Clinical trial NCT02303392
Conditions: Prolymphocytic Leukemia Recurrent Adult Diffuse Large Cell Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia
Sponsor: Jennifer Woyach
Start date: 2015-06-09; Completion date: 2022-04-18
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I trial studies the side effects and best dose of selinexor when given together with ibrutinib in treating patients with chronic lymphocytic leukemia or aggressive non-Hodgkin lymphoma that has returned after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as selinexor, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving selinexor together with ibrutinib may be a better treatment for chronic lymphocytic leukemia or aggressive non-Hodgkin lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose for the combination of selinexor and ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia(SLL)/B-cell prolymphocytic leukemia (PLL) or aggressive non-Hodgkin lymphoma (NHL).

SECONDARY OBJECTIVES:

I. To characterize the safety and tolerability of the combination of selinexor and ibrutinib in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL.

II. To characterize the pharmacokinetic (PK) properties of the combination of selinexor and ibrutinib in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL.

III. To obtain preliminary evidence on efficacy of the combination of selinexor and ibrutinib in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL.

IV. To obtain preliminary evidence of response in CLL/SLL/PLL and diffuse large B-cell lymphoma (DLBCL) patients receiving the combination of selinexor and ibrutinib as related to CLL/SLL/PLL karyotype and immunoglobulin variable heavy chain (IgVH) mutational status and DLBCL subtype, respectively.

V. To evaluate the inhibition of the B-cell receptor signaling pathway in patients with relapsed or refractory CLL/SLL/PLL who receive the combination of selinexor and ibrutinib.

VI. To evaluate the change in localization of tumor suppressor and growth regulation proteins in patients with relapsed or refractory CLL/SLL/PLL following treatment with selinexor in general and as related to response.

VII. To preliminarily assess potential causes for primary and secondary resistance to selinexor and ibrutinib.

VIII. To measure intracellular levels of selinexor and metabolites in peripheral blood mononuclear cells and to identify how this relates to pharmacodynamics effects and clinical outcomes.

OUTLINE: This is a dose-escalation study of selinexor.

Patients receive ibrutinib orally (PO) on days 8-28 of course 1 and on days 1-28 on subsequent courses and selinexor PO twice daily (BID) weekly on day 1 or bi-weekly on days 1 and 3. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks and then every 6 months thereafter.

Arms: arm 1: Patients receive ibrutinib PO on days 8-28 of course 1 and on days 1-28 on subsequent courses and selinexor PO BID weekly on day 1 or bi-weekly on days 1 and 3. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Selinexor intervention 2: Ibrutinib intervention 3: Pharmacological Study intervention 4: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
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TITLE:  A Dose Escalation Study of Selinexor (KPT-330), a Selective Inhibitor of Nuclear 
Export, and Ibrutinib, a Bruton’s Tyrosine Kinase Inhibitor, in Patients with Relapsed and 
Refractory Chronic Lymphocytic Leukemia or Aggressive Non-Hodgkin Lymphoma 
 
 
Principal Investigator: 
Jennifer A Woyach, MD 
 
455A Wiseman Hall 
 
410 W 12th Ave 
 
 
Columbus, Ohio 43210 
 
(614) 685-5667 
 
Jennifer.woyach@osumc.edu 
 
 
 
Laboratory Co-Investigators: Mitch Phelps, PhD 
 
Rosa Lapalombella, PhD 
 
Larry Schaaf, PhD 
 
Statistician: 
Amy S. Ruppert, MAS 
 
Multi-Center Trial Program 
Clinical Trials Office 
The Ohio State University Comprehensive Cancer Center 
Fax: 614-366-6652 
E: OSUCCC-CTO-MCTP@osumc.edu  
 
Initial Protocol 
14 Nov 2014 
Amendment 1 
25 Jan 2016 
Amendment 2 
03 May 2016 
Amendment 3 
10 Jan 2017 
Amendment 4 
03 Oct 2017 
Amendment 5 
12 Jun 2018 
Amendment 6 
07 April 2020 
Amendment 7        03 August 2021 
 
 
 


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Investigational Agent  
IND# 
IND Sponsor  
Selinexor (KPT-330) 
124150 
The Ohio State University 
 
Study Cohorts: 
 
 
 
 
 
 
 
 
 
SCHEMA 
Eligibility Criteria* 
Required Initial 
Laboratory Values 
1.Histologically confirmed chronic lymphocytic leukemia, small 
lymphocytic leukemia, B-cell prolymphocytic leukemia, or 
variants of this or B-cell non-Hodgkin’s lymphoma (NHL) of any 
of the following subtypes recognized by the WHO classification: 
mantle cell lymphoma, diffuse large B-cell lymphoma not 
otherwise specified, or transformed lymphoma. 
2.At least one prior therapy 
3.ECOG performance status 0-1 
4.Age ≥ 18 years 
5.Patients are excluded who: 
• Have received chemotherapy or radiotherapy ≤ 4 weeks, 
nitrosoureas or mitomycin C ≤ 6 weeks, or immunotherapy/ 
targeted agents (such as kinase inhibitors) ≤ 2 weeks (except 
patients already on ibrutinib). 
• Require anticoagulation with warfarin. 
• Require therapy with strong inducers or inhibitors of CYP3A4/5. 
ANC# ≥ 1,000/mm3 
Platelets$ ≥ 50,000/mm3 
Creatinine clearance ≥ 
30ml/min 
Total bilirubin^ ≤ 2.0 x 
ULN 
AST/ALT# < 2.5 ULN 
 
 
 
 
*Please refer to Section 3 for the complete eligibility criteria. #Unless these values are secondary to bone marrow 
involvement of CLL/NHL. $Platelets ≥ 30,000/mm3 in the setting of bone marrow involvement. ^Unless due to Gilberts. 
 
Regimen Description 
Agent 
Precautions 
Dose 
Route 
Schedule 
Cycle Length 
Ibrutinib 
Take with 8 oz of water, 
30 min before meal 
Capsule 
or 
tablet* 
Oral 
Cycle 1 Days 8-
28**, Cycles 2+ 
Days 1-28 
28 days (4 
weeks) 
Selinexor 
Take with at least 120 
mL (4 ounces) of fluids 
(water, juice, etc.) 
Tablet* 
Oral 
Days 1,8, and 15 of 
each cycle* 
*Doses/schedule as appropriate for assigned dose level. 
Cohort 1: 
Selinexor Dose 
Escalation 
Cohort 2: 
Selinexor + 
Ibrutinib 
Expansion Cohort
Cohort 3: 
Selinexor added 
to frontline 
Ibrutinib in CLL 


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**Patients continuing on ibrutinib should take ibrutinib days 1-28 of Cycle 1  
 
 
Dose 
Level 
Selinexor 
Dose 
Selinexor 
Schedule 
Ibrutinib 
Dose  
Ibrutinib 
Schedule 
1* 
40 mg 
Weekly (oral) 
420 mg 
Daily (oral) 
2 
20 mg 
Bi-weekly (oral) 
420 mg 
Daily (oral) 
 
 
 
For the phase I study, an adaptive dose finding design using a modified continuous reassessment 
method will be followed. Once the MTD of selinexor in combination with ibrutinib is identified, 
an expansion cohort of up to 10 CLL patients and 10 lymphoma patients will be accrued to better 
describe the toxicity profile, evaluate feasibility of pharmacodynamics studies, and to gain 
additional efficacy data. Dose-limiting toxicity (DLT) will be assessed during cycle 1 only.  
Provided the patient does not experience significant toxicity, patients may continue treatment 
until disease progression. Response will be assessed by PET/CT, CT, and/or peripheral blood 
immunophenotyping every 3 cycles during the 1st year of therapy and then every 6 months until 
disease progression or as medically indicated.  PET/CT is preferred in lymphoma patients.  In 
patients with bone marrow involvement at the start of therapy, a bone marrow biopsy will be 
performed to confirm a complete response (CR).  Additionally, bone marrow biopsy will be 
performed at 1 year and then yearly provided other criteria for CR exist.  
 
Definition of DLT for patients receiving selinexor and ibrutinib* 
General 
• 
Treatment delays >28 days for any toxicity  
• 
Any grade 5 toxicity 
Non-hematologic 
• 
Grade 3 nausea/vomiting or diarrhea lasting for ≥7 days while taking optimal 
supportive medications# 
• 
Grade 3 anorexia or fatigue lasting for ≥7 days while taking optimal supportive care# 
and with correction of dehydration, anemia, endocrine, or electrolyte abnormalities 
• 
Grade ≥ 3 AST or ALT elevation lasting for ≥7 days OR any Grade ≥ 3 AST or ALT 
elevation in the setting of bilirubin elevation > 2x ULN 
Any other Grade 3 non-hematological toxicity except alopecia, rash that resolves to 
Grade 1 in ≤ 7 days, or electrolytes abnormalities correctable with supportive therapy# 
• 
Any Grade 4 non-hematologic toxicity not specifically listed above 
Hematologic 
• Grade 4 neutropenia [absolute neutrophil count (ANC) < 500/mm3] lasting ≥7 days$; 
• Grade 4 thrombocytopenia (platelet count <25,000/mm3) that persists for ≥7 days$; 
• Grade ≥ 3 thrombocytopenia-associated bleeding; or  
• Grade 4 febrile neutropenia (ANC < 1000/mm3 with a single temperature ≥ 38.3ºC or 
sustained temperature of >38°C for over 1 hour). 
*Assessed during Cycle 1 by CTCAEv4 criteria #Section 4.4 provides detailed supportive care $Only for patients 
with normal cell counts at study start (See Section 4.2) ^For patients with Gilbert’s syndrome: >2X baseline 


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TABLE OF CONTENTS 
 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objectives...................................................................................................7 
1.2 
Secondary Objectives...............................................................................................7 
1.3 
Exploratory Correlative and Pharmacodynamic Objectives ....................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Chronic Lymphocytic Leukemia and Non-Hodgkin’s Lymphoma .........................7 
2.2 
B-cell Receptor Pathway in Lymphoid Malignancies .............................................8 
2.3 
Ibrutinib in Chronic Lymphocytic Leukemia ..........................................................8 
2.4 
Ibrutinib in Mantle Cell Lymphoma ........................................................................9 
2.5 
Ibrutinib in Diffuse Large B-cell Lymphoma ........................................................10 
2.6 
Tumor Suppressor Protein (TSP) and Growth Regulatory Protein (GRP) 
Nuclear Export .......................................................................................................11 
2.7 
Inhibition of XPO1 in Human Cancer ...................................................................12 
2.8 
Selective Inhibitors of Nuclear Export (SINE) ......................................................12 
2.9 
Selinexor Preclinical and Clinical Data .................................................................13 
2.10 
Rationale for the Study ..........................................................................................15 
2.11 
Rationale for the Dose/Dosing Schedule ...............................................................15 
2.12 
Correlative Studies Background ............................................................................16 
3. 
PATIENT SELECTION ....................................................................................................17 
3.1 
Eligibility Criteria ..................................................................................................17 
3.2 
Exclusion Criteria ..................................................................................................19 
3.3 
Inclusion of Women and Minorities ......................................................................21 
4. 
REGISTRATION PROCEDURES ...................................................................................21 
5. 
TREATMENT ...................................................................................................................22 
5.1 
Overview ................................................................................................................22 
5.2 
Agent Administration.............................................................................................23 
5.3 
Definition of Dose Limiting Toxicity ....................................................................26 
5.4 
Concomitant Medications ......................................................................................27 
5.5 
Prevention of Pregnancy ........................................................................................27 
5.6 
Blood Products .......................................................................................................27 
5.7 
Radiation Treatment...............................................................................................27 
5.8 
Glucocorticoid Therapy .........................................................................................28 
5.9 
Anti-diarrheal Medications ....................................................................................28 
5.10 
General Medications ..............................................................................................28 
5.11 
Procedures ..............................................................................................................28 
5.12 
Anticancer Therapy ................................................................................................28 
5.13 
Investigational Agents ...........................................................................................28 
5.14 
Drugs undergoing Glutathione conjugation ...........................................................29 
5.15 
Drugs that inhibit or induce CYP 3A4/5................................................................29 


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5.16 
Warfarin .................................................................................................................29 
5.17 
Concomitant Treatments for Selinexor ..................................................................29 
5.18 
Supportive Care Guidelines for selinexor ..............................................................30 
Table:  Supportive Care and Selinexor Dose Adjustment Guidelines for AEs related to 
Selinexora,b .........................................................................................................................30 
1. 
aFor all Grade ≥3 hematologic or non-hematologic AEs that are NOT selinexor related, 
after consultation with the Medical Monitor and at the discretion of the Investigator, 
selinexor dosing may be maintained. .................................................................................33 
2. 
bFor all selinexor-related AE’s, if the below prescribed dose reductions/interruptions 
result in a stabilization of ≥4 weeks, a re-escalation may be considered after approval 
from the Medical Monitor. .................................................................................................33 
3. 
All dose modifications should be based on the worst preceding toxicity. .........................33 
4. 
Note: When toxicities due to selinexor have returned to baseline levels or the patient has 
stabilized, the dose of selinexor may be re-escalated in consultation with the Medical 
Monitor. .............................................................................................................................33 
5.19 
Duration of Therapy ...............................................................................................33 
5.20 
Duration of Follow Up ...........................................................................................34 
5.21 
Criteria for Removal from Treatment ....................................................................34 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................34 
6.1 
Dose adjustment guidelines for hematologic ibrutinib or selinexor-related 
toxicities .................................................................................................................35 
6.2 
Dose adjustment guidelines for non-hematologic ibrutinib or selinexor-
related toxicities .....................................................................................................37 
6.3 
Dose Reduction for Decreased Glomerular Filtration Rate (GFR) .......................44 
6.4 
Dose Adjustment for Infection ...............................................................................44 
6.5 
Conditions not Requiring Dose Reduction ............................................................45 
6.6 
Missed or Vomited Doses ......................................................................................45 
6.7 
Delays, Modifications and Reintroduction ............................................................45 
7. 
ADVERSE EVENTS (AEs):  LIST AND REPORTING REQUIREMENTS ..................45 
7.1 
Definition of an Adverse Event .............................................................................46 
7.2 
Recording of Adverse Events ................................................................................46 
7.3 
Laboratory Test Abnormalities ..............................................................................46 
7.4 
Adverse Events of Special Interest ........................................................................47 
7.5 
Adverse Event Severity Assessments ....................................................................47 
7.6 
Adverse Event Causality ........................................................................................48 
7.7 
Adverse Event Reporting .......................................................................................48 
7.8 
Serious Adverse Events .........................................................................................48 
7.9 
Recording of Serious Adverse Events ...................................................................49 
7.10 
Reporting of Serious Adverse Events ....................................................................49 


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7.11 
Suspected Unexpected Serious Adverse Reactions ...............................................50 
7.12 
Procedures for Handling Special Situations ..........................................................50 
7.13 
Abuse, Misuse, Medication Errors, Overdose, and Occupational Exposure .........51 
7.14 
Data Safety Monitoring Plan .................................................................................52 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................52 
8.1 
Selinexor Description/Availability ........................................................................52 
8.2 
Ibrutinib Description/Availability ..........................................................................55 
9. 
CORRELATIVE STUDIES ..............................................................................................56 
9.1 
Ibrutinib Steady State Plasma Levels ....................................................................56 
9.2 
Pharmacodynamic (PD) properties of Selinexor ...................................................57 
9.3 
Pharmacogenomics (PGx) .....................................................................................58 
9.4 
Primary and Secondary Resistance Studies ...........................................................58 
10. 
STUDY CALENDAR .......................................................................................................60 
11. 
MEASUREMENT OF EFFECT..........................................................................................0 
11.1 
Response Criteria .....................................................................................................0 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .............................................4 
12.1 
Patient Protection .....................................................................................................4 
12.2 
Patient Information ..................................................................................................4 
12.3 
Informed Consent.....................................................................................................5 
12.4 
Data Submission ......................................................................................................5 
13. 
STATISTICAL CONSIDERATIONS.................................................................................5 
13.1 
Study Design ............................................................................................................5 
13.2 
Sample Size/Accrual Rate ........................................................................................5 
13.3 
Evaluability ..............................................................................................................6 
13.4 
Definition of Primary Endpoint ...............................................................................6 
13.5 
Definition of Secondary Endpoints ..........................................................................6 
13.6 
Definition of Exploratory Endpoints .......................................................................7 
13.7 
Analytic Plan for Primary Objective........................................................................7 
13.8 
Analytic Plan for Secondary Objectives ..................................................................9 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................14 
APPENDIX B 
INDUCERS AND INHIBITORS CYP3A4/5 ...........................................15 
APPENDIX C  
STAGING SYSTEMS ...............................................................................16 
Appendix D Karyopharm SAE Report form .................................................................................17 
 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To determine the maximum tolerated dose for the combination of selinexor and ibrutinib in 
patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic 
leukemia(SLL)/B-cell prolymphocytic leukemia (PLL) or aggressive non-Hodgkin lymphoma 
(NHL). 
 
1.2 
Secondary Objectives 
 
1.2.1 To characterize the safety and tolerability of the combination of selinexor and 
ibrutinib in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL. 
1.2.2 To obtain preliminary data on efficacy of the combination of selinexor and ibrutinib 
in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL. 
1.2.3 To obtain preliminary data on response in CLL/SLL/PLL and diffuse large B-cell 
lymphoma (DLBCL) patients receiving the combination of selinexor and ibrutinib 
as related to CLL/SLL/PLL karyotype and IgVH mutational status and DLBCL 
subtype, respectively.  
1.2.4 To obtain preliminary data on the ability of selinexor to improve response depth 
with ibrutinib when given to patients receiving initial therapy (Cohort 3) 
 
1.3 
Exploratory Correlative and Pharmacodynamic Objectives 
1.3.1 To evaluate the inhibition of the B-cell receptor signaling pathway in patients with 
relapsed or refractory CLL/SLL/PLL who receive the combination of selinexor and 
ibrutinib. 
1.3.2 To characterize the pharmacokinetic (PK) properties of the combination of selinexor 
and ibrutinib in patients with relapsed or refractory CLL/SLL/PLL or aggressive 
NHL.  
 
1.3.3 To evaluate the change in localization of tumor suppressor and growth regulation 
proteins in patients with relapsed or refractory CLL/SLL/PLL following treatment 
with selinexor in general and as related to response. 
1.3.4 To preliminarily assess potential causes for primary and secondary resistance to 
selinexor and ibrutinib. 
1.3.5 To measure intracellular levels of selinexor and metabolites in peripheral blood 
mononuclear cells and to identify how this relates to pharmacodynamics effects and 
clinical outcomes. 
 
2. BACKGROUND 
 
2.1 
Chronic Lymphocytic Leukemia and Non-Hodgkin’s Lymphoma   
 
Chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), including mantle cell 
lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are the most common types of 


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adult hematologic malignancies in the United States1.  In 2012, the estimated number of new 
cases of CLL and NHL were 16,060 and 70,130, respectively1.  The same year, 4,580 and 18,940 
people were projected to die as a cause of CLL or NHL, respectively1.  Over the years, 
significant advances in the treatment of these cancers were achieved and the therapy evolved 
from standard chemotherapy agents to chemotherapy agents in combination with 
immunotherapeutic compounds such as monoclonal antibodies.   However, despite this progress, 
there is currently no cure for relapsed or refractory CLL or NHL outside of aggressive therapy 
with hematopoietic stem cell transplantation.  Therefore, there has been much interest in 
developing novel therapeutic options for this group of patients.  Of late, targeted agents have 
shown great promise in CLL and NHL therapy with a focus on the B-cell receptor pathway.      
 
2.2 
B-cell Receptor Pathway in Lymphoid Malignancies 
 
Chronic activation of the B-cell receptor pathway has been shown to play a crucial role in the 
survival of CLL2, MCL3, and DLBCL cells4.  Therefore, inhibition of the components of the B-
cell receptor pathway has become an attractive therapeutic target in the treatment of these 
malignancies.  A critical component of this pathway is Bruton’s agammaglobulinemia tyrosine 
kinase (BTK), a non-receptor tyrosine kinase in the Tec kinase family, which is expressed 
predominantly in B-lymphocytes but not in T- or NK-cells and is also down-regulated in plasma 
cells5.  BTK is critical for B-cell development, differentiation, signaling, proliferation, and 
survival5.  Mutation of the BTK gene leads to X-linked agammaglobulinemia in humans, which 
results in lack of circulating B-cells, inability to produce immunoglobulins and significant 
susceptibility to infection6.  Functional BTK is essential for activation of several survival 
pathways including the Akt, extracellular signal–regulated kinase (ERK), and nuclear factor 
kappa light-chain enhancer of activated B cells (NF-κB) pathways7.  Ibrutinib is an orally 
bioavailable, potent, irreversible inhibitor which covalently binds to the cysteine-481 amino acid 
of the BTK enzyme8.  Over the past few years, research using ibrutinib to target multiple B-cell 
malignancies has been wildly successful. 
 
2.3 
Ibrutinib in Chronic Lymphocytic Leukemia 
 
There is significant evidence to suggest that the viability of CLL cells is dependent on B-cell 
receptor signaling.  Unmutated status of the immunoglobulin variable heavy chain (IgVH) is one 
of the strongest predictive factors for poor prognosis in CLL patients9, 10.  This finding has been 
attributed to enhanced signaling and dependence on the B-cell receptor pathway in this patient 
subset.  ZAP70 and CD38 are additional molecules that modify B-cell receptor signaling and are 
associated with poor prognosis in CLL patients10, 11.  These prognostic observations gave strong 
rationale to use B-cell receptor pathway inhibitors, such as ibrutinib, in CLL patients. 
 
Preclinical studies with ibrutinib in CLL cells and models have demonstrated multiple cellular 
effects, including abrogation of the ERK, phosphatidylinositide 3-kinase (PI3K), and NF-κB 
survival pathways.  Ibrutinib inhibited activation-induced proliferation of CLL cells and blocked 
survival signals to CLL cells from the microenvironment, including soluble factors (CD40L, 
BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact.  Importantly, 
ibrutinib did not interfere with T-cell survival12.   


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Due to this research and other strong preclinical data, ibrutinib entered clinical trials in patients 
with relapsed and refractory CLL.  Sixteen of the 56 patients with B-cell malignancies in an 
early phase I trial of ibrutinib13 were patients with CLL.  Eleven of these 16 patients experienced 
rapid reduction of lymphadenopathy during cycle one of treatment, which was accompanied by 
an increase in peripheral lymphocytosis suggesting a redistribution of CLL cells from the lymph 
nodes into the peripheral blood.  Ibrutinib was generally well-tolerated and of all toxicities, the 
most common adverse events were typically grade 1 or 2, including diarrhea (42.9%), nausea 
(41.1%), fatigue (37.5%), myalgia (37.5%), and dyspepsia (30.4%)13.  This trial led to a 
landmark phase Ib/II study in 85 relapsed and refractory CLL patients8 where patients were 
assigned to receive either 420mg (n=51) or 840mg (n=34) of oral ibrutinib daily until disease 
progression or intolerable adverse events.  The overall response rate (ORR) was 71% in both 
dose cohorts when based on standard response criteria14.  An additional 20% and 15% of patients 
in the 420mg and 840mg cohorts, respectively, achieved a partial response with residual 
lymphocytosis8.  Prolonged lymphocytosis during ibrutinib therapy has subsequently been found 
not to indicate a suboptimal response to therapy15.  Response rates were not different between 
several known high-risk populations, with the exception of a worse response seen in patients 
with mutated-IgVH.  Correlative analyses demonstrated a greater than 90% occupancy of the 
pharmacodynamics BTK probe and similar response rates between the groups that received 420 
mg and 840 mg, which provided support for the use of the 420 mg dose in CLL patients.  Again, 
ibrutinib was well-tolerated and the most common adverse events were grade 1 or 2 and included 
diarrhea (47%), and upper respiratory tract infection (33%), fatigue (28%), and most adverse 
events resolved without holding therapy.  The 26-month estimated rates of progression-free 
survival (PFS) and overall survival (OS) were 75% and 83%, respectively.  This study led to the 
ultimate approval of ibrutinib for relapsed/refractory CLL patients by the US Food and Drug 
Administration (FDA).  Although these results are very promising, there remains a subset of high 
risk, most notably patients with del(17p13.1) karyotype, who demonstrated a shorter PFS and OS 
of 57% and 70%, respectively8.   
 
This finding indicates that there is a subset of patients that will become resistant to therapy with 
ibrutinib and will need alternative therapeutic options.  Six CLL patients who relapsed while 
treated with single-agent ibrutinib on clinical trial were analyzed to detect mechanisms of 
resistance. Whole exome sequencing was performed at baseline and relapse on samples from 
these patients.  In 5 of the patients, a cysteine-to-serine substitution at position of 481 of BTK 
(C481S; binding site of ibrutinib) was identified.  In 2 patients, three distinct gain of function 
mutations were identified in PLCᵧ2 (S707Y, R665W, and L845F), which lead to autonomous B-
cell receptor signaling pathway.  Both types of mutations indicate an acquired resistance to 
ibrutinib and further emphasize the need for alternate or combination therapies for these patients.  
Although only a small portion of patients have developed acquired resistance to ibrutinib, the 
study of the 6 patients suggest that patients with more genomic instability, including those with 
del(17p13.1), del(11q22.3), and complex karyotype may be at particular risk for relapse on 
ibrutinib16 (unpublished data Byrd laboratory).   
 
2.4 
Ibrutinib in Mantle Cell Lymphoma 
 


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Preclinical data has also pointed to the importance of B-cell receptor signaling in MCL.  
Although IgVH stereotypes discovered in MCL were distinct from those in CLL, highly 
restricted immunoglobulin genes are thought to imply a role for antigen-driven selection of the 
clonogenic progenitors17.  When constitutively activated, signal transducer and activator of 
transcription 3 (STAT3), promotes cell growth and survival through dysregulated protein 
expression and contributes to the malignant phenotype in numerous cancer types18.  STAT3 was 
found to be activated in primary MCL cells in response to B-cell receptor engagement3.  Another 
preclinical study using genomic and expression profiling identified spleen tyrosine kinase, a 
protein upstream from BTK in the B-cell receptor signaling pathway, as a potential therapeutic 
target for MCL19.  These observations provided rationale to target the B-cell receptor pathway in 
clinical trials for MCL patients with agents such as ibrutinib. 
 
In the initial ibrutinib phase I trial that encompassed multiple relapsed and refractory B-cell 
malignancies, seven of the nine MCL patients achieved a response with three complete 
responses. Pharmacodynamic studies indicated that a fixed continuous dose of 560mg daily led 
to full BTK occupancy in a range of individual body weights and was well tolerated, leading to 
the selection of this dose for phase II studies13.  Toxicities were minimal as described above in 
Section 2.3.  
 
In the landmark phase II study, 111 relapsed or refractory MCL patients were treated with 
560mg daily of oral ibrutinib20.  Again, ibrutinib was well tolerated with grade 1 or 2 diarrhea 
(44%), fatigue (37%), and nausea (30%) as the most common adverse events.  An overall 
response rate of 68% was observed.  The estimated PFS was 13.9 months (95%CI=7.0 to not 
reached) and the median OS was not reached.  At 18 months, the estimated rate of OS was 
58%20.  Secondary to the response data from this trial, ibrutinib was approved by the US FDA as 
a single-agent in relapsed and refractory MCL patients. 
 
In attempt to improve upon the single-agent success of ibrutinib in MCL patients, multiple trials 
are ongoing with ibrutinib in combination with various immunochemotherapy agents21, 22.  There 
still remains a great need for combination therapy with ibrutinib and other non-cytotoxic agents, 
especially for elderly or unfit patients that cannot tolerate these aggressive therapies.  
 
2.5 
Ibrutinib in Diffuse Large B-cell Lymphoma 
 
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic category with multiple 
distinct subtypes.  Patients with the activated B-cell-like (ABC) subtype of DLBCL have been 
shown to have poor response and survival when treated with standard chemoimmunotherapy 
regimens23.  This subtype has been found to rely on constituitive NFκB signaling to block 
apoptosis24, which is moderated by the signaling adaptor CARD11.  In ~10% of ABC DLBCL, 
CARD11 is mutated to cause this constituitive activation25.  In the ABC DLBCL patients with 
wild-type CARD11, RNA interference genetic screen revealed that BTK is essential for the 
survival of these cells and knockdown of proximal B-cell receptor signaling killed these 
lymphoma cells4.  These data provided preclinical rationale to targeting BTK in ABC DLBCL 
patients. 
 


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In the initial phase I study of ibrutinib in relapsed/refractory hematologic malignancy, two of the 
seven DLBCL patients achieved response13.  Secondary to preclinical data indicating that the 
ABC subtype is more dependent on the B-cell receptor signaling pathway, a phase II study was 
designed to test the hypothesis that ibrutinib would be more active in these patients than an 
alternative germinal center B-cell-like (GCB) subtype26.  Seventy patients with 
relapsed/refractory DLBCL enrolled on the trial received 560 mg of oral ibrutinib daily.  Of the 
25 evaluable ABC DLBCL patients, 10 (40%) achieved response with 2 (8%) complete 
responses.  In the ABC DLBCL responders, the median PFS was 5.5 months at the time of 
analysis.  In contrast, only 1 of the 19 (5.3%) GCB DLBCL patients achieved a partial response.  
The results of this trial were consistent with an essential role of B-cell receptor signaling in ABC 
DLBCL patients26.  As the response rate was 40% in these patients, there is room to augment the 
success of ibrutinib in these patients via combining this agent with other agents with alternative 
targets and mechanism of action.    
 
2.6 
Tumor Suppressor Protein (TSP) and Growth Regulatory Protein (GRP) Nuclear 
Export 
 
Many important TSP/GRPs have been identified in cancer pathogenesis, including but not 
limited to TP53, FOXO3a, iκB, BRCA1, APC, and Rb27. TSP/GRPs mediate tumor suppression 
pathways via various functions including recognition of cellular damage, arrest of the cell cycle 
until repairs can be made, and induction of apoptosis in cells that are beyond repair28.   
 
These proteins function primarily in the nucleus and exportation out of the nucleus can inactivate 
their abilities to regulate cellular processes29 and cancer cells can exploit these normal functions 
to successfully evade anti-neoplastic therapy. The majority of known TSP/GRPs must traverse 
structures imbedded in the nuclear envelope called nuclear pore complexes (NPC)27.  One 
primary component of the NPC is called chromosomal region maintenance protein 1 (CRM1) in 
mice or exportin 1 (XPO1) in humans27.  XPO1 can identify these cargo proteins (including 
TSP/GRPs) via canonical Nuclear Export Sequences (NES), which are typically leucine-rich 
repeats in the cargo protein, which are exposed on the protein surface in response to 
microenvironment signals29.  Once the cargo protein forms a complex with XPO1 (CRM1) and 
RanGTP (energy source) the protein can 
be transported out of the nucleus30, in a 
process promoted by Ran-binding protein 
RanBP327 (as shown in Figure 1).   XPO1 
overexpression has been reported in many 
types of human cancer, including both 
solid tumors and hematologic 
malignancies27.  XPO1 overexpression 
and subsequent increased export and 
inactivation of TSP/CRPs may fuel the 
growth of these cancers and lead to 
chemotherapy resistance. 
 


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2.7 
Inhibition of XPO1 in Human Cancer 
 
FOXO3 is a transcription factor that is a crucial regulator of hematopoietic cell fate that plays a 
role in proliferation and apoptosis as a component of the phosphatidylinositol 3-kinase 
(PI3K)/AKT pathway31 that is commonly activated in various cancers.  FOXO3 was found to be 
constitutively inactivated in mantle cell lymphoma cell lines and to have cytoplasmic localization 
in patient-derived cells31.  These FOXO3 defective cells were resistant to PI3K/AKT inhibitors 
in vitro31.  Non-specific inhibition of nuclear export with a non-specific small molecule 
(Psammaplysene A), drastically reduced viability of the malignant cells and made those cells 
more susceptible to cytotoxicity from doxorubicin31.  Another group showed that plasmid-based 
overexpression of constitutively active FOXO3 in cells from chronic lymphocytic leukemia 
(CLL) reduced their survival32. 
 
Based on the suspected mechanism of CRM1 in driving malignancy and chemotherapy 
resistance, the molecule is promising as an oncologic therapeutic target.  CRM1 blockade of 
causes a transient nuclear retention of TSP/GRPs, re-establishing their tumor suppressing effects 
on cancer cells and potentially reversing mechanisms leading to chemotherapy resistance (which 
holds possible future implications for combination therapies)33.  In normal cells, XPO1 inhibition 
transiently arrests cell cycle without cytotoxicity followed by recovery after the inhibitor is 
removed33.  Several attempts to develop this class of anti-cancer drug have failed secondary to 
off target effects of the drugs, which led to significant fatigue and weight loss in the early clinical 
trials34-36. 
 
2.8 
Selective Inhibitors of Nuclear Export (SINE) 
 
SINE, a new generation of CRM1/XPO1 inhibitors, was designed to more selectively inhibit 
XPO1 for increased efficacy and reduced toxicity secondary to off-target effects.  KPT-185 and 
KPT-251, two SINEs, were initially evaluated for CLL in our laboratory at Ohio State University 
(OSU)37.  These data showed that the SINEs induced significant time and dose-dependent 
cytotoxicity in CLL cells (even in patient samples with known poor prognostic factors such as 
unmutated IgVH status), while causing only modest apoptosis in normal B-cells37.  In CLL cells, 
the SINEs demonstrated specific inhibition of nuclear export via analysis of increased 
accumulation of important TSP/GRPs (AKT, p53, FOXO3a, and IκB) in the nucleus37.  In a 
mouse model of CLL (Eµ-TCL1-SCID mouse), treatment with KPT-251 showed a significant 
improvement over survival when compared to fludarabine- or vehicle-treated mice.  The drug 
was well tolerated, resulting on only moderate wt loss (≤10% of body wt)37.  Another group 
studied SINEs (KPT-185 and KPT-276) in mantle cell lymphoma (MCL), an aggressive subtype 
of non-Hodgkin’s (NHL) B-cell lymphoma38.  In MCL cell lines and primary cells, the SINEs 
induced significant apoptosis in a manner independent of p53 status38.  Oral administration of 
KPT-276 significantly suppressed tumor growth in a MCL-bearing SCID mouse, with minimal 
wt loss and no other clinically observed toxicities38.  Another similar SINE (KPT-335) was 
administered to dogs with spontaneous NHL at doses up to 2mg/kg twice weekly39.  This single-
agent therapy demonstrated disease stabilization and tumor reduction with a main side effect of 
anorexia, which was largely overcome by food supplementation39.  Secondary to the success of 
these SINEs in preclinical study, selinexor (KPT-330) was developed with the goal of improved 


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pharmacokinetic (PK) and oral bioavailability.  
 
2.9 
Selinexor Preclinical and Clinical Data 
 
Selinexor, the newest generation of SINE, has been tested in our lab and in our clinics with a 
nearly complete phase I study in advanced hematologic malignancy.  In CLL cells, selinexor 
induced similar levels of cytotoxicity while preserving normal B-cells when compared to KPT-
25140.  The compound also showed enhanced cytotoxicity in high-risk CLL cells including 
patient samples with del(17p) cytogenetics and unmutated IgVH status40.  In CLL patient 
samples with unmutated IgVH status, XPO1 inhibition prevents CpG-induced phosphorylation 
of ERK and AKT, thereby preventing expression of cMyc and cyclin A2 and downstream 
proliferation of these CLL cells.  SINEs induce BTK downmodultion in CLL cells.  Selinexor 
abrogated phosphorylation of AKT and ERK in primary CLL cells, possibly through targeted 
inhibition of AKT or ERK pathways40.  Additionally, selinexor was found to significantly inhibit 
CXCL12-mediated signaling in CLL cells, which prevents trafficking of CLL cells to the 
protective stromal environment and decreases the cells ability to survive40. 
 
In Eµ-TCL1-SCID mouse model of CLL, mice were treated with selinexor either twice (BIW; 5 
or 15mg/mL) or thrice (TIW; 3 or 10mg/mL) weekly and compared with vehicle-treated mice for 
36 weeks.  The mice treated with 15mg/mL BIW and all mice treated TIW, showed significant 
survival improvement over vehicle40.  Additionally, selinexor was well-tolerated with initial 
weight loss, which was fully reversed by the end of the study and did not appear to adversely 
affect the animals40.  
 
Preclinical PK and toxicology parameters have been studied in mouse (CD1), rat (Sprague-
Dawley), and monkey (cynomolgus) models (unpublished data from Karyopharm Therapeutics, 
Natick, MA).  Oral bioavailability was consistently >60% in all species.  Based on these studies 
and work with similar compounds in dogs, the minimal area under the curve (AUC) values were 
determined to be ~5,000ng*hr/mL in mice and ~2,000ng*hr/mL in dogs.  These values 
correspond to anticipated AUC values of >3,000ng*hr/mL in humans, which should be achieved 
at projected doses of 15-45mg/m2.  In toxicology studies, the rats and monkeys demonstrated a 
dose limiting toxicity (DLT) of wt loss with atrophy of the gastrointestinal tract and noncritical 
effects on other major organs.  Majority of adverse events (AEs) were completely reversed after 
a 2-week break period. At projected doses of ≤45mg/m2, observed AEs were rare.  For the rats, 
the severely toxic dose (STD) was found to be 30mg/m2 and for monkeys, the highest non-
severely toxic dose (HNSTD) was 18mg/m2.  Therefore, based on International Conference in 
Harmonization (ICH) guidelines, the initial starting dose for selinexor humans in the phase I trial 
was 3mg/m2 (rat STD/10=3mg/m2; monkey HNSTD/6=3mg/m2). 
 
Selinexor is currently under clinical investigation for the treatment of patients with advanced 
hematologic and advanced solid malignancies. Three Phase 1 studies (KCP-330-001 in 
hematologic malignancies, KCP-330-002 in solid tumor malignancies, KCP-330-00: food effect 
in sarcoma) are in progress.   In addition, Phase 2 studies in multiple hematologic and solid 
tumor indications are currently ongoing or in process of being initiated (protocol submitted to 
FDA).  These studies and current safety and efficacy results are described in detail in the 


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Investigator’s Brochure. 
 
In a food effect study, the presence of food (high- or low-fat meals) delayed selinexor absorption 
(tmax from 1.7 to approximately 4 hours), however, there was minimal impact on exposures 
(geometric mean ratio [GMR] was 114.7% and 125.5% for low- and high-fat meals, 
respectively) and this was not clinically relevant. Therefore, selinexor should be taken with water 
and can be administered with or without food. 
To date, broad anti-tumor activity has been reported during the dose-escalation phase with single 
agent selinexor in patients heavily pretreated, with relapsed/refractory, progressive solid tumor 
and hematologic malignancies. The most common adverse effects (AEs) have been similar to those 
reported in nonclinical studies and include anorexia, weight loss, nausea and fatigue. These AEs 
can be prevented or mitigated with dietary counselling and prophylactic supportive medications.  
No major organ toxicities have been observed to date, and no clinically significant cumulative 
toxicities have been observed in >10 months of dosing.  Overall, oral selinexor pharmacokinetics 
was predictable, reasonably dose-proportional, and exhibited moderate to moderately high inter-
patient variability across a wide dose range in male and female patients with advanced solid tumor 
or hematological malignancies. 
The phase I study in advanced hematologic malignancies (KCP-330-001) is ongoing at multiple 
institutions, with 148 patients enrolled as of 28 February 2014. Of the 68 patients assessed for 
efficacy in Arm 1 (B cell malignancies) as of 28 February 2014, 55 patients (81%) had partial 
responses (14 patients, 21%), minimal responses (6 patients, 9%), or stable disease (35 patients, 
51%).  A total of 13 patients (19%) had progressive disease.  These data are summarized in the 
table below. 
Best Responses in Patients with B Cell Malignancies in KCP-330-001 as of 28 February 
2014  
Cancer Type 
Number of 
Patients 
Evaluated 
Total PRs, 
MRs and 
SD (%) 
PR (%) 
MR (%) 
SD (%) 
PD (%) 
Multiple Myeloma 
28 
22 (79%) 
1 (4%) 
4 (14%) 
17 (61%) 
6 (35%) 
CLL 
4 
4 (100%) 
2* (50%) 
-- 
2 (50%) 
-- 
Richter’s 
Transformation 
4 
3 (100%) 
1 (25%) 
-- 
2 (50%) 
1 (25%) 
Other types 
1 
1 (100%) 
-- 
-- 
1 (100%) 
-- 
Non-Hodgkin’s lymphomas 
 
 
 
 
 
Diffuse Large B 
Cell Lymphoma 
18 
13 (72%) 
5 (28%) 
-- 
8 (44%) 
5 (28%) 
Follicular 
Lymphoma 
6 
6 (100%) 
1 (17%) 
-- 
5 (83%) 
-- 
Mantle Cell 
Lymphoma 
2 
2 (100%) 
1 (50%) 
-- 
1 (50%) 
-- 
Transformed 
DLBCL 
3 
1 (33%) 
1 (33%) 
-- 
-- 
2 (67%) 


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Waldenstrom’s 
Macroglobulinemia 
3 
3 (100%) 
1 (33%) 
2 (67%) 
-- 
-- 
Total 
68 
55 (81%) 
14 (21%) 
6 (9%) 
36 (51%) 
13 (19%) 
Abbreviations: PR=partial response, MR=minimal response, SD=stable disease, PD=progressive disease, NE=not 
evaluable, WC=withdrew consent.  *These PRs in CLL patients refer to Lymph Node responses only. 
 
In summary, this early analysis has also demonstrated tolerability and preliminary signals of 
response in the hematologic malignancies population (unpublished data Karyopharm). 
Constitutional symptoms of weight loss, fatigue, and anorexia were common but can be 
prevented or mitigated using aggressive prophylactic supportive measures.   
 
2.10 
Rationale for the Study 
 
Although ibrutinib has shown significant efficacy in CLL and NHL as a single agent, relapses 
have occurred via binding site mutations and certain subgroups of each disease continue to lag in 
PFS.  Additionally, this treatment requires continuous treatment and does not produce complete 
remissions.  Thus, efforts to diminish the frequency of ibrutinib relapse and also increase the 
depth of remission with combination based therapies is a priority moving forward in the field of 
CLL and NHL.  In both CLL and NHL the importance of BTK as a true therapeutic target has 
been genetically, pharmacologically, and clinically validated.  Preclinical and clinical data have 
shown that CLL and NHL are susceptible to single-agent cytotoxicity by selinexor. Selinexor has 
been shown to inhibit the BCR pathway in an alternate way than ibrutinib by depleting BTK 
protein level, which provides rationale to combine these drugs.  Indeed, targeting a 
kinase/protein/pathway in two or more different ways is a classic pharmacologic strategy to 
prevent emergence of drug resistance.  In phase I clinical trials in this population, selinexor has 
shown tolerability and early signals of clinical efficacy.  Ibrutinib which is approved for NHL 
and CLL has similar promising results.  We hypothesize the combination will be active and 
tolerable in this population and want to proceed with phase I investigation.  Ultimately, we 
anticipate this approach moving to larger randomized phase II trials comparing the combination 
treatment to monotherapy with ibrutinib. 
 
2.11 
Rationale for the Dose/Dosing Schedule 
 
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.   
 
In Phase I study, the lowest dose that selinexor inhibits XPO1 completely for ~24 hours is 
12mg/m2  (about 20 mg) on a 10 doses per cycle schedule, however,  prolonged inhibition of 
XPO1 mRNA were observed at doses >23 mg/m2, allowing twice weekly dosing.   Therefore, 40 
mg weekly will be our lowest dose administered, with goals to use twice weekly dosing if 


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tolerated.  The phase I study has reached a dose level of 60mg/m2 twice weekly, and our 
proposed study’s top dose level (100 mg twice weekly) is equivalent to this dose.   We are 
starting at this lower dose of selinexor to assure tolerability of the combination.    
 
The starting dose of 420 mg of ibrutinib for CLL patients is based on the standard recommended 
dosing from the phase II study of patients with relapsed/refractory CLL.   In this study, 
correlative analyses demonstrated a greater than 90% occupancy of the pharmacodynamics BTK 
probe and similar response rates between the groups that received 420 mg and 840 mg, which 
provided support for the use of the 420 mg dose in CLL patients8.   
 
The starting dose of 560 mg of ibrutinib for NHL patients is based on the standard recommended 
dosing from the phase I study of patients with relapsed/refractory lymphoid malignancies.  In 
this trial, pharmacodynamic studies indicated that a fixed continuous dose of 560mg daily led to 
full BTK occupancy in a range of individual body weights and was well tolerated, leading to the 
selection of this dose for phase II studies13.   
 
2.12 
Correlative Studies Background 
 
We plan to evaluate the inhibition of the B-cell receptor signaling pathway via assessment of 
phosphorylation of BTK, PLcᵧ, AKT, and ERK in patients with relapsed or refractory CLL who 
receive the combination of selinexor and ibrutinib.  In primary CLL cells, ibrutinib has been 
shown to inhibit these components of the B-cell receptor signaling pathway12.   In CLL patient 
samples with unmutated IgVH status, XPO1 inhibition with selinexor prevents CpG-induced 
phosphorylation of ERK and AKT, thereby preventing expression of cMyc and cyclin A2 and 
downstream proliferation of these CLL cells.  Selinexor induced BTK downmodulation in CLL 
cells.  Selinexor abrogated phosphorylation of AKT and ERK in primary CLL cells, possibly 
through targeted inhibition of AKT or ERK pathways40.  Evaluation of B-cell receptor pathway 
inhibition in patients on this trial will provide evidence for potential drug synergy or interactions. 
 
We plan to evaluate the change in localization of tumor suppressor proteins in patients with 
relapsed or refractory CLL following treatment with selinexor with the aid of confocal 
microscopy and immunoblot of downstream targets of these proteins (NFKB, Mcl1, Tcl1, BTK, 
p21, BCLxL, cMyc).   As selinexor inhibits the exportation of nuclear tumor suppressor 
proteins40, this correlative study will allow exploratory investigation of potential drug 
interactions on this clinical trial.    
 
Baseline characteristics of tumor samples, plasma and microenvironment will be assessed at 
baseline to preliminary examine for features of primary resistance. For patients who respond to 
therapy and then relapse, we will characterize the features of resistance to ibrutinib and 
selinexor.  As both of these are irreversible inhibitors, we will focus on the primary target (BTK, 
XPO1) and also down-stream molecules (PLCγ2) .  We will also take a more global approach 
through examination of next generation sequencing methods examining the genome, 
transcriptome, and epigenetic changes from baseline samples to those obtained at relapse.   
Expression and biochemical studies of pathways of resistance will also be pursued.  For CLL this 
will be done on blood, bone marrow aspirate, and lymph nodes (when available).  For NHL, this 


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will be examined predominately from nodal material (including archival material if available 
from previous biopsy) along with blood/marrow if positive for NHL.   Buccal swabs or other 
germ line material (marrow fibroblasts, saliva) will be collected for interpretation of next 
generation sequencing data differentiation of SNP versus acquired mutations.   
 
We also plan to characterize plasma pharmacokinetics of selinexor and steady-state plasma 
concentrations of ibrutinib. We will compare selinexor pharmacokinetics (full 24-hour profiles) 
in the absence and presence of ibrutinib, and we will compare ibrutinib steady state 
concentrations with historical data to identify any significant differences in pharmacokinetics 
since there is a small potential for drug-drug interactions via CYP3A4/5. We will also 
characterize concentration vs. time of selinexor in white blood cells. These cells will be obtained 
from samples collected at the same time points as the plasma pharmacokinetic samples for 
selinexor. Given KPT-330 chemically reacts with glutathione and may also be metabolized to 
form glutathione and glucuronide conjugates, we hypothesize intracellular conjugation will vary 
among patients, and intracellular selinexor exposures will better correlate with 
pharmacodynamic measures and clinical response to this agent relative to plasma exposures. In 
addition to selinexor, we will also measure and pseudo-quantify selinexor hydroxylated and 
conjugated (glutathione and glucuronide) metabolites. The ratio of intracellular metabolites to 
parent drug may be expected to be higher at baseline or to increase during the first few weeks of 
combined therapy for patients less sensitive or resistant to selinexor. 
 
A single whole blood sample or lymph node aspirate and buccal swab will be obtained for DNA 
extraction. DNA will be extracted and stored for potential analysis later if patients relapse on 
therapy or if relevant pharmacogenetic questions arise during clinical development of selinexor. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have: 
 
• A histologically confirmed diagnosis of CLL/SLL/B-cell PLL according the International 
Workshop on CLL/SLL/B-cell PLL or variant of these [IWCLL14 or World Health 
Organization (WHO) Criteria] and meet criteria for treatment or have need for 
cytoreduction for stem cell transplantation or alternative cell therapy. 
 
OR 
 


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A histologically confirmed diagnosis of mantle cell lymphoma (MCL) or diffuse large B-
cell lymphoma (DLBCL) de novo or in the setting of transformation from an indolent 
lymphoma (including DLBCL not otherwise specified) according to the World Health 
Organization criteria for diagnosis of NHL.  
 
AND 
 
• Patients must have received at least one prior therapy for CLL or NHL, need additional 
treatment (or have need for cytoreduction as mentioned above), and meet criteria for 
relapsed or refractory disease. They may not be a candidate for curative therapy.  
Relapsed disease is defined as a patient who previously achieved a CR or a PR, but after 
a period of six or more months demonstrates evidence of disease progression. Refractory 
disease is defined as progression within six months of the last anti-leukemic or anti-
lymphoma therapy, or any response less than a CR or PR.   
EXCEPT 
• Patients in Cohort 3 (selinexor added to ibrutinib for patients receiving frontline therapy) 
must be receiving ibrutinib as their initial therapy for CLL or SLL. These patients must 
have been receiving ibrutinib for at least 1 year before enrollment 
 
3.1.2 Patients must be ≥ 18 years of age. 
 
3.1.3 Patients must have an Eastern Cooperative Oncology Group (ECOG) performance 
status of < 2.  (See Appendix A.) 
 
3.1.4 Patients with NHL must have objective, documented evidence of disease prior to 
study entry. 
 
3.1.5 Patients must have normal organ function defined as:   
• Platelet count ≥ 50,000/mm3 in the absence of bone marrow involvement; 
patients with bone marrow involvement only require a platelet count of > 
30,000/mm3 
• Absolute neutrophil count ≥ 1000/mm3 in the absence of bone marrow 
involvement; patients with bone marrow involvement are not required to have 
a minimum absolute neutrophil count 
• Creatinine clearance [as calculated by Cockroft Gault equation=(140-age) * 
Mass (kg)*(0.85 if female)/(72 * creatinine mg/dL] ≥ 30mL/min 
• AST/ALT < 2.5 times upper limit of normal (ULN) 
• Total bilirubin ≤ 2.0 x ULN. 
 


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3.1.6 Female patients capable of reproduction and male patients who have partners capable 
of reproduction must agree to use an effective contraceptive method during the course 
of the study and for -1 month  following the completion of their last treatment. 
Acceptable methods of contraception are condoms with contraceptive foam, oral, 
implantable or injectable contraceptives, contraceptive patch, intrauterine device, 
diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or 
post-menopausal. 
 
3.1.7 Female of childbearing potential must have a negative serum β-Hcg pregnancy test 
result within 3 days of first study dose.  Female patients who are surgically sterilized 
or who are > 45 years old and have not experienced menses for > 2 years may have β-
Hcg pregnancy test waived. 
 
3.1.8 Patients with a history of hepatitis B (surface antigen or core antibody positive and 
PCR positive) must take lamivudine or equivalent drug during study therapy and for 
one year after completion of all therapy.  Patients on IVIG who are core antibody 
positive but PCR negative are not mandated to take prophylaxis. 
 
3.1.9 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.10 Patients enrolled into cohort 3 must have high-risk disease with higher risk of relapse on 
ibrutinib.  This includes patients with complex karyotype (3 or more cytogenetic abnormalities) 
or high/very high risk by CLL-IPI (https://www.mdcalc.com/international-prognostic-index-
chronic-lymphocytic-leukemia-cll-ipi) 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who are concurrently receiving any other investigational agents. 
 
3.2.2 Patients who have received: 
-Radiation or chemotherapy ≤ 4 weeks, 
-Mitomycin C, nitrosureas, or radio-immunotherapy ≤ 6 weeks, or  
-Immunotherapy or targeted therapy (such as kinase inhibitors) ≤2 weeks prior to 
cycle 1 day 1. Patients who are on ibrutinib at study entry are not required to 
discontinue ibrutinib for any period of time.  
Palliative steroids for disease related symptoms are allowed as long as dose is tapered 
down to an equivalent of ≤ 10mg of oral prednisone daily on cycle 1 day 1.  
 
3.2.3 Patients who have underwent autologous or allogeneic stem cell transplant ≤ 4 weeks 
prior to cycle 1 day 1 or have active graft-versus-host disease are excluded.  
 


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3.2.4 Patients unable to swallow tablets or capsules, those with uncontrolled vomiting or 
diarrhea or disease significantly affecting gastrointestinal function and/or inhibiting 
small intestine absorption such as; malabsorption syndrome, resection of the small 
bowel, or poorly controlled inflammatory bowel disease affecting the small intestine 
 
3.2.5 Patients who are 20% below their ideal body weight (BMI calculator can be found at 
http://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/english_bmi_calculator/b
mi_calculator.html)  
 
 
3.2.6 Patients must not be receiving systemic anticoagulation with warfarin.  Patients must 
be off warfarin for 30 days prior to enrollment.  Patients who require anticoagulation 
with an agent other than warfarin will not be excluded, but must be reviewed by the 
principal investigator prior to enrollment. 
 
3.2.7 As ibrutinib is extensively metabolized by CYP3A4/5, and patients must not require 
continued therapy with a strong inhibitor or inducer of CYP3A4/5.  See Appendix B 
for a list of these medications. 
 
3.2.8 Patients with active HIV or Hepatitis C.  (HIV-positive patients on combination 
antiretroviral therapy or Hepatitis C-positive patients on antiviral therapy are 
ineligible because of the potential for pharmacokinetic interactions with ibrutinib or 
selinexor.  In addition, HIV patients are at increased risk of lethal infections when 
treated with potentially marrow-suppressive therapy.) 
 
3.2.9 Patients with secondary malignancy that requires active systemic therapy that will 
interfere with interpretation of efficacy or toxicity of selinexor.  (Note:  Patients with 
basal or squamous skin carcinoma, cervical carcinoma in situ, localized breast cancer 
requiring hormonal therapy or localized prostate cancer (Gleason score <5 are 
allowed). 
 
3.2.10 Patients with active known central nervous system (CNS) involvement of CLL or 
lymphoma.  (Patients with history of CNS CLL or lymphoma now in remission are 
eligible for the trial.) 
 
3.2.11 Patients who are pregnant or breast feeding.  (Pregnant women are excluded from this 
study because it is unknown if selinexor has teratogenic or abortifacient effects.  
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with selinexor, breastfeeding should be 
discontinued if the mother is treated with selinexor.) 
 
3.2.12 Patients must have recovered all toxicities from prior therapy or radiation to grade 1 
or less (excluding alopecia). 
 


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3.2.13 Patients may not have had major surgery within 10 days of enrollment, or minor 
surgery within 7 days of enrollment. Examples of minor surgery include dental 
surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint. The 
decision about whether a surgery is major or minor can be made at the discretion of 
the treating physician. 
 
3.2.14 Patients with uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
3.2.15 Patients enrolling in Cohort 3 must not have ongoing Grade 3 or higher toxicity 
due to ibrutinib at study entry (except hypertension that is medically managed). 
 
 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
For subsite patients, sites must send the signed consent form, documentation of the consent 
process, and the Screening Form (refer to Supplemental Forms Document) within 2 business 
days of initial consent. 
 
Patients will be registered after meeting all entry requirements, clearance by the Protocol 
Coordinator, and signing of the informed consent. 
 
OSU patients will be registered by the OSU research coordinator, as per their standard 
practice. 
 
Subsite patients will have eligibility verified and will be entered on study centrally at the 
Ohio State University by the Multi-Center Trial Program (MCTP_. All subsites must email 
the MCTP to verify slot availability prior to consenting patients. The required forms, 
including Eligibility Criteria Checklist and Registration Form, can be found in the 
Supplemental Forms Document. 
 
To register a subsite patient, the following documents must be completed by the subsite 
research team and faxed or securely e-mailed to the MCTP: 
• Copy of all baseline tests required per the protocol calendar. Tests must be 
within the specified window. 
• Signed Patient Consent Form 
• Signed Patient HIPAA Authorization Form 
• Consent Documentation Note 


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• Completed & Signed Eligibility Checklist (refer to Supplemental Forms 
Document) 
• Registration Form (refer to Supplemental Forms Document) 
• Source documents verifying every inclusion & exclusion criteria 
o Note: every inclusion and exclusion criteria must be documented in the 
patient’s medical record (emails or other notes outside the medical 
record will not be considered source documentation) 
 
Upon receipt of registration documents, the MCTP will send an email confirmation of 
receipt. If confirmation of receipt is not received within 1 hour of submission, please call or 
page the MCTP. 
 
Upon receipt of all required registration documents and upon verification the subsite patient 
meets all eligibility criteria, the MCTP will: 
• Register the patient on the study 
• Fax and/or e-mail to the subsite the completed Registration Form with the 
assigned study ID as confirmation of patient registration 
 
Following registration, patients should begin protocol treatment within 7 business days.  
Issues that would cause treatment delays should be discussed with the Principal Investigator 
and MCTP as soon as possible. If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study may be canceled, after discussion with the 
PI and MCTP. 
 
Each participating institution will order study agents directly.  Agents may be ordered by a 
participating site only after the initial IRB approval for the site has been forwarded to the 
MCTP. 
 
 
 
5. TREATMENT  
 
5.1 
Overview 
 
The study will enroll patients with CLL and NHL in a dose escalation and subsequent expansion.  
First, patients with relapsed or refractory disease will be enrolled in a dose finding study that will 
assign doses for each patient using a modified continuous reassessment method using software 
developed by Piantadosi (Modified Continual Reassessment Method, version 4.0). Up to 10 
patients with CLL and 10 patients with NHL will be treated at the estimated MTD as part of the 
expansion. 
 
In August 2016 after 2 patients were treated at dose level 2 for 1 cycle, both reported significant 
fatigue and anorexia.  While not technically DLT, these AEs were concerning to the 
investigators, and after discussion with the DSMC it was decided to return to dose level 1 for 
continued expansion.  This was discussed with Karyopharm, who reported increased tolerability 


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and efficacy using once weekly dosing strategies in other studies.   
 
Cohort 3, which will initiate after the dose escalation and expansion, will add selinexor 
administered weekly (days 1, 8, and 15 of each cycle) at 40 mg PO, to patients receiving 
ibrutinib as frontline therapy for at least 12 months.  Selinexor plus ibrutinib will be administered 
for 14 cycles, with discontinuation of selinexor after 14 cycles.  At the end of 14 cycles, patients 
who achieve a minimal residual disease (MRD) negative response may have both drugs 
discontinued at the discretion of the treating physician.  Patients who are MRD positive at the 
end of 14 cycles will discontinue selinexor and are recommended to continue ibrutinib.  
 
 
 
   
5.2 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 5.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Regimen Description 
Agent 
Precautions 
Dose 
Route 
Schedule 
Cycle Length 
Ibrutinib 
Take with 8 oz of water, 
30 min before meal 
Capsule 
or 
tablet* 
Oral 
Cycle 1 Days 8-
28**, Cycles 2+ 
Days 1-28 
28 days (4 
weeks) 
Selinexor 
Take with at least 120 
mL (4 ounces) of fluids 
(water, juice, etc.) 
Tablet* 
Oral 
Days 1, 8, and 15 of 
each cycle* 
*Doses/schedule as appropriate for assigned dose level. 
**Patients continuing on ibrutinib should take ibrutinib days 1-28 of Cycle 1  
 
 
Dose 
Level 
Selinexor 
Dose 
Selinexor 
Schedule 
Ibrutinib 
Dose  
Ibrutinib 
Schedule 
1* 
40 mg 
Weekly (oral) 
420 mg 
Daily (oral) 
2 
20 mg 
Bi-weekly (oral) 
420 mg 
Daily (oral) 
 
 
 
5.2.1 Study Drugs Description 
 
5.2.1.1 
Selinexor is an oral selective inhibitor of nuclear export.   


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Selinexor is manufactured by KABS Laboratories (Montreal, ON) for Karyopharm, 
Therapeutics (Newton, MA) using methods in accordance with Food and Drug 
Administration (FDA) guidelines for the manufacture and testing of antineoplastic 
agents for human use.  The tablets are prepared from a common blend of excipients 
and all tablet excipients are GRAS (generally regarded as safe) listed and suitable for 
use in pharmaceuticals.  Selinexor is an investigational agent supplied to investigators 
of this study by Karyopharm Therapeutics at no cost. 
 
 
5.2.1.2 
Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase.  The compound is 
manufactured by Pharmacyclics, Inc (Sunnyvale, CA) using methods in accordance 
with Food and Drug Administration (FDA) guidelines for the manufacture and testing 
of antineoplastic agents for human use.   
 
5.2.2 
Drug Products Composition and Preparation 
 
5.2.2.1 
Selinexor 
Selinexor will be supplied in 20 mg tablets in wallet-sized blister packs (12 tablets per blister 
pack).  Each wallet-size blister package of selinexor tablets will be labeled in accordance with 
current International Conference on Harmonization (ICH), Good Clinical Practice (GCP), and 
specific regulatory requirements, e.g., FDA, Health Canada, EMA, etc.  Blister packages for 
take-home use may require additional in-pharmacy labeling with take-home and patient-specific 
instructions (such as exact dose) depending on country-specific regulations or laws. 
 
5.2.2.2 
Ibrutinib  
 
Ibrutinib for oral administration is supplied as either capsules or tablets.  The capsules are hard 
gelatin capsules containing micronized ibrutinib and the following excipients: microcrystalline 
cellulose; croscarmellose sodium; sodium lauryl sulfate; may contain magnesium stearate. 
Capsules are manufactured as 140mg in a size 0, gray, hard gelatin capsule. Capsules are 
packaged in high-density polyethylene (HDPE) bottles with an induction seal and a child 
resistant screw top cap. Each bottle contains 92 capsules. Ibrutinib capsules are to be dispensed 
in their original containers.  The tablet formulation is manufactured as 140, 280, or 420 mg and 
is dispensed as a blister pack. 
 
5.2.3 
Selinexor Administration 
 
Each dose will consist of selinexor tablet(s) for oral administration on a fixed dose basis.  Dose 
levels for the study are 40 mg once weekly and 20 mg twice weekly.  If needed, the level (-1) de-
escalation dose level will be 20 mg weekly.  Selinexor oral doses are given Days 1, 8, and 15 of 
each 28 day cycle. 
 
Selinexor tablets are to be taken with at least 120 mL (4 ounces) of fluids (water, juice, etc.) at 
approximately the same time each day.  Selinexor tablets should not be crushed because of 
increased risk of dermatologic toxicity if the powder comes in contact with skin. 


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5.2.4 
Ibrutinib Administration 
 
Ibrutinib should be taken with 8 ounces (approximately 240 mL) of water (avoid grapefruit or 
Seville orange juice due to CYP450 3A4 inhibition). Each dose of ibrutinib should be taken at 
least 30 minutes before meal, at approximately the same time each day. The capsules or tablets 
should be swallowed intact and subjects should not attempt to open capsules or dissolve them in 
water.  
 
If a dose is missed, it can be taken up to 6 hours after the scheduled time with a return to the 
normal schedule the following day. If it has been greater than 6 hours, the dose should not be 
taken and the subject should take the next dose at the scheduled time the next day. The missed 
dose will not be made up and must be reported at the next scheduled visit. 
 
Ibrutinib should be held for any procedure using the following guidelines:  
 
• For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
should be held at least 7 days prior to the intervention and should be held at least 7 days 
after the procedure and restarted at the discretion of the investigator when the surgical 
site is reasonably healed without serosanguineous drainage or the need for drainage 
tubes.  
• For minor procedures (i.e. such as a central line placement, needle biopsy, thoracentesis, 
or paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and 
should not be restarted for at least 3 days after the procedure. For bone marrow biopsies 
that are performed while the subject is on ibrutinib, it is not necessary to hold ibrutinib 
for these procedures.  
• For emergency procedures, ibrutinib should be held after the procedure until the surgical 
site is reasonably healed, for at least 7 days after the urgent surgical procedure. 
 
5.2.5 Patient Compliance and Replacement 
 
To the extent possible, patients must strictly follow the standard dosing schedule. Patients who 
miss 2 of the doses of selinexor or 1/4 of the doses of ibrutinib within the first cycle of treatment 
in the absence of study drug related toxicity will be discontinued unless these are consecutively 
missed doses due to a required medical procedure that is unrelated to study drug or an anticipated 
personal emergency, in which case they should restart the cycle. 
 
Compliance to study medication will be ascertained by use of patient diaries for the days where 
patient administers the study drug themselves at home and for the drug administration days in the 
clinic, compliance to study medication will be done by the investigator or delegate and recorded 
in source documents. The date, time and number of capsules or tablets consumed will be 
recorded as per study drug schedule. The principal investigator or the designee will account for 
the number of capsules or tablets dispensed against those returned by the patient. Any deviations 
and missed doses will be recorded in the case report form and drug accountability logs for 
verification with the reasons. The investigator / designee will try to ensure complete compliance 


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with the dosing schedule by providing timely instructions to the patients. Patients withdrawn in 
cycle 1 because of non-compliance not related to study drug related toxicity will be replaced. 
 
5.3 
Definition of Dose Limiting Toxicity 
 
CTCAE version 4.0 is used to grade all adverse events and to provide management guidelines for 
administrational toxicity.   A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
 
Definition of DLT for patients receiving selinexor and ibrutinib* 
General 
• 
Treatment delays >28 days for any toxicity  
• 
Any grade 5 toxicity 
Non-hematologic 
• 
Grade 3 nausea/vomiting or diarrhea lasting for ≥7 days while taking optimal 
supportive medications# 
• 
Grade 3 anorexia or fatigue lasting for ≥7 days while taking optimal supportive care# 
and with correction of dehydration, anemia, endocrine, or electrolyte abnormalities 
• 
Grade ≥ 3 AST or ALT elevation lasting for ≥7 days OR any Grade ≥ 3 AST or ALT 
elevation in the setting of bilirubin elevation > 2x ULN 
• 
Any other Grade 3 non-hematological toxicity except alopecia, rash that resolves to 
Grade 1 in ≤ 7 days, or electrolytes abnormalities correctable with supportive therapy# 
Any Grade 4 non-hematologic toxicity not specifically listed above 
Hematologic 
• Grade 4 neutropenia [absolute neutrophil count (ANC) < 500/mm3] (for patients with 
baseline ANC ≥ 1000/mm3) or ≥ 75% reduction of neutrophils (for patients with 
baseline ANC < 1000/mm3) lasting ≥7 days; 
• Grade 4 thrombocytopenia [platelet count <25,000/mm3] (for patients with baseline 
platelets ≥ 100,000/mm3) ≥ 75% reduction of platelets (for patients with baseline 
platelets < 100,000/mm3)  that persists for ≥7 days; 
• Grade ≥ 3 thrombocytopenia-associated bleeding; or  
• Grade 4 febrile neutropenia (ANC < 1000/mm3 with a single temperature ≥ 38.3ºC or 
sustained temperature of >38°C for over 1 hour). 
*Assessed during Cycle 1 by CTCAEv4 criteria #Section 4.4 provides detailed supportive care ^For patients with 
Gilbert’s syndrome: >2X baseline 
 
AEs meeting the above definitions but that are clearly unrelated to study drugs will not be 
considered DLTs. 
 
Patients will be considered eligible for DLT assessment if they receive at least 2 of 3 planned 
doses of selinexor and 19 of 21 planned doses of ibrutinib.    
 
In rare instances, an event may fall within the definition of a DLT as defined above, but the event 
may not be considered a DLT (ie: not clinically meaningful/significant). If this occurs, a meeting 


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with all investigators, PI and Sponsor will take place to thoroughly review the event and 
supporting data and the reasons for not considering the event a DLT will be clearly documented 
with supporting rationale. Conversely, other events may occur which do not meet the definition 
of a DLT but are concerning to the investigators and sponsor and may be then considered to be 
DLTs.  We will also consult the DSMC team for input. 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 5. 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.   
 
5.4 
Concomitant Medications 
 
Concomitant medication is defined as any prescription or over-the-counter preparation, including 
vitamins and supplements. All of a patient’s concomitant medications must be recorded on the 
case report form from 14 days before Day 1 through the end of the patient’s study participation.  
 
5.4.1.1 
Permitted Concomitant Medications  
 
5.5 
Prevention of Pregnancy  
 
Female patients of child-bearing potential must agree to use dual methods of contraception and 
have a negative serum pregnancy test at screening, and male patients must use an effective 
barrier method of contraception if sexually active with a female of child-bearing potential. 
Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or 
injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal 
gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and 
female patients, effective methods of contraception must be used throughout the study and for -
one month following the last dose.  
 
5.6 
Blood Products  
 
During the administration of selinexor and ibrutinib, patients may receive red blood cell (RBC) 
or platelet transfusions, if clinically indicated, per institutional guidelines. These transfusions 
should be leukopore filtered and irradiated.  Patients who require repeated transfusion support 
should be discussed with the principal investigator.  
 
Patients may receive supportive care with G-CSF or GM-CSF in accordance with institutional 
guidelines prior to entry and throughout the study.  
 
5.7 
Radiation Treatment  
 
If clinically indicated, palliative radiation therapy to non-target lesions is permitted but study 
drug should be held for 3-5 days before the start of palliative radiation therapy and 3-5 days after 


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palliative radiation therapy. Treatment with selinexor and ibrutinib shall not be discontinued 
solely due to palliative radiation.  Additionally for patients responding to this treatment, if local 
radiation to a secondary cancer (prostate, skin, DCIS, etc.) is required, this can be considered 
after discussion with the PI. 
 
5.8 
Glucocorticoid Therapy  
 
Glucocorticoids ≤ 10 mg oral prednisone (or equivalent) per day are permitted at baseline and 
during the study for non-malignant conditions (i.e., asthma, IBD, etc.) as needed.  
 
As part of supportive care (e.g. for nausea or anorexia), oral or parenteral dexamethasone, up to 
30 mg/week, may be given to patients, in consultation with the principal investigator. Doses of 2-
4mg po qd, or 10mg with each dose of selinexor, can reduce fatigue, increase appetite, and 
improve energy in patients on study. 
 
5.9 
Anti-diarrheal Medications 
 
Over-the-counter anti-diarrheal medications (such as loperamide or equivalent) may be used by 
the patient to control loose stools associated with the study medications.  The medications should 
be used as directed by the package insert, pharmacist or treating physician. 
 
5.10 
General Medications 
 
Medications to treat concomitant diseases like diabetes, hypertension, etc. are allowed.  
 
5.11 
Procedures 
 
Refer to section 5.2.4 for guidelines on holding ibrutinib for procedures.  
 
5.11.1.1 
Prohibited Concomitant medications  
 
Patients should minimize the use of products containing Acetaminophen. For combination 
painkillers containing acetaminophen it is recommended that single agent opiates or aspirin 
combinations (when clinically acceptable) be substituted.  
 
5.12 
Anticancer Therapy  
 
Concurrent therapy with a systemic approved or investigative anticancer therapeutic, other than 
glucocorticoids as specified herein, is not allowed (this includes bone marrow transplantation for 
any reasons).  Hormonal therapy is permitted.  
 
5.13 
Investigational Agents  
 
Other investigational agents should not be used during the study.  
 


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5.14 
Drugs undergoing Glutathione conjugation  
 
The primary metabolism of selinexor in vitro appears to inactivation by glutathione conjugation. 
This process can be mediated in the absence of proteins, indicating that it is thermodynamically 
favorable. In vitro studies using human liver microsomes confirm in vivo findings that selinexor 
undergoes minimal CYP450 metabolism. Therefore, administration of selinexor with drugs 
which undergo substantial glutathione conjugation should be minimized or avoided. These drugs 
include acetaminophen (paracetamol). It should be noted that no studies selinexor in combination 
with acetaminophen have been performed to date and that these recommendations are empirical. 
There are no restrictions on the use of acetaminophen or acetaminophen-containing products in 
combination with selinexor, EXCEPT on days of selinexor dosing, when acetaminophen use 
must not exceed a total daily dose of 1 g. 
 
5.15 
Drugs that inhibit or induce CYP 3A4/5 
 
Because there is a potential for interaction of ibrutinib with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies. The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes. Appendix B presents guidelines for identifying 
medications/substances that could potentially interact with ibrutinib. 
 
5.16 
Warfarin 
 
Patients who must receive systemic anticoagulation with warfarin will be excluded secondary to 
severe bleeding when ibrutinb and warfarin have been used concurrently.  Patients must be off 
warfarin for 30 days prior to enrollment.  If individuals develop a DVT or other complications 
requiring anticoagulation, low molecular weight heparin or thrombin inhibitors may be used.  
Ibrutinib should be held for a minimum of 7 days to assure acceptable tolerance of this treatment.  
For patients with low risk atrial fibrillation, aspirin (325 mg/day) is recommended unless the 
patient is at high risk for thromboembolic complications.  
 
5.17 
Concomitant Treatments for Selinexor 
 
Dexamethasone (12 mg) will be given as a concomitant medication with each dose of selinexor.  
For patients with partial intolerance to glucocorticoids, a minimum dose of 8 mg dexamethasone 
is permitted.  Patients who are tolerating selinexor well may have the dose of dexamethasone 
decreased or eliminated at the discretion of the treating physician. Dexamethasone, like the other 
recommended prophylactic treatments in this study, is an approved drug.  It will be provided in 
tablet form by prescription from the treating physician and obtained from the clinic pharmacy. 
Required 5-HT3 Antagonists:  In order to minimize nausea, unless contraindicated, all patients 
must receive 5-HT3 Antagonists (ondansetron 8 mg or equivalent) starting before the first dose 
of selinexor and continued bid – tid prn.  
 


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5.18 
Supportive Care Guidelines for selinexor 
 
TABLE:  SUPPORTIVE CARE AND SELINEXOR DOSE ADJUSTMENT 
GUIDELINES FOR AES RELATED TO SELINEXORA,B 
Toxicity and Intensity 
Supportive Care and Dose Adjustment Guidelines 
Fatigue  
Grade 1  
Maintain dose. Rule out other causes. If found to be anemic and 
symptomatic, consider transfusing even with hemoglobin >8 g/dL (anemia 
Grade <3). 
Patients with significant fatigue after several doses of selinexor may have 
an antitumor response. Consider an unscheduled assessment of tumor 
response as part of the patient’s evaluation.  
Grade 2 lasting ≤7 days 
As per the NCCN guidelines, consider stimulants such as methylphenidate 
5mg QD in the morning only. 
Grade 2 lasting >7 days or 
Grade ≥3 
Rule out other causes. If found to be anemic and symptomatic, consider 
transfusions for hemoglobin >8 g/dL (Grade <3); transfusions usually 
indicated for Hb <8 g/dL (Grade ≥3). Interrupt selinexor dosing until 
resolved to Grade 1 or baseline.  
For first occurrence, restart selinexor at current dose.  
For ≥ second occurrence, reduce selinexor by 1 dose level. 
Patients with significant fatigue after several doses of selinexor may have 
an antitumor response. Consider an unscheduled assessment of tumor 
response as part of the patient’s evaluation. 
As per the NCCN guidelines, consider stimulants such as methylphenidate 
5mg QD in the morning only. 
Anorexia or Weight loss 
Grade 1 anorexia  
Maintain dose. Rule out other causes. Consider nutritional consultation 
and use nutritional supplements (eg, Ensure®, Boost®). 
For persistent symptoms, start appetite stimulants, such as olanzapine (2.5 
to 5 mg PO every morning) or megesterol acetate (400 mg QD), per 
NCCN guidelines. 
Grade1 weight loss  
Grade 2 anorexia 
Initiate appetite stimulants, such as olanzapine (2.5 to 5 mg PO every 
morning) or megesterol acetate (400 mg QD), as per NCCN guidelines. 
Grade 2 weight loss 
Grade 3 anorexia,  
or Grade 3 weight loss 
Interrupt selinexor dosing until improved to Grade 1 or baseline and weight 
stabilizes. Reduce selinexor by 1 dose level. 
Rule out other causes. Consider nutritional consultation and use nutritional 
supplements (eg, Ensure®, Boost®)  
Start appetite stimulants as above, 


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Toxicity and Intensity 
Supportive Care and Dose Adjustment Guidelines 
Nausea, Acute  
Grade 1 or 2 
 
Maintain dose. Rule out other causes. Use standard additional anti-nausea 
medications to supplement the protocol-required 5-HT3 antagonists. 
Use additional anti-nausea medications to supplement the protocol-
required 5-HT3 antagonist(s). Olanzapine 2.5 to 5 mg PO every morning, 
per NCCN guidelines, can mitigate nausea and anorexia. 
Grade 3 
Rule out other causes. Use additional anti-nausea medications to 
supplement the protocol-required 5-HT3 antagonist(s). Olanzapine 2.5 to 
5 mg PO every morning, per NCCN guidelines, can mitigate nausea and 
anorexia. 
Interrupt selinexor dosing until resolved to Grade ≤2 or baseline and 
reduce selinexor by 1 dose level.  
Patients with significant nausea/vomiting after several doses of selinexor 
may have an antitumor response. Consider an unscheduled assessment of 
tumor response as part of the patient’s evaluation. 
Hyponatremia  
Grade 1 (sodium levels < Normal to 
130 mmol/L)  
Maintain dose. Rule out other causes including drug (eg, diuretic) effects. 
Be certain that reported sodium level is corrected for concurrent 
hyperglycemia (serum glucose >150 mg/dL).  
Treat hyponatremia per institutional guidelines including dietary review.  
Provide supplemental oral and/or intravenous fluids if dehydration is 
present. Consider addition of salt tablets to patient’s diet. 
Grade 3 with sodium levels 
<130-120 mmol/L without 
symptoms  
Rule out other causes including drug (eg, diuretic) effects. 
Be certain that reported sodium level is corrected for concurrent 
hyperglycemia (serum glucose >150 mg/dL).  
If (corrected) sodium is Grade ≤3 and continues to be asymptomatic, then 
patient may continue current dosing without interruption provided that IV 
saline and/or salt tablets are provided and patient is followed closely.  
If Grade 3 is persistent or worsens or does not respond to treatment, 
interrupt selinexor dosing until resolved to Grade 1 or baseline and reduce 
selinexor by 1 dose level. 
Grade 3 with sodium levels 
<130-120 mmol/L with symptoms 
or Grade 4 (<120 mmol/L) 
Rule out other causes including drug (eg, diuretic) effects. 
Be certain that reported sodium level is corrected for concurrent 
hyperglycemia (serum glucose > 150 mg/dL).  
Interrupt selinexor dosing until resolved to Grade 1 or baseline and 
without symptoms. Reduce selinexor by 1 dose level. 
Diarrhea  
Grade 1 
Maintain dose. Rule out other causes including drug effects. Treat per 
institutional guidelines with anti-diarrheals, such as loperamide. 
Grade 2 
Rule out other causes including drug effects. Treat per institutional 
guidelines with anti-diarrheals. Interrupt selinexor dosing until resolved to 
Grade 1 or baseline.  
For first occurrence, restart selinexor at current dose.  
For ≥ second occurrence, reduce selinexor by 1 dose level. 
Grade 3 or 4  
Interrupt selinexor dosing until resolved to Grade 1 or baseline and patient 
is clinically stable. Reduce selinexor dose by 1 dose level. 
Thrombocytopenia 
Grade 1 or 2 
Maintain dose. Rule out other causes including drug effects. 


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32 
Toxicity and Intensity 
Supportive Care and Dose Adjustment Guidelines 
Grade 3 without bleeding 
Rule out other causes including drug effects.  
For first occurrence: skip 1 dose and reduce selinexor by 1 dose level. 
If recurrent, unless contraindicated, start treatment with moderate to high 
doses of thrombopoietin stimulating agents such as romiplostim 5 to 
10 µg/kg SC weekly (preferred) or eltrombopag 100 to 150 mg QD. 
In cases where there is significant disease involvement in the bone marrow 
or pre-existing compromised marrow function (eg, due to prior marrow-
toxic therapy),  or if there is baseline thrombocytopenia Grade 2-4 at 
baseline, the Investigator in consultation with the Medical Monitor may 
decide to continue selinexor dosing without dose reductions and/or 
interruptions as specified above, provided that platelet counts and bleeding 
symptoms/signs are closely monitored. Thrombopoietin stimulating agents 
are recommended. 
Grade 4 without bleeding 
Rule out other causes including drug effects.  
Interrupt selinexor until patient recovers to Grade 2 or baseline. Selinexor 
dosing may be reduced by 1 dose level (it is recommended to have only 1 
dose modification per cycle). 
If recurrent, unless contraindicated, start treatment with moderate to high 
doses of thrombopoietin stimulating agents as above. 
In cases where there is significant disease involvement in the bone marrow  
or pre-existing compromised marrow function (eg, due to prior marrow-
toxic therapy), the Investigator in consultation with the Medical Monitor 
may decide to continue selinexor dosing without dose reductions and/or 
interruptions as specified above, provided that platelet counts and bleeding 
symptoms/signs are closely monitored. 
Grade ≥3 with bleeding 
 
Interrupt selinexor dosing and check platelet counts weekly until the 
bleeding has stopped, patient is clinically stable and the platelets have 
recovered to Grade 2 or baseline. When resuming selinexor, reduce by 
1 dose level. 
If recurrent, unless contraindicated, start treatment with moderate to high 
doses of thrombopoietin stimulating agents as above. 
Neutropenia 
Grade 3 or 4 neutropenia (afebrile)  
OR 
Febrile neutropenia 
Institute colony stimulating factors and prophylactic antibiotics as 
clinically indicated per institutional guidelines. 
Interrupt selinexor and check neutrophils at least weekly until recovers to 
Grade 2 or baseline and without fever (if febrile) and the patient is 
clinically stable. Reinitiate selinexor therapy and colony stimulating 
factors per institutional guidelines. 
If recurrent, continue colony stimulating factors, interrupt selinexor until 
neutrophil counts improve to Grade ≤2 or baseline levels, and reduce dose 
of selinexor 1 dose level. 
Anemia 
Treat per institutional guidelines including blood transfusions and/or erythropoietins. Consider transfusing for 
symptoms with hemoglobin >8 g/dL (Grade <3) or for any Grade 3 (hemoglobin <8 g/dL). If possible, maintain 
selinexor dose as long as patient is clinically stable, but if a dose reduction or interruption is desired, consult with 
the Medical Monitor. 


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Toxicity and Intensity 
Supportive Care and Dose Adjustment Guidelines 
Tumor lysis syndrome 
If TLS risk factors are identified, provide prophylactic IV hydration and regular monitoring of hydration 
(especially when increasing the dose of selinexor), renal function, urine output, and clinical laboratory measures 
of interest for TLS (eg, phosphorus, potassium, calcium, LDH, uric acid). Consider administration of 
hypouricemic agents to reduce the risk of TLS. 
Hold selinexor in patient with hyperkalemia (≥7.0 mmol/L) and/or symptoms of hyperkalemia, an increase in uric 
acid, or other changes in biochemical blood parameters suggestive of TLS. Start IV hydration, and consider 
hypouricemic agent until levels return to normal. Selinexor can be reintroduced at the normal or reduced dose. 
Other selinexor-related adverse events 
Grade 1 or 2 
Rule out other causes. Maintain dose. Start treatment and/or standard 
supportive care per institutional guidelines. 
Grade 3 or 4 
Rule out other causes. Interrupt selinexor until recovers to Grade 2 or 
baseline and reduce selinexor by 1 dose level. 
Isolated values of Grade ≥3 alkaline phosphatase do NOT require dose 
interruption. Determination of liver versus bone etiology should be made, 
and evaluation of gamma-glutamyl transferase, 5'-nucleotidase, or other 
liver enzymes should be performed. 
1. 
AFOR ALL GRADE ≥3 HEMATOLOGIC OR NON-HEMATOLOGIC 
AES THAT ARE NOT SELINEXOR RELATED, AFTER CONSULTATION WITH THE 
MEDICAL MONITOR AND AT THE DISCRETION OF THE INVESTIGATOR, 
SELINEXOR DOSING MAY BE MAINTAINED. 
2. 
BFOR ALL SELINEXOR-RELATED AE’S, IF THE BELOW PRESCRIBED DOSE 
REDUCTIONS/INTERRUPTIONS RESULT IN A STABILIZATION OF ≥4 WEEKS, A RE-
ESCALATION MAY BE CONSIDERED AFTER APPROVAL FROM THE MEDICAL 
MONITOR. 
3. ALL DOSE MODIFICATIONS SHOULD BE BASED ON THE WORST PRECEDING 
TOXICITY. 
4. NOTE: WHEN TOXICITIES DUE TO SELINEXOR HAVE RETURNED TO BASELINE 
LEVELS OR THE PATIENT HAS STABILIZED, THE DOSE OF SELINEXOR MAY BE RE-
ESCALATED IN CONSULTATION WITH THE MEDICAL MONITOR. 
 
5.19 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue indefinitely 
or until one of the following criteria applies: 
 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
• 
Patients enrolled in Cohort 3 will discontinue therapy in a response-adapted manner.  
All patients will discontinue selinexor after 14 cycles.  Patients who achieve a MRD 
negative CR at 14 cycles will discontinue both selinexor and ibrutinib.  Patients who 
achieve a MRD – PR will discontinue both selinexor and ibrutinib at discretion of 
treating physician.  Patients with any other response are recommended to continue 
ibrutinib indefinitely.  


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5.20 
Duration of Follow Up 
 
Patients will be followed every 6 months until progression or an alternative therapy is started.  
Patients removed from study for unacceptable adverse event(s) will be followed until resolution 
or stabilization of the adverse event.  Follow-up data will be required unless consent is 
withdrawn. 
 
5.21 
Criteria for Removal from Treatment 
 
At the discretion of the Investigator, the investigator may remove a patient from the study 
treatment for the following reasons:  
 
• 
Death, 
• 
Disease progression, 
• 
Noncompliance with study procedures, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Need of treatment with medications not allowed by the study protocol, 
• 
Unacceptable adverse event(s), 
• 
Other treatments become available, 
• 
Treatment delays exceeding 28 days, 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
 
The reason for study removal and the date the patient was removed must be documented in the 
Case Report Form.  Patients who are removed from protocol therapy will still be followed for 
progression and survival. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Toxicities that occur in cycle 1 that are DLTs (Section 4.2) will result in protocol removal. 
Adverse events that are not defined as DLTs and / or occur in cycles 2 and higher will lead to 
dose delays and modifications as detailed below. No dose reduction below ibrutinib 140 mg and 
selinexor 20 mg/week will be allowed. If a patient experiences several adverse events, and there 
are conflicting recommendations, the investigator should use the recommended dose adjustment 
that reduces the dose to the lowest level. Missed doses will not be replaced. Treatment delays for 
adverse events exceeding 28 days will lead to protocol removal unless approved by the principal 
investigator. 
 
Ibrutinib-related lymphocytosis, for the purposes of this protocol, is defined as an elevation in 
blood lymphocyte count of ≥50% compared with baseline count in conjunction with unequivocal 
improvement in at least 1 other disease-related parameter including lymph node size, spleen size, 


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hematologic parameters (hemoglobin or platelets), or disease-related symptoms. Ibrutinib-
associated treatment-related lymphocytosis generally occurs within the first few weeks of 
therapy, peaks within the first few months, and resolves slowly.  Patients with isolated 
lymphocytosis in the setting of reduced disease burden or improvement in hemoglobin/platelets 
should not be considered to have progressive disease. 
 
Asymptomatic treatment-related lymphocytosis should not be considered an adverse event. 
Subjects with treatment-related lymphocytosis in the absence of other disease-related symptoms 
should be encouraged to remain on study treatment and continue with all study-related 
procedures. 
 
 
6.1 
Dose adjustment guidelines for hematologic ibrutinib or selinexor-related toxicities 
 
Toxicities that are clearly not related to ibrutinib or selinexor will not require a dosing 
modification.  Similarly, toxicities that are clearly attributable to an individual drug will only 
require modification of that drug, with modifications following the tables below. 
  
Event Name 
Neutropenia, Anemia, or Thrombocytopenia 
For Patients with Baseline Absolute Neutrophil Count ≥ 1000/mm3; 
Hemoglobin ≥ 11g/dL; or Platelets ≥ 100,000/mm3 
Grade of 
Event 
Management/Next Dose Ibrutinib* 
Management/Next Dose of Selinexor* 
< Grade 3 
No change in dose 
No change in dose 
≥ Grade 3 
Hold until neutrophils, hemoglobin, 
or platelets have returned to < Grade 
3.   
• 1st occurrence: No change in dose 
• 2nd occurrence: Cohort 1 and 3= No 
change in dose; Cohort 2 = 
Decrease ibrutinib to next lowest 
dose level 
• 3rd occurrence: Decrease ibrutinib 
to next lowest dose level 
• 4th occurrence: Patient comes off 
study 
Hold until neutrophils, hemoglobin, or 
platelets have returned to < Grade 3. 
• 1st occurrence: No change in dose 
• 2nd occurrence: Decrease selinexor to 
next lowest dose. 
• 3rd occurrence: No change in dose 
• 4th occurrence: Patient comes off 
study 
*Dose reductions < ibrutinib 140mg daily or selinexor 20 mg weekly are not permitted.  
Recommendations:   
-Full supportive care, growth factors, and transfusions should be given as medically indicated. 
- If the patient tolerates a reduced dose for two cycles, patient may be dose escalated to the 
dose they received prior to the reduction after authorization from Principal Investigator. 
 
Event Name 
Neutropenia, Anemia, or Thrombocytopenia 
For Patients with Baseline Absolute Neutrophil Count ≤ 1000/mm3; 
Hemoglobin ≤ 11g/dL; or Platelets ≤ 100,000/mm3 


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Grade of AE 
Management/Next Dose Ibrutinib* 
Management/Next Dose of Selinexor* 
<Grade 3 
No change in dose 
No change in dose 
≥ Grade 3 
Hold until neutrophils, hemoglobin, 
or platelets have returned to within 
50% of pretreatment values.  If 
initial value is within 50% of 
pretreatment value, no hold is 
needed. 
• 1st occurrence: No change in dose 
• 2nd occurrence: Cohort 1 and 3= 
No change in dose; Cohort 2  = 
Decrease ibrutinib to the next 
lowest dose level. 
• 3rd occurrence: Decrease ibrutinib 
to the next lowest dose level. 
• 4th occurrence: Patient comes off 
study 
Hold until neutrophils, hemoglobin, or 
platelets have returned to within 50% 
of pretreatment values.  If initial value 
is within 50% of pretreatment value, 
no hold is needed. 
 
• 1st occurrence: No change in dose.  
Initiate granulocyte colony-
stimulating factors for grade >3 
neutropenia. 
• 2nd occurrence: Decrease selinexor to 
next lowest dose. 
• 3rd occurrence: No change in dose 
• 4th occurrence: Decrease selinexor to 
the next lowest dose 
• 5th occurrence:  No change in dose 
• 6th occurrence: Discontinue selinexor 
*Dose reductions < ibrutinib 140mg daily or selinexor 20 mg weekly are not permitted.  
Recommendations:   
-Full supportive care, growth factors, and transfusions should be given as medically indicated. 
- If the patient tolerates a reduced dose for two cycles, patient may be dose escalated to the 
dose they received prior to the reduction after authorization from Principal Investigator. 
 
Event Name 
Bleeding 
Grade of 
Event 
Management/Next Dose Ibrutinib* 
Management/Next Dose of Selinexor* 
≤ Grade 2 
(mild to 
moderate) 
Hold ibrutinib for at least 7 days 
after last bleeding and until platelets 
return to ≥ 50% of baseline value.  
• 1st occurrence: Restart ibrutinib at 
next lowest dose level.  In cases 
where no bleeding is observed 
after 6 days of dosing return to full 
dose at the physician’s discretion.    
• 2nd occurrence: Restart ibrutinib at 
next lowest dose level. 
• 3rd occurrence: Patient comes off 
study.  
Hold selinexor for at least 7 days after 
last bleeding and until platelets return 
to ≥ 50% of baseline value.  
• 1st occurrence: Restart selinexor at 
next lowest dose level. In cases 
where no bleeding is observed after 
6 days of dosing return to full dose 
at the physician’s discretion.    
• 2nd occurrence: Restart selinexor at 
next lowest dose level.   
• 3rd occurrence: Patient comes off 
study.  


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≥ Grade 3 
(severe) 
 
Hold ibrutinib for at least 7 days 
after last bleeding and until platelets 
return to ≥ 50% of baseline value.  
• 1st occurrence: Restart ibrutinib at 
next lowest dose level.   
• 2nd occurrence: Patient comes off 
study.  
Hold selinexor for at least 7 days after 
last bleeding and until platelets return 
to ≥ 50% of baseline value.  
• 1st occurrence: Restart selinexor at 
next lowest dose level.   
• 2nd occurrence:  Patient comes off 
study.  
*Dose reductions < ibrutinib 140mg daily or selinexor 20 mg weekly are not permitted. 
Recommendations:   
-Full supportive care, growth factors, and transfusions should be given as medically indicated. 
 
 
Event Name 
Neutropenic Fever 
Grade of 
Event 
Management/Next Dose Ibrutinib* 
Management/Next Dose of Selinexor* 
Grade 3 
 
Hold until toxicity ≤ Grade 2 or 
baseline.   
• 1st occurrence: No change in dose. 
• 2nd occurrence: Decrease ibrutinib 
to next lowest dose level. 
• 3rd occurrence:  Patient comes off 
study. 
Hold until toxicity ≤ Grade 2 or 
baseline.  
• 1st occurrence: Decrease selinexor to 
next lowest dose. 
• 2nd occurrence: No change in dose. 
• 3rd occurrence:  Patient comes off 
study. 
Grade 4 
 
Hold until toxicity ≤ Grade 2 or 
baseline.   
• 1st occurrence: Decrease ibrutinib 
to next lowest dose level. 
• 2nd occurrence: Decrease ibrutinib 
to next lowest dose level. 
• 3rd occurrence:  Patient comes off 
study 
Hold until toxicity ≤ Grade 2 or 
baseline.  
• 1st occurrence: Decrease selinexor to 
next lowest dose. 
• 2nd occurrence: Decrease selinexor to 
next lowest dose level. 
• 3rd occurrence:  Patient comes off 
study 
*Dose reductions < ibrutinib 140mg daily or selinexor 20 mg weekly are not permitted. 
Recommendations: 
-Full supportive care and/or growth factors should be given as medically indicated. 
 
6.2 
Dose adjustment guidelines for non-hematologic ibrutinib or selinexor-related 
toxicities  
 
Specific guidelines are provided below for non-hematologic toxicities. For all other grade 3 non-
hematologic toxicities possibly related to study therapy, hold the causative agent, or if the 
causative agent cannot be determined, hold both ibrutinib and selinexor. Once the toxicity is 
improved to ≤ Grade 2 or until baseline pre-treatment value, resume treatment with a decrease in 
the dose of ibrutinib by 140 mg or selinexor by one dose level. No dose reduction below 
ibrutinib 140 mg and selinexor 20 mg/week will be allowed. If a patient experiences several 
adverse events, and there are conflicting recommendations, the investigator should use the 


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recommended dose adjustment that reduces the dose to the lowest level. Missed doses will not be 
replaced. Treatment delays for adverse events exceeding 28 days will lead to protocol removal.  
 
Any Grade 4 toxicities (lasting ≥7 days for transaminase or electrolyte abnormalities) that are at 
least possibly attributed to selinexor or ibrutinib should result in permanent discontinuation of 
the causative agent.  If attribution to a single drug cannot be made, both drugs should be 
discontinued. 
 
Event Name 
Nausea 
Grade of 
Event 
Management/Next Dose Ibrutinib 
Management/Next Dose of Selinexor 
Grade 1 
No change in dose 
5-HT3-antagonists, D2-antagonists or 
NK1 antagonists, or dronabinol or 
combinations can prevent nausea in 
the majority of patients.  Consider 
additional anti-emetics (see the NCCN 
Clinical Practice Guideline for 
antiemesis). Provide guidance on diet 
as described above for anorexia as 
increased caloric intake may reduce 
nausea. 
Grade 2 
No change in dose 
Implement one or more combinations 
of anti-nausea medications. Consider 
additional anti-emetics (see the NCCN 
Clinical Practice Guideline for 
antiemesis).  If Grade 2 nausea 
persists, reduce dose of selinexor by 
one dose level.  If patient’s nausea is 
Grade ≤1 for 4 weeks, then the dose of 
selinexor may be increased back to the 
previous dose level. 
Grade 3 
No change in dose 
Interrupt dosing of selinexor and 
implement one or more combinations 
of anti-nausea medications.  Consider 
additional anti-emetics (see the NCCN 
Clinical Practice Guideline for 
antiemesis).  Ensure adequate caloric 
and fluid intake.  Restart selinexor 
with one dose level reduction when 
nausea is Grade ≤ 2 and adequate 
caloric and fluid intake have been 
achieved. If patient’s nausea is Grade 
≤1 for 4 weeks, then the dose of 
selinexor may be increased back to the 
previous dose level. 


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Recommendations:   
-Full supportive care and antiemetics.  See Section 4.4. 
- If the patient tolerates a reduced dose for two cycles, patient may be dose escalated to the 
dose they received prior to the reduction after authorization from Principal Investigator. 
 
Event Name 
Vomiting 
Grade of 
Event 
Management/Next Dose Ibrutinib 
Management/Next Dose of Selinexor 
≤ Grade 2 
No change in dose 
No change in dose 
Grade 3 
No change in dose 
Hold until toxicity ≤ Grade 1.  
Decrease by one dose level.   
Recommendations:   
-Full supportive care and antiemetics.  See Section 4.4. 
 
Event Name 
Diarrhea 
Grade of 
Event 
Management/Next Dose Ibrutinib 
Management/Next Dose of Selinexor 
Grade 1 
No change in dose 
Rule out other causes of diarrhea, 
including infectious agents. At the first 
sign of abdominal cramping, loose 
stools, or onset of diarrhea, it is 
recommended that the patient be 
treated according to institutional 
standard of care, e.g., loperamide 
(Immodium®).  Maintain dose level of 
selinexor. 
Grade 2 
No change in dose 
If diarrhea is present despite maximal 
anti-diarrheal medication, rule out 
other causes of diarrhea, including 
infectious agents. Reduce selinexor by 
one dose level until resolved to 
≤ Grade 1, then re-start at the current 
dose level. 
If diarrhea returns as Grade ≥ 2, then 
reduce selinexor dose by one dose 
level.  If patient is stable and diarrhea 
resolves (Grade 0 or baseline with or 
without anti-diarrheals) for 4 weeks, 
then the patient’s dose may be re-
escalated 
Grade 3  
Hold until ≤ Grade 1.  Decrease 
ibrutinib to next lowest dose level. 
If diarrhea is present despite maximal 
anti-diarrheal medication, rule out 
other causes of diarrhea, including 
infectious agents. Delay selinexor until 


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resolved to Grade ≤2, then reinitiate 
selinexor at one dose level below. If 
patient is stable and diarrhea resolves 
(Grade 0 or baseline with or without 
anti-diarrheals) for 4 weeks, then the 
patient’s dose may be re-escalated. 
Recommendations:   
-Full supportive care and antidiarrheal agents.  See Section 4.4. 
 
Event Name 
Fatigue 
Grade of 
Event 
Management/Next Dose Ibrutinib 
Management/Next Dose of Selinexor 
Grade 1 
No change in dose 
Ensure adequate caloric intake and 
assess volume status.  Recommend 
high calorie and/or energy drinks 
and/or foods.  Adjust other 
medications.  Rule out other causes of 
fatigue such as adrenal insufficiency, 
hypothyroidism, etc. 
Grade 2 
No change in dose 
Ensure adequate caloric and fluid 
intake and assess volume status.  Add 
supportive care for fatigue, or reduce 
the dose of selinexor by one level.  If 
patient’s fatigue is Grade ≤1 for 4 
weeks, then the dose of selinexor may 
be increased back to the previous dose 
level. 
Grade 3 
No change in dose 
Ensure adequate caloric and fluid 
intake and assess volume 
status.  Interrupt selinexor dosing until 
resolved to Grade ≤ 2, reduce dose of 
selinexor by 1 level. If patient’s 
fatigue is Grade ≤1 for 4 weeks, then 
the dose of selinexor may be increased 
back to the previous dose level. 
Recommendations:   
- Optimize supportive care including caloric and fluid intake.  Add glucocorticoids when not 
contra-indicated.  See Section 4.4. 
 
Event Name 
Rash - Maculopapular 
Grade of 
Event 
Management/Next Dose Ibrutinib* 
Management/Next Dose of Selinexor* 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume same 
dose. 
No change in dose 


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Grade 3 
Hold until toxicity ≤ Grade 1.   
• 1st occurrence: Decrease ibrutinib 
to next lowest dose level. 
• 2nd occurrence: Decrease ibrutinib 
to next lowest dose level. 
Hold until toxicity ≤ Grade 1 or 
baseline.  
• 1st occurrence: No change in dose. 
• 2nd occurrence: Decrease selinexor to 
next lowest dose level. 
*Dose reductions < ibrutinib 140 mg daily or selinexor 20 mg weekly are not permitted. 
Recommendations:   
- Review medication list and discontinue any medications that commonly cause rash if 
possible. 
-Consider skin biopsy. 
 
Event Name 
Thrombosis/Thromboembolic Event 
Grade of 
Event 
Management/Next Dose Ibrutinib 
Management/Next Dose of Selinexor 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 or 3 
Hold until therapeutically 
anticoagulated and platelets are ≥ 
50,000/mm3. Resume at the same 
dose level.   
Hold until therapeutically 
anticoagulated and platelets are ≥ 
50,000/mm3. Resume at the same dose 
level.   
Recommendation: Anticoagulation (warfarin prohibited) 
 
Event Name 
Hyponatremia 
Grade of 
Event 
Management/Next Dose Ibrutinib 
Management/Next Dose of Selinexor 
Grade 1 
(Lower Limit 
of Normal to 
130 nM) 
No change in dose 
Maintain selinexor dose and frequency 
level, assure adequate fluid, electrolyte 
and caloric intake, adjust other 
medications, and consider salt 
supplementation 1-3 times per 
day. Correct sodium level for 
hyperglycemia (serum glucose 
>150 mg/dL).  Rule out other causes 
of low sodium (e.g., SIADH, cardiac, 
hepatic, adrenal, renal, and thyroid 
diseases, Fanconi Syndrome, diuretic 
use, etc.). 
Grade 3 (126-
129 mmol/L)  
No change in dose 
Ensure patient is euvolemic and has 
sufficient fluid and electrolyte 
intake.  Replace fluids orally or IV if 
patient is dehydrated.  Correct sodium 
level for hyperglycemia.  Rule out 
other causes of low sodium (see above 
for Grade 1). 
Hold selinexor until hyponatremia 


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resolves to Grade ≤1 (≥130 nM) and 
initiate aggressive salt 
supplementation 2-3 times per 
day.  Restart at the same dose and 
frequency of selinexor and monitor 
serum sodium closely.  If this recurs, 
measure urine sodium and creatinine 
levels to investigate for other causes of 
hyponatremia. 
Grade 3 (120-
125 mmol/L ) 
No change in dose 
Hold selinexor dose until sodium ≥ 
125 mmol/L*.  Decrease selinexor to 
the next lowest dose level for initial 
and each subsequent occurrence. 
*If sodium does not recover to ≥ 125 mmol/L within 14 days of holding selinexor, selinexor 
should be permanently discontinued 
• In marked hyperglycemia, ECF osmolality rises and exceeds that of ICF, since glucose 
penetrates cell membranes slowly in the absence of insulin, resulting in movement of water 
out of cells into the ECF. Serum Na concentration falls in proportion to the dilution of the 
ECF, declining 1.6 mEq/ L for every 100 mg/dL (5.55 mmol/L) increment in the plasma 
glucose level above normal. This condition has been called translational hyponatremia 
because no net change in total body water (TBW) has occurred. No specific therapy is 
indicated, because Na concentration will return to normal once the plasma glucose 
concentration is lowered. Corrected Sodium = Measured sodium + 0.024 * (Serum 
glucose - 100). 
 
Event Name 
Anorexia 
Grade of 
Event 
Management/Next Dose Selinexor 
Grade 1 
 
Assess dietary options (e.g., try a 
variety of other foods).  Add high-
calorie supplements (e.g., Ensure®). 
Consider an appetite stimulant(s) (see 
the NCCN Clinical Practice Guideline 
for anorexia). 
Grade 2 
 
Add high-calorie supplements (e.g., 
Ensure®).  Add an appetite stimulant(s) 
(see the NCCN Clinical Practice 
Guideline for anorexia).  Selinexor 
dosing may be interrupted 
intermittently while supportive 
medications are instituted, usually for 
<1 week.  If Grade 2 anorexia does not 
resolve after institution of supportive 
medications, reduce selinexor dose by 
1 level .  If patient’s anorexia is Grade 


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≤1 for 4 weeks, then the dose of 
selinexor may be increased back to the 
previous dose level. 
Grade 3 
 
Interrupt dosing with selinexor until 
resolution to Grade ≤2.  Add high 
calorie supplements.  As described 
above, initiate supportive medications 
for anorexia.  Restart selinexor at 1 
dose level reduction .  once anorexia 
resolves to Grade ≤ 2 and follow the 
guidelines above. If patient’s anorexia 
is Grade ≤1 for 4 weeks, then the dose 
of selinexor may be increased back to 
the previous dose level. 
 
 
Event Name 
Weight Loss 
Grade of 
Event 
 
Management/Next Dose of Selinexor  
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 
corticosteroids on day of and day after 
selinexor dosing. Consider an appetite 
stimulant(s) (see the NCCN Clinical 
Practice Guideline for anorexia and 
anti-emesis). 
Grade 2 
 
Add high-calorie supplements (e.g., 
Ensure®).  Consider corticosteroids on 
day of and day after selinexor dosing. 
Consider an appetite stimulant(s) (see 
the NCCN Clinical Practice Guideline 
for anorexia and anti-emesis).  
Consider megesterol acetate 80-400mg 
daily. Consider anabolic steroids such 
as oxandrolone. Consider dronabinol 
(Marinol®). If Grade 2 weight loss 
does not resolve after institution of 
supportive medications, reduce 
selinexor dose by 1 level.  
Grade 3 
 
Interrupt dosing with selinexor.  Add 
high calorie supplements.  Use 
supportive medications from above 
alone or in combinations.  Restart 


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selinexor at 1 dose level reduction 
once weight loss resolves to Grade ≤2.  
If Grade 2 weight loss persists with 
supportive medications, reduce dose of 
selinexor by 2 levels. If patient’s 
weight loss is Grade ≤1 for 4 weeks, 
then the dose of selinexor may be 
increased back to the previous dose 
level. 
 
Event Name 
Hypertension 
Grade of 
Event 
Management/Next Dose Ibrutinib 
Management/Next Dose of Selinexor 
Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
 No change in dose if hypertension 
is medically managed. 
No change in dose 
Grade 4 
If possibly, probably, or definitely 
related to ibrutinib, consider holding 
dose until hypertension improves to 
baseline with medical management 
of hypertension.  Ibrutinib can then 
be reinsituted at the same dose at 
first occurrence.  At second 
occurrence, reduce dose to 280 mg 
daily. 
No change in dose 
 
 
6.3 
Dose Reduction for Decreased Glomerular Filtration Rate (GFR)  
 
Selinexor is not significantly eliminated by the kidney; therefore, no dose alteration of selinexor 
is required with renal dysfunction.  If dialysis is implemented during selinexor treatment, then 
selinexor should always be given after dialysis.  Selinexor tablets are to be taken with at least 
120 mL (4 ounces) of fluids (water, juice, etc.) at approximately the same time each day. 
 
6.4 
Dose Adjustment for Infection 
 
Patients with active uncontrolled serious or suspected serious infections (i.e. Grade 3 or higher, 
or Grade 2 or higher at the discretion of the treating physician) should have selinexor and 
ibrutinib treatment withheld until infection has clinically resolved or stabilized. Dexamethasone 
should be adjusted per institutional guidelines, and adrenal suppression considered.  After the 
infection has resolved clinically, or the patient’s clinical condition has stabilized, treatment with 
selinexor may continue at the original dose.  Missed doses will not be replaced.  Patients may 
continue on antibiotics or other anti-microbial agents for prolonged periods while re-initiating 


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their selinexor regimen at the discretion of the investigator.  Note: selinexor has not been 
associated with opportunistic infections in approximately 400 patients treated as of 1 August 
2014. 
 
6.5 
Conditions not Requiring Dose Reduction 
 
The following conditions are exceptions to the above guidelines. selinexor does not need to be 
held in the following cases:  
• Alopecia of any grade  
• Electrolytes abnormalities that are reversible with standard interventions  
 
6.6 
Missed or Vomited Doses 
 
Selinexor missed doses- If the dose was missed for more than 48 hours, the dose will be skipped 
and the next dose will be taken as per schedule. If the dose was missed within 48 hours, then it 
will be replaced.  
 
If a patient missed a full week of dosing for non-study drug related events (eg. a required 
medical procedure or an unanticipated personal emergency), the days missed will not be 
replaced. For example, if patient missed C2D7 to C2D14, then patient will start on C2D15. 
 
Ibrutinib missed doses- If a dose is missed, it can be taken up to 6 hours after the scheduled time 
with a return to the normal schedule the following day. If it has been greater than 6 hours, the 
dose should not be taken and the subject should take the next dose at the scheduled time the next 
day. The missed dose will not be made up and must be reported at the next scheduled visit. 
 
Selinexor or ibrutinib vomited doses- If a dose is vomited within one hour of ingestion, it will be 
replaced. If vomiting occurs more than 1 hour after dosing, it will still be considered a complete 
dose.  
 
6.7 
Delays, Modifications and Reintroduction 
 
All delays, modifications, and reintroductions of selinexor or ibrutinib dosing will be made in 
consultation with the principal investigator. 
 
7. ADVERSE EVENTS (AES):  LIST AND REPORTING REQUIREMENTS  
 
All patients must be carefully monitored for AEs, including clinical laboratory tests.  AEs should 
be assessed in terms of their seriousness, intensity, and relationship to the study drug.  For 
consistency, events are to be graded using the CTCAE version 4.0.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
If CTCAE criterion does not exist for a particular AE, the investigator should use the grade or 
adjectives as described below: 


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• Grade 1=Mild=Does not interfere with patient’s usual function 
• Grade 2=Moderate=Interferes to some extent with patient’s usual function 
• Grade 3=Severe=Interferes significantly with patient’s usual function 
• Grade 4=Life-Threatening=Results in a threat to life or in an incapacitating disability. 
 
7.1 
Definition of an Adverse Event 
 
Adverse event (AE): Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of study treatment, whether or not considered related to the study 
treatment.  
 
7.2 
Recording of Adverse Events 
 
All AE will be reported and recorded from the time of the first dose of study drug through 30 
days after the last dose of study drug or until the start of subsequent antineoplastic therapy, 
whichever occurs first.  That is, if a patient begins a new antineoplastic therapy, the AE reporting 
period for nonserious AEs ends at the time the new treatment is started. 
AE monitoring should be continued for at least 30 days following the last dose of study treatment 
(i.e., through 30 days following last dose or until resolution or through the end of the study for 
events considered related to study treatment by the Investigator). AEs (including laboratory 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be recorded as a separate AE. 
 
The Investigator should ask the patient non-leading questions to determine if AEs occur during 
the study. AEs may also be recorded when they are volunteered by the patient, or through 
physical examination, laboratory tests, or other clinical assessments. 
 
An AE should be followed until its resolution or until it is judged to be permanent, and 
assessment should be made at each visit (or more frequently, if necessary) of any changes in 
severity of the event, the suspected relationship to the study treatment, the interventions required 
to treat the event, and the outcome. 
 
7.3 
Laboratory Test Abnormalities 
 
Laboratory abnormalities that constitute an AE in their own right (i.e., are considered to be 
clinically significant, induce clinical signs or symptoms, require concomitant therapy, or require 
changes in study treatment), should be recorded as an AE. Whenever possible, a diagnosis rather 
than a symptom should be recorded (e.g., anemia instead of low hemoglobin). Laboratory 
abnormalities that meet the criteria for an AE should be followed until they have returned to 
normal or an adequate explanation of the abnormality is identified. When an abnormal laboratory 
or test result corresponds to a sign/symptom of an already reported AE, it is not necessary to 


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separately record the laboratory/test result as an additional event. 
 
A laboratory abnormality that does not meet the definition of an AE should not be recorded as an 
AE. A laboratory abnormality that results in a dose being held or modified would, by definition, 
be an AE. A Grade 3 or 4 event (severity per the current version of NCI CTCAE) does not 
automatically indicate an SAE unless it meets the definition of serious as defined in Section 5.11 
and/or as per the Investigator’s discretion. 
 
7.4 
Adverse Events of Special Interest 
 
AESIs for selinexor include cataracts and acute cerebellar syndrome. All cases of cerebellar 
toxicity, Grade 3 or higher must be reported. 
 
All cases of Grade 3 or higher cerebellar toxicities occurring in patients enrolled in the study from the 
informed consent signature and up to 30 days after the last drug administration, or after if related to study 
drug, must be immediately reported as SAE (even if not meeting the definition of a SAE) to the 
Sponsor by the investigator within 24 hours of first knowledge of the event by study personnel, using 
the SAE form provided by the Sponsor (follow reporting rules for SAE in section 13.3).  
Reporting of Cataracts  
Sponsor is closely monitoring the occurrence of cataracts during treatment with selinexor as adverse 
events of special interest. Ophthalmic examinations are planned on regular basis to identify cataracts or 
worsening of existing cataracts. Any cataracts or worsening of existing cataracts has to be reported as an 
AE irrespectively of grade. 
 
 
 
7.5 
Adverse Event Severity Assessments 
 
The severity* of the AE should be graded by the Investigator according to the NCI CTCAE 
Grading Scale, utilizing a current version of NCI CTCAE.  NCI CTCAE files can be accessed 
online at the following URL: http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
• If NCI CTCAE grading does not exist for an AE, the severity should be characterized as 
‘mild,’ ‘moderate,’ ‘severe,’ ‘life-threatening’, or ‘fatal’ (corresponding to Grades 1 to 5) 
according to the following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily activities. 
• Moderate events introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities. 
• Severe events interrupt the patient’s usual daily activities. 
• Life-threatening  
• Fatal event. 
*Severity ≠ Seriousness:  The term ‘severe’ is used to describe the intensity of an AE; the event 
itself could be of relatively minor clinical significance (e.g., ‘severe’ headache). This is not the 
same as a ‘serious’ AE.  Grades do not define seriousness. 
 


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7.6 
Adverse Event Causality 
 
The Investigator will make a judgment regarding the relationship of the AE to study treatment, as 
outlined in Table 1. 
Table 1:        Classification of Adverse Events by Causality 
Not related 
The lack of a temporal relationship of the event to the study 
treatment makes a causal relationship not reasonably possible, or 
other drugs, therapeutic interventions, or underlying conditions 
Related 
The temporal relationship of the event to the study treatment 
makes a definitive relationship, and the event is more likely 
explained by exposure to the study treatment than by any other 
drugs, therapeutic interventions, or underlying conditions. 
  
7.7 
Adverse Event Reporting 
 
The Investigator will report all AEs (including all non-serious AEs) to Karyopharm 
Pharmacovigilance twice per year in the form of line-listings. Karyopharm will supply the cut-
off dates. The line listings will contain the following information:  study ID, unique subject ID, 
adverse event term, serious event (yes or no), onset date (complete or partial), end date (complete 
or partial), action taken with selinexor, causality to selinexor, event ongoing (yes or no), outcome 
of AE, severity CTCAE Grade (1-5), subject dosed with selinexor (yes or no), date of first dose 
of selinexor, preferred term (optional, system organ class (optional) 
 
7.8 
Serious Adverse Events 
 
An AE is considered an SAE if at least one of the following conditions applies:  
• Death was an outcome of an adverse event;  
• Life threatening AE (i.e., an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe);  
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Emergency room visits that do not result in admission to the hospital should be evaluated 
for one of the other serious outcomes (e.g., life-threatening; required intervention to 
prevent permanent impairment or damage; other serious medically important event);  
• Results in persistent or significant disability/incapacity;  
• Is a congenital anomaly/birth defect;  
• A new cancer diagnosed during the study (histopathologically different from the cancer 
under study; and  
Any important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 1 of 
the outcomes listed in this definition. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in in-patient hospitalization, or the development of drug dependency or drug 


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abuse. Hospitalizations for elective surgery or other medical procedures that are not due to an AE 
are not considered SAEs. A hospitalization meeting the regulatory definition for ‘serious’ is any 
inpatient hospital admission that includes a minimum of an overnight stay in a health care 
facility. An emergency room visit is not considered a hospitalization unless it results in an 
official admission to the hospital. 
 
Progression of the malignancy (including fatal outcomes) should not be reported as an SAE 
during the study or within the safety reporting period. Sudden and unexplained death should be 
reported as an SAE. If there is any uncertainty about a finding being due solely to progression of 
malignancy, the finding should be reported as an AE or SAE, as appropriate. 
 
7.9 
Recording of Serious Adverse Events 
 
Per the Good Clinical Practices, it is recommended that Investigator has the responsibility to 
record and document all SAEs occurring from the signing of the Informed Consent Form until at 
least 30 days after the patient has stopped study treatment. 
 
7.10 
Reporting of Serious Adverse Events 
 
Every SAE, regardless of the causal relationship to the Karyopharm medications, occurring after 
the patient has signed informed consent until 30 days after the patient has stopped study 
treatment must be reported to the Karyopharm Pharmacovigilance within 24 hours of awareness. 
A Karyopharm SAE Report Form template is provided for this purpose (Appendix D). For 
reporting any SAE to Karyopharm Pharmacovigilance Department, a completed and signed (by 
the Investigator) SAE Report Form will be submitted to Karyopharm Pharmacovigilance: 
 
Completed and signed SAE report forms must be emailed or faxed to: 
 
Pharmacovigilance Department 
Karyopharm Therapeutics Inc. 
Email: pharmacovigilance@karyopharm.com 
Fax:     +1-617-334-7617 (USA) 
 
Any SAE observed after the 30-day follow-up period should only be reported to Karyopharm if 
the Investigator suspects that the SAE has causal relationship to study treatment.  
 
An SAE should be followed until its resolution or until it is judged to be permanent, and 
assessment should be made at each visit (or more frequently, if necessary) of any changes in 
severity of the event, the suspected relationship to the study treatment, the interventions required 
to treat the event, and the outcome.  New information, recurrences, complications, or progression 
of the initial SAE must be reported as follow-up to the initial report within 24 hours of the 
Investigator receiving the follow-up information. 
 
Investigators are responsible as applicable for notifying their appropriate Health Authorities, 
Institutional Review Board or Local and Central Ethics Committees (EC) of all SAEs in 


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accordance with local regulations.  
 
Karyopharm Therapeutics will report applicable SAEs to other applicable Regulatory Agencies 
and Investigators utilizing the Karyopharm product, as may be required. 
 
7.11 
Suspected Unexpected Serious Adverse Reactions 
 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Karyopharm to be related to the study treatment administered.  
 
SUSARs will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with the FDA’s ‘Safety Reporting Requirements for Investigational 
New Drugs and Bioanalytical/Bioequivalence Studies’ or as per national regulatory requirements 
in participating countries. 
 
7.12 
Procedures for Handling Special Situations 
 
7.12.1 Pregnancy 
 
Note: Pregnancy per se is not considered to be an AE; however, it is discussed here because of 
the importance of reporting pregnancies that occur during studies and because a medical 
occurrence observed in the mother or fetus/newborn would be classified as an AE. 
 
To ensure patient safety, a pregnancy occurring while the patient is on study treatment must be 
reported to Karyopharm Pharmacovigilance by email or fax within 24 hours of first knowledge 
of its occurrence. A pregnancy report form is provided Karyopharm Therapeutics Inc.  
 
The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
 
A pregnancy in a female partner of a male patient must be reported to Karyopharm within 24 
hours of learning of its occurrence.  
 
Pregnancies must be reported to Karyopharm, regardless of whether the patient withdraws from 
the study or the study is completed, for 3 months after the patient receives his/her last dose of 
study treatment. Patients should be instructed to inform the investigator regarding any 
pregnancies.  
 
Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, birth defect) and reported within 24 hours in accordance with the procedure 
for reporting SAEs. 
 


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7.13 
Abuse, Misuse, Medication Errors, Overdose, and Occupational Exposure 
 
All incidences of abuse, misuse, medication errors, overdose, and occupational exposure are 
required to be reported to Karyopharm pharmacovigilance on an SAE report form emailed to 
pharmacovigilance@karyopharm.com, regardless of whether or not there is an associated AE or 
SAE.   
 
7.13.1 Overdose 
 
An overdose is a deliberate or accidental administration of any Karyopharm treatment to a study 
patient, at a dose greater than that which was assigned to that patient per the study protocol. If an 
overdose occurs, Karyopharm should be notified immediately, and the patient should be 
observed closely for AEs. Resulting symptoms should be treated, as appropriate, and the incident 
of overdose and related AEs and/or treatment should be recorded. Overdose is to be reported on 
an SAE report form to Karyopharm pharmacovigilance regardless of whether or not an AE or 
SAE has occurred due to the overdose. If the overdose is associated with an SAE, the SAE report 
form must be submitted to Karyopharm pharmacovigilance within 24 hours of awareness.  If 
there is no AE or SAE, the overdose report must be submitted within 24 hours of awareness. 
 
7.13.2 Abuse, Misuse, or Medication Error 
 
Abuse is the persistent or sporadic, intentional excessive use of the study drug which is 
accompanied by harmful physical or psychological effects.  
 
A medication error is any preventable incident that may cause or lead to inappropriate 
medication use or patient harm while the medication is in the control of the health care 
professionals or patients. Such incident may be due to health care professional practice, product 
labeling, packaging and preparation, procedures for administration, and systems, including 
prescribing; order communication; and nomenclature; compounding; dispensing; distribution; 
administration; education; monitoring; and use.’ 
 
All occurrences of abuse, misuse or medication error with Karyopharm drug are to be reported 
on an SAE report form to Karyopharm pharmacovigilance regardless of whether or not an AE or 
SAE has occurred due to the abuse, misuse or medication error.  If the abuse, misuse or 
medication error is associated with an SAE, the SAE report form must be submitted to 
Karyopharm pharmacovigilance within 24 hours of awareness.  If there is no AE or SAE, the 
report must be submitted as soon as possible. 
 
7.13.3 Occupational Exposure 
 
Occupational exposure is the exposure to a study drug as a result of one’s professional or non-
professional occupation.   
 
All occurrences of occupational exposure with Karyopharm drug are to be reported on an SAE 
report form to Karyopharm pharmacovigilance regardless of whether or not an AE or SAE has 


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occurred due to the occupational exposure.  If the occupational exposure is associated with an 
SAE, the SAE report form must be submitted to Karyopharm pharmacovigilance within 24 hours 
of awareness.  If there is no AE or SAE, the report must be submitted as soon as possible. 
 
7.14 
Data Safety Monitoring Plan 
 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
and data timeliness. Investigators will conduct continuous review of data and patient safety at 
their regular Disease Group meetings (at least monthly) and the discussion will be documented in 
minutes. For each dose level, the Principal Investigator, study coordinator, and statistician, in 
consultation with treating physicians as appropriate will review all toxicities at a given dose level 
to inform the model for dose level adjustments.  The Principal Investigator of the trial will 
review toxicities and responses of the trial where applicable at these disease center meetings and 
determine if the risk/benefit ratio of the trial changes. Frequency and severity of adverse events 
will be reviewed by the Principal Investigator and compared to what is known about the 
agent/device from other sources; including published literature, scientific meetings and 
discussions with sponsors, to determine if the trial should be terminated before completion. 
Serious adverse events will be reviewed by the OSUCCC Data and Safety Monitoring 
Committee (DSMC). The Principal Investigator will also submit a biannual progress report that 
will be reviewed by the committee per the DSMC plan. All reportable SAEs will be reported to 
the IRB of record as per the policies of the IRB. 
 
Mandatory safety and trial review teleconferences will be scheduled and moderated by the Multi-
Center Trial Program (MCTP). All sites involved in the study are expected to have a 
representative present every month to review and discuss patients on study and other applicable 
agenda items. Meeting minutes will be used to document each monthly teleconference. The 
minutes will be stored in the MCTP protocol files. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with selinexor and ibrutinib can be 
found in Sections 7.1 and 7.2, respectively. 
 
8.1 
Selinexor Description/Availability 
Selinexor is manufactured by KABS Laboratories (Montreal, ON) for Karyopharm, Therapeutics 
(Newton, MA) using methods in accordance with Food and Drug Administration (FDA) guidelines 
for the manufacture and testing of antineoplastic agents for human use.  The tablets are prepared 
from a common blend of excipients and all tablet excipients are GRAS (generally regarded as safe) 
listed and suitable for use in pharmaceuticals.  Selinexor is an investigational agent supplied to 
investigators of this study by Karyopharm Therapeutics at no cost. 
 
Sites must request study drug by submitting an order form directly to the drug depot in order for 
the study drug to be shipped to the site pharmacy. The drug order forms will also be used for re-
supply of study medication.  Instructions for re-orders are included on the form.  Requests should 


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be made to allow for 5-7 days for delivery. The investigator (or designee) will verify and 
acknowledge receipt of all study drug shipment by signing and returning all required forms.  
 
8.1.1 Selinexor Composition and Preparation 
 
Selinexor will be supplied in 20 mg tablets in wallet-sized blister packs (12 tablets per blister 
pack).  Each wallet-size blister package of selinexor tablets will be labeled in accordance with 
current International Conference on Harmonization (ICH), Good Clinical Practice (GCP), and 
specific regulatory requirements, e.g., FDA, Health Canada, EMA, etc.  Blister packages for 
take-home use may require additional in-pharmacy labeling with take-home and patient-specific 
instructions (such as exact dose) depending on country-specific regulations or laws. 
 
8.1.2 Selinexor Administration 
 
Each dose will consist of selinexor tablet(s) for oral administration on a fixed dose basis.  
Selinexor oral doses are given Days 1, 8, and 15 of each 28 day cycle. 
 
Selinexor tablets are to be taken with at least 120 mL (4 ounces) of fluids (water, juice, etc.) at 
approximately the same time each day. Selinexor tablets should not be crushed because of 
increased risk of dermatologic toxicity if the powder comes in contact with skin. 
Selinexor for the study are provided by Karyopharm Therapeutics and will be labeled as per the 
applicable regulations. Study drug must be requested by submitting an order form directly to the 
drug depot in order for the study drug to be shipped to the site pharmacy. The Investigator (or 
designee) will verify and acknowledge receipt of all study drug shipments by signing and 
returning all required forms.  
 
Selinexor accountability records will be maintained at each participating institution and must be 
available for review when requested for auditing purposes and at time of study close out.  
 
All medication must be stored in a secure area under the proper storage requirements with access 
restricted to the site staff pharmacist or designee(s).  
 
Selinexor should not be used for any purpose outside the scope of this protocol, nor can selinexor 
be transferred or licensed to any party not participating in the clinical study. Data for selinexor 
are confidential and proprietary and shall be maintained as such by the Investigators. 
 
8.1.3 Drug Storage 
 
Selinexor tablets will be stored at or below 30 ˚C (86 ˚F) in white high-density polyethylene 
(HDPE) bottles or in blister packs, in a locked and secured area with restricted access.  Selinexor 
tablets can be stored at room temperature (recommended) or refrigerated, but should not be 
stored frozen or at freezer temperatures. Selinexor tablets are currently in on-going stability 
studies. The current expiry is 24 months from date of manufacture, and will be extended when 
further stability data becomes available.  All medication must be stored in a secure area under the 


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proper storage requirements with access restricted to the site staff pharmacist or designee(s). 
 
8.1.4 Accountability and Destruction of Investigational Medicinal Product  
 
The Principal Investigator (or an authorized designee) at each participating institution must 
maintain a careful record of the inventory of the Investigational medicinal product received using 
the Drug Accountability Form. The study drug will be destroyed as per site’s destruction policies 
and documentation of study drug destruction will be kept.  Both used and unused study drug may 
be returned to the sponsor if requested by the sponsor. 
 
8.1.5 Safety Considerations 
 
Anorexia/Weight Loss 
 
Selinexor treatment can cause reduced food (caloric) intake and concomitant weight loss. 
Patients should be advised to monitor their weight carefully, and to try different foods in order to 
maintain a healthy caloric intake.  See Section 4.4 and 4.5 for detailed supportive care 
recommendations for anorexia. 
 
Fatigue 
 
Fatigue may be related to underlying malignancy, selinexor side effects, side effects of other 
agents, or concurrent morbidities. Fatigue may also be related to anorexia and/or dehydration, so 
caloric and fluid intake should be optimized in all patients.  See Section 4.5 for detailed 
supportive care recommendations for anorexia and fatigue. 
 
Nausea/Vomiting 
 
Supportive care for nausea and vomiting should be given promptly. Prophylactic treatment can 
be considered in case of previous side effect of nausea and vomiting with prior anti-cancer 
therapy. The treatment should start with the first sign of nausea. Standard anti-emetics are 
allowed and strongly recommended.  See Section 4.4 and 4.5 for detailed supportive care 
recommendations for emesis. 
 
Thrombocytopenia 
 
The etiology of thrombocytopenia in patients treated with selinexor is unclear, but has been 
experienced by patients on the phase I study.  See Section 5.1 for dose adjustments related to 
thrombocytopenia. 
 
Infection 
 
Selinexor may lead to neutropenia.  Patients should report any symptoms or signs of infection 
such as fever, pain, sweating, redness to their physician immediately. Section 5.4 for dose 
adjustments related to infection. 


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Liver Function Abnormalities 
 
In some species such as dogs (but not rodents or monkeys), selinexor can cause increases in liver 
function tests and these should be followed carefully. Patients should minimize their use of  
acetaminophen on dosing days as these drugs can cause liver toxicity.  
 
8.2 
Ibrutinib Description/Availability 
 
Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase.  The compound is manufactured by 
Pharmacyclics, Inc (Sunnyvale, CA) using methods in accordance with Food and Drug 
Administration (FDA) guidelines for the manufacture and testing of antineoplastic agents for 
human use.   
 
8.2.1 Ibrutinib Composition and Preparation 
 
Ibrutinib for oral administration is supplied as either capsules or tablets.  The capsules are hard 
gelatin capsules containing micronized ibrutinib and the following excipients: microcrystalline 
cellulose; croscarmellose sodium; sodium lauryl sulfate; may contain magnesium stearate. 
Capsules are manufactured as 140mg in a size 0, gray, hard gelatin capsule. Capsules are 
packaged in high-density polyethylene (HDPE) bottles with an induction seal and a child 
resistant screw top cap. Each bottle contains 92 capsules. Ibrutinib capsules are to be dispensed 
in their original containers.  The tablet formulation is manufactured as 140, 280, or 420 mg and 
is dispensed as a blister pack. 
 
 
8.2.2 Ibrutinib Administration 
 
Ibrutinib should be taken with 8 ounces (approximately 240 mL) of water (avoid grapefruit or 
Seville orange juice due to CYP450 3A4 inhibition). Each dose of ibrutinib should be taken at 
least 30 minutes before eating or at least 2 hours after a meal, at approximately the same time 
each day. The capsules or tablets should be swallowed intact and subjects should not attempt to 
open capsules or dissolve them in water. 
 
If a dose is missed, it can be taken up to 6 hours after the scheduled time with a return to the 
normal schedule the following day. If it has been greater than 6 hours, the dose should not be 
taken and the subject should take the next dose at the scheduled time the next day. The missed 
dose will not be made up and must be reported at the next scheduled visit. 
 
Ibrutinib should be held for any procedure using the following guidelines:  
 
• For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
should be held at least 7 days prior to the intervention and should be held at least 7 days 
after the procedure and restarted at the discretion of the investigator when the surgical 
site is reasonably healed without serosanguineous drainage or the need for drainage 


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tubes.  
• For minor procedures (i.e. such as a central line placement, needle biopsy, thoracentesis, 
or paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and 
should not be restarted for at least 3 days after the procedure. For bone marrow biopsies 
that are performed while the subject is on ibrutinib, it is not necessary to hold ibrutinib 
for these procedures.  
• For emergency procedures, ibrutinib should be held after the procedure until the surgical 
site is reasonably healed, for at least 7 days after the urgent surgical procedure. 
 
Ibrutinib will be provided as standard of care through individual patient insurance authorization. 
 
Ibrutinib accountability records will be maintained at each participating institution and must be 
available for review when requested for auditing purposes and at time of study close out.  
 
All medication must be stored in a secure area under the proper storage requirements with access 
restricted to the site staff pharmacist or designee(s).  
 
8.2.3 Ibrutinib Safety Considerations 
 
Nausea/Vomiting 
 
Supportive care for nausea and vomiting should be given promptly. The treatment should start 
with the first sign of nausea. Standard anti-emetics are allowed and strongly recommended.  See 
Section 4.4 for detailed supportive care recommendations for emesis. 
 
Diarrhea 
 
Supportive care for diarrhea should be given promptly.  See Section 4.4 for detailed supportive 
care recommendations for diarrhea. 
 
Bleeding 
 
Life-threatening bleeding adverse events were recorded in patients who were concurrently taking 
ibrutinib and warfarin.  If a patient requires warfarin therapy, they are ineligible for this trial. 
 
Atrial fibrillation 
 
Ibrutinib has been noted to lower the heart rate and patients taking this drug have a slightly 
increased risk of atrial fibrillation.  ECG is required prior to initiation of ibrutinib. 
 
9. CORRELATIVE STUDIES 
 
9.1 
Ibrutinib Steady State Plasma Levels (Cohorts 1 and 2 only) 
9.1.1 Objective: To measure steady-state levels of ibrutinib for comparison with historical 
data to assess for significant drug-drug interactions with selinexor.   


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9.1.2 Collection of Specimen(s): Two plasma samples will be collected predose on Cycle 1, 
days 15 and 16. Each sample must be drawn prior to the ibrutinib dose that day. 
9.1.3 Handling of Specimens(s) Approximately 5 mL of blood will be collected in sodium 
heparin (green top) tubes, placed on ice and immediately centrifuged at 1,200 x g for 
10 minutes to isolate plasma. Plasma will be frozen in two separate vials and stored in 
a -70°C (or less) freezer. Each sample will be labeled with the protocol number, 
patient number, reference time point relative to the protocol, date and time the sample 
was obtained, and date and time the sample was placed in the -70°C freezer.  
9.1.4 Shipping of Specimen(s): 
Samples will be retained until a batch of samples is available for each subject. 
Samples will then be shipped in batches on dry ice via FedEx Monday through 
Thursday to: 
The OSU Pharmacoanalytical Shared Resource (PhASR) 
Attn: Jiang Wang, PhD 
441 Biomedical Research Tower 
460 West 12th Avenue 
Columbus, Ohio 43210 
Phone: (614) 688-0578 
Fax: (614) 292-7766 
Email: PhASR@osumc.edu 
8.2.5  Sites Performing Correlative Study: OSU PhASR 
 
9.2 
Pharmacodynamic (PD) properties of Selinexor  
9.2.1 Objectives:   
To evaluate the inhibition of the B-cell receptor signaling pathway in patients with 
relapsed or refractory CLL who receive the combination of selinexor and ibrutinib. 
To evaluate the change in localization of tumor suppressor proteins (such as P53, p73, 
Bcl-2, c-myc, Bcl-6, NFκB/IκB, FOXO3a and FOXO1) in patients with relapsed or 
refractory CLL following treatment with selinexor and ibrutinib. 


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9.2.2 Collection of Specimen(s): Markers of B-cell receptor signaling pathway activation 
(such as phosphorylation of BTK, Plcᵧ, AKT, and ERK) will be assessed via 
immunoblot.  Localization of tumor suppressor proteins will be assessed with 
confocal microscopy.  Expression of targets regulated by these proteins (NFκB, Mcl1, 
Tcl1, BTK, p21, BCLxL, cMyc) will be assessed by real time PCR and immunoblot. 
Four 8.5-mL ACD yellow top tubes and two 6-mL purple (EDTA) topped Vacutainer 
tubes of whole blood will be collected pretreatment and 4 hours post-treatment on 
Cycle 1 Day 1, pretreatment on Cycle 1 Day 2, Cycle 1 Day 8, and Cycle 2 Day1. For 
cohort 3, samples will be collected C1D1, C2D1, C6D1, and C14D1 
9.2.3 Handling of Specimens(s): Specimens should be stored at room temperature until sent 
to the laboratory for processing.   
9.2.4 Shipping of Specimen(s): Ship to: 
OSU CLL Experimental Therapeutics Laboratory 
410 W 12th Avenue 
4th Floor CCC Building 
Columbus, OH 43210 
Phone (614) 292-8824 
9.2.5 Site(s) Performing Correlative Study:  Ohio State University 
 
9.3 
Pharmacogenomics (PGx) (Cohorts 1 and 2 only) 
9.3.1 Collection of Specimen(s): A single whole blood sample will be collected in a 6 mL 
lavender top (K2EDTA) collection tube prior to treatment on day 1 of cycle 1. 
9.3.2 Handling of Specimens(s): The tube should be inverted 8-10 times then whole blood 
immediately separated into two equal volumes into cryo-storage tubes and 
immediately stored in a freezer maintained at or less than -70°C. DNA will later be 
extracted, and PGx analysis will be conducted using multiplexed or gene-specific 
methods to assess polymorphisms in drug metabolizing enzymes, transporters, target 
genes and/or genes relevant in the targeted BTK or XPO1 pathways. 
9.3.3 Shipping of Specimen(s):  
The OSU Pharmacoanalytical Shared Resource 
Attn: Ming Poi, PhD 
441 Biomedical Research Tower 
460 West 12th Avenue 
Columbus, Ohio 43210 
Phone: (614) 688-0578 
Fax: (614) 292-7766 
Email: PhASR@osumc.edu 
9.3.4 Site Performing Correlative Study: OSUCCC, Pharmacoanalytical Shared Resource 
 
9.4 
Primary and Secondary Resistance Studies 
9.4.1 To preliminarily assess potential causes for primary and secondary resistance to 
selinexor and ibrutinib. 
9.4.2 Collection of Specimen(s):  Buccal swab will be obtained at baseline for germline 
DNA and SNP filtering. Subjects relapsing during ibrutinib will be examined for 
baseline characteristics and will potentially be subjected to extensive molecular 


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59 
characterization to determine the reason for drug resistance. This could include 
genomic, transcriptome, proteomic, biochemical, plasma (including exosomes) or 
epigenetic studies of baseline and serial samples.  Additionally, as common mutations 
of ibrutinib resistance have been characterized by our group, we will monitor serially 
(Q 3m) from blood/plasma mRNA of C381S BTK and PLCγ2 and XPO1 by ion 
torrent analysis. Four 8.5 mL yellow ACD tubes and one 6-mL lavender EDTA tubes 
will be obtained every 3 months and transported to the OSU CLL Experimental 
therapeutics laboratory. Additionally, five 8.5-mL yellow ACD tubes and one 6-mL 
lavender EDTA tube at time of relapse should be drawn and transported to the OSU 
CLL Experimental Therapeutics laboratory.  Lymph node material in excess to that 
required for clinical diagnosis (pre-treatment or at relapse) may also be used for these 
studies.  This will be obtained from pathology and fresh tissue preferred. Excess 
material from samples may be used for additional studies related to mechanism action 
and toxicity of these two drugs or biology of CLL. These samples may be shared with 
other investigators working collaboratively with OSU. 
9.4.3 Handling of Specimens(s): Material should be transported or shipped to the OSU 
CLL Experimental Therapeutics Laboratory. 
9.4.4 Shipping of Specimen(s): Ship to: 
OSU CLL Experimental Therapeutics Laboratory 
410 W 12th Avenue 
4th Floor CCC Building 
Columbus, OH 43210 
Phone (614) 292-8824 
9.4.5 Site Performing Correlative Study: OSU CLL Experimental Therapeutics Laboratory 
 
 


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60 
10. STUDY CALENDAR 
Pre-study evaluations must be completed within 2 weeks of study registration, unless otherwise 
noted. Karyotype, FISH, bone marrow biopsy, peripheral blood immunophenotyping, and CT 
scans must be performed within 45 days of study registration. Informed consent must be 
obtained within the time frame specified by local policy.  IgVH mutational status does not need 
to be repeated if performed previously. It is acceptable for individual cycles to begin ≤ a 24-hour 
(business day) window before and after the protocol-defined date for Day 1 of a new cycle. For 
example, if the treatment due date is a Friday, the window for treatment includes the preceding 
Thursday through the following Monday. In addition, patients are permitted to have a new cycle 
of therapy delayed up to 7 days for major life events (e.g., serious illness in a family member, 
major holiday, vacation that cannot be rescheduled) without this being considered a protocol 
violation. New cycles of ibrutinib can be started up to 7 days before the protocol-defined date for 
major life events. Documentation to justify a delay or advance of a cycle should be provided.  
Additionally, all tests and observations associated with the beginning of a cycle may be 
performed up to 48 hours prior to beginning the cycle of therapy. 
 
Calendar for dose escalation and expansion cohorts 
General Study Calendar 
Cycle 
Pre- 
Study 
1 
2-3 
4-
6 
7+k 
Off 
Treatment 
Follow-
upl 
Day 
1 
8 
15 
22 
1 
15 
1 
1 
Eligibility checklist 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Historya 
X 
 
 
 
 
 
 
 
 
 
 
Progress noteb 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Ophthalmologic 
examc 
X 
 
 
 
 
 
 
 
 
X 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs/weight/ 
height/BSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOGd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC, dif, platelets 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistryf, Ca, Mg, 
Phos 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Liver function testsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LDH 
X 
X 
 
 
 
X 
 
 
 
 
 
Uric acid 
X 
X 
 
 
 
 
 
 
 
 
 
Peripheral blood 
immunophenotyping 
X 
 
 
 
 
Xm 
 
Xn 
Xo 
X 
Xl 
Quant 
immunoglobulins 
X 
 
 
 
 
 
 
 
 
 
 
SPEP with 
X 
 
 
 
 
 
 
 
 
 
 


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61 
immunofixation 
CLL karyotype, 
FISH panelh & 
IgVH mutational 
analysis 
Xi 
 
 
 
 
 
 
 
 
 
 
Pregnancy testj 
X 
 
 
 
 
 
 
 
 
 
 
HIV/Hep 
X 
 
 
 
 
 
 
 
 
 
 
Buccal swab 
X 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
Dispense KPT-330 
 
X 
 
 
 
X 
 
X 
X 
 
 
Adverse event 
evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
PET/CT or CT 
scans 
X 
 
 
 
 
Xm 
 
Xn 
Xo 
X 
Xh 
Bone marrow 
biopsy and aspirate 
Xp 
 
 
 
 
 
 
Xq 
Xq 
 
Xq 
Histologic review 
Xr 
 
 
 
 
 
 
 
 
 
 
Correlative studies 
See Correlative Study Calendar 
 
 
a. Initial medical history should include: baseline symptoms; a detailed history of prior 
cancer therapies including start and stop dates, disease progression during or after 
therapy, as well as discontinuations due to intolerability or any other serious illness; 
family and social history; calculation of Rai Stage (for CLL patients), MIPI (for MCL 
patients), or IPI (NHL patients other than MCL; see Appendix C). 
b. Progress notes should include: new symptoms or adverse events, ECOG performance 
status (Appendix A), documentation of physical exam, status of disease. 
c. Ophthalmologic exam: required at screening, if clinically indicated during study, and at 
final visit. Prior to dilation: best corrected visual acuity, visual field examination via 
automated perimetry, tonometry, and color vision test.  Dilated fundoscopy and slit lamp 
exam including anterior segment photos to document lens clarity. 
d. For ECOG performance status, see Appendix A 
e. Prothrombin time, international normalization ratio, and activated partial thromboplastin 
time 
f. Sodium, potassium, bicarbonate, BUN, calcium, chloride, creatinine 
g. Albumin, alkaline phosphatase, total bilirubin, total protein, SGOT [AST], SGPT [ALT] 
h. FISH panel will use probes to detect for abnormalities in chomosomes 13q, 12, 11q, and 
17p. 
i. For CLL patients only. 
j. Pregnancy tests for females of childbearing potential. A female of childbearing potential 
(FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea 
following cancer therapy does not rule out childbearing potential) for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive 
months). Female of childbearing potential must have a negative serum β-Hcg pregnancy 


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62 
test result within 3 days of first study dose. 
k. For cycles 7 and higher, patient will be required to return for evaluation and to receive 
KPT-330 every 3rd month (eg. Cycle 7 Day 1, Cycle 10 Day 1, Cycle 13 Day 1….) 
l. Reassessment off therapy will occur 4 weeks from the last dose of study therapy.  For 
patients removed from study for reasons other than disease progression, reassessment will 
then occur then every 6 months until progression or an alternative therapy is started. 
m. Cycle 2 Day 1 only. 
n. Cycle 4 Day 1 only. 
o. Restaging scans and immunophenotyping will be performed every 3 cycles for the first 
year and then every 6 months thereafter. 
p. Bilateral bone marrow biopsies are preferred for lymphoma patients. 
q. A bone marrow biopsy and aspirate should be performed to confirm a complete response 
if there was bone marrow involvement at diagnosis, clinical MRD flow should be 
performed in this case. 
r. For patients with DLBCL only: Paraffin block must be submitted for 
immunohistochemistry evaluation of CD10, bcl-6, and MUM-1 to determine ABC vs 
GCB subtype. Biopsy to confirm histologic review does not need to be repeated for pre-
study requirements, so long as previously obtained tissue confirms patient meets 
histologic eligibility criteria prior to study registration. 
 
 
 


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63 
Cohort 3 Study 


OSU Protocol #:14087 
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1 
Calendar 
Cycle 
Pre- 
Study 
Day 1, 
Cycles 1-3 
Day 1, Cycles 
6, 9, 12 
Cycle 14 Day 1 
Day 1, every 3 
cycles following 
cycle 14 
(continue 
ibrutinib) C17, 
20, 23, 26, etc. 
Day 1, every 
3 cycles 
following 
cycle 14 (off 
therapy)  
Follow-up 
(off 
therapy)j 
Eligibility checklist 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Historya 
X 
 
 
 
 
 
 
Progress noteb 
 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
Ophthalmologic 
examc 
X 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
 
X 
 
 
Vital signs/weight/ 
height/BSA 
X 
X 
X 
 
X 
X 
 
ECOGd 
X 
X 
X 
 
X 
X 
 
CBC, dif, platelets 
X 
X 
X 
 
X 
X 
 
Coagulatione 
X 
X 
X 
 
X 
 
 
Chemistryf, Ca, Mg, 
Phos 
X 
X 
X 
 
X 
X 
 
Liver function testsg 
X 
X 
X 
 
X 
 
 
LDH 
X 
 
 
 
 
 
 
Uric acid 
X 
 
 
 
 
 
 
Peripheral blood 
immunophenotyping 
X 
 
X 
 
 
X 
X 
Quant 
immunoglobulins 
X 
 
X 
 
 
 
 
SPEP with 
immunofixation 
 
 
 
 
 
 
 


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Date: 03 August 2021 
 
2 
CLL karyotype, 
FISH panelh & 
IgVH mutational 
analysish 
X 
 
 
 
 
 
 
Pregnancy testi 
X 
 
 
 
 
 
 
HIV/Hep 
X 
 
 
 
 
 
 
Buccal swab 
X 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
Adverse event 
evaluation 
X 
X 
 
 
X 
 
 
PET/CT or CT 
scans 
X 
 
 
 
 
Xk 
X 
Bone marrow 
biopsy and aspirate 
X 
 
 
X 
 
 
 
Correlative studies 
X 
X 
X 
X 
X 
X 
 
a. Initial medical history should include: baseline symptoms; a detailed history of prior cancer therapies including start and stop 
dates, disease progression during or after therapy, as well as discontinuations due to intolerability or any other serious illness; 
family and social history; calculation of Rai Stage (for CLL patients) 
b. Progress notes should include: new symptoms or adverse events, ECOG performance status (Appendix A), documentation of 
physical exam, status of disease. 
c. Ophthalmologic exam: required at screening and if clinically indicated during study. Prior to dilation: best corrected visual 
acuity, visual field examination via automated perimetry, tonometry, and color vision test.  Dilated fundoscopy and slit lamp 
exam including anterior segment photos to document lens clarity. 
d. For ECOG performance status, see Appendix A 
e. Prothrombin time, international normalization ratio, and activated partial thromboplastin time 
f. Sodium, potassium, bicarbonate, BUN, calcium, chloride, creatinine 
g. Albumin, alkaline phosphatase, total bilirubin, total protein, SGOT [AST], SGPT [ALT] 
h. Only if not done prior to initiation of ibrutinib 
i. Pregnancy tests for females of childbearing potential. A female of childbearing potential (FCBP) is a sexually mature female 
who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months). Female of childbearing potential must have a negative serum β-


OSU Protocol #:14087 
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Date: 03 August 2021 
 
3 
Hcg pregnancy test result within 3 days of first study dose. 
j. Reassessment off therapy will occur 4-6 weeks from the last dose of study therapy.  For patients removed from study for 
reasons other than disease progression, reassessment will then occur then every 6 months until progression or an alternative 
therapy is started. 
k. Restaging scans and immunophenotyping will be performed every 3 cycles for the first year and then every 6 months 
thereafter. 
Bilateral bone marrow biopsies are preferred for lymphoma patients. 
l. A bone marrow biopsy and aspirate should be performed to confirm a complete response if there was bone marrow 
involvement at diagnosis, clinical MRD flow should be performed in this case. 


4 
 
 
 
 
Cycle 
1 
2 
Q3 
Cy
cles 
Rela
pse 
Day 
1 
2 
8 
15 
16 
1 
1 
Time* 
Pr
e-
do
se1 
30
-
mi
n 
po
st 
do
se2 
1-
hr 
po
st 
do
se1 
2-
hr 
po
st 
do
se1 
4-
hr 
po
st 
do
se3 
8-
hr 
po
st 
do
se4 
24
-hr 
po
st 
do
se5 
Pr
e-
do
se1 
Pr
e-
do
se1 
30
-
mi
n 
po
st 
do
se2 
1-
hr 
po
st 
do
se1 
2-
hr 
po
st 
do
se1 
4-
hr 
po
st 
do
se3 
8-
hr 
po
st 
do
se4 
24
-hr 
po
st 
do
se5 
Pr
e-
do
se1 
 
Any 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ibruti
nib 
PK 
(Secti
on 
9.2) 
 
 
 
 
 
 
 
 
A 
 
 
 
 
 
A 
 
 
 
PD B-
cell 
Recep
tor 
Signal
ing 
Pathw
ay and 
tumor 
suppre
ssor 
localiz
ation 
(Secti
on 
9.3)$ 
B 
 
 
 
C 
 
C 
C 
 
 
 
 
 
 
 
C 
 
 
Pharm
aco-
geno
mics 
(PGx) 
(Secti
on 
9.5) 
D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resist
ance 
Studie
s 
(Secti
on 
9.6) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E 
F 


OSU Protocol #:14087 
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5 
 
A. For Ibrutinib PK plasma: Approximately 5 mL of blood will be collected in sodium 
heparin (green top) tubes, placed on ice and immediately centrifuged at 1,200 x g for 10 
minutes to isolate plasma. Plasma will be frozen in two separate vials and stored in a -
70°C (or less) freezer. Each sample will be labeled with the protocol number, patient 
number, reference time point relative to the protocol, date and time the sample was 
obtained. 
B. Correlative study samples (4 x 8.5-mL ACD yellow top tube, and 6-mL potassium EDTA 
[lavender-top vacutainer] from blood) should be drawn at baseline. 
C. Correlative study samples (2 x 8.5-mL ACD yellow top tube and 6-mL potassium EDTA) 
should be drawn on Cycle 1 Day 1; 4 hours post-treatment and Cycle 1 Day 8 and Cycle 
2 Day 1 pretreatment. Cohorts 1 and 2 only 
D. A PGx blood sample (1 x 6-mL EDTA lavender top) should be collected prior to dosing 
on Cycle 1 Day 1. Cohorts 1 and 2 only 
E. To monitor for resistance:  Four x 8.5 mL ACD yellow top tubes and 1 x 6-mL EDTA 
lavender tubes will be obtained every 3 cycles and transported or shipped to the OSU 
Experimental Therapeutics Laboratory.  This will start at cycle 4.  Lymph node material 
in excess to that required for clinical diagnosis (pre-treatment or at relapse) may also be 
used for these studies. Cohorts 1 and 2 only   
F. To evaluate resistant samples:  Five x 8.5-mL ACD yellow top tubes and 1 x 6-mL 
EDTA lavender top tube at time of relapse should be drawn and transported shipped to 
the OSU Experimental Therapeutics Laboratory.  Lymph node material in excess to that 
required for clinical diagnosis (pre-treatment or at relapse) may also be used for these 
studies. Cohorts 1 and 2 only    
 


0 
11. MEASUREMENT OF EFFECT 
 
11.1 
Response Criteria 
 
Response will be assessed by the International Working Group (IWG) Response Criteria for 
NHL patients42 and the International Workshop on CLL (IWCLL) criteria14 for CLL patients 
after 1  and 3 months of therapy, then every 3 months for 1 year, and then every 6 months 
thereafter until disease progression with no maximum treatment length.   
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with selinexor. 
 
Evaluable for response.  Only those patients who have received at least four weeks of 
therapy and have had their disease re-evaluated will be considered 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 4 weeks will also be considered evaluable.) 
 
11.1.2 Response Criteria for NHL 
 
Definition of Response for NHL Patients:  Criteria for response will utilize the IWG Response 
Criteria for NHL patients42. 
 
Complete Response (CR):  
Complete disappearance of all detectable clinical evidence of disease and disease related 
symptoms if present before therapy. 
• In patients with no pre-treatment PET scan, or if the PET scan was positive before 
therapy, a post-treatment residual mass of any size is permitted as long as it is PET- 
negative. 
• The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should 
be considered normal size by imaging studies, and nodules related to lymphoma should 
disappear.  However, determination of splenic involvement is not always reliable 
because a spleen considered normal in size may still contain lymphoma, whereas an 
enlarged spleen may reflect variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or causes other than lymphoma. 
• If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy.  The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core). If 
the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry. A sample that is negative by immunohistochemistry, but that 
demonstrates a small population of clonal lymphocytes by flow cytometry, will be 
considered a CR until data become available demonstrating a clear difference in patient 
outcome. 


OSU Protocol #:14087 
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1 
 
Partial Response (PR): 
• At least a 50% decrease in the sum of the product of the diameters (SPD) of up to six 
of the largest dominant nodes or nodal masses. These nodes or masses should be 
selected prior to initiation of therapy according to all of the following: a) they should 
be clearly measurable in at least two perpendicular dimensions; b) if possible, they 
should be from disparate regions of the body; and c) they should include mediastinal 
and retroperitoneal areas of disease whenever these sites are involved. 
• No increase should be observed in the size of other nodes, liver, or spleen. 
• Splenic and hepatic nodules must regress by ≤ 50% in their SPD, or, for single nodules, 
in the greatest transverse diameter. 
• With the exception of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present. 
• Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, if positive, the cell type should be specified (e.g., 
large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR by the 
above criteria, but who have persistent morphologic bone marrow involvement, will be 
considered partial responders. When the bone marrow was involved before therapy and 
a clinical CR was achieved, but with no bone marrow assessment after treatment, 
patients should be considered partial responders. 
• No new sites of disease should be observed. 
• If performed, the post-treatment PET should be positive in at least one previously 
involved site. 
 
Stable Disease (SD): 
Patient fails to attain the criteria needed for a CR or PR, but does not fulfill those for progressive 
disease (see below). If performed, the PET should be positive at prior sites of disease, with no new 
areas of involvement on the post-treatment CT or PET. 
 
Progression (PD) or Relapse: 
• Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless of 
the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be 
considered abnormal if its short axis is > 1.0. Lymph nodes ≤ 1.0 by ≤ 1.0 will not be 
considered as abnormal for relapse or progressive disease. 
• Appearance of any new lesion > 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size. Increased FDG uptake in a previously 
unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
• At least a 50% increase from nadir in the SPD of any previously involved nodes, or in 
a single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To 
be considered progressive disease, a lymph node with a diameter of the short axis of < 


OSU Protocol #:14087 
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Date: 03 August 2021 
 
2 
1.0 cm must increase by ≥ 50% and to a size of 1.5 x 1.5 cm, or > 1.5 cm in the long 
axis. 
• At least a 50% increase in the longest diameter of any single previously identified node 
> 1.0 cm in its short axis. 
Lesions should be PET-positive if a typical FDG-avid lymphoma or the lesion was 
PET- positive prior to therapy unless the lesion is too small to be detected with 
current PET systems (< 1.5 cm in its long axis by CT). 
 
11.1.3 Response Criteria for CLL Patients 
 
Definition of Response for CLL Patients:  Criteria for response will utilize the IWCLL 
Response criteria14. 
 
Complete response (CR): 
CR requires all of the following criteria as assessed at least 2 months after completion of therapy: 
• Peripheral blood lymphocytes (evaluated by blood and differential count) below 4 x 
109/L (4000/μL).  The presence of minimal residual disease (MRD) after therapy 
should be assessed.  The sensitivity of the method used to evaluate for MRD should 
be reported. 
• Absence of significant lymphadenopathy (e.g., lymph nodes >1.5 cm in diameter) by 
CT scan  of the abdomen, pelvis, and thorax. 
• No hepatomegaly or splenomegaly by physical examination. 
• Absence of constitutional symptoms.  
• Blood counts above the following values:  
o Neutrophils more than 1.5 x 109/L (1500/μL) without need for exogenous 
growth factors. 
o Platelets more than 100 x 109/L (100 000/μL). 
o Hemoglobin more than 110 g/L (11.0 g/dL) without red blood cell transfusion 
or need  for exogenous erythropoietin.  
• A marrow aspirate and biopsy should be performed at least 2 months after the last 
treatment  and if clinical and laboratory results as above demonstrate that a CR has 
been achieved.  
o To define a CR, the marrow sample must normocellular for age, with less than 
30% of nucleated cells being lymphocytes. Lymphoid nodules should be 
absent. If lymphoid nodules are present then these nodules should be recorded 
as nodular PR. However, immunohistochemistry should be performed to 
define whether these nodules are composed primarily of T cells or 
lymphocytes other than CLL cells or of CLL cells. If the marrow is 
hypocellular, a repeat determination should be performed after 4 weeks, or 
until peripheral blood counts have recovered. However, this time interval 
should not exceed 6 months after the last treatment. A marrow biopsy should 
be compared with that of pretreatment marrow.  The quality of the CR should 
be assessed for MRD by flow cytometry or by immunohistochemistry (IHC).  
 


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3 
CR with incomplete marrow recovery (CRi): 
All the criteria for a CR (including the marrow examination) have been met though there is 
persistent anemia or thrombocytopenia or neutropenia apparently unrelated to CLL but related to 
drug toxicity.   
 
Partial response (PR)  PR is defined as follows: 
• A decrease in the number of blood lymphocytes by 50% or more from the value 
before  therapy.  
• Reduction in lymph node size by 50% or more either in the sum products of up to 
6 lymph nodes, or in the largest diameter of the enlarged lymph node(s) detected 
prior to therapy.  
• No increase in any lymph node, and no new enlarged lymph node. In small lymph 
nodes (< 2 cm), an increase of less than 25% is not considered to be significant.  
• A reduction in the noted pretreatment enlargement of the spleen or liver by 50% 
or more, as detected by CT scan.  
• The blood count should show one of the following results:  
• Neutrophils more than 1.5 x 109/L (1500/μL) without need for exogenous growth 
 factors.  
• Platelet counts greater than 100 x 109/L (100 000/μL) or 50% improvement over 
baseline. 
• Hemoglobin greater than 110 g/L (11.0 g/dL) or 50% improvement over baseline 
without requiring red blood cell transfusions or exogenous erythropoietin. 
 
Progressive Disease: 
Characterized by at least one of the following: 
• Appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), 
splenomegaly, hepatomegaly, or other organ infiltrates.  
• An increase by 50% or more in greatest determined diameter of any previous site.  
• An increase in the previously noted enlargement of the liver or spleen by 50% or 
more or the de novo appearance of hepatomegaly or splenomegaly.  
• An increase in the number of blood lymphocytes by 50% or more with at least 
5000 B-lymphocytes per microliter.  
• Transformation to a more aggressive histology (e.g., Richter syndrome). 
Whenever possible, this diagnosis should be established by lymph node biopsy.  
• Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable 
to CLL.  During therapy, cytopenias cannot be used to define disease 
progression.  
• The progression of any cytopenia (unrelated to autoimmune cytopenia), as 
documented by a  decrease of Hb levels by more than 20 g/L (2 g/dL) or to less 
than 100 g/L (10 g/dL), or by a decrease of platelet counts by more than 50% or to 
less than 100 x 109/L (100 000/μL), which occurs at least 3 months after 
treatment, defines disease progression, if the marrow biopsy demonstrates an 
infiltrate of clonal CLL cells.  


OSU Protocol #:14087 
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Date: 03 August 2021 
 
4 
 
Stable Disease: 
Patients who do not fulfill the criteria for complete or partial response as defined above but do 
not exhibit progressive disease will be considered as having stable disease.  
 
11.1.4 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. 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive 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, including the baseline measurements.  
 
11.1.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 6.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Patient Protection 
 
The study will be conducted in accordance with the ethical principles of the Declaration of 
Helsinki and the ICH-GCP guidelines. The Principal Investigator is responsible for ensuring that 
the study will be conducted in accordance with the protocol, the ethical principles of the 
Declaration of Helsinki, current ICH guidelines on Good Clinical practice (GCP) and applicable 
local regulatory requirements. 
 
12.2 
Patient Information 
 
Before entry into the trial all eligible patients will receive written patient information describing 
the aim of the study, as well as probable and possible side effects and risks.  Oral information 
from one of the investigators or a delegated person at the institution will also be given, and the 
patient must have the opportunity to ask questions, and to consider participation together with 
his/her family members if applicable. It will be emphasized that the participation is voluntary 
and that it is the right of the patient to refuse further participation in the study whenever he/she 
wants and that this will not influence his/her subsequent care. 


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12.3 
Informed Consent 
 
Patient / legally acceptable representative (as applicable) written consent must be obtained 
according to local Institutional Review Board requirements and must conform to the ICH 
guidelines for Good Clinical Practice, prior to any study-specific screening procedures and trial 
entry. The written informed consent form should be signed and personally dated by the patient or 
by the patient’s legally acceptable representative. A copy of the signed informed consent will be 
given to the patient or patient’s legally authorized representative. The original signed consent 
must be maintained by the Investigator at each participating site and available for inspection by 
regulatory authority at any time. A copy of all external participating site consents must also be 
sent to the OSU Multi-Institution Program Coordinator to be filed in the OSU multi-institution 
regulatory files. 
 
12.4 
Data Submission 
 
The study will be managed per the Multi-Center Trial Program (MCTP) policies. Subsite data 
must be submitted to the MCTP as outlined in the protocol-specific monitoring plan, which will 
be provided to external participating sites. Data will be submitted using case report forms and the 
Data Submission Form cover sheet (refer to Supplemental Forms Document) supplied by the 
MCTP. All data submitted must be accompanied by supporting source documents, where 
applicable and as outlined in the protocol-specific monitoring plan. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
 
Cohorts 1 and 2 of this study represent a prospective, multi-center, phase I dose escalation study 
in two diseases: CLL and NHL.  Dose-finding will proceed using a modified continual 
reassessment method and targeting a probability of DLT<0.30. To ensure safety, the starting 
dose level will be the lowest dose level and dose escalation will proceed by increasing only one 
dose level at a time. Groups of 2-3 patients will be treated until convergence on an MTD, defined 
as 10-12 patients treated at a particular dose level which is also a subsequently suggested dose 
level by the model or a maximum of 36 evaluable patients, whichever occurs first. At the MTD, 
up to 10 CLL patients and 10 NHL patients will be accrued.     
 
13.2 
Sample Size/Accrual Rate 
 
For cohort 1 and 2, with groups of 2-3 patients per month enrolled in the dose finding study, it is 
expected that approximately 9 groups of patients will be treated over 18-30 months. Expansion at 
the MTD is expected to accrue over 6-12 months.  Thus, the total study duration is estimated to 
be 24-42 months. On average, we expect 32 patients to be enrolled, but the total sample size 
could be as many as 50 patients and will depend on the dose escalation and composition of CLL 
and NHL patients treated at the estimated MTD as part of the dose-finding portion of the study. 
 


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Cohort 3 will be a pilot study to gain data on the ability of selinexor to deepen responses with 
ibrutinib. Ten patients who have been treated with ibrutinib as their frontline therapy for 
CLL/SLL for at least 12 cycles and have obtained PR will be accrued to this cohort, and 
selinexor will be added to ibrutinib for 14 more cycles. The deepening of response rate is defined 
as the percentage of patients who convert to a MRD negative complete response (MRD- CR) 
from PR at the end of 14 cycles of selinexor plus ibrutinib among this cohort. If we observe 3 or 
more patients out of 10 who achieve the conversion from PR to MRD-CR, we will consider this 
regimen promising and move it forward for further study. For various true deepening of response 
rates, the table below shows the probability of observing at least 3 MRD-CRs in 10 patients. For 
example, if the true deepening response rate is 30%, then the probability of declaring the 
regimen promising is 61.7% with 10 patients.  
 
True Deepening of Response 
Rate 
Probability of Observing 3 or 
More MRD-CR in 10 Patients 
0.1 
0.070 
0.2 
0.322 
0.25 
0.474 
0.3 
0.617 
0.35 
0.738 
0.4 
0.833 
 
With an accrual rate of 2 patients per month, we expect accrual to be complete in 5 months. 
 
13.3 
Evaluability 
 
Any patient who is eligible for the trial and has received at least one dose each of the selexinor 
and ibrutinib will be evaluated for toxicity (descriptive summary as well as dose escalation 
determination in the first two cohorts) and for response.  Patients who are not evaluable for 
toxicity at a given dose level will be replaced.   
 
13.4 
Definition of Primary Endpoint 
 
The primary endpoint is DLT.  DLT has been defined in Section 4.2 above. 
 
13.5 
Definition of Secondary Endpoints 
  
13.5.1 Toxicity will be graded by CTCAEv4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
13.5.2 Clinical response and survival will be measured by: 
• International Working Group Criteria for NHL patients. 
• IWCLL 2008 Guidelines for CLL patients.  
Response criteria are detailed in Section 10. 


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Responders will be defined as those with complete response (CR) or partial response 
(PR).  Overall response rate (ORR) will be calculated as the number of evaluable 
responders divided by the total number of evaluable patients and will be analyzed by 
cohort. All patients who receive at least one dose of study medication will be included in 
the ORR and progression free survival. 
 
Progression Free Survival (PFS): PFS will be calculated from the date of study 
enrollment to disease progression or death, whichever occurs first.  Patients who do not 
progress or die will be censored at the time of last contact with response assessment by 
physical exam and laboratory studies.  
 
Overall Survival (OS): OS will be calculated from the date of study enrollment to death.  
Patients who do not die will be censored at the time of last contact. This will be analyzed 
in each cohort independently. 
 
13.5.3 Response as related to chronic lymphocytic leukemia (CLL) karyotype and IgVH 
mutational status.  Response criteria are detailed in Section 10. 
 
13.5.4 For Cohort 3, the rate of deepening of response is defined as the percentage of patients 
who attain a MRD negative complete response (MRD- CR) at the end of 14 cycles of 
selinexor plus ibrutinib. 
 
13.6 
Definition of Exploratory Endpoints 
 
13.6.1 Pharmacodynamic endpoints for patients with CLL include:   
• Markers of downmodulation or inhibition of the B-cell receptor pathway 
including BTK expression and phosphorylation of SYK, AKT, and ERK will be 
assessed pretreatment and post-treatment where feasible, and reported as a 
continuous measure. 
• Change in localization of tumor suppressor and oncogene proteins and mRNAs 
(P53, p73, Bcl-2, c-myc, Bcl-6, NFκB/IκB, FOXO3a and FOXO1) will be will be 
assessed pretreatment and post-treatment where feasibile. Change in localization 
will be measured through blood sample collection, analyzed by immunoblot, and 
reported as percentage of protein fragments observed in the nucleus at each time 
point. 
• Potential predictive biomarkers will be assessed before and after in vitro treatment 
of patients’ pretreatment leukocytes via qRT-PCR and results will be reported as 
fold change from baseline. 
 
13.7 
Analytic Plan for Primary Objective 
The primary objective is to identify the highest dose level of selinexor administered with 
ibrutinib that corresponds to an acceptable probability of DLT, defined as <0.30, in 
relapsed/refractory CLL and NHL patients. We do not expect that toxicity will be different 
between CLL and NHL, thereby justifying the use of both groups in dose escalation. Dosing 


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decisions will be made throughout the course of the trial based on a modified continual 
reassessment method (MRCM),43-45 combining information assumed a priori with observed data 
to update the estimate of the true dose-toxicity curve. A priori, it is assumed that the dose 
toxicity curve is monotonically increasing and belongs to the family of two-parameter logistic 
models, allowing the scale and slope to vary as described by Piantadosi et al.45 To implement the 
model, including input of prior assumptions, data collection, and estimation of the dose-toxicity 
curve, software developed by Piantadosi (Modified Continual Reassessment Method, version 
4.0) will be used. For model initiation, the a priori curve has been defined using three 
coordinates elicited from the clinical investigators to represent a “safe”, “moderately risky” and 
“risky” weekly dose level of selinexor when combined with the standard dose of ibrutinib in this 
patient population (Figure 2). The information represented in the a priori curve is equivalent to 
that of only 1.5 subjects, and hence, observed data accumulated throughout the trial is expected 
to outweigh any pseudo-data pre-specified when making dosing decisions. The target dose for 
each cohort will be identified by the software, but the starting dose and dose escalation will be 
constrained by design to ensure safety, as suggested in Garrett-Mayer’s 2006 tutorial, using the 
following rules: 1) the starting dose level will be the lowest dose level, 2) the dose level assigned 
for each successive cohort will be the highest dose level less than or equal to the target dose 
identified by the software provided there is not escalation by more than one dose level; 
otherwise, the target dose identified by the software will be disregarded and an increase in only 
one dose level at a time will be permitted, and 3) in the absence of DLT, decisions will be made 
following cohorts of 2 or 3 patients, cohort sizes that have been shown to balance accurate MTD 
information and safety.46 We will only escalate dosing when <33% of patients at a dose level 
experience DLT, and patients will not be assigned to an escalated dose level if there is a high 
probability that the DLT rate at that dose level is >30%.  It is planned that groups of 2 patients 
will be treated at lower dose levels of selinexor and groups of 3 patients will be treated beginning 
with dose level 3 in order to expedite the dose finding process. The trial will stop when the 
MCRM is deemed to have adequately converged on an MTD. Specifically, the trial will stop 
when 10-12 patients (depending on cohort size) are treated at a particular dose level which is also 
subsequently a suggested dose level by the model or a maximum of 36 evaluable patients have 
been treated, whichever occurs first (approximately 6-14 cohorts). At the time the trial 
terminates, the MTD will correspond to the highest dose level with probability of DLT<0.30. 
The MCRM process will be summarized, including number of DLTs observed in each cohort 
and the recommended dose at the end of each cohort. Using the parameter and covariance 
estimates from the model, and assuming parameters are from a bivariate normal distribution, 
repeated sampling will be used to construct an empirical distribution of the probability of DLT at 
the selected dose level to obtain 95% confidence intervals.  At the MTD, we will accrue up to 10 
CLL patients and 10 NHL patients in an expansion.  
 


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13.8 
Analytic Plan for Secondary Objectives 
 
13.8.1 Toxicity 
 
Toxicities will be tabulated by type and grade and displayed in summary form. In 
addition, the number of cycles started/completed, number of patients requiring dose 
reductions, and the reason for going off treatment may be summarized to assess treatment 
tolerability. 
 
13.8.2 Clinical Response an Survival 
 
The degree of response will be summarized within each disease group and at each dose 
level. ORR will be presented for those patients treated at the MTD with an exact 95 % 
confidence interval.  Also among patients who are treated at the MTD, PFS and OS will 
be described using Kaplan-Meier curves for each disease group. In cohort 3, the 
deepening of response rate will be calculated as percentage of patients who achieve 
MRD-CR, and will be provided with an exact 95% confidence interval. 
 
13.8.3 Correlative endpoints 
 
Formal statistical tests of hypotheses will not be performed given the nature of early 
clinical trials. Descriptive statistics such as mean, standard deviation, median, range, etc, 
for continuous variables and proportions for discrete variables will be used to summarize 
correlative endpoints in each of the defined strata. Graphical summaries will also be used 
extensively to visualize the data. 
 
Pharmacokinetic (PK) and pharmacodynamics (PD) properties of selinexor in patients 
with relapsed and refractory CLL and aggressive NHL will be assessed (See Section 
12.4-5). PK endpoints will be computed using non-compartmental and compartmental 
methods and summarized with descriptive statistics. 
 
For expression data collected serially over time (i.e. tumor suppressor proteins and 
phosphoproteins), changes in expression will be explored graphically using boxplots 
and/or individual line plots, as well as analytically with repeated measures models.  
 
Relationships between PK and PD endpoints with response will be largely exploratory, 
but may identify particular patterns of interest.  
 
 
Potential predictive Biomarker qRT-PCR fold change data will be correlated to patients’ 
clinical response once it becomes available. Predictive power of NGFR and other 
potential marker will be statistically tested when data of at least 100 patients will be 
collected from all clinical trials.  
 
 


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14. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of 
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26. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton's Tyrosine Kinase (BTK) Inhibitor, 
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39. Shacham S, Barnard S, Kisseberth W, et al. Results of a Phase I Dose Escalation Study of the 
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41. Razak ARA, Soerensen MM, Mahipal A, et al. First-in-class, first-in-human phase I trial of 
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43 O'Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase 1 
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44 Moller S. An extension of the continual reassessment methods using a preliminary up-and-
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APPENDIX A 
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 B 
INDUCERS AND INHIBITORS CYP3A4/5 
 
A strong inhibitor is one that causes a >5-fold increase in plasma AUC values or >80% decrease 
in clearance.  Strong inducers and inhibitors are in bold. 
 
CYP3A4/5 INDUCERS 
CYP3A4/5 INHIBITORS 
 
 
Efavirenz 
Cyclosporine 
Nevirapine 
Indinavir 
 
Miconazole 
Barbiturates 
Nelfinavir 
Carbamazepine 
Poscanazole 
Modafinil 
Ritonavir 
Oxcarbazepine 
Clarithromycin 
Phenobarbital 
Itraconazole 
Phenytoin 
Ketoconazole 
Pioglitazone 
Nefazodone 
Rifabutin 
Saquinavir 
Rifampin 
Telithromycin 
St. John's wort 
Voriconazole 
Troglitazone 
 
 
Aprepitant 
 
Atazanavir 
 
Clotrimazole 
 
Conivaptan 
 
Cimetidine 
 
Delavirdine 
 
Desipramine 
 
Diltiazem 
 
Efavirenz 
 
Erythromycin 
 
Fluconazole 
 
Fosaprepitant 
 
Grapefruit juice 
 
Haloperidol 
 
Isoniazid 
 
Metronidazole 
 
Nicardipine 
 
Norfloxin 
 
Quinidine 
 
Tetracycline 
 
 
 
 
 


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APPENDIX C  
STAGING SYSTEMS 
 
 
Rai Stage – CLL Patients Only*** (Rai, 1975) 
Stage 
Definition 
0 
Lymphocytosis 
I 
Lymphocytosis and lymphadenopathy 
II 
Lymphocytosis with splenomegaly or hepatomegaly 
III 
Lymphocytosis with anemia (hemoglobin < 11g/dL) 
IV 
Lymphocytosis with thrombocytopenia (platelets < 100,000/mm3) 
 
 
International Prognostic Index – NHL Patients (Except MCL) 
Patients will receive one point for each of the following 
characteristics: 
Age greater than 60 years 
Stage III or IV disease 
Elevated serum LDH 
ECOG performance status of 2, 3, or 4 
More than 1 extranodal site 
 
 
Mantle Cell Lymphoma International Prognostic Index – MCL Patients Only  
(Hoster, Blood 2008) 
Point(s) 
Age (years) 
ECOG PS 
LDH 
WBC (/mm3) 
0 
< 50 
0-1 
< 0.67 x ULN 
< 6,700 
1 
50-59 
 
0.67-0.99 x ULN 
6,700-9,999 
2 
60-69 
2-4 
1.00-1.49 x ULN 
10,000-14,999 
3 
≥ 70 
 
≥ 1.50 x ULN 
≥ 15,000 
LDH = lactate dehydrogenase, MCL = mantle cell lymphoma, PS = performance status, ULN 
= upper limit of normal, WBC = white blood cell 
 
 
 
 


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APPENDIX D KARYOPHARM SAE REPORT FORM 
 
 


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ICF_001.pdf: 
CONSENT 
Biomedical/Cancer 
OSU-14087 
IRB Protocol Number: 
2014C0180 
IRB Approval date:  07/01/2022 
Version 10:  11/23/2021 
Page 1 of 27 
The Ohio State University Combined Consent to Participate in 
Research and HIPAA Research Authorization 
Study Title: 
A Dose Escalation Study of Selinexor (KPT-330), a 
Selective Inhibitor of Nuclear Export, and Ibrutinib, a 
Bruton’s Tyrosine Kinase Inhibitor, in Patients with 
Relapsed and Refractory Chronic Lymphocytic Leukemia 
or Aggressive Non-Hodgkin Lymphoma 
Principal Investigator: 
Jennifer Woyach, M.D. 
IND Sponsor/Institution: 
The Ohio State University 
Selinexor Drug Provider: 
Karyopharm Therapeutics Inc. 
•
This is a consent form for research participation.  It contains important information
about this study and what to expect if you decide to participate.  Please consider the
information carefully. Feel free to discuss the study with your friends and family and to
ask questions before making your decision whether or not to participate.
•
Your participation is voluntary.  You may refuse to participate in this study.  If you
decide to take part in the study, you may leave the study at any time.  No matter what
decision you make, there will be no penalty to you and you will not lose any of your
usual benefits.  Your decision will not affect your future relationship with The Ohio
State University.  If you are a student or employee at Ohio State, your decision will not
affect your grades or employment status.
•
You may or may not benefit as a result of participating in this study.  Also, as
explained below, your participation may result in unintended or harmful effects for you
that may be minor or may be serious depending on the nature of the research.
•
You will be provided with any new information that develops during the study that
may affect your decision whether or not to continue to participate.  If you decide to
participate, you will be asked to sign this form and will receive a copy of the form.  You
are being asked to consider participating in this study for the reasons explained below.


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1.   Why is this study being done? 
This is a phase I study designed to test the safety of the combination of two cancer drugs, 
Ibrutinib plus Selinexor at different doses in subjects with the following types of cancer: 
 
• CLL (chronic lymphocytic leukemia)  
• SLL (small lymphocytic lymphoma)  
• PLL (prolymphocytic leukemia) or 
• Aggressive NHL (non-hodgkin lymphoma).   
 
You are being asked to participate in this study because you have been diagnosed with one of 
the cancers listed above. 
 
When ibrutinib and selinexor are combined in the lab and in animal studies, the two drugs 
appear to work better when given together.  Mice with cancer that no longer responds to 
treatment with ibrutinib respond to treatment with selinexor.   During this study researchers 
hope to discover what effects if any, the study drugs have on people when given at the same 
time and also to determine the dose and schedule of each drug to be administered.   
 
Outside of the goals described above, researchers are also interested in studying how these 
drugs affect CLL cancer cells specifically, and the immune system of CLL patients.  This will 
be studied using special laboratory tests on blood samples taken during the course of treatment.  
These research blood draws are described below.  
  
In this investigational study, researchers utilize drugs which have not been approved by the 
FDA, or have not been approved by the FDA for use in your type of cancer.  The FDA stands 
for Food and Drug Administration. The FDA is a federal governmental body within the U.S. 
Department of Health and Human Services. This office is charged with protecting the public 
health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, 
vaccines and other biological products, medical devices, most of our nation’s food supply, all 
cosmetics, dietary supplements, and products that give off radiation. 
 
Selinexor is an oral cancer drug which when taken, inhibits certain biological pathways in the 
body that allow for the spread of your type of cancer and also induce cancer cell death. This 
drug has not yet been approved by the FDA and is therefore considered an experimental drug. 
 
Ibrutinib is also a cancer drug which works similarly to Selinexor, but inhibits a different 
biological pathway to stop cancer cell growth.    Although Ibrutinib has been FDA approved to 
treat MCL or mantle cell lymphoma and CLL, its use in this study is considered experimental 
because it is being combined with Selinexor and it has not been FDA approved to treat NHL 
SLL or PLL  
 
For patients enrolled into cohort 3, who will already be taking ibrutinib prior to the study, the 
use of testing for minimal residual disease, and using minimal residual disease to guide therapy 
is investigational. 


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2.   How many people will take part in this study? 
Up to 48 patients will participate in this study at The Ohio State University and University of 
Utah. 
 
3.   What will happen if I take part in this study? 
While you are part of this study, the research staff will follow you closely to check whether 
you have any problems that need medical care.  By agreeing to take part in this study, you are 
agreeing to: 
• Finish all of the study requirements as listed below in the sections titled “Before you 
begin the study” and “During the study”.  
• Keep all of your appointments and follow all instructions given to you by the study 
doctor or staff.  
• Tell the study doctor about any new medications you begin taking after signing this 
consent form. This includes medicines you buy without a prescription, so called “over 
the counter” medicines.  
• Inform the study doctor of any problems or side effects you may experience while on 
the study.   
• Ask questions about anything you do not understand. 
• Tell the research staff if your telephone number or address changes. 
• Tell your regular doctor about your participation in this study. 
 
After signing this consent form, you must complete a pre-treatment evaluation.  During this 
evaluation, you will be required to complete multiple tests to determine whether or not you are 
eligible to participate in this study.   
 
A description of tests and visits required for the medical evaluation are listed below. 
 
Pre-treatment Evaluation 
To find out if you qualify for the study, you will undergo several tests and procedures, as well 
as a complete medical examination.   These exams, tests and procedures are part of regular 
cancer care and may be done even if you do not join the study.  If you have had some of them 
recently, they may not need to be repeated.  This will be up to your study doctor. 
 
• 
Review of your medical history, medications, and previous treatments 
• 
Assessment of your activity level (This is also called performance status) 
• 
You will be asked for a complete list of medicines you are taking, including 
supplements and vitamins. 
• 
Physical Examination (including vital signs, height and weight, blood pressure, heart 
rate, and temperature) 
• 
Information regarding prior HIV or hepatitis testing.  If you have been tested before 
the doctor will want to know these results. 


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• 
Routine Blood Tests: 
o Blood tests 
o Blood counts 
o Kidney and liver function tests 
o Hepatitis B and C 
o HIV 
o A blood test that can find cancer cells if they are currently in your 
blood 
o A blood test that checks for any abnormal markers that cancer cells 
might make   
o If you are a woman who could become pregnant (still has periods), you 
will have a pregnancy test. 
o If you have CLL, a blood test that will look at the genes of your cancer 
cells.   
• 
An ECG (electrocardiogram), a record of electrical activity of the heart. 
• 
A CT (computed tomography) or PET (positron emission tomography)-CT scans will 
be performed to measure the size of the cancer in your body.  
o A CT scan is a computerized x-ray that gives your doctor clearer pictures of 
the inside of your body. CT scans are routine procedures used to help doctors 
diagnose and follow the size and location of your cancer. 
o PET-CT is a new method that combines two scanning techniques in one test 
procedure. It is often used to diagnose cancer, measure cancer progression, and 
evaluate the response to treatment. During the PET procedure, you will be 
injected with a small amount of radioactive glucose. This substance is easily 
eliminated from the body either through radioactive decomposition or via the 
urine. A PET scan may cause you to feel “closed in” while lying in the 
scanner. However, the scanner is open at both ends and an intercom allows you 
to talk with doctors and staff. If you feel ill or anxious during scanning, doctors 
and/or technicians will give comfort or the scanning will be stopped. The PET-
CT scan exposes your body to radiation. The radioactive solution does not 
remain in your system for a long period of time. However, you should wait 2 
hours before holding an infant or getting close to a pregnant woman to avoid 
exposing them to radiation. You should drink fluids after the scan to help 
remove the solution from your system. 
• 
Bone Marrow Biopsy and Aspirate (an extra amount of bone marrow, about 1 
teaspoon, will be collected for research). 
o This is a test done in the clinic.  You do not have to stay in the hospital for this 
test.  You will lay on your stomach or side.  A small needle will be used to 
numb the back side of your hip bone with a medication called lidocaine.  
Another needle will be placed into your hip bone and fluid inside the bone will 
be taken out.  Then, another needle will be placed into the same spot in your 
hip bone and a small piece of the bone will be taken out. 


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• 
Research Buccal Swab (a swab will be taken of the inside of your cheek to look at the 
genes of your normal cells) 
• 
Ophthalmologic exam or eye exam to examine your vision and clarity of vision 
 
During the Study 
If you are found to be eligible you may begin the study.  Before treatment, you will start 
medications that will help you with some of the side effects that are possible.  These medications 
treat nausea and loss of appetite or energy. 
 
Cohort 1 and 2 
One cycle of treatment lasts 28 days or about one month.  You will start the selinexor first, 
which is a pill that you will take by mouth one day per week. Selinexor should be taken with at 
least 120ml (about 4 ounces) of fluid such as water or juice. The first day of treatment (Cycle 
1, Day 1), you will have blood drawn before you take the selinexor, and 30 minutes, 1 hour, 2 
hours, 4 hours, and 8 hours after you take the first dose.  You will need to come back the next 
day (Cycle 1, Day 2) to see how you are doing and for another lab test. 
 
After one week of treatment (Cycle 1, Day 8), you will start the ibrutinib, which is a pill that 
you will take every day. Patients who are on ibrutinib at study entry are not required to 
discontinue ibrutinib for any period of time. Patients continuing on ibrutinib should take 
ibrutinib days 1-28  starting of Cycle 1.  You will also have an examination and blood drawn at 
this visit. 
 
For the third week of treatment, you will return on the first day of the week (Cycle 1, Day 15), 
for an examination. You will have blood drawn before you take the selinexor, and 30 minutes, 
1 hour, 2 hours, 4 hours, and 8 hours after you take the first dose.  You will need to come back 
the next day (Cycle 1, Day 16) to see how you are doing and for another lab test.  
 
For the fourth week of treatment, you will return on the first day of the week (Cycle 1, Day 22), 
for an examination and blood draw. 
 
During the second and third cycles, you will need to come back every other week on Days 1 
and 15 of both cycles to have an examination to see how you are doing and to have your blood 
drawn. 
 
During the fourth through the sixth cycles, you will need to come back once a month on Day 1 
of all cycles to have an examination to see how you are doing and to have your blood drawn. 
 
From the seventh cycle on, you will need to come back every three months on Day 1 of those 
cycles to have an examination to see how you are doing and to have your blood drawn. 
 
Number of Required Visits and Timing of the Visits 
Cycle* 
1 
2-3 
4-6 
7± 
Day 
1 
2 
8 
15 
16 
1 
15 
1 
1 


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Total Visit # for Each Cycle 
6 
2 
1 
1± 
* One cycle = 28 days; ±One visit every 3 months. 
 
At each visit or the indicated visit, you will have the following tests: 
 
Exam/Test 
Time 
Physical Exam 
Before each treatment 
Assessment for Side Effects to 
Treatment 
At any time during treatment 
Routine Blood Tests* 
Before each treatment 
Research Blood Tests* 
Before each treatment 
CT scan or PET Scan 
Cycle 2, Day 1; Cycle 4, Day 1; Cycle 7, Day 1± 
Bone Marrow Biopsy 
This test will only be done if all cancer cells have been 
cleared from your blood. 
*Amount of blood taken will range from 1-9 teaspoons at each test 
±Starting with Cycle 7, CT/PET scans will be done every 3 months for one year and then 
every 6 months after this time. 
 
Cohort 3 
One cycle of treatment lasts 28 days or about one month.  You will start the selinexor first, 
which is a pill that you will take by mouth one day per week. Selinexor should be taken with at 
least 120ml (about 4 ounces) of fluid such as water or juice. The first day of treatment (Cycle 
1, Day 1), you will have an examination to see how you are doing and have blood drawn.  
 
After one week of treatment (Cycle 1, Day 8), you will start the ibrutinib, which is a pill that 
you will take every day. Patients who are on ibrutinib at study entry are not required to 
discontinue ibrutinib for any period of time. Patients continuing on ibrutinib should take 
ibrutinib days 1-28  starting of Cycle 1.   
 
During the second and third cycles, you will return on Day 1 of each cycle for an examination 
to see how you are doing and to have your blood drawn.  
 
You will not have any study visits during the fourth and fifth cycles.  
 
During the sixth through twelve cycles, you will return once every three cycles (Day 1 of Cycle 
6, Cycle 9, and Cycle 12) for an examination to see how you are doing and to have your blood 
drawn. 
 
You will not have any study visits during the thirteenth cycle.  
 
From the fourteenth cycle on, you will need to come back on Day 1 every three cycles for an 
examination to see how you are doing and to have your blood drawn. At the fourteenth cycle 
only, you will have a bone marrow biopsy and aspirate performed. 
 
Number of Required Visits and Timing of the Visits 


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Cycle* 
1 
2-3 
6-12 
14+ 
Day 
1 
15 
1 
1 
1 
Total Visit # for Each Cycle 
2 
1 
1± 
1± 
* One cycle = 28 days; ±One visit every 3 months. 
 
 
 
At each visit or the indicated visit, you will have the following tests: 
 
Exam/Test 
Time 
Physical Exam 
Before each treatment 
Assessment for Side Effects to 
Treatment 
At any time during treatment 
Routine Blood Tests* 
Before each treatment 
Research Blood Tests* 
Before each treatment 
CT scan or PET Scan 
Cycle 14, Day 1± 
Bone Marrow Biopsy 
Cycle 14, Day 1 
*Amount of blood taken will range from 1-9 teaspoons at each test 
±Starting with Cycle 14, CT/PET scans will be done every 3 months 
 
 
At the End of Treatment 
You may stop treatment with the study drug for several reasons:   
• because your cancer is not responding to this treatment 
• because the treatment has caused too many side effects 
• or because you choose to stop treatment.  
 
No matter the reason for stopping treatment, you will continue to be followed.  Within 30 days 
(4 weeks) of completing treatment, or the start of a new anticancer therapy, your doctor will 
repeat a medical history and perform a physical examination, including measurements of your 
lymph nodes, liver, and spleen.  You will also have routine laboratory tests that are part of the 
regular care for patients with your cancer.  An ophthalmologic exam or eye exam will be 
performed to examine your vision and clarity of vision.  Bone marrow biopsy and aspirate 
samples will be repeated at this time, for patients who relapse or for patients who have a 
complete response.  Approximately 40 ml (10 teaspoons) of blood will be collected for research 
purposes from patients that relapse or have a complete response.  Residual nodal material may 
also be collected at this time for patients who have a complete response or relapse.  Additional 
blood tests, x-rays, and procedures may be requested if your doctor feels they are medically 
necessary. 
 
4.   How long will I be in the study? 
 
Response Follow Up: 
You will be required to have a clinic visit to be seen by the study staff at least once every six 
months until your disease progresses, an alternative therapy is started, death or the study closes. 


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You can remain on the study unless your cancer worsens, you have side effects that you cannot 
accept, you develop another medical problem that prevents you from taking the treatment, or 
you no longer want to participate. 
 
If you stop the study because of a side effect to the treatment, you will be seen by your regular 
doctor until the side effect goes away. 
 
5. Can I stop being in the study? 
You may leave the study at any time.  If you decide to stop participating in the study, there will 
be no penalty to you, and you will not lose any benefits to which you are otherwise entitled.  It 
is important to tell your doctor if you are thinking about stopping or decide to stop so any risks 
from the treatment can be evaluated and your doctor can inform you what follow-up care and 
testing could be most helpful for you.  Your decision will not affect your future relationship 
with The Ohio State University.  
 
6.   What risks, side effects or discomforts can I expect from being in the study? 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
• You may be asked sensitive or private questions about subjects which you normally do 
not discuss 
• There is a risk someone could get access to the personal information in your medical 
records or other information researchers have kept about you.  Someone might be able 
to trace this information back to you.  The researchers believe the chance that someone 
will identify you is very small but the risk may change in the future as people come up 
with new ways of tracing information.  In some cases, this information could be used 
to make it harder for you to get or keep a job.  A federal law, called the Genetic 
Information Nondiscrimination Act (GINA), generally makes it illegal for health 
insurance companies, group health plans, and most employers to discriminate against 
you based on your genetic information. This law generally will protect you in the 
following ways:  
• 
Health insurance companies and group health plans may not request your 
genetic information from this research.  
• 
Health insurance companies and group health plans may not use your genetic 
information when making decisions about your eligibility or premiums.  
• 
Employers with 15 or more employees may not use your genetic information 
from this research when making a decision to hire, promote, or fire you or 
when setting the terms of your employment.  
All health insurance companies and group health plans must follow this federal law. 
This law does not protect you against genetic discrimination by companies that sell 
life insurance, disability insurance, or long-term care insurance. Under Ohio law, 
health insurance companies cannot ask about the results of a genetic test or use any 
information obtained from genetic testing to make decisions about providing coverage 


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or benefits for health care services. The researchers believe the chance these things 
will happen is very small, but cannot promise that they will not occur.   
• There can also be a risk in finding out new genetic information about you.  New health 
information about inherited traits that might affect your or your blood relatives could 
be found during a study.  Results obtained from genetic testing will generally not be 
disclosed to the patient or the treating physician. 
 
The drugs used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never 
go away. 
• It is possible that side effects of the combination of selinexor and ibrutinib may 
interfere with ability to receive standard ibrutinib therapy. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
 
The information below shows the most common and the most serious side effects that 
researchers know about. There might be other side effects that researchers do not yet know 
about. If important new side effects are found, the study doctor will discuss these with you 
 
 
Selinexor 
 
You may experience certain unwanted effects and symptoms as a result of treatment with 
Selinexor.  
Side effects of Selinexor (KPT-330): 
Very common side effects (≥10% of patients): 
In 100 people receiving selinexor more than 10 people may have: 
 
• Nausea 


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• Vomiting 
• Diarrhea 
• Weight loss 
• Constipation 
• Fatigue and asthenia – loss of energy; weakness 
• Decreased appetite 
• Dehydration 
• Abdominal pain 
• Dysgeusia – change in taste 
• Shortness of breath 
• Cough 
• Dizziness 
• Fever 
• Blurred vision 
• Headache 
• Difficulty falling asleep 
• Low platelets in the blood (thrombocytopenia), which may increase the risk of 
bleeding 
• Decrease in red blood cells (anemia) causing fatigue  
• Decrease in white blood cells (leukopenia), which may increase the risk of 
infection  
• Decrease in neutrophils (a type of white blood cell that helps fight infections)  
• Pneumonia  
• Low blood sodium which may increase the risk of seizures  
• Low potassium which may cause weakness, muscle cramps and spasms  
• Peripheral edema – swelling in extremities due to accumulation of fluid, usually in 
legs 
• High blood sugar which may cause fatigue, increased thirst/hunger, frequent 
urination, weight loss, numbness and tingling in hands/feet 
 
Common side effects (≥1-10% of patients) 
In 100 people receiving selinexor about 1 to 10 people may have: 
 
• Rash 
• Eye disorders including cataract (new or worsened), dry eye, visual impairment, 
seeing flashes of light 
• Night sweats 
• Dry mouth 
• Stomatitis – a condition that causes painful swelling and sores inside the mouth 
• Dyspepsia – indigestion 
• Chills 
• Hypotension – low blood pressure 
• Hypertension 


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• Tachycardia – fast heart rate 
• Nosebleed 
• Contusion (bruise due to body injuries such as fall) 
• Electrolyte disturbances including: 
o low phosphate which may cause muscle weakness and fatigue 
o low magnesium which may cause muscle twitches and cramps 
o low calcium which may cause numbness and tingling in hands/feet/face, 
muscle stiffness and cramps 
o high potassium which may cause muscle weakness, palpitations or 
irregular heartbeats and chest pain 
• Low albumin (which may cause swelling especially of the hands/feet, weakness or 
exhaustion) 
• Peripheral neuropathy – weakness, numbness, and pain from nerve damage, 
usually in the hands and feet 
• Decrease in lymphocytes – a specific type of white blood cell that are part of your 
immune system 
• Increase of creatinine in the blood due to a reduction in kidney function, often 
related to dehydration 
• Elevated liver enzymes including alanine aminotransferase increased, aspartate 
aminotransferase increased, blood alkaline phosphatase increased 
• Elevated pancreatic enzymes including high amylase and high lipase 
• muscle weakness 
• Febrile neutropenia - fever in the absence of a normal white blood cell response 
that may mean you have an infection 
• Respiratory tract infection (including upper) 
• Urinary tract infection 
• Sepsis (including septic shock) – potentially life-threatening complication of an 
infection 
• Pain in joints and muscles 
• Malaise (a general feeling of being ill or bodily weakness) 
• Muscle spasms 
• Gait disturbance 
• Hair loss 
• Itching 
• Depression 
• Syncope – fainting 
• Cognitive disorder 
• Mental status changes including confusion 
 
Uncommon side effects (>0.1-1% of patients) 
In 1,000 people receiving selinexor about 1 to 10 people may have: 
 


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• Tumor lysis syndrome – potentially a life-threatening side effect caused by the 
rapid breakdown of tumor cells and may cause irregular heartbeat, kidney failure 
or abnormal blood test results which included elevated uric acid level, elevated 
serum potassium and phosphorus levels, and a decreased calcium level. 
• Enterocolitis infectious (inflammation of digestive tract caused by infection) 
• Gastroenteritis (stomach flu) 
• Rhinovirus infection (common cold; infection of nose, ear, sinuses; very rarely 
leading to pneumonia or bronchitis) 
 
Rare side effects (>0.01-0.1% of patients) 
In 10,000 people receiving selinexor about 1 to 10 people may have: 
 
• Acute cerebellar syndrome – symptoms can include a sudden loss of coordination, 
balance, or slurred speech  
 
 
Serious adverse effects (≥3 cases reported as related by the principal investigator): 
• Cardiac failure 
• General physical health deterioration 
• Multiple organ dysfunction syndrome 
• Lung infection 
• Bacteremia – bacterial infection in the blood 
• Bronchitis – infection of tubes that carry air to and from lungs 
• Decreased ejection fraction – reduction in amount of blood pumped out of heart 
• Encephalopathy – brain disease, damage, or malfunction, which can present different 
symptoms that range from mild, such as some memory loss or subtle personality 
changes, to severe, such as dementia, seizures, or coma 
• Delirium – state of acute confusion 
• Acute kidney injury 
• Pulmonary embolism – pulmonary embolism occurs when a clump of material, most 
often a blood clot, gets wedged into an artery in your lungs. 
• Hypoxia – an absence of oxygen supply at tissue level 
 
Avoid acetaminophen-containing medications such as Tylenol, Vicodin, Lortab, or Norco 
within 2 hours before and 2 hours after you take Selinexor. Acetaminophen may interfere with 
the breakdown of Selinexor in the body.  Use of acetaminophen and acetaminophen-
containing drugs, particularly on days of Selinexor therapy, should be minimized.  If you need 
it for pain control, your doctor can provide you with alternative agents on selinexor dosing 
days. 
 
Ibrutinib 
You may develop side effects while participating in this study. You should tell the study doctor 
about any side effects that you develop.  


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The side effects listed below have been reported by patients who have received ibrutinib in 
clinical trials and from post-marketing sources.  
 
The most common side effects, occurring in at least 1 of every 5 patients (≥ 20%), have been:  
 
• Occurrence or increase in frequency of loose or watery stools (Diarrhea)  
• Muscle and bone pain (Musculoskeletal pain) 
• Nausea 
• Low white blood cell count (cells that help fight infection) (Neutropenia) 
• Low platelet count (cells that help blood to clot) (Thrombocytopenia) 
• Rash 
• Fever (Pyrexia)  
• Common cold (upper Respiratory Tract Infection) 
 
Side effects that have been seen in at least 1 of every 10 (≥ 10%) patients include:  
 
• Pneumonia 
• Constipation 
• Swelling of the hands or feet (Oedema peripheral)  
• Muscle spasms  
• Vomiting 
• Joint aches (Arthralgia) 
• Sores in mouth (Stomatitis) 
• Headache 
• High Blood pressure (Hypertension) 
• Skin infection 
• Weakness, tingling, numbness, and pain from nerve damage, usually in the hands and 
feet (Peripheral neuropathy) 
• Dizziness 
• Urinary tract infection 
 
Side effects that have been seen in at least 1 of every 100 (≥ 1%) patients include:  
 
• Sinus infection (Sinusitis) 
• Increased level of uric acid in the blood (Hyperuricemia) 
• Abnormal heart rhythm (Atrial fibrillation) 
• Non-melanoma skin cancer 
• Blurry vision (Vision blurred)  
• Low white blood cell counts with fever (Febrile neutropenia) 
• Severe infection throughout the body (Sepsis) 
• Redness of the skin (Erythema) 
• Increase in specific white blood cell counts (Leukocytosis, Leukocytosis) 


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• Breaking of the nails (Onychoclasis)  
• Inflammation within the lungs that may lead to permanent damage (Interstitial lung 
disease)Increased level of “creatinine” in the blood (blood creatinine increased) 
 
Side effects that have been seen in less than 1 of every 100 (<1%) patients include: 
 
• Unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells, 
which may lead to changes in kidney function, abnormal heartbeat, or seizures. (Tumor 
lysis syndrome) 
• Itchy rash (Urticaria)  
• Inflammation of the fatty tissue underneath the skin (Panniculitis) 
• Swollen face, lip, mouth, tongue or throat (Angioedema)  
• High WBC count with abnormal clumping that can lead to bleeding (Leukostasis 
syndrome) 
• Severe rash with blisters and peeling skin, particularly around the mouth, nose, eyes and 
genitals (Stevens-Johnson syndrome)  
• Liver failure (Hepatic failure) 
• Abnormal rapid and/or irregular heart rhythm that starts from the lower chambers 
(ventricles) of the heart (Ventricular tachyarrhythmia).  
• Temporary or permanent decrease of brain or nerve function due to reduced blood flow 
to the brain (mini-stroke or stroke) 
  
Most of these side effects listed above have been mild to moderate in severity; however severe 
side effects have occurred. Some side effects have been severe enough to lead to study drug 
discontinuation, dose modification or reduction, hospitalization, disability, and sometimes 
death.  
 
You should tell your study doctor or medical team about any side effects you are having. Your 
study doctor may be able to give you medications to help treat the side effects and prevent them 
from becoming worse. Your study doctor may also choose to stop ibrutinib for a short time or 
reduce its dose to allow you to recover from any side effects.  
  
Bleeding 
 
You may experience bruising or nosebleeds during treatment with ibrutinib. Rarely, serious 
internal bleeding, such as bleeding in your stomach, intestine, or brain may occur, sometimes 
resulting in death. If you take other medicines or supplements that increase your risk of 
bleeding, such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) or medicines used 
to prevent or treat blood clots or stroke, ibrutinib may increase this risk. Blood thinners such as 
warfarin or other vitamin K antagonists should not be taken together with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided while taking 
ibrutinib. Call your study doctor if you have signs or symptoms of serious bleeding, such as 
blood in your stools or urine or bleeding that lasts for a long time or that you cannot control. 
 


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Effects on the heart 
 
Abnormal rapid and/or irregular heart rhythm (atrial fibrillation, atrial flutter, and/or ventricular 
tachyarrhythmia with some fatal events) have been reported in patients treated with ibrutinib, 
especially when they also have heart conditions, increased blood pressure, infections, or had 
abnormal heartbeat in the past. The heartbeat may be fast or irregular causing symptoms such 
as a pounding or racing heart, dizziness, weakness, feeling light-headed, shortness of breath, 
chest discomfort or fainting. If you develop any of these symptoms while on the study drug, 
you should tell your study doctor immediately.  
 
Infections 
 
You may experience viral, bacterial, or fungal infections during treatment with ibrutinib. Some 
of these infections have led to hospitalization and death. Contact your study doctor immediately 
if you have fever, chills, weakness, confusion, body aches, cold or flu symptoms, vomiting, 
jaundice, feel tired or feel short of breath - these could be signs of an infection. Your study 
doctor may start or continue medication to help prevent or treat an infection. 
 
A rare and usually fatal viral disease in the brain, Progressive Multifocal Leukoencephalopathy 
(PML), has been reported in patients treated with ibrutinib in combination with rituximab and 
in patients who were previously treated with rituximab. If you experience symptoms such as 
weakness, paralysis, vision loss and/or impaired speech, you should tell your study doctor 
immediately. 
 
Lymphocytosis and leukostasis 
 
You may experience an increase in the number of lymphocytes, which is a specific type of 
white blood cell, in your blood (lymphocytosis). This may occur in the first few weeks of 
treatment and you should not assume that this increase in white blood cells means that your 
disease is worsening. This increase may last for several weeks to months.  
 
In rare cases, increased number of white blood cells in your bloodstream may change the blood 
flow, resulting in bleeding or clotting (leukostasis). Isolated cases of these events have been 
reported in patients treated with ibrutinib. Your study doctor will monitor your blood counts 
and may administer additional therapy as needed. Talk to your study doctor about what your 
test results mean.  
 
Decreased blood counts  
 
Severe decreases in white blood cells, red blood cells, and platelets (neutropenia, anemia, and 
thrombocytopenia) were reported in subjects treated with ibrutinib. If you experience symptoms 
such as fever, weakness, or easy bruising and/or bleeding, you should tell your study doctor 
immediately. 
 
Allergic reactions  


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Sometimes people have allergic reactions to drugs. Serious allergic reactions can be 
life-threatening. If you have an allergic reaction to ibrutinib, you might develop a rash, 
difficulty breathing, wheezing when you breathe, sudden low blood pressure with light-
headedness, swelling around the mouth, throat or eyes, a racing heartbeat, and/or sweating.  
 
Before starting the study drug, you must tell your study doctor about any drug allergies. You 
should tell the study doctor right away if you have any allergy symptoms listed above.  
 
Rash 
 
A maculopapular rash (flat, red areas on the skin with small bumps) has been commonly 
reported in patients treated with ibrutinib alone or in combination with other drugs. Most rashes 
are mild to moderate in severity and begin 2 to 3 weeks or longer after starting ibrutinib.  
 
There have been rare reports of severe skin reactions (known as severe cutaneous adverse 
reaction or “SCAR”, involving more than 50% of the body) or rash with blisters and peeling 
skin, which may include open ulcers or sores in the mouth and other areas of the body (Stevens-
Johnson syndrome). These skin rashes could be life-threatening. You should notify your study 
doctor immediately if you develop a rash that spreads quickly, or if you notice peeling of your 
skin, with or without ulcers or sores in your mouth. 
 
Non-Melanoma Skin Cancer and Other Cancers 
 
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma of the skin) 
have been reported with more frequency and may be related to the use of ibrutinib. Other 
cancers have been reported such as solid tumors and blood cancers, the relationship to the use 
of ibrutinib is unknown. You should tell your study doctor if you develop a new cancer while 
in the study.  
 
Tumor Lysis Syndrome (TLS) 
 
Unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells have 
happened during treatment of cancer and sometimes even without treatment. This may lead to 
changes in kidney function, abnormal heartbeat, or seizures. Your study doctor may do blood 
tests to check for TLS. 
 
Hypertension 
Hypertension is also called high blood pressure, and has been commonly reported in subjects 
treated with ibrutinib. Sometimes, people with high blood pressure may have headaches, 
dizziness, nervousness, sweating, difficulty in sleeping, facial flushing or nosebleeds, but in 
some cases, there may be no symptoms and it may go undetected. After starting ibrutinib, your 
doctor may measure your blood pressure regularly. You should let your study doctor know if 
you have any of the symptoms of high blood pressure which may mean that you have developed 


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hypertension or that your hypertension is getting worse. Your study doctor may adjust existing 
anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate. 
Stroke 
 
Cases of stroke, with and without changes in heartbeat rhythm and/or hypertension have been 
reported with the use of ibrutinib.  Some of these cases have led to death. Seek immediate 
medical attention if you notice or someone notices in you: sudden numbness or weakness in the 
limbs (especially on one side of the body), sudden confusion, trouble speaking or understanding 
speech, sight loss, difficulty walking, loss of balance or lack of coordination, sudden severe 
headache with no known cause. These may be signs and symptoms of stroke. 
 
Liver Failure 
 
Rare cases of liver failure have been reported in patients treated with ibrutinib. Symptoms of 
liver failure include yellowing of the eyes and skin (jaundice), itching of the skin, dark colored 
urine, gray or clay-colored stools, confusion, nausea, loss of appetite, and fatigue or diarrhea. 
You should tell your study doctor immediately if you have any of these symptoms which may 
suggest liver disease. Your study doctor may be able to diagnose and provide you required 
medical care. 
Interstitial lung disease  
 
Interstitial lung disease is a group of lung disorders in which the tissues become inflamed and 
may become damaged. Interstitial lung disease is not associated with infections (e.g., bacteria, 
viruses, fungi) and has been reported in patients treated with ibrutinib. You should report to 
your physician if you have cough, any signs of new or worsening respiratory symptoms such 
as shortness of breath or difficulty breathing.  
 
Interference with other drugs  
 
Some foods like grapefruit juice and Seville oranges, as well as some medications, may interfere 
with the way your body processes ibrutinib. This interference could cause the amount of 
ibrutinib in your body to be higher or lower than expected. It is also possible that taking the 
study drug with your regular medications or supplements, including fish oil, Vitamin E, or other 
vitamins, may change how your regular medications, or your regular supplements, work. It is 
very important that you avoid grapefruit juice and Seville oranges and tell the study doctor 
about all medications, supplements, or herbal medicine like St. John’s wort that you are taking 
during the study. You should notify your study doctor immediately about any side effects to 
avoid possible harm.  
 
Drug interruption for any surgical procedures  
 


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Ibrutinib may increase the risk of bleeding with any surgical procedure. Ibrutinib should be held 
at least 3 to 7 days before and after surgery depending upon the type of surgery and the risk of 
bleeding. Please contact your study doctor if you have any planned surgical procedures. For 
emergency surgical procedures, ibrutinib should be discontinued (stopped) after the procedure 
until the surgical site is reasonably healed (not oozing fluid). 
 
Please contact your study doctor as soon as possible and your study doctor will tell you when 
to stop ibrutinib and when to restart it following a surgical procedure. 
 
In addition to the risks listed above, there could be unknown or unexpected side effects 
associated with the use of ibrutinib. You will be told in a timely manner, verbally and in writing, 
of any new information, findings, or changes to the way the research will be done that might 
influence your willingness to continue your participation in this study.  
 
You may have all, some, or none of the listed side effects of ibrutinib. Your study doctors and 
nurses will check you closely for side effects. You may receive medicines or other treatments 
to prevent or reduce some of these effects. Please tell the study doctor or study staff right away 
if you have any side effects. Please tell them if you have any other problems with your health 
or the way you feel during the study, whether or not you think they are related to the study drug.  
 
You should get medical help and contact the study doctor or study staff if you have any of these 
or any other side effects during the study.  
 
Reproductive effects  
 
The effects of ibrutinib on a developing baby are unknown; therefore, women who are pregnant 
or nursing are not allowed to be in this study. Nobody knows what these risks are right now. 
Some drugs cause women to have their babies prematurely (early) or to have babies with birth 
defects.  
 
Women: If you are able to have children, you must use a highly effective method of birth control 
and a barrier method, or sexual abstinence (which is defined as refraining from all aspects of 
sexual activity), while taking study treatment, as well as for 1 month after you stop taking study 
treatment, to prevent pregnancy in either you or your partner, unless your partner is sterilized. 
A “highly effective method of birth control” is defined as a method that has a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly and includes implants, 
injectables, birth control pills with 2 hormones, some intrauterine devices (IUDs). If you are 
using hormonal contraceptives such as birth control pills or devices, a second barrier method 
of contraception (e.g., condoms) must be used.  
 
Men: You must use a barrier method while on treatment with ibrutinib and for 1 month after 
the last dose of treatment to prevent pregnancy of your partner. You should not donate sperm 
while you are taking the study drug and for 1 month after you stop taking the study drug. 
 


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Note: Some birth control pills may not work when you are taking certain drugs. If you have any 
questions about this, please discuss this with the study doctor.  
 
Be aware that you can still become pregnant even if you use a highly effective method of birth 
control.  
 
Women: If you become pregnant while you are on study treatment or within 1 month of your 
last dose of ibrutinib you must notify the study staff. If you become pregnant on the study, you 
must immediately stop taking the study treatment. The Sponsor will continue to collect 
information about your pregnancy and the birth of your baby even after study treatment is 
stopped. 
 
Men: If your partner becomes pregnant while you are on study treatment, or within 3 months 
of your last dose of ibrutinib, you must notify the study staff. The study staff will discuss this 
with you further. 
 
Breast-feeding 
It is not known whether ibrutinib or its metabolites are excreted in human milk. Because many 
drugs are excreted in human milk and because of the potential for serious adverse reactions in 
nursing infants from ibrutinib, breast-feeding should be discontinued during ibrutinib treatment. 
 
Additional Risks 
 
Blood drawing risks: 
There may be bruising, bleeding or inflammation at the sites where blood samples are taken.  
Care will be provided to avoid these complications. Infection, excess bleeding, and/or fainting 
also are possible, although unlikely.   
 
Bone Marrow Biopsy risks: A small amount of bone marrow will be collected using a needle 
inserted into your hipbone.  You may feel a mild to moderate degree of pain or discomfort 
during the procedure.  Serious side effects of this procedure are rare.  Potential risks are minor 
skin bleeding and skin infection at the site of the needle insertion.  Other potential but rarely 
reported side effects after sample collection are fainting, dizziness or lightheadedness 
accompanied by nausea and clammy skin.  You must tell your doctor if you have any reactions 
during or shortly after the procedure. 
 
PET-CT Scan: PET-CT is a new method that combines two scanning techniques in one test 
procedure.  It is often used to diagnosis cancer, measure cancer progression, and evaluate the 
response to treatment.  During the scan, you will have to lie still on your back in the PET scanner 
which is a tight space.  This may make you anxious. 
During the PET procedure, you will be injected with a small amount of radioactive glucose.  
This substance is easily eliminated from the body either through radioactive decomposition or 
via the urine.  Over 90% of the radioactive glucose will either have decomposed or left the body 
before you leave the clinic, because the level of radiation is very low.  This test is safe for 


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diabetics who must control their glucose.  A minor risk of the procedure is temporary soreness 
or redness in the arm where the IV is inserted. 
For the CT Scan which is performed simultaneously, you will be exposed to a small amount of 
radiation and will receive an injection of contrast dye which will help your healthcare team 
better visualize the results of the test.  The contrast injection may cause you to feel side effects 
such a feeling of warmth or flushing, a metallic taste in your mouth, lightheadedness, nausea, 
itching and/or hives.  The amount of radiation you will be exposed to is very small and the risk 
of damage to your body is very low. 
 
ECG (Electrocardiogram):An ECG is a test that measures the electrical activity of your heart.  
It involves putting sticky pads on your skin while the electrical activity of the heart is recorded.  
Skin irritation from the ECG electrodes or pain when removing the ECG leads is a possible 
risk.  
 
Eye Examination:  
Your eyes will need to be dilated for the eye exam.  Dilating drops are used to dilate or enlarge 
the pupils of the eye to allow the eye doctor to get a better view of the inside of your eye.  
Dilating drops frequently blur vision for a length of time, which varies from person to person.  
They may also make bright lights bothersome.  It is not possible for your ophthalmologist to 
predict how much your vision will be affected but the side effects are temporary and will 
eventually wear off.  Driving may be difficult immediately after an examination, so it is best if 
you make arrangements not to drive yourself when you leave the clinic. 
 
Reproductive risks:  
Selinexor can harm an unborn or nursing baby.  Therefore, women who are pregnant or nursing 
a child cannot participate in this study.  You must confirm, to the best of your knowledge, that 
you are not now pregnant, and that you do not intend to become pregnant during the study. 
 
Female patients of child-bearing potential must agree to use dual methods of  
contraception and have a negative serum pregnancy test at screening, and male patients must 
use an effective barrier method of contraception if sexually active with a female of child-
bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, 
oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, 
diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-
menopausal. For both male and female patients, effective methods of contraception must be 
used throughout the study and for three months following the last dose.  
 
Loss of Confidentiality:   
Any time information is collected there is a potential risk for loss of confidentiality.  Every 
effort will be made to keep your personal and health information confidential; however, this 
cannot be guaranteed. 
 


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7.   What benefits can I expect from being in the study? 
There is no guarantee that this treatment will cure your cancer.  Benefits you may receive 
from this treatment include: 
 
• Making symptoms related to your cancer better 
• Decrease in the amount of your cancer, which may mean that the treatment is helping 
your cancer 
• Longer time until you would need a different therapy for your cancer 
• Longer time you will live. 
 
If you take part in this study, it may result in a better understanding of this treatment in other 
cancer patients.  This understanding could benefit cancer patients like yourself in the future.  
However, you must understand that you may not benefit from taking part in this study. 
 
You may also change your mind at any time during the study to stop your participation.  If 
you do stop after you have begun the study drug, information and blood samples already 
collected from you may still be used for the tests described in the study but further blood 
samples will not be taken.  Any samples provided to Karyopharm Therapeutics Inc or its 
vendors will not be returned and the data may still be used by Karyopharm. 
 
You may receive other therapy for your CLL or lymphoma at any time if your doctor thinks 
this is best for you which will mean your participation in this study will stop.     
 
8.   What other choices do I have if I do not take part in the study? 
You may choose not to participate without penalty or loss of benefits to which you are 
otherwise entitled. 
 
Before you decide whether or not to be in this study, your doctor will discuss the other options 
that are available to you.  Instead of being in this study, you could: 
• Not participate in this study 
• Get treatment or supportive care for your cancer without being in a study 
• Take part in another study 
• Get no treatment 
 
Your study doctor will explain what options are available to you.   
9.   Will my study-related information be kept confidential? 
Efforts will be made to keep your study-related information confidential.  However, there may 
be circumstances where this information must be released.  For example, personal information 
regarding your participation in this study may be disclosed if required by state law.   
 
Also, your records may be reviewed by the following groups (as applicable to the research): 
• 
Office for Human Research Protections or other federal, state, or international 
regulatory agencies; 


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• 
U.S. Food and Drug Administration; 
• 
The Ohio State University Institutional Review Board or Office of Responsible 
Research Practices; 
• 
The sponsors (OSU) supporting the study, their agents or study monitors; and 
• 
Your insurance company (if charges are billed to insurance). 
• 
Karyopharm Therapeutics, the drug provided 
 
If this study is related to your medical care, your study-related information may be placed in 
your permanent hospital, clinic, or physician’s office records. Authorized Ohio State University 
staff not involved in the study may be aware that you are participating in a research study and 
have access to your information.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. law.  This website will not include information that can identify you.  At most, 
the website will include a summary of the results.  You can search the website at any time.  
 
By signing this form, you authorize the use and disclosure of your entire study record and any 
medical or other records. The purpose for the uses and disclosures you are authorizing is to 
conduct the study explained to you during the informed consent and research authorization 
process and to ensure that the information relating to that study is available to all parties who 
may need it for research purposes. 
 
The NIH issues Certificates of Confidentiality for all NIH-funded studies, including this 
study. This Certificate provides extra protection for you and your study information, 
documents, or samples (blood, tissue, etc.). The Certificates are issued so that we cannot be 
required to disclose any identifiable information collected about you as a part of this study in 
a lawsuit or legal proceeding. This is a layer of protection over and above the already existing 
protections in place for you and your information, documents, or samples. 
 
However, these protections do not apply in some situations. For example, we may have to 
release your information if a law requires us to do so, if the National Institute of Health that is 
funding this study requests the information, or if the FDA tells us to release this information. 
Please talk to your study team, or contact the Office of Responsible Research Practices at 
614-688-8641, if you have questions. 
 
Please visit the NIH website at https://humansubjects.nih.gov/coc/faqs to learn more. 
 
 
10. What are the costs of taking part in this study? 
The study agent, Selinexor, will be provided by Karyopharm Therapeutics Inc., the 
pharmaceutical company who manufactures the study drug and will not be billed to you or your 
insurance company.  Standard medical care that you receive under this research study will be 
billed to your insurance provider and/or you in the ordinary manner. These standard of care 
tests/procedures include: 
• physician visits 


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• various blood tests 
• CT/PET scans 
• hepatitis B and C tests 
• Pregnancy test 
• bone marrow biopsy and aspirate  
• medication treatments given before and while you are being treated on this study 
 
Before taking part in this study, you may ask about which parts of the research-related care 
may be provided without charge, which costs your insurance provider may pay for, and which 
costs may be your responsibility. In addition, you may ask that a financial counselor be made 
available to you to talk about the costs of this study. You are responsible for any co-pays, co-
insurance, and deductibles as required by your insurance company or charges your insurance 
company does not pay. 
 
11. Will I be paid for taking part in this study? 
You will not be paid to take part in the study.  Karyopharm Therapeutics Inc. is not providing 
any compensation for participating it the Study. There is a chance that some commercial value 
may result from the use of your data or sample(s). If that should happen, you will not be 
eligible to share in any profits. 
 
12. What happens if I am injured because I took part in this study? 
If you suffer an injury from participating in this study, you should notify the researcher or 
study doctor immediately, who will determine if you should obtain medical treatment at The 
Ohio State University Medical Center.   
 
OHIO STATE UNIVERSITY LIABILITY 
If you are injured as a result of your participation in this study, you may obtain immediate 
care at the Ohio State University Medical Center.  The cost of this treatment will be charged 
to you or your insurance company.  Your health insurance company may or may not pay for 
treatment of injuries as a result of your participation in this study.  The Ohio State University 
has no funding set aside for the payment of health care expenses for this study. 
 
DRUG PROVIDER LIABILITY 
Karyopharm Therapeutics will pay the cost for any reasonable medical expenses for the 
treatment of injury or illness that is proven to be caused by any manufacturing defect in the 
Study Drug or defects with labeling and written instructions for use of the Study Drug. 
 
By signing this consent form, you will not be waiving any of the legal rights which you 
otherwise would have as a subject in a research study. 
 
13. What are my rights if I take part in this study? 
If you choose to participate in the study, you may discontinue participation at any time without 
penalty or loss of benefits.  Your authorization to use your health information will not expire 
and any data or samples collected before your withdrawal will continue to be used as necessary 
to preserve the integrity of the study, however no additional information or samples will be 


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collected after you withdraw your authorization.  By signing this form, you do not give up any 
personal legal rights you may have as a participant in this study. 
 
You will be provided with any new information that develops during the course of the research 
that may affect your decision whether or not to continue participation in the study. 
 
You may refuse to participate in this study without penalty or loss of benefits to which you are 
otherwise entitled. 
 
An Institutional Review Board responsible for human subjects research at The Ohio State 
University reviewed this research project and found it to be acceptable, according to applicable 
state and federal regulations and University policies designed to protect the rights and welfare 
of participants in research. 
 
14. HIPAA AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
      RESEARCH PURPOSES  
 
I. 
What information may be used and given to others? 
 
• Past and present medical records; 
• Research records; 
• Records about phone calls made as part of this research; 
• Records about your study visits; 
• Information that includes personal identifiers, such as your name, or a number 
associated with you as an individual; 
• Information gathered for this research about: 
HIV / AIDS 
Hepatitis infection 
Sexually transmitted diseases 
Other reportable infectious diseases 
Physical exams 
Laboratory, x-ray, and other test results 
Diaries and questionnaires 
The diagnosis and treatment of a mental health condition 
• Records about any study drug you received; 
• Records about the study device; and  
 
II. 
Who may use and give out information about you? 
 
Researchers and study staff.   
 
III. Who might get this information? 
 
• The sponsor of this research.  “Sponsor” means any persons or companies that are: 


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• working for or with the sponsor; or  
• owned by the sponsor. 
• Authorized Ohio State University staff not involved in the study may be aware that 
you are participating in a research study and have access to your information; 
• If this study is related to your medical care, your study-related information may be 
placed in your permanent hospital, clinic or physician’s office record; 
 
IV. 
 Your information may be given to: 
  
• The U.S. Food and Drug Administration (FDA), Department of Health and Human 
Services (DHHS) agencies, and other federal and state entities; 
• Governmental agencies in other countries; 
• Governmental agencies to whom certain diseases (reportable diseases) must be 
reported; and  
• The Ohio State University units involved in managing and approving the research 
study including the Office of Research and the Office of Responsible Research 
Practices. 
 
V. 
Why will this information be used and/or given to others? 
 
• To do the research;  
• To study the results; and  
• To make sure that the research was done right.   
 
VI. 
 When will my permission end? 
 
There is no date at which your permission ends. Your information will be used 
indefinitely. This is because the information used and created during the study may be 
analyzed for many years, and it is not possible to know when this will be complete. 
 
VII. May I withdraw or revoke (cancel) my permission? 
 
Yes. Your authorization will be good for the time period indicated above unless you 
change your mind and revoke it in writing. You may withdraw or take away your 
permission to use and disclose your health information at any time. You do this by 
sending written notice to the researchers. If you withdraw your permission, you will not 
be able to stay in this study. When you withdraw your permission, no new health 
information identifying you will be gathered after that date. Information that has already 
been gathered may still be used and given to others. 
 


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VIII. What if I decide not to give permission to use and give out my health 
information? 
 
Then you will not be able to be in this research study and receive research-related 
treatment.  However, if you are being treated as a patient here, you will still be able to 
receive care. 
 
IX. 
 Is my health information protected after it has been given to others? 
 
There is a risk that your information will be given to others without your permission. Any 
information that is shared may no longer be protected by federal privacy rules. 
 
X. 
May I review or copy my information? 
 
Signing this authorization also means that you may not be able to see or copy your study-
related information until the study is completed.   
 
15. Who can answer my questions about the study? 
For questions, concerns, or complaints about the study you may contact:  
 
Jennifer Woyach, MD 
455A Wiseman Hall 
Columbus, OH 43210 
Ph:  614-293-8165 
24 hrs:  614-293-8000 ext. 5806 
 
For questions about your rights as a participant in this study or to discuss other study-related 
concerns or complaints with someone who is not part of the research team, you may contact 
Ms. Sandra Meadows in the Office of Responsible Research Practices at 1-800-678-6251. 
 
If you are injured as a result of participating in this study or for questions about a study-
related injury, you may contact: 
 
Jennifer Woyach, MD 
455A Wiseman Hall 
Columbus, OH 43210  
Ph:  614-293-8165 
24 hrs:  614-293-8000 ext. 5806 
 
 


CONSENT 
Biomedical/Cancer 
 
OSU-14087 
 
IRB Protocol Number: 
2014C0180 
IRB Approval date:  PENDING 
Version 10:  11/23/2021 
 
 
Page 27 of 27 
 
 
Signing the consent form 
 
I have read (or someone has read to me) this form and I am aware that I am being asked to 
participate in a research study.  I have had the opportunity to ask questions and have had them 
answered to my satisfaction.  I voluntarily agree to participate in this study.  
 
I am not giving up any legal rights by signing this form.  I will be given a copy of this form. 
 
 
 
 
 
Printed name of subject 
 
Signature of subject 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
 
 
 
 
Printed name of person authorized to consent for subject 
(when applicable) 
 
Signature of person authorized to consent for subject  
(when applicable) 
 
 
 
 
 
AM/PM 
Relationship to the subject 
 
Date and time 
 
 
 
 
Investigator/Research Staff 
 
I have explained the research to the participant or his/her representative before requesting the 
signature(s) above.  There are no blanks in this document.  A copy of this form has been given 
to the participant or his/her representative. 
 
 
 
 
 
Printed name of person obtaining consent 
 
Signature of person obtaining consent 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
Witness(es) - May be left blank if not required by the IRB 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
 
AM/PM 
 
 
Date and time