Clinical trial NCT02215161
Conditions: Castration Levels of Testosterone Hormone-Resistant Prostate Cancer Metastatic Prostate Carcinoma in the Soft Tissue Prostate Carcinoma Metastatic in the Bone PSA Progression Stage IV Prostate Adenocarcinoma AJCC v7
Sponsor: University of California, San Francisco
Start date: 2014-09-02; Completion date: 2018-04-02
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies selinexor in treating patients with prostate cancer that has spread to other parts of the body (metastatic), keeps growing even when the amount of testosterone in the body is reduced to very low levels (castration-resistant), and did not respond to treatment (refractory) with abiraterone acetate and/or enzalutamide. Selinexor may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To describe radiographic progression free survival (rPFS) associated with selinexor in patients with abiraterone (abiraterone acetate) refractory metastatic castration-resistant prostate cancer (mCRPC).

SECONDARY OBJECTIVES:

I. To measure prostate-specific antigen (PSA) changes at 12 weeks post-selinexor initiation.

II. To assess time to PSA progression. III. To measure time to development of \>= 2 new bone lesions. IV. To compare the relationship of abiraterone-resistance status (primary vs acquired) and treatment outcome.

V. To determine the effect of selinexor on persistent pain associated with bone metastasis using the brief pain inventory (BPI) short form.

VI. To describe the safety profile of selinexor in patients with metastatic castration-resistant prostate cancer.

VII. To determine the effect of selinexor on circulating leukocyte exportin 1 (XPO-1) expression, leukocyte gene expression profile and macrophage inhibitory cytokine-1 (MIC-1) messenger ribonucleic acid (mRNA) expression.

VIII. To assess serum selinexor trough levels as a function of dose and time since last dose.

TERTIARY OBJECTIVES:

I. To describe the relationship of XPO-1 expression to PSA decline. II. To describe the expression profile of metastatic tumor and outcome. III. To describe the type of progression (e.g. pain, bone etc). IV. To define XPO-1 expression in patients for whom pre- and post-treatment biopsy is obtained.

OUTLINE:

Patients receive selinexor orally (PO) on days 1 and 3 of weeks 1-3. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 6 months thereafter.

Arms: arm 1: Patients receive selinexor PO on days 1 and 3 of weeks 1-3. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Selinexor
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 
Phase II Single Agent Study of Selinexor (KPT-330) in 
Patients with Metastatic Castration-Resistant Prostate 
Cancer (mCRPC) and Prior Therapy with Abiraterone and/or 
Enzalutamide 
Protocol Number:  14552 
Study Drug:  Selinexor (KPT-330) 
Version Number:  3.1 
Version Date:  April 27, 2016 
IND Number:  122,157 
Principal Investigator (Sponsor-Investigator) 
Charles J. Ryan, MD   
University of California San Francisco 
1825 4th Street, 4th Floor, San Francisco, CA 94158  
Telephone:  415-353-9279 
Fax:  415-353-7779 
E-mail:  ryanc@medicine.ucsf.edu 
Co-Investigators 
Eric Small, MD   
Amy Lin, MD   
Lawrence Fong, MD 
Terence Friedlander, MD 
Rahul Aggarwal, MD 
Won Kim, MD  
Adam Siegel MD  
Tammy Rodvelt, NP 
Statistician 
Li Zhang PhD   
Revision History 
Version 1.0  
11-07-2013   
Version 1.1 
01-21-2014 
Version 1.2 
03-13-2014 
Version 1.3 
04-08-2014 
Version 2.0 
Version 3.0 
Version 3.1 
06-08-2014 
03-10-2015 
04-27-2016 
 


 
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Protocol CC#: 14552 
Phase II – Selinexor (KPT-330) 
 
Page 2 of 70 
Protocol Signature Page 
Protocol No.: 14552 
Version Date:  April 27, 2016 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review 
Committee (PRC), Institutional Review Board (IRB), and Data Safety Monitoring 
Committee (DSMC).  
2. I will conduct the study in accordance with applicable IRB requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and 
welfare of study participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol.  
4. I have read and understand the information in the Investigators’ Brochure (or 
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to conduct 
the protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable 
ethical principles, the Statement of Investigator (Form FDA 1572), and with local 
regulatory requirements. In accordance with the FDA Modernization Act, I will ensure 
the registration of the trial on the www.clinicaltrials.gov website.  
5. I agree to maintain adequate and accurate records in accordance with IRB policies, 
Federal, state and local laws and regulations. 
UCSF Principal Investigator / Study Chair 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
Participating Site(s) 
        
        
        
Telephone:        
E-mail:        
        
        
        
Telephone:        
E-mail:        
        
        
        
Telephone:        
E-mail:        
 
Principal Investigator 
 
Site 
Printed Name 
 
 
Signature 
 
Date 
 
 


 
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Abstract 
Title 
Phase II Single Agent Study of Selinexor (KPT-330) in Patients with Metastatic 
Castration-Resistant Prostate Cancer (mCRPC) and Prior Therapy with 
Abiraterone and/or enzalutamide  
Patient 
population 
Patients with abiraterone- or enzalutamide-refractory mCRPC. 
Rationale for 
Study 
Abiraterone acetate is now considered the standard of care for patients with 
metastatic castrate-resistant prostate cancer (mCRPC) in the pre-chemotherapy 
setting.  Patients with primary or acquired abiraterone resistance typically have 
rapidly progressive, refractory disease for which limited treatment options are 
available.  The development of new therapies in mCRPC requires a focus on 
patients with primary or acquired resistance to abiraterone. Patients with 
abiraterone-refractory mCRPC have a poor prognosis overall with median 
survival after progression of disease at approximately 19 months.  While 
chemotherapy is a standard approach in this setting, it is refused by many 
patients and clinicians due to toxicity concerns.  
Selinexor is a first in class Selective Inhibitor of Nuclear Export (SINE) that 
specifically blocks the karyopherin protein Exportin 1 (XPO1/Exportin 1). XPO1 is 
a key regulatory protein responsible for the nuclear export leading to functional 
inactivation of tumor suppressor proteins (TSPs) and is up-regulated 2-4 fold in 
all cancers studied to date.  Selinexor, given orally, has demonstrated potent 
anti-cancer activity in animal models of prostate cancer including inhibition of 
PC3 driven bone metastasis. 
The goal of this trial is to evaluate the potential for a progression free survival 
benefit associated with selinexor administration in patients with abiraterone-
refractory mCRPC.   
 
Primary 
Objective 
To describe radiographic progression free survival (rPFS) associated with 
selinexor in patients with abiraterone- and/or enzalutamide-refractory mCRPC 
Secondary 
Objectives 
• 
To measure PSA changes at 12 weeks post-selinexor initiation 
• 
To measure time to PSA progression 
• 
To measure time to development of ≥ 2 new bone lesions 
• 
To compare the relationship of abiraterone-resistance status (primary vs 
acquired) and treatment outcome 
• 
To describe the safety profile of selinexor 
• 
To measure reduction in pain for symptomatic patients based on the 
brief pain inventory short form. 
• 
To determine the effect of selinexor on XPO-1 expression, leukocyte 
gene expression profile, and macrophage inhibitory cytokine-1 (MIC-1) 
mRNA expression 
• 
To assess serum levels of selinexor as a function of dose and time since 
last dose 
  


 
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Study Design 
Single agent phase II open label study of selinexor in patients with mCRPC with 
prior therapy with standard hormone ablation agents and abiraterone. 
 
Number of 
patients 
A maximum of 54 evaluable patients will be accrued for this study, provided the 
early stopping criteria are not met.  
Duration of 
Therapy 
In the absence of treatment delays due to adverse events, treatment may 
continue until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s), including any occurrence of grade 4 
neurotoxicity 
• 
Patients decides to withdraw from the study 
• 
Significant patient non-compliance with protocol 
• 
General or specific changes in the patients’ condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
Duration of 
Follow up 
Patients will be followed for 30 days after completion of treatment or removal 
from study, or until death, whichever occurs first.  Patients removed from study 
for unacceptable treatment related adverse event(s) will be followed until 
resolution or stabilization of all treatment related adverse events to Grade 2 or 
lower. 
 
Duration of 
study 
The study will reach the final procedure for primary outcome 24 months from the 
time the study opens to accrual.  Data collection will be completed 36 months 
after the study opens to accrual. 
 
Study Drugs 
The starting dose for all patients will be an oral dose of 60 mg, given twice per 
week at least 48 hours apart (Mon/Wed, Tue/Thurs or Wed/Fri) on Weeks 1, 2 
and 3 of a 4-week cycle. Selinexor will not be taken during Week 4 (total six 
doses per cycle). Cycles are repeated every 28 days until disease progression.  
Tablets for selinexor oral administration will be supplied in two (2) strengths: 10 
and 25 mg of active ingredient per tablet. Ondansetron 8 mg q8h and olanzapine 
5 mg PO qbedtime will be administered on the day of dosing 
Safety 
Assessments 
Each patient receiving selinexor will be evaluable for safety.  The safety 
parameters include all laboratory tests and hematological abnormalities, physical 
findings, and spontaneous reports of adverse events reported to the investigator 
by patients. 
We will monitor for anorexia, loss of appetite, fatigue, thrombocytopenia, 
neutrocytopenia, diarrhea, blurred vision, liver enzyme increase, and 
hyponatremia.  
Efficacy 
Assessments 
Response and progression will be evaluated in this study using the international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 criteria. Changes in only the longest diameter (unidimensional measurement- 
LD) of the tumor lesions are used in the RECIST criteria.  


 
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Unique 
Aspects of 
this Study 
This trial represents will assess a first-in-class SINE selinexor in treatment of 
metastatic castrate resistant prostate cancer.  Not only does selinexor reflect a 
novel treatment modality in mCRPC, this may reflect a potential therapeutic 
option for patients with primary or acquired abiraterone resistance.    
 
 


 
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List of Abbreviations 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CRM1 
Chromosome Region Maintenance 1 
CT 
computerized tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
DLT 
dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCT 
Hematocrit 
HDFCCC 
Helen Diller Family Comprehensive Cancer Center 
HGB 
Hemoglobin 
ICH 
International Conference on Harmonization 
IND 
investigational new drug application 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
LMB 
Leptomycin B 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 


 
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List of Abbreviations 
ORR 
overall response rate 
PD 
disease progression 
PO 
Per os (by mouth, orally) 
PR 
partial response 
PRC 
Protocol Review Committee (UCSF) 
PRN 
Pro re nata (as needed) 
RBC 
red blood cell (count) 
SD 
stable disease 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SINE 
Selective Inhibitor of Nuclear Export  
SU2C 
Stand-up 2 Cancer 
ULN 
upper limit of normal 
XPO1 
Exportin 1 
 
 


 
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Table of Contents 
Protocol Signature Page 
Abstract 
3 
List of Abbreviations 
Table of Contents 
1 
Introduction 
1.1 
Background on Indication 
1.2 
Background on the Selinexor 
1.2.1 
SINE XPO1 inhibition 
1.3 
Rationale for the Proposed Study 
1.4 
Rationale for Proposed Dose 
1.5 
Correlative Studies 
2 
Objectives of the Study 
2.1 
Primary 
2.2 
Secondary 
2.3 
Exploratory Objectives, Other Assessments 
2.4 
Endpoints 
2.4.1 
Primary Endpoints 
2.4.2 
Secondary Endpoints 
2.4.3 
Exploratory Endpoints 
3 
Study Design 
3.1 
Characteristics 
3.2 
Number of Subjects 
3.3 
Eligibility Criteria 
3.3.1 
Inclusion Criteria 
3.3.2 
Exclusion Criteria 
3.4 
Duration of Therapy 
3.5 
Duration of Follow Up 
3.6 
Study Timeline 
3.6.1 
Primary Completion 
3.6.2 
Study Completion 
4 
Study Drug 
4.1 
Description, Supply and Storage of selinexor 
4.2 
Drug Accountability 
4.3 
Drug Ordering 
4.4 
Packaging and Labeling of Study Drug 
5 
Treatment Plan 
5.1 
Dosage and Administration 
5.2 
Dose Modifications and Dosing Delays 
5.3 
Monitoring and Toxicity Management 
6 
Study Procedures and Observations 
6.1 
Schedule of Procedures and Observations 


 
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Table of Contents 
6.1.1 
Pretreatment Period 
6.1.2 
Treatment Period 
6.1.3 
End-of-Treatment Study Procedures 
6.1.4 
End-of-treatment long-term follow-up 
6.1.5 
Discontinuation of Therapy 
6.2 
PK and PD Calendar 
6.3 
Dietary Restrictions 
6.4 
Prohibited Medications 
7 
Reporting and Documentation of Results 
7.1 
Evaluation of Efficacy (or Activity) 
7.2 
Definitions 
7.3 
Disease Parameters 
7.4 
Evaluation of Safety 
7.5 
Definitions of Adverse Events 
7.5.1 
Adverse Event 
7.5.2 
Adverse reaction 
7.6 
Recording of an Adverse Event 
7.7 
Follow-up of Adverse Events 
7.8 
Adverse Events Monitoring 
7.9 
Expedited Reporting 
8 
Statistical Considerations and Evaluation of Results 
8.1 
Study Endpoints 
8.1.1 
Study Design 
8.2 
Determination of Sample Size and Accrual Rate 
8.2.1 
Sample Size and Power Estimate 
8.2.2 
Replacement Policy 
8.2.3 
Accrual estimates 
8.3 
Interim Analyses and Stopping Rules 
8.4 
Analyses Plans 
8.4.1 
Analysis Population 
8.4.2 
Primary Analysis (or Analysis of Primary Endpoints) 
8.4.3 
Secondary Analysis (or Analysis of Secondary Endpoints) 
8.4.4 
Pharmacokinetic and pharmacodynamic analyses 
8.4.5 
Other Analyses/Assessments 
8.5 
Evaluation of Safety 
9 
Study Management 
9.1 
Pre-study Documentation 
9.2 
Institutional Review Board Approval 
9.3 
Informed Consent 
9.4 
Changes in the Protocol 
9.5 
Registration/Enrollment 
9.6 
Handling and Documentation of Clinical Supplies 


 
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Table of Contents 
9.7 
Case Report Forms (CRFs) 
9.8 
Oversight and Monitoring Plan 
9.9 
Record Keeping and Record Retention 
9.10 
Coordinating Center Documentation of Distribution 
10 
Protection of Human Subjects 
10.1 
Protection from Unnecessary Harm 
10.2 
Protection of Privacy 
Selected References. 
Appendix 1 
Performance Status Criteria 
Appendix 2 
Data and Safety Monitoring Plan for Multicenter Institutional Study 
Appendix 3 
UCSF Policy/Procedure for Required Regulatory Documents for a UCSF 
Multicenter Investigator-Initiated Oncology Clinical Trials with an 
Investigator held Investigational New Drug (IND) 
Appendix 4 
Full Ophthalmological Exam 
List of Tables 
Table 1.1 
Oncogenic Pathways and TSP/GRP Functions Enhanced by XPO1 
Inhibition 
12 
Table 5.1.1 
Regimen Description .........................................................................................
Table 5.3 
Criteria for dose adjustments of selinexor -related toxicities ............................
 
 
 
 


 
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1 Introduction 
1.1 
Background on Indication 
Prostate cancer is the second most common cancer in men representing approximately 
30% of all cancers diagnosed in men. When confined to the prostate gland the disease is 
curable with local therapy. However approximately 50% of men fail local therapy and 
develop incurable metastatic disease.  
Abiraterone acetate (Zytiga®) is now considered the standard of care for patients with 
metastatic castration resistant prostate cancer (mCRPC) who are asymptomatic or 
minimally symptomatic and have not been treated with docetaxel chemotherapy [1].  In its 
current clinical use, approximately 30% of such patients do not experience a significant 
reduction in tumor burden or decline in PSA level and thus have primary resistance. Of the 
remaining approximately 70% of patients, the vast majority will experience benefit but 
develop acquired resistance within a median period of time of approximately 16 months. 
Following the development of resistance, the disease is often virulent and can be rapidly 
fatal. The median survival after progression of disease is approximately 19 months. To 
date, no therapy has been shown to consistently improve outcomes in patients with 
abiraterone-refractory mCRPC. 
Thus, the development of new therapies in mCRPC requires a focus on patients with 
primary or acquired resistance to abiraterone. Further, it is likely that subsequent 
therapies, to be active, will be required to be agents with a unique mechanism of action, 
and not be antagonists of the androgen receptor and its related pathways.  
1.2 
Background on the selinexor 
Selinexor is an oral, first in class, slowly reversible covalent, potent, Selective Inhibitor of 
Nuclear Export (SINE) that specifically blocks the karyopherin protein Exportin 1 
(XPO1/Exportin 1), also called chromosome region maintenance 1 (CRM1).  XPO1 is 
overexpressed 2-4 fold in all cancers studied to date, including prostate cancer (Fesstucia, 
AACR).  XPO1 is an exclusive nuclear transporter for shuttling the major Tumor 
Suppressor Proteins (TSPs) and other growth regulators out of the nucleus. Because 
TSPs require nuclear localization to mediate their deoxyribonucleic acid (DNA) damage 
assessment/tumor suppressing functions, nuclear export leads to their functional 
inactivation.  In addition, many TSPs are degraded by the proteasome when they are 
transported to the cytoplasm.  Blockade of XPO1 leads to marked accumulation of TSPs in 
the nucleus of all cells, leading to cell cycle arrest at the G1±G2 checkpoints.  Cells with 
damaged genomes – i.e., cancer cells – undergo apoptosis, whereas undamaged normal 
cells remain in cell cycle arrest until the XPO1 block is released.  Consistent with its 
activation of multiple TSPs, selinexor has shown broad anti-cancer activity in nonclinical 
murine xenograft, orthotopic, primagraft, and leukemograft models including activity in 
xenograft of androgen independent prostate cancer cells and prostate cancer bone 
metastatic models and largely independent of the resistance profile of the cancer cell line 
being investigated.   
Complete information is available in the Investigational Drug Brochure. 
1.2.1 SINE XPO1 inhibition 
Blockade of XPO1 has been studied for over 10 years, mainly with the naturally occurring, 
non-drug-like bacterial toxin Leptomycin B (LMB) (Kau et al., 2003; Kudo et al., 1999).  


 
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LMB is a potent, selective, irreversible XPO1 inhibitor used as a tool to study nuclear 
export. 
LMB and other natural product XPO1 inhibitors have potent antitumor activity in vitro, but 
are also toxic to normal cells, probably because they irreversibly block all XPO1 functions 
(Kudo et al., 1999).  Despite marked toxicities in animals, LMB was administered 
intravenously to patients with refractory solid tumors in the 1980’s (Newlands et al., 1996).  
It showed the expected GI toxicities (nausea, vomiting, watery diarrhea) along with marked 
fatigue/asthenia and malaise; as a result, its development was halted.  Typical cytotoxic 
agent side effects such as neutropenia, mucositis, and alopecia were not observed.  
Transient tumor marker responses in ovarian adenocarcinoma and trophoblastic tumor, 
and stable disease in a refractory sarcoma were observed. 
Kosan Biosciences Inc., prior to its acquisition by Bristol-Myers Squibb, created derivatives 
of LMB with improved pharmacologic properties, which showed a superior therapeutic 
window across multiple tumor xenografts, although transient anorexia remained (Mutka et 
al., 2009).  Consistent with observed minimal effects on normal cells, myelosuppression, 
mucositis or bloody diarrhea, and alopecia were not observed.  Although the development 
of these semi-synthetic derivatives of LMB has not progressed into the clinic to date, these 
data suggest that XPO1 inhibitors with adequate therapeutic windows can be created.  
Drug-like, small-molecule SINE compounds exemplified by selinexor have shown 
markedly improved therapeutic windows and oral bioavailability in animal studies. 
XPO1 inhibitors have been shown to block the nuclear export of key TSP and GRP, 
leading to accumulation of these proteins in the nucleus, as nuclear import appears to 
proceed unimpeded.  Moreover, nuclear retention appears to prevent proteasome-
mediated degradation (which is typically cytoplasmic).  Forced nuclear retention of 
TSP/GRP can counteract a multitude of oncogenic (and inflammatory) pathways that 
perpetuate the neoplastic phenotype (Table 1.1).  Moreover, certain proteins such as 
survivin (Stauber et al., 2007) and p21CIP1 (Gartel and Tyner, 2002) can be anti-apoptotic 
when in the cytoplasm; forcing their nuclear retention by XPO1 inhibition can prevent their 
anti-apoptotic functions and, for p21, expose its antitumor activities. 
Table 1.1 
Oncogenic Pathways and TSP/GRP Functions Enhanced by XPO1 
Inhibition 
Oncogenic Pathway 
TSP/GRP Enhanced 
by XPO1 inhibition 
Oncogenic Pathway 
TSP/GRP Enhanced 
by XPO1 inhibition 
AKT↑, PI3K↑, 
PTEN↓ 
FOXO, p27 
CDK2-CyclinE-
E2F1 
pRb, p27KIP, p21CIP1 
deletion p53, 
MDM2↑ 
p21CIP1, p53, p14ARF 
Cyclin D-CDK4/6 
INK4, pRb, p21, p27 
HER2, EGF-R 
(HER1) 
FOXO, pRB 
NPM1c Mutation 
p53, p14ARF, NPM1 
p16INK4A↓ or p14ARF↓ 
pRB, p53, E2F4 
c-Myc ↑ 
PP2A, p21CIP1 
mTOR↑ 
p53, p27, FOXO 
Bcr-Abl 
PP2A, Abl 
Wnt / ß-Catenin ↑ 
APC, HMGBP1 
Bcl2 ↑, Bcl-xL ↑ 
p53, p16INK4A 
deletion pRb 
p27 
Notch ↑ 
FOXO 


 
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survivin - 
cytoplasmic 
survivin – nuclear 
NF-κB ↑ 
I-κB 
Transient XPO1 (CRM1) inhibition (~4 hours) appears to be sufficient for nuclear retention 
of TSP/GRP and activation of the genomic survey (Figure 1).  As normal (undamaged) 
cells have an intact genome, they remain in cell cycle arrest following XPO1 inhibition.  
Malignant cells, in contrast “fail” their genomic survey, and a death pathway is initiated 
(Figure 1).  Along these lines, small interfering ribonucleic acid (siRNA) knockdown of 
XPO1 specifically induces apoptosis in malignant cervical cells, but not in their normal cell 
counterparts (van der Watt et al., 2009). 
Figure 1: 
XPO1 (CRM1) inhibition activates TSP/GRP and induces selective 
tumor cell death 
 
In summary, as the restoration of multiple tumor suppressor and growth regulatory 
pathways results in the death of cancer cells, this mechanism of action represents a 
unique approach to achieve an antitumor effect. 
1.3 
Rationale for the Proposed Study 
The development of new therapies in mCRPC requires a focus on patients with primary or 
acquired resistance to abiraterone. Patients with abiraterone-refractory mCRPC have a 
poor prognosis overall with median survival after progression of disease at approximately 
19 months.  While chemotherapy is a standard approach in this setting, it is refused by 
many patients and clinicians due to toxicity concerns.  


 
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Selinexor, given orally, has demonstrated potent anti-cancer activity in animal models of 
prostate cancer including inhibition of PC3 driven bone metastasis.  In a Phase 1 clinical 
study, selinexor showed acceptable tolerability with clear signs of anti-cancer activity in 
both hematological and solid tumors. Seven patients with mCRPC  were enrolled in the 
expansion phase of the ongoing Phase 1 study in patients with advance solid tumors 
(NCT01607905), one patient with abiraterone and enzalutamide refractory prostate cancer 
showed stable disease (~20% reduction in PSA and stable disease according to RECIST, 
>180 days on study) with marked reduction in pain scale. A second patient with mCRPC 
and 7/10 pain on study initiation had ~50% reduction in PSA with stable disease according 
to RECIST; he is now pain free and continues >180 days on study. A third mCRPC has 
also achieved stable disease and is doing well (>150 days on study with stable PSA). One 
patients achieved >50% reduction in PSA and continues >20 days on study. One patient is 
still cycle 1 >20 days on study.  Two mCRPC patients withdrew consent due to poor 
tolerability; however, there was no evidence of disease progression. All of these Phase 1 
patients have received standard hormone ablation therapies, and most have also received 
docetaxel. 
Further, it is likely that subsequent therapies, to be active, will be required to be agents 
with a unique mechanism of action, and not be antagonists of the androgen receptor and 
its related pathways. As a potent, oral, first in class, slowly reversible covalent Selective 
Inhibitor of Nuclear Export (SINE) that specifically blocks the karyopherin protein Exportin 
1 (XPO1), also called chromosome region maintenance 1 (CRM1), the therapy targets a 
unique pathway not actively explored in prostate cancer research.  XPO1 is 
overexpressed 2-4 fold in all cancers studied to date.  XPO1 exclusively exports the major 
Tumor Suppressor Proteins (TSPs) and other growth regulators out of the nucleus. 
Blockade of XPO1 leads to marked accumulation and activation of TSPs in the nucleus 
resulting in selective apoptosis in cancer cells, while undamaged normal cells remain in 
cell cycle arrest until the XPO1 block is released. 
1.4 
Rationale for Proposed Dose 
More than 200 patients with advanced cancers have received KPT-330 orally in two Phase 
1 studies of KPT-330.  KCP-330-001 is a dose escalation study in patients with advanced 
hematologic malignancies.  KCP-330-002 is a dose escalation study in patients with 
advanced solid tumors. The DLTs were anorexia/nausea and fatigue at 40 mg/m2 (10 
times per 4-week cycle) in KCP-330-002 and the maximum tolerated dose (MTD) was 
30mg/m2. The recommended phase 2 dose (RP2D) for 10 times per cycle dosing is 
30mg/m2 in both solid and hematologic malignancies.  However, pharmacodynamics 
analyses suggest that at doses > 6 mg/m2, selinexor inhibits XPO1 activity for >48 hrs. 
Therefore a reduced intensity dosing at twice weekly (8 times per cycle) was initiated and 
has shown improved tolerability.   Doses of 65 mg/m2 twice weekly have cleared DLT 
assessment and this is the MTD in advanced solid tumors, KCP-330-002 (IND 114044). It 
should also be noted that a dose of 70 mg/m2 cleared DLT in the AML arm of the ongoing 
Phase1 study in patients with heavily pretreated hematological malignancies (KCP-330-
001, IND 11404X). The most common AEs in KCP-330-002 are GI in nature, typically 
fatigue (73%), nausea (70%), anorexia (57%), and vomiting (49%).  Most of these AEs, 
which are Grade 1-2 events, are generally responsive to standard supportive care 
including serotonin antagonists, dopamine D2 blockers, low dose glucocorticoids, etc.  
Olanzapine, (or mirtazapine), megesterol acetate (Megace®), and glucocorticoids have 
been most useful in improving appetite in many patients treated with KPT-330.  
Aggressive prophylaxis with glucocorticoids, appetite stimulating agents, and anti-nausea 


 
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agents can greatly reduce or eliminate these AEs. In over >290 patients treated as of 1-
April-2014, no specific organ toxicity was observed at doses ≤ 70 mg/m2. Several patients 
have continued on single agent selinexor for >12 months. 
 
This Phase 2 study will begin dosing selinexor at 60 mg flat dose, twice per week at least 
48 hours apart (Mon/Wed, Tue/Thurs or Wed/Fri) on Weeks 1, 2 and 3 of a 4-week cycle. 
Recent analysis of the existing PK data from Phase 1 trials KCP-330-001 and KCP-330-
002 supports the use of fixed rather than BSA-based dosing.   The 5th and 95th percentile 
for BSA values encountered to date in Phase 1 trials KCP-330-001 and KCP-330-002 are 
1.5 and 2.3 m2, respectively (N=331). PK values (Cmax and AUC(0-∞)) for a given flat (fixed) 
dose of selinexor were similar across this typical BSA range, indicating that exposure is 
not strongly correlated with BSA.  Selinexor will not be taken during Week 4 (total six 
doses per cycle). Cycles are repeated every 28 days until disease progression. For each 
patient, dose reductions of Selinexor is allowed until the dose has been reduced below 20 
mg dose per week, at which time treatment will be discontinued. 
1.5 
Correlative Studies 
Correlative studies seeking predictive biomarkers for selinexor treatment and associations 
between biomarkers and treatment outcomes will be performed on blood and biopsy tissue 
collected, when available.  Blood (10 mL) will be collected at baseline, 8 and 16 weeks 
post initiation of treatment, and at time of progression.  Histologic confirmation of 
adenocarcinoma will be required prior to initiating treatment. Pre-therapy tumor biopsy 
may be obtained under the auspices of a separate protocol active at UCSF exploring 
adaptive responses and mechanisms of resistance to abiraterone.  Leftover tissue will be 
used for genetic and histology studies.  Patients will be asked to participate in the 
companion Radiologically Guided Biopsy protocol of mCRPC; participation in the biopsy 
study is optional but will be strongly encouraged.   
Circulating tumor cells (CTC) may be isolated and quantified from blood per a companion 
CTC study protocol.  Quantitative circulating tumor cell (CTC) counting has demonstrated 
promise as a biomarker of response in men with CRPC treated with abiraterone and with 
chemotherapy and has been used as a prognostic indicator of survival in metastatic 
prostate cancer..  
Biopsy of metastatic tissue offers a similar potential to describe the expression profile of 
metastatic tumors and explore genetic changes.  Left-over pre-therapy biopsy tissue will 
be used for mRNA sequencing and histology studies.  Tissue will be evaluated for the 
presence of proteins such as XPO-1, P27, P21, IkB, pRB. For those patients with a pre-
treatment biopsy available through the Stand Up 2 Cancer Dream Team initiative (also 
mentioned above), an exploratory analysis comparing pre- and post-treatment XPO-1 
expression will be performed.   XPO1 is the exclusive mediator of nuclear export of p53, 
p73, pRb, FOXO, p21, p27, BRCA1, the endogenous inhibitor of Nuclear Factor kB (NF-
kB) known as IkB, and other tumor suppressor and growth regulatory proteins. Nuclear 
export of these key proteins leads to their functional inactivation. Blockade of XPO1 with 
SINEs forces the accumulation and activation of tumor suppressor and growth regulatory 
proteins in the nucleus, leading to potent and selective tumor cell apoptosis while sparing 
normal cells. Exploratory analysis of XPO1 expression either at the transcription level or 
protein, may inform the further development of selinexor. 
Analyses of tissue biopsies, in combination with exploratory CTC analysis per our 
companion study protocol, therefore has the potential to generate a wealth of data about 
the expression profile of metastatic tumor.  The relationship of XPO-1 expression to PSA 


 
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decline will also be evaluated along with the expression profile of metastatic tumor and 
clinical outcomes.    
In the ongoing Phase 1 study in patients with advance solid tumors (NCT01607905), 
patients with mCRPC reported reduction in pain.  The study will further determine which, if 
any, type of progression (e.g. pain, bone, etc.) is mitigated by selinexor therapy.  
2 Objectives of the Study 
2.1 
Primary 
• 
To describe radiographic progression free survival (rPFS) associated with selinexor 
in patients with abiraterone refractory mCRPC 
2.2 
Secondary 
• 
To measure PSA changes at 12 weeks post-selinexor initiation 
• 
To assess time to PSA progression 
• 
To measure time to development of ≥ 2 new bone lesions 
• 
To compare the relationship of abiraterone-resistance status (primary vs acquired) 
and treatment outcome 
• 
To determine the effect of selinexor on persistent pain associated with bone 
metastasis using the brief pain inventory (BPI) short form. 
• 
To describe the safety profile of selinexor in patients with metastatic castration-
resistant prostate cancer.  
• 
To determine the effect of selinexor on circulating leukocyte XPO-1 expression, 
leukocyte gene expression profile and macrophage inhibitory cytokine-1 (MIC-1) 
mRNA expression 
• 
To assess serum selinexor trough levels as a function of dose and time since last 
dose 
2.3 
Exploratory Objectives, Other Assessments 
• 
To describe the relationship of XPO-1 expression to PSA decline 
• 
To describe the expression profile of metastatic tumor and outcome 
• 
To describe the type of progression (e.g. Pain, bone etc) 
• 
To define XPO-1 expression in patients for whom pre- and post-treatment biopsy is 
obtained 
2.4 
Endpoints 
2.4.1 Primary Endpoints 
Radiographic progression free survival (rPFS). This is defined from study start until one of 
the following events occurs:  
• 
≥2 new bone lesions on Technetium bone scan. If ≥2 new lesions are detected at 
or 12 weeks following initiation of treatment, progression must be confirmed by the 
presence of ≥2 or more additional lesions to rule out bone scan flare as a cause of 
the radiographic changes. 


 
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• 
RECIST-defined tumor progression.  
• 
Clinical deterioration requiring a change in prostate cancer therapy, or at clinician 
discretion 
• 
Surgery or Radiation to treat a prostate cancer related indication 
• 
Death from any cause. 
2.4.2 Secondary Endpoints 
• 
PSA decline of ≥50% at 12 weeks post therapy initiation 
• 
Time to PSA progression. Defined as a rise in PSA of 50% above nadir value or 
25% above baseline if there is no decline.  
• 
Relationship of abiraterone resistance status (primary vs acquired) and outcome 
• 
Time to confirmed development of ≥ 2 new bone lesions that cannot be attributable 
to bone scan flare 
• 
Reduction in pain for symptomatic patients  
• 
Safety  
• 
Serum selinexor levels as a function of dose and time 
• 
Pharmacodynamic analysis of selinexor impact on XPO-1 expression, leukocyte 
gene expression profile, and macrophage inhibitory cytokine-1 (MIC-1) mRNA 
expression  
2.4.3 Exploratory Endpoints 
• 
Relationship of XPO-1 expression to PSA decline.  
• 
Expression profile of metastatic tumor and outcome. 
• 
Type of progression (e.g. Pain, bone etc) 
• 
Comparison of pre- and post-treatment XPO-1 expression in patients for whom pre-
treatment biopsy is available through the Stand Up 2 Cancer “Dream Team” program. 
3 Study Design 
3.1 
Characteristics 
Single agent phase II open label study of selinexor in patients with mCRPC with prior 
therapy with standard hormone ablation agents and abiraterone. We anticipate the 
involvement of at least 3-5 centers participating in the SU2C West Coast Dream Team 
(SU2C WCDT - UCSF, UCLA, UC Davis, Oregon Health Sciences University, University of 
British Columbia), as well as participating sites of the Prostate Cancer Clinical Trials 
Consortium. Pre therapy and end of therapy biopsies will be offered to patients at the 
SU2C WCDT centers only. 
3.2 
Number of Subjects 
A maximum of 54 evaluable patients will be accrued for this study, provided the early 
stopping criteria are not met. The early stopping rules are described in the statistical 
section. 


 
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3.3 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and 
must meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly 
informed about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent.  The written informed 
consent must be obtained from the patient prior to enrollment.  The following criteria apply 
to all patients enrolled onto the study unless otherwise specified. 
3.3.1 Inclusion Criteria 
1. Age ≥ 18 years. 
2. Histologically confirmed adenocarcinoma of the prostate. 
3. Patients must have castrate levels of testosterone (< 50 ng/dL) on GnRH analogues 
or have had prior orchiectomy.  GnRH analogues must be continued while on study. 
4. Tumor tissue submitted for molecular and genetic analysis through the companion 
SU2C radiologically guided biopsy of abiraterone and/or enzalutamide refractory 
mCRPC protocol. 
a. Patients who consent to participate in the companion biopsy protocol and are 
subsequently determined to be ineligible for biopsy are eligible to participate 
in the current protocol.    
5. Progressive disease as demonstrated by a rising PSA (at least two determinations) 
prior to study entry, and/or radiographic evidence of tumor progression in soft tissue 
according to modified RECIST criteria or identification of new lesions by bone scan 
(i.e., ≥ 2 new lesions). 
6. Primary resistance or acquired resistance (i.e., acquired resistance will be defined as 
disease progression following a period of response defined as ≥50% decline in PSA 
within 12 weeks of starting therapy and not otherwise meeting criteria for primary 
resistance) to any of the following agents/combinations of therapy: 
a. Abiraterone acetate.  Primary resistance to abiraterone will be defined as: 
 
No PSA decline 
 
PSA decline less than 50% after 12 weeks of abiraterone therapy 
 
PSA progression within 12 weeks of AA treatment (by PCWG2 criteria), 
after initial response to therapy 
 
Objective progression, by RECIST criteria for soft tissue lesions and by 
modified PCWG2 criteria for bone lesions within 12 weeks of starting 
abiraterone treatment 
 
Unequivocal clinical progression (per the treating provider’s discretion) 
within 12 weeks of starting abiraterone treatment 
b. Enzalutamide.  Primary resistance to enzalutamide will be defined as: 
 
No PSA decline 
 
PSA decline less than 50% after 12 weeks of enzalutamide therapy 


 
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 
PSA progression within 12 weeks of enzalutamide treatment (by 
PCWG2 criteria), after initial response to therapy 
 
Objective progression, by RECIST criteria for soft tissue lesions and by 
modified PCWG2 criteria for bone lesions within 12 weeks of starting 
enzalutamide treatment 
 
Unequivocal clinical progression (per the treating provider’s discretion) 
within 12 weeks of starting enzalutamide treatment 
c. Other second-generation investigational anti-androgen/androgen-receptor 
targeted therapies, including ARN-509.  Primary resistance will be defined as: 
i. No PSA decline 
ii. PSA decline less than 50% after 12 weeks of enzalutamide therapy 
iii. PSA progression within 12 weeks of enzalutamide treatment (by 
PCWG2 criteria), after initial response to therapy 
iv. Objective progression, by RECIST criteria for soft tissue lesions and 
by modified PCWG2 criteria for bone lesions within 12 weeks of 
starting enzalutamide treatment 
v. Unequivocal clinical progression (per the treating provider’s 
discretion) within 12 weeks of starting enzalutamide treatment 
d. Combination therapy with abiraterone,enzalutamide and/or other second-
generation investigational anti-androgen/androgen-receptor targeted 
therapies, including ARN-509.  Primary resistance to combination therapy will 
be defined as: 
 
No PSA decline 
 
PSA decline less than 50% after 12 weeks of abiraterone and 
enzalutamide therapy 
 
PSA progression within 12 weeks of abiraterone and enzalutamide 
treatment (by PCWG2 criteria), after initial response to therapy 
 
Objective progression, by RECIST criteria for soft tissue lesions and by 
modified PCWG2 criteria for bone lesions within 12 weeks of starting 
abiraterone and enzalutamide treatment 
 
Unequivocal clinical progression (per the treating provider’s discretion) 
within 12 weeks of starting abiraterone and enzalutamide treatment 
e. Sequenced therapy, including any of the following: 
i. Abiraterone acetate followed by enzalutamide 
1. Primary resistance will be defined per criteria for abiraterone 
monotherapy primary resistance, section 3.3.1, item 5a 
ii. Enzalutamide followed by abiraterone acetate  
1. Primary resistance will be defined per criteria for enzalutamide 
monotherapy primary resistance, section 3.3.1, item 5b 
iii. Other second-generation investigational anti-androgen/androgen-
receptor targeted therapies, including ARN-509.   


 
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1. Primary resistance will be defined per criteria for other 
investigational anti-androgen monotherapy primary resistance, 
section 3.3.1, item 5c 
7. Presence of 1 or more bone metastasis. 
8. ECOG Performance status 0 or 1. 
9. Prior and ongoing zoledronic acid or denosumab therapy is allowed. 
10. Prior therapy with radium-223 is allowed. 
11. Discontinuation of prior therapy for mCRPC:  A Washout period of 28 days for the 
following therapies is required: Abiraterone, enzalutamide, fluconazole, itraconazole, 
flutamide, bicalutamide, nilutamide, and other experimental hormonal agents 
(ARN509, TAK-700, etc.), sipuleucel-T (Provenge), other experimental vaccines 
(PROSTVAC-V/F, etc.), Strontium-89, Samarium, and Radium-223 chloride. 
12. Baseline laboratory parameters: 
 
Adequate bone marrow function: 
 
Leukocytes 
> 3,000/mcL 
absolute neutrophil 
count 
> 1,500/mcL 
Platelets 
Hemoglobin 
 
> 125,000/mcL 
≥ 5.59 mmol/L or 9 g/dL  
Up to 5% deviation is tolerated. Transfusions and growth factors are allowe
Adequate hepatic function: 
 
Total bilirubin 
within normal institutional limits 
AST(SGOT) 
< 3 X institutional upper limit of normal 
ALT(SGPT) 
< 3 X institutional upper limit of normal 
Adequate renal function: 
 
Creatinine 
within normal institutional limits 
OR 
creatinine clearance  
> 60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal 
 
13. Ability to understand a written informed consent document, and the willingness to 
sign it 
14. Life expectancy of at least 12 weeks 
15. Able to swallow and retain oral medication 
3.3.2  Exclusion Criteria 
1. Untreated brain metastases.  Brain metastases ≤1 cm and not associated with any 
focal neurologic deficits are allowed. 


 
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2. Prior docetaxel or other chemotherapy for mCRPC.  Patients who have received 
docetaxel for metastatic hormone-sensitive prostate cancer are eligible.   
3. Active or symptomatic viral hepatitis or chronic liver disease 
4. Clinically significant heart disease as evidenced by myocardial infarction, or arterial 
thrombotic events in the past 6 months, severe or unstable angina, or New York 
Heart Association (NYHA) Class II-IV heart disease or known cardiac ejection 
fraction measurement of <50 % at baseline.   
5. Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled 
vomiting or diarrhea or other gastrointestinal disorders (medical disorders or 
extensive surgery) that may interfere with the absorption of the study agents 
6. Pure small cell carcinoma of the prostate or any mixed histology cancer of the 
prostate (eg: neuroendocrine) that contains <50% adenocarcinoma, as observed on 
biopsy obtained at the time of diagnosis or on any subsequent biopsies.Any 
“currently active” second malignancy, other than non-melanoma skin cancer.  
Patients are not considered to have a "currently active” malignancy, if they have 
completed therapy and are considered by their physician to be at least less than 30% 
risk of relapse over next year. 
7. Any condition, which in the opinion of the investigator, would preclude participation in 
this trial. 
8. Active psychiatric illnesses/social situations that would limit compliance with protocol 
requirements. 
9. Patients in whom urgent treatment with docetaxel is indicated, per clinician 
discretion.  This includes, but is not limited to patients with symptomatic visceral 
metastatic disease 
10. Uncontrolled infection or concomitant medical illness that is not adequately controlled 
with current medical management, as determined per clinician discretion.   
11. Active bleeding disorders or evidence of evidence of chronic or acute disseminated 
intravascular coagulation (DIC) 
12. Severely compromised immunological state, including known human 
immunodeficiency virus (HIV) 
13. Any acute toxities due to prior anti-cancer treatments and/or radiotherapy that have 
not resolved to a NCI CTCAE Grade of ≤1 (except alopecia) 
14. Prior radiation therapy completed <3 weeks or single fraction of palliative 
radiotherapy <14 days prior to first dose of KPT-330 
15. Initiation of bisphosphonate therapy <4 weeks prior to first dose of KPT-330.  
Patients receiving bisphosphonate or denosumab therapy must be on stable doses 
for at least 4 weeks prior to first dose of KPT-330. 
16. Men unable or unwilling to employ 2 forms of highly effective contraception 
throughout the study and for 8 weeks after the end of study treatment 


 
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3.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s), including any occurrence of grade 4 neurotoxicity 
• 
Patients decides to withdraw from the study 
• 
Significant patient non-compliance with protocol 
• 
General or specific changes in the patients’ condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
3.5 
Duration of Follow Up 
Patients will be followed for 30 days after completion of treatment or removal from study, 
or until death, whichever occurs first.  Patients removed from study for unacceptable 
treatment related adverse event(s) will be followed until resolution or stabilization of all 
treatment related adverse events to Grade 2 or lower. 
3.6 
Study Timeline 
3.6.1 Primary Completion 
The study will reach the final procedure for primary outcome 24 months from the time the 
study opens to accrual. 
3.6.2 Study Completion 
The study will reach primary completion of data collection 36 months from the time the 
study opens to accrual. 
4 Study Drug 
4.1 
Description, Supply and Storage of Selinexor  
Tablets for selinexor oral administration will be supplied in two (2) strengths: 10 and 25 mg 
of active ingredient per tablet. Bulk bottles of 50 tablets per bottle will be supplied for each 
of the two strengths. The tablets are clear coated with Opadry II clear and prepared from a 
common blend prepared from a wet granulation of active compound (selinexor), Kollidon® 
30 (polyvinyl pyrrolidone), sodium lauryl sulfate, croscarmellose sodium, and Avicel PH-
101 (Microcrystalline cellulose). The granulation is adjusted to final compression blend 
with Avicel PH-102 (Microcrystalline cellulose), Aerosil® (colloidal silicon dioxide), 
magnesium stearate, and additional croscarmellose sodium. All tablet excipients are 
GRAS and suitable for use in pharmaceuticals.) 
 
Classification - Cell biological modifier: Apoptosis-inducing agent 
 
Mechanism of Action - Selinexor is a small molecule, potent, oral Selective Inhibitor of 
Nuclear Export (SINE).  Selinexor forms a slowly reversible (t1/2 ~24 hours) covalent bond 
with XPO1 (also called CRM1) at cysteine 528. Selinexor is a potent inhibitor (IC50 ~20nM) 
of XPO1-mediated nuclear export in intact cells and to have minimal activity (>10 µM) 


 
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against 114 other proteins including enzymes, receptors, transporters, ion channels and 
other Cysteinyl-active site kinases and proteases in binding assays. 
 
Metabolism - preliminary analysis from a subset of patients (N=22) suggests that the 
primary metabolism of selinexor in plasma is through glucuronidation as well as 
hydroxylation and addition of cysteine/glycine groups (derived from GSH conjugation) to 
the parent compound.   Relative proportions of the putative metabolites are low, typically 
less than 1% of parent at peak selinexor concentrations and these metabolites are not 
expected to be pharmacologically active.  
 
Availability - Selinexor will be supplied by Karyopharm Therapeutics Inc. 
 
Storage and handling - Selinexor tablets will be stored at ambient or refrigerated 
temperatures between (36 – 86 °F) or (2–30 °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. Tablets will be supplied in white high density polyethylene (HDPE) 
bottles.   
 
Side Effects – >200 patients have been treated with selinexor to date. The most common 
adverse events (AEs) are gastrointestinal in nature: nausea, anorexia, vomiting.  Fatigue 
is also observed, and, like the nausea, is sometimes associated with anorexia. Mucositis 
or stomatitis are not observed, consistent with nonclinical toxicological studies. Active 
administration of appetite stimulating agents, leads to markedly improved tolerability.  In 
addition, anorexia appears to decline with longer treatment on selinexor.  Idiosyncratic 
reductions in platelets have been observed; these were not seen in any of the nonclinical 
models.  No cases of clinically significant bleeding have been reported to date. 
Neutropenia and anemia are minimal, consistent with a lack of myelosuppression 
observed in nonclinical studies.  Ocular symptoms of various kinds (blurred vision is the 
most common one) have been reported by a number of patients. Other than changes in 
visual acuity, corrected with new prescriptions in a few cases, no objective findings on 
ophthalmological examination have been associated with these ocular symptoms, except 
for five patients that had experience worsening of pre-existing cataracts. No major organ 
toxicities or drug-related deaths have been observed to date.  Patients with advanced 
cancers have remained on selinexor for >10-12 months. Complete and updated adverse 
event information is available in the Investigational Drug Brochure. 
 
Based on the experience of >200 patients, each patient in this study will be assessed 
periodically for the development of any toxicity as outlined in Section 6 of this protocol. 
Toxicity will be assessed according to the NCI CTCAE v4.0.  Dose adjustments will be 
made according to the system showing the greatest degree of toxicity, as described in 
Section 5.2.  
4.2 
Drug Accountability 
The Investigational Pharmacist will manage drug accountability records. 
4.3 
Drug Ordering 
UCSF will obtain selinexor directly from Karyopharm Therapeutics as study supply. 


 
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4.4 
Packaging and Labeling of Study Drug 
Each bottle of selinexor tablets will be labeled in accordance with current ICH GCP, FDA 
and specific national requirements. 
Drugs will be packaged and labeled per UCSF institutional standards, adhering to 
applicable local and federal laws. 
5 Treatment Plan 
5.1 
Dosage and Administration 
Treatment will be administered on an outpatient basis.  Patients will be provided with a 
study diary for documentation of selinexor administration. Study diaries will be collected 
every cycle. 
Table 5.2.1 Regimen Description 
Study Drug 
Premedication; 
precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Selinexor 
Pre-medicate with 
ondansetron 8 mg 
PO q8h on D0-D3 
and olanzapine (2.5-
5.0 mg QHS) on D1 
and D3* 
60 mg 
Oral 
Ondansetron: 
four-times 
weekly (D0 –
D3) of each 
4-week cycle. 
 Olanzapine: 
Twice weekly 
(D1 and D3 
of each week 
1 – 3 of each 
4-week cycle.  
Drug holiday 
on week 4). 
4 weeks 
(28 days) 
*Prophylaxis prior to initiation of therapy with selinexor is recommended. 
 
Selinexor will be administered at a starting dose of 60 mg on D1 and D3 of weeks 1 – 3 of 
each 4 week cycle, with subsequent dose titration for dose limiting toxicity (Table 5.3).   
• 
All adjustments of dose must be maintained either in the pharmacy records or 
subject’s medical records.  
 


 
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Number of Tablets per Total 
Mg Dose 
  
Mg Dose 
(from 
Rounded 
Dose 
Table) 
Number of 
Tablets of Each 
Strength 
  
10 mg 
tablets 
25 mg 
tablets 
  
20 
2 
0 
  
40 
4 
0 
  
60 
1 
2 
  
 
Patients will receive prophylactic treatment to prevent anorexia and nausea, which will 
include the following: 
• 
Ondansetron 8 mg PO q8h on day prior to and day of dosing (D0-D3) 
• 
Olanzapine 5 mg PO qbedtime or 2.5 mg PO BID on day of dosing (D1, D3) 
 
If nausea and/or anorexia persist despite administration of ondansetron and olanzapine on 
the days of dosing, additional prophylactic treatment may include the addition of any of the 
following: 
• 
Dexamethasone 2-4 mg PO BID on days of dosing (D1, D3) 
AND/OR 
 
• 
Olanzapine 5 mg PO qbedtime or 2.5 mg PO BID on days prior to dosing (D0, D2) 
AND/OR 
• 
Megestrol acetate 160-400 mg daily, 0-3 days before the first dosing day of KPT- 
330  
AND/OR 
 
• 
Mirtazapine 15 mg qd (qpm/qhs), 0-3 days before the first dosing day of KPT-330  
AND/OR 
 
• 
Marinol 5 mg PO BID 
 AND/OR 
 
• 
NK1R antagonist:  Aprepitant 120 mg PO x1 on D1, then 80 PO qAM on D2-D3 of 
each dosing week or equivalent should be considered and will be covered for 
selected patients who have severe nausea and vomiting. 
 
If the patient is on steroids coming on the study, megestrol acetate should be added 
prophylactically to prevent anorexia. Other androgenic-anabolic steroids including 
exogenous testosterone or synthetic testosterone derivatives (e.g., oxandrolone) are 
contraindicated in patients with metastatic castration resistant prostate cancer, and 
therefore must not be administered at any point during trial participation.   


 
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If an increased risk of adverse effects due to olanzapine is anticipated, olanzapine can be 
omitted. However, it is recommended that mirtazapine or other appetite stimulating 
serotonergic agent be used. Additional standard supportive care agents may be used as 
needed (prn), and as per table 5.3.   
Supportive care may be tapered or discontinued in Cycle 2 or later in patients who tolerate 
selinexor well in Cycle 1.  
5.2 
Dose Modifications and Dosing Delays 
If a patient experiences an intolerable toxicity (CTCAE v4.0 Grade 3 or 4) selinexor should 
be held.  Following resolution of the toxicity to Grade 1 or to the patient’s baseline value 
the patient may resume treatment with study drug. In general, patients who resume 
therapy following toxicity should resume treatment at a lower dose level assessed to be 
safe. However, following recovery from toxicity that was not considered clinically 
important, and that could be managed if it were to recur (e.g., replacement of an 
electrolyte), the patient may resume therapy without dose reduction if the Investigator 
considers this to be in the best interest of the patient.   Provisional dose levels for 
selinexor are listed in Table 5.2.   
Management of severe or intolerable adverse reactions may require dose reduction and/or 
interruption of the study drug. Recommendation of dose reduction, interruption or 
discontinuation in the management of adverse reactions are summarized below.  Clinical 
judgment of the treating physician should guide the management plan of each patient 
based on individual benefit/risk assessments. 
If a patient requires a dose delay > 21 days due to a study drug-related toxicity, then the 
patient must be discontinued from the study unless the patient has experienced evidence 
of clinical benefit. If the patient has experienced evidence of clinical benefit, and in the 
opinion of the Investigator it is in the best interest of the patient to remain on treatment, the 
patient may continue on study after discussion and with approval by Karyopharm.  
Table 5.2 
Dose Modifications and Dosing Delays for patients demonstrating 
clinical response or stable disease 
Dose level 
Dose of selinexor 
Dose level 0 
60 mg twice weekly (D1, D3 on weeks 1, 2, 
3 of each 4 week cycle) 
Dose level -1 
40 mg twice weekly (D1, D3 on weeks 1, 2, 
3 of each 4 week cycle) 
Dose level -2 
20 mg twice weekly (D1, D3 on weeks 1, 2, 
3 of each 4 week cycle) 
Dose level -3 
20 mg once weekly (D1 on weeks 1, 2, 3 of 
each 4 week cycle) 
Dose level -4 
Discontinue dosing 
 
Patients will continue to receive selinexor until they need to have their dose reduced below 
20 mg once weekly dose, at which time treatment will be discontinued. 
Treatment or visit delays for public holidays or weather conditions do not constitute a 
protocol violation.   


 
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5.3 
Monitoring and Toxicity Management 
Each patient receiving selinexor will be evaluable for safety.  The safety parameters 
include all laboratory tests and hematological abnormalities, physical findings, and 
spontaneous reports of adverse events reported to the investigator by patients. 
Each patient will be assessed periodically for the development of any toxicity as outlined 
in Section 6 Study Procedures and Observations. Toxicity will be assessed according to 
the NCI CTCAE v4.0.  Dose adjustments will be made according to the system showing 
the greatest degree of toxicity.  
We will monitor for anorexia, loss of appetite, fatigue, thrombocytopenia, neutrocytopenia, 
diarrhea, blurred vision, liver enzyme increase, and hyponatremia.  
Acute toxicity will be managed by supportive care or delay of dose.  Further management 
will depend upon the judgment of the clinician, and may include dose reduction.  
Treatment will be started at a dose of 60 mg administered twice weekly.  For those 
patients experiencing dose limiting toxicity (as defined below) yet thought to be benefiting 
from therapy (i.e., reduction in PSA, reduced pain, or reduction in size and/or number of 
bony metastases), the treatment dose will be reduced per Table 5.2.  Subsequent 
reductions for persistent grade 3 toxicities will include dose reduction per Table 5.2. 
 
 Table 5.3 
Criteria for dose adjustments of Selinexor-related toxicities 
Toxicity and Intensity 
Dose Modification 
Fatigue (common) 
Grade 1 
Insure adequate caloric intake and assess volume status. Adjust 
other medications. Consider addition/increased dose of 
corticosteroids (e.g., 2-4 mg BID dexamethasone the day of 
selinexor dosing).  Rule out other causes of fatigue such as 
adrenal insufficiency or thyroid dysfunction.  
Grade 2 
Insure adequate caloric and fluid intake and assess volume 
status.  May consider additional corticosteroid, per clinician 
discretion.    If fatigue dose not resolve to Grade 1, reduce dose of 
selinexor by one level (Table 5.2). 
 
Grade 3 
Insure adequate caloric and fluid intake and assess volume 
status.  Interrupt selinexor dosing until resolved to Grade ≤2, 
reduce dose of selinexor by 1 level (Table 5.2) 
. 
Anorexia (common) 
 
Grade 1 
Assess dietary options (e.g. try a variety of other foods). Add high-
calorie supplements (e.g., Ensure®). If fatigue or nausea also 
present, consider addition/increased dose of dexamethasone 
(e.g., 2-4 mg dexamethasone BID on the day of selinexor dosing), 
or consider addition of other anti-emetic per section 5.1 


 
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Toxicity and Intensity 
Dose Modification 
Grade 2 
Add high-calorie supplements (e.g., Ensure®). Consider 
addition/increased dose of dexamethasone (e.g., 2-4mg 
dexamethasone BID on the day of selinexor dosing and/or on the 
day prior to dosing, or consider addition of other anti-emetic per 
section 5.1.  Consider dronabinol (Marinol®).  Skip intermittent 
doses of selinexor while supportive medications are instituted. If 
Grade 2 anorexia does not resolve after institution of supportive 
medications, reduce selinexor dose by 1 level (Table 5.2).  
Grade 3 
Interrupt dosing with selinexor.  Add high calorie supplements.  
Use supportive medications alone or in combinations.  Restart 
selinexor at 1 dose level reduction (Table 3) once anorexia 
resolves to Grade ≤2.  If Grade 2 anorexia persists with 
supportive medications, reduce dose of selinexor another level 
(Table 5.2). 
 
Nausea/Emesis (common) 
 
Grade 1 
D2 antagonists, addition/increased dose of corticosteroids (e.g., 
2-4mg dexamethasone with each dose of selinexor  the day prior 
to dosing), NK1 antagonists, or dronabinol (Marinol) or 
combinations can prevent nausea in the majority of patients. 
Grade 2 
Implement one or more combinations of additional anti-nausea 
medications per section 5.1.  If nausea does not resolve to Grade 
≤1, reduce dose of selinexor by one dose level (Table 5.2). 
 
Grade 3 
Implement one or more combinations of anti-nausea medications 
per section 5.1 and interrupt dosing of selinexor.  Selinexor may 
be restarted with one dose level reduction (Table 5.2) 
when 
nausea is Grade ≤2 and adequate caloric and fluid intake have 
been achieved. 
Hematologic 
Neutropenia (rare) 
Grade 1  
(ANC < LLN - 1500/mm3) 
Grade 2  
(ANC < 1500 - 1000/mm3)  
Grade 3  
(ANC < 1000 - 500/mm3) 
Maintain dose level 
 
The use of growth factors during selinexor treatment is permitted 
and in patients with poor marrow function, encouraged. If ANC 
drops to <1000/mm3, growth factors are encouraged to reduce 
dose interruptions. 
Grade 4 (ANC < 500/mm3) 
Delay study treatment until ANC returns to  >800/mm3, then: 
If increased to >800/mm3 by ≤ 7 days after suspending selinexor, 
maintain dose level 
If increased to >800/mm3 by > 7 days after suspending selinexor, 
then reduce by 1 dose level (Table 5.2). The use of growth factors 
during selinexor treatment is encouraged. 


 
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Toxicity and Intensity 
Dose Modification 
Febrile neutropenia, or fever 
of unknown origin without 
clinically or microbiologically 
documented infection (ANC 
<1.0 x 109/L, fever ≥ 
38.5°C)  
Delay study treatment until patient has stabilized, then reduce 
selinexor by 1 dose level (Table 5.2). 
 
Selinexor may be re-initiated at the reduce dose when patient’s 
condition has stabilized following initiation of antibiotic therapy. 
Selinexor dose may be re-escalated up one level (Table 5.2)
 
after ≥1 cycle at the reduced dose provided ANC is 
adequate. 
Thrombocytopenia (Platelets) (uncommon) 
Grade 1 (PLT < LLN - 
75,000/mm3) 
Maintain dose level. 
 
Grade 2 (PLT < 75,000 - 
50,000/mm3) 
Delay selinexor treatment until resolved to ≤ grade 1 
Grade ≥3 (PLT < 50,000 - 
25,000/mm3) without 
bleeding 
 
Delay selinexor treatment until resolved to ≤ grade 1 and restart at 
one dose level below (Table 5.2 ).   
All patients with Grade 4 thrombocytopenia should have a manual 
blood smear analysis to determine if clumping (e.g., “pseudo-
thrombocytopenia”) and/or giant platelets are present. 
Platelet transfusions may be given to support platelet levels in 
patients with clear clinical benefit from selinexor. 
 
Grade 4 (PLT < 
25,000/mm3) without 
bleeding 
Delay study treatment until resolved to ≤ grade 3, then follow 
guidelines above. 
Platelet Stimulators 
The use of platelet stimulators may be considered in patients with 
a history of thrombocytopenia or compromised marrow function, 
or in patients in whom selinexor is having demonstrable clinical 
benefit.  IL-11 (oprelvekin, Neumega®), eltrombopag 
(Promacta®), or romiplastim (N-Plate®) should be considered.   
Hyponatremia (common) 
Grade 1 (Lower Limit of 
Normal to 130nM) 
Maintain dose level, assure adequate fluid, electrolyte and caloric 
intake, adjust other medications, consider salt supplementation, 
rule out other causes. 
Grade 3 (120-130nM) 
Discontinue selinexor until resolved to grade ≤1 then reduce dose 
by 1 level.  Check renal function, serum and urinary electrolytes, 
and rule out other causes. 
Renal (rare) 
Serum creatinine 
Calculated or measured 
creatinine clearance  
≥ 20 cc/min 
Maintain dose level 
Calculated or measured 
creatinine clearance  
< 20cc/min 
Reduce selinexor by 1 dose level until resolved. Dose may also 
be re-escalated if lower dose is tolerated after 1 full cycle. 
 
Hepatic (rare) 
Bilirubin 
Total bilirubin < 1.5 x ULN 
Maintain dose level 


 
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Toxicity and Intensity 
Dose Modification 
Total bilirubin 1.5 - 3 x ULN 
Reduce selinexor to once weekly dosing until resolved to ≤ Grade 
1, then restart twice weekly dosing 
Grade 3 (> 3.0 - 10.0 x 
ULN) 
Grade 4 (> 10.0 x ULN) 
Discontinue selinexor until resolved to Grade ≤2, then follow 
guidelines above. 
Note: If Grade 3 or Grade 4 hyperbilirubinemia is due to the 
indirect component only, and hemolysis as the etiology has been 
ruled out as per institutional guidelines (e.g. review of peripheral 
blood smear and haptoglobin determination), then reduce 
selinexor dose by 1 level (Table 5.2) and continue treatment at 
the discretion of the investigator. 
Discontinuation of selinexor is required if concurrent elevations of 
total bilirubin > 2.0 X upper limit of normal (ULN) and ALT or AST 
> 3.0 X ULN are observed and other causes have been ruled out. 
In order to characterize hepatic toxicity more precisely, 
fractionation of bilirubin and alkaline phosphatases will be 
required for elevated values > 2.0 X ULN and ≥ CTCAE Grade 2, 
respectively. 
AST or ALT (rare) 
Grade 1 (> ULN - 2.5 x 
ULN) 
Maintain dose level 
Grade 2 (> 2.5 - 5.0 x ULN) 
Delay selinexor until resolved to Grade ≤1, then maintain dose 
level.  Consider addition of S-adenosylmethionine (SAM) 400mg 
qd-bid. 
Grade 3 (> 5.0 - 20.0 x 
ULN) 
Delay selinexor until resolved to ≤ grade 2, then reduce by 1 dose 
level (Table 5.2 ). 
Consider addition of S-adenosylmethionine (SAM) 400mg qd-qid. 
If no further AST or ALT elevations occur during one cycle (4 
weeks) at the reduced dose level, then dose may be continued at 
the reduced dose. 
Discontinuation of selinexor is required if concurrent elevations of 
direct bilirubin > 2.0 X upper limit of normal (ULN) and ALT or 
AST > 3.0 X ULN are observed. 
In order to characterize hepatic toxicity more precisely, 
fractionation of bilirubin and alkaline phosphatases will be 
required for elevated values > 2.0 X ULN and ≥CTCAE grade 2, 
respectively. 
 
Grade 4 (> 20.0 x ULN) 
Delay selinexor until resolved to ≤ Grade 2, then reduce by 2 dose 
levels 
Cardiac (rare) 
Hypertension 
Treatment-emergent hypertension should be treated as per 
standard cardiology practice. Recommended agents for the 
management of blood pressure elevations on selinexor include 
angiotensin-converting enzyme inhibitors and calcium channel 
blockers. 
Grade 1 
Maintain dose level 


 
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Toxicity and Intensity 
Dose Modification 
Grade 2 / 3 
Delay selinexor and initiate/intensify antihypertensive therapy. 
Selinexor may be restarted in conjunction with standard anti-
hypertensive medication if BP is controlled (i.e BP ≤ 150/100 
mmHg). 
If BP is controlled ≤ 7 days after suspending selinexor, maintain 
dose level 
If BP is controlled > 7 days after suspending selinexor, then 
reduce by 1 dose level 
Grade 4 
Delay the selinexor and initiate/intensify antihypertensive therapy, 
then reduce by 1 dose level. 
Selinexor may be restarted in conjunction with anti-hypertensive 
medication if BP is controlled (i.e BP ≤ 150/100 mmHg).  
Cardiac – Other (rare) 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Delay selinexor until resolved to ≤ Grade 1, then reduce by 1 dose 
level (Table 5.2). 
 
Grade 4 
Discontinue study treatment 
Diarrhea (uncommon) 
Grade 1 (despite maximal 
anti-diarrheal medication) 
At the first sign of abdominal cramping, loose stools, or onset of 
diarrhea, it is recommended that the patient be treated according 
to institutional standard of care. Maintain dose level of selinexor. 
Grade 2 (despite maximal 
anti-diarrheal medication) 
 
Reduce to selinexor to one weekly until resolved to ≤ grade 1, 
then re-start twice weekly at the current dose level.  
If diarrhea returns as ≥ Grade 2, then reduce selinexor dose by 
one dose level and dose once weekly until resolved to ≤ grade 1, 
then re-start twice weekly at reduced dose level 
Grade 3/4  (despite maximal 
anti-diarrheal medication) 
Delay selinexor until resolved to ≤ grade 2, then re-start twice 
weekly at reduced dose level 
Neurotoxicity (not observed to date) 
CTCAE grade 1 / 2 
 
Grade 0 → Grade 1: maintain dose level 
Grade 0 or 1 → Grade 2 : delay study treatment until resolved to ≤ 
Grade 1, then reduce by 1 dose level (Table 5.2). 
 
CTCAE grade 3 
Discontinue study treatment until resolved to Grade ≤1 then 
reduce by 2 dose levels (Table 5.2 
). 
CTCAE grade 4 
Discontinue study treatment.   
Amylase and/or lipase elevations (rare) 
Grade 1 or 2 
Maintain dose level 
Asymptomatic  
Grade 3 or 4 
Delay selinexor until ≤ Grade 2, then restart at 1 dose level 
reduction (Table 3). Rule out other causes of amylase/lipase 
elevation.  If levels have not returned to ≤ Grade 2 within 3 weeks 
then no further selinexor may be given and the patient should 
discontinue permanently from the study. A CT scan or other 
imaging study to assess the pancreas, liver and gallbladder must 
be performed within 1 week of the first occurrence of any grade 3 
elevation of amylase and/or lipase. 


 
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Toxicity and Intensity 
Dose Modification 
Symptomatic  
Grade 3 or 4 
Selinexor must be stopped immediately and proper supportive 
care provided. Evaluate enzyme levels at least twice weekly until 
resolution to ≤ Grade 1. Clinical manifestations should be 
monitored as needed until resolution or stabilization of the disease 
condition. Selinexor may be re-started at 2 dose levels below 
(Table 5.2) 
after resolution to ≤ Grade 1. 
Pancreatitis  
(not observed to date) 
 
Grade 1 
Maintain dose level 
Grade 2, 3 or 4 
Discontinue study treatment. 
Other Selinexor-related adverse events 
Grade 1 or 2 
Maintain dose level and initiate standard supportive care. 
Grade 3 
Delay dose until resolved to ≤ Grade 1, then reduce by 1 dose 
level  
Grade 4 
Discontinue selinexor and rule out other causes.  If other causes 
of Grade 4 adverse event are uncovered, selinexor may be re-
initiated at 1 dose level reduction (Table 5.2). 
 
Notes: All dose modifications should be based on the worst preceding toxicity. 
Isolated values of ≥ grade 3 alkaline phosphatase values will NOT require dose interruption.  
Determination of liver vs. bone etiology should be made, and evaluation of GGT, 5’NT, or other 
liver enzymes should be performed. 
≥ Grade 3 anemia judged to be a hemolytic process secondary to study drug will require 
interruption of study treatment until resolved to ≤Grade 1.  Selinexor may then be re-instituted at 
2 levels below original dose (Table 5.2 ).   
≥ Grade 3 lymphopenia considered clinically significant will require dose interruption until 
resolved to ≤ grade 2, then reduce by 1 dose level. 
Patients are allowed dose reductions to a minimum dose of 35 mg/m2 as described in Table 5.2
 
.   
If a patient requires a dose interruption of >21 days due to a study drug related toxicity, then the 
patient must be discontinued from the study. Patients who discontinue the study for a study 
related adverse event or abnormal laboratory value must be followed at least once a week for 28 
days and subsequently at 28 day intervals until resolution or stabilization of the event, whichever 
comes first. 
 
6 Study Procedures and Observations 
6.1 
Schedule of Procedures and Observations 
The study-specific assessments are detailed in this section and outlined in Section 6.  
Screening assessments must be performed within 28 days prior to the first dose of 
investigational product.  Any results falling outside of the reference ranges may be 
repeated at the discretion of the investigator. All on-study visit procedures are allowed a 
window of ± 3 days unless otherwise noted.  Treatment or visit delays for public holidays 
or weather conditions do not constitute a protocol violation. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a 


 
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copy will be filed in the medical record.  The original will be kept on file with the study 
records.   
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller 
Family Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The 
system is password protected and meets HIPAA requirements. 
6.1.1 Pretreatment Period 
6.1.1.1 Screening Assessments  
With the exception of CT or MRI imaging for the purposes of tumor/lesion assessment, all 
screening procedures and assessments must be completed within 28 days of the Day 1 
Visit.  Any requisite imaging must be obtained within 42 days of day 1 of study 
participation. 
• 
Physical examination 
• 
Vital signs 
• 
Complete medical history 
• 
Baseline conditions assessment 
• 
ECOG Performance status  
• 
Ophthalmologic exam including slit lamp examination and visual acuity prior to 
dilation, and a dilated fundoscopic evaluation and slit lamp examination.   
• 
Neurological evaluation 
• 
Pulse oximetry 
• 
History of prior treatments and any residual toxicity relating to prior treatment 
• 
Baseline medications taken within 28 days of Day 1 
• 
Brief Pain Inventory (BPI) short form  
• 
Laboratory evaluations 
o Complete blood count (CBC) with differential and platelet count and 
coagulation tests 
 
Coagulation indices including international normalized ratio (INR), 
prothrombin time (PT) and activated partial thromboplastin time (aPTT) 
do not need to be repeated at screening if patients have already 
completed a biopsy through the companion radiologically guided 
mCRPC protocol or they have been deemed ineligible for biopsy. 
o Blood chemistry assessment, including: 
 
Alkaline phosphatase, aspartate aminotransferase/alanine 
aminotransferase (ALT/AST), total bilirubin, calcium, phosphorus, blood 
urea nitrogen (BUN), creatinine, total protein, albumin, fasting glucose, 
potassium, sodium, chloride, bicarbonate, uric acid, lactate 
dehydrogenase (LDH), fasting lipid panel (low-density lipoprotein [LDL], 
total cholesterol, triglycerides)  
o Prostate Specific Antigen (PSA) 
o Serum total testosterone 


 
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• 
Imaging (CT or MRI) of chest, abdomen and pelvis for tumor/lesion assessment, 
contrast is to be used unless clinically contraindicated. 
• 
Electrocardiogram (ECG) 
• 
Bone scan (Technetium) 
• 
Prophylactic therapy (initiated 0-3 days prior to first selinexor dose) 
• 
Tumor biopsy -- optional, per companion Radiologically Guided Biopsy protocol of 
mCRPC, offered to patients treated at UCSF, UCLA, UC Davis, Oregon Health 
Sciences University, University of British Columbia 
6.1.2 Treatment Period 
6.1.2.1 Study Procedures, Cycle 1, Day 1 
• 
Physical examination  
• 
Vital signs 
• 
Performance status 
• 
Evaluation of adverse events 
• 
Concomitant medications 
• 
Brief Pain Inventory (BPI) short form  
• 
Laboratory evaluations 
o CBC with differential and platelet count 
o Blood chemistry assessment 
o PSA 
o Selinexor serum levels – obtained 10 minutes prior to first dose, then 2 hours 
after first dose, and 4 hours after first dose. 
o Treated leukocyte lysate collection– obtained 10 minutes prior to first dose  
o Serum macrophage inhibitory cytokine-1 (MIC-1) – obtained 10 minutes prior to 
first dose 
o Leukocyte collection for XPO1 inhibition analysis - obtained 10 minutes prior to 
first dose, then 4 hours after first dose 
6.1.2.2 Study Procedures, Cycle 1, Day 3 – via telephone 
• 
Evaluation of adverse events 
6.1.2.3 Study Procedures, Cycle 1, Day 15 
o Serum macrophage inhibitory cytokine-1 (MIC-1) – obtained 10 minutes prior to 
first dose 
o Leukocyte collection for XPO1 inhibition analysis - obtained 10 minutes prior to 
first dose, then 4 hours after first dose 
6.1.2.4 Study Procedures Cycle 2+, Day 1 
These procedures must be completed within 3 days of Day 1 


 
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• 
Physical examination 
• 
Vital signs 
• 
Performance status 
• 
Evaluation of adverse events 
• 
Concomitant medications 
• 
Brief Pain Inventory (BPI) short form  
• 
Imaging (CT or MRI) for tumor/lesion assessment - at completion of cycle 2, cycle 4, 
cycle 6, day 22-28, and then every 12 three cycles weeks thereafter 
• 
Bone scan (Technetium) - at completion of cycle 2, cycle 4, cycle 6, day 22-28 and  
every 12 weeks thereafter 
• 
Ophthalmologic exam to be performed every 3 months while on study if cataracts are 
identified at screening and/or as clinically indicated.  This exam will include slit lamp 
examination and visual acuity prior to dilation, and a dilated fundoscopic evaluation 
and slit lamp examination.  Ophthalmalogic evaluations will be performed by the 
Department of Ophthalmology at the participating study institution.   
• 
Laboratory evaluations 
o CBC with differential and platelet count 
o Blood chemistry assessment 
o PSA -  monthly and at time of progression 
o Serum macrophage inhibitory cytokine-1 (MIC-1) – at cycles 2 and 3 – 
obtained 10 minutes prior to dose 
o Leukocyte collection for XPO1 inhibition analysis – at cycles 2 and 3 - 
obtained 10 minutes prior to dose, then 4 hours after dose 
6.1.3 End-of-Treatment Study Procedures 
• 
To be completed within 30 days of the last dose of study drug. 
• 
Physical examination 
• 
Vital signs 
• 
Performance Status 
• 
Evaluation of adverse events 
• 
Concomitant medications 
• 
Brief Pain Inventory (BPI) short form  
• 
Tumor biopsy -- optional, per companion Radiologically Guided Biopsy protocol of 
mCRPC, offered to patients treated at UCSF, UCLA, UC Davis, Oregon Health 
Sciences University, University of British Columbia 
• 
Ophthalmologic exam including slit lamp examination and visual acuity prior to 
dilation, and a dilated fundoscopic evaluation and slit lamp examination.   
• 
Laboratory evaluations 
o CBC with differential and platelet count 
o Blood chemistry assessment 
o PSA 


 
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6.1.4 End-of-treatment long-term follow-up  
• 
To be completed at 6 month intervals after the last dose of study drug.  
• 
Telephone visit for assessment of adverse events, concomitant medications and 
subsequent antitumor therapy. 
6.1.5 Discontinuation of Therapy 
The Investigator will withdraw a patient whenever continued participation is no longer in 
the patient’s best interests.  Reasons for withdrawing a patient include, but are not limited 
to, disease progression, the occurrence of an adverse event or a concurrent illness, a 
patient’s request to end participation, a patient’s non-compliance or simply significant 
uncertainty on the part of the Investigator that continued participation is prudent.  There 
may also be administrative reasons to terminate participation, such as concern about a 
patient’s compliance with the prescribed treatment regimen.   


 
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Table 6.1 
Schedule of Study Procedures and Assessments 
Visits must occur ±7 days of planned visit unless otherwise noted.  
Period/ 
Procedure 
Screening 
Cycle 1 
Cycle 2 and 
future 
Cycles 
End of 
Treatment 
visit 
Follow-
up visits 
Study Day/Visit 
Day 
-28 to 0 
1 
39 
15 
1 
Within 30 days 
of last dose 
By 
phone 
Every 6 
months 
Informed consent 
X 
 
 
 
 
 
 
Baseline 
conditions  
X 
 
 
 
 
 
 
AE assessment 
 
X 
X 
 
X 
X 
X 
Concomitant 
medications 
 
X 
 
 
X 
X 
X 
Treatment/Drug Administration 
 
 
 
 
 
Selinexor 
 
Oral, twice weekly  
(On Days 1 and 3 of each week 1-3 of each 4 
week cycle) 
 
 
Clinical procedures 
 
 
 
 
 
 
Physical exam 
X 
X 
 
 
X 
X 
 
Vital signs 
X 
X 
 
 
X 
X 
 
Medical history 
X 
 
 
 
 
 
 
Disease 
assessment  
X 
 
 
 
X 
 
 
Performance 
status 
X 
X 
 
 
X 
X 
 
Neurologic 
evaluation 1 
X 
 
 
 
 
 
 
Ophthalmic 
evaluation  
X8 
 
 
 
X8 
X8 
 
Pulse oximetry 1 
X 
 
 
 
 
 
 
BPI Short Form 
X 
X 
 
 
X 
X 
 
Tumor 
biopsy(optional) 
X 2 
 
 
 
 
X 2 
 
Laboratory procedures 
 
 
 
 
 
 
CBC w/ Diff & 
platelets 
X 
X 
 
 
X 
X 
 
Coagulation 1 
X 
 
 
 
 
 
 
Blood chemistry 3 
X 
X 
 
 
X 
X 
 
PSA 
X 
 
 
 
X 4 
X 
 
Leukocyte 
collection for 
XPO1 inhibition6 
 
X 
 
X 
X 
 
 


 
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Table 6.1 
Schedule of Study Procedures and Assessments 
Visits must occur ±7 days of planned visit unless otherwise noted.  
Period/ 
Procedure 
Screening 
Cycle 1 
Cycle 2 and 
future 
Cycles 
End of 
Treatment 
visit 
Follow-
up visits 
Study Day/Visit 
Day 
-28 to 0 
1 
39 
15 
1 
Within 30 days 
of last dose 
By 
phone 
Every 6 
months 
Treated leukocyte 
lysate 6 
 
X 
 
 
 
 
 
Serum MIC-1 
mRNA 6 
 
X 
 
X 
X 
 
 
Selinexor PK 6 
 
X 
 
 
 
 
 
Testosterone 
X 
 
 
 
 
 
 
Imaging 
procedures 
 
 
 
 
 
 
 
CT c/a/p with 
contrast  or MRI 
X 
 
 
 
X 7 
 
 
ECG/EKG 
X 
 
 
 
 
 
 
Bone scan 
(Technetium) 
X 
 
 
 
X 7 
 
 
1 Required at screening and as clinically indicated while on study. Coagulation labs include PT, PTT/INR. 
2 Only offered to patients at UCSF, UCLA, UC Davis, Oregon Health Sciences University, University of British Columbia. If 
no intervening therapy is initiated, the tumor biopsy can be performed within a 2-month window (60 days) of day 1 of 
Selinexor.  
3 Including alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, (BUN), creatinine, total protein, albumin, 
fasting glucose, potassium, sodium, chloride, bicarbonate, uric acid, LDH, fasting lipid panel (LDL, total cholesterol, 
triglycerides). 
4 Monthly and at time of progression 
5 Only Cycle 2 and Cycle 4, Day 22-28, and at time of progression 
6 PK samples will be collected on Cycle 1 Day 1 only.  PD Samples will be collected on Cycle 1 Day 1 and 15, Cycle 2 Day 
1, and cycle 3 Day 1.  Refer to section 6.3 for PK and PD collection schedule.   
7 At the completion of Cycle 2, Cycle 4, Cycle 6, Day 22-28, and every 12 weeks thereafter 
8 Required at screening, every 3 months thereafter if cataracts identified at screening and if clinically indicated, and at the 
end of treatment study visit.   
9 C1D3 visit will be conducted via telephone call 
 


 
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6.2 
PK and PD Calendar 
TIME POINT 
Total 
Volume of 
blood (ml) 
PK 
PDn 
Plasma  
 
(1 tube x 1ml) 
Cytokines    
 
(1 tube x 1ml) 
Leukocytes 
 
(2 PAX gene 
tubes x 2.5ml) 
Leukocytes 
  
(1 tube x 3ml) 
Cycle 1, Day 1  
  
  
  
  
Pre-dose  
(within 10 min 
before 
administration) 
13 
X 
X 
X 
X 
2 hr  (~10 min) 
post dose  
2 
X 
 
 
 
4 hr  (~20 min) 
post dose  
7 
X 
 
X 
 
Cycle 1, Day 15 
Pre-dose  
(within 10 min 
before 
administration) 
7 
 
X 
X 
 
4 hr  (~20 min) 
post dose 
5 
 
 
X 
 
Cycle 2 and 3, Day 1 
Pre-dose 
(within 10 min 
before 
administration) 
7 
 
X 
X 
 
4 hr  (~20 min) 
post dose 
5 
 
 
X 
 
 
 
 
 
 
 
6.3 
Dietary Restrictions 
Patients should be encouraged to always take selinexor within 30 minutes before or after a 
meal, so as to prevent variations in plasma KPT-330 exposure related to prandial state.  
There are no specific restrictions on meal size nor content.   


 
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Patients will be instructed to avoid alcohol consumption within 4 hours of selinexor 
administration, given concern for glutathione depletion and subsequent impaired clearance 
of selinexor (see section 6.3).   
6.4 
Prohibited Medications 
The primary metabolism of selinexor in vitro and in vivo appears to be inactivation by 
glutathione (GSH) 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.  There was also no induction of CYP450 activity observed for CYP1A2 or 
CYP3A4.   
Therefore, administration of selinexor with drugs which undergo substantial GSH 
conjugation should be minimized until further data are available.  These drugs include 
acetaminophen (paracetamol) and alcohol (ethanol).  Alcohol ingestion should be avoided 
4 hours before and after selinexor administration in order to minimize GSH depletion.  In 
the event that GSH depletion is believed to be contributing to patients’ symptoms, signs or 
laboratory findings, replenishment with S-adenosylmethionine (SAM) oral (e.g., 400 mg 
PO BID-TID) or N-acetylcysteine (e.g., up to 140 mg/kg PO loading dose followed by 70 
mg/kg PO Q4 hours thereafter) until symptoms resolve.  It should be noted that no studies 
of selinexor in combination with acetaminophen have been performed to date and that 
these recommendations are empirical. 
Androgenic-anabolic steroids including exogenous testosterone or synthetic testosterone 
derivatives (e.g., oxandrolone) are contraindicated in patients with metastatic castration 
resistant prostate cancer, and therefore must not be administered at any point during trial 
participation.   
Complete and updated information is available in the Investigational Drug Brochure. 
7 Reporting and Documentation of Results 
7.1 
Evaluation of Efficacy (or Activity) 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. 
Changes in only the longest diameter (unidimensional measurement- LD) of the tumor 
lesions are used in the RECIST criteria. 
Note: lesions are either measurable or non-measurable using the criteria provided below. 
The term “evaluable” in reference to measurability will not be used because it does not 
provide additional meaning or accuracy.  
7.2 
Definitions 
Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with the study 
drug. 
Evaluable for objective response 
Only those patients who have measurable disease present at baseline, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 


 
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evaluable for response.  These patients will have their response classified according to the 
definitions stated below.  (Note:  Patients who exhibit objective disease progression prior 
to the end of Cycle 1 will also be considered evaluable.) 
7.3 
Disease Parameters 
Measurable disease 
Measurable disease is defined as lesions (or tumors) that can be accurately measured in 
at least one dimension (longest diameter to be recorded) with a minimum size of 10mm by 
CT scan (irrespective of scanner type) or bone scan. All tumor measurements will be 
recorded in millimeters or decimal fractions of centimeters.  Previously irradiated lesions 
are considered non-measurable except in cases of documented progression of the lesion 
since the completion of radiation therapy. 
Target lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions 
per organ) representative of all involved organs should be identified as target lesions and 
recorded and measured at baseline.  Target lesions will be selected on the basis of their 
size (lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically).  A sum of the longest diameter 
(LD) for all target lesions will be calculated and reported as the baseline sum LD.  The 
baseline sum LD will be used as reference by which to characterize the objective tumor 
response. 
Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 
5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  It is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”).  Bone lesions may be measureable if ≥ 1 cm on MRI.    
Measurements of these lesions are not required, but the presence or absence of each will 
be noted throughout follow-up. 
Non-measurable disease (PSA) 
All patients will be evaluated for PSA decline.  Patients with disease that is not measurable 
will be eligible for this study and will be assessed for response based on changes in PSA 
and serial bone scans (if appropriate). Patients who show PSA increases will not be 
evaluated for PSA progression prior to 12 weeks of study therapy. 
50% PSA Decline: PSA decline of at least 50% from baseline confirmed by a second 
measurement at least 3 weeks later. The reference for these declines should be a PSA 
measured within 2 weeks prior to starting therapy.  
PSA Progression: Prostate Cancer Working Group 2 (PCWG2) Criteria will be reported. 
PSA progression occurs when the PSA has increased 25% or greater above nadir and an 
absolute increase of 2 ng/mL or more from the nadir is documented. Where no decline is 
observed, PSA progression similarly occurs when a 25% increase from baseline value 
along with an increase in absolute value of 2 ng/mL or more. Patients will receive a 
minimum of 12 weeks of therapy prior to being evaluable for this endpoint.  PSA 
progression (without evidence of progression on scans) will not be a criterion for 
discontinuation of study therapy. 


 
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PSA Response Duration: The PSA response duration commences on the date of the first 
50% decline in PSA. The response duration ends when the PSA value increases by 25% 
above the nadir, provided that the increase in the absolute-value PSA level is at least 5 
ng/mL or back to baseline, whichever is lower. 
Progressive Disease by PSA (as defined by PSA Progression, above) 
Time to PSA Progression: The start of the time to PSA progression is the day treatment 
is initiated. The end date is the time of PSA progression as defined above. 
Evaluation of non-measurable bone disease  
Bone scans obtained after the baseline evaluation will be used to evaluate post-treatment 
changes. Bone scans obtained will be evaluated as either “no new lesions” or “new 
lesions” on the tumor measurement forms.  Progression is defined as the appearance of 2 
or more new lesions. 
PSAWG2 Criteria for Bone Scan Evaluation:  For the first scheduled reassessment: 
New lesions at the first scheduled evaluation (8 weeks) will require a confirmatory bone 
scan 6 or more weeks later. If no new lesions are observed on the confirmatory bone 
scan, study therapy is continued. If additional new lesions (a minimum of 2 more additional 
new lesions) are observed, then the patient has experienced progression.  Progression in 
this situation is dated as the time of the first reassessment scan. 
For subsequent scheduled reassessments: If no new lesions are observed, study therapy 
will continue. If new lesions are observed, this is evidence of disease progression.  Date of 
progression is the date at which the scan was obtained. 
7.3.1.1 Methods for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations will be performed as closely as possible to the beginning of 
treatment and never more than 28 days before the beginning of the treatment, with the 
exception of imaging which may be performed up to 42 days before the beginning of the 
treatment. 
The same method of assessment and the same technique will be used to characterize 
each identified and reported lesion at baseline and during follow-up.  
7.3.1.2 Methods for Evaluation of Non-Measureable Disease 
PSA levels will be monitored monthly. 
Bone scans obtained after the baseline evaluation will be used to evaluate post-treatment 
changes. Outcome is listed as new lesions or no new lesions.  Progression is defined as 
the appearance of 2 or more new lesions. This is based on the PCWG2 criteria in standard 
practice for trials in metastatic CRPC. 
7.3.1.3 Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions, determined by two separate observations conducted 
not less than 4 weeks apart.  Any pathological lymph nodes (whether target or non-target) 


 
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must have reduction in short axis to <10 mm (the sum may not be “0” if there are target 
nodes).  There can be no appearance of new lesions. 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking 
as reference the baseline sum LD.  There can be no appearance of new lesions. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the 
smallest sum SLD recorded since the treatment started and minimum 5 mm increase over 
the nadir, or the appearance of one or more new lesions. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum LD since the treatment started. 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Incomplete Response/Stable Disease (SD) 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
Table 7.1 
Response Criteria 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this Category 
Also Requires 
CR 
CR 
No 
CR 
> 4 weeks confirmation 
CR 
Non-CR/ 
Non-PD 
No 
PR 
> 4 weeks confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once > 4 
weeks from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


 
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* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression 
 
 
Duration of Response 
 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started.  
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to 
time of progression. 
 
7.4 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug.  
The study will use the CTCAE v4.0 for reporting of non-hematologic adverse events and 
modified criteria for hematologic adverse events. 
For multicenter studies, the Principal Investigator at the UCSF Coordinating Center will 
hold the role of Study Chair.  The Study Chair is responsible for the overall conduct of the 
study and for monitoring its safety and progress at all participating sites. 
7.5 
Definitions of Adverse Events 
7.5.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward 
medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  More specifically, an adverse event (can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, without any judgment about causality.  An adverse 
event can arise from any use of the drug (e.g., off-label use, use in combination with 
another drug) and from any route of administration, formulation, or dose, including an 
overdose.  
7.5.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  
Adverse reactions are a subset of all suspected adverse reactions for which there is 
reason to conclude that the drug caused the event. 


 
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7.5.2.1 Suspected  
A suspected adverse reaction is defined as any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of IND 
safety reporting, “reasonable possibility” indicates that there is evidence to suggest a 
causal relationship between the drug and the adverse event.  A suspected adverse 
reaction implies a lesser degree of certainty about causality than an adverse reaction. 
7.5.2.2 Unexpected  
An adverse event or suspected adverse reaction is considered unexpected if it is not listed 
in the investigator brochure or package insert(s), or is not listed at the specificity or 
severity that has been observed, or, if an investigator brochure is not required or available, 
is not consistent with the risk information described in the general investigational plan or 
elsewhere in the current application.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in 
the investigator brochure.  For example, a certain number of non-acute deaths in a cancer 
trial would be anticipated as an outcome of the underlying disease, but such deaths would 
generally not be listed as a suspected adverse reaction in the investigator brochure. 
Some adverse events are listed in the Investigator Brochure as occurring with the same 
class of drugs, or as anticipated from the pharmacological properties of the drug, even 
though they have not been observed with the drug under investigation.  Such events 
would be considered unexpected until they have been observed with the drug under 
investigation. For example, although angioedema is anticipated to occur in some patients 
exposed to drugs in the ACE inhibitor class and angioedema would be described in the 
investigator brochure as a class effect, the first case of angioedema observed with the 
drug under investigation should be considered unexpected for reporting purposes. 
7.5.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes:  
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
• 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 


 
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medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
7.5.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death.  
7.6 
Recording of an Adverse Event 
All grade 3 and above adverse events will be entered into OnCore®, whether or not the 
event is believed to be associated with use of the study drug.  Data about these events 
and their severity will be recorded using the NCI CTCAE v4.0.   
The Investigator will assign attribution of the possible association of the event with use of 
the investigational drug, and this information will be entered into OnCore® using the 
classification system listed below:  
Relationship  
Attribution  
Description  
Unrelated to 
investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention  
Unlikely 
The AE is doubtfully related to the 
intervention  
Related to investigational 
drug/intervention 
Possible 
The AE may be related to the intervention  
Probable 
The AE is likely related to the intervention  
Definite 
The AE is clearly related to the intervention  
 
Signs or symptoms reported as adverse events will be graded and recorded by the 
Investigator according to the CTCAE.  When specific adverse events are not listed in the 
CTCAE they will be graded by the Investigator as none, mild, moderate or severe 
according to the following grades and definitions: 


 
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Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 
3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
Grade 
4: 
Life-threatening consequences; urgent intervention indicated 
Grade 
5: 
Death related to AE 
7.7 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  For selected adverse events for which 
administration of the investigational drug was stopped, a re-challenge of the subject with 
the investigational drug may be conducted if considered both safe and ethical by the 
Investigator. 
7.8 
Adverse Events Monitoring  
All adverse events, whether or not unexpected, and whether or not considered to be 
associated with the use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to 
the UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional 
Review Board, the Institutional Review Board (IRB); and, when the study is conducted 
under an Investigational New Drug Application (IND), to the Food and Drug Administration 
(FDA) if it meets the FDA reporting criteria. 
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a monthly basis.  The Site Committee 
will review and discuss at each monthly meeting the selected toxicity, the toxicity grade, 
and the attribution of relationship of the adverse event to the administration of the study 
drug(s). 
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the Site Committee meetings. The Site Committee will review and discuss the selected 
toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s). 
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, 
will be reviewed and monitored by the Data and Safety Monitoring Committee on an 
ongoing basis and discussed at DSMC meetings, which take place every six weeks. 
For a detailed description of the Data and Safety Monitoring Plan, please refer Appendix 2 
Multicenter Institutional Studies. 


 
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7.9 
Expedited Reporting  
Reporting to the Data and Safety Monitoring Committee 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study 
drug(s) or to a study procedure, the Investigator or his/her designee must notify the DSMC 
Chair (or qualified alternate) within 1 business day of knowledge of the event.  The contact 
may be by phone or e-mail. 
Reporting to UCSF Committee on Human Research (Institutional Review Board) 
The Principal Investigator must report events meeting the UCSF IRB definition of 
“Unanticipated Problem” (UP) within 10 business days of his/her awareness of the event.  
Expedited Reporting to the Food and Drug Administration 
The Sponsor-Investigator is responsible for determining whether or not the suspected 
adverse reaction meets the criteria for expedited reporting in accordance with Federal 
Regulations (21 CFR §312.32).  
The Investigator must report in an IND safety report any suspected adverse reaction that 
is both serious and unexpected.  The Sponsor-Investigator needs to ensure that the event 
meets all three definitions:  
• 
Suspected adverse reaction 
• 
Unexpected  
• 
Serious  
• 
If the adverse event does not meet all three of the definitions, it should not be 
submitted as an expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days 
after the Investigator determines that the suspected adverse reaction qualifies for reporting 
(21 CFR 312.32(c)(1)).  
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to 
FDA no later than 7 calendar days after the Investigator’s initial receipt of the information 
(21 CFR 312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety 
report will be submitted to FDA as a Follow-up IND Safety Report without delay, as soon 
as the information is available (21 CFR 312.32(d)(2)).  
Reporting to Pharmaceutical Company providing Study Drug 
Any clinical adverse event or abnormal laboratory test value that is serious occurring 
during the course of the study from the date of signing the informed consent, irrespective 
of the treatment received by the patient, must be reported to the study drug sponsor within 
one working day of knowledge (expedited reporting). For each patient, all serious adverse 
events must be reported up to 30 days after the last dose of investigational product. 
Serious adverse events occurring more than 30 days after a patient is discontinued from 
the study treatment may be reported at the discretion of the investigator. 
In addition to reporting to the FDA, the Sponsor-Investigator will forward completed SAE 
and pregnancy forms to representatives of the pharmaceutical company providing Study 
Drug. All forms will be completed and emailed to pvg@karyopharm.com 


 
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The study drug sponsor will medically review all SAEs.  
The following detailed information must be recorded for each serious adverse event in the 
SAE report form: 
• 
 A description of the AE in medical terms according to NCI-CTC Version 4.0, not as 
reported by the subject 
• 
The severity grade as assessed by the investigator according to the definitions in 
NCI-CTC Version 4.0 
• 
The date of becoming serious and the date of becoming known (if different) 
• 
The reason for seriousness 
• 
The outcome of the SAE at the time of the report 
• 
Information on administration of the study drug and chemotherapy and any action 
taken 
• 
Information on any treatment procedures necessary for the SAE, concomitant 
medications, relevant lab tests and relevant medical history 
If in any one subject the same SAE occurs on several occasions, then the SAE in question 
must be documented and assessed anew each time. 
The investigator is required to submit SAE Follow-up reports until the SAE has resolved or 
stabilized and all queries have been answered. 
8 Statistical Considerations and Evaluation of Results 
8.1 
Study Endpoints 
The primary endpoint is radiographic progression free survival (rPFS).  
The secondary endpoints are to describe the following: 
• 
PSA decline of ≥50% at 12 weeks post therapy initiation 
• 
Time to PSA progression. Defined as a rise in PSA of 50% above nadir value or 25% 
above baseline if there is no decline.  
• 
Relationship of abiraterone resistance status (primary vs acquired) and outcome 
• 
Time to confirmed development of ≥ 2 new bone lesions that cannot be attributable 
to bone scan flare. 
• 
Safety  
• 
Exploratory endpoints are to describe the following: 
• 
Relationship of XPO-1 expression to PSA decline.  
• 
Expression profile of metastatic tumor and outcome. 
• 
Type of progression (e.g. Pain, bone etc) 
• 
Comparison of pre- and post-treatment XPO-1 expression in patients for whom pre-
treatment biopsy is available through the Stand Up 2 Cancer “Dream Team” 
program. 


 
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8.1.1 Study Design 
This is a single agent, phase II open label study of selinexor in patients with mCRPC with 
prior therapy with standard hormone ablation agents and abiraterone.  Up to 54 patients 
could be enrolled in the study.   
8.2 
Determination of Sample Size and Accrual Rate 
8.2.1 Sample Size and Power Estimate 
In the first stage, 18 patients will be accrued. If there are 10 or fewer patients classified as 
progression-free at 16 weeks in these 18 patients, the study will be stopped. Otherwise, up 
to 36 additional patients will be accrued for a maximum total of 54.  The null hypothesis is 
that 55% of patients are progression-free at 16 weeks.  The alternative hypothesis is 75% 
are progression-free at 16 weeks.  The null hypothesis will be rejected if 36 or more 
patients classified as progression-free at 16 weeks are observed in 54 patients. There is a 
60.9% chance of stopping early for futility. This design yields a type I error rate of 0.048 
and power of 90.0%. 
8.2.2 Replacement Policy 
Patients removed from study for unacceptable treatment related adverse event(s) will be 
followed until resolution or stabilization of all treatment related adverse events to Grade 2 
or lower; however, they will not be replaced. 
8.2.3 Accrual estimates  
Five patients per month are estimated to be accrued. 
8.3 
Interim Analyses and Stopping Rules 
Toxicity is continuously monitored for all patients. However, a full safety assessment will 
also be carried out after the first ten patients have completed Cycle 1 of therapy.  If 3 or 
more of the initial 10 patients experience grade 3 or 4 toxicity within 4 weeks of starting 
therapy, then accrual will be suspended. This indicates that greater than 25% of the 
patients have experienced unacceptable toxicity.  The study may continue to proceed 
while the safety analysis is performed.  
Additionally, in the first stage, 18 patients will be accrued. If there are 10 or fewer patients 
classified as progression-free at 16 weeks in these 18 patients, the study will be 
suspended.  Further, if >33% (i.e., >6 of 18 patients) have experienced unacceptable 
toxicity (i.e., defined as toxicity precluding the administration of selinexor at any dose level) 
at the time of interim analysis, the accrual will be suspended.  Otherwise, 36 additional 
patients will be accrued for a total of 54.  There is a 60.9% chance of stopping early for 
futility.   
8.4 
Analyses Plans 
8.4.1 Analysis Population 
All patients who receive at least 1 dose of selinexor will be evaluated for response. 
Only those patients who have measurable disease present at baseline, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  All analyses will be performed with respect to all patients treated 


 
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with selinexor, regardless of prior therapy, with a separate analysis performed according to 
prior treatment status with cohorts of patients as follows: 
(A) Prior abiraterone only 
(B) Prior enzalutamide only 
(C) Prior concomitant therapy with abiraterone and enzalutamide 
(D) Prior sequenced therapy with abiraterone and enzalutamide 
8.4.2 Primary Analysis (or Analysis of Primary Endpoints) 
The primary end point is proportion of patients without evidence of radiographic 
progression at 16 weeks.  This is defined from study start until one of the following events 
occurs:  
• 
≥2 new bone lesions on Technetium bone scan 
• 
RECIST defined tumor progression 
• 
Cancer related pain requiring opiate analgesics 
• 
Surgery or Radiation to treat a prostate cancer related indication 
• 
Death from any cause 
Radiographic PFS will be defined as the time from treatment initiation to the occurrence of 
either tumor progression in soft tissue according to modified RECIST criteria, identification 
of new lesions by bone scan (≥ 2 new lesions confirmed ≥ 12 weeks later). If no such 
event exists, then rPFS will be defined as time from start of study until clinical deterioration 
requiring a change in prostate cancer therapy or at clinician discretion, surgery and/or 
radiation therapy to treat a prostate-cancer related indication, or death from any cause.  
PFS will be censored at the last scheduled disease assessment on study. PFS of living 
patients with no assessment on-study, and PFS of patients with no baseline assessment 
will be censored at enrollment. 
rPFS will be estimated using the Kaplan-Meier product limit method. The median times to 
event with two-sided 95% confidence intervals will be estimated, together with the 
estimate of event rates at 6 and 12 months.  The score statistic from the cox proportional 
hazards model will be used in the estimation of the hazard ratio and the associated 95% 
confidence interval will also be provided. 
8.4.3 Secondary Analysis (or Analysis of Secondary Endpoints) 
PSA decline of ≥50% at 12 weeks post therapy initiation 
The proportion of patients experiencing a PSA decline from baseline of at least 50% in 
PSA at 12 weeks following the initiation of study therapy will be presented with a 95% 
confidence interval.  
Time to PSA progression (TTPP). 
Time to PSA progression, is defined as the time interval between the date of treatment 
initiation and the date of either first documented PSA progression, or death due to any 
cause, whichever comes first.  PSA is measured monthly until PSA progression as defined 
by the PSAWG2 criteria.   


 
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Duration of PSA response defined as the time between the first evaluation at which the 
response criteria are met and the first documentation of PSA progression or death. Early 
increase in PSA within 12 weeks, when followed by subsequent decline, is ignored in 
determining this endpoint. 
Kaplan-Meier methods will be used to estimate the median time to PSA progression with a 
95% confidence interval. 
Relationship of abiraterone resistance status (primary vs acquired) and outcome 
Radiographic progression free survival will be compared for patients with primary 
abiraterone resistance and acquired abiraterone resistance using a Cox proportional 
hazards model, and will be presented with a 95% confidence interval.   
Time to confirmed development of ≥ 2 new bone lesions 
Time to development of ≥ 2 new bone lesions, defined as the time interval between the 
date of treatment initiation and the date of documented new lesions.  Bone scans will be 
performed at week 8, 16, 24, and every 12 weeks thereafter; evaluation criteria is defined 
by the PSAWG2 criteria for bone scan evaluation. The time will be ‘backdated’ to when the 
≥2 new lesions were detected if a second scan is done to confirm progression.   
Kaplan-Meier methods will be used to estimate the median time to development of ≥ 2 
new bone scans with a 95% confidence interval. 
Safety  
Safety endpoints include incidence of worst grade adverse events; incidence of deaths 
and other serious and significant adverse events; and incidence of worst grade laboratory 
abnormalities.  All recorded adverse events will be listed and tabulated by system organ 
class, preferred term, and by dose group and cohort and coded according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Vital signs, physical examinations, clinical 
laboratory test, medical history, ECOG, and ECGs  results will be listed and summarized 
by dose groups.   
8.4.4  Pharmacokinetic and pharmacodynamic analyses 
Serum selinexor concentrations, leukocyte collection, treated leukocyte lysate, and 
macrophage inhibitory cytokine-1  (MIC-1 mRNA) will be submitted to Karyopharm 
Therapeutics for analysis.  
Summary statistics will be tabulated for the pharmacokinetic parameters of selinexor and 
study day.  Geometric means and coefficients of variation will be presented for Cmin,Cmax, 
AUC(TAU),  and AUC(INF).  Medians, minima, maxima will be presented for Tmax. Means 
and standard deviations will be provided for the remaining pharmacokinetic parameters.  
To describe the dependency on dose, scatter plots of Cmin and AUC(TAU) or AUC(INF) 
versus dose will be provided for each day measured.  To assess the attainment of steady 
state, geometric mean Cmin values will be plotted by study day and dose.   
Isolated leukocytes and serum samples will be studied for the temporal effects of KPT-330 
on XPO1 inhibition and induction of macrophage-inhibitory cytokine 1 (MIC-1), a secreted 
biomarker reflecting the activation of p53 mediated apoptosis.  Total RNA will be isolated 
from leukocytes of patients and the expression of XPO1 and MIC-1 will be measured by 
quantitative polymerase chain reaction analysis (qPCR).  XPO1 mRNA induction will then 


 
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be assessed by comparing the fold increase of XPO-1 and MIC-1 expression from 
predose levels as a function of selinexor dose and total time on treatment.   
8.4.5 Other Analyses/Assessments 
Additional correlative studies including pain scale changes measured by the brief pain 
inventory short form will be descriptively summarized. 
8.5 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug.  
The study will use the NCI CTCAE v4.0. 
9 Study Management 
9.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP 
and all applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject 
recruitment materials, and any other written information to be provided to subjects before 
any protocol related procedures are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study 
under the Investigational Drug Application (IND) is allowed to proceed or the Investigator 
has received a letter from FDA stating that the study is exempt from IND requirements.  
The Investigator must comply with the applicable regulations in Title 21 of the Code of 
Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable 
regulatory requirements.  The IRB must comply with the regulations in 21 CFR §56 and 
applicable regulatory requirements. 
9.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB (Institutional Review Board).  Prior to obtaining IRB approval, 
the protocol must be approved by the Helen Diller Family Comprehensive Cancer Center 
Site Committee and by the Protocol Review Committee (PRC).  The initial protocol and all 
protocol amendments must be approved by the IRB prior to implementation.   
9.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient 
information for each participant to make an informed decision regarding their participation.  
Participants must sign the IRB-approved informed consent form prior to participation in 
any study specific procedure.  The participant must receive a copy of the signed and dated 
consent document.  The original signed copy of the consent document must be retained in 
the medical record or research file.  


 
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9.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must 
be documented in the form of an amendment.  The amendment must be signed by the 
Investigator and approved by PRC and the IRB prior to implementation.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, 
an amendment may be implemented prior to IRB approval.  In this circumstance, however, 
the Investigator must then notify the IRB in writing within five (5) working days after 
implementation.  The Study Chair and the UCSF study team will be responsible for 
updating any participating sites. 
9.5 
Registration/Enrollment 
Screening procedures will occur when a subject and investigator signs and dates an 
informed consent form and the subject provides authorization to use protected health 
information. The informed consent form will be completed prior to any study-specific 
procedures. Screening procedures that are standard of care and were performed prior to 
consent, do not need to be repeated if they were conducted within the eligible screening 
period, unless otherwise specified. 
To initiate enrollment, the investigator will verify eligibility according to all inclusion and 
exclusion criteria. All eligible subjects must be centrally registered through the GU Clinical 
Research Office.  To complete the registration process, the study site must fax or email 
the signed completed study-specific eligibility checklist, all source documents verifying 
eligibility, any supporting documents, and the signed informed consent to the GU Clinical 
Research Office.  These data must also be entered into the OnCore database.  Once the 
enrollment packet is received at UCSF, the Study Chair will review the packet and if 
eligibility is confirmed, assignment to treatment can occur.  Subjects failing to meet all 
study eligibility requirements will not be registered.   
9.6 
Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  
The date, quantity and batch or code number of the drug, and the identification of patients 
to whom study drug has been dispensed by patient number and initials will be included.  
The sponsor-investigator will maintain written records of any disposition of the study drug. 
The Principal Investigator shall not make the investigational drug available to any 
individuals other than to qualified study patients.  Furthermore, the Principal Investigator 
will not allow the investigational drug to be used in any manner other than that specified in 
this protocol. 
9.7 
Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  
Study specific Case Report Forms (CRFs) will document safety and treatment outcomes 
for safety monitoring and data analysis.  All study data will be entered into OnCore® via 
standardized CRFs in accordance with the CTMS study calendar, using single data entry 
with a secure access account.  The Clinical Research Coordinator (CRC) will complete the 
CRFs as soon as possible upon completion of the study visit; the Investigator will review 
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The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained 
by UCSF personnel.  All source documentation should be kept in separate research 
folders for each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.  
All source documentation and CTMS data will be available for review/monitoring by the 
UCSF DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study 
data.  At study completion, when the CRFs have been declared to be complete and 
accurate, the database will be locked.  Any changes to the data entered into the CRFs 
after that time can only be made by joint written agreement among the Study Chair, the 
Trial Statistician, and the Protocol Project Manager. 
Each participating site will complete study specific CRFs for safety monitoring and data 
analysis.  Each site will enter the study data into OnCore® via standardized CRFs in 
accordance with the CTMS study calendar, using single data entry with a secure access 
account. The participating site’s Clinical Research Coordinator (CRC) will complete the 
CRFs; the Investigator will review and approve the completed CRFs – this process must 
be completed within 3 business days of the visit. Study data from the participating site will 
be reported and reviewed in aggregate with data from patients enrolled at the coordinating 
center, UCSF.  All source documentation and CTMS data will be available for 
review/monitoring as needed. 
9.8 
Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the 
monitoring entity for this study.  The UCSF DSMC will monitor the study in accordance 
with the NCI-approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely 
review all adverse events and suspected adverse reactions considered “serious”.  The 
DSMC will audit study-related activities to ensure that the study is conducted in 
accordance with the protocol, local standard operating procedures, FDA regulations, and 
Good Clinical Practice (GCP).  Significant results of the DSMC audit will be communicated 
to the IRB and the appropriate regulatory authorities at the time of continuing review, or in 
an expedited fashion, as applicable.  See Appendix 2 Data and Safety Monitoring Plan for 
additional information. 
9.9 
Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the 
disposition of the drug when the study ends.   
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the 
investigation. Case histories include the case report forms and supporting data including, 
for example, signed and dated consent forms and medical records including, for example, 
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The case history for each individual shall document that informed consent was obtained 
prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 
years following the date a marketing application is approved for the drug for the indication 
for which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and FDA 
is notified. 
9.10 Coordinating Center Documentation of Distribution  
It is the responsibility of the Study Chair to maintain adequate files documenting the 
distribution of study documents as well as their receipt (when possible). The HDFCCC 
recommends that the Study Chair maintain a correspondence file and log for each 
segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.). 
Correspondence file: should contain copies (paper or electronic) of all protocol versions, 
cover letters, amendment outlines (summary of changes), etc., along with distribution 
documentation and (when available) documentation of receipt. 
Correspondence log: should be a brief list of all documents distributed including the date 
sent, recipient(s), and (if available) a tracking number and date received. 
At a minimum, the Study Chair must keep documentation of when and to whom the 
protocol, its updates and safety information are distributed. 
10 Protection of Human Subjects 
10.1 Protection from Unnecessary Harm  
Each clinical site is responsible for protecting all subjects involved in human 
experimentation. This is accomplished through the IRB mechanism and the process of 
informed consent. The IRB reviews all proposed studies involving human experimentation 
and ensures that the subject’s rights and welfare are protected and that the potential 
benefits and/or the importance of the knowledge to be gained outweigh the risks to the 
individual. The IRB also reviews the informed consent document associated with each 
study in order to ensure that the consent document accurately and clearly communicates 
the nature of the research to be done and its associated risks and benefits.  
10.2 Protection of Privacy 
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, 
they will be asked to sign the HIPAA form and informed consent documents. The original 
signed document will become part of the patient’s medical records, and each patient will 


 
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receive a copy of the signed document. The use and disclosure of protected health 
information will be limited to the individuals described in the informed consent document. 
 
 


 
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Selected References. 
Davies B, Morris T. Physiological parameters in laboratory animals and humans. 
Pharmaceutical Research 1993;10(7):1093-95. 
Dong X, Biswas A, Chook YM. Structural basis for assembly and disassembly of the 
CRM1 nuclear export complex. Nat Struct Mol Biol. 2009a May;16(5):558-60.  
Dong X, Biswas A, Süel KE, Jackson LK, Martinez R, Gu H, Chook YM. Structural basis 
for leucine-rich nuclear export signal recognition by CRM1. Nature. 2009b Apr 
30;458(7242):1136-41.  
Etchin J, Sun Q, Kentsis A, Farmer A, Zhang ZC, Sanda T, Mansour MR, Barcelo C, 
McCauley D, Kauffman M, Shacham S, Christie AL, Kung AL, Rodig SJ, Chook YM, Look 
AT. Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. 
Leukemia. 2013 Jan;27(1):66-74. 
Salas Fragomeni RA, Chung HW, Landesman Y, Senapedis W, Saint-Martin JR, Tsao H, 
Flaherty KT, Shacham S, Kauffman M, Cusack JC. CRM1 and BRAF inhibition synergize 
and induce tumor regression in BRAF-mutant melanoma. Mol Cancer Ther. 2013 Jun 27. 
[Epub ahead of print]. 
Fornerod M, van Deursen J, van Baal S, Reynolds A, Davis D, Murti KG, et al. The human 
homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel 
nuclear pore component Nup88. EMBO J. 1997 Feb 17;16(4):807-16. 
Gartel AL, Tyner AL. The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. 
Mol Cancer Ther. 2002 Jun;1(8):639-49. 
Gravina GL, Tortoreto M, Mancini A, Muzi P, Ventura L, D'ascenzo S, Addis A, 
Landesman Y, McCauley D, Dolo V, Kauffman M, Shacham S, Zaffaroni N, Festuccia C.  
CRM1-Selective Inhibitors of Nuclear Export (SINE) reduce the incidence of tumor 
spreading and improve overall survival in preclinical models of prostate cancer.  Abstract 
3440, AACR 2013. 
Jin S, Pang RP, Shen JN, Huang G, Wang J, Zhou JG. Grifolin induces apoptosis via 
inhibition of PI3K/AKT signalling pathway in human osteosarcoma cells. Apoptosis. 2007 
Jul;12(7):1317-26. 
Johnson AJ, Lucas DM, Muthusamy N, Smith LL, Edwards RB, De Lay MD et al. 
Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for 
human chronic lymphocytic leukemia. Blood 2006;108:1334-38. 
Kau TR, Schroeder F, Ramaswamy S, Wojciechowski CL, Zhao JJ, Roberts TM, 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 Dec;4(6):463-76. 
Kudo N, Matsumori N, Taoka H, Fujiwara D, Schreiner EP, Wolff B, et al. Leptomycin B 
inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central 
conserved region. Proc Natl Acad Sci U S A. 1999 Aug 3; 96(16): 9112-9117. 
Lapalombella R, Sun Q, Williams K, Tangeman L, Jha S, Zhong Y, Goettl V, Mahoney E, 
Berglund C, Gupta S, Farmer A, Mani R, Johnson AJ, Lucas D, Mo X, Daelemans D, 
Sandanayaka V, Shechter S, McCauley D, Shacham S, Kauffman M, Chook,YM, Byrd JC. 


 
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Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic 
lymphocytic leukemia. Blood. 2012 Nov 29;120(23):4621-34. 
Landesman Y, Senapedis W, Saint-Martin JR, Kashyap T, Plamondon L, Sandanayaka V 
et al. Pharmacokinetic (PK)/pharmacodynamic (PDn) and efficacy relationship of selective 
inhibitors of nuclear export. AACR 2012. 
London, CA, Barnard, S, Kisseberth, W, Plamondon, L,, Shacham, S, Kauffman, M.  
Preliminary results of a phase I study of the novel CRM1 inhibitors KPT-276 and KPT-335 
in dogs with spontaneous cancer.  Abstract LB-232, AACR 2012. 
McCauley, D , Landesman, Y, Senapedis, B, Kashyap, T, Saint-Martin, J-R, Plamondon, 
L, Sandanayaka, V, Shechter, S, Froim, D, Nir, R, Williams, J, Chin, L, Benes, C, Raza 
Mirza, M,Kauffman, M, Shacham, S.  Preclinical evaluation of selective inhibitors of 
nuclear export (SINE) in basal-like breast cancer (BLBC).  J Clin Oncol 30, 2012 (suppl; 
abstr 1055). 
Miyake,TM, Pradeep,S, Zand, B, Dalton, HJ, Wen, Y, Armaitz Pena, GN, Kauffman, M, 
McCauley,D, Shacham, S, Wiktorowicz, JE, Sood, AK. Therapeutic targeting of CRM1 in 
ovarian cancer.  Abstract 5541, AACR 2013. 
Mutka SC, Yang WQ, Dong SD, Ward SL, Craig DA, Timmermans PB, et al. Identification 
of nuclear export inhibitors with potent anticancer activity in vivo. Cancer Res. 2009 Jan 
15;69(2):510-7. 
Newlands ES, Rustin GJ, Brampton MH. Phase I trial of elactocin. Br J Cancer. 1996 
Aug;74(4):648-9. 
Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N, et al. Whole-
genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. 
Nature. 2011 Jun 5;475(7354):101-5. doi: 10.1038/nature10113. 
Razak,ARA, Mau Soerensen,M, Mahipal,A, Shacham,S, Yau,CYF, Lassen, UN, 
McCauley, D, Cooksey, J, Tan, DSP, Saint-Martin, J-R, Landesman, Y, Pond, G, Oza, 
AM, Kauffman, M, Siu, LL, Raza Mirza, M.  First-in-class, first-in-human phase I trial of 
KPT-330, a selective inhibitor of nuclear export (SINE) in patients (pts) with advanced 
solid tumors.  J Clin Oncol 31, 2013 (suppl; abstr 2505) 
Sakakibara K, Saito N, Sato T, Suzuki T, Hasegawa Y, Friedman JM et al. CBS9106 is a 
novel reversible oral CRM1 inhibitor with CRM1 degrading activity. Blood 
2011;118(14):3922-31. 
Senapedis, W, Landesman Y, Richard J, Kashyap T, Plamondon L, Sandanayaka V et al. 
KPT-SINE (Selective Inhibitors of Nuclear Export) induces apoptosis in colon cancer cells 
in vitro and in vivo through nuclear localization of tumor suppressor proteins (TSPs).  
AACR 2012. 
Sharpless NE, DePinho RA. Gone but not forgotten. Nature 2007;445:606-7. 
Siddiqui N, Borden KL. mRNA export and cancer. Wiley Interdiscip Rev RNA. 2012 
Jan;3(1):13-25. doi: 10.1002/wrna.101. Epub 2011 Jul 27. 


 
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Stauber RH, Mann W, Knauer SK. Nuclear and Cytoplasmic Survivin: Molecular 
Mechanism, Prognostic, and Therapeutic Potential. Cancer Res. 2007 July 1; 
67:(13):5999-6002. 
Van der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D. The 
Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer 
and are critical for cancer cell survival and proliferation. Int J Cancer. 2009 Apr 
15;124(8):1829-40. 
Wolff B, Sanglier JJ, Wang Y. Leptomycin B is an inhibitor of nuclear export: inhibition of 
nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev 
protein and Rev-dependent mRNA. Chem Biol. 1997 Feb;4(2):139-47. 
Wu Z. A new classification system of anticancer drugs- based on cell biological 
mechanisms. Medical Hypotheses 2006;66:883-7. 
Xu D, Farmer A, Chook YM. Recognition of nuclear targeting signals by Karyopherin-ß 
proteins. Current Opinion in Structural Biology. 2010 20(6):782-790. 
Yang H, Filipovic Z, Brown D, Breit SN, Vassilev LT. Macrophage inhibitory cytokine-1: a 
novel biomarker for p53 pathway activation. Mol Cancer Ther. 2003 Oct;2(10):1023-9. 
Youdim MB, Wadia A, Tatton W, Weinstock M. The anti-Parkinson drug rasagiline and its 
cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in 
cell culture and in vivo. Ann N Y Acad Sci. 2001 Jun;939:450-8. 
Zhang K, Wang M, Tamayo AT, Shacham S, Kauffman M, Lee J, Zhang L, Ou Z, Li C, 
Sun L, Ford RJ, Pham LV. Novel selective inhibitors of nuclear export CRM1 antagonists 
for therapy in mantle cell lymphoma. Exp Hematol. 2013 Jan;41(1):67-78. 
 
 
 


 
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Appendix 1 Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance 
without restriction 
100 
Normal, no complaints, no 
evidence of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease 
1 
Symptoms, but ambulatory 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (e.g., light housework, 
office work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities 
Up and about more than 50% 
of waking hours 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours 
40 
Disabled, requires special care 
and assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
 
 


 
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Appendix 2 Data and Safety Monitoring Plan for Multicenter Institutional 
Study 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject 
safety for all HDFCCC institutional clinical studies.  A summary of DSMC activities for this 
study includes:  
• 
Review of subject data 
• 
Review of suspected adverse reactions considered “serious” 
• 
Monthly monitoring (depending on study accrual) 
• 
Minimum of a yearly regulatory audit 
Monitoring and Reporting Guidelines 
All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk 
assessment. The data is monitored every six months, with twenty percent of the subjects 
monitored (or at least three subjects if the calculated value is less than three). 
The UCSF Coordinating Center provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter clinical trial. 
The UCSF Coordinating Center will also coordinate quarterly conference calls with the 
participating sites to communicate the review of adverse events, safety data, and other 
study matters. 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study 
Chair. The Study Chair is responsible for the overall conduct of the study and for 
monitoring its safety and progress at all participating sites. The Study Chair will conduct 
continuous review of data and subject safety and discuss each subject’s treatment at 
monthly UCSF Site Committee meetings. The discussions are documented in the UCSF 
Site Committee meeting minutes. 
Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter clinical trial.  
The UCSF Coordinating Center will also coordinate, at minimum, quarterly conference 
calls with the participating sites at the completion of each cohort or more frequently as 
needed to discuss risk assessment.  The following issues will be discussed as appropriate: 
• 
Enrollment information  
• 
Adverse events (i.e. new adverse events and updates on unresolved adverse events 
and new safety information) 
• 
Protocol violations 
• Other issues affecting the conduct of the study 
Adverse events reporting to the DSMC will include reports from both the UCSF 
Coordinating Center, as well as the participating sites.  The DSMC will be responsible for 
monitoring all data entered in OnCore® at the UCSF Coordinating Center and the 
participating sites.  The data (i.e. copies of source documents) from the participating sites 
will be sent electronically or faxed over to the UCSF Coordinating Center prior to the 


 
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monitoring visits in order for the DSMC to monitor the participating site’s compliance with 
the protocol, patient safety, and to verify data entry. 
 
 


 
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Adverse Event Review and Monitoring 
Adverse Event Monitoring 
All Grade 3-5 Adverse Events, whether or not unexpected, and whether or not considered 
to be associated with the use of study drug, will be entered into OnCore®, UCSF’s Clinical 
Trial Management System. 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at 
the UCSF Site Committee meetings. All clinically significant adverse events must be 
reported to the UCSF Coordinating Center by the participating sites within 10 business 
days of becoming aware of the event or during the next scheduled quarterly conference 
call, whichever is sooner. The UCSF Site Committee will review and discuss the selected 
toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s) from the UCSF Coordinating Center and the 
participating sites. 
In addition, all suspected adverse reactions considered “serious” must be entered in 
OnCore® and reported to the UCSF Coordinating Center within 1 business day. The 
suspected adverse reactions considered “serious” will be reviewed and monitored by the 
Data and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC 
meeting, which take place every six (6) weeks. 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the 
investigational drug or any research related procedure, the Study Chair at the UCSF 
Coordinating Center or the assigned designee must be notified within 1 business day from 
the participating site(s) and the Study Chair must then notify the DSMC Chair or qualified 
alternate within 1 business day of this notification. The contact may be by phone or e-mail. 
Increase in Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in 
the Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating 
Center is responsible for notifying the DSMC at the time the increased rate is identified.  
The report will indicate if the incidence of adverse events observed in the study is above 
the range stated in the Investigator Brochure or package insert. 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail.  The 
DSMC must receive a formal letter within 10 business days and the IRB must be notified. 
Data and Safety Monitoring Committee Contacts: 
DSMC 
Chair:  
Thierry Jahan, MD 
DSMC Monitors  
Phone:  
Email: 
Address:  
415-353-7065 
Thierry.Jahan@ucsf.edu 
Box 1674 
UCSF 
San Francisco, CA 94115 
Box 0128 
UCSF Helen Diller Family 
Comprehensive Cancer Center 
San Francisco, CA 94158 
*  DSMP approved by NCI 09/February2012 
 
 


 
Version date: 04-27-2016 
 
Protocol CC#: 14552 
Phase II – Selinexor (KPT-330) 
 
Page 65 of 70 
Appendix 3 UCSF Policy/Procedure for Required Regulatory Documents for 
a UCSF Multicenter Investigator-Initiated Oncology Clinical Trials with an 
Investigator held Investigational New Drug (IND) 
Purpose 
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive 
Cancer Center (HDFCCC) where the Principal Investigator (PI) holds the IND. 
Background 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) 
Guidelines define Essential Regulatory Documents as those documents which individually 
and collectively permit evaluation of the conduct of a trial and the quality of data produced. 
These documents serve to demonstrate compliance with standards of GCP and with all 
applicable regulatory requirements. Filing essential documents in a timely manner can 
greatly assist in the successful management of a clinical trial. 
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, 
as well as paper files in the Regulatory Binders for both the Coordinating Site and the 
Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials. 
Procedures 
1.   HDFCCC Essential Regulatory Documents 
Documents Filed in iMedRIS: 
• 
IRB approvals for initial submission of application, all modifications, and continuing 
annual renewals 
• 
Current and prior approved protocol versions with signed protocol signature 
page(s) 
• 
Institutional Review Board (IRB) approval letters and Informed Consent Form(s) 
(ICF) 
• 
Current and prior versions of the Investigator Brochure (IB). 
• 
Serious Adverse Event Reporting 
• 
Protocol Violations and Single Patient Exception (SPE) Reports to IRB with 
supporting fax documentation 
Documents Filed in OnCore®: 
• 
Package Insert (if the study drug is commercial) or Investigator Brochure 
• 
Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC) 
• 
Patient handouts 
• 
Screening/enrollment log 
• 
Data and Safety Monitoring Committee (DSMC) monitoring reports 
• 
OnCore® Case Report Form (CRF) completion manual 
 
 


 
Version date: 04-27-2016 
 
Protocol CC#: 14552 
Phase II – Selinexor (KPT-330) 
 
Page 66 of 70 
Documents Filed in Regulatory Binder: 
• 
Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature 
• 
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will 
need Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency 
(DEA) Licenses, and Staff Training Documents (i.e. Collaborative Institute Training 
Initiative (CITI), etc.) 
• 
Site Initiation Visit (SIV) minutes and correspondence with participating site(s). 
• 
As applicable, approvals for Biosafety Committee, Radiation Committee, and 
Infusion Center 
• 
Serious Adverse Event (SAE) reports to IRB and sponsor. 
• 
MedWatch reporting to FDA and sponsor 
• 
Delegation of Authority Form 
• 
Drug Destruction Standard Operating Procedure (SOP) 
• 
For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges 
2.  Additional Essential Documents for Multicenter Trials for the Coordinating 
Center (filed in Regulatory Binder or OnCore) 
• 
Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent 
Form (ICF), and Health Insurance Portability and Accountability Act (HIPAA) 
Consent Form for the Participating Site(s) 
• 
For all Principal Investigators and Sub-Investigators listed on the 1572 at the 
Participating Site(s) – Financial Disclosure Forms, CVs, MD Licenses, and Staff 
Training documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for 
Investigational New Drug Application 
• 
Site Initiation Visit (SIV) minutes and correspondence with Participating Site(s).  
• 
As applicable, approvals for Biosafety Committee, Radiation Committee, and 
Infusion Center for the Participating Site(s) 
• 
Protocol Violations and Single Patient Exception (SPE) reports to IRB with 
supporting fax documentation for Participating Site(s) 
• 
Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s) 
• 
Data and Safety Monitoring Committee (DSMC) monitoring reports for the 
Participating Site(s) 
• 
For all laboratories listed on FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges 
for the Participating Site(s) 
• 
Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all 
participating site(s) in Multicenter studies or Contract Research Organization 
(CRO) Monitoring Plan (if an outside CRO is used for the study) 
• 
Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor for 
the Participating Site(s) 
 
 
27 April 2012 
 


 
Version date: 04-27-2016 
 
Protocol CC#: 14552 
Phase II – Selinexor (KPT-330) 
 
Page 67 of 70 
3.  Required Regulatory Documents for Sub-sites Participating in a UCSF 
Investigator Initiated Multicenter Trial (Checklist) 
Directions:  
1)  Scan the documents and email to the UCSF Coordinating center or  
2)  Scan the documents and upload to OnCore® and create a Note to File for the on-site 
Regulatory binder to indicate where these documents may be found 
1572 
  PI and Sub investigators: 
CV and Medical license  
Financial disclosure form 
NIH or CITI human subject protection training certification 
  Laboratories   
CLIA and CAP 
CV of Lab Director and Lab Licenses 
Laboratory reference ranges 
Local Institutional Review Board  
  IRB Approval letter 
  Reviewed/Approved documents 
• 
Protocol version date:   
___________ 
• 
Informed consent version date:  ___________ 
• 
Investigator Brochure version date:  ___________ 
• 
HIPAA  
  Current IRB Roster 
Other  
  Delegation of Authority Log  
• 
Include NIH or CITI human subject protection training certificates or GCP training 
certification 
  Pharmacy 
• 
Drug destruction SOP and Policy 
  Protocol signature page  
  Executed sub contract 
 
27.apr.2012 
 


 
Version date: 04-27-2016 
 
Protocol CC#: 14552 
Phase II – Selinexor (KPT-330) 
 
Page 68 of 70 
Appendix 4 Full Ophthalmological Exam 
Full ophthalmological exam:  required of all patients in all selinexor studies at screening, 
every 3 months if cataracts present at screening and if clinically indicated during study.   
1. Prior to dilation: 
• 
best corrected visual acuity 
• 
slit lamp examination including tonometry 
2. Dilated: 
• 
fundoscopy 
• 
slit lamp examination  
o if a cataract is seen during the exam, cataract will be graded according to the 
Lens Opacities Classification System III (LOCS III) 
• 
 
 
 
 


 
Version date: 04-27-2016 
 
Protocol CC#: 14552 
Phase II – Selinexor (KPT-330) 
 
Page 69 of 70 
Ophthalmological Exam Assessments 
Best Corrected Visual Acuity (BCVA): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adnexa 
 
 
 
Normal 
Abnormal  
Description 
 
 
 
 
 
 
 
 
 
lids 
 
 
 
 
 
 
 
 
lashes 
 
 
 
 
 
 
 
 
conjunctiva 
 
 
 
 
 
 
 
cornea 
 
 
 
 
 
 
 
 
ant. Chamber 
 
 
 
 
 
 
 
iris 
 
 
 
 
 
 
 
 
lens*(1) 
 
 
 
 
 
 
 
 
Intraocular pressure 
 
 
 
 
 
 
 
 
Fundus 
 
 
 
 
 
 
 
 
vitreous 
 
 
 
 
 
 
 
 
optic disc*(2) 
 
 
 
 
 
 
 
macula 
 
 
 
 
 
 
 
 
retina 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*(1) Does lens show cataract change, follow grading system in description 
 
*(2) Cup/disc ratio and any abnormalities if seen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 5: Selinexor (cc# 14552) Response Assessment Patient Name: ____________________________
MRN: ______________________
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(All measurable lesions up to a maximum of 5 lesions total and maximum of two lesions per organ)
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Lesion #
Location
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Baseline
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Date: _____________________
Date: _____________________
Date: _____________________
Date: _____________________
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Scan Type: __________ FdG +/- : _______ Scan Type: __________ FdG +/- : _______
Scan Type: __________ FdG +/- : _______
Scan Type: __________ FdG +/- : _______


Longest Diameter
Cross 
Measurement
Longest Diameter
Cross Measurement
Longest Diameter
Cross Measurement Longest Diameter
Cross 
Measurement


(cm)

(cm)
(cm)
(cm)
(cm)
(cm)
(cm)
(cm)
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1 
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2 
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3 
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4 
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5 
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SUM:
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From BL
From nadir From BL
From nadir From BL
From nadir
From BL
From nadir
From BL
From nadir
From BL
From nadir
From BL
From nadir
From BL From nadir
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% Change:
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Overall Response of Target Lesions
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පPD  පSD
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පPD  පSD
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පPD  පSD
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(All other lesions or sites of disease including any measurable lesions over and above the 5 target lesions)
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Lesion #
Location
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
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1 
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පPresent
පPresent පAbsent පPD
පPresent පAbsent පPD
පPresent පAbsent පPD









5 

පPresent
පPresent පAbsent පPD
පPresent පAbsent පPD
පPresent පAbsent පPD









6 

පPresent
පPresent පAbsent පPD
පPresent පAbsent පPD
පPresent පAbsent පPD









4 

පPresent
පPresent පAbsent පPD
පPresent පAbsent පPD
පPresent පAbsent පPD









5 

පPresent
පPresent පAbsent පPD
පPresent පAbsent පPD
පPresent පAbsent පPD









6 

පPresent
පPresent පAbsent පPD
පPresent පAbsent පPD
පPresent පAbsent පPD
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Overall Response of Non-Target Lesions
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පCR  පSD  පPD
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පCR  පSD  පPD
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පCR  පSD  පPD
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
No. of lesions total
No. of new 
lesions
No. of lesions total
No. of new 
lesions
No. of lesions total
No. of new 
lesions


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



c/w BL


c/w BL


c/w BL

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


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
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Overall Response of Non-Measurable Bone Lesions (see 7.3)

පPD
පNot PD

පPD
පNot PD

පPD
පNot PD
OVERALL RESPONSE (see 7.3.1.3, table 7.1) 



පCR  පPR  පPD  
පSD

පCR  පPR  පPD  
පSD

පCR  පPR  පPD  
පSD


Signature _______________________
Signature _______________________ Signature _______________________
Signature _______________________


Date _________________________
Date _________________________
Date _________________________
Date _________________________