if a patient has been enrolled. 
 
Monthly screening and enrollment logs are to be sent to the KCI Lead Study Coordinator.  
 
12.8  Data Monitoring: 
The investigators who accrue the patients will be responsible for patient assessment and 
documentation of patient status in the patient records. All adverse events will be duly 
recorded by investigators. All study personnel have access to data. Our data managers and 
coordinators are highly experienced in running complex trials. 
 
The GI MDT has a weekly meeting whereby attendings, research nurses, data managers and 
other staff attend and discuss the studies and monitor patient accrual. Regular 
communication will be established with collaborating institutions by phone on a 1-2 
weekly basis and whenever necessary.  


 
Page 68 of 76                         
 
Patient survival will always be known and if death happens is recorded in the electronic 
chart and all study personnel have access to it.  
 
12.9  Maintenance of Study Records  
To enable evaluations and/or audits from Regulatory Authorities, the Investigator agrees 
to keep records, including the identity of all participating patients (sufficient information to 
link records, CRFs and hospital records), all original signed informed consent forms, copies 
of all CRFs, source documents, and detailed records of treatment disposition.  
 
According to 21 CFR 312.62(c), the Investigators shall retain records required to be 
maintained under this part for a period of two years following the date a marketing 
application is approved for the drug for the indication for which it is being investigated. If 
no application is to be filed or if the application is not approved for such indication, the  
Investigator shall retain these records until two years after the investigation is 
discontinued and the FDA is notified.  
 
The Investigator must retain protocols, amendments, IRB approvals, copies of the Form  
FDA 1572, signed and dated consent forms, medical records, case report forms, drug 
accountability records, all correspondence, and any other documents pertaining to the 
conduct of the study.  
 
If the investigator relocates, retires, or for any reason withdraws from the study, then the  
Sponsor should be prospectively notified. The study records must be transferred to an 
acceptable designee, such as another investigator, another institution, or to the Sponsor.  
The investigator must obtain the Sponsor’s written permission before disposing of any 
records.  
 
13  
QUALITY ASSURANCES AND QUALITY CONTROL  
As per the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), Karmanos Cancer 
Institute will be responsible for implementing and maintaining quality assurance and 
quality control systems.  
 
13.1  Data and Safety Monitoring 
Scheduled meetings will be held monthly or more frequently depending on the activity of the 
protocol. Meetings will include the protocol investigators and study coordinator involved 
with the conduct of the protocol. 
 
During these meetings, the investigators will discuss matters related to:  
• 
Safety of protocol participants (Adverse Event reporting) 
• 
Validity and integrity of the data 
• 
Enrollment rate relative to expectation of target accrual, characteristics of 
participants 
• 
Retention of participants, adherence to the protocol (potential or real protocol 
violations) 


 
Page 69 of 76                         
• 
Data completeness on case report forms and complete source Documentation 
 
Following these meetings, the study coordinator will complete a protocol specific Data Safety 
and Monitoring form that will include summaries of all accrual data, all AE’s grade 3+, 
regardless of attribution, protocol deviations and IRB amendments. These reports will be 
cumulative and will also include reasons that patients are taken off study. 
 
Completed Data and Safety Monitoring Reports of these regular investigator meetings will 
be kept on file in the office of the Clinical Trials Office at KCI per SOP #35. These reports will 
be completed monthly and submitted quarterly according to the quality assurance schedule 
by the study coordinator and given to the Clinical Trials Quality Assurance Manager for 
review and processing with the Data and Safety Monitoring Committee (DSMC). 
 
The Barbara Ann Karmanos Cancer Institute DSMC will meet on a monthly basis to review 
the prior months Serious Adverse Event forms and Data and Safety Monitoring Reports 
that have been filed. 
 
14  
ADMINISTRATIVE PROCEDURES  
14.1  Protocol Deviations and Violations  
All violations or deviations are to be reported to the site’s IRB/REB/IEC (as per the ethics 
board’s guidelines). All IRB/REB/IEC correspondence is to be forwarded to the sponsor. 
The site must notify the sponsor immediately of any protocol violations.  
 
14.2  Premature Discontinuation of the Study  
The Sponsor reserves the right to discontinue the trial for any reason but intends only to 
exercise this right for valid scientific or administrative reasons. After such a decision, the  
Investigators must contact all participating patients immediately after notification.  
Standard therapy and follow-up for patients will be assured and, where required by the 
applicable regulatory requirement(s), the relevant regulatory authority (ies) will be 
informed.  
 
The REB/IRB/IEC will be informed promptly and provided with a detailed written 
explanation for the termination or suspension.  
 
As directed by the Sponsor, all study materials must be collected and all CRFs completed to 
the greatest extent possible in the case of a premature discontinuation of study.  
 
15  
PUBLICATION POLICY  
The results, both positive and negative, will be published in a peer reviewed journal. 
Authorship will follow the Vancouver Publication rules. Specifically, for the main  
publication:  
• 
First author will be decided by Dr. Mohammed Najeeb Al Hallak  who will be the 
senior author.  
• 
Subsequent authors in decreasing order of accrual.  
 


 
Page 70 of 76                         
16.  
APPENDICES 
16.1  Appendix 1: Eastern Cooperative Oncology Group Performance Status Criteria  
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction.  
1 
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 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair 
5 
Dead. 
 
16.2  Appendix 2:  
Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03  
Published: May 28, 2009 (v4.03: June 14, 2010)  
 
16.3  Appendix 3: Template for Line Listing of Adverse Events 
 


 
Page 71 of 76                         
16.4 Appendix 4: Serious Adverse Event Report Form
 


 
Page 72 of 76                         
 


 
Page 73 of 76                         
 


 
Page 74 of 76                         
16.5.  Appendix 5: Memo Regarding Cross-reported SUSAR form KPT CSTs 
 
 
 


 
Page 75 of 76                         
17  
REFERENCES  
 
1. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
2. 
Sharpless, N.E. and R.A. DePinho, Cancer biology: gone but not forgotten. Nature, 
2007. 445(7128): p. 606-7. 
3. 
Turner, J.G., J. Dawson, and D.M. Sullivan, Nuclear export of proteins and drug 
resistance in cancer. Biochem Pharmacol, 2012. 83(8): p. 1021-32. 
4. 
Turner, J.G. and D.M. Sullivan, CRM1-mediated nuclear export of proteins and drug 
resistance in cancer. Curr Med Chem, 2008. 15(26): p. 2648-55. 
5. 
Xu, D., A. Farmer, and Y.M. Chook, Recognition of nuclear targeting signals by 
Karyopherin-beta proteins. Curr Opin Struct Biol, 2010. 20(6): p. 782-90. 
6. 
Kau, T.R., J.C. Way, and P.A. Silver, Nuclear transport and cancer: from mechanism to 
intervention. Nat Rev Cancer, 2004. 4(2): p. 106-17. 
7. 
Siddiqui, N. and K.L. Borden, mRNA export and cancer. Wiley Interdiscip Rev RNA, 
2012. 3(1): p. 13-25. 
8. 
Jang, B.C., et al., Leptomycin B, an inhibitor of the nuclear export receptor CRM1, 
inhibits COX-2 expression. J Biol Chem, 2003. 278(5): p. 2773-6. 
9. 
van der Watt, P.J. and V.D. Leaner, The nuclear exporter, Crm1, is regulated by NFY 
and Sp1 in cancer cells and repressed by p53 in response to DNA damage. Biochim 
Biophys Acta, 2011. 1809(7): p. 316-26. 
10. Golomb, L., et al., Importin 7 and exportin 1 link c-Myc and p53 to regulation of 
ribosomal biogenesis. Mol Cell, 2012. 45(2): p. 222-32. 
11. Brown, C.J., et al., Reactivation of p53: from peptides to small molecules. Trends 
Pharmacol Sci, 2011. 32(1): p. 53-62. 
12. Maas, A.M., et al., Targeting p73 in cancer. Cancer Lett, 2011. 
13. Kloet, D.E. and B.M. Burgering, The PKB/FOXO switch in aging and cancer. Biochim 
Biophys Acta, 2011. 1813(11): p. 1926-37. 
14. Kau, T.R., et al., A chemical genetic screen identifies inhibitors of regulated nuclear 
export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell, 
2003. 4(6): p. 463-76. 
15. Castro-Alcaraz, S., et al., NF-kappa B regulation in human neutrophils by nuclear I 
kappa B alpha: correlation to apoptosis. J Immunol, 2002. 169(7): p. 3947-53. 
16. Gupta, S.C., et al., Inhibiting NF-kappaB activation by small molecules as a therapeutic 
strategy. Biochim Biophys Acta, 2010. 1799(10-12): p. 775-87. 
17. Chapuis, N., et al., IkappaB kinase overcomes PI3K/Akt and ERK/MAPK to control 
FOXO3a activity in acute myeloid leukemia. Blood, 2010. 116(20): p. 4240-50. 
18. Grisendi, S., et al., Nucleophosmin and cancer. Nat Rev Cancer, 2006. 6(7): p. 493-
505. 
19. Vassiliou, G.S., et al., Mutant nucleophosmin and cooperating pathways drive leukemia 
initiation and progression in mice. Nat Genet, 2011. 43(5): p. 470-5. 
20. Mutka, S.C., et al., Identification of nuclear export inhibitors with potent anticancer 
activity in vivo. Cancer Res, 2009. 69(2): p. 510-7. 
21. Sharon Shacham, J.T., Raphael Nir, Giulio Draetta, Keith Stewart, Sharon , V.S. 
Shechter, Dilara McCauley, Michael Kauffman and Daniel , and D.M. Sullivan, KPT-
0127 Induces Selective Apoptosis of Malignant Cells by CRM1 Inhibition and Elevation 


 
Page 76 of 76                         
of Regulatory Proteins p53, p21, FOXO and IkB. ASH Annual Meeting Abstracts, 2010. 
116: p. Abstract 3012. 
22. Daniel D. Von Hoff, T.J.E., Francis P. Arena, E. Gabriela Chiorean, Jeffrey R. Infante, 
Malcolm J. Moore, Thomas E. Seay, Sergei Tjulandin, Wen Wee Ma, Mansoor N. Saleh, 
Marion Harris, Michele Reni, Ramesh K. Ramanathan, Josep Tabernero, Manuel 
Hidalgo, Eric Van Cutsem, David Goldstein, Xinyu Wei, Jose Luis Iglesias, Markus 
Frederic Renschler, Randomized phase III study of weekly nab-paclitaxel plus 
gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of 
the pancreas (MPACT). J Clin Oncol 30: 2012 (suppl 34; abstr LBA148), 2013. 
23. Vaccaro, V., I. Sperduti, and M. Milella, FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. N Engl J Med, 2011. 365(8): p. 768-9; author reply 769. 
24. Fernandes BM, B.R., Sabbaga J, Hoff PM, Is gemcitabine effective for pancreatic cancer 
after progression to FOLFIRINOX? Journal of Clinical Oncology, 2017. 35(4_suppl): p. 
489-489. 
25. Sarabi, M., et al., Use of gemcitabine as a second-line treatment following 
chemotherapy with folfirinox for metastatic pancreatic adenocarcinoma. Oncol Lett, 
2017. 13(6): p. 4917-4924. 
26. da Rocha Lino, A., et al., Role of gemcitabine as second-line therapy after progression 
on FOLFIRINOX in advanced pancreatic cancer: a retrospective analysis. J Gastrointest 
Oncol, 2015. 6(5): p. 511-5. 
27. Kazim, S., et al., Selective Nuclear Export Inhibitor KPT-330 Enhances the Antitumor 
Activity of Gemcitabine in Human Pancreatic Cancer. Mol Cancer Ther, 2015. 14(7): 
p. 1570-81. 
28. Lawless, J., Statistical Models and Methods for Lifetime Data. 1982: John Wiley and 
Sons.