Conditions: Malignant Glioma Recurrent Brain Neoplasm Recurrent Childhood Central Nervous System Neoplasm Recurrent Childhood Glioblastoma Recurrent Lymphoma Recurrent Malignant Solid Neoplasm Refractory Lymphoma Refractory Malignant Solid Neoplasm Refractory Primary Central Nervous System Neoplasm WHO Grade 3 Glioma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 59
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of selinexor in treating younger patients with solid tumors or central nervous system (CNS) tumors that have come back (recurrent) or do not respond to treatment (refractory). Drugs used in chemotherapy, such as selinexor, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) or the maximum tolerated dose (MTD) of the tablet formulation of selinexor in children with recurrent/refractory solid and CNS tumors.

II. To describe the toxicities of selinexor in children with recurrent/refractory solid and CNS tumors.

III. To characterize the pharmacokinetics of the tablet formulation of selinexor in children with recurrent/refractory solid and CNS tumors.

SECONDARY OBJECTIVES:

I. To determine the antitumor effect of selinexor in a preliminary manner in children with recurrent/refractory solid and CNS tumors.

II. To determine the pharmacodynamic properties of selinexor in children and adolescents with refractory solid tumors in plasma proteins and whole blood ribonucleic acid (RNA).

III. To explore the penetration, pharmacodynamic effects, and biologic effects of selinexor in tumor tissue of patients with recurrent/refractory high-grade gliomas (HGG) requiring resection.

IV. To further assess the toxicity and antitumor effects of selinexor in children with recurrent/refractory HGG in expanded cohorts following dose-escalation by measuring rate of objective radiographic response (medical patients) and rate of progression-free survival (PFS) six months from the start of treatment (surgical patients).

OUTLINE: This is a dose escalation study.

Patients receive selinexor orally (PO) on either a twice weekly (days 1, 3, 8, 10, 15, 17) or once weekly (days 1, 8, 15, and 22) schedule. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Arms:
arm 1: Patients receive selinexor PO on either a twice weekly (days 1, 3, 8, 10, 15, 17) or once weekly (days 1, 8, 15, and 22) schedule. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Pharmacological Study intervention 2: Selinexor
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO

Protocol document:
Prot_SAP_000.pdf: 
  
ADVL1414 
 
1 
Version Date: 11/10/2020 
 
 
Activated: 
October 5, 2015 
Version Date:  
11/10/20 
Closed: 
   January 14, 2022 
Amendment #:  
5A 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
ADVL1414 
 
A PHASE 1 STUDY OF SELINEXOR (KPT-330, 
), A SELECTIVE XPO1 
INHIBITOR, IN RECURRENT AND REFRACTORY PEDIATRIC SOLID TUMORS, 
INCLUDING CNS TUMORS 
 
Lead Organization: COG Pediatric Early Phase Clinical Trials Network (PEP-CTN) 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED 
OR USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN 
THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY 
ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT 
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL 
HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
       
 
 
 
 
For PEP-CTN Operations and Data/Statistics Contacts see: http://members.childrensoncologygroup.org 


                             
ADVL1414 
                                                                                                                                                                
Version Date: 11/10/2020 
 
2 
 
TABLE OF CONTENTS 
SECTION 
PAGE 
 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Aims 
8 
1.2 
Secondary Aims 
8 
2.0 
BACKGROUND 
8 
2.1 
Tumor suppressor function and selinexor 
8 
2.2 
Rationale for the Current Study 
9 
2.3 
Preclinical Studies 
9 
2.4 
Adult Studies 
14 
2.5 
Pediatric Studies 
16 
2.6 
Overview of Proposed Pediatric Study 
17 
2.7 
Rationale for Change in Dosing Schedule (Amendment #1) 
17 
2.8 
Rationale for Change in Dosing Schedule (Amendment #4) 
18 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
19 
3.1 
Current Study Status 
20 
3.2 
IRB Approval 
20 
3.3 
Patient Registration in the COG Registry 
21 
3.4 
Reservation and Contact Requirements 
21 
3.5 
Informed Consent/Assent 
21 
3.6 
Screening Procedures 
21 
3.7 
Eligibility Checklist 
21 
3.8 
Institutional Pathology Report 
22 
3.9 
Study Enrollment 
22 
3.10 
Dose Assignment 
22 
4.0 
PATIENT ELIGIBILITY 
22 
4.1 
Inclusion Criteria 
23 
4.2 
Exclusion Criteria 
25 
5.0 
TREATMENT PROGRAM 
26 
5.1 
Treatment Overview 
26 
5.2 
Criteria for Starting Subsequent Cycles 
27 
5.3 
Dose Escalation Schema 
27 
5.4 
Grading of Adverse Events 
29 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
29 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
30 
6.1 
Dose Modifications for Hematological Toxicity 
30 
6.2 
Dose Modifications for Non-Hematological Dose-Limiting Toxicity 
31 
6.3 
Dose Modifications for Anorexia/Weight Loss 
31 
6.4 
Dose Modifications for Nausea/Vomiting/Dehydration 
31 
6.5 
Dose Modifications for Diarrhea 
31 
6.6 
Dose Modifications for Hyponatremia 
32 
6.7 
Dose Modifications for Hepatic Adverse Events 
33 


                             
ADVL1414 
                                                                                                                                                                
Version Date: 11/10/2020 
 
3 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
33 
7.1 
Concurrent Anticancer Therapy 
33 
7.2 
Investigational Agents 
33 
7.3 
Supportive Care 
33 
7.4 
Growth Factors 
37 
7.5 
Concomitant Medications 
37 
7.6 
Part C (HGG Surgical Expansion Cohort) 
37 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
38 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
38 
8.2 
Radiology Studies 
39 
8.3 
Pharmacology (Required) 
39 
8.4 
Pharmacodynamics 
41 
8.5 
Tissue Studies (Part C only) 
41 
9.0 
AGENT INFORMATION 
42 
9.1 
Selinexor 
42 
9.2 
Agent Accountability 
45 
9.3 
Obtaining the Agent 
45 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
45 
10.1 
Criteria for Removal from Protocol Therapy 
45 
10.2 
Off Study Criteria 
46 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
46 
11.1 
Sample Size and Study Duration 
46 
11.2 
Definitions 
48 
11.3 
Dose Escalation and Determination of MTD 
49 
11.4 
Inclusion of Children, Women and Minorities 
50 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
51 
12.0 
EVALUATION CRITERIA 
51 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
51 
12.2 
Response Criteria for Patients with Solid Tumors 
52 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
56 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
57 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
58 
12.6 
Response Criteria for Patients with CNS Tumors 
59 
12.7 
Best Response 
61 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
63 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
63 
13.2 
When to Report an Event in an Expedited Manner 
66 
13.3 
Expedited Reporting Methods 
66 
13.4 
Definition of Onset and Resolution of Adverse Events 
67 
13.5 
Other Recipients of Adverse Event Reports 
67 
13.6 
Reporting Secondary AML/MDS 
67 
13.7 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
68 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
69 
14.1 
Categories of Research Records 
69 
14.2 
Access to Rave for Data Submission/ Data Reporting 
70 
14.3 
CDUS 
71 


                             
ADVL1414 
                                                                                                                                                                
Version Date: 11/10/2020 
 
4 
 
14.4 
Data and Safety Monitoring Plan 
71 
REFERENCES 
72 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
74 
APPENDIX II: CORRELATIVE STUDIES GUIDE 
75 
APPENDIX III: PHARMACOKINETIC STUDY FORM 
76 
APPENDIX IV-A: PHARMACODYNAMICS STUDY FORM- PLASMA PROTEINS 
77 
APPENDIX IV-B: PHARMACODYNAMICS STUDY FORM- WHOLE BLOOD RNA 
78 
APPENDIX V: TISSUE STUDIES FORM (PART C ONLY) 
79 
APPENDIX VI: SELINEXOR DOSING NOMOGRAM 
80 
Selinexor Dose Assignment: 35 mg/m2 
80 
Selinexor Dose Assignment: 45 mg/m2 
80 
Selinexor Dose Assignment: 55 mg/m2 
81 
APPENDIX VII:  MEDICATION DIARY FOR SELINEXOR 
82 
APPENDIX VIII: TOXICITY SPECIFIC GRADING 
83 
APPENDIX IX: BMI GROWTH CHARTS 
84 
APPENDIX X:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
88 
APPENDIX XI: CTEP AND CTSU REGISTRATION PROCEDURES 
90 
APPENDIX XII: YOUTH INFORMATION SHEETS 
95 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
5 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AGENT NSC# AND IND#’s 
 
Selinexor (KPT-330, NSC#781780, 
) 
 
 
 
 
 
 
SEE SECTION 8.3.5 AND APPX. IV-V FOR SPECIMEN SHIPPING ADDRESSES 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
7 
 
This trial is covered by a Certificate of Confidentiality from the federal government, which will help us protect the 
privacy of our research subjects.  The Certificate protects against the involuntary release of information about subjects 
collected during the course of our covered studies.  The researchers involved in the studies cannot be forced to disclose 
the identity or any information collected in the study in any legal proceedings at the federal, state, or local level, 
regardless of whether they are criminal, administrative, or legislative proceedings.  However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain circumstances.  For example, if 
the subject or his/her guardian requests the release of information in writing, the Certificate does not protect against 
that voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, such 
as a DHHS request for information for an audit or program evaluation or an FDA request under the Food, Drug and 
Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of information on 
suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self or others. 
 
ABSTRACT 
Recurrent pediatric brain and solid tumors, especially high-grade gliomas (HGG), have few effective 
treatments and are a major source of mortality in pediatric oncology. XPO1 (CRM1) is a nuclear export 
protein that selectively transports tumor suppressor (TSP) and growth regulatory (GRP) proteins out of the 
nucleus, effectively inhibiting their function. Selinexor (KPT-330), a novel small molecule, slowly 
reversible inhibitor of XPO1, is the first-in-class Selective Inhibitor of Nuclear Export (SINE). Selinexor 
causes the retention, accumulation, and activation of TSP/GRP in the nucleus, which in turn induce cell 
cycle arrest wherein neoplastic cells with genomic deoxyribonucleic acid (DNA) damage undergo 
apoptosis. Selinexor has demonstrated preclinical efficacy in multiple pediatric cancer models, including 
intracranial xenografts of HGG. In phase 1 trials in adults, selinexor has been generally well tolerated with 
common side effects of fatigue, nausea, vomiting, diarrhea, and dehydration, which can be effectively 
managed with supportive care. Selinexor has received accelerated FDA approval for the treatment of 
relapsed or refractory multiple myeloma in combination with dexamethasone in adult patients who have 
received at least 4 prior therapies and whose disease was refractory to at least 2 proteasome inhibitors, 2 
immunomodulatory agents, and an anti-CD38 monoclonal antibody. Selinexor has also demonstrated 
promising preliminary clinical activity in acute myeloid leukemia, glioblastoma multiforme (GBM), 
sarcoma, and other solid tumors. We will conduct a phase 1 trial of selinexor in children with recurrent 
brain and solid tumors using the Rolling Six design. The aims of the trial will be to establish the maximum 
tolerated pediatric dose of selinexor; to investigate the toxicities, pharmacokinetics, and pharmacodynamics 
of selinexor in children with these tumors; and to preliminarily explore efficacy in pediatric solid and CNS 
tumors, including medical and surgical expansion cohorts of HGG patients.  
 
EXPERIMENTAL DESIGN SCHEMA 
 
(Pre-Amendment #1): 
Week 
Day 
Agent: Selinexor (KPT-330) 
1 
1, 3 (Dose 1,2) 
X 
2 
8, 10 (Dose 3,4) 
X 
3 
15, 17 (Dose 5,6) 
X 
4* 
22, 24 (Dose 7,8) 
X 
   * Evaluations will occur at the end of cycle 1, every other cycle x 2, then every 3 cycles 
    
(Amendment #1):  
Week 
Day 
Agent: Selinexor (KPT-330) 
1 
1, 3 (Doses 1,2) 
X 
2 
8, 10 (Doses 3,4) 
X 
3 
15, 17 (Doses 5,6) 
X 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
8 
 
4 
Rest 
 
 
 
 
 
 
 
Amendment #4:  
Week 
Day 
Agent: Selinexor (KPT-330) 
1 
1 
X 
2 
8 
X 
3 
15 
X 
4 
22 
X 
 
With Amendment #4, patients will receive selinexor once weekly, on Days 1, 8, 15, and 22 of a 28-day 
cycle. Therapy will be discontinued if there is evidence of progressive disease or drug-related dose-limiting 
toxicity that requires removal from protocol therapy.  
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To determine the recommended phase 2 dose (RP2D) or the maximum tolerated 
dose (MTD) of the tablet formulation of selinexor in children with 
recurrent/refractory solid and CNS tumors. 
 
1.1.2 
To describe the toxicities of selinexor in children with recurrent/refractory solid 
and CNS tumors. 
 
1.1.3 
To characterize the pharmacokinetics of the tablet formulation of selinexor in 
children with recurrent/refractory solid and CNS tumors. 
 
1.2 
Secondary Aims 
 
1.2.1 
To determine the antitumor effect of selinexor in a preliminary manner in 
children with recurrent/refractory solid and CNS tumors. 
 
1.2.2 
To determine the pharmacodynamic properties of selinexor in children and 
adolescents with refractory solid tumors in plasma proteins and whole blood 
RNA. 
 
1.2.3 
To explore the penetration, pharmacodynamic effects, and biologic effects of 
selinexor in tumor tissue of patients with recurrent/refractory HGG requiring 
resection. 
 
1.2.4 
To further assess the toxicity and antitumor effects of selinexor in children with 
recurrent/refractory HGG in expanded cohorts following dose-escalation by 
measuring rate of objective radiographic response (medical patients) and rate of 
progression-free survival (PFS) six months from the start of treatment (surgical 
patients). 
 
2.0 
BACKGROUND 
 
2.1 
Tumor suppressor function and selinexor 
Over 10 major tumor suppressor pathways have evolved in order to prevent the development 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
9 
 
and progression of carcinogenesis. The majority of the tumor suppressor (TSP) and growth 
regulatory (GRP) proteins mediating these pathways act in the cell nucleus.  Accumulating 
data suggest that in order to maintain their malignant behavior, neoplastic cells must 
inactivate most or all of the known TSP and GRP pathways.1 Active nuclear export of 
TSP/GRP is one very efficient and rapid means of overcoming normal cell cycle regulation 
and the genomic stability assessment mediated by these proteins.  
 
Essentially all known TSP/GRP utilize a single non-redundant nuclear export protein 
complex to exit the nucleus.  Exportin 1 (XPO1), also known as chromosomal region 
maintenance protein 1 (CRM1), is the primary component of this export complex, and is 
overexpressed in many types of cancer.2 Approximately 200 different mammalian XPO1 
cargo proteins are known,3 including the vast majority of the TSP and GRP.  XPO1 
“recognizes” most of these cargo proteins for nuclear export through canonical Nuclear 
Export Sequences (NES) in the cargo protein.  These NES are often buried within the cargo 
proteins and only unmasked when cells receive specific signals from their environments.  
XPO1 itself has a very specific cargo-binding groove that allows it to accommodate a 
diverse array of NES-bearing proteins.3 In addition, XPO1 mediates the export of a small 
number of RNAs,4 though most RNAs are exported by alternative mechanisms.4 
 
Human cancers frequently overexpress XPO1 and/or show inappropriate cytoplasmic 
expression of TSP/GRPs, suggesting dysfunctional nuclear-cytoplasmic transport. XPO1 
is upregulated in a range of solid tumors and hematologic malignancies, including high-
grade glioma, and its overexpression is correlated with poor prognosis, suggesting that 
alterations in nuclear-cytoplasmic transport, and hence mislocalization of tumor suppressor 
proteins, cell cycle regulators, and/or pro-apoptotic proteins, could promote oncogenesis 
and resistance to chemotherapy. 5-9 
 
Selinexor is a Selective Inhibitor of Nuclear Export (SINE) that binds and inactivates XPO1 
in a reversible manner, thereby forcing the nuclear retention of key TSP/GRP.  Transient 
retention of TSP/GRP in the nucleus at high levels via XPO1 blockade activates cell cycle 
checkpoint and genomic surveying.  This leads to the death of nearly all types of malignant 
cells, whereas normal cells undergo transient cell cycle arrest and recovery when the export 
block is released. 
 
2.2 
Rationale for the Current Study 
Survival following chemotherapy for pediatric malignancy remains one of the most 
stunning successes of modern medicine.  Overall, nearly 80% of children with cancer 
treated in developed countries will be cured of their disease.10 Nevertheless, despite 
significant intensification of therapy, there remains a subset of patients with aggressive 
non-hematologic malignancies, notably pediatric and adolescent sarcoma and brain 
tumors, for whom treatment gains have been relatively modest over the past two decades.11  
The situation is especially dire in pediatric high-grade gliomas (HGG). HGG are defined 
as World Health Organization grade III and IV tumors of glial origin. They occur in both 
adults and children. Preclinical studies of selinexor in pediatric brain and solid tumors, 
combined with promising safety and efficacy data seen so far in adults, make selinexor an 
excellent candidate for use in this early-phase clinical trial in children with 
recurrent/progressive brain and solid tumors, who have few treatment options. 
 
2.3 
Preclinical Studies 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
10 
 
2.3.1 
Antitumor Activity in Pediatric Malignancies 
XPO1 is overexpressed in osteosarcoma when compared to normal tissue and is 
associated with higher grade and inferior progression-free and overall survival 
rates.9 Similarly, in high-grade glioma (HGG), overexpression of XPO1 correlates 
with tumor grade and survival.7 Investigators from Dana-Farber and Columbia 
University recently published data showing dose-response curves in multiple adult 
and pediatric primary human HGG lines to XPO1 inhibitors KPT-276, selinexor, 
and KPT-251.12 Cells in neurosphere culture in triplicate in 96-well plates from 
each line were treated with a log-scale range of drug concentrations, from 0.1 nM 
to 100 uM, for a period of five days. Control cells were treated with DMSO alone.  
Survival was measured using the CellTiter Blue assay. IC50 values fell within a 
narrow, sub-micromolar range as seen in figure 1 (with 95% CI).  
Figure 1: 
 
Three groups of 10 mice each were then injected intracranially with adult primary 
human glioma cells infected with a luciferase virus to allow serial imaging. When 
the bioluminescence level of the tumors was steadily increasing, treatment began 
with KPT-276, selinexor, or control vehicle. Both XPO1 inhibitors had a 
significant effect on the rate of tumor growth and survival.  The main side effect 
in the mice was weight loss, which could be overcome with dosing adjustments. 
 
 
The Pediatric Preclinical Testing Program (PPTP) also recently tested selinexor 
against their panel of pediatric cell lines both in vitro and in vivo (Houghton PJ et 
al, AACR Annual Meeting 2013, Poster LB-354). The median relative IC50 (rIC50) 
was 125 nM (range 13 nM to > 10 μM), with a trend for greater sensitivity for the 
Ewing sarcoma cell lines (median rIC50 = 57 nM) and lesser sensitivity for the 
neuroblastoma cell lines (median rIC50 = 235 nM). In subcutaneous murine 
models, selinexor was administered at 10 mg/kg orally on a 3-day/week schedule 
(M-W-F) for 4 weeks with a total treatment/observation period of 6 weeks.  
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
11 
 
selinexor showed tumor regression in 3 of 38 (4%) solid tumor xenografts, 
including a maintained complete response (MCR) in a Wilms (1 of 3), a CR in a 
slow growing ependymoma (1 of 2) and a CR in a medulloblastoma (1 of 2) 
xenograft. Tumor growth inhibition meeting criteria for intermediate or high 
activity was demonstrated  in 11 of 32 (34%) of the solid tumor panel, most 
frequently for the Wilms (2 of 3) and Ewing sarcoma (4 of 5) models.13 
Investigators at the Children’s Hospital of Philadelphia (CHOP) have 
demonstrated that XPO1 mRNA expression is higher in neuroblastoma cell lines 
and MYCN amplified primary tumors when compared to low-risk tumors. They 
tested a panel of 17 neuroblastoma cell lines in vitro over a 5-log range of 
selinexor.14 All cell lines tested were sensitive to selinexor with IC50 values ranging 
from 51-568 nM.  While the in vivo models of the PPTP showed progressive 
disease in six neuroblastoma models with selinexor at 10 mg/kg MWF, the data 
from CHOP show objective responses at higher selinexor doses. Flank xenografts 
of the neuroblastoma cell line SH-SY5Y showed tumor size reduction after oral 
administration of selinexor at 15 mg/kg MWF. Perhaps more importantly, 
resistance was not observed. After allowing the tumors to grow following 28 days 
of drug withdrawal, re-exposure to the drug again showed growth suppression 
(Figure 3).  Selinexor was also tested in a model of disseminated neuroblastoma 
created by tail vein injection of a luciferase-expressing SH-SY5Y line. Tumor 
growth was monitored by luciferase imaging which was correlated with serial 
necropsies (Figure 4A). Mice treated with selinexor (15 mg/kg MWF) showed 
suppression of tumor growth (Figure 4B) and prolonged survival. Liver metastases 
harvested at necropsy showed decreased Ki-67 and increased caspase-3 staining in 
treated tumors as compared to controls. Similar results were seen with the IMR5 
and Be2c neuroblastoma cell lines. 14-16 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
12 
 
Selinexor, as well as other SINE compounds, have also been studied in preclinical 
leukemia models. The dosing regimen was every other day x 3 each week 
(QoDx3/wk); anti-tumor activity has also been shown with twice weekly dosing. 
Efficacy was demonstrated at doses of 15-60 mg/m2 (5-20 mg/kg) in mouse models 
of T-cell acute lymphocytic leukemia (T-ALL) xenografts. Moreover, efficacy, 
including significant survival advantages, was demonstrated in acute myeloid 
leukemia (AML) [MV4-11 (FLT3-ITD)], chronic myeloid leukemia in blast crisis 
(CML-BC), and T-ALL leukemografts.15,16 
 
2.3.2 
Animal Toxicology 
Sprague-Dawley rats and cynomolgus monkeys were chosen as the toxicology 
species for the selinexor nonclinical safety program.  In both species, the primary 
effects of selinexor were dose-dependent reductions in food intake and body 
weight (or reductions in body weight gain), with minimal clinical symptoms (no 
or mild non-bloody diarrhea), associated primarily with gastrointestinal atrophy.  
Similar effects are observed in mice and dogs given selinexor and related SINE 
compounds.  Increases in amylase and/or lipase, ALT (with less effects on AST), 
CK, and LDH were observed, but generally were not indicative of organ failure 
across species.  Dose-dependent lymphocyte depletion in lymphoid organs was 
observed, with alterations in blood hematology parameters generally considered to 
be clinically insignificant. In summary, dose limiting toxicity (DLT)/mortality in 
both rats and monkeys is related primarily to marked weight loss at high repeated 
doses of selinexor with atrophy of the gastrointestinal (GI) tract and noncritical 
effects on other major organs.   
 
In rats, DLT was related to subacute progressive weight loss and GI tract atrophy 
across all of the studies.  Acute single PO gavage doses of selinexor at up to 3,000 
mg/m2 (500 mg/kg) showed no mortality at up to 24 hours post-dose.  There were 
dose-dependent reductions in food and water intake and body weight, and non-
bloody diarrhea was observed.  Clinically significant changes in serum chemistry 
(LFTs, CK, LDH) were observed at the highest dose tested, with no clinically 
significant changes in hematological or coagulation parameters.  Gross necropsy 
showed thinning of the gastrointestinal wall. Monkeys showed similar DLTs as 
observed in rats, namely dose-dependent weight loss associated with reduced food 
intake that were both rapidly reversible. Animals that had >7.5% body weight loss 
were given Ensure® and additional food supplements during the study.  The body 
weights of the recovery group animals returned to approximately baseline levels 
by the end of the recovery period (two weeks) and substantial recovery had already 
occurred by 4-5 days after dosing. 
 
No CNS-related adverse side effects and no microscopic changes in the brain were 
observed in the rat and monkey Good Laboratory Practice (GLP), 4-week toxicity 
studies. However, in monkeys at doses >72 mg/m2,  marked rapid weight loss was 
observed and associated with abnormal muscle movements and histopathological 
changes in the cerebellar granular neurons and inner cell nuclear layer of the eye. 
No CNS-related toxicities observed after a single dose of selinexor or repeated 
doses <72 mg/m2 in the monkey.  Doses of 300 mg/m2 in rats were also associated 
with cerebellar granular neuron changes without any CNS behavioral changes 
(Irwin test). The dose that resulted in 10% mortality over the duration of the study 
(STD10) in rats was >30 mg/m2, and the highest non-severely toxic dose (HNSTD) 
in monkeys was 18 mg/m2.16 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
13 
 
Selinexor has been studied at 10 µM in an in vitro selectivity assay including 
receptors, kinases, and cysteine proteases (including caspases and matrix 
metalloproteinases), with none of the targets significantly affected by selinexor 
except for Monoamine Oxidase B (MAO-B; binding IC50 of >5 µM and minimal 
functional activity).  Given the minimal inhibition of human Ether-à-go-go Related 
Gene (hERG) tail current density (hERG IC50) for selinexor is 20.6 µM in the 
absence of serum, and given the high plasma protein binding, it is unlikely for 
selinexor to have any clinically significant impact on hERG or associated cardiac 
conduction in humans.  In the pivotal, GLP, 4-week monkey study, ECGs were 
recorded on all animals during the pretest period, and on all animals assigned to 
the study during the final dosing cycle (1-2 hours post dose on Day 21) and during 
the last week of the recovery period on Day 39.  There was no ECG evidence of a 
direct or indirect effect of selinexor on the morphology and intervals of the ECG 
at up to 36 mg/m2 (3 mg/kg).  Based on these results, QT prolongation or other 
cardiac effect does not appear to be a safety concern for selinexor.  
 
Selinexor was not mutagenic in a bacterial reverse mutation (Ames) test. 
 
No preclinical toxicity studies in juvenile animals have been performed. Please 
refer to the Investigator’s brochure for full details of preclinical toxicology studies. 
 
 
2.3.3 
Preclinical Pharmacokinetic Studies 
Preclinical PK parameters were assessed in three species: mouse (CD1), rat 
(Sprague-Dawley), and monkey (cynomolgus). Oral bioavailability (F%) of 
selinexor was remarkably consistent among the three species, with average values 
of 66.5%, 61.2%, and 67.5% in mice, rats, and monkeys, respectively. Protein 
binding of selinexor was high in all species (>90%). Overall, systemic exposure 
was generally dose-proportional in all studies that involved multiple dose levels.  
No accumulation was observed. The drug underwent minimal metabolism in vitro 
by liver microsomes as well as minimal metabolism by the human liver S9 fraction; 
the major product of metabolism is GSH conjugation, with the formation of 
inactive metabolites including N-acetylcysteinyl- and cysteinyl-derivatives. 
Selinexor showed no significant in vitro interactions with any of the cytochrome 
P450 (CYP450) enzymes (i.e., IC50 >10 µM), except for one substrate of CYP3A4 
(testosterone) which displayed an IC50 of 4.7 µM (the IC50 for midazolam, the other 
CYP3A4 substrate, was >10 µM). No induction of CYP450 activity was observed 
for CYP1A2 or CYP3A4. 
 
Higher Cmax and earlier Tmax values were observed in monkeys that were fasted 
versus fed prior to dosing.  Systemic exposure (AUClast) was not affected by the 
feeding status in monkeys. Delivery of drug product was studied using gelatin 
capsules and suspension. When cynomolgus monkeys were given a suspension 
formulation by nasogastric tube, exposure increased by 40%, and Cmax increased 
threefold versus capsule dosing.  Assessment of brain penetration two hours after 
single oral dosing of selinexor revealed brain:plasma ratios averaging 0.72 in rats 
and 0.61 in cynomolgus monkeys. Using standard techniques and allometric 
scaling the predicted human clearance of selinexor is 227 ml/h/kg, or 
approximately half the clearance rate observed in monkeys. Thus, the predicted 
exposure in humans is not expected to significantly vary from that observed in 
monkeys. Anticancer activity is anticipated at doses of 15-45 mg/m2.  At these 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
14 
 
doses, Cmax is expected to be 0.9-2.8 μM. 17 
 
2.4 
Adult Studies 
In phase 1 clinical trials in adults with advanced solid or hematological malignancies 
(NCT01607905, NCT01607892, and NCT01896505). Selinexor was administered to over 
240 patients. The dose limiting toxicities (DLTs) on the initial solid tumor trial were 
anorexia/nausea/dehydration and fatigue at 40 mg/m2 (10 times per 4-week cycle; Days 1, 
3, 5 of weeks 1 & 3 and Days 1 & 3 of weeks 2 & 4). The MTD and recommended phase 
2 dose (RP2D) for 10 times per cycle dosing is 30 mg/m2.  Reduced intensity dosing at 
twice weekly (8 times per cycle, Days 1 & 3 of each week) has shown improved 
tolerability, with an approximately 50% reduction in the observed rate of adverse effects. 
One of 6 patients at a dose of 35 mg/m2 on the twice weekly schedule experienced a DLT 
of Grade 3 nausea, vomiting and fatigue; this patient also experienced concomitant C. 
difficile infection. 18  Dose escalation cleared the 40 mg/m2, 50 mg/m2 and 65 mg/m2 levels 
without DLT, but there were 2 DLTs at 85 mg/m2: hyponatremia and reversible cerebellar 
syndrome. Based on these results, MTD and RP2D of selinexor twice weekly is determined 
to be 65 mg/m2. 19  
 
The most common grade 1/2 AEs were nausea (78%), fatigue (70%) and anorexia (68%) 
vomiting (60%).  Other toxicity included dysgeusia, diarrhea, dehydration, and weight loss.  
Aggressive supportive care, including prophylactic administration of appetite stimulants 
and anti-nausea agents, improves tolerability, 20 and symptoms abate with time. Idiopathic 
reductions in platelets (10-20% Grade ≥ 3) have been observed but without clinically 
significant bleeding; anemia and neutropenia have been minimal. Patients have reported 
blurred or diminished vision, but without objective findings on ophthalmological 
examination. Dehydration was determined to be responsible for at least some of the 
instances of blurred vision. There were 8 events of worsening for pre-existing cataracts, 
and 5 of these required operation. The attribution to selinexor is hard to determine, as phase 
1 patients tend to be older and very heavily pre-treated with chemotherapy and 
dexamethasone. Because it is impossible to exclude selinexor as a contributing factor to 
worsening of cataracts, it is our recommendation that patients with pre-existing cataracts 
be excluded from the trial. 
 
There has been evidence of clinical activity with disease stabilization ≥ 24 weeks in 
hormone- and chemotherapy-refractory prostate cancer, colorectal cancer, squamous head 
and neck cancer, and endometrial sarcoma, and partial responses seen in a Kras mutant 
colorectal cancer, a BRAF WT melanoma, and an ovarian cancer. 21,19 
 
The ongoing hematologic malignancies phase 1 study includes patients with relapsed and 
refractory hematologic malignancies who enter the study with documented progressive 
disease. No DLTs were observed in the initial five cohorts at doses ranging from 16.8 to 
55 mg/m2 on the 10 dose per 4-week cycle schedule.  On each of the 16.8 mg/m2 and 23 
mg/m2 dose levels, 1 of 6 patients had non-dose-limiting Grade 3/4 thrombocytopenia.  The 
most common AEs were similar to those observed in patients with advanced metastatic 
solid tumors and were mainly gastrointestinal (GI) in nature. Escalation proceeded with the 
twice weekly schedule at dose levels 35 mg/m2, 45 mg/m2 and 60 mg/m2 levels without 
DLT. 22 Clear evidence of anti-tumor activity, including remission, in these heavily 
pretreated hematologic malignancy patients has been demonstrated in diseases including 
AML and NHL, with higher doses noted to be associated with greater reductions in AML 
blast count.22-24 Prolonged administration of over four months has been found to be 
feasible, and no drug-associated deaths have occurred.25 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
15 
 
 
(Amendment 4) On July 3, 2019, the FDA granted accelerated approval to selinexor in 
combination with dexamethasone for adult patients with relapsed or refractory multiple 
myeloma who have received at least 4 prior therapies and whose disease was refractory to 
at least 2 proteasome inhibitors, 2 immunomodulatory agents, and an anti-CD38 
monoclonal antibody. Approval was based on a subgroup analysis of 83 heavily pretreated 
patients enrolled on the STORM trial (KCP-330-012; NCT02336815) and treated with 80 
mg selinexor (45 mg/m2) in combination with dexamethasone on Days 1 and 3 of each 
week. Overall response rate was 25.3% (95% CI: 16.4, 36) with a median response duration 
of 3.8 months (95% CI: 2.3, not estimable). Adverse events reported in at least 20% of 
patients include thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased 
weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, 
and upper respiratory tract infection.26  
 
Several Phase 2 studies in solid and CNS tumors have recently opened or are in the late 
planning stages. In the phase 2, two-tier KING study (NCT01986348) evaluating the 
efficacy and safety of single-agent selinexor in patients with recurrent GBM after failure 
of radiation therapy and temozolomide, designed to start at 50 mg/m2, nearly half of 
patients enrolled  needed to de-escalate to 35 mg/m2 during the first 8-dose cycle due to 
anorexia, nausea, dehydration and fatigue. The study was subsequently amended to begin 
at 35 mg/m2 (60 mg flat dosing) twice weekly and to study 45 mg/m2 (80 mg flat dosing) 
given once weekly. Both amended dosing schedules showed improved tolerability and 
similar efficacy. Investigators have reported results showing a 30% 6 cycle PFS rate and a 
10% overall response rate at the 45 mg/m2 weekly dosing.27 No Grade 3 or 4 non-
hematologic adverse events were reported on this arm; out of 30 subjects, Grade 3 
neutropenia developed in 3 patients, and Grade 3 leukopenia, Grade 3 lymphopenia, and 
Grade 4 lymphopenia developed in 1 patient each.  
  
2.4.1 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
Detailed pharmacokinetic (PK) and pharmacodynamic (PD) analyses suggest a 
fairly proportional increase in Cmax and AUC with increasing dose, with no 
accumulation and without affecting half-life or clearance. At 30 mg/m2, AUC0-last. 
(4375 ng*h/mL) was comparable to the anti-tumor exposure observed in mice and 
dogs. Tmax (~3 h) and T1/2 (6-7 h) were consistent across doses. Selinexor undergoes 
moderately rapid oral absorption, with median time to maximal plasma levels 
(Tmax) of 1-8 hours. The volume of distribution is 1.5-2.5 L/kg, indicating good 
distribution to tissues beyond the central (vascular) compartment. The primary 
metabolic route is glucuronidation and hydroxylation of the parent drug. In 
addition, GSH conjugates with selinexor to form inactive metabolites including N-
acetylcysteinyl- and cysteinyl-derivatives. Selinexor is not metabolized by 
CYP450. 
 
Significant increase (2-20x) in XPO1 messenger ribonucleic acid (mRNA) levels 
in circulating leukocytes was observed at all doses, with higher doses 
demonstrating higher levels of XPO1 mRNA induction. Analysis of tumor 
biopsies confirmed nuclear localization of TSPs (e.g., p53, FOXO3A, IκB) and 
apoptosis of cancer cells following selinexor administration.28 
 
As part of KCP-330-002 (the adult Solid Tumor phase 1), one patient (043-013) 
with mandibular cancer received selinexor through a feeding tube by opening 
capsules and adding the powder to water. This patient exhibited rapid selinexor 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
16 
 
absorption, with an AUC0-inf  of 4,520 ng*h/mL  and Cmax of 1,150 ng/mL.  While 
exposure for patient 043-013 was similar to the mean exposure for the other 16 
patients in the trial treated at 30 mg/m2 with oral capsules, Cmax was 3-fold higher 
than the corresponding mean. The rapid absorption and subsequent elevated Cmax 
is likely related to the dose formulation, consistent with the preclinical finding in 
cynomolgus monkeys for the suspension formulation. Of note, there were no 
clinically significant AEs associated with this high Cmax. 
 
Data from KCP-330-003, a food effect study in patients with sarcomas 
(NCT01896505) has shown a 15% increased exposure to selinexor when patients 
take the medication with food, regardless of fat content, versus the fasting state.20 
 
Several correlative biological studies have been initiated as part of the phase 1 trial, 
including study of XPO1 levels in peripheral white blood cells pre- and post-
treatment. In addition, the KING trial includes a surgical arm allowing study of 
resected tumors after up to three doses of selinexor. This has included 
administration of the medication on the morning of surgery with a sip of water, up 
to two hours before induction of anesthesia. Patients have then been allowed to 
resume oral selinexor after recovery (1 to 5 weeks after surgery). There have been 
no adverse effects associated with this pre and post-operative administration of 
selinexor, including on wound healing (personal communication, Andrew 
Lassman). Studies on this tissue included measurement of intra-tumoral drug 
levels, as well as other assays examining pharmacodynamic effect of selinexor on 
tumor cells, including induction of apoptosis, and XPO1 mRNA and protein levels. 
Preliminary data from 7 patients showed that selinexor reached therapeutic 
concentrations of ~50-300 nM within brain tumor tissues, with a median plasma 
concentration of 122 nM in adult GBM after ~2 hours.29 
 
2.5 
Pediatric Studies 
 
2.5.1 
Prior Experience in Children (Updated with amendment 4):  
In a pediatric Phase 1 trial of selinexor in children with recurrent/progressive 
leukemia run through the Dana-Farber Leukemia Consortium (DFCI), the 
recommended Phase 2 dose was determined to be 40 mg/m2 twice weekly, 8 doses 
in a 28 day cycle.30 Two DLTs were encountered: pancreatitis (30 mg/m2) and 
cognitive disturbance (56 mg/m2). Single agent activity was noted with an ORR of 
12.5% [1 CRp (AML), 1 PR (ALL)] and 2 of 4 patients with ALL experienced 
Grade 4 tumor lysis syndrome.30 In addition, as part of a St. Jude Hospital 
investigator sponsored trial evaluating selinexor (Days 1, 3, 8, 10, 22, and 24) with 
fludarabine and cytarabine (Days 15 through 19) for treatment of refractory or 
relapsed leukemia or myelodysplastic syndrome, the MTD of selinexor was 55 
mg/m2.31 The dose-limiting toxicity at 70 mg/m2 was reversible cerebellar toxicity, 
but at and above 40 mg/m2, all patients treated demonstrated evidence of XPO1 
target inhibition.31  
 
2.5.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
The below table depicts pharmacokinetic results obtained from four pediatric 
patients dosed at 30 mg/m2 twice weekly with selinexor. The data shows that 
pharmacokinetic parameters observed in pediatric patients (n=4) at 30 mg/m2 are 
comparable to those observed in adult patients administered with the same 
selinexor dose.     


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
17 
 
 
   
NC = not calculable 
a One patient collected on Day 15 
(Amendment 4) The updated pharmacokinetic data from the DFCI trial continue 
to demonstrate that the pharmacokinetics of selinexor in children are dose 
proportional and achieve exposures similar or slightly higher than that of adults. 
(Place et al ASH 2018). 
 
 
2.6 
Overview of Proposed Pediatric Study 
We will conduct a phase 1 trial of selinexor in children with recurrent or refractory solid 
tumors, including CNS tumors using the Rolling Six design. The aims of the trial will be 
to establish the maximum tolerated pediatric doses of tablet formulation; to investigate the 
toxicities, pharmacokinetics, and pharmacodynamics of selinexor in children with cancer; 
and to preliminarily explore efficacy in pediatric solid and CNS tumors, including medical 
and surgical expansion cohorts of HGG patients.  
 
After the recommended Phase 2 dose has been determined on the dose-escalation portion 
Part A, Parts B and C will open concurrently. During the initial cohort, patients received 
selinexor twice weekly (once on each day) on a days 1,3 schedule (Mon/Wed,Tue/Thurs, 
or Wed/Fri). One cycle was 28 days or 8 doses. Due to unanticipated hematological toxicity 
the schedule was revised (Amendment #1 April 2016) and subsequent patients received 
selinexor twice weekly (once on each day) on a days 1,3 schedule (Mon/Wed,Tue/Thurs, 
or Wed/Fri) during weeks 1-3, followed by a 7 day break. One cycle was 28 days or 6 
doses. With Amendment #4, given evidence from adult trials showing equivalent efficacy 
of once and twice weekly dosing with increased tolerability when given once weekly, the 
once weekly dosing schedule will be tested. Each 28 day cycle will consist of selinexor 
given once a week for 4 doses.  
 
Toxicity will be assessed using CTCAE v5.0. Imaging for disease evaluation during the 
dose escalation phase will occur at the end of Cycle 1, every other cycle x 2, and every 3 
cycles thereafter. Disease response will be assessed according to RECIST v1.1 criteria for 
solid tumors and 2-dimensional measurement for CNS tumors. 
 
2.7 
Rationale for Change in Dosing Schedule (Amendment #1) 
Upon initiation of ADVL1414 Part A, 6 patients were enrolled at Dose Level 1, 35 mg/m2 
of selinexor by mouth twice weekly on a days 1 and 3 schedule for 8 doses within a 28-
day course. Four patients completed course 1, were fully evaluable for toxicity for the 
purposes of dose escalation, and did not experience a DLT. Two patients were inevaluable 
for DLT during cycle 1: one for a protocol deviation regarding the use of cyproheptadine, 
which has been addressed in this amendment, and one for having received a platelet 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
18 
 
transfusion when platelets were at a grade 2 (53K), wherein grade 3 thrombocytopenia 
(<50K) might have constituted a DLT.  In addition, one patient who did not experience a 
DLT during cycle 1, developed a grade 4 neutropenia during cycle 2 (a protocol defined 
DLT), which recurred after dose reduction, and subsequently required removal from 
protocol therapy despite disease stabilization. This observed hematologic toxicity was 
beyond that which was anticipated based on the data from previous adult trials.  
Selinexor is known to block megakaryocyte maturation. Neutropenia is rare.  According to 
the Investigator’s Brochure version 9.0, dated 13 August 2019, the incidence of grade 3/4 
thrombocytopenia in patients with solid tumors was 12% and the incidence of grade 4 
neutropenia was 0.3% (34.7% and 6.4% respectively, when including patients with 
hematologic malignancy). In our recent discussions, the drug company, Karyopharm, 
provided new data from several adult trials in which it was noted that selinexor induced 
thrombocytopenia. The platelet nadir occurred after one cycle. The magnitude of 
thrombocytopenia was independent of dose occurring at selinexor doses of 30-150 mg 
when given 2x wkly, for 7-8 doses/28 cycle. The percent decrease in platelet count was 
relatively constant (~50%) regardless of baseline platelet count. In our discussions with 
Karyopharm, dose reductions for hematological toxicity in adult receiving selinexor were 
not standardized.  However, in review of data we concluded that interruption of selinexor 
therapy, and in cases of prolonged recovery (>3 weeks), decrease in dose frequency 
represent the optimal management for grade 3/4 thrombocytopenia. The mechanism of 
neutropenia is not currently known, less data is available but data indicates that neutropenia 
may be dose dependent and is responsive to granulocyte colony stimulating factor. Data on 
cumulative myelosuppression is not available.  
Selinexor has a unique mechanism of action that allows this scheduling strategy. It acts by 
slowly reversibly inhibiting nuclear export of tumor suppressor proteins, which causes 
cancer cells to undergo a genomic fidelity review with each dose, leading to apoptosis. In 
the past, irreversible inhibition of the nuclear exporter XPO1 has been found to be highly 
toxic to normal cells, leading to the current requirement for intermittent dosing. The half-
life of selinexor is approximately six hours.  
 
2.8 
Rationale for Change in Dosing Schedule (Amendment #4)  
Over 2,601 patients have received selinexor to date through numerous clinical trials for a 
variety of malignancies, both as a single agent and in combination.17 Despite the MTD 
determination of 65 mg/m2/dose in adult single agent Phase 1 studies on the twice weekly 
(8 dose/ cycle) schedule, most studies are now using reduced doses of 35-45 mg/m2/dose 
due to analysis of safety and pharmacokinetic data showing acceptable efficacy and 
improved long-term tolerability. The most recent FDA approval for multiple myeloma uses 
selinexor in combination with dexamethasone at the equivalent of 45 mg/m2/dose (80mg 
flat dosing). Furthermore, it is clear from multiple adult trials of selinexor that weekly 
dosing, even at higher individual doses, reduces myelosuppression and neurotoxicity 
compared to twice weekly dosing. Positive results have been presented in patients with 
sarcoma,32 acute myeloid leukemia, diffuse large B cell lymphoma, and others.  
 
In the Phase 2 trial of selinexor in recurrent glioblastoma (the KING trial), investigators 
have reported results showing a 30% 6 cycle PFS rate and a 10% overall response rate 
using the flat 80 mg weekly schedule (equivalent to 45 mg/m2).27 No Grade 3 or 4 non-
hematologic adverse events were reported using this dose and schedule which was the 
regimen that was most effective and best tolerated; out of 30 subjects, there were no non-
hematologic Grade 3/4 events, Grade 3 neutropenia developed in 3 patients, and Grade 3 
leukopenia, Grade 3 lymphopenia, and Grade 4 lymphopenia developed in 1 patient each.  


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
19 
 
Investigators also demonstrated average intratumoral drug levels of 122 nM, on par with 
the in vitro IC50 described in the preclinical studies in adult and pediatric HGG.6  
 
Comparative pharmacokinetic (PK) analysis between ADVL1414 and multiple adult 
studies suggest Cmax and AUC values at 20 mg/m2 were similar to those seen at 35 mg/m2 
dosing in adults, and values at 35 mg/m2 compared favorably to those seen at doses up to 
60 mg/m2 in adults. 35 mg/m2 dosing in children would therefore appear to produce at 
least equivalent PK values to the 80 mg flat dosing that produced the best responses in 
the KING trial, even when given weekly. A dose of 20 mg/m2, on the other hand, is 
unlikely to produce adequate exposure for CNS tumor response, based on available 
clinical and preclinical data. Since progress in the trial to this point has demonstrated 20 
mg/m2 twice weekly (40 mg/m2 cumulative per week) to be tolerable, we will use 45 
mg/m2 (a 12.5% increase in dose intensity) as our starting dose on the once weekly 
schedule which is anticipated to be less toxic than twice weekly dosing. We will have one 
dose escalation to 55 mg/m2 and one available de-escalation to 35 mg/m2, the lowest dose 
considered likely to produce adequate CNS exposure to be efficacious based on available 
evidence. We hypothesize that tolerability will be improved, that the RP2D for weekly 
dosing will be higher than the current RP2D for twice weekly dosing, and that Cmax and 
AUC values equivalent or higher will be achieved and compare favorably to the dosing 
levels in adults at which responses have been observed. 
 
 
Table A: 
 
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in 
conjunction with the Oncology Patient Enrollment Network (OPEN) a web-based registration 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
20 
 
system available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or Theradex 
Interactive Web Response System (IWRS) for retrieval of patient registration/randomization 
assignment. OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
 
Requirements for OPEN access: 
• A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations: Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must hold 
the OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, crediting, 
consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in OPEN, the 
IVR or NPIVR must list the IRB number used on the site’s IRB approval on their Form FDA 1572 
in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned the appropriate 
OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. Further 
instructional information is in the OPEN section of the CTSU website at https://www.ctsu.org or 
https://open.ctsu.org. For any additional questions, contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
3.1 
Current Study Status  
Investigators should refer to the COG website to determine if the study is currently open 
for accrual.  If the study is listed as active, investigators should then access the Studies 
Requiring Reservations page to ensure that a reservation for the study is available. To 
access the Studies Requiring Reservations page:  
1. Log in to https://open.ctsu.org/open/ 
2.  Click the Slot Reservation Tab. The Site Patient page opens.  
3.  Click the Report Tab. The Slot Reservation Report opens. Available Slots are 
detailed per study strata. 
 
3.2 
IRB Approval 
Local IRB approval of this study must be obtained by a site prior to enrolling patients. Sites 
must submit IRB approvals to the NCI’s Cancer Trials Support Unit (CTSU) Regulatory 
Office and allow 3 business days for processing. The CTSU IRB Certification Form may 
be submitted in lieu of the signed IRB approval letter. All CTSU forms can be located on 
the CTSU web page (www.ctsu.org). Any other regulatory documents needed for access 
to the study enrollment screens will be listed for the study on the CTSU Member’s Website 
under the Regulatory Tab. 
 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
21 
 
are not required to submit separate IRB approval documentation to the CTSU Regulatory 
Office for initial, continuing or amendment review. This information will be provided to 
the CTSU Regulatory Office from the CIRB at the time the site’s Signatory Institution 
accepts the CIRB approval. The Signatory site may be contacted by the CTSU Regulatory 
Office or asked to complete information verifying the participating institutions on the 
study. 
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
 
3.3 
Patient Registration in the COG Registry 
Prior to enrollment on study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry system once authorization for the release of 
protected health information (PHI) has been obtained. 
 
3.4 
Reservation and Contact Requirements 
Once a slot-reservation confirmation is obtained after making a reservation in OPEN, the 
Study Chair or Vice Chair should be notified and site staff may then proceed to enroll 
patients to this study. (The patient will need a COG patient ID number in order to obtain a 
reservation). Patients must be enrolled within 7 calendar days of making a reservation.  
 
Reservations may be obtained 24-hours a day through the OPEN website.  
 
3.5 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
3.6 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  This can be accomplished 
through one of the following mechanisms: a) the COG screening protocol, b) an IRB-
approved institutional screening protocol or c) the study-specific protocol.  Documentation 
of the informed consent for screening will be maintained in the patient’s research chart. 
Studies or procedures that were performed for clinical indications (not exclusively to 
determine eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
3.7 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
22 
 
into RAVE immediately following enrollment. 
 
3.8 
Institutional Pathology Report 
Immediately following enrollment, the institutional pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into RAVE. Note: See Section 
4.1.3 for exceptions. 
 
The report must include the associated study number and COG patient registration and 
accession numbers. Personal identifiers, including the patient’s name and initials must be 
removed from the institutional pathology report prior to submission. 
 
3.9 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Patients who give informed consent for the protocol in order to undergo 
screening for eligibility are not considered enrolled and should not be enrolled until the 
screening is completed and they are determined to meet all eligibility criteria. Study 
enrollment is accomplished by going to the CTSU OPEN (Oncology Patient Enrollment 
Network) https://open.ctsu.org/open/. For questions, please contact the ADVL1414 COG 
Study 
Assigned 
Research 
Coordinator, 
or 
the 
CTSU 
OPEN 
helpdesk 
at 
https://www.ctsu.org/CTSUContact.aspx.  Patients must be enrolled before treatment 
begins.  The date protocol therapy is projected to start must be no later than five (5) calendar 
days after the date of study enrollment. Patients must not receive any protocol therapy 
prior to enrollment. 
 
3.10 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
 
4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies must be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging 
if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01).  All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the 
time of audit. 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
23 
 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age:  Patients must be ≥ than 12 months and ≤ 21 years of age at the time of 
study enrollment. 
 
4.1.2 
BSA:  Patients must have a BSA ≥ 0.84 m2. 
 
4.1.3 
Diagnosis:  
4.1.3.1 Part A: Patients with recurrent or refractory solid tumors, including 
lymphoma and CNS tumors, are eligible. Patients must have had histologic 
verification of malignancy at original diagnosis or relapse except in 
patients with intrinsic brain stem tumors, optic pathway gliomas, or 
patients with pineal tumors and elevations of CSF or serum tumor markers 
including alpha-fetoprotein or beta-HCG. 
 
4.1.3.2 Part B: Patients with recurrent or refractory high grade glioma (WHO 
Grade III/IV) including disseminated tumors (excluding DIPG), not 
requiring surgical resection. Patients must have had histologic verification 
of malignancy at original diagnosis or relapse. 
 
4.1.3.3 Part C: Patients with recurrent or refractory high grade glioma (WHO 
Grade III/IV) and requiring surgical resection (excluding DIPG and 
disseminated tumors), who in the opinion of treating physicians, are 
medically stable to receive 2 doses of selinexor (8-10 days of treatment) 
before undergoing surgery without compromising the success of the 
procedure. Note that if, in the opinion of treating physicians, current 
symptoms necessitate surgery before 2 doses will be able to be received, 
surgery should not be delayed to administer selinexor, and the patient 
would be ineligible for protocol therapy. 
 
4.1.4 
Disease Status:  
Part A: Patients must have either measurable or evaluable disease (see Sections 
12.2 and 12.3 for definitions).  
Parts B & C:  Patients must have measurable disease on imaging.  
 
4.1.5 
Therapeutic Options: Patient’s current disease state must be one for which there 
is no known curative therapy or therapy proven to prolong survival with an 
acceptable quality of life. 
  
4.1.6 
Performance Level:  Karnofsky ≥ 50% for patients > 16 years of age and Lansky 
≥ 50 for patients ≤ 16 years of age (See Appendix I).  Note:  Neurologic deficits 
in patients with CNS tumors must have been relatively stable for at least 7 days 
prior to study enrollment.  Patients who are unable to walk because of paralysis, 
but who are up in a wheelchair, will be considered ambulatory for the purpose of 
assessing the performance score. 
  
4.1.7 
Prior Therapy 
 
4.1.7.1 Patients must have fully recovered from the acute toxic effects of all prior 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
24 
 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g. blood count 
criteria, the patient is considered to have recovered adequately. 
 
a. Myelosuppressive chemotherapy:  At least 21 days after the last dose 
of myelosuppressive chemotherapy (42 days if prior nitrosourea).  
b. Hematopoietic growth factors: At least 14 days after the last dose of a 
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting 
growth factor.  For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair.  
c. Biologic (anti-neoplastic agent):  At least 7 days after the last dose of 
a biologic agent.  For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair. 
d. Immunotherapy: At least 42 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines. 
e. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1 
f. Corticosteroids: See Section 4.2.2.1. If used to modify immune 
adverse events related to prior therapy, ≥ 14 days must have elapsed 
since last dose of corticosteroid. 
g. XRT:  At least 14 days after local palliative XRT (small port); At least 
150 days must have elapsed if prior TBI, craniospinal XRT or if ≥ 50% 
radiation of pelvis; At least 42 days must have elapsed if other 
substantial BM radiation. 
h. Stem Cell Infusion without TBI:  No evidence of active graft vs. host 
disease and at least 56 days must have elapsed after transplant or stem 
cell infusion. 
i. 
Patients must not have received prior exposure to selinexor. 
  
4.1.8 
Organ Function Requirements 
 
4.1.8.1 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 
- 
Platelet count ≥ 100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
- 
Hemoglobin ≥  8.0 g/dL at baseline (may receive RBC 
transfusions) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study if they meet the blood counts in 4.1.8.1.a (may 
receive transfusions provided they are not known to be refractory 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
25 
 
to red cell or platelet transfusions). These patients will not be 
evaluable for hematologic toxicity. At least 5 of every cohort of 6 
patients must be evaluable for hematologic toxicity for the dose-
escalation part of the study. If dose-limiting hematologic toxicity 
is observed, all subsequent patients enrolled on Part A must be 
evaluable for hematologic toxicity. 
 
4.1.8.2 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR ≥ 70 ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
4.1.8.3 Adequate Liver Function Defined as: 
- 
Total Bilirubin ≤ 1.5 × upper limit of normal (ULN) for age  
- 
SGPT (ALT) ≤ 3 × ULN = 135 U/L.  For the purpose of this study, 
the ULN for SGPT is 45 U/L.  
- 
Serum albumin ≥ 2 g/dL. 
 
4.1.8.4 Adequate Pancreatic Function Defined as: 
-    
Serum amylase ≤ 1.5 x ULN 
-    
Serum lipase ≤ 1.5 x ULN 
  
4.1.9 
Patients with seizure disorder may be enrolled if on anticonvulsants and well 
controlled. 
 
4.1.10 Patients must be able to swallow tablets whole. 
 
4.1.11 Part C: Archived paraffin-embedded tissue (20 unstained slides or a tumor block) 
from a prior resection must be available as a control for correlative studies. If tissue 
blocks or slides are unavailable, the study chair must be notified prior to 
enrollment.  
 
4.1.12 Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines.  
 
 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
26 
 
Pregnant or breast-feeding women will not be entered on this study, since there is 
yet no available information regarding human fetal or teratogenic toxicities. Based 
on its mechanism of action and findings in animals, selinexor may cause fetal harm 
when administered to a pregnant woman. Pregnancy tests must be obtained in girls 
who are post-menarchal. Males with female partners of reproductive potential or 
females of reproductive potential may not participate unless they have agreed to 
use two effective methods of birth control- including a medically accepted barrier 
method of contraceptive method (e.g., male or female condom) for the entire 
period in which they are receiving protocol therapy and for at least 1 week 
following their last dose of study drug. Abstinence is an acceptable method of birth 
control. 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of 
corticosteroid (See Section 4.1.7.1.f). 
 
4.2.2.2 Investigational Drugs: Patients who are currently receiving another 
investigational drug are not eligible. 
 
4.2.2.3 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible. 
 
4.2.3 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.4 
Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.5 
Patients who, in the opinion of the investigator, may not be able to comply with 
the safety monitoring requirements of the study are not eligible. 
 
4.2.6 
Patients with BMI < 3rd percentile for age, as defined by WHO criteria for 
patients 1-2 years of age and CDC criteria for patients > 2 years of age, are not 
eligible. (See Appendix IX) 
 
4.2.7 
Patients with grade 3 ataxia or grade >1 extrapyramidal movement disorder are 
not eligible. 
 
4.2.8 
Patients with known macular degeneration, uncontrolled glaucoma, or cataracts 
are not eligible. 
 
5.0 
TREATMENT PROGRAM 
 
5.1 
Treatment Overview  
(Pre-Amendment #1): 
Week 
Day 
Agent: Selinexor 
1 
1, 3 (Doses 1,2) 
X 
2 
8, 10 (Doses 3,4) 
X 
3 
15, 17 (Doses 5,6) 
X 
4 
22, 24 (Doses 7,8) 
X 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
27 
 
 
Patients will receive selinexor twice weekly on a days 1,3 schedule (Mon/Wed, 
Tues/Thurs, or Wed/Fri).  A cycle of therapy will be 28 days or 8 doses. The drug will be 
administered in tablet form with food. Patients may continue for a maximum of 24 cycles. 
Refer to section 7.3 for recommended supportive care guidelines. 
 
(Amendment #1):  
Week 
Day 
Agent: Selinexor 
1 
1, 3 (Doses 1,2) 
X 
2 
8, 10 (Doses 3,4) 
X 
3 
15, 17 (Doses 5,6) 
X 
4 
Rest 
 
 
With Amendment #1, patients will receive selinexor twice weekly on a days 1,3 schedule 
(Mon/Wed, Tues/Thurs, or Wed/Fri) on Weeks 1-3, followed by a one-week rest period.  
A cycle of therapy will be 28 days or 6 doses. The drug will be administered in tablet form 
with food. Patients may continue for a maximum of 24 cycles. Refer to section 7.3 for 
recommended supportive care guidelines. 
 
Amendment #4: 
Week 
Day 
Agent: Selinexor 
1 
1 
X 
2 
8 
X 
3 
15 
X 
4 
22 
X 
 
With Amendment #4, patients will receive selinexor once weekly, on Days 1, 8, 15, and 22 
of a 28-day cycle. The drug will be administered in tablet form with food. Patients may 
continue for a maximum of 24 cycles. Refer to Section 7.3 for recommended supportive 
care guidelines. 
 
Drug doses should be adjusted based on the BSA calculated from height and weight 
measured within 7 days prior to the beginning of each cycle (See Appendix VI).  If a dose 
is vomited within 30 minutes of administration and there is visible evidence of the tablet, 
the dose should be repeated. If the tablet is not visible, or the dose is vomited later than 30 
minutes after administration, the dose should not be repeated. The patient/caregiver should 
make a note of the vomited dose and whether there is visible evidence of the tablet on the 
pill diary and proceed with the next dose at the next scheduled time of administration.  
 
Selinexor is supplied by Karyopharm Therapeutics. Do not use commercial supply.  
 
5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0.  
 
5.3 
Dose Escalation Schema 
 
5.3.1 
Inter-Patient Escalation: Part A 
The starting dose will be 35 mg/m2 (dose level 1), with dose levels for 
subsequent groups of patients as follows.  
 
(Pre-Amendment #4): Twice weekly dosing 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
28 
 
Table for Dose Levels 1-3. 
Dose Level** 
Selinexor Dose (mg/m2) 
-1 
20 
1* 
35 
2 
45 
3 
  60^ 
* Starting Dose Level 
^ Further dose escalation will be considered after evaluation of the pharmacokinetics and 
toxicity profile 
 
Amendment #4: Once weekly dosing 
Table for Dose Levels 1 & 2:  
Dose Level** 
Selinexor Dose (mg/m2) 
-1 
35 
1* 
45 
2 
55 
* Starting Dose Level 
 
Amendment #4: With amendment #4, the starting dose will be 45 mg/m2. 
Prophylactic treatment of nausea and emesis (such as 5-HT3 antagonists +/- 
another agent [e.g., dexamethasone, NK1 receptor antagonist, etc]) is strongly 
recommended during Cycles 1 and 2 (see Section 7.3). In adult patients, double 
antiemetic coverage (5HT3 antagonist + another agent) is preferred. If DLT of 
vomiting or dehydration is experienced in ≥ 2/6 evaluable patients at a dose level 
outlined in the dose level tables above, the dose level will be repeated with required 
maximal antiemetic therapy (5-HT3 antagonist PLUS antiemetic agent(s)) prior to 
each dose during Cycles 1 and 2. Once the requirement for prophylaxis during 
Cycles 1 and 2 has been made, this will be carried forward for all subsequent 
patients entered at the same or higher dose level. Dose levels which require 
antiemetic prophylaxis will be denoted with the suffix letter “A” (e.g. Dose Levels 
-1A, 1A, or 2A).    
 
Selinexor is supplied by Karyopharm Therapeutics. Do not use commercial 
supply.  
 
5.3.2 
Part B: Non-Surgical HGG Expansion Cohort 
Patients with HGG not requiring resection will be treated at the recommended 
phase 2 dose (RP2D) determined from the phase 1 component (Part A) of this 
trial. 
 
5.3.3 
Part C: Surgical HGG Expansion Cohort 
Patients with HGG requiring resection (Part C) will be treated at the recommended 
phase 2 dose (RP2D) determined from the phase 1 component (Part A) of this trial 
for 2 doses prior to undergoing scheduled resection of their tumors (i.e. Surgical 
resection should occur after dose on Day 8 but before dose on Day 15 of Cycle 1). 
After recovery from surgery with wound healed (minimum 3 weeks) and meeting 
criteria in Section 5.2, patients can resume selinexor at the same dose and schedule 
and continue therapy to complete Cycle 1 and continue with Cycle 2. Patients who 
fail to recover from surgery within 6 weeks will be removed from protocol therapy. 
 
5.3.4 
Intra-Patient Escalation 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
29 
 
Intra-patient dose escalation is not allowed. 
 
5.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be 
downloaded 
from 
the 
CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Any 
suspected or confirmed dose-limiting toxicity should be reported immediately (within 24 
hours) to the Study Chair. 
 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to selinexor.  The DLT observation period for the purposes of dose-escalation 
will be the first cycle of therapy. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.   
 
5.5.1 
Non-hematological dose-limiting toxicity 
• 
Any Grade 4 non-hematological toxicity 
• 
Any Grade 3 non-hematological toxicity with the specific exception of: 
- 
Grade 3 nausea, vomiting, or dehydration that resolves to Grade ≤ 2 
within 3 days. For the purposes of this pediatric study, tube feeding 
should not be considered a Grade 3 DLT. See Section 7.3 for supportive 
care guidelines. 
- 
Grade 3 anorexia. See Section 7.3 for supportive care guidelines 
- 
Grade 3 weight changes. See Section 7.3 for supportive care guidelines. 
- 
Grade 3 diarrhea that resolves to Grade ≤ 2 within 7 days  
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to 
levels that meet initial eligibility criteria or baseline within 7 days. See 
Appendix VIII for values that represent thresholds between CTCAE 
grades.  
- 
Grade 3 bilirubin that returns to meet eligibility criteria within 7 days. 
See Appendix VIII for values that represent thresholds between CTCAE 
grades.  
- 
Grade 3 infection of < 5 days duration 
- 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia, 
hypomagnesemia, or asymptomatic hyponatremia responsive to oral 
supplementation 
• 
Fever greater than 40°C of ≥ 5 days duration will be considered dose-limiting 
• 
Any ≥ grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires two doses omitted in a cycle. 
• 
Any toxicity that requires treatment interruption as outlined in Sections 6.3- 
6.7 and does not resolve within the specified time frame will be considered 
dose-limiting. 
 
5.5.2 
Hematological dose limiting toxicity 
In patients evaluable for hematological toxicity (See Section 4.1.8.1), 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
30 
 
• 
Grade 4 thrombocytopenia (platelet count < 25,000/mm3), Grade 4 anemia,  
or Grade 4 neutropenia, not due to malignant infiltration  
• 
Grade 3 thrombocytopenia that persists for ≥ 7 days 
• 
Grade 3 thrombocytopenia requiring a platelet transfusion on 2 separate days, 
within a 7 day period 
• 
Grade 3 thrombocytopenia with clinically significant bleeding, petechiae or 
purpura  
• 
Myelosuppression that causes a delay of >14 days between treatment cycles. 
 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair and Vice Chair must be notified of any dosage modification or use of 
myeloid growth factor. 
 
6.1 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
If a patient experiences Grade 4 neutropenia, selinexor should be held. Institute 
short acting granulocyte colony stimulating factor (filgrastim or biosimilar) as 
per institutional guidelines. Counts should be checked every 2 – 3 days until 
recovery to Grade < 2 or baseline and without fever (if febrile) and the patient is 
clinically stable. If this is a first occurrence, and myelosuppression has lasted < 7 
days, the patient may continue at the same dose. If lasting for > 7 days or this is a 
second occurrence resulting in a missed dose, reduce selinexor by 1 dose level. If 
the occurrence falls on Day 1 of a cycle, delay start of the cycle, institute short 
acting granulocyte colony stimulating factor as per institutional guidelines, and 
check neutrophils every 2 – 3 days until recovery to Grade < 2 and eligibility is 
met to begin the next cycle. If the toxicity recurs, the patient may resume 
treatment at the currently assigned dose with a change in the schedule to weekly 
dosing for 3 weeks followed by a 1 week rest.   
 
6.1.2 
If a patient experiences either Grade 4 or dose-limiting Grade 3 
thrombocytopenia as defined in Section 5.5.2, selinexor should be held.  Counts 
should be checked every 2 – 3 days until any bleeding has stopped, patient is 
clinically stable, and the platelets have recovered to meet eligibility to begin the 
next cycle. When resuming selinexor, reduce by 1 dose level. If the occurrence 
falls on Day 1 of a cycle, delay start of the cycle and check platelet counts every 
2 – 3 days until the platelets have recovered to meet eligibility to begin the next 
cycle. When resuming selinexor, reduce by 1 dose level. If the toxicity recurs, the 
patient may resume treatment at the currently assigned dose with a change in the 
schedule to weekly dosing for 3 weeks followed by a 1-week rest.  
 
6.1.3 
If a patient experiences myelosuppression not otherwise specified above that 
causes a delay of >14 days between treatment cycles, counts should be checked 
every 3 – 4 days for thrombocytopenia and for neutropenia during this time. 
Upon resolution to eligibility criteria, the patient may resume the subsequent 
cycle reduced by one dose level. If the toxicity recurs, the patient may resume 
treatment at the currently assigned dose with a change in the schedule to weekly 
dosing for 3 weeks followed by a 1 week rest.   
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
31 
 
6.1.4 
Patients who experience Grade 4 anemia that is at least possibly attributable to 
selinexor must be removed from protocol therapy. 
 
6.1.5 
If toxicity does not resolve to meet starting parameters (section 5.2) within 21 
days after the planned start of the next treatment cycle, the patient must be 
removed from protocol therapy. 
 
6.1.6 
If dose-limiting hematological toxicity recurs in a patient who has resumed 
treatment at Dose Level -1 and is already on the modified selinexor dosing 
schedule (3 weeks on/1 week off), the patient must be taken off protocol therapy.  
 
6.2 
Dose Modifications for Non-Hematological Dose-Limiting Toxicity 
 
6.2.1 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.5.1, the treatment will be held.  If the toxicity resolves to meet 
eligibility parameters or baseline within 14 days after the planned start of the 
next treatment cycle, the patient may resume treatment reduced by one dose 
level. If the toxicity recurs, the patient may resume treatment at the currently 
assigned dose with a change in the schedule to weekly dosing for 3 weeks 
followed by a 1 week rest. Dosing schedules modified for toxicity will not be re-
escalated, even if there is minimal or no toxicity with the modified dose.  
 
6.2.1.1 Note that patients who experience Grade ≥ 3 anaphylaxis should be 
permanently removed from protocol therapy and should not resume 
treatment. 
 
6.2.2 
If toxicity does not resolve to meet eligibility or baseline parameters within 21 
days after the planned start of the next treatment cycle, the patient must be 
removed from protocol therapy. 
 
6.2.3 
If the same dose-limiting toxicity recurs in a patient who has resumed treatment 
at Dose Level -1  and is already on the modified selinexor dosing schedule (3 
weeks on/1 week off), the patient must be taken off protocol therapy. 
 
6.3 
Dose Modifications for Anorexia/Weight Loss 
 
6.3.1 
Anorexia and weight loss are anticipated toxicities and should be proactively 
managed. If a patient experiences Grade 3 anorexia or weight loss, dosing should 
continue as planned and maximal supportive care (e.g. appetite stimulants, 
nutritional supplements, tube feeding) should be implemented as outlined in 
Section 7.3.1. 
 
6.4 
Dose Modifications for Nausea/Vomiting/Dehydration 
If a patient experiences Grade 3 nausea, vomiting, or dehydration, the treatment will be 
held. Patients should be treated with anti-emetic therapy as outlined in Section 7.3.2. If 
toxicity resolves to Grade ≤ 2 nausea/vomiting/dehydration within 3 days, drug may 
resume at same dose. Grade 3 nausea, vomiting, or dehydration that persists ≥ 3 days will 
be considered dose-limiting and require dose modification per Section 6.2. 
 
6.5 
Dose Modifications for Diarrhea 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
32 
 
Grade  
Action 
Dose Modification  
Grade 1 
 
• Dietary recommendations: avoid lactose 
containing foods, apple juice  
Maintain dose. 
Grade 2 
• Dietary recommendations: avoid lactose 
containing foods, apple juice, “BRAT” 
diet 
• Rule out other causes of diarrhea, 
including infectious agents. In case of 
opportunistic infection, withdraw all 
steroids (with tapering if medically 
appropriate) until culture is negative. 
• Institute standard anti-diarrheal therapy 
with loperamide (see Appendix X)  
• After the first occurrence of diarrhea, 
loperamide 
can 
be 
considered  
prophylactically approximately 1 – 2 
hours before the administration of 
selinexor and repeated every 4 hours for 
the first 12 hours 
Maintain dose.  
Grade 3/4 
 
• Dietary recommendations: avoid lactose 
containing foods, apple juice, “BRAT” 
diet 
• Rule out other causes of diarrhea, 
including infectious agents. In case of 
opportunistic infection, withdraw all 
steroids (with tapering if medically 
appropriate) until culture is negative 
• Institute standard anti-diarrheal therapy 
with loperamide (see Appendix X)  
• After the first occurrence of diarrhea, 
loperamide should be considered  
prophylactically approximately 1 – 2 
hours before the administration of 
selinexor and repeat every 4 hours for the 
first 12 hours 
Hold selinexor 
until Grade ≤ 2. If 
> 7 days, resume at 
lower dose level. 
 
If a patient experiences Grade ≥ 3 diarrhea, treatment will be held. If diarrhea resolves to 
Grade ≤ 2 within 7 days, the drug may be resumed at the same dose. Grade ≥ 3 diarrhea 
that persists ≥ 7 days will be considered dose-limiting and require dose modification per 
Section 6.2. If Grade ≥ 3 diarrhea recurs at the lower dose and persists ≥ 7 days despite 
maximal use of antidiarrheal therapy, the patient will be removed from protocol therapy. 
 
6.6 
Dose Modifications for Hyponatremia 
 
Grade  
Action 
Dose Modification  
Grade 1  
130 mmol/L to <LLN 
 
• Be certain sodium level is corrected for 
hyperglycemia (serum glucose > 150 
mmol/L).   
Maintain dose. 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
33 
 
• Rule out other causes of low sodium 
(e.g., cardiac, hepatic, adrenal, renal and 
thyroid diseases, SIADH, Fanconi 
Syndrome, hyperglycemia, diuretic use). 
• Consider salt supplementation one – two 
times per day. 
129 – 126 mmol/L 
(asymptomatic) 
• Be certain sodium level is corrected for 
hyperglycemia (serum glucose > 150 
mmol/L).   
• Rule out other causes of low sodium 
(e.g., cardiac, hepatic, adrenal, renal and 
thyroid diseases, SIADH, Fanconi 
Syndrome, hyperglycemia, diuretic use). 
• Initiate salt supplementation two-three 
times per day. 
Hold selinexor 
until Grade ≤ 1, 
resume at same 
dose level. 
≤ 125 mmol/L or any 
symptomatic Grade 3 
 
• Correct sodium as per institutional 
guidelines 
• Initiate salt supplementation two-three 
times per day. 
Hold selinexor 
until Grade ≤ 1, 
resume at lower 
dose level. 
  
6.7 
Dose Modifications for Hepatic Adverse Events 
 
6.7.1 
If a patient experiences Grade ≥ 2 total bilirubin increase, treatment will be held. 
If toxicity resolves to Grade ≤ 1 within 7 days, the drug may be resumed at the 
same dose. Grade ≥ 2 total bilirubin increase that persists ≥ 7 days will be 
considered dose-limiting and require dose modification per Section 6.2. 
 
6.7.2 
If a patient experiences Grade ≥ 3 ALT or AST, treatment will be held. If toxicity 
resolves to Grade ≤ 1 within 7 days, the drug may be resumed at the same 
dose. Grade ≥ 3 ALT or AST that persists ≥ 7 days will be considered dose-
limiting and require dose modification per Section 6.2. 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on protocol therapy. 
 
7.3 
Supportive Care 
Clinical observations in over 400 adult patients treated with selinexor have indicated that 
the dose limiting toxicities (DLTs) are primarily related to anorexia, fatigue, nausea, 
vomiting, and diarrhea and with poor caloric and fluid intake leading to dehydration and 
weight loss. Significant fatigue and somnolence have also been noted in pediatric studies. 
Prophylactic use of 5-HT3 anti-nausea / antiemetic therapy is strongly recommended, and 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
34 
 
further supportive care with acid suppression (proton pump inhibitors and/or H2-blockers), 
glucocorticoids, and other standard treatments should be administered as per institutional 
guidelines for symptomatic patients, keeping in mind that nausea and vomiting related to 
selinexor is often delayed.   
 
Below are recommendations based on the experience of the adult clinical trials and the  
DFCI pediatric leukemia trial but do not represent required treatment approaches should 
the toxicities occur.  The administration of supportive care is as per institutional guidelines 
and the treating provider. 
 
7.3.1 
Anorexia/Weight loss 
Selinexor treatment can lead to anorexia, decreased food intake with subsequent 
weight loss. Participants should be weighed at least weekly during study-required 
outpatient visits during cycle 1 and biweekly during cycles 2 and 3. If the patient 
is admitted for dehydration or malnutrition, more frequent weight assessment is 
recommended. It is strongly recommended that patients receive ongoing 
nutritional assessment and dietary support consultation. Administration of high 
caloric beverages (e.g., Pediasure®) should be considered for all patients. The use 
of supplemental tube feeding is acceptable. 
 
Patients who experience decreased food/liquid/caloric intake secondary to 
anorexia should have a patient log of food and drink with monitoring by the 
treatment team. Fresh juices, simple carbohydrates, as well as ginger-containing 
foods and beverages can improve appetite. 
 
Supportive care should be escalated for ≥ Grade 1 anorexia or weight loss. 
Guidelines for standard appetite stimulants are provided in the table below. 
The use of low dose olanzapine has been the most helpful in the control of 
nausea and anorexia in adult studies using selinexor. Olanzapine for appetite 
stimulation and the treatment of chemotherapy induces nausea and vomiting, has 
not been thoroughly studied in children, and may have overlapping side effects 
with selinexor, including sedation and dizziness. For pediatrics, the suggested 
starting dose of olanzapine is approximately 0.06 mg to 0.1 mg/kg for patients < 
10 years, 1.25 mg PO qPM for patients 10 – 12 years old or 2.5 mg PO qPM for 
patients > 12 years old.33 Patients who exhibit no response after 4 weeks, defined 
as no weight gain or further loss, may increase by 1.25 mg/day weekly to 
maximum 2.5 mg/day for children < 10 years, 5 mg/day for children ages 10 – 12, 
and 10 mg/day for children older than 12 years; use caution escalating olanzapine 
doses in patients younger than 10 years. Olanzapine may be given in combination 
with a corticosteroid. Either dexamethasone < 0.25 mg/kg daily (max dose: 10 mg) 
or prednisone < 0.5 mg/kg daily (max dose: 20 mg) is recommended on the days 
of, and 1 day after, selinexor dosing. 
 
Additional recommended agents are megestrol acetate (10 mg/kg/dose by mouth 
once daily; max dose: 800 mg/day) or cyproheptadine at a dose of 0.25 mg/kg/day 
orally in two divided doses and as second line. Dronabinol has also shown some 
activity in both nausea/emesis and anorexia in patients treated with selinexor. 
 
Anorexia or Weight Loss 
Grade  
Action 
Dose Modification  
Grade 1  
• Rule out other causes of anorexia. 
Maintain dose. 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
35 
 
• Assess dietary options (e.g., try a variety of other 
foods).  
• Add high-calorie supplements (e.g., Pediasure®).  
• Consider adding olanzapine: the suggested starting 
dose of olanzapine is 0.06 mg to 0.1 mg/kg for 
patients < 10 years, 1.25 mg PO qPM for patients 
10 – 12 years old or 2.5 mg PO qPM for patients > 
12 years old.33 
Grade ≥ 2 
• Rule out other causes of anorexia. 
• Assess dietary options (e.g., try a variety of other 
foods).  
• Add high-calorie supplements (e.g., Pediasure®).  
• Consider adding olanzapine: the suggested starting 
dose of olanzapine is 0.06 mg to 0.1 mg/kg for 
patients < 10 years, 1.25 mg PO qPM for patients 
10 – 12 years old or 2.5 mg PO qPM for patients > 
12 years old.33 Patients who exhibit no response 
after 4 weeks may increase by 1.25 mg/day weekly 
to maximum 5 mg/day for children ages 10 – 12 
and 10 mg/day for children older than 12 years; use 
caution escalating olanzapine doses in patients 
younger than 10 years. 
• Consider addition of < 0.25 mg/kg (max 10 
mg/dose) dexamethasone or equivalent with each 
dose of selinexor +/- the day after selinexor. 
• Consider megestrol acetate (10 mg/kg/dose by 
mouth once daily; max 800 mg/day) or 
cyproheptadine at a dose of 0.25 mg/kg/day orally 
in two divided doses 
• Consider anabolic steroids such as oxandrolone, or 
dronabinol or other cannabinoid, mainly for 
patients who can’t tolerate steroids or at high risk to 
progress. 
See Section 6.3 
 
7.3.2 
Nausea and Emesis 
Prophylactic treatment of nausea and emesis is strongly recommended during 
Cycles 1 and 2 and will be required for any dose level with the suffix “A” (e.g. 
1A, 2A). See https://childrensoncologygroup.org/downloads/COG_SC_CINV
_Guidelines_Document_Feb_2018.pdf for COG-endorsed antiemetic guidelines. 
If not instituted prophylactically, antiemetic therapy should begin once there is any 
indication of nausea as outlined in Section 6.4. 
 
7.3.2.1 Acute Emesis (occurring within 24 hours of administration of selinexor) 
Acute emesis has not frequently occurred with selinexor, but has been 
reported. Selinexor associated nausea/emesis generally responds to D2-
antagonists (e.g.hydroxyzine), 5-HT3 antagonists (e.g. ondansetron), or 
combinations of agents. 5-HT3 receptor antagonists all appear equally 
effective at preventing nausea/emesis at standard doses. The efficacy of 5-
HT3 receptor antagonists is significantly improved when combined with 
glucocorticoids. As QTc prolongation is the main side effect, magnesium 
and potassium should be corrected prior to use. 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
36 
 
 
Neurokinin-1 receptor antagonists (e.g., aprepitant) should be considered 
once uncontrolled emesis persists despite the use of the above 
recommended standard treatments. Neurokinin-1 receptor antagonists can 
be given with combination of dexamethasone and 5-HT3 receptor 
antagonists. 
 
Additional treatment: Metoclopramide hydrochloride has been effective 
when given prior to meals (up to 4 times a day) in adult patients. 
Dronabinol has shown some activity in both nausea/emesis and anorexia 
in patients treated with selinexor. Lorazepam can be added to the 
combination treatment of 5-HT3 receptor antagonists and dexamethasone, 
e.g., at night, but has been less effective in selinexor associated nausea and 
emesis. 
 
7.3.2.2 Delayed Emesis (occurring greater than 24 hours after administration of 
selinexor)  
Selinexor is infrequently associated with delayed, resistant emesis. Many 
of the regimens associated with delayed emesis are classified as high-
emetic risk, and professional guidelines recommend the use of an NK1 
receptor antagonist (either NK-1 blockers e.g., aprepitant on days 1 to 3 or 
fosaprepitant on day 1 only), plus a glucocorticoid on days 1 to 4, along 
with a 5-HT3 receptor antagonist (particularly second generation agents) 
on day 1. This regimen is effective against both acute and delayed emesis. 
 
Conventional antiemetics are more successful at preventing emesis than in 
preventing nausea, particularly delayed nausea. As previously noted, in 
adult studies, olanzapine given once daily (typically given at night to 
mitigate sedative effects) was effective in both antiemetic and nausea 
control. It may also be useful for management of breakthrough emesis, and 
to improve food intake in patients with anorexia. Olanzapine for the 
treatment of chemotherapy induced nausea and vomiting, has not been 
thoroughly studied in children, and may have overlapping side effects with 
selinexor, including sedation and dizziness. Guidelines for olanzapine use 
in pediatrics can be found in Section 7.3.1. 
 
The following additional agents have been administered in the adult 
population: lorazepam, alprazolam, dopaminergic D2-antagonists (eg, 
prochlorperazine, thiethylperazine, haloperidol), or substituting high-dose 
intravenous metoclopramide for the 5-HT3 antagonist. 
 
7.3.3 
Diarrhea 
 
 
 
Refer to Section 6.5.  
 
7.3.4 
Dysgeusia 
Suggested foods that can reduce metallic taste include sour foods that are rich in 
citric acid like orange juice or vitamin C drops. Avoid sweets. Oral hygiene should 
be optimized. 
 
7.3.5 
Ophthalmic Toxicities 
Some episodes of blurred vision in adult clinical studies of selinexor have 
responded to IV hydration and have been attributed to dehydration. Therefore, IV 
hydration to correct any clinical deficits should be considered for blurred vision. 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
37 
 
For blurred vision that does not improve with hydration within 24 hours, or any 
other ophthalmic toxicity grade 2 or higher, assessment by an ophthalmologist is 
strongly recommended. As of June 19, 2020, 2 of 42 patients enrolled on 
ADVL1414 have reported a serious adverse event of grade 4 vision loss, both of 
whom had tumors affecting the optic chiasm in the setting of tumor progression. 
Blurred vision is a known side effect of selinexor and described as generally mild, 
not accompanied by objective changes on ophthalmologic exam and nearly always 
resolves. However, a contribution of selinexor to blurred vision cannot be ruled 
out. 
 
 
7.3.6 
Fatigue/Somnolence  
Fatigue has been noted as an adverse effect of selinexor in adult studies, and more 
significant fatigue, accompanied by somnolence, has been noted in pediatric 
studies to date, potentially associated with cerebral edema.31 Glucocorticoid 
premedication continued for 48 hours post-dosing has been an effective 
management to date. Consideration may also be given to the use of 
methylphenidate (Initial: 0.3 mg/kg/dose PO qAM. Maintenance: 0.3-1 mg/kg PO 
qAM; maximum daily dose: 60 mg/day).34,35 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can be used in the 
setting of Grade 4 neutropenia and thrombocytopenia. The Study Chair should be notified 
before growth factors are initiated. 
 
7.5 
Concomitant Medications 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary (see Section 7.3). Clinical evidence suggests that 
selinexor can be safely given with acetaminophen, but given the theoretical potential for GSH 
depletion, acetaminophen should not be taken within 2 hours of administration of selinexor, 
and it is recommended that the total daily dose of acetaminophen should not exceed 20 mg/kg 
(maximum 1 gram/day) on days of selinexor dosing. 
 
7.6 
Part C (HGG Surgical Expansion Cohort) 
For HGG patients who temporarily discontinue protocol therapy to undergo scheduled tumor 
resection, therapy may not be restarted until wound healed (minimum 3 weeks) and until 
recovery to eligibility requirements (Section 4.0). Although patients will not be taking 
selinexor during the recovery period, platelets should be monitored as part of the twice weekly 
CBCs required during Cycle 1 as per Section 8.1, and platelets should be maintained at a safe 
level to prevent post-operative bleeding as per institutional standards. Failure to adequately 
recover from surgery within 6 weeks after surgery will require removal from protocol 
therapy. 
  
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
38 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of therapy.  Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess 
eligibility.  If a post-enrollment lab value is outside the limits of eligibility, or laboratory 
values are older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum creatinine.  If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies must 
be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging if 
necessary). 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 18 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Neurologic Exam 
X 
Weekly 
X 
Pregnancy Test1 
X 
End of Cycle 11 
Every other cycle x 2 
then q 3 cycles 1 
Height, weight  
X 
Weekly 
Every other week 
during cycles 2 and 3 
then prior to each 
cycle 
BSA 
X 
 
X 
Performance Status 
X 
 
 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 days)2 
Weekly2 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, AST, bilirubin 
X 
Weekly 
X 
Albumin 
X 
 
X 
Amylase, Lipase 
X 
 
X 
Tumor Disease Evaluation 
X 
End of Cycle 19 
Every other cycle x 2 
then q 3 cycles 3 
Patient Diary4 
 
Weekly 
X 
Pharmacokinetics5 
X 
X 
 
Pharmacodynamic Studies6 
X 
X 
 
Tissue Studies7 (Part C) 
X 
 
 
Snellen Eye Chart10 
X 
 
Every other cycle x 2 
then q 3 cycles 10 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 
active patients must use two effective methods of birth control- including a medically accepted barrier 
method of contraceptive method (e.g., male or female condom).  Abstinence is an acceptable method of 
birth control. Pregnancy testing is required prior to tumor imaging per institutional guidelines. 
2 
If patients develop Grade 4 neutropenia then CBCs should be checked every 3 to 4 days until recovery 
to Grade 3 
3 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
39 
 
of either a PR or CR.  Please note that for solid tumor patients, if the institutional investigator determines 
that the patient has progressed based on clinical or laboratory evidence, he/she may opt not to confirm 
this finding radiographically. 
4 
Patient diary (see Appendix VII) should be reviewed and uploaded into RAVE weekly during Cycle 1, 
and after completion of each treatment cycle. 
5 
See Section 8.3 for timing of PK studies. 
6 
In consenting patients. See Section 8.4 for timing of Pharmacodynamic studies. 
7 
See Section 8.5 for details of tissue studies. 
8 
Part C: Observations are required as scheduled during protocol treatment only; i.e. weekly labs and 
observations are not required during the “surgery window” and may be held until resuming protocol 
therapy. 
9 
Patients in Part C who interrupt treatment of Cycle 1 due to required resection should have scans 
repeated prior to resuming protocol therapy. 
10 
Snellen eye chart should be used to assess visual acuity. If a decline in visual acuity occurs or other 
visual symptoms occur, the patient should be referred to an ophthalmologist for an examination. 
 
8.2 
Radiology Studies 
 
8.2.1 
Central Radiology Review for Response:  Patients who respond (CR, PR, or MR) 
to therapy or have long term stable disease (SD) (≥ 6 cycles) on protocol therapy 
will be centrally reviewed. COG Operations Center will notify the Imaging 
Center of any patient requiring central review. The Imaging Center will then 
request that the treating institution forward the requested images for central 
review. The central image evaluation results will be entered into RAVE for 
review by the COG Operations Center and for data analysis.  
 
The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the LifeImage.   
 
COG institutions that are not connected via the LifeImage can send the images on 
hard copy film, CD ROM, USB flash drive or by FTP.  Submitted imaging studies 
should be clearly marked with the COG patient ID, study number (ADVL1414) 
and date and shipped to Syed Aamer at the address below: 
 
Syed Aamer, MBBS, CRP 
Administrator, Imaging Research Center 
Children’s Hospital Los Angeles  
4650 Sunset Boulevard, MS # 81 
Los Angeles, CA 90027 
Phone: (323) 361-3898 
Fax: 
(323) 361-3054 
E-mail: saamer@chla.usc.edu 
 
8.3 
Pharmacology (Required) 
 
8.3.1 
Description of Studies and Assay 
Pharmacokinetics (PK) will be performed to determine the PK of selinexor in 
children. Pharmacokinetic analysis will be conducted at a bioanalytical 
laboratory using a validated assay. 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
40 
 
8.3.2 
Sampling Schedule  
 
Blood samples will be obtained at the time points specified in Appendix III and 
just before tumor resection for patients on part C. 
 
8.3.3 
Sample Collection and Processing Instructions 
Blood samples (1 ml) will be collected in the provided Vacutainer K2EDTA 
tubes. (Please note the provided tubes may be larger than the required blood 
volume per sample so should not be filled completely). Record the exact time 
that the sample is drawn along with the exact time that the drug is administered. 
1. Invert the tube gently at least 8 to 10 times to ensure mixing of the 
K2EDTA and blood. 
2. Immediately after collection place K2EDTA tube on ice or at 4°C for no 
longer than 30 minutes. 
3. Centrifuge tube within 30 minutes of collection at 2000 g for 10 minutes 
at 4°C until red cells and plasma are separated by a well–formed polymer 
barrier.  
4. Transfer the plasma sample equally, using a transfer pipette, into two pre-
labeled LoBind™ Eppendorf protein tubes (Aliquot A and B). Do not 
transfer the Buffy coat or any of the red cell pellet into the plasma sample 
as this will render the sample unusable for analysis. 
• 
The aliquot A sample should be ≥ 0.2 ml, so if total plasma 
sample is < 0.4 ml, place most of the sample in Aliquot A.  
• 
Please be sure to parafilm the tops of the Eppendorf 
LoBind™ Protein Tubes.   
5. Immediately after transfer of the plasma to the pre-labeled LoBind™ 
Eppendorf protein tubes, freeze the plasma aliquots on dry ice, snap-freeze 
in liquid nitrogen, or place directly into a -80°C freezer. Store samples at 
-80°C until shipping. 
 
8.3.4 
Sample Labeling 
Each tube must be labeled with the study ID number, the patient ID number, the 
nominal time the sample was drawn, the aliquot (A or B), and a barcode ID 
number. All information on the PK labels is pre-printed with the exception of the 
patient ID number, which the site must write on each label using a fine-tip 
permanent marker.  
 
Data should be recorded on the Pharmacokinetic Study Form, which must 
accompany the sample(s) when shipped. Record the actual collection date and 
time associated with the scheduled collection time point. Any handwritten 
changes made to the pre-printed barcode labels will not be captured when the 
barcodes are scanned. 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
41 
 
8.3.5 
Sample Shipping Instructions: Batch and ship all Aliquots A for each patient 
together in the same shipment on dry ice to AIT Bioscience. Note: If samples for 
more than 1 patient are being shipped, samples must be grouped (e.g., separate 
boxes or paper sleeves for each patient). Retain Aliquot B samples until 
requested by study assigned Research Coordinator to be shipped. 
 
 
 
 
 
 
 
 
Shipment notification with tracking number should be sent to 
 
 lab@karyopharm.com; 
samples@aitbioscience.com) and the study assigned Research Coordinator, along 
with a copy of the PK Study form. 
 
8.4 
Pharmacodynamics 
 
8.4.1 
Description of Studies: Plasma proteins analysis will be performed for the 
identification of predictive biomarkers of response to selinexor (Appendix IV-A). 
Whole blood RNA will be collected for gene expression analysis using 
quantitative PCR (Appendix IV-B). 
 
8.4.2 
Sampling Schedule  
On cycle 1, day 1, samples will be collected pre- and 4 hours after dose is given in 
consenting patients. 
 
8.4.3 
Sample Collection and Handling Instructions 
Blood samples (2-2.5 ml) will be collected. Record the exact time that the sample 
is drawn along with the exact time that the drug is administered. 
 
8.4.4 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn.  Data should be recorded on 
the Correlative Study Form, which must accompany the sample(s). 
 
8.4.5 
Sample Processing and Shipping Instructions: Refer to Appendix IV-A and 
Appendix IV-B for sample processing and shipping details. 
 
8.5 
Tissue Studies (Part C only) 
Archival tumor tissue should be submitted for all patients in Part C.  If a patient does not 
have tissue available, the study chair must be notified prior to enrollment. 
 
8.5.1 
Description of Studies 
Tissue will be collected from original diagnosis or most recent resection and the 
resection that occurs as part of Part C.   
 
8.5.1.1 Pharmacokinetics: Levels of selinexor will be determined in the tumor as 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
42 
 
well as in blood at the time of resection to calculate blood/tumor ratio. 
 
8.5.1.2 Pharmacodynamics: 
a. Immunohistochemistry studies will be performed on fixed tumor tissue 
from pre-treatment and post-treatment specimens. Targets for analysis 
include XPO1, XPO1 cargos (p53, IKB alpha, pRb, FOXO3A, Survivin), 
cell cycle regulating proteins (c-Myc, Cyclin B, Cyclin D, ERK1, AKT1), 
and cell viability and cell death markers (H&E, Masson's trichrome, KI67, 
cleaved Caspase 3, TUNEL, Bcl2, Mcl1, FAS, ARRDC3, p75 NGFR). 
b. Quantitative PCR will be performed on pre- and post-treatment tumor 
specimens for the following: XPO1, cell viability and cell death markers 
(NFKB, IKB alpha, BID, PUMA, CHOP, BAX), and genes that are 
upregulated once XPO1 is inactivated (based on Karyopharm gene chip 
studies) (ARRDC3, NGFR, SLC family, PCLO). 
 
8.5.2 
Sample Collection, Handling, and Shipment  
Tissue from the on-therapy resection will be preserved at the time of resection. 
Detailed instructions regarding collection, handling, and shipping of tissue 
samples are located in Appendix V. 
 
9.0 
AGENT INFORMATION 
 
9.1 
Selinexor 
(Xpovio™, KPT-330) NSC# 781780 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
44 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
45 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12.0). 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
46 
 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6.0). 
c) 
Refusal of further protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of 24 cycles 
f) 
Physician determines it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of selinexor (See Section 8.1). 
h) 
Failure to adequately recover from surgery within 6 weeks after surgery (patients in Part 
C) 
i) 
Study is terminated by Sponsor. 
j) 
Pregnancy 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent. Patients who are removed from protocol therapy in subsequent cycles should 
have the necessary observations to ensure adequate clinical care.  
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Ongoing adverse events, or adverse events that emerge after the patient 
is removed from protocol therapy, but within 30 days of the last dose of investigational 
agent, must be followed and reported via RAVE and CTEP-AERS (if applicable).  Follow-
up data will be required unless consent is withdrawn. 
 
 
10.2 
Off Study Criteria 
 
a) 
Thirty days after the last dose of the investigational agent. 
b) 
Death 
c) 
Lost to follow-up 
d) 
Withdrawal of consent for any further required observations or data submission. 
e) 
Enrollment onto another COG therapeutic (anti-cancer) study  
f) 
The patient does not receive protocol treatment after study enrollment 
 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
Strata: 
Part A: 
Patients with relapsed or refractory solid tumors (Phase 1) 
 
Part B:  Patients with relapsed or refractory HGG (excluding DIPG) who do not require 
resection 
Part C: 
Patients with relapsed or refractory HGG for whom resection is required  
 
For Part A, a minimum of 2 evaluable patients with relapsed or refractory solid tumors 
including CNS tumors will be entered at each dose level for determination of MTD. Once 
the MTD or recommended Phase 2 dose has been defined, up to 6 additional patients with 
relapsed/refractory solid tumors without restrictions on heme evaluability may be enrolled 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
47 
 
to acquire PK data in a representative number of young patients (i.e. patients < 12 years 
old). A maximum of 29 patients is anticipated in this Part, assuming 6 evaluable patients 
are required for each dose level, 6 additional patients are needed for PK analysis, and a 
20% inevaluable rate. Review of the enrollment rate into previous COG new agent studies 
indicates that 1-2 patients per month are available, which will permit completion of the 
study within 15-29 months. In the unlikely event that all dose levels require expansion to 
12 patients per Section 11.2.2, then a maximum of 51 patients would be required allowing 
for a 20% inevaluable rate. This would require about 26-51 months for study completion. 
 
With Amendment #1, an additional 29 patients is anticipated for Part A, assuming 6 
evaluable patients are required for each dose level, 6 additional patients are needed for PK 
analysis, and a 20% inevaluable rate. The maximum accrual for the study (accounting for 
all parts of the study) will increase from 75 to 81 patients, assuming 20% inevaluability. 
 
Amendment #4 will require a minimum of 4 evaluable patients. The maximum is expected 
to be 30 allowing for 6 patients at each of three dose levels, 6 for PK, and 20% 
inevaluability. This is expected to be completed within 15-30 months.  
 
However, a dose level will be repeated with required maximal antiemetic therapy (5-HT3 
antagonists and another antiemetic) prior to each dose during Cycles 1 and 2 if DLTs of 
vomiting or dehydration is experienced in ≥ 2/6 evaluable patients at a dose level. This 
condition would increase the expected maximum to 38 which allows for 12 patients at one 
dose level, 6 at the two other dose levels, 6 PK, and 20% inevaluability. This would be 
expected to be completed within 19-38 months. 
 
In the unlikely event that all dose levels required expansion to 12 patients per Section 
11.2.2, then the absolute maximum would be 68 patients. This includes 24 patients at a 
single dose level requiring expansion due to both 1) toxicities of different classes and 2) 
DLTs of vomiting or dehydration as well as 12 patients at each of the other two dose levels, 
6 PK, and 20% inevaluability. This would be expected to be completed within 34-68 
months. 
 
The study has currently enrolled 31 patients (Fall 2019 SPR). 
 
Non-Surgical Cohort (Part B): 10 evaluable patients with recurrent/progressive HGG 
(excluding DIPG) who do not require resection will be enrolled in a medical dose-
expansion cohort (Part B) and will be treated at the MTD on the same schedule. If at any 
time greater than one out of three patients (or 33%) of the cohort of patients experience 
DLT, the cohort will be closed to further accrual. All patients enrolled on Part A who meet 
the eligibility criteria for Part B of the study who are evaluable for response as outlined in 
Section 11.2.3 of this protocol will be included in the evaluation rule. 
 
Surgical Cohort (Part C): Up to 10 evaluable patients with recurrent/progressive HGG 
(excluding DIPG and disseminated tumors) for whom resection is recommended by their 
treating teams will be enrolled in a surgical dose-expansion cohort. These patients will be 
allowed to receive up to four doses of selinexor prior to resection. After their resection and 
when medically cleared, they will restart selinexor on the prior schedule. The purpose of 
this cohort will be to perform pharmacokinetic and pharmacodynamic studies on the tumor 
tissue, and to explore preliminarily the effectiveness of selinexor in this disease. If at any 
time greater than one out of three patients (or 33%) of the cohort of patients experience 
DLT, the cohort will be closed to further accrual. 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
48 
 
 
Accrual to Parts B and C will only open once the MTD or recommended phase 2 dose has 
been determined in Part A, and may open concurrently with the PK expansion described 
above.  
 
A maximum of 24 patients are expected to enroll in Parts B and C combined, assuming an 
inevaluability rate of 20%. We anticipate that each part of the study will require 6-12 
months for enrollment.  
 
Response for Part B will be defined as either MR, PR or CR on two consecutive 2D 
measurements on standard imaging done 4 weeks apart (See Section 12.6). Sustained 
responses are very rare in this cohort of recurrent non-DIPG HGGs. 36-38 We will consider 
the agent of sufficient interest for further evaluation in this disease category if at least one 
PR or CR, or at least two MRs, is observed among 10 enrolled patients. A response rate of 
20% or more would be evidence of sufficient activity. If the true response rate is 20%, then 
the probability of observing one or more responses among 10 evaluable patients is about 
89.3%. If the response rate is 5%, then the probability of observing at least one response is 
about 40.1%.  
 
Clinical benefit for Part C will be evaluated separately using the criteria of no visible 
disease progression six months from the start of treatment. If two or more of a cohort of 
up to six patients are unable to resume therapy within 6 weeks after surgery, the surgical 
arm will be declared not feasible. If Part B has fully accrued, Part C will close to further 
accrual.  
 
11.2 
Definitions 
 
11.2.1 Evaluable For Adverse Events 
For all parts of the study, any patient who receives at least one dose of the study 
drug(s) and who experiences a dose-limiting toxicity is considered evaluable for 
Adverse Events. In addition, for the dose-escalation portion (Part A), during Cycle 
1, patients must have the appropriate toxicity monitoring studies performed to be 
considered evaluable for dose limiting toxicity. In Part A, patients who do not have 
DLT and do not receive at least 5 out of 6 of the prescribed doses (~85%) within 
the first cycle for reasons other than toxicities (e.g. progressive disease) will not 
be considered evaluable for toxicity and will be replaced. 
 
11.2.2 Maximum Tolerated Dose 
• 
The MTD will be the maximum dose at which fewer than one-third of 
patients experience DLT (See Section 5.5) during Cycle 1 of therapy.  
 
• 
In the unlikely event that two DLTs observed out of 6 evaluable patients are 
different classes of Adverse Effects (e.g. hepatotoxicity and 
myelosuppression) AND all of the following conditions are met, expansion 
of the cohort to 12 patients will be considered:  
 
•  One of the DLTs does not appear to be dose-related 
•  The Adverse Effects are readily reversible 
•  The study chair, DVL statistician, DVL committee chair or vice chair, 
and IND sponsor all agree that expansion of the cohort is acceptable 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
49 
 
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting 
toxicities, the dose escalation can proceed. 
 
• 
The DLTs observed in the pharmacokinetic (PK) expansion cohort will be 
counted towards the total number of DLTs observed at the MTD during the 
dose escalation portion of the study. If ≥ 1/3 of the cohort of patients at the 
MTD (the dose escalation plus the PK expansion) experience DLT then the 
MTD will be exceeded.  
 
11.2.3 Evaluability for Response 
Any patient who is enrolled who meets eligibility criteria for Part B and receives 
at least one dose of selinexor will be considered evaluable for response provided: 
(1) the patient demonstrates progressive disease or death while on protocol 
therapy; or (2) the patient is observed on protocol therapy for at least one cycle and 
the tumor is not removed surgically prior to the time complete response or partial 
response is confirmed, or (3) the patient demonstrates a complete or partial 
response as confirmed according to protocol criteria. Patients who demonstrate a 
complete or partial response confirmed by central review will be considered to 
have experienced a response for the application of the rule given in Section 11.1. 
All other patients will be considered non-responders. All patients considered to 
have a response (CR, PR, or MR) must have imaging studies reviewed centrally at 
the COG. Centers will be notified by the COG about requests for scans of patients 
with stable disease. See Section 8.2 regarding image submission instructions. The 
central review by COG will be provided as the final reviewed assessment of 
response when such becomes available. 
 
11.3 
Dose Escalation and Determination of MTD 
 
The rolling six phase 1 trial design will be used for the conduct of this study.39  Two to six 
patients can be concurrently enrolled onto a dose level, dependent upon (1) the number of 
patients enrolled at the current dose level, (2) the number of patients who have experienced 
DLT at the current dose level, and (3) the number of patients entered but with tolerability 
data pending at the current dose level.  Accrual is suspended when a cohort of six has 
enrolled or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the 
cohort, the number of DLTs observed, and the number of participants at risk for developing 
a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). For example, 
when three participants are enrolled onto a dose cohort, if toxicity data is available for all 
three when the fourth participant entered and there are no DLTs, the dose is escalated and 
the fourth participant is enrolled to the subsequent dose level. If data is not yet available 
for one or more of the first three participants and no DLT has been observed, or if one DLT 
has been observed, the new participant is entered at the same dose level. Lastly, if two or 
more DLTs have been observed, the dose level is de-escalated. This process is repeated for 
participants five and six. In place of suspending accrual after every three participants, 
accrual is only suspended when a cohort of six is filled. When participants are inevaluable 
for toxicity, they are replaced with the next available participant if escalation or de-
escalation rules have not been fulfilled at the time the next available participant is enrolled 
onto the study. 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
50 
 
The following table provides the decision rules for enrolling a patient at (i) the current dose 
level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study 
is suspended to accrual: 
 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
3 
0 
3 
0 
Escalate** 
 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
 
4 
0 
4 
0 
Escalate** 
 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
 
5 
0 
5 
0 
Escalate** 
 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
the MTD has been exceeded and dose escalation will be stopped (see Section 11.2.2 for 
exception to rule). 
 
In addition to determination of the MTD, a descriptive summary of all toxicities will be 
reported. 
 
11.4 
Inclusion of Children, Women and Minorities 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual 
to past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies.  Efforts will be made to extend the accrual to a 
representative population, but in a Phase 1 trial which will accrue a limited number of 
patients, a balance must be struck between patient safety considerations and limitations on 
the number of individuals exposed to potentially toxic or ineffective treatments on the one 
hand and the need to explore gender, racial, and ethnic aspects of clinical research on the 
other. If differences in outcome that correlate to gender, racial, or ethnic identity are noted, 
accrual may be expanded or additional studies may be performed to investigate those 
differences more fully. 
 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
51 
 
PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Hispanic or Latino 
Not Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
3 
0 
3 
Native 
Hawaiian 
or 
Other 
Pacific 
Islander 
0 
0 
0 
0 
0 
Black 
or 
African 
American 
0 
0 
15 
3 
18 
White 
3 
3 
29 
24 
59 
More Than One 
Race 
0 
0 
0 
0 
0 
Unknown 
3 
3 
3 
3 
12 
Total 
6 
6 
47 
33 
92 
 
11.5 
Pharmacokinetic and Correlative Studies and Response Analysis 
A descriptive analysis of pharmacokinetic (PK) parameters of selinexor will be performed 
to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The 
PK parameters will be summarized with simple summary statistics, including means, 
medians, ranges, and standard deviations (if numbers and distribution permit).   
 
While the primary aim of this study is to evaluate the toxicity of selinexor, patients will 
have disease evaluations performed as indicated in Section 8.1.  Disease response will be 
assessed according to RECIST criteria for patients with solid tumors, or the criteria 
specified in Section 12.6 for patients with CNS tumors, and will be reported descriptively. 
 
Clinical benefit for Part B will be defined in one of two ways, either PR or CR on two 
consecutive 2D measurements on standard imaging (see Section 12.6) or as > 12 weeks 
from first dose without progressive disease, while clinical benefit in Part C will be 
defined as no visible disease progression six months from the start of treatment.  Clinical 
benefit rate will be summarized separately for each of Parts B and C with 95% 
confidence intervals.  
 
All these analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
52 
 
12.2 
Response Criteria for Patients with Solid Tumors  
See the table in section 8.0 for the schedule of tumor evaluations. In addition to the 
scheduled scans, a confirmatory scan should be obtained on the next consecutive cycle 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).40  Key points are 
that 5 target lesions are identified and that changes in the largest diameter (unidimensional 
measurement) of the tumor lesions but the shortest diameter of malignant lymph nodes are 
used in the RECIST v 1.1 criteria. 
 
12.2.1 Definitions 
 
12.2.1.1 Evaluable for objective response: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will be considered evaluable for 
response. For all other patients, only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, 
and have had their disease re-evaluated will be considered evaluable for 
response.  
 
12.2.1.2 Evaluable Non-Target Disease Response: Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for non-
target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
12.2.2 Disease Parameters 
 
12.2.2.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 
mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable.  If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
12.2.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed 
by CT scan (CT scan slice thickness no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
12.2.2.3 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm short axis), are considered non-measurable 
disease. 
Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
53 
 
inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
12.2.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion that can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
 
12.2.2.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
12.2.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
12.2.3.1 Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and ≥10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
54 
 
 
12.2.3.2 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable.  
 
12.2.3.3 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 
12.2.3.4 PET-CT:  At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.2.3.5 Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
 
12.2.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.2.3.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
55 
 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
 
12.2.4 Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.2.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 
is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
12.2.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
56 
 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
12.2.5 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7.1 from a sequence of overall response assessments. 
 
 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
12.3.1 Evaluable Disease 
The presence of at least one lesion, with no lesion that can be accurately measured 
in at least one dimension.  Such lesions may be evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers or other reliable 
measures.  
 
12.3.2 Complete Response 
Disappearance of all evaluable disease. 
 
12.3.3 Partial response 
Partial responses cannot be determined in patients with evaluable disease 
 
12.3.4 Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), 
or Progressive Disease. 
 
12.3.5 Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. 
 
12.3.6 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7.1 from a sequence of overall response assessments. 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
57 
 
 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
12.4.1 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
12.4.2 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions 
 
12.4.3 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2.1 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
58 
 
 
 
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
12.4.4 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Table 5 in Section 12.8.1. 
 
 
12.5 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
12.5.1 Bone Marrow Involvement  
Bone marrow obtained within 28 days prior to study enrollment with tumor cells 
seen on routine morphology (not by immunohistochemical staining only) of 
bilateral aspirate or biopsy on one bone marrow sample. 
 
Bone Marrow responses are determined by H&E Staining of bilateral bone marrow 
biopsies and aspirates. 
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
59 
 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 
morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 
tumor is detected in 2 consecutive bone marrow biopsies 
or aspirations done at least 21 days apart. 
 
Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
12.5.2 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.7.1. 
 
12.6 
Response Criteria for Patients with CNS Tumors 
 
12.6.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
12.6.2 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
12.6.3 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 
 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
12.6.4 Response Criteria for Target Lesions 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
60 
 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 
• 
Complete Response (CR): Disappearance of all target lesions. 
 
• 
Partial response (PR): ≥50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements. 
 
• 
Minor Response (MR): A greater than or equal to 25% but less than 50% 
reduction in the product of the greatest tumor diameter and its perpendicular 
diameter on MRI scan, on a stable or decreasing dose of steroids with a stable 
or improving neurologic examination. 
 
• 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of 
the two perpendicular diameters of all target lesions to qualify for PR, nor 
sufficient increase in a single target lesion to qualify for PD. 
 
• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
12.6.5 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
12.6.6 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
12.6.7 Overall Response Assessment 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
61 
 
 
Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
MR 
CR, IR/SD 
CR, IR/SD 
Any 
Any 
No 
No 
PR 
MR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.7.1 from a sequence of overall response assessments. 
 
 
12.7 
Best Response 
 
12.7.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>28 days Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>28 days Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once 
>28 days from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
62 
 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Table 3.  Sequences of overall response assessments with corresponding best response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
Table 4: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
Table 5: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly identified lesion by 
CT/MRI that occurs during therapy would be considered progressive disease. 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
63 
 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
12.7.2 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR, PR, or MR (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that 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.  
 
 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the data collection packet 
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source.  The NCI, rather than a commercial distributor, may on some occasions 
distribute commercial agents for a trial. 
 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 5.0. All 
appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
64 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
Note:  This includes all events that occur within 30 days of the last dose of protocol 
treatment.  Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the 
agent(s) must also be reported according to the instructions in the table 
below. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
Table A: Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via CTEP-AERS within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
65 
 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific 
expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or 
birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration 
on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 1 
Trials Utilizing an Agent under a CTEP-IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not clearly due 
to progressive disease must be reported via CTEP-AERS for an agent under a CTEP or non-CTEP 
IND agent per the timelines outlined in the table above. 
 
• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), does 
not require expedited reporting, unless it is associated with hospitalization. 
Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD AND LYMPHATIC SYSTEM 
DISORDERS 
Anemia 
 
• Grade 1 and 2 adverse events listed in the table below do not require expedited reporting via CTEP-
AERS: 
Category 
Adverse Events 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Febrile neutropenia 
EYE DISORDERS 
Blurred vision 
GASTROINTESTINAL DISORDERS 
Constipation 
GASTROINTESTINAL DISORDERS 
Diarrhea 
GASTROINTESTINAL DISORDERS 
Dry mouth 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
GASTROINTESTINAL DISORDERS 
Nausea 
GASTROINTESTINAL DISORDERS 
Vomiting 
GENERAL DISORDERS AND 
Other, specify (asthenia) 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
66 
 
ADMINISTRATION SITE CONDITIONS 
GENERAL DISORDERS AND 
ADMINISTRATION SITE CONDITIONS 
Fatigue 
GENERAL DISORDERS AND 
ADMINISTRATION SITE CONDITIONS 
Peripheral edema 
INFECTIONS AND INFESTATIONS 
Other, specify 
INFECTIONS AND INFESTATIONS 
Sepsis 
INVESTIGATIONS 
Creatinine increased  
INVESTIGATIONS 
Weight loss 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
METABOLISM AND NUTRITION DISORDERS 
Dehydration 
METABOLISM AND NUTRITION DISORDERS 
Hyperglycemia 
METABOLISM AND NUTRITION DISORDERS 
Hypokalemia 
METABOLISM AND NUTRITION DISORDERS  
Hypomagnesemia 
METABOLISM AND NUTRITION DISORDERS 
Hyponatremia 
NERVOUS SYSTEM DISORDERS 
Dizziness 
NERVOUS SYSTEM DISORDERS 
Dysgeusia 
NERVOUS SYSTEM DISORDERS 
Headache 
NERVOUS SYSTEM DISORDERS 
Insomnia 
PSYCHIATRIC DISORDERS 
Confusion 
RESPIRATORY, THORACIS AND 
MEDIASTINAL DISORDERS 
Dyspnea 
 
As referenced in the CTEP Adverse Events Reporting Requirements, an AE that resolves and then recurs 
during a subsequent cycle does not require CTEP-AERS reporting unless (1) the Grade increases; or (2) 
hospitalization is associated with the recurring AE. 
 
13.2 
When to Report an Event in an Expedited Manner  
• 
Some adverse events require notification within 24 hours (refer to Table A) via the web 
at http://ctep.cancer.gov (email the ADVL1414 COG Study Assigned Research 
Coordinator within 24 hours of becoming aware of the event if the CTEP-AERS 24-Hour 
Notification web-based application is unavailable) and by telephone call to the Study 
Chair. Once internet connectivity is restored, a 24-hour notification phoned in must be 
entered electronically into CTEP-AERS by the original submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page https://eapps-
ctep.nci.nih.gov/ctepaers. 
 
13.3 
Expedited Reporting Methods  
 
13.3.1 CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the NCI’s Adverse Event 
Expedited 
Reporting 
System 
(CTEP-AERS) 
that 
can 
be 
found 
at 
http://ctep.cancer.gov. 
 
An CTEP-AERS report must be submitted electronically via the CTEP-AERS 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
67 
 
Web-based application located at https://eapps-ctep.nci.nih.gov/ctepaers.  If 
prompted 
to 
enter 
a 
sponsor 
email 
address, 
please 
type 
in: 
PEPCTNAERS@childrensoncologygroup.org. 
 
Email supporting documentation to the ADVL1414 COG Study Assigned 
Research Coordinator.  ALWAYS include the ticket number on all emailed 
documents. 
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG data 
submission forms and do not alter the guidelines for CTEP-AERS reporting. 
 
13.4.1 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
13.4.2 If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
13.4.3 The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
13.4.4 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than Grade 1, whichever level is higher (note that the resolution 
date may therefore be different from the date at which the grade of the AE 
decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."   
 
13.4.5 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
13.5 
Other Recipients of Adverse Event Reports 
 
13.5.1 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the data 
form packet (See Section 14.1). 
 
13.5.2 COG will forward reports and supporting documentation to the Study Chair, to 
the FDA (when COG holds the IND) and to the pharmaceutical company (for 
industry sponsored trials). 
 
13.5.3 Adverse events determined to be reportable must also be reported according to 
the local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
13.6 
Reporting Secondary AML/MDS 
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that 
occur in patients following their chemotherapy for cancer must be reported to the 
Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation Program 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
68 
 
(CTEP) via CTEP-AERS and included as part of the second malignant neoplasm reporting 
requirements for this protocol (see data submission packet).  Submit the completed CTEP-
AERS report within 14 days of an AML/MDS diagnosis occurring after treatment for 
cancer on trials. 
 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
All secondary malignancies that occur following protocol treatment be reported via CTEP-
AERS. Three options are available to describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified. 
 
13.7 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and emailed along with any 
additional medical information to the ADVL1414 COG Study Assigned Research 
Coordinator. The potential risk of exposure of the fetus to the investigational agent should 
be documented in the “Description of Event” section of the CTEP-AERS report, along with 
the source of exposure (mother, father, breastfeeding). 
 
13.7.1 Pregnancy 
• 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should be reported in an expedited manner via CTEP-AERS as 
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other 
(Pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. 
 
• 
Pregnancy should be followed until the outcome is known. If the baby is 
born with a birth defect or anomaly, then a second CTEP-AERS report is 
required.  
 
 
13.7.2 Pregnancy Loss (Fetal Death) 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
 
• 
 Any pregnancy loss should be reported expeditiouslyd as Grade 4 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
69 
 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 
 
13.7.3 Death Neonatal 
• 
Neonatal death, defined in CTCAE as “Newborn deaths occurring during 
the first 28 days after birth” that is felt by the investigator to be at least 
possibly due to the investigational agent/intervention, should be reported 
expeditiously. 
 
• 
A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the General disorders and administration SOC when the 
death is the result of a patient pregnancy or pregnancy in partners of 
men on study.  
 
• 
Do NOT report a neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men as a Grade 5 event as CTEP-AERS 
recognizes any Grade 5 event as a patient death. 
 
Pregnancy should be followed up until the outcome of the pregnancy is known at intervals 
deemed appropriate by her physicians. The “Pregnancy Information Form” should be used 
for 
all 
necessary 
follow-ups. 
This 
form 
is 
available 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyRepo
rtForm.pdf.  
 
13.7.4 Abuse, Misuse or Medication Error 
Abuse is the persistent or sporadic, intentional excessive use of the study 
treatment which is accompanied by harmful physical or psychological effects. A 
medication error is any preventable incident that may cause or lead to 
inappropriate study treatment use or patient harm while the study treatment is in 
the control of the health care professionals or patients. Such incident may be due 
to health care professional practice, product labeling, packaging and preparation, 
procedures for administration, and systems, including the following: prescribing, 
order communication, nomenclature, compounding, dispensing, distribution, 
administration, education, monitoring, and use. All occurrences of abuse, misuse, 
or medication error with any study treatment are to be recorded on an SAE report 
form and sent to Karyopharm Pharmacovigilance, regardless of whether or not an 
AE or SAE has occurred due to the abuse, misuse, or medication error. If the 
abuse, misuse, or medication error is associated with an SAE, the SAE report 
form must be submitted to Karyopharm Pharmacovigilance within 24 hours of 
awareness. If there is no AE or SAE, the report must be submitted within 24 
hours of awareness. 
 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
70 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the case report form (CRF) 
packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
14.2 
Access to Rave for Data Submission/ Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-
mail from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password 
and click on the accept link in the upper right-corner of the iMedidata page. Site staff will 
not be able to access the study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings) 
and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. 
If an eLearning is required and has not yet been taken, the link to the eLearning will appear 
under the study name in iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will be granted, 
and a Rave EDC link will display under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website in the Data Management section under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > 
Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
71 
 
5923 or by e-mail at ctsucontact@westat.com.   
 
14.3 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports 
are due January 31, April 30, July 31 and October 31.  This is not a responsibility of institutions 
participating in this trial. 
 
 
14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.4.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the PEP-CTN scientific 
committee; and a member from the NCI. The DSMC meets at least every 6 months 
to review current study results, as well as data available to the DSMC from other 
related studies. Approximately 6 weeks before each meeting of the Phase 1 and 2 
DSMC, study chair will be responsible for working with the study statistician to 
prepare study reports for review by the DSMC. The DSMC will provide 
recommendations to the COG PEP-CTN Chair and the Group Chair for each study 
reviewed to change the study or to continue the study unchanged. Data and Safety 
Committee reports for institutional review boards can be prepared using the public 
data monitoring report as posted on the COG Web site. 
 
14.4.2 Monitoring by the Study Chair and Developmental Therapeutics Leadership  
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the COG 
PEP-CTN Chair, Vice Chair and Statistician on a weekly conference call. 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
72 
 
REFERENCES 
 
1. 
Sharpless NE, DePinho RA: Cancer biology: gone but not forgotten. Nature 445:606-7, 2007 
2. 
Turner JG, Dawson J, Sullivan DM: Nuclear export of proteins and drug resistance in cancer. 
Biochem Pharmacol 83:1021-32, 2012 
3. 
Xu D, Grishin NV, Chook YM: NESdb: a database of NES-containing CRM1 cargoes. Mol Biol 
Cell 23:3673-6, 2012 
4. 
Siddiqui N, Borden KL: mRNA export and cancer. Wiley Interdiscip Rev RNA 3:13-25, 2012 
5. 
Huang WY, Yue L, Qiu WS, et al: Prognostic value of CRM1 in pancreas cancer. Clin Invest Med 
32:E315, 2009 
6. 
Noske A, Weichert W, Niesporek S, et al: Expression of the nuclear export protein chromosomal 
region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer. Cancer 
112:1733-43, 2008 
7. 
Shen A, Wang Y, Zhao Y, et al: Expression of CRM1 in human gliomas and its significance in p27 
expression and clinical prognosis. Neurosurgery 65:153-9; discussion 159-60, 2009 
8. 
van der Watt PJ, Maske CP, Hendricks DT, et al: The Karyopherin proteins, Crm1 and Karyopherin 
beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. 
Int J Cancer 124:1829-40, 2009 
9. 
Yao Y, Dong Y, Lin F, et al: The expression of CRM1 is associated with prognosis in human 
osteosarcoma. Oncol Rep 21:229-35, 2009 
10. 
Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA Cancer J Clin 59:225-49, 2009 
11. 
Smith MA, Seibel NL, Altekruse SF, et al: Outcomes for children and adolescents with cancer: 
challenges for the twenty-first century. J Clin Oncol 28:2625-34, 2010 
12. 
Green AL, Ramkissoon SH, McCauley D, et al: Preclinical antitumor efficacy of selective exportin 
1 inhibitors in glioblastoma. Neuro Oncol, 2014 
13. 
Houghton PJ, Kang M, Reynolds PC, et al: Preclinical Testing Program (PPTP) Stage 1 Evaluation 
of the XPO1/CRM1 Inhibitor KPT-330. Proceedings of the AACR LB-354 2013 
14. 
Attiyeh E, McKeon-Fish A, Trillo R, et al: Inhibition of Exportin 1 (XPO 1) potently suppresses 
growth of human neuroblastoma cell lines. AACR: Pediatric Cancer at the Crossroads:Poster B36, 
2013 
15. 
Etchin J, Sanda T, Mansour MR, et al: KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear 
export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic 
leukaemia and acute myeloid leukaemia. Br J Haematol 161:117-27, 2013 
16. 
Etchin J, Sun Q, Kentsis A, et al: Antileukemic activity of nuclear export inhibitors that spare 
normal hematopoietic cells. Leukemia 27:66-74, 2013 
17. 
KPT-330 Investigational Brochure v8.0, in Therapeutics K (ed), 2018 
18. 
Development Safety Update Report, in NPM Pharma I (ed), 2013 
19. 
Mau-Soerensen M, Razak ARA, Shields AF, et al: A first-in-class, first-in-human phase I trial of 
KPT-330 (selinexor), a selective inhibitor of nuclear export (SINE) in patients (pts) with advanced 
solid tumors. ASCO Meeting Abstracts 32:2537, 2014 
20. 
Gounder MM, Loong HHF, Nyquist-Schultz K, et al: A phase 1b food effect study of the first-in-
class, oral, selective inhibitor of nuclear export (SINE) selinexor (KPT-330) in patients (pts) with 
advanced sarcomas. ASCO Meeting Abstracts 32:10587, 2014 
21. 
Martignetti J, Razak ARA, Chen Y, et al: Preclinical and early clinical activity of the oral selective 
inhibitor of nuclear export (SINE) exportin 1 (XPO1) antagonist KPT-330 (Selinexor) in patients 
(pts) with platinum-resistant/refractory ovarian cancer (OvCa). ASCO Meeting Abstracts 32:5522, 
2014 
22. 
Gutierrez M, Goy A, Byrd JC, et al: A phase 1 dose-escalation study of the oral selective inhibitor 
of nuclear export (SINE) KPT-330 (selinexor) in patients (pts) with heavily pretreated non-
Hodgkin lymphoma (NHL). ASCO Meeting Abstracts 32:8518, 2014 
23. 
Kuruvilla J, Gutierrez M, Shah B, et al: Preliminary Evidence Of Anti Tumor Activity Of Selinexor 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
73 
 
(KPT-330) In a Phase I Trial Ofa First-In-Class Oral Selective Inhibitor Of Nuclear Export (SINE) 
In Patients (pts) With Relapsed / Refractory Non Hodgkin’s Lymphoma (NHL) and Chronic 
Lymphocytic Leukemia (CLL) ASH Annual Meeting and Exposition:Abstract 90, 2013 
24. 
Savona M, Garzon R, de Nully Brown P, et al: Phase I Trial  of Selinexor (KPT-330), A First-In-
Class Oral Selective Inhibitor Of Nuclear Export (SINE) In Patients (pts) With Advanced Acute 
Myelogenous Leukemia (AML) ASH Annual Meeting and Exposition:Abstract 1440, 2013 
25. 
Yee KWL, Savona M, Sorensen M, et al: A phase 1 dose-escalation study of the oral selective 
inhibitor of nuclear export (SINE) KPT-330 (selinexor) in patients (pts) with relapsed/refractory 
acute myeloid leukemia (AML). ASCO Meeting Abstracts 32:7032, 2014 
26. 
FDA grants accelerated approval to selinexor for multiple myeloma, U.S. Food & Drug 
Administration, 2019 
27. 
Lassman AB, Wen PY, Bent MJVD, et al: Efficacy and safety of selinexor in recurrent 
glioblastoma. Journal of Clinical Oncology 37:2005-2005, 2019 
28. 
Razak AR SM, Mahipal A, Shacham S, Yau CYF, Lassen UN, et al. : First-in-class, first-in-human 
phase I trial of KPT-330, a selective inhibitor of nuclear export (SINE) in patients (pts) with 
advanced solid tumors. . J Clin Oncol 2013;31((suppl; abstr 2505)). 2013 
29. 
Lassman AB, Bent MJVD, Wen PY, et al: OS07.5 Interim analysis data from Phase 2 study on 
efficacy, safety &amp; intratumoral pharmacokinetics of oral Selinexor (KPT-330) in patients with 
recurrent glioblastoma (GBM). Neuro-Oncology 19:iii14-iii14, 2017 
30. 
Place AE, Blonquist TM, Stieglitz E, et al: Phase I Study of the Selinexor in Relapsed/Refractory 
Childhood Acute Leukemia. Blood 132:1405-1405, 2018 
31. 
Alexander TB, Lacayo NJ, Choi JK, et al: Phase I Study of Selinexor, a Selective Inhibitor of 
Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or 
Refractory Acute Leukemia. J Clin Oncol 34:4094-4101, 2016 
32. 
Development Safety Update Report, in NPM Pharma (ed), 2013 
33. 
Flank J, Schechter T, Gibson P, et al: Olanzapine for prevention of chemotherapy-induced nausea 
and vomiting in children and adolescents: a multi-center, feasibility study. Support Care Cancer 
26:549-555, 2018 
34. 
Chin WC, Huang YS, Chou YH, et al: Subjective and objective assessments of sleep problems in 
children with attention deficit/hyperactivity disorder and the effects of methylphenidate treatment. 
Biomed J 41:356-363, 2018 
35. 
Golubchik P, Levy T, Weizman A: The effect of methylphenidate treatment on psychopathic 
behavior of patients having attention-deficit hyperactivity disorder with and without oppositional 
defiant disorder. Int Clin Psychopharmacol 33:330-333, 2018 
36. 
Fouladi M, Stewart CF, Blaney SM, et al: A molecular biology and phase II trial of lapatinib in 
children with refractory CNS malignancies: a pediatric brain tumor consortium study. J Neurooncol 
114:173-9, 2013 
37. 
Gururangan S, Chi SN, Young Poussaint T, et al: Lack of efficacy of bevacizumab plus irinotecan 
in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor 
Consortium study. J Clin Oncol 28:3069-75, 2010 
38. 
Warren KE, Gururangan S, Geyer JR, et al: A phase II study of O6-benzylguanine and 
temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem 
gliomas: a Pediatric Brain Tumor Consortium study. J Neurooncol 106:643-9, 2012 
39. 
Skolnik JM BJ, Jayaraman B, Patel D, Adamson PC. : Shortening the timeline of pediatric phase I 
trials: the rolling six design. J Clin Oncol. 2008 Jan 10;26(2):190-5., 2008 
40. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
74 
 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
75 
 
APPENDIX II: CORRELATIVE STUDIES GUIDE  
 
Correlative Study 
Appx. 
Tube Type 
Blood 
Volume per 
Sample 
Cycle 1 
Volume 
Pharmacokinetics (Parts A 
and B) 
III 
Lavender Top  
1 mL 
9 mL 
Pharmacokinetics (Part C) 
III 
Lavender Top 
1 mL 
10 mL 
PD- Plasma Proteins  
IV-A 
Lavender Top  
2 mL  
4 mL  
PD- Whole Blood 
IV-B 
PAXgene tube 
2.5 mL 
10 mL 
Total Blood Volume –Cycle 1 
(Parts A and B) 
 
23 mL 
Total Blood Volume –Cycle 1 
(Parts C) 
 
24 mL 
Tumor Tissue (Part C) 
V 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
76 
 
 
APPENDIX III: PHARMACOKINETIC STUDY FORM 
 
COG Pt ID # _______________ 
ACC # _______________ 
 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|    Dose Level: _______mg/m2   Dose Administered: ______mg 
 
 
 
Plasma samples (1 mL) will be collected for pharmacokinetic studies at the time points listed in the table below. 
Record the exact date and time each sample is drawn and the time of the selinexor administration. In the event the 
dose is vomited within 30 minutes after administration on Cycle 1, Day 1 and there is no visible evidence of the 
tablet, the PK samples #2-9 should be collected after the second dose on Cycle 1, Day 3.  
 
Blood 
Sample 
No. 
Barcode # (from 
Sample Label) 
Time Point 
Scheduled Sample Collection 
Time 
Scheduled  
Selinexor 
Time Point 
Actual Date 
Sample 
Collected or 
Dose Given 
Actual Time Sample 
Collected or Dose 
Given (24-hr clock) 
1 
 
Cycle 1, Day 1 
Prior to Dose on Cycle 1, Day 1 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, Day 1 
___/___/___ 
|__|__| : |__|__| 
2 
 
Cycle 1, Day 1 
30 min. after Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
3 
 
Cycle 1, Day 1 
1 hour after Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
4 
 
Cycle 1, Day 1 
2 hour after Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
5 
 
Cycle 1, Day 1 
3 hour after Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
6 
 
Cycle 1, Day 1 
4 hour after Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
7 
 
Cycle 1, Day 1 
6 hour after Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
8 
 
Cycle 1, Day 1 
8 hour after Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
9 
 
Cycle 1, Day 2 
24 (± 2) hr after Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
 
 
Part C: An additional PK sample will be collected after 2 doses prior to Tumor Resection. Surgical resection 
should occur after dose on Day 8 but before dose on Day 15 of Cycle 1.   
 
Blood 
Sample 
No. 
Barcode # (from 
Sample Label) 
Time Point 
Scheduled Sample Collection 
Time 
Scheduled  
Tumor 
Resection 
Date 
Actual Date 
Sample 
Collected or 
Date of 
Resection 
Actual Time Sample 
Collected or Dose 
Given (24-hr clock) 
10 
 
After 2 doses 
Prior to Tumor Resection 
 
___/___/___ 
|__|__| : |__|__| 
 
___/___/___ 
___/___/___ 
|__|__| : |__|__| 
 
  
Refer to Section 8.3 processing and shipping details. One copy of this Pharmacokinetic Study Form should 
be uploaded into RAVE.  
 
 
 
  
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: ______________________________________________                    Date: __________________________ 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
77 
 
APPENDIX IV-A: PHARMACODYNAMICS STUDY FORM- PLASMA PROTEINS 
 
COG Pt ID # _______________ 
ACC # _______________ 
 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|    Dose Level: _______mg/m2   Dose Administered: ______mg 
 
 
 
Plasma samples (2 mL) will be collected for Plasma Protein studies on cycle 1, day 1, pre- and 4 hours after dose is given in 
consenting patients. Record the exact date and time each sample is drawn and the time of the selinexor administration.  
 
Blood 
Sample 
No. 
Time Point 
Scheduled Sample Collection Time 
Scheduled  
Selinexor Time 
Point 
Actual Date 
Sample Collected 
or Dose Given 
Actual Time Sample 
Collected or Dose 
Given (24-hr clock) 
1 
Cycle 1, Day 1 
Prior to Dose on Cycle 1, Day 1 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, Day 1 
___/___/___ 
|__|__| : |__|__| 
2 
Cycle 1, Day 1 
4 hr after Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
 
 
Sample Processing Procedures: 
1. Ensure all tubes are labeled appropriately with site number, patient number and initials, and collection date prior 
to collection. Use a fine-point black permanent marker or lab marker to label tubes. 
2. Collect 2 ml of blood into one BD Vacutainer tube for each time point. Be sure to use the correct tube for each 
time point.  
3. Invert sample at least 8 to 10 times to ensure mixing of the EDTA and blood.  
4. Immediately after collection place EDTA tube on ice or at 4°C for no longer than 30 minutes. 
5. Centrifuge tube within 30 minutes of collection at 1000 g for 10 minutes at 4°C until red cells and plasma are 
separated by a well–formed polymer barrier. 
6. Transfer the plasma sample equally, using a transfer pipette, into two cryogenic vials (Aliquot A and B). Do not 
transfer the Buffy coat or any of the red cell pellet into the plasma sample as this will render the sample unusable 
for analysis.  
7. Immediately after transfer, the aliquots are stored at -70°C to -80°C. 
 
Sample Shipping Instructions:  
Batch and ship all Aliquots A for each patient together in the same shipment on dry ice to Karyopharm 
Therapeutics. Note: If samples for more than 1 patient are being shipped, samples must be grouped (e.g., separate 
boxes or paper sleeves for each patient). Retain Aliquot B samples until requested by Karyopharm Therapeutics to 
be shipped. 
 
 
 
 
 
 
 
Shipment notification with tracking number should be emailed to lab@karyopharm.com and study assigned Research 
Coordinator along with a copy of this PD Study form. 
 
 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: ______________________________________________                    Date: __________________________ 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
78 
 
APPENDIX IV-B: PHARMACODYNAMICS STUDY FORM- WHOLE BLOOD RNA 
 
COG Pt ID # _______________ 
ACC # _______________ 
 
Please do not write patient names on this form or on samples. 
 
Cycle 1, Day 1 Date: |__/__|__/__|__/__|    Dose Level: _______mg/m2   Dose Administered: ______mg 
 
 
 
 
Whole blood RNA (two x 2.5 mL samples per time point) will be collected for gene expression analysis on cycle 1, day 1, pre- 
and 4 hours post dose administration. Record the exact date and time each sample is drawn and the time of the selinexor 
administration.  
 
Blood 
Sample 
No. 
Time Point 
Scheduled Sample Collection Time 
Scheduled  
Selinexor Time 
Point 
Actual Date 
Sample Collected 
or Dose Given 
Actual Time Sample 
Collected or Dose 
Given (24-hr clock) 
1 
Cycle 1, Day 1 
Prior to Dose on Cycle 1, Day 1 
 
___/___/___ 
|__|__| : |__|__| 
 
Cycle 1, Day 1 
___/___/___ 
|__|__| : |__|__| 
2 
Cycle 1, Day 1 
4 hr after Day 1 dose 
 
___/___/___ 
|__|__| : |__|__| 
 
 
Sample Processing Procedures: 
1. Ensure PAXgene® Blood RNA Tube is at 18°C to 25°C prior to sample collection. To prevent contamination, 
the PAXgene® tube should be the last tube drawn for the correlative studies. 
2. Allow at least 10 seconds for a complete blood draw to take place. Ensure that the blood has stopped flowing into 
the tube before removing the tube from the holder. The PAXgene® tube with its vacuum is designed to draw up 
to 2.5 mL of blood into one tube. 
3. Collect 2.5 ml of blood into each of the two PAXgene® tubes required at every time point. Label tubes as Aliquot 
(A) and Aliquot (B). 
4. Immediately after blood collection, gently invert the PAXgene® tube 8 – 10 times.  
5. Store the PAXgene® tube upright at room temperature (18°C to 25°C) for a minimum of 2 hours and a maximum 
of 72 hours before transferring to a -20°C freezer.  
6. When freezing samples, stand the PAXgene® tube upright in a wire rack. Do not freeze tubes upright in a 
styrofoam tray as this may cause the tubes to crack. 
7. The PAXgene® tubes can be stored at -20°C and below. If tubes are to be kept at temperatures below -20°C, 
freeze them first at -20°C for 24 hours, then transfer them to -70°C or -80°C. 
 
Sample Shipping Instructions:  
Batch and ship all Aliquots A for each patient together in the same shipment on dry ice to Karyopharm 
Therapeutics. Note: If samples for more than 1 patient are being shipped, samples must be grouped (e.g., separate 
boxes or paper sleeves for each patient). Retain Aliquot B samples until requested by Karyopharm Therapeutics to 
be shipped. 
 
 
 
 
 
 
 
Shipment notification with tracking number should be emailed to lab@karyopharm.com and study assigned Research 
Coordinator, along with a copy of this PD Study form. 
 
 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: ______________________________________________                    Date: __________________________ 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
79 
 
APPENDIX V: TISSUE STUDIES FORM (PART C ONLY) 
 
COG Pt ID # _______________ 
ACC # _______________     Date:__________ 
(Please do not write patient names on this form or on samples) 
 
Sample Labeling: Samples should be labeled with the following information: 
Protocol number:    ADVL1414     Institution:        _________________   Sample Date:    _________________ 
 
Site of Acquired Tissue:  __________________ 
 
Tissue obtained at (check one option below):  Diagnosis           Relapse         Subsequent Resection/Biopsy 
 
Tissue sample is from a:                                   Resection     or      Biopsy 
 
Tissue Type:      Fresh Frozen Tissue                                      Formalin Fixed Tissue        
                           Paraffin Embedded Tissue Block                 Unstained Slides 
 
All blocks or slides must be labeled with the patient’s study registration number (COG Patient ID #), the study I.D. 
(ADVL1414), and the sample collection date. Data should be recorded on this Tissue Studies Form, which must 
accompany the sample(s).  
 
Archived Tissue Samples: Archived paraffin-embedded tissue must be available for any previous resections for that 
patient (approximately 20 unstained slides or tumor block). The blocks or slides of tumor material should be sent at 
room temperature via Federal Express. During the warmer months (June – August), it is advisable to ship the block(s) 
with a frozen gel ice-pack in order to prevent the melting of paraffin-embedded tissue blocks during transit. Ensure 
cold pack is not in direct contact with specimen. 
 
Tumor Biopsy Collected at Surgical Resection 
Tumor tissue will be obtained upon surgical resection during cycle 1 from Part C patients only. At least 500 mg of 
tumor tissue should be collected by standard surgical procedures. Approximately 0.5 ml will be fresh frozen with 
preservatives in 2 mL screw cap cryogenic vials, while the remainder will be preserved in 10% buffered formalin in 
15 ml conical tubes. 
 
a. Fresh (flash frozen) biopsy (approximately 0.5 ml collected). Please collect in the 2 mL screw cap cryogenic vials. 
Please do not fill tube more than ~1/3 full (~0.6 ml). Biopsy samples should be stored frozen at or below -70°C until 
shipment. Frozen samples will be shipped on dry ice. 
 
b. Formalin-fixed biopsy (remainder of sample collected during surgery after collection of fresh non-preserved 
tissue). Biopsy samples that are fixed in 10% buffered formalin will be stored at 4°C at the study sites until shipment. 
Parafilm all tubes. Fixed samples will be batched and shipped at 4°C. 
 
Please ship specimens along with email notification (with a copy to the Research Coordinator) of sample 
shipment and tracking number to:  
• Archived Tissue Samples  
• Formalin-Fixed Biopsy 
 
 
 
• Fresh (flash frozen) Biopsy 
 
 
 
 
 
 
One copy of this form should be uploaded into RAVE. If this form will be used as a source document, the site personnel 
who collected the samples must sign and date this form below: 
 
Signature: _______________________________               Date:__________________________________ 
(site personnel who collected samples) 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
80 
 
APPENDIX VI: SELINEXOR DOSING NOMOGRAM 
 
Selinexor Dose Assignment: 35 mg/m2 
(Dose Level -1) 
BSA (m2) 
Total Daily Dose (mg/day) 
 
   0.84-0.92 
30 
0.93-1.07 
35 
1.08-1.21 
40 
1.22-1.35 
45 
1.36-1.5 
50 
1.51-1.64 
55 
1.65-1.78 
60 
1.79-1.92 
65 
1.93-2.07 
70 
2.08-2.21 
75 
≥ 2.22 
80 
 
Selinexor Dose Assignment: 45 mg/m2 
(Dose Level 1) 
BSA (m2) 
Total Daily Dose (mg/day) 
          0.84-0.94 
40 
0.95-1.05 
45 
1.06-1.16 
50 
1.17-1.27 
55 
1.28-1.38 
60 
1.39-1.50 
65 
1.51-1.61 
70 
1.62-1.72 
75 
1.73-1.83 
80 
1.84-1.94 
85 
1.95-2.05 
90 
2.06-2.16 
 
 95 
2.17-2.27 
100 
≥ 2.28 
105 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
81 
 
 
Selinexor Dose Assignment: 55 mg/m2 
(Dose Level 2) 
BSA (m2) 
Total Daily Dose (mg/day) 
          0.84-0.86 
45 
0.87-0.95 
50 
0.96-1.04 
55 
1.05-1.13 
60 
1.14-1.22 
65 
1.23-1.31 
70 
1.32-1.4 
75 
1.41-1.5 
80 
1.51-1.59 
85 
1.6-1.68 
90 
1.69-1.77 
95 
1.78-1.86 
100 
1.87-1.95 
105 
1.96-2.04 
110 
2.05-2.13 
115 
2.14-2.22 
120 
≥ 2.23 
125 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
82 
 
APPENDIX VII:  MEDICATION DIARY FOR SELINEXOR 
 
COG Patient ID:___________   
Acc#_________   Institution :________________________________  
Please do not write patient names on this form. 
 
Complete each day with the time and dose given for selinexor. If a dose is not due or is accidentally skipped leave that day 
blank. Make note of other drugs and supplements taken under the Comments section below. Selinexor tablets should be 
swallowed whole. Selinexor should be taken with food. If a dose is vomited within 30 minutes of administration and there is 
visible evidence of the tablet, the dose should be repeated. If the tablet is not visible, or the dose is vomited later than 30 minutes 
after administration, the dose should not be repeated. The patient/caregiver should make a note of if there is visible evidence 
of tablet on the pill diary and proceed with the next dose at the next scheduled time of administration. Add the dates to the 
calendar below and return the completed diary to your institution after each treatment cycle. 
EXAMPLE 
 
 
Number of  
Selinexor tablets 
Comments 
 
 
Date 
Time 
10 mg 
25 mg 
 
Day 1 
1/15/14 
8:30 AM 
2 
1 
He felt nauseated an hour after taking the drug but did not vomit. 
Cycle #: _____  Selinexor Dose: _______mg   Start Date: |__/__|__/__|__/__|   End Date: |__/__|__/__|__/__| 
Day 
Date 
Time 
10 mg 
25 mg 
Comments 
Day 1 
 
Selinexor:  _______ 
 
 
 
Day 2 
 
 
 
 
 
Day 3 
 
 
 
 
 
Day 4 
 
 
 
 
 
Day 5 
 
 
 
 
 
Day 6 
 
 
 
 
 
Day 7 
 
 
 
 
 
Day 8 
 
Selinexor:  _______ 
 
 
 
Day 9 
 
 
 
 
 
Day 10 
 
 
 
 
 
Day 11 
 
 
 
 
 
Day 12 
 
 
 
 
 
Day 13 
 
 
 
 
 
Day 14 
 
 
 
 
 
Day 15 
 
Selinexor:  _______ 
 
 
 
Day 16 
 
 
 
 
 
Day 17 
 
 
 
 
 
Day 18 
 
 
 
 
 
Day 19 
 
 
 
 
 
Day 20 
 
 
 
 
 
Day 21 
 
 
 
 
 
Day 22 
 
Selinexor:  _______ 
 
 
 
Day 23 
 
 
 
 
 
Day 24 
 
 
 
 
 
Day 25 
 
 
 
 
 
Day 26 
 
 
 
 
 
Day 27 
 
 
 
 
 
Day 28 
 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
83 
 
APPENDIX VIII: TOXICITY SPECIFIC GRADING 
 
Bilirubin 
 
Grade 1: 
≤ 1.5X 
Grade 2: 
> 1.5X- 3X 
Grade 3: 
> 3X-10X 
Grade 4: 
> 10X 
 
 
ALT: For the purpose of this study, the ULN for SGPT is 45 U/L regardless of baseline.  
 
Grade 1: 
≤ 135 
Grade 2: 
136- 225 
Grade 3: 
226- 900 
Grade 4: 
> 900 
 
 
AST: For the purpose of this study, the ULN for SGPT is 50 U/L regardless of baseline. 
 
Grade 1: 
≤ 150 
Grade 2: 
151-250 
Grade 3: 
251-1000 
Grade 4: 
> 1000 
 
 
GGT: 
 
Grade 1: 
≤ 2.5X 
Grade 2: 
> 2.5X- 5X 
Grade 3: 
> 5X-20X 
Grade 4: 
> 20X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
84 
 
APPENDIX IX: BMI GROWTH CHARTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
85 
 
 
APPENDIX IX: BMI GROWTH CHARTS, cont. 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
86 
 
 
APPENDIX IX: BMI GROWTH CHARTS, cont. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*20 yr. cut-off should be used for patients 21 years old.  
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
87 
 
 
APPENDIX IX: BMI GROWTH CHARTS, cont. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*20 yr. cut-off should be used for patients 21 years old. 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
88 
 
APPENDIX X:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
 
Guidelines for the Treatment of Diarrhea 
 
Institutional practice may be used in place of these guidelines. 
 
You should purchase or will be given a prescription for loperamide to have available to begin treatment at 
the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent 
than normally expected for the patient. Patients will also be instructed to contact their physician if any 
diarrhea occurs. Patients will be given loperamide based on body weight.  
 
Be aware of your child's bowel movements. At the first sign they become softer than usual or if your child 
has any notable increase in the number of bowel movements over what is normal for him/her, begin taking 
loperamide (Imodium).  
 
Please follow these directions carefully, using dosing guidelines below: 
• 
Take _____________  at the first sign of diarrhea. 
• Continue taking __________ every __ hours until the diarrhea slows or the normal pattern of 
bowel movements returns. Repeat the same doses and frequency if the diarrhea returns. 
• Do not exceed ___________ in a 24 hour period. 
• Please call your doctor if you have any questions about taking loperamide, if your child's diarrhea 
is not under control after two days, or if he/she is feeling extremely weak, lightheaded, or dizzy. 
• Make an extra effort to give your child lots of fluids (several glasses of pedialyte, fruit juices, 
soda, soup, etc.) while your child is participating in this study. 
• Side effects may include tiredness, drowsiness or dizziness. If your child experiences these side 
effects, or if your child is urinating less frequently than usual, please contact your child's 
physician. 
• 
Do not give your child any laxatives without consulting with his/her physician. 
 
 
 
 
 
 
 
 
 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
89 
 
 
LOPERAMIDE DOSING RECOMMENDATIONS 
(NOTE: maximum dose of loperamide for adults is 16 mg/day) 
ALL patients: discontinue loperamide when the patient is no longer experiencing significant diarrhea. 
Weight (kg) 
ACTION 
<13 kg   
Take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral solution) after 
the first loose bowel movement, followed by 0.5 mg (2.5 mL [one-half 
teaspoonful] of the 1 mg/5 mL oral solution) every 3 hours. During the night, the 
patient may take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral 
solution) every 4 hours. Do not exceed 4 mg (20 mL or 4 teaspoonfuls) per day. 
 
≥ 13 kg to < 20 kg 
Take 1 mg (5 mL [1 teaspoonful] of the 1 mg/5 mL oral solution or one-half  
tablet) after the first loose bowel movement, followed by 1 mg (5 mL [one 
teaspoonful] of the 1 mg/5 mL oral solution or one-half tablet) every 3 hours. 
During the night, the patient may take 1 mg (5 mL [one teaspoonful] of the 1 mg/5 
mL oral solution or one-half tablet) every 4 hours. Do not exceed 6 mg (30 mL or 
6 teaspoonfuls) per day. 
 
≥ 20 kg to < 30 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] 
of the 1 mg/5 mL oral solution or one-half tablet) every 3 hours. During the night, 
the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution 
or 1 tablet) every 4 hours. Do not exceed 8 mg (40 mL or 8 teaspoonfuls) per day. 
 
≥ 30 kg to < 43 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] 
of the 1 mg/5 mL oral solution or one-half tablet) every 2 hours. During the night, 
the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution 
or 1 tablet) every 4 hours. Do not exceed 12 mg (60 mL or 12 teaspoonfuls) per 
day. 
 
Over 43 kg 
Take 4 mg (20 mL [4 teaspoonfuls] of the 1 mg/5 mL oral solution or 2 capsules 
or tablets) after the first loose bowel movement, followed by 2 mg (10 mL 
[2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 capsule or tablet) every 
2 hours. During the night, the patient may take 4 mg (20 mL [4 teaspoonfuls] of 
the 1 mg/5 mL oral solution or 2 capsules or tablets) every 4 hours. Do not exceed 
16 mg (80 mL or 16 teaspoonfuls) per day. 
 
 
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
90 
 
APPENDIX XI: CTEP AND CTSU REGISTRATION PROCEDURES  
 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program 
(CTEP) Identity and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam. In 
addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator 
(NPIVR), or Associate Plus (AP) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the  Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs 
must list all clinical practice sites and Institutional Review Boards (IRBs) covering their practice 
sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
91 
 
consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must be rostered 
at the enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at https://ctep.cancer.gov/
investigatorResources/default.htm. For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov. 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
IRB Approval  
U.S. sites participating in the PEP-CTN network are required to use the NCI CIRB as of March 1, 
2019.  Local IRB review will continue to be accepted for studies that are not reviewed by the CIRB, 
or if the study was previously open at the site under the local IRB. International sites should continue 
to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office following country-
specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local Context 
(SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. The NCI 
CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory Office, but 
sites are required to contact the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to 
establish site preferences for applying NCI CIRB approvals across their Signatory Network. Site 
preferences can be set at the network or protocol level. Questions about establishing site preferences 
can be addressed to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office using 
the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
Registration and Credential Repository (RCR) profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
92 
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
 
Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents is 
restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Protocol Organization (PO) 
on the protocol. One way to search for a protocol is listed below.  
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select COG, and 
protocol number (*insert study number*). 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.) 
 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Checking Your Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory  at the top of the screen; 
• 
Click on Site Registration; and  
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
93 
 
affiliated networks. 
 
Requirements For ADVL1414 Site Registration: 
 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB 
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB 
Certification, 
and/or 
Protocol 
Human 
Subjects 
Assurance 
Identification/IRB 
Certification/Declaration of Exemption Form. 
 
 
Data Submission / Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
.   
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are available 
to access details and reports of unanswered queries, delinquent forms, and timeliness 
reports. Review the DQP modules on a regular basis to manage specified queries and 
delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
94 
 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.   
 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
95 
 
 
APPENDIX XII: YOUTH INFORMATION SHEETS 
 
 
INFORMATION SHEET REGARDING RESEARCH STUDY 
(for children from 7 through 12 years of age) 
 
A study of selinexor in patients with recurrent and refractory solid tumors, including CNS tumors 
 
1. We have been talking with you about taking part in a research study because you have cancer. A 
research study is when doctors work together to try out new ways to help people who are sick. In 
this study, we are trying to learn more about how to treat the kind of cancer you have. We will do 
this by trying a new medicine to treat your cancer.  
 
2. Children who are part of this study will be treated with a cancer fighting medicine called 
selinexor. You will have regular tests and exams done more often while you are in this study. The 
doctors want to see if selinexor will work well to get rid of your cancer. That is why we are doing 
this study.  
 
3. Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is selinexor 
may cause your cancer to shrink or go away but we don’t know for sure if there is any benefit of 
being part of the study. 
 
4. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks.” The risks to you from this study are that you may have problems or side effects 
from selinexor. Other things may happen to you that we don’t yet know about. 
 
5. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
6. If you decide to be treated with selinexor you will have some tests and check-ups done more 
often than you might if you weren’t part of the study. Some of these needed tests will require 
extra needle sticks to collect additional blood samples. 
 
7. We are asking your permission to collect additional blood. We want to see if there are ways to tell 
how the cancer will respond to treatment. Some of these samples are collected when you may not 
need to have a blood sample taken and may require extra needle sticks. You can still take part in 
this study even if you don't allow us to collect the extra blood samples for research. 
 
 
 


                        ADVL1414 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
Version Date: 11/10/2020 
 
96 
 
 
 
INFORMATION SHEET REGARDING RESEARCH STUDY 
(for teens from 13 through 17 years of age) 
 
A study of selinexor in patients with recurrent and refractory solid tumors, including CNS tumors 
 
1. We are asking you to take part in a research study because you have cancer. A research study is when 
doctors work together to try out new ways to help people who are sick. In this study, we are trying to 
learn more about how to treat the kind of cancer you have. We will do this by trying a new medicine 
to treat your cancer.  
 
2. Children and teens who are part of this study will be treated with a cancer fighting medicine called 
selinexor. You will have regular tests and exams done more often while you are in this study. The 
doctors want to see if selinexor will work well to get rid of your cancer. That is why we are doing this 
study. 
 
3. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is selinexor may cause 
your cancer to shrink or go away but we don’t know for sure if there is any benefit of being part of 
the study. 
 
4. Sometimes bad things can happen to people when they are in a research study.  These bad things are 
called “risks.” The risks to you from this study are that you may have problems or side effects from 
selinexor. Other things may happen to you that we don’t yet know about. 
 
5. Your family can choose to be part of this study or not. Your family can also decide to stop being in 
this study at any time once you start. There may be other treatments for your illness that your doctor 
can tell you about. Make sure to ask your doctors any questions that you have. 
 
6. If you decide to be treated with selinexor you might have some tests and check-ups done more often 
than you might if you weren’t part of the study. Some of these needed tests will require extra needle 
sticks to collect additional blood samples. 
 
7. We are asking your permission to collect additional blood. We want to see if there are ways to tell 
how the cancer will respond to treatment. Some of these samples are collected when you may not 
need to have a blood sample taken and may require extra needle sticks. You can still take part in this 
study even if you don't allow us to collect the extra blood samples for research.