Clinical trial NCT02991456
Conditions: Chemo-radiation Induced Nausea and Vomiting
Keywords: malignant glioma temozolomide temodar radiation emesis nausea vomiting chemotherapy Affronti Peters 00076418
Sponsor: Duke University
Start date: 2017-10-09; Completion date: 2022-06-20
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this phase 2 study is to assess the efficacy and patient satisfaction of oral rolapitant plus ondansetron vs. oral ondansetron monotherapy in malignant glioma (MG) patients receiving standard of care radiation (RT) and temozolomide (TMZ) therapy. This is a randomized phase 2 trial of rolapitant plus ondansetron vs. ondansetron monotherapy for the prevention of chemo-radiation induced nausea and vomiting in primary MG subjects receiving RT and concomitant multi-dose TMZ.

Detailed description:
All eligible subjects should receive a planned total dose of 54-60 gray (GY) of radiation and 75 mg/m2 of TMZ daily for a total of six weeks. Patients will be randomized to receive one of two antiemetic treatment sequences: sequence A that involves administration of ondansetron alone for 3 weeks followed by a single dose of rolapitant (day 22) plus daily ondansetron for 3 weeks or sequence B that involves a single dose of rolapitant (day 1) plus daily ondansetron for 3 weeks followed by 3 weeks of daily ondansetron alone. The study has one primary endpoint: complete response (CR) rate. Participation in this study may result in reduced chemo-radiation induced nausea and vomiting, however, risks include the common side effects of rolapitant including decreased appetite, neutropenia, dizziness, dyspepsia, urinary tract infection, stomatitis, and anemia.

Arms: arm 1: Daily ondansetron alone for 3 weeks, followed by the use of rolapitant (one dose on day 22) plus continued daily ondansetron for 3 weeks. arm 2: Single dose of rolapitant (one dose on day 1) plus daily ondansetron for 3 weeks, followed by daily ondansetron alone for 3 weeks.
Interventions: intervention 1: Rolapitant intervention 2: Ondansetron
Intervention descriptions: intervention 1: single 180 mg dose by mouth intervention 2: 8 mg by mouth daily

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
The Preston Robert Tisch Brain Tumor Center  
Duke University Medical Center 
A Phase II Study 
 
Phase II randomized study to evaluate efficacy, patient satisfaction, and 
compliance of the oral combination of Rolapitant (Varubi®) plus ondansetron vs. 
ondansetron monotherapy in malignant glioma patients receiving radiotherapy 
(RT) and concomitant temozolomide 
NCT02991456 
 
 
 
 
 
 
 
Sponsor:  
PI – Duke Cancer Institute 
 
 
Funding Source: 
TerSera Therapeutics  
 
 
Protocol Source: 
PI – Duke Cancer Institute 
 
 
Duke IRB#: 
Pro00076418 
 
 
IND# 
Protocol Version Date: 
133107 (Exempt)  
February 18, 2022 
 
                                                                                             
 
Principal Investigator 
Mary Lou Affronti D.N.P., R.N., 
A.N.P., M.H.Sc 
047 Baker House 
DUMC 3624, Durham N.C., 27710 
919-684-6239 
919-684-6674 
affro002@mc.duke.edu 
 
Co-Principal Investigator(s) 
Katherine Peters, M.D., Ph.D. 
katherine.peters@dm.duke.edu 
047 Baker House 
DUMC 3624, Durham N.C., 27710 
 
 
Sub-Investigator(s) 
Annick Desjardins, M.D., F.R.C.P.C 
annick.desjardins@dm.duke.edu 
 
Margaret Johnson, M.D. 
margaret.o.johnson@duke.edu  
 
John Kirkpatrick, M.D., Ph.D. 
john.kirkpatrick@duke.edu 
 
Henry Friedman, M.D. 
henry.friedman@dm.duke.edu 
 
Mallika Weant, PharmD 
mallika.weant@duke.edu 
 
Statistician 
James E. Herndon II, Ph.D. 
james.herndon@dm.duke.edu 
 
Lead Study Coordinator 
Erin Severance 
erin.k.bell@.duke.edu 
 
Regulatory Coordinator 
Kendra Boyd 
kendra.boyd@duke.edu  
 
Data Manager 
Eric Lipp  
eric.lipp@dm.duke.edu 
 
Original version: 
Date 11/29/16 
 
Amended version: 
Date 01/12/17  
 
 
Lead study coordinator changed, rolapitant dose (180 mg) added to 
study schema (Section 6) and study design (Section 9.1).  Extensive 
information on past palonosetron study was removed in sections 


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Date 8/8/17 
5.2, 7.1, and 7.3.  A clarification of a total of 80 randomized 
patients for interim analysis was added to section 15.6.  Primary 
endpoint and KEY secondary endpoint clarification to headings in 
section 15.7.  Hyperlinks modified appropriately. 
 
Updated eligibility to include patients that may want to participate 
in a clinical trial AFTER standard of care radiation and temodar 
(Section 5.4 and 11.2).  Removed redundant inclusion criteria 
(Section 5.4 and 11.1).  Removed excess pregnancy tests (Table 7).   
 
 
 
Date 2/19/18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 1/31/19 
Added ECOG to inclusion criteria, removed redundant radiotherapy 
criteria that is covered by the broad criteria – “prior cancer 
chemotherapy or radiotherapy” in exclusion criteria, removed urine 
pregnancy test from exclusion criteria because only serum 
pregnancy test will be used (Section 5.4 and 11).  Removed SGOT 
from Inclusion Criteria #5 given that AST limits are set in Inclusion 
Criteria #6 (Section 11.1).  Removed the “Xs” from the Adverse 
Events line and replaced it with continuous, added urinalysis, 
removed medication log from screening, increased screening 
period to 4 weeks, and added a footnote for Laboratory Evaluations 
at screening (Table 7).  Added urinalysis to screening procedures 
text (Section 12.1).  Removed the reference to only clinically 
significant abnormal lab findings will be recorded as Adverse Events 
because ALL abnormal laboratory findings will be recorded and 
then clinical significance will be decided (Section 13.1).  Various 
new Adverse Event and other reporting criteria updated per new 
company standards (Section 13) including addition of an AESI 
section (Section 1.1.1). an SAE exception (Section 13.2), SEA 
reporting to Tesaro (Sections 13.2.1 and 1.1.1), a pregnancy section 
(Section 13.3.2.1), Special Situations (Section 1.1.1), and Reporting 
Product Complaints (Section 1.1.1).  Removed Karen Allen and 
Gordana Vlahovic from Sub-Investigators.  Added Margaret 
Johnson to sub-investigators.  Changed Lead Study Coordinator to 
Edy Parker and Lead Regulatory Coordinator to Jennifer Jackman.  
Some minor administrative edits. 
Changed Lead Regulatory Coordinator to Deborah Iden. Updated all 
references of Tesaro to TerSera, the new sponsor. Exclusion criteria 
#1 removed and combined with #2 to indicate that co-medication 
interaction with rolapitant will be reviewed by the pharmacist for 
eligibility and added exclusion criteria for contraindicated 
medications (Sections 5.4 and 11.2). Added a sentence after 
exclusion criterion 18 that says to refer to a study Memo to File for 
exceptions to the exclusion criteria. (Sections 5.4 and 11.2)  
Reordered the Inclusion and Exclusion criteria numbering  to better 
lend itself to how the questions are reviewed when screening by 
the CRC.  Removed collection of every 2 week standard of care 
blood draw at the request of the PI who determined it was 
unnecessary to collect the data (Table 7) and throughout the 
protocol. Section 13, Safety Monitoring and Reporting, was 
significantly revised to both include language suggested by the new 
sponsor TerSera and to remove sections that had only been 
included based on the previous sponsor’s requirements. Corrected 
inconsistencies in the language related to screening time points. 
Removed overall duration of study. Other minor administrative 
changes. 
 
Date 2/18/2022 
The accrual target for this study is reduced to 57 patients.  The 
decision to terminate early has not been influenced by the data 
collected to date, as no interim analyses have been conducted.  The 
analyses as described below will be conducted; however, they may 
no longer have the power to detect the hypothesized effect size 


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1 
TABLE OF CONTENTS 
2 
LIST OF FIGURES ................................................................................................................ 6 
3 
LIST OF TABLES .................................................................................................................. 6 
4 
LIST OF ABBREVIATIONS ................................................................................................. 7 
5 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY .................................................. 8 
5.1 
Purpose ............................................................................................................................. 8 
5.2 
Background and Significance ........................................................................................... 8 
5.3 
Design and Procedure ....................................................................................................... 9 
5.4 
Selection of Subjects ...................................................................................................... 10 
5.5 
Subject Recruitment and Compensation ........................................................................ 12 
5.6 
Consent Process .............................................................................................................. 12 
5.7 
Subject’s Capacity to Give Legally Effective Consent .................................................. 13 
5.8 
Risk/Benefit Assessment ................................................................................................ 13 
5.9 
Costs to the Subject ........................................................................................................ 14 
5.10 
Duration of Study ....................................................................................................... 14 
5.11 
Data Analysis and Statistical Considerations ............................................................. 14 
6 
STUDY SCHEMA................................................................................................................ 15 
7 
BACKGROUND AND SIGNIFICANCE ............................................................................ 16 
7.1 
Study Disease ................................................................................................................. 16 
7.2 
Study Agent .................................................................................................................... 16 
7.2.1 
Pre-clinical experience (as noted in the Rolapitant Investigator’s brochure) ......... 20 
7.2.2 
Clinical experience (as noted in the Rolapitant Investigator’s brochure and the 
package insert) ...................................................................................................................... 20 
7.3 
Study Purpose/Rationale ................................................................................................ 28 
8 
OBJECTIVES AND ENDPOINTS ...................................................................................... 30 
9 
INVESTIGATIONAL PLAN ............................................................................................... 31 
9.1 
Study Design .................................................................................................................. 31 
9.2 
Standard of Care Chemotherapy Treatment Plan ........................................................... 31 
9.3 
Standard of Care Radiation Treatment Plan ................................................................... 32 
9.3.1 
Dose Definition and Schedule ................................................................................ 32 
9.3.2 
Physical Factors ...................................................................................................... 32 
9.3.3 
Localization, Simulation, and Immobilization ........................................................ 32 
9.3.4 
Treatment Planning and Safety ............................................................................... 32 


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9.3.5 
Dose Limitations to Critical Structures ................................................................... 33 
9.3.6 
Safety Considerations ............................................................................................. 33 
9.4 
Anti-emetic Treatment ................................................................................................... 33 
9.4.1 
Antiemetic Treatment Plan ..................................................................................... 33 
9.4.2 
Missed Doses .......................................................................................................... 33 
9.4.3 
Concomitant Medications ....................................................................................... 33 
9.5 
Study Drug Blinding ...................................................................................................... 34 
9.6 
Randomization ............................................................................................................... 34 
9.7 
Rationale for Selection of Dose, Regimen, and Treatment Duration ............................. 34 
9.8 
Definition of Evaluable Subjects, On Study, and End of Study .................................... 34 
9.9 
Early Study Termination ................................................................................................ 34 
10 STUDY DRUG ..................................................................................................................... 34 
10.1 
Names, Classification, and Mechanism of Action ..................................................... 34 
10.2 
Packaging and Labeling.............................................................................................. 35 
10.3 
Supply, Receipt, and Storage ...................................................................................... 35 
10.4 
Dispensing and Preparation ........................................................................................ 35 
10.5 
Compliance and Accountability ................................................................................. 35 
10.6 
Disposal and Destruction ............................................................................................ 35 
10.7 
Other Study Drugs (Ondansetron) .............................................................................. 35 
10.7.1 Description .............................................................................................................. 35 
10.7.2 Source ..................................................................................................................... 35 
10.7.3 Dosage and Administration..................................................................................... 35 
10.7.4 Drug Ordering ......................................................................................................... 35 
11 SUBJECT ELIGIBILITY ..................................................................................................... 36 
11.1 
Inclusion Criteria ........................................................................................................ 36 
11.2 
Exclusion Criteria ....................................................................................................... 36 
12 SCREENING AND ON-STUDY TESTS AND PROCEDURES........................................ 36 
12.1 
Screening Examination ............................................................................................... 37 
12.2 
Treatment Period ........................................................................................................ 37 
12.3 
End of Treatment ........................................................................................................ 38 
12.4 
Follow-up Period ........................................................................................................ 38 
12.5 
End of Study ............................................................................................................... 38 
12.6 
Early Withdrawal of Subject(s) .................................................................................. 38 
12.6.1 Criteria for Early Withdrawal ................................................................................. 38 


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12.6.2 Follow-up Requirements for Early Withdrawal ..................................................... 38 
12.6.3 Replacement of Early Withdrawal(s) ...................................................................... 39 
12.7 
Study Assessments ..................................................................................................... 39 
12.7.1 Medical History ...................................................................................................... 39 
12.7.2 Physical Exam ......................................................................................................... 39 
12.7.3 MASCC Antiemesis Tool (MAT) .......................................................................... 39 
12.7.4 Treatment Satisfaction Questionnaire for Medication (TSMQ-9) .......................... 39 
13 SAFETY MONITORING AND REPORTING .................................................................... 40 
13.1 
Adverse Events ........................................................................................................... 40 
13.1.1 Reporting of AEs .................................................................................................... 40 
13.2 
Serious Adverse Events .............................................................................................. 40 
13.2.1 Reporting of SAEs .................................................................................................. 41 
13.2.2 Reporting Product Complaints for TerSera Products ............................................. 41 
13.3 
Special Warnings and Precautions ............................................................................. 41 
13.4 
Safety Oversight Committee (SOC) ........................................................................... 41 
14 QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 42 
14.1 
Monitoring .................................................................................................................. 42 
14.2 
Audits.......................................................................................................................... 42 
14.3 
Data Management and Processing .............................................................................. 43 
14.3.1 Case Report Forms (CRFs) ..................................................................................... 43 
14.3.2 Data Management Procedures and Data Verification ............................................. 43 
14.3.3 Study Closure .......................................................................................................... 43 
15 STATISTICAL METHODS AND DATA ANALYSIS ...................................................... 43 
15.1 
Analysis Sets .............................................................................................................. 43 
15.2 
Patient Demographics and Other Baseline Characteristics ........................................ 43 
15.3 
Treatments .................................................................................................................. 44 
15.4 
Primary Objective ....................................................................................................... 44 
15.4.1 Variable ................................................................................................................... 44 
15.4.2 Statistical Hypothesis, Model, and Method of Analysis ......................................... 44 
15.5 
Secondary Objectives ................................................................................................. 44 
15.5.1 Key Secondary Objective ....................................................................................... 45 
15.5.2 Other Secondary Objectives ................................................................................... 45 
15.6 
Interim Analysis ......................................................................................................... 46 
15.7 
Sample Size Calculation ............................................................................................. 46 


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15.7.1 Original Study Design............................................................................................. 46 
15.7.2 Modified Study Design ........................................................................................... 47 
16 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ............................................. 47 
16.1 
Regulatory and Ethical Compliance ........................................................................... 47 
16.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee ................. 48 
16.3 
Informed Consent ....................................................................................................... 48 
16.4 
Study Documentation ................................................................................................. 48 
16.5 
Privacy, Confidentiality, and Data Storage ................................................................ 49 
16.6 
Data and Safety Monitoring ....................................................................................... 49 
16.7 
Protocol Amendments ................................................................................................ 49 
16.8 
Records Retention....................................................................................................... 49 
17 REFERENCES ..................................................................................................................... 50 
18 APPENDICES ...................................................................................................................... 51 
18.1 
Appendix 1: Sequence A-TSQM9/MAT Questionnaire ............................................ 51 
18.2 
Appendix 2: Sequence B-TSQM9/MAT Questionnaire ............................................ 51 
18.3 
Appendix 3: Medication Log:   Sequence A .............................................................. 51 
18.4 
Appendix 4: Medication Log:   Sequence B ............................................................... 51 
18.5 
Appendix 5: Birth Control Recommendations ........................................................... 51 
 
 
 


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2 LIST OF FIGURES 
Figure 1: No Emesis and No Nausea Interfering with Daily Life over Cycles 2-6 ....................... 27 
 
3 LIST OF TABLES 
Table 1: The study of drug, Varubi® (rolapitant) with MEC can cause the following effects:... 13 
Table 2: Effects of Rolapitant on the Pharmacokinetics of Co-administered Drugs* ................ 19 
Table 3: Complete Response by CINV Phase and Study ............................................................. 24 
Table 4: Treatment Regimens in Studies 1 and 2 ........................................................................ 25 
Table 5: Treatment Regimens in Study 3 .................................................................................... 26 
Table 6:  Percent of Patients Receiving Emetogenic Chemotherapy Responding by Treatment 
Group for the HEC Studies 1 and 2 and for the MEC Study 3 ..................................................... 26 
Table 7: Screening and Study-related Tests and Procedures ..................................................... 37 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 LIST OF ABBREVIATIONS 
5HT3-RA        5-hydroxytryptamine receptor antagonist  
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ASCO              American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
H&P 
History & Physical Exam 
HEC                 Highly emetic chemotherapy 
HRPP 
Human Research Protections Program 
IV (or iv) 
Intravenously 
MASCC           Multinational Association of Supportive Care in Cancer 
MAT                MASCC Antiemesis Tool     
MEC                Moderately emetic chemotherapy 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCCN             National Comprehensive Caner Network 
NK1-RA           Neurokinin-1 receptor antagonist 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PET                 Positron Emission Tomography 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PRTBTC          Preston Robert Tisch Brain Tumor Center 
p.o. 
per os/by mouth/orally 
RT                   Radiation Therapy 
RINV               Radiation Induced Nausea and Vomiting 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
TSQM-9         Treatment Satisfaction Questionnaire for Medication  
WBC 
White Blood Cells 
 
 


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5 PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
5.1 Purpose 
The purpose of this two-arm randomized phase 2 study is to assess the efficacy and patient satisfaction of oral 
rolapitant plus ondansetron vs. oral ondansetron monotherapy in malignant glioma (MG) patients receiving six 
weeks of standard cranial radiation therapy (RT) and concomitant temozolomide (TMZ). 
       
Primary Objective: 
1. Compare the efficacy of rolapitant plus ondansetron vs. ondansetron mono therapy in the prevention 
of chemoradiation-induced nausea and vomiting (chemo-RINV), as measured by the overall complete 
response (CR) rate (where CR is defined as no emesis, no rescue antiemetic), among malignant glioma 
patients during the standard ~ 6 weeks of RT and concomitant multi-dose TMZ 
 
Secondary Objectives: 
1. KEY secondary objective: Assess whether malignant glioma patients receiving RT and concomitant TMZ 
are more satisfied with rolapitant plus ondansetron vs. ondansetron monotherapy for the prevention of 
chemo-RINV 
2. Describe the rationale behind a patient’s satisfaction with antiemetic preference based upon 
effectiveness, convenience and global satisfaction  
3. Compare the efficacy of rolapitant plus ondansetron vs. ondansetron monotherapy in the prevention of 
nausea and vomiting separately, as measured by the respective CIN, CIV -CR rates, among malignant 
glioma patients during RT and concomitant TMZ 
4. Evaluate compliance of rolapitant plus ondansetron vs. ondansetron monotherapy 
5. Assess the safety of rolapitant plus ondansetron vs. ondansetron monotherapy in the prevention of 
RINV in glioma patients receiving RT and concomitant TMZ 
 
Hypotheses 
1. This is a hypothesis-testing protocol. Hypothesis: rolapitant plus ondansetron will produce an equally or 
a more effective RINV CR rate when compared to ondansetron monotherapy in glioma patients 
receiving RT and concomitant TMZ.  
5.2 Background and Significance  
Radiation-induced nausea and vomiting (RINV) is a clinically distressing symptom in patients undergoing 
radiotherapy. The RINV risk in patients receiving cranial/cranio spinal radiation without concurrent 
chemotherapy is estimated to be around 30-60%.1 Although there is limited evidence to suggest that the RINV 
incidence is higher with the addition of temozolomide to RT than without, one would only predict that the 
incidence of RINV without emetic prophylaxis among patients treated with combination therapy (i.e. radiation 
and concurrent temozolomide) is higher. In two recent clinical studies, 35% or more of cranial RT patients 
experienced RINV.2,3 The risk of RINV increases when concomitant chemotherapy with TMZ is added to brain 
RT,4 as TMZ is moderately emetogenic.5,6 Temozolomide prescribing information reports nausea and vomiting 
rates of 36% and 20% respectively for concomitant RT+TMZ and concomitant RT+TMZ with standard 
antiemetic treatment.7 Comparable rates of nausea (35%) and vomiting (26%) were reported in a recent study 
of Korean MG patients receiving such treatment.8 The National Comprehensive Cancer Network (NCCN), 
Multinational Association of Supportive Care in Cancer (MASCC), and American Society of Clinical Oncology 
(ASCO) publish current clinical practice guidelines addressing the issue of RINV  9,10,6 and these guidelines 
recommend that patients receiving concomitant chemotherapy and RT treatment should be given antiemetic 
prophylaxis according to the emetogenicity of the chemotherapy prescribed, unless the emetic risk of the 
radiotherapy is higher. Given the moderate emetogenicity of TMZ therapy, patients with brain tumors are 
classified as a moderate-risk group for RINV. 
 
At Duke PRTBTC, we estimate the RINV rate to be approximately 50% without the use of ondansetron. Despite 
prophylaxis against nausea and vomiting during cranial RT and concomitant temozolomide therapy, Stupp 4,11 


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reported a threefold (14% - 40/287) increase in the grade 2-4 nausea/vomiting rate compared to a 4% 
(11/286) nausea/vomiting rate with radiotherapy alone. Without prophylaxis, up to 60% of patients receiving 
cranial radiation may experience acute nausea and vomiting, which can lead to various adverse effects 
including dehydration, electrolyte imbalance, malnutrition, and aspiration pneumonia. These complications 
can further delay/decrease the therapeutic effect of temozolomide and radiation treatment, ultimately 
leading to lower response rates and decreased health-related quality of life (HRQoL).  
 
We conducted the first phase 2 single arm trial of palonosetron (PAL), a long acting 5-hydroxytryptamine (5-
HT3) receptor antagonist (5HT3-RA), for the prevention of RINV in primary MG subjects receiving RT (54-60 Gy) 
and concomitant multi-dose, daily TMZ (75 mg/m2) +/- bevacizumab.  Results from this study demonstrate 
that a 5HT3-RA, such as PAL or ondansetron, can be safe and effective, however based on the results, there is 
still room for improvement of anti-emetic response related to CR rates and HRQoL, which could be addressed 
by combining a 5-HT3-RA and NK-1-RA12. PAL was safe and effective; however, there is room for improvement 
in the CR rates and HRQoL, which may be achieved with rolapitant plus ondansetron, a potentially more 
effective combination anti-emetic regimen. The most studied agents in the RINV settings are the 5HT3-RAs, 
with overall moderate response and low toxicity. However, agents such as the tachykinin NK-1 receptor 
antagonist may play a role in improving response rates, but there needs to be further studies in randomized 
controlled trials.13 
 
Rolapitant, an FDA-approved, long-acting, highly selective NK1 receptor antagonist (RA), in combination with a 
5-HT3 RA (ondansetron, granisetron) and dexamethasone is a well-tolerated antiemetic combination that has 
demonstrated superiority for the prevention of highly-emetic chemotherapy induced nausea and vomiting 
(CINV)14. In a global, randomized, double-blind, active-controlled, phase 3 multi-center study, 1369 patients 
receiving moderately-emetic chemotherapy or regimens containing an anthracycline and cyclophosphamide 
were randomly allocated (after stratification by sex) to receive either one 180 mg dose of oral rolapitant or a 
placebo (active control) 1-2 hours before administration of chemotherapy. All patients also received 
granisetron (2 mg orally) on days 2-3 and dexamethasone (20 mg orally) on day 115, on cycles of a minimum of 
14 days. The primary efficacy endpoint was complete response (CR indicated by no emesis or rescue 
medication) during the delayed (>24-120 hours) phase.  A significantly larger proportion of patients receiving 
rolapitant had complete responses in the delayed phase than did those receiving active control (475 [71%] vs 
410 [62%]; odds ratio 1.6, 95% CI 1.2-2.0; p=0.0002).15 Toxicities were similar in the rolapitant and control 
groups, with the most frequently reported treatment-related treatment-emergent adverse events being 
fatigue, constipation, and headache.15 No serious adverse event was treatment-related, and no treatment-
related adverse event resulted in death.15 
 
The oral combination of rolapitant plus ondansetron has not been studied in the prevention of RINV in 
patients receiving RT and multi-dose chemotherapy for MG. Additional advantages to using rolapitant plus 
ondansetron in the setting of radiation with concurrent multi-dose oral chemotherapy are that it avoids side 
effects associated with intravenous administration (e.g. palonosetron) and eliminates treatment room costs. 
Furthermore, rolapitant, as opposed to the aprepitant or netupitant, is not a CYP3A4 inhibitor or inducer of 
common drugs used in glioma patients (e.g. dexamethasone, enzyme-inducing anticonvulsants, or irinotecan) 
thus reducing drug-induced side effects. Ultimately, rolapitant plus ondansetron may improve overall 
efficacy (CR rates), cost, HRQoL and patient satisfaction. 
5.3 Design and Procedure 
This proposed study is a randomized phase 2 trial of rolapitant plus ondansetron vs. ondansetron 
monotherapy for the prevention of chemo-RINV in primary malignant glioma subjects receiving radiation 
therapy (RT) and concomitant multi-dose temozolomide (TMZ).  All eligible subjects should receive a planned 
total dose of 54-60 Gy of radiation and 75 mg/m2 of temozolomide daily for a total of six weeks. Glioma 
patients will be randomized in an unblinded fashion to receive one of two treatment sequences of antiemetic 
therapy for the prevention of nausea and vomiting associated with RT and concomitant TMZ.  
 


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Sequence A involves administration of ondansetron alone for 3 weeks followed by the use of rolapitant X 1 
dose plus daily ondansetron for 3 weeks; whereas, sequence B involves the use of rolapitant X 1 dose plus 
daily ondansetron for 3 weeks followed by 3 weeks of daily ondansetron alone.  For the rolapitant plus 
ondansetron weeks (1 or 4), patients will self-administer the oral rolapitant pill 1-2 hours before the first 
fraction of radiation on the planned week (see schema). Subjects will be given a prescription for ondansetron 
8 mg pills to be taken 30 minutes before their TMZ dose.  After the start of radiation therapy, the type of 
additional rescue antiemetic medication, if needed, will be left up to the investigator’s discretion.  Subjects 
will be informed that they are allowed to take rescue antiemetic medication while participating in either arm 
of the study.  If the subject experiences nausea and vomiting and does take a rescue antiemetic, the subject 
will be asked to record the use of additional antiemetic in a medication log provided to them. Subjects will 
complete weekly medication logs and surveys (see Appendices) to capture study outcomes. Subjects will be 
told that the study is voluntary and that they may exit at any time if they wish.  
 
Approximately 170 patients will provide informed consent in order for 160 patients to be randomized to either 
treatment sequence A or B. The 170 estimate is to allow for screen failures and dropout rates. All subjects 
must give written informed consent to participate in the study. Patients will be screened -28 to 0 days prior to 
the start of the study. During this time period the following information will be recorded: physical 
examination; vital signs and weight; laboratory studies (complete blood count with differential, blood 
chemistries, liver function tests and urinalysis): medical history; concomitant medications (steroids and 
anticonvulsants) and predictors of RINV (irradiation site, planned dose treatment field, alcohol intake, gender, 
age etc.). Laboratory evaluations, performance status, concomitant medications, and adverse events for final 
eligibility should be confirmed within 2 weeks of initiating radiation with concomitant TMZ 
 
Patients will obtain standard of care blood work (per local oncologistduring treatment complete blood count 
with differential, blood chemistries, liver function tests). Toxicity will be assessed based on the Common 
Toxicity Criterion (CTC version 4). The patient will be asked to complete the MASCC nausea and vomiting 
questionnaire on day 0 (baseline), and days 1, 2, 4, and 7 (for days 7, 1, 2-3, and 4-6, respectively) of each 
week of radiation therapy.   
 
At the end of weeks 3 & 6, the subject will be asked to fill out a Treatment Satisfaction Questionnaire for 
Medication (TSQM-9, Section 18.1 and 18.2) and will be asked at the end of week 6 to choose which 
antiemetic they prefer. 
5.4 Selection of Subjects 
Selection of Subjects: Patients with a malignant glioma who plan to undergo standard RT with concomitant 
daily temozolomide (TMZ) therapy 
 
Inclusion Criteria:  
1. Patients must have histologically-confirmed, newly-diagnosed malignant glioma (glioblastoma, 
gliosarcoma, anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic pleomorphic 
xanthoastrocytoma, or anaplastic oligodendroglioma) and are scheduled to receive radiotherapy (for a 
total of 54-60 Gy) and concomitant daily temozolomide therapy (at a dose of 75 mg/m2 for one complete 
6-week cycle). 
2. Age ≥ 18 years 
3. Karnofsky ≥ 60% or ECOG 0-2 
4. For patients on higher than physiological level of corticosteroids, they must have been on a stable dose 
for 1 week prior to initiating study drug, and the dose should not be escalated over entry dose level, if 
clinically possible 
5. Ability and willingness to give informed consent 
6. Female patients of childbearing potential must have a negative pregnancy test at Screening 
7. Female patients of childbearing potential must agree to use an acceptable method of birth control (please 
refer to the attached document, Birth Control Recommendations (Appendix 18.5)) from the signing of 


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informed consent form and to continue its use during the study and for at least 90 days after the final 
dose 
8. Male patients must agree to use an acceptable form of birth control (please refer to the attached 
document, Birth Control Recommendations (Appendix 18.5) from study Day 1 through at least 90 days 
after the final dose 
9. Hematocrit >29%, ANC >1,000 cells/mm3, platelets >100,000 cells/ mm3 
10. Serum creatinine <1.4 mg/dl, bilirubin <1.5 times upper limit of normal 
11. Aspartate aminotransferase (AST) ≤2.5 x upper limit of normal range (ULN).  For subjects with known liver 
metastases ≤5 x ULN, and alanine aminotransferase (ALT) ≤2.5 x ULN.  For subjects with known liver 
metastases ≤5 x ULN 
 
 
Exclusion Criteria: 
1. Co-medications that may interact with rolapitant as reviewed by Duke Preston Robert Tisch Brain Tumor 
investigator pharmacist  
2. Co-medications that are contraindicated in patients on rolapitant including pimozide, thioridazine, 
carbamazepine, colchicine, dabigatran (Pradaxa), edoxaban (Savaysa), fosphenytoin, metoprolol, 
phenobarbital, phenytoin, primidone, and warfarin 
3. Inability or unwillingness to cooperate with the study procedures 
4. Prophylactic medication for the prevention of nausea and vomiting 24 hours prior to the start of radiation 
therapy through the full course of radiation therapy is prohibited, with the exception of the study drug. 
Corticosteroids will be allowed for treatment of cerebral swelling 
5. Ongoing vomiting from any organic etiology 
6. Previous participation in any clinical trial involving rolapitant     
7. Received rolapitant within 21 days prior to study enrollment 
8. Prior cancer chemotherapy or radiotherapy 
9. Any current treatment, medical history, or uncontrolled condition, other than malignancy, (e.g., 
alcoholism or signs of alcohol abuse, seizure disorder, medical or psychiatric condition) that, in the 
opinion of the investigator, would confound the results of the study or pose any unwarranted risk in 
administering study drug to the subject  
10. Patient has a known hypersensitivity to the administration of rolapitant or its excipients  
11. Patient has a history of severe renal or hepatic impairment, severe bone marrow suppression, or systemic 
infection  
12. Patient is a woman with a positive serum pregnancy test at Screening, is pregnant, breast-feeding, or is 
planning to conceive children within the projected duration of the study treatment 
13. Patient has taken the following agents within the last 48 hours prior to the start of treatment with study 
drug:  
• 
5-HT3 antagonists (ondansetron, granisetron, dolasetron, tropisetron, etc.).  
• 
Benzamides (metoclopramide, alizapride, etc.)  
• 
Domperidone  
• 
Cannabinoids  
• 
NK1 antagonist (aprepitant)  
• 
Benzodiazepines (lorazepam, alprazolam, etc.) 
• 
herbal medications or preparations in doses designed to ameliorate nausea or emesis  
14. Patient has taken phenothiazines (prochlorperazine, fluphenazine, perphenazine, thiethylperazine, 
chlorpromazine, etc.) for any indication within the last 48 hours prior to the start of treatment with study 
drug 
15. Palonosetron is not permitted within 7 days prior to administration of investigational product  
16.  Any vomiting, retching, dry heaves, or clinically significant nausea (i.e., NCI Common Toxicity Criteria 
version 4.0 grade 2-4 nausea) caused by any etiology in the 24 hrs. preceding day 1 of the study 
intervention (ondansetron or ondansetron with rolapitant) as scheduled to begin on day 1 of radiation 
and chemotherapy. Or a patient who has a history of anticipatory nausea and vomiting.  


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17. Patient must not have been dosed with test drug or blinded study drug in another investigational study 
within 30 days or 5 half-lives of the biologic activity of the test drug, whichever is longer, before the time 
of first study dose 
18. Patient who is receiving investigational agent(s) as part of another clinical study at the time of screening 
or who anticipates receiving investigational agent(s) during their scheduled radiotherapy and concomitant 
daily temozolomide therapy. (Please refer to study Memo to File regarding exceptions to this exclusion 
criteria)  
 
5.5 Subject Recruitment and Compensation 
Subjects will be recruited for this study as follows:   
Subjects will be identified from patients referred to the Preston Robert Tisch Brain Tumor Center Clinic. Upon 
determination that a subject’s tumor histology and radiographic findings are compatible with the eligibility 
criteria for this study protocol, the study will be briefly explained to the subject by the clinical research 
coordinator (CRC) or Mary Lou Affronti DNP, RN, MSN, ANP, MHSc, or Dr. Katherine Peters, the principal 
investigators (PIs), or a member of the research team in the PRTBTC (may include RNs, CRCs, MDs or advanced 
practice providers).  If the subject indicates interest in study participation, study education sheets will be 
provided by the research nurse clinicians as this provides the most comprehensive explanation of the study in 
lay terms. If the patient shows continued interest, the PI or member of the research study staff will thoroughly 
explain the required elements of informed consent and all aspects of the study to the subject including but not 
limited to inclusion/exclusion criteria, risks, benefits, and alternatives to study participation. If the patient 
desires additional time to consider participation in the study, the study staff will send the patient home with 
the consent form. If the patient takes the consent form home and decides to participate, a return 
appointment to the PRTBTC will be scheduled with the study nurse and study coordinator to complete the 
informed consent process face to face with the patient. 
 
No compensation for participation will be given to subjects.  The study medication, rolapitant, is FDA-
approved and will be provided at no charge by the study supporter, TerSera.  A third party insurance carrier 
will be responsible for the cost of clinic visits, laboratory tests, dexamethasone, and routine care and 
treatment for the brain tumor (including ondansetron and rescue medication).  How much subjects will have 
to pay, depends on whether or not they have insurance or what costs the insurance will cover. Insurance 
coverage cannot be guaranteed for all tests and treatments related to this study. Treatment to help control 
side effects may also result in added costs.   
5.6 Consent Process 
Subjects must give informed consent according to institutional review board (IRB) guidelines prior to 
registration.  The subject will receive a copy of the signed consent document. The original signed consent 
document will be retained by the PRTBTC in a study binder. The PI or designee will fully explain the purpose 
and potential risks and benefits of the study to the subject prior to enrollment and address any questions 
posed by the subject. In addition, the PI or designee will explain to each subject the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits involved and any 
additional discomfort that may be anticipated from taking this antiemetic drug combination. Each subject will 
be informed that participation in the study is voluntary and that he/she may withdraw from the study at any 
time and that withdrawal of consent will not affect his/her subsequent medical treatment or relationship with 
the treating physician.   
 
The prospective participant will have as much time as he/she may need to make an informed decision about 
the study, and all treatment-related questions will be answered.  Prospective participants will be consented in 
an exam room where only the research staff, the patient, and his/her family (if desired) are present.  Before, 
during, and after the consent process, the research team and investigators will be available in person and by 
phone to answer any questions the participants may have.  Any and all other available treatment options are 


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offered to the patient in order to avoid undue influence.  Participants are not offered compensation for this 
study, in order to avoid any monetary coercion/influence. 
 
For those prospective participants who cannot read or are blind, the consent document will be read out loud 
verbatim to the participant, who is encouraged to have a caregiver or family member present as a witness 
who can read along as the consent form is read.  If the prospective participant cannot read or understand 
English, an approved, translated, short form consent document will be provided to the participant.  A 
translator and a translator/witness, along with the Brain Tumor Center attending physician, nurse, or 
coordinator, will review the short form consent document and the full English version of the consent and all 
relevant study documents with the subject.  If a subject has a physical impairment that limits their ability to 
provide a signature, an impartial witness will be utilized as part of the informed consent process. This impartial 
witness will date and sign the Informed Consent along with the person obtaining the informed consent.   
5.7 Subject’s Capacity to Give Legally Effective Consent 
Subjects participating in this study are competent to sign informed consent, based upon inclusion criteria and 
investigator assessment. Subjects who do not have the capacity to give legally effective consent will not be 
enrolled. 
5.8 Risk/Benefit Assessment 
The natural progression of this type of brain tumor and standard treatment modalities are associated with 
potentially life-threatening complications and side effects.  The antiemetic study drug (rolapitant) may 
increase the risk of side effects.  
Table 1: The study of drug, Varubi® (rolapitant) with MEC can cause the following effects: 
VARUBI Regimen 
(VARUBI, Dexamethasone, and 5-HT3 
Receptor Antagonist) 
N = 670 
Control 
(Placebo, Dexamethasone, and 
5-HT3 Receptor Antagonist) 
N = 674 
Decreased appetite 
9% 
7% 
Dizziness 
6% 
4% 
Dyspepsia 
4% 
2% 
Urinary tract infection 
4% 
3% 
Stomatitis 
4% 
2% 
 
Allergic reactions may occur rarely.  Hives; tightness of the throat; difficulty breathing or swallowing; 
hoarseness should be reported to the study doctor immediately. 
 
Note:  The Reference Safety Information for the study will be the United States Package Insert (USPI). 
 
Ondansetron 
Most common side effects (occurring in 9 to 24% of subjects): 
• 
Headache 
• 
Fatigue 
• 
Constipation 
 
Side effects occurring in 5-6% of subjects: 
• 
Diarrhea 
• 
Dizziness 
 


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Other side effects that have been reported by people who have taken ondansetron (intravenous  
[by vein] or by mouth) in clinical studies include the following: 
• 
Low oxygen level in the blood (Hypoxia) 
• 
Fever 
• 
Slow heart rate (Bradycardia) 
• 
Urinary retention 
• 
Itching 
• 
Drowsiness/sedation 
• 
Shivers  
 
Serotonin syndrome has been reported when ondansetron has been taken at the same time as another 
medication that affects serotonin, a type of neurotransmitter (a chemical produced by the body). Such 
medications include certain types of anti-depressants and migraine medications. The study team will 
review your list of medications with you to find out if you are taking any of these medications. Please 
seek immediate medical attention if you experience any of the following symptoms of serotonin 
syndrome: changes in mental status, autonomic instability (this could include fainting or dizziness, 
exercise intolerance, sweating too much or too little, difficulty with urinating, sexual problems, and 
visual problems), neuro-muscular symptoms, and gastrointestinal symptoms, such as loss of appetite, 
bloating, diarrhea, constipation, or difficulty swallowing. 
 
Other medications: 
Subjects should tell the study doctor about all drugs that they have been taking recently and are taking while 
enrolled in this study. Also, if a severe side effect occurs, the study doctor may permanently stop the study 
drug. Subjects must tell their study doctor and research staff of their concern of any of these side effects, as 
listed above.  
5.9 Costs to the Subject 
The study drug, rolapitant, is FDA-approved and will be provided at no charge. Ondansetron is commercially 
available and will not be covered by the study. The subject or their third party insurance carrier will be 
responsible for the cost of his/her clinic visits, laboratory tests, dexamethasone (as needed), and the routine 
care and treatment of their brain tumor, e.g. the radiation therapy and temozolomide.  How much one will 
have to pay, depends on whether or not the subject has insurance and those costs that his/her insurance will 
cover. Insurance coverage cannot be guaranteed for all tests and treatments related to this study. Treatment 
to help control any side effects that may occur may also result in added costs to the subject or their insurance 
company. Subjects will not be paid for taking part in this study. 
5.10 Duration of Study 
 Participants will be in the study for 8 weeks which includes ~6 weeks of treatment and 2 weeks of monitoring 
for adverse events following the end of radiation and concurrent temozolomide treatment. 
5.11 Data Analysis and Statistical Considerations 
One hundred seventy (170) glioma patients will be enrolled with the expectation that 160 patients will be 
randomized (unblinded) to receive one of two treatment sequences of anti-emetic therapy for the prevention 
of nausea and vomiting associated with RT and concomitant TMZ. Sequence A involves a 3-week regimen of 
daily ondansetron followed by a 3-week regimen consisting of rolapitant (day 22 only) and daily ondansetron; 
whereas, Sequence B involves a 3-week regimen of rolapitant (day 1 only) and daily ondansetron followed by a 
3-week regimen of daily ondansetron.    
 
The primary endpoint of this study is CR rate.  Though the primary CR rate endpoint will focus on treatment 
during the first 2 weeks of RT and TMZ, a cross-over design is proposed so that a patient will experience both 
modes of treatment, and be equipped to make a comparative assessment of preference, which is a key 


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secondary outcome.  An interim analysis (as described in 15.6) will be conducted by the study statistician or 
designee after 40 patients are accrued to each sequence. 
 
We expect that 152 of the 160 randomized patients to provide an assessment of their experience during the 
first 2 weeks of treatment with the first regimen.  With 152 patients, there is 80% power to detect an increase 
in the CR rate from 75% with ondansetron to 90% with the combination of ondansetron and rolapitant 
(α=0.05; one-tailed) with a chi-square test. 
6 STUDY SCHEMA 
 
 
 
 
 


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7 BACKGROUND AND SIGNIFICANCE 
7.1 Study Disease 
Radiation-induced nausea and vomiting (RINV) is a clinically distressing symptom in patients undergoing 
radiotherapy. The RINV risk in patients receiving cranial/craniospinal radiation without concurrent 
chemotherapy is estimated to around 30-60%.1 Although there is limited evidence to suggest what the RINV 
incidence is higher with the addition of temozolomide to RT than without, one would only predict that the 
addition of concurrent chemotherapy with brain irradiation would only increase the RINV rate.  In two recent 
clinical studies, 35% or more of cranial RT patients experienced RINV.2,3 The risk of RINV increases when 
concomitant chemotherapy with TMZ is added to brain RT,4 as TMZ is moderately emetogenic.5,6 
Temozolomide prescribing information reports nausea and vomiting rates of 36% and 20% respectively for 
concomitant RT+TMZ and concomitant RT+TMZ with standard antiemetic treatment.7 Comparable rates of 
nausea (35%) and vomiting (26%) were reported in a recent study of Korean malignant glioma patients 
receiving such treatment.8 The National Comprehensive Cancer Network (NCCN), Multinational Association of 
Supportive Care in Cancer (MASCC), and American Society of Clinical Oncology (ASCO) publish current clinical 
practice guidelines addressing the issue of RINV  9,10,6 These guidelines recommend that patients receiving 
concomitant chemotherapy and RT treatment should be given antiemetic prophylaxis according to the 
emetogenicity of the chemotherapy prescribed, unless the emetic risk of the radiotherapy is higher. Given the 
moderate emetogenicity of TMZ therapy, patients with brain tumors are classified as a moderate-risk group 
for RINV. 
 
At Duke PRTBTC, we estimate the RINV rate to be approximately 50% without the use on ondansetron. 
Despite prophylaxis against nausea and vomiting during cranial RT and concomitant temozolomide therapy, 
Stupp 4,11 reported a threefold (14% - 40/287) increase in the grade 2-4 nausea/vomiting rate compared to a 
4% (11/286) nausea/vomiting rate with radiotherapy alone. Without prophylaxis, up to 60% of patients 
receiving cranial radiation may experience acute nausea and vomiting, which can lead to various adverse 
effects including dehydration, electrolyte imbalance, malnutrition, and aspiration pneumonia. These 
complications can further delay/decrease the therapeutic effect of temozolomide and radiation treatment, 
ultimately leading to lower response rates and decreased health-related quality of life (HRQoL).  
 
We conducted the first phase 2 single arm trial of palonosetron (PAL), a long acting 5-hydroxytryptamine (5-
HT3) receptor antagonist (5HT3-RA), for the prevention of RINV in primary MG subjects receiving RT (54-60 Gy) 
and concomitant multi-dose, daily TMZ (75 mg/m2) +/- bevacizumab.  Results from this study demonstrate 
that a 5HT3-RA, such as PAL or ondansetron, can be safe and effective, however based on the results, there is 
still room for improvement of anti-emetic response related to CR rates and HRQoL, which could be addressed 
by combining a 5-HT3-RA and NK-1-RA12. PAL was safe and effective; however, there is room for improvement 
in the CR rates and HRQoL, which may be achieved with rolapitant plus ondansetron, a potentially more 
effective combination anti-emetic regimen.  Additionally, PAL is only available as an IV injection in the United 
States whereas ondansetron can be administered orally, making it a more patient-friendly drug.  The most 
studied agents in the RINV settings are the 5HT3-RAs, with overall moderate response and low toxicity. 
However, agents such as the tachykinin NK-1 receptor antagonist may play a role in improving response rates, 
but there needs to be further studies in randomized controlled trials.13 
7.2 Study Agent 
Rolapitant, an FDA-approved, novel, long-acting, new highly-selective neurokinin-1 (NK1) receptor antagonist 
(RA), in combination with a 5HT3-RA (i.e. ondansetron, granisetron) and dexamethasone is a well-tolerated 
antiemetic combination that has demonstrated superiority for the prevention of highly-emetic chemotherapy 
(HEC) induced nausea and vomiting (CINV)14.   
 
In a global, randomized, double-blind, active-controlled, phase 3 multi-center study, 1369 patients receiving 
moderately-emetic chemotherapy (MEC) or regimens containing an anthracycline and cyclophosphamide 
were randomly allocated (after stratification by sex) to receive either one 180 mg dose of oral rolapitant or a 


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placebo (active control) 1-2 hours before administration of chemotherapy. All patients also -received 
granisetron (2 mg orally) and dexamethasone (20 mg orally) on day 1 and granisetron (2 mg orally) on days 2-
3.15   The median cycle duration was 21 days with the recommended minimum dosing for Rolapitant at no less 
than 14 day intervals. The primary efficacy endpoint was complete response (CR: no emesis, no rescue 
medication) during the delayed (>24-120 hours) phase.  A significantly larger proportion of patients receiving 
rolapitant had complete responses in the delayed phase than did those receiving active control (475 [71%] vs 
410 [62%]; odds ratio 1.6, 95% CI 1.2-2.0; p=0.0002).15 Toxicities were similar in the rolapitant and control 
groups, with the most frequently reported treatment-related treatment-emergent adverse events being 
fatigue, constipation, and headache.15 No serious adverse event was treatment-related, and no treatment-
related adverse event resulted in death.15 
 
Mechanism of action: Rolapitant is a selective and competitive antagonist of human substance P/NK1 
receptors. Rolapitant does not have significant affinity for the NK2 or NK3 receptors or for a battery of 
other receptors, transporters, enzymes and ion channels.   Rolapitant is also active in animal models of 
chemotherapy-induced emesis. 
 
Pharmacodynamics: NK1 Receptor Occupancy - A Human Positron Emission Tomography (PET) study with 
rolapitant demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK1 receptors.  A 
dose-dependent increase in mean NK1 receptor occupancy was observed in the dose range from 4.5 mg to 180 
mg of rolapitant. At the 180 mg dose of rolapitant, the mean NK1 receptor occupancy was 73% in the striatum 
at 120 hours after a single dose administration in healthy subjects.  The relationship between NK1 receptor 
occupancy and the clinical efficacy of rolapitant has not been established. 
 
Cardiac Electrophysiology - In a thorough QT study, rolapitant at doses up to 4 times higher than the 
recommended dose had no significant effects on the QT intervals 
 
Pharmacokinetics:  Absorption - Following a single dose administration of 180 mg rolapitant under fasting 
conditions to healthy subjects, rolapitant was measurable in plasma between 30 minutes and the peak plasma 
concentration (Cmax) for rolapitant was reached in about 4 hours, and mean Cmax was 968ng/mL (%CV:28%).  
Following multiple oral doses 9 to 45 mg once daily of rolapitant; accumulation of rolapitant was 
approximately 5-fold.  The systemic exposures (Cmax and AUC) to rolapitant increased in a dose-proportional 
manner when the dose of rolapitant increased from 4.5 mg to 180 mg.  With an increase in dose by 4 times 
from the recommended clinical dose of 180 mg, the Cmax and AUC of rolapitant increased by 3.1 fold and 3.7 
fold, respectively. Concomitant administration of a high fat meal did not significantly affect the 
pharmacokinetics of rolapitant after administration of 180 mg rolapitant.  
 
Distribution - Rolapitant was highly protein bound to human plasma (99.8%).  The apparent volume of 
distribution (Vd/F) was 460 L in healthy subjects, indicating an extensive tissue distribution of rolapitant.  In a 
population pharmacokinetic analysis of rolapitant, the Vd/F was 387 L in cancer patients. 
 
Elimination - Following single oral doses (4.5 to 180 mg) of rolapitant, the mean terminal half-life (t1/2) of 
rolapitant ranged from 169 to 183 hours (approximately 7 days) and was independent of dose. In a population 
pharmacokinetic analysis, the apparent total clearance (CL/F) of rolapitant was 0.96L/hour in cancer patients.  
 
Metabolism - Rolapitant is metabolized primarily by CYP3A4 to form a major active metabolite, M19 (C4- 
pyrrolidine-hydroxylated rolapitant). In a mass balance study, the metabolite M19 was the major circulating 
metabolite. The formation of M19 was significantly delayed with the median Tmax of 120 hrs. (range: 24-168 
hours) and the mean half-life of M19 was 158 hours.  The exposure ratio of M19 to rolapitant was 
approximately 50% in plasma. 
  
Excretion - Rolapitant is eliminated primarily through the hepatic/biliary route.  Following administration of a 
single oral 180 mg dose of [14C]-rolapitant, on average 14.2% (range 9% to 20%) and 73% (range 52% to 89%) 


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of the dose was recovered in the urine and feces, respectively over ~ 6 weeks. In pooled samples collected over 
2 weeks, 8.3% of the dose was recovered in the urine primarily as metabolites and 37.8% of the dose was 
recovered in the feces primarily as unchanged rolapitant. Unchanged rolapitant or M19 were not found in 
pooled urine sample.  
 
Specific Populations - Age, Sex and Race/Ethnicity - Population pharmacokinetic analyses indicated that age, 
sex and race had no significant impact on the pharmacokinetics of rolapitant. 
 
Pregnancy: There are no available data on rolapitant use in pregnant women to inform any drug-associated 
risks.  In animal reproduction studies, there were no teratogenic or embryo-fetal effects observed with oral 
administration of rolapitant hydrochloride in rats and rabbits during the period of organogenesis at doses up 
to 1.2 times and 2.9 times, respectively, the maximum recommended human dose (MRHD).  In the U.S. 
general population, the estimated background risk of major birth defects and miscarriage in clinically 
recognized pregnancies is 2% to 4% and15% to 20%, respectively. 
 
Hepatic Impairment- Following administrations of a single dose of 180 mg rolapitant to patients with mild 
hepatic impairment (Child-Pugh Class A), the pharmacokinetics of rolapitant were comparable with those of 
healthy subjects. In patients with moderate hepatic impairment (Child-Pugh Class B), the mean Cmax was 25% 
lower while mean AUC of rolapitant was similar compared to those of healthy subjects.  The median Tmax for 
M19 was delayed to 204 hours in patients with mild or moderate hepatic impairment compared to 168 hours 
in healthy subjects.  The pharmacokinetics of rolapitant was not studied in patients with severe hepatic 
impairment (Child-Pugh Class C). 
 
Renal Impairment- In population pharmacokinetic analyses, creatinine clearance (CLcr) at baseline did not 
show a significant effect on rolapitant pharmacokinetics in cancer patients with mild (CLcr: 60 to 90 mL/min) or 
moderate (CLcr: 30 to 60 mL/min) renal impairment compared to cancer patients with normal kidney function.  
Information is insufficient for the effect of severe renal Impairment. The pharmacokinetics of rolapitant was 
not studied in patients with end-stage renal disease requiring hemodialysis. 
 
Drug  Interaction Studies-Effect of Other Drugs on Rolapitant - Rolapitant is a substrate for CYP3A4.  
 
CYP3A4   inducers - Concomitant administration of a CYP3A4 inducer significantly decreased the systemic 
exposure to rolapitant. When 600 mg rifampin (CYP3A4 inducer) was administered once daily for 7 days before 
and 7 days after administration of a single dose of 180 mg rolapitant, the mean Cmax of rolapitant was 
reduced by 30% and the mean AUC was reduced by 85% compared to administration of rolapitant alone.  The 
mean half-life of rolapitant decreased from 176 hours without rifampin to 41 hours with concurrent rifampin.  
Strong CyP3A4 inducers (e.g.,  rifampin) significantly reduced plasma concentrations of rolapitant, which can 
decrease the efficacy of rolapitant; avoid use of rolapitant in patients who require chronic administration of 
such drugs. 
 
CYP3A4   inhibitors: No clinically significant effect was seen on the pharmacokinetics of rolapitant when 
ketoconazole, a strong CYP3A4 inhibitor was administered with rolapitant.  Concurrent administration of 400 
mg ketoconazole once daily for 21 days following a single 90 mg dose of rolapitant, did not significantly affect 
the Cmax of rolapitant while the AUC increased by 21%. 
 
Effect of Rolapitant on Other Drugs – Effects of rolapitant on CYP450 enzymes and transporters is summarized 
below: 
 
CYP3A4  substrates: Rolapitant is neither an inhibitor nor an inducer of CYP3A4, therefore, no dosage 
adjustment for dexamethasone (CYP3A4 substrate) is needed when co-administered with rolapitant. 
 


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Dexamethasone:  Rolapitant had no significant effects on the pharmacokinetics of dexamethasone when oral 
dexamethasone was administered days 1-3 after a single 180 mg dose of rolapitant was co-administered on 
Day 1.  
 
Ondansetron: Rolapitant had no significant effects on the pharmacokinetics of intravenous ondansetron 
when concomitantly administered with a single 180 mg dose of rolapitant on the same day. 
CYP2D6   inhibitor: 
Rolapitant is a (1) moderate inhibitor of CYP2D6 (i.e. concomitant use with Thioridazine is contraindicated due 
to QT prolongation and Torsa des de Pointes. Avoid use of rolapitant with pimozide,); (2) an inhibitor of Breast-
Cancer-Resistance Protein-BCRP (i.e. Topetecan, Methotrexate; Use the lowest effective dose of rosuvastatin), 
and (3) an inhibitor of P-glycoprotein (P-gp) (increased plasma concentrations of digoxin, or other P-gp 
substrates, may result in potential adverse reactions. Monitor for increased digoxin concentrations).  Refer to 
package insert.  The Table below is a summary of the effects of the clinical dose of rolapitant on the 
pharmacokinetics of co- administered drugs: 
 
Table 2: Effects of Rolapitant on the Pharmacokinetics of Co-administered Drugs* 
 
 
Enzyme/ 
Co-administered drug 
Day 1 
% Change for Co-Administered Drug 
with rolapitant 
Day 8 without rolapitant 
transporter 
Change in 
Cmax 
Change in 
AUC 
Change in 
Cmax 
Change in 
AUC 
CYP2D6 
Dextromethorphan 30mg 
120% ↑ 
160% ↑ 
180% ↑ 
230% ↑ 
BCRP 
Sulfasalazine 500 mg 
140% ↑ 
130% ↑ 
17% ↑ 
32% ↑ 
P-gp 
Digoxin 0.5 mg 
70% ↑
30% ↑ 
n/a 
n/a 
* A single dose of 180 mg rolapitant was administered on day 1; the interacting drug was administered on day 1 with rolapitant 
and alone on day 8; ↑ Denotes an average increase in exposure by the percentage indicated. n/a: Not studied 
 
Rationale for use in gliomas: The oral combination of rolapitant plus ondansetron has not been studied in the 
prevention of RINV using multi-dose chemotherapy in individuals with malignant glioma. Additional 
advantages to using rolapitant plus ondansetron in the setting of radiation with concurrent multi-dose oral 
chemotherapy are that it avoids side effects associated with intravenous administration (e.g. palonosetron) 
and eliminates treatment room costs. Furthermore, rolapitant, as opposed to the aprepitant or netupitant, is 
not a CYP3A4 inhibitor or inducer of for common drugs used in glioma patients (e.g. dexamethasone, enzyme-
inducing anticonvulsants, or irinotecan) thus reducing drug-induced side effects. The NK1 antagonist EMEND® 
(aprepitant) was approved by the US Food and Drug Administration and by the European Medicines Agency for 
the prevention of acute and delayed CINV associated with highly emetic chemotherapy (HEC- i.e. high dose 
cisplatin) and MEC when used in combination with a 5-HT3 antagonist and a corticosteroid. Dosage adjustment 
of concomitantly administered drugs is necessary with aprepitant, which is a mixed inducer/inhibitor of 
cytochrome P450 (CYP) 3A4 and also affects other CYP enzymes. Rolapitant has been free of clinically relevant 
drug interactions in studies conducted to date, has rapid and good brain penetration, which may contribute to 
its quick onset of action, and a long half-life that allows for dosing only once during each cycle of 
chemotherapy. PET occupancy studies as well as clinical efficacy data support the use of only a single dose of 
rolapitant to protect patients for 5 days from CINV. Rolapitant has been selected as a promising agent to 
address this and other shortcomings of existing therapy. Ultimately, rolapitant plus ondansetron may 
improve overall efficacy (CR rates), cost, HRQoL and patient satisfaction. 


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7.2.1 
Pre-clinical experience (as noted in the Rolapitant Investigator’s 
brochure)  
Rolapitant has been evaluated in a series of non-clinical toxicity studies of up to 6 months duration in 
rats and up to 9 months duration in monkeys by oral administration and up to 14 days duration in rats 
and up to 1 month duration in monkeys by intravenous (IV) infusion. Developmental and reproductive 
toxicity studies, genetic toxicity studies, and safety pharmacology studies were also conducted. In 
addition, genetic toxicity studies and a safety pharmacology study were conducted with the 
pharmacologically active metabolite SCH720881. Furthermore, 2-year oral carcinogenicity studies of 
rolapitant in rats/mice have been completed. 
 
Major findings in the non-clinical toxicity studies reported to date are convulsions in rats, mice, and 
monkeys at high lethal or near lethal doses (oral administration) and in monkeys (after IV infusion) as 
well as developmental and reproductive findings in female rats. For convulsions, exposure margins have 
been identified in the non-clinical species relative to clinical exposure data at an oral dose of 200 mg and 
there has been no evidence of treatment- related seizures in the completed clinical trials. Since the 
rolapitant clinical development program has not nor will include women who are pregnant or 
attempting to become pregnant, the findings in the developmental and reproductive studies in rats are 
not considered relevant for the CINV clinical trials. The mouse carcinogenicity study with rolapitant was 
negative; the rat carcinogenicity study showed a non-significant increase in thyroid follicular cell tumors 
and benign adrenal medullary tumors. 
7.2.2 
Clinical experience (as noted in the Rolapitant Investigator’s brochure 
and the package insert) 
The total number of subjects exposed to oral rolapitant is approximately 2,800 which include 1,567 CINV 
patients and 1,231 healthy volunteers or patients from several additional Phase 1 and Phase 2 studies. 
Rolapitant was well tolerated at single doses up to 800 mg or as a once- daily dose up to 50 mg for 10 
days. Orally administered rolapitant was completely bioavailable, rapidly absorbed, and slowly cleared. 
Maximum concentrations of a 200 mg dose were approximately 1000 ng/mL and were achieved by 
approximately 4 hours. The half-life was approximately 170 hours (average), suggesting that a single 
dose may be sufficient to prevent CINV during both the acute and delayed phases of CINV. Rolapitant is 
highly bound to plasma proteins, with an unbound (free) fraction of <1%. Urinary excretion of the dose 
is minor, and the major route of elimination is via the feces. Rolapitant is extensively metabolized by 
oxidation, primarily to SCH 720881, an equipotent human NK1 RA. The formation and elimination of SCH 
720881 are slow. 
 
In phase 1 drug interaction studies, administration of rolapitant did not alter the pharmacokinetics of 
midazolam, dexamethasone or ondansetron, drugs metabolized by cytochrome P450 3A4. This indicates 
lack of a clinically relevant inhibition of CYP3A4 by rolapitant. Moreover, the PK of repeated doses of 
dexamethasone was also unaffected by a single 200 mg oral dose of rolapitant, indicating a lack of 
significant CYP3A4 induction by rolapitant or its metabolite. Inhibition of CYP3A4 by concomitant agents 
is unlikely to affect the PK of single doses of rolapitant, since concentrations of both rolapitant and the 
active metabolite SCH 720881 were unaffected by repeated daily oral doses (400 mg) of the potent 
CYP3A4 inhibitor ketoconazole. 
 
Repeated administration of daily rifampin 600 mg (as 2 x 300 mg), a strong CYP3A4 inducer, was 
observed to induce the metabolism of rolapitant (4 x 50 mg) such that a 1.5-fold reduction in Cmax and 
a 6- to 8-fold reduction in AUC0-last and AUC0-inf were observed along with a reduction in half-life from 
176 hrs. to 41 hours. 
 
Co-administration of a single 200 mg oral dose of rolapitant with a single 0.5 mg oral dose of digoxin led 
to increases in Cmax and AUC0-96h values for digoxin by 71% and 30%, respectively. No clinically 


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meaningful effects on pharmacodynamic responses to digoxin were observed; therefore, rolapitant may 
have modest effects as an inhibitor of P-glycoprotein (P-gp). 
 
In a recently conducted drug interaction study to assess the effect of rolapitant on the pharmacokinetics 
of specific probe substrates, preliminary results indicate that rolapitant inhibited the metabolism of 
dextromethorphan, a CYP2D6 substrate, and sulfasalazine, a BCRP substrate suggesting that rolapitant is 
a mild to moderate inhibitor of these enzymes. Therefore, dosage adjustments may be warranted for 
sensitive CY2D6 substrates and/or BCRP transporter substrates when given concomitantly with 
rolapitant, Rolapitant did not, however, alter the pharmacokinetics of tolbutamide, omeprazole, 
efavirenz or repaglinide, drugs metabolized by CYP2C9, CYP2C19, CYP2B6, or CYP2C8 respectively. In a 
recently conducted PK study in subjects with impaired hepatic function, preliminary results indicate 
comparable rolapitant PK profiles were observed in subjects with mild hepatic impairment and a slight 
decrease in exposure with subjects with moderate hepatic impairment when compared to healthy 
subjects. Therefore, dose adjustment for rolapitant when administered to patients with mild to 
moderate hepatic impairment is not required.  Subjects with severe hepatic impairment were not 
evaluated in this study. 
 
A human ECG study demonstrated no effects of rolapitant 200 mg or 800 mg (4 times the therapeutic 
dose) on the QTc interval. A clinical PET study demonstrated that single oral doses of rolapitant ranging 
from 5 to 200 mg can block the occupancy of cortical NK1 receptors by the selective PET ligand11 C-
GR205171. After a 200 mg dose, over 90% of central NK1 receptors remained blocked for at least 5 days. 
 
A multicenter, randomized, double-blind, active- and placebo-controlled Phase 2 study was conducted in 
patients undergoing surgical procedures to evaluate the effect of rolapitant monotherapy at doses of 5 
to 200 mg for the prevention of PONV post-anesthesia. Response rates for the primary endpoint (no 
emetic episodes during the first 24 hrs. post-operatively increased with increasing rolapitant dose, with 
maximum response rate of 86.5% in the rolapitant 200-mg group. Subjects administered rolapitant 
doses of 20, 70, or 200 mg were significantly more likely to have no emetic episodes for 0 to 24 hrs. than 
subjects given placebo, and the level of significance was dose related. In this study there was no pattern 
of dose or treatment dependency in the incidence of AEs. The most common (≥10% of subjects) 
treatment-emergent AEs were constipation, headache, pruritus, postoperative GI disorder, hypotension, 
and dizziness. A total of 90 subjects (17%) in the active treatment groups experienced AEs that were 
considered at least possibly or probably related to treatment compared with 17 (17%) of 103 placebo 
subjects. There were no appreciable safety concerns and no dose-related effects noted in clinical 
laboratory, vital sign, or ECG data. 
 
In study P04351 a dose range-finding phase 2 study was conducted in 454 patients receiving HEC (≥70 
mg/m2 cisplatin-based chemotherapy). The primary objective was to demonstrate that administration of 
rolapitant, at doses between 10 and 200 mg, along with ondansetron and dexamethasone, reduced the 
incidences of both acute and delayed CINV. A dose-response trend was generally observed for all 
efficacy endpoints, including complete response (defined as no emetic episodes and no rescue 
medication), no emesis, no nausea, no significant nausea, total control, and complete protection 
(defined as no emesis, no rescue medication, and maximum nausea VAS <25 mm on a 0 to 100 mm 
scale). For the 200 mg group, the overall (0-120 hrs.) complete response rate was 62.5% compared with 
46.7% for placebo (p = 0.032).  For the acute phase, the response rate was 87.6% vs. 66.7% (p = 0.001); 
for the delayed phase, the response was 63.6% vs. 48.9% (p = 0.045). At lower rolapitant dosage levels, 
complete response rates did not achieve statistical significance. The rolapitant 200 mg dose group also 
demonstrated significantly greater rates of no emesis and no significant nausea in the overall, acute and 
delayed phases than the control group. Kaplan-Meier curves comparing time to first event showed 
separation from control starting before 6 hrs. which represents a quicker onset of action that has been 
demonstrated with other agents in its class. 
 


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In this dose range-finding study the incidences of treatment-emergent adverse events (AE) and serious 
adverse events (SAE) were similar across all treatment groups. The most common (≥10% of subjects) 
treatment-emergent adverse events in the active treatment groups were nausea, fatigue, vomiting, 
constipation, and diarrhea. Overall, SAEs occurred in 52 (11%) of 454 randomized subjects during Cycle 
1 of chemotherapy. The most common (≥1% of subjects) SAEs were febrile neutropenia, neutropenia, 
vomiting, dehydration, nausea, pneumonia, and renal failure. All SAEs were considered unlikely related 
to treatment except for one occurrence each of dizziness (10-mg dose group), elevated blood creatinine 
(100-mg dose group), and convulsions (100-mg dose group) which were considered by the investigator 
to be at least possibly related to treatment. Confounders for dizziness and elevated creatinine were 
concomitant chemotherapy and for convulsion was a previous history of convulsions and hyponatremia 
at the time of the event. The incidence of study drug discontinuation because of AEs was similar across 
treatment groups and ranged from 2% to 7%. Results from clinical laboratory tests, measurements of 
vital signs, and ECGs showed no appreciable safety concerns and no dose-related effects. 
 
The results from the dose range-finding study showed rolapitant administered as a single dose of 200 
mg with a 5-HT3 receptor antagonist and dexamethasone to be highly effective in the prevention of CINV 
following HEC, together with data from the Phase 1 PET study, led to the dose selection and design of 
three global multicenter, randomized, parallel-group, double-blind, active-controlled phase 3 studies 
conducted in subjects receiving HEC (P04832 and Study P04833) and in subjects receiving MEC (Study 
P04834). 
 
These studies were designed to evaluate the efficacy of a single dose of rolapitant 200 mg administered 
orally with granisetron and dexamethasone compared to placebo administered with granisetron and 
dexamethasone for the prevention of delayed phase CINV (>24 to 120 hrs.). The primary endpoint of all 
three studies was achieved.  Specifically, the proportion of subjects who had no emesis and no use of 
rescue medication during the delayed phase of CINV, following initiation of HEC or MEC, was significantly 
higher for subjects receiving rolapitant compared with subjects receiving placebo (71.4% vs. 60.9%, 
respectively, p < 0.001). Likewise, the proportion of subjects who had no emesis and no use of rescue 
medication was significantly higher for subjects receiving rolapitant compared with subjects receiving 
placebo during the acute phase (< 24 hrs.) (83.5% vs. 78.7%, respectively, p = 0.003) and during the 
overall phase (0-120 hrs.) (68.7% vs. 58.1%, respectively, p < 0.001). Multiple secondary and tertiary 
endpoint comparisons favored the rolapitant group in the individual studies and in the pooled analyses 
and contribute additional support for the benefit of rolapitant during the delayed, acute and overall at 
risk period (0 to 120 hrs.) for patients receiving emetogenic chemotherapy.  In addition, rolapitant was 
safe and well tolerated. No AEs were clearly attributable to administration of rolapitant. Neurological 
and other clinical /laboratory examinations did not detect specific safety signals ascribed to rolapitant. 
 
A single ascending dose (SAD) and multiple ascending dose (MAD) assessment study of intravenous 
rolapitant in healthy volunteers was completed. The study’s primary objective was to assess the safety 
and tolerability of intravenous (IV) rolapitant.  A total of 57 subjects with a similar mean age of 37 years 
across each dose group were enrolled into Part 1 (SAD) and a total of 20 subjects with a similar mean 
age of 38 years across each dose group were enrolled into Part 2 (MAD). 
 
Part 1 evaluated the safety and tolerability of intravenous rolapitant administered as a single ascending 
dose (20, 50, 100, 150, 185 and 200 mg) over 30 or 45 minutes. Intravenous (IV) rolapitant administered 
as a single ascending dose of up to 200 mg was well tolerated. There were no TEAEs resulting in death 
or SAEs reported in this study.  All TEAEs were mild or moderate and had a single occurrence. The 
majority of TEAEs resolved spontaneously. No dose-dependent adverse events were observed, as 
indicated by the similarity of incidences of treatment-emergent and treatment-related emergent AEs 
among the different dose groups. 
 
Part 2 evaluated the safety/tolerability of intravenous rolapitant administered as a multiple ascending 
doses (20, 40, and 60 mg) over 30 minutes.  Intravenous (IV) rolapitant of 60 mg IV administered for 10 


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days was well tolerated. There were no serious TEAEs or TEAEs resulting in death and no TEAEs leading 
to discontinuation of dosing or discontinuation in this study. TEAEs were primarily mild and resolved 
spontaneously.  Infusion-related adverse events, when they occurred, were generally mild, limited to 
the catheter site (mild pain or erythema), resolved and required only ice pack or removal of the IV and 
were most likely associated with the placement and manipulation of catheters, and PK sampling. There 
were no clinically significant laboratories, vital signs, physical or ECG findings in any of the subjects 
overall or within each dose group. 
 
Rolapitant Efficacy in the CINV prevention 
The efficacy of rolapitant for the prevention of CINV was initially evaluated in a phase 2, dose range-
finding study (Study P04351).  In this study, a statistically significant improvement in the primary 
efficacy endpoint of complete response (CR) (defined as no vomiting and no use of rescue medication 
during the overall 120-hour phase of CINV following initiation of chemotherapy) was observed in the 
rolapitant 200 mg group compared to control.  Further, a statistically significant greater proportion of 
subjects in the rolapitant 200 mg group achieved CR in the acute and delayed phases compared with 
control.  As further support to the effectiveness of rolapitant in the treatment of CINV following HEC, a 
statistically significant difference in the rates of emesis and no significant nausea were observed in all 
3 phases compared to control. The results of this study, together with data from the phase 1 PET 
study led to the dose selection and design of three phase 3 studies, including two studies conducted in 
subjects receiving HEC (Study P04832 and Study P04833) and one conducted in subjects receiving MEC 
(Study P04834). 
 
All three phase 3 studies were designed to evaluate the efficacy of a single dose of rolapitant 200 mg 
administered orally with granisetron and dexamethasone compared to placebo administered with 
granisetron and dexamethasone for the prevention of delayed phase CINV (>24 to 120 hrs.).  Studies 
P04832 and P04833 were conducted in subjects receiving HEC (i.e., that receiving ≥60 mg/m2 and Study 
P04834 was conducted in subjects receiving MEC. 
 
The primary endpoint of all three phase 3 studies was achieved. Specifically, the proportion of 
subjects who did not experience emesis or use rescue medication during the delayed phase, >24 
through 120 hrs., following initiation of HEC or MEC, was significantly higher for subjects receiving 
rolapitant compared with subjects receiving control. Multiple secondary and tertiary endpoint 
comparisons favored the rolapitant group in all studies and further support the benefit of rolapitant 
during the entire at risk period (0-120 hrs.) for patients receiving HEC or MEC. Efficacy findings for 
rolapitant were shown to be generalizable across multiple subgroups including gender, region, age, 
and race, and receipt of concomitant emetogenic chemotherapy. The Kaplan-Meier curve depicting 
time to first emesis or use of rescue medication which suggests that rolapitant provides a protective 
effect in the acute phase, with separation of the curves occurring early after administration of 
chemotherapy.  This separation continues to increase during both the acute and delayed phases.  In 
addition, the impact of rolapitant in reducing the negative effects of CINV on daily life, was clearly 
indicated by the higher proportion of subjects treated with rolapitant who reported less impact on 
daily life with respect to both the vomiting and nausea domains of the FLIE. 
 
In conclusion, rolapitant demonstrated statistically and clinically meaningful prevention of CINV 
across four global, adequate, well-controlled clinical studies and the findings support an indication 
for rolapitant, when used in combination with a 5-HT3-RA and dexamethasone, for the prevention of 
nausea and vomiting associated with initial and repeat courses of HEC or MEC. The studies enrolled a 
broad population of subjects based on age, gender, race and region with considerable comorbidities 
who were undergoing myelosuppressive chemotherapy for a variety of cancers. A summary of 
results for complete response by CINV Phase are presented in Table 3. 
 
 


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Table 3: Complete Response by CINV Phase and Study 
 
Study Endpointa 
Rolapitant 
n / N (%) 
Control 
n / N (%) 
Rolapitant 200 mg vs. Control 
Odds Ratio (95% CI)b 
P-valueb 
Complete Response – Delayed Phase 
HEC (P04351) 
56/ 88  (63.6) 
44/ 90 (48.9) 
1.9 (1.0, 3.4) 
0.045 
HECs Pooled 
382/ 535 (71.4) 
322/ 535 (60.2) 
1.6 (1.3, 2.1) 
<0.001 
HEC (P04832) 
192/ 264 (72.7) 
153/ 262 (58.4) 
1.9 (1.3, 2.7) 
<0.001 
HEC (P04833) 
190/ 271 (70.1) 
169/ 273 (61.9) 
1.4 (1.0, 2.1) 
0.043 
MEC (P04834) 
475/ 666 (71.3) 
410/ 666 (61.6) 
1.6 (1.2, 2.0) 
<0.001 
HECs/MEC Pooled c 
857/1201 (71.4) 
732/1201 (60.9) 
1.6 (1.3, 1.9) 
<0.001 
Complete Response – Acute Phase 
HEC (P04351) 
78/ 89 (87.6) 
60 /90 (66.7) 
3.6 (1.7, 7.8) 
0.001 
HECs Pooled 
447/ 535 (83.6) 
410/ 535 (76.6) 
1.6 (1.1, 2.1) 
0.004 
HEC (P04832) 
221/ 264 (83.7) 
193/ 262 (73.7) 
1.8 (1.2, 2.8) 
0.005 
HEC (P04833) 
226/ 271 (83.4) 
217/ 273 (79.5) 
1.3 (0.8, 2.0) 
0.233 
MEC (P04834) 
556/ 666 (83.5) 
535/ 666 (80.3) 
1.2 (0.9, 1.6) 
0.143 
HECs/MEC Pooled c 
1003/1201 (83.5) 
945/1201 (78.7) 
1.4 (1.1, 1.7) 
0.003 
Complete Response – Overall Phase 
HEC (P04351) 
55/ 88 (62.5) 
42/ 90 (46.7) 
1.9 (1.1, 3.5) 
0.032 
HECs Pooled 
368/ 535 (68.8) 
313/ 535 (58.5) 
1.6 (1.2, 2.0) 
<0.001 
HEC (P04832) 
185/ 264 (70.1) 
148/ 262 (56.5) 
1.8 (1.3, 2.6) 
0.001 
HEC (P04833) 
183/ 271 (67.5) 
165/ 273 (60.4) 
1.4 (1.0, 1.9) 
0.084 
MEC (P04834) 
457/ 666 (68.6) 
385/ 666 (57.8) 
1.6 (1.3, 2.0) 
<0.001 
HECs/MEC Pooled c 
825/1201 (68.7) 
698/1201 (58.1) 
1.6 (1.3, 1.9) 
<0.001 
    Abbreviations:  
    CI=confidence interval; CMH=Cochran-Mantel Haenszel; HEC=highly emetogenic chemotherapy; MEC=moderately emetogenic chemotherapy. 
a Complete response is defined as no emesis or use of rescue medication. 
b P04351:  Odds ratio, CI and p-value are from logistic regression model with effects for treatment, concomitant emetogenic chemotherapy, and sex. P04832, 
P04833, P04834: Odds ratio, CI and p-value are from the CMH test adjusted for study (where studies are pooled) and gender effect. 
     c HECs/MEC Pooled=P04832, P04833, P04834. 
 
 
 
 


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Summary of Three Robust Clinical Studies  
In two multicenter, randomized, double-blind, parallel group, controlled clinical studies (Study 1 and Study 
2), the rolapitant (VARUBI) regimen (VARUBI, granisetron and dexamethasone) was compared with control 
therapy (placebo, granisetron and dexamethasone) in patients receiving a HEC chemotherapy regimen that 
included cisplatin >60 mg/m2. See Table 4 for the treatment regimens. 
 
Table 4: Treatment Regimens in Studies 1 and 2 
Day 1 
Day 2 to 4 
VARUBI Regimen 
Oral VARUBI† 
180 mg 
none 
Oral Dexamethasone 
20 mg‡ 
8 mg  twice daily 
Intravenous Granisetron 
10 mcg/kg § 
none 
Control Regimen* 
Oral Dexamethasone 
20 mg‡ 
8 mg twice daily 
Intravenous Granisetron 
10 mcg/kg § 
none 
* VARUBI placebo was used to maintain blinding 
† VARUBI was administered 1 to 2 hrs. prior to chemotherapy treatment on Day 1 
‡ Dexamethasone was administered 30 minutes prior to chemotherapy on Day 1. There is no drug 
interaction between VARUBI and dexamethasone, so no dosage adjustment for dexamethasone required  
§ The dose of granisetron was administered 30 minutes prior to chemotherapy on Day 1. 
 
 
Study 1 
A total of 532 patients were randomized to either the rolapitant (VARUBI) regimen (N =266) or 
control therapy (N =266). A total of 526 patients were included in the evaluation of efficacy.  Of 
those randomized 42% were women, 58 % men, 67% White, 23% Asian, 1% Black, and 9% multi- 
racial/other/unknown. The proportion of patients from North America was 16%. Patients in this 
clinical study ranged from 20 to 90 years of age, with a mean age of 57 years. In Study 1, 26% of 
patients were 65 years or older, with 3% of patients being 75 years or older.  The mean cisplatin 
dose was 77 mg/m2. During this study, 82% of the patients received a concomitant 
chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common 
concomitant chemotherapeutic agents administered during Cycle 1 were: gemcitabine (17%), 
paclitaxel (12%), fluorouracil (11%), etoposide (10%), vinorelbine (9%), docetaxel (9%), 
pemetrexed (7%), doxorubicin (6%) and cyclophosphamide (5%). 
 
 
Study 2 
A total of 555 patients were randomized to either the rolapitant (VARUBI) regimen (N =278) or 
control therapy (N =277). A total of 544 patients were included in the evaluation of efficacy. Of 
those randomized 32% were women, 68 % men, 81% White, 14% Asian, 1% Black, and 5% multi- 
racial/other/unknown. The proportion of patients from North America was 7%. Patients in this 
clinical study ranged from 18 to 83 years of age, with a mean age of 58 years. In this study, 27% 
of patients were 65 years or older, with 3% of patients being 75 years or older. The mean 
cisplatin dose was 76 mg/m2. During this study, 85% of the patients received a concomitant 
chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common 
concomitant chemotherapy agents administered during Cycle 1 were: vinrorelbine (16%), 
gemcitabine (15%), fluorouracil (12%), etoposide (11%), pemetrexed (9%), docetaxel (7%), 
paclitaxel (7%), epirubicin (5%) and capecitabine (4%). 
 
The primary endpoint in both studies was complete response (defined as no emetic episodes 
and no rescue medication) in the delayed phase (25 to 120 hrs.) of CINV. 
 


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Study 3 
In Study 3, a multicenter, randomized, double-blind, parallel group, controlled clinical study in 
moderately emetogenic chemotherapy (MEC), the rolapitant (VARUBI) regimen (VARUBI, 
granisetron and dexamethasone) was compared with control therapy (placebo, granisetron and 
dexamethasone) in patients receiving a moderately emetogenic chemotherapy regimen that 
included at least 50% of patients receiving a combination of anthracycline and 
cyclophosphamide. The percentage of patients who received carboplatin in Cycle 1 was 30%. 
Treatment regimens for the VARUBI and control arms are summarized in Table 5. 
 
Table 5: Treatment Regimens in Study 3 
Day 1 
Day 2 to 4 
VARUBI Regimen 
Oral VARUBI† 
180 mg 
none 
Oral Dexamethasone 
20 mg‡ 
          none 
Oral  Granisetron 
2 mg § 
             2 mg once daily 
Control Regimen* 
Oral Dexamethasone 
20 mg‡ 
           none 
Oral Granisetron 
2 mg § 
             2 mg once daily 
* VARUBI placebo was used to maintain blinding 
† VARUBI was administered 1 to 2 hrs. prior to chemotherapy treatment on Day 1 
‡ Dexamethasone was administered 30 minutes prior to chemotherapy on Day 1.  
§ The dose of granisetron was administered 30 minutes prior to chemotherapy on Day 1. 
 
A total of 1369 patients were randomized to either the rolapitant (VARUBI) regimen (N = 684) or 
control therapy (N = 685). A total of 1332 patients were included in the evaluation of efficacy. Of 
those randomized 80% were women, 20% men, 77% White, 13% Asian, 4% Black, and 6% multi- 
racial/other/unknown. The proportion of patients from North America was 33%. Patients in this 
clinical study ranged from 22 to 88 years of age, with a mean age of 57 years. In this study, 28% of 
patients were 65 years or older, with 7% of patients being 75 years or older. The primary endpoint 
was complete response (defined as no emetic episodes and no rescue medication) in the delayed 
phase (25 to 120 hrs.) of chemotherapy-induced nausea and vomiting. A summary of the study 
results from HEC Studies 1 & 2, and for the MEC Study 3 is shown in Table 6. 
 
Table 6:  Percent of Patients Receiving Emetogenic Chemotherapy Responding by Treatment Group for the HEC 
Studies 1 and 2 and for the MEC Study 3 
Endpoint 
HEC Study 1 
HEC Study 
MEC Study 3 
VARUBI† 
(N=264) 
Rate (%) 
Control† 
(N=262) 
Rate (%) 
P-Value 
Treatment 
Difference 
(95% C.I.) 
VAR 
UBI† 
(N=27 
1) 
Rate 
(%) 
Control 
† 
(N=273 
) Rate 
(%) 
P-Value 
Treatment 
Difference 
(95% C.I.) 
VARUB 
I† 
(N=666) 
Rate 
(%) 
Control† 
(N=666) 
Rate (%) 
P-Value 
Treatment 
Difference 
(95% C.I.) 
Primary 
Endpoint 
: Complete 
Response 
in the 
Delayed 
Phase 
72.7 
58.4 
<0.001* 
14.3 
(6.3,22.4) 
70. 
1 
61.9 
0.043* 
8.2 (0.3, 
16.1) 
71.3 
61.6 
<0.001* 
9.8 (4.7, 
14.8) 
 
† Granisetron and dexamethasone were used as concomitant drugs. 
* Results were obtained based on the Cochran-Mantel-Haenszel test stratified by gender. 


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Multiple-Cycle Extension: In Studies 1, 2, and 3, patients had the option of continuing into a multiple-
cycle extension for up to 5 additional cycles of chemotherapy receiving the same treatment as 
assigned in cycle 1.  At day 6 to 8 following initiation of chemotherapy, patients were asked to recall 
whether they had any episode of vomiting or retching or nausea that interfered with normal daily life. 
The results are summarized by study and treatment group in the figure below. 
 
 
 
Study 1 
Study 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 3 
 
 
Figure 1: No Emesis and No Nausea Interfering with Daily Life over Cycles 2-6 
 


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7.3 Study Purpose/Rationale 
The purpose of this randomized study is to primarily assess efficacy, in addition to patient preference, patient   
satisfaction and patient compliance of rolapitant plus ondansetron vs. ondansetron monotherapy for the 
prevention of chemo-radiation-induced nausea and vomiting (chemo-RINV) in malignant glioma patients 
receiving standard RT and concomitant TMZ (Stupp regimen).   
 
We conducted the first phase 2 single arm trial of palonosetron (PAL), a long acting 5-hydroxytryptamine (5-
HT3) receptor antagonist (5HT3-RA), for the prevention of RINV in primary MG subjects receiving RT (54-60 Gy) 
and concomitant multi-dose, daily TMZ (75 mg/m2) +/- bevacizumab.  Results from this study demonstrate 
that a 5HT3-RA, such as PAL or ondansetron, can be safe and effective, however based on the results, there is 
still room for improvement of anti-emetic response related to CR rates and HRQoL, which could be addressed 
by combining a 5-HT3-RA and NK1-RA12. PAL was safe and effective; however, there is room for improvement 
in the CR rates and HRQoL, which may be achieved with rolapitant plus ondansetron, a potentially more 
effective combination anti-emetic regimen. Additionally, PAL is only available as an IV injection in the United 
States whereas ondansetron can be administered orally, making it a more patient-friendly drug.  The most 
studied agents in the RINV settings are the 5HT3-RAs, with overall moderate response and low toxicity. 
However, agents such as the tachykinin NK-1 receptor antagonist may play a role in improving response rates, 
but there needs to be further studies in randomized controlled trials.13 
 
The oral combination of rolapitant plus ondansetron has not been studied in the prevention of RINV using 
multi-dose chemotherapy especially in individuals with malignant glioma. Additional advantages to using 
rolapitant plus ondansetron in the setting of radiation with concurrent multi-dose oral chemotherapy are that 
it avoids side effects associated with intravenous administration (e.g. palonosetron) and eliminates treatment 
room costs. Furthermore, rolapitant, as opposed to the aprepitant or netupitant, is not a CYP3A4 inhibitor or 
inducer of for common drugs used in glioma patients (e.g. dexamethasone, enzyme-inducing anticonvulsants, 
or irinotecan) thus reducing drug-induced side effects. The NK1 antagonist EMEND® (aprepitant) was approved 
by the US Food and Drug Administration and by the European Medicines Agency for the prevention of acute 
and delayed CINV associated with highly emetic chemotherapy (HEC- i.e. high dose cisplatin) and MEC when 
used in combination with a 5-HT3 antagonist and a corticosteroid. Dosage adjustment of concomitantly 
administered drugs is necessary with aprepitant, which is a mixed inducer/inhibitor of cytochrome P450 (CYP) 
3A4 and also affects other CYP enzymes. Rolapitant has been free of clinically relevant drug interactions in 
studies conducted to date, has rapid and good brain penetration which may contribute to its quick onset of 
action, and a long half-life that allows for dosing only once during each cycle of chemotherapy. Rolapitant has 
been selected as a promising agent to address this and other shortcomings of existing therapy. As described 
above, PET occupancy studies as well as clinical efficacy data support the use of only a single dose of rolapitant 
to protect patients from CINV. Efficacy or complete response be assessed during weeks 1-2. Complete 
response (CR) is defined as the proportion of patients without an emetic episode or use of rescue medication 
while receiving radiation and concomitant temozolomide). 
 
Patient-centered care as it relates to patient preference and satisfaction has become one of the major goals in 
healthcare reform and transformation. Patient centeredness is a dimension of health care quality because of 
its connection with desired aims, like safety and effectiveness. Patient centeredness and satisfaction shifts the 
control from the hands of those who give care into the hands of those who receive it. Patient satisfaction with 
healthcare medications has been shown to affect treatment-related behaviors such has their likelihood of 
complying and continuing to use their medication correctly.16Thus, patient satisfaction translates into 
improved patient-centered outcomes and quality of care.  The basis for this assessment will be overall patient 
medication satisfaction/preference at the end of week 3 and 6.  More descriptive data (effectiveness, 
convenience and global satisfaction) relating to a patient’s choice will be measured as a secondary outcome by 
the reliable and validated TSQM-9 tool.   
 
Standard practice within the PRTBTC for prophylactically preventing nausea and vomiting associated with 
chemoradiation is the administration of ondansetron.  With the administration of ondansetron orally 1 - 3 


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times a day for multiple days, compliance is a problem within this patient population. Newer approaches to 
treatment such as a single dose rolapitant should have fewer or minimal compliance problems.  Hence, there 
is interest in understanding patient efficacy and preference relative to ondansetron. Compliance of 
ondansetron vs. rolapitant and ondansetron is also of interest. 
 
Evidenced-based guidelines and clinical research recommend that future studies should consider the use of 
5HT3-RAs and NK1=RA with current therapies and in other clinical settings, such as radiation therapy. Studies 
at the PRTBTC at Duke have evaluated intravenous palonosetron in RINV. However, rolapitant has not been 
studied in the prevention of RINV in malignant glioma. Rolapitant plus ondansetron in the setting of radiation 
with concurrent oral chemotherapy (e.g. temozolomide) is advantageous in avoiding intravenous 
administration side effects and treatment room costs. Furthermore, rolapitant and ondansetron as opposed to 
ondansetron monotherapy (up to three times a day for seven day/week) may ultimately increase compliance 
and decrease costs. The single dose rolapitant in combination with ondansetron may be beneficial to the brain 
tumor patient population for three specific reasons: (1) rolapitant may increase antiemetic efficacy and (2) 
compliance in patients with gliomas who often “forget” to take multiple oral dosed medications due to 
memory impairment (3) and may prevent toxicity (e.g. interaction with enzyme inducing anticonvulsants) that 
is associated with administration of other longer acting antiemetics (e.g. aprepitant). Ultimately, rolapitant 
plus ondansetron may improve overall efficacy (CR rates), cost, HRQoL and patient satisfaction. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8 OBJECTIVES AND ENDPOINTS 
 
 
Objective 
Endpoint 
Analysis 
Primary 
Compare the efficacy of 
rolapitant plus ondansetron vs. 
ondansetron monotherapy in the 
prevention of nausea and 
vomiting, as measured by the 
overall complete response (CR) 
rate, among malignant glioma 
patients during RT and 
concomitant TMZ 
Complete response (CR) rate associated 
with rolapitant plus ondansetron and 
ondansetron alone during the first two 
weeks of RT and concomitant TMZ. The CR 
rate is defined as the proportion of patients 
with no emetic episode or use of rescue 
medication while receiving radiation and 
concomitant TMZ.  The CR rate will be 
assessed via the modified MASCC 
Antiemesis Tool (MAT) within daily diary.17 
18 
See section 15.4 
  
KEY  
Secondary 
Assess whether malignant glioma 
patients receiving RT and 
concomitant TMZ are more 
satisfied with rolapitant plus 
ondansetron vs. ondansetron 
monotherapy for the prevention 
of RINV 
The percentage of patients who prefer 
rolapitant plus ondansetron over 
ondansetron alone, as determined by 
response to the question with “Which 
nausea medication regimen was I most 
satisfied with?” 
See section 15.5.1 
Secondary  Describe  the rationale behind a 
patient’s satisfaction with 
antiemetic preference based 
upon effectiveness, convenience 
& global satisfaction 
Mean patient satisfaction scores during 
weeks 3 and 6 for effectiveness, 
convenience, and global satisfaction for 
ondansetron pill and rolapitant plus 
ondansetron using the 9-item TSQM-9 
patient satisfaction survey.16 Three subscales 
are computed: effectiveness (3 items), 
convenience (3 items), and global 
satisfaction (3 items).   
See section 15.5.2 
Secondary Compare the efficacy of 
rolapitant plus ondansetron vs. 
ondansetron monotherapy in the 
prevention of nausea and 
vomiting separately, as 
measured by the respective CIN, 
CIV -CR rates, among malignant 
glioma patients during RT and 
concomitant TMZ 
The CR outcomes for nausea will be defined 
in comparable terms (no use of rescue 
medication for nausea). The CR outcome for 
vomiting will be defined in comparable 
terms (no use of rescue medication for 
vomiting).  The CIN, CIV CR rate will be 
assessed via the modified MASCC Antiemesis 
Tool (MAT) within daily diary. 
See section 15.5.2 
Secondary Evaluate patient compliance with 
rolapitant plus ondansetron and 
ondansetron monotherapy 
The compliance rate defined as the 
percentage of days that rolapitant plus 
ondansetron or ondansetron alone were 
used during the six weeks 
See section 15.5.2 
Secondary Assess the safety of rolapitant 
plus ondansetron in the 
prevention of   RINV in primary 
glioma patients receiving RT and 
concomitant TMZ 
The percentage of patients experiencing a 
grade ≥3 treatment-related toxicity. 
Toxicity (adverse events) will be assessed 
throughout the 6-week treatment period. 
This data will be collected via NCI Common 
Toxicity Criteria (CTC) (vs 4) 
See section 15.5.2 


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9 INVESTIGATIONAL PLAN 
9.1 Study Design 
This proposed single center study is a randomized phase II trial of rolapitant plus ondansetron vs. ondansetron 
monotherapy for the prevention of RINV in primary malignant glioma subjects receiving radiation therapy (RT) 
and concomitant multi-dose temozolomide (TMZ). All eligible subjects should receive a planned total dose of 
54-60 Gy of radiation and 75 mg/m2 of temozolomide daily for a total of six weeks. Glioma patients will be 
randomized in an unblinded fashion to receive one of two treatment sequences of antiemetic therapy for the 
prevention of nausea and vomiting associated with RT and concomitant TMZ. 
 
Sequence A involves administration of ondansetron alone for 3 weeks followed by the use of rolapitant X 1 
dose plus daily ondansetron for 3 weeks; whereas, sequence B involves the use of rolapitant X 1 dose plus 
daily ondansetron for 3 weeks followed by 3 weeks of daily ondansetron alone.  For the rolapitant plus 
ondansetron weeks (1 or 4), patients will self-administer the oral rolapitant pills (180 mg dose) X 1 dose, 1-2 
hours before the planned week of radiation fraction (see schema). Subjects will be given a prescription for 
ondansetron 8 mg pills to be taken 30 minutes before their TMZ dose.  After the start of radiation therapy, the 
type of additional rescue antiemetic medication, if needed will be left up to the investigator’s discretion, with 
what is in the best interest of the subject.  Subjects will be educated that they are allowed to take rescue 
antiemetic medication in either arm.  If the subject experiences nausea and vomiting and does take a rescue 
antiemetic, the subject will be asked to record the use of additional antiemetic in a medication log provided to 
them. Subjects will complete weekly medication logs and surveys (see appendices) to capture study outcomes. 
Subjects will be told that the study is voluntary and that they may exit at any time if they wish.  
 
Approximately 170 patients will provide informed consent in order that 160 patients be randomized to either 
treatment sequence A or B. The 170 estimate is to allow for screen failures and dropout rates. All subjects 
must give written informed consent to participate in the study. Patients will be screened -28 - 0 days prior to 
the start of the study. During this time period the following information will be recorded: physical 
examination; vital signs and weight; laboratory studies (complete blood count with differential, blood 
chemistries, liver function tests and urinalysis): medical history; concomitant medications (steroids and 
anticonvulsants) and predictors of RINV (irradiation site, planned dose treatment field, alcohol intake, gender, 
age etc.). Laboratory evaluations, performance status, concomitant medications, and adverse events for final 
eligibility should be confirmed within 2 weeks of initiating radiation with concomitant TMZ . Patients will 
obtain standard of care blood work (per local oncologist) (complete blood count with differential, blood 
chemistries, liver function tests).  Toxicity will be assessed based on the Common Toxicity Criterion (CTC 
version 4). The patient will be asked to complete the MASCC Antiemesis Tool (MAT- see appendices) nausea 
and vomiting questionnaire on day 0 (baseline) and days 1, 2, 4, and 7 of each week of radiation therapy. In 
addition, they will be asked to record their use of any antiemetic rescue medication.   
 
At the end of weeks 3 & 6, the subject will be asked to fill out a Treatment Satisfaction Questionnaire for 
Medication (TSQM-9- see appendices) and will be asked at the end of week 6 to choose which antiemetic they 
prefer. 
9.2 Standard of Care Chemotherapy Treatment Plan 
Temozolomide is an oral alkylating agent which has demonstrated anti-tumor activity as a single agent in the 
treatment of recurrent glioma. As stated previously, Stupp et al (2005) have demonstrated an increase in 
efficacy of temozolomide in combination with radiation therapy in the adjuvant treatment of primary 
malignant gliomas. In addition, the regimen was considered safe. Non-hematological grade 2 toxicities 
included: Fatigue (26%), other constitutional symptoms (7%), rash and dermatologic side effects (9%), 
infection (1%), vision (14%), and nausea and vomiting (13%). Grade 3 / 4 non-hematological toxicities occurred 
<10%: Fatigue (7%), other constitutional symptoms (2%), rash and dermatologic side effects (1%), infection 
(3%), vision (1%), and nausea and vomiting with a 5HT3-RA (<1%). Thus, this safe and standard regimen will be 
utilized in this protocol. Daily temozolomide therapy will be calculated at a dose of 75 mg per square meter of 


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body surface area per day and be administered 7 days a week from the first until the last day of radiation 
therapy or a total of 42 days.   Additional clinical and laboratory assessments will be at the discretion of the 
radiation therapist and oncologist. 
9.3 Standard of Care Radiation Treatment Plan 
As dictated by the Stupp (2005) regimen, radiation therapy will be administered as fractionated focal 
irradiation in daily fractions of 1.8-2 Gy given 5 days a week for ~ 6 weeks for a total of 54-60 Gy. Patients will 
be followed closely by a local radiation therapist throughout treatment. The radiation therapist and oncologist 
will conduct the standard physical exams and obtain the lab work necessary for the eligibility. Additional 
clinical and laboratory assessments will be at the discretion of the radiation therapist and oncologist. 
9.3.1 
Dose Definition and Schedule 
The external beam radiation therapy (XRT) plan will be determined at the discretion of the local 
radiation therapist dependent on tumor size and location.  It should begin 2-6 weeks after surgery.  One 
treatment of 1.8-2.0 Gy will be given daily, 5 days per week, (30-33 fractions over less than seven 
weeks) for a total of 54-60 Gy. All portals shall be treated during each treatment session. Doses are 
prescribed at the maximum dose line encompassing > 95% of the target volume.  
9.3.2 
Physical Factors 
Treatment shall be delivered on megavoltage machines of energy ranging from 4 to 18 MV photons. 
Selection of the appropriate photon energy should be based on optimizing the RT dose distribution 
within the target volume and minimizing dose to non-target normal tissue. Photon energies > 10 MV 
should be utilized only in dual energy beam arrangements using at least one beam with energy < 10 
MV. Source skin distance for SSD techniques or source axis distance for SAD techniques must be at least 
80 cm.  
9.3.3 
Localization, Simulation, and Immobilization 
The patient shall be treated in the supine or another appropriate position for the location of the lesion. 
A head-holding device that is transparent to x-rays and provides adequate immobilization must be 
utilized at all times during planning and therapy to ensure reproducibility. 
 
The initial target volume shall include the contrast-enhancing lesion and surrounding edema (if it exists) 
demonstrated on the pre-operative MRI plus a 2.0-cm margin. If no surrounding edema is present, the 
initial target volume should include the contrast-enhancing lesion plus a 2.5-cm margin.  This primary 
target volume will be treated to 45-46 Gy in 23-25 daily fractions, at 1.8-2.0 Gy per fraction.    
 
The boost volume will be based on the post-operative MRI performed during treatment planning.  After 
45-46 Gy, the boost volume will include the contrast-enhancing lesion plus a 1.5-cm margin or, if 
minimal contrast-enhancing lesion is present at a portion of the resection cavity on MRI, the surgical 
defect plus a 2.0-cm margin, whichever is greater at that segment of the MRI image.  The boost volume 
will be treated to an additional 14-14.4 Gy in 7-8 daily fractions, 1.8-2.0 Gy per fraction. This will bring 
the total target dose to 54-60 Gy in 30-33 fractions. All parts of the target volumes are to receive at 
least 100% but no more than 110% of the dose at the prescription isodose line. 
9.3.4 
Treatment Planning and Safety 
Treatment plans may include opposed lateral fields, a wedge pair of fields, rotation, or multiple-field 
techniques, including intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy 
(VMAT). MRI-guided 3D treatment planning is necessary to assure accuracy in the selection of field 
arrangements. Isodose distributions for the primary and boost target volume are required on all 
patients, including those treated with parallel-opposed fields. A composite plan is required showing the 
respective target volumes. The inhomogeneity across the target volume shall be kept to a minimum. 


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The maximum dose should be no higher than 112% of the prescription. Possible side effects include 
swelling of the brain, hair loss, localized skin irritation, low blood counts, fatigue, memory loss, hearing 
loss, nausea and/or vomiting, loss of appetite, headaches, radiation necrosis (death of tissue or skin), 
and secondary cancer.   
9.3.5 
Dose Limitations to Critical Structures 
The lens and cervical spine must be shielded from the direct beam at all times. The maximum dose to 
the optic apparatus (optic chiasm, optic nerves, and eyes) must be limited to 54 Gy, and the brain stem 
limited to 60 Gy. 
9.3.6 
Safety Considerations 
Safety will be assessed throughout the six weeks of radiation and 2 weeks post radiation using adverse 
event reporting by the clinical research nurse (CRN) using the Common Toxicity Criterion (CTC version 
4.0). Monthly meetings conducted to review all adverse events and safety events with the PI, CRN, and 
CRC is standard of practice within the PRTBTC. 
9.4 Anti-emetic Treatment 
9.4.1 
Antiemetic Treatment Plan 
           Sequence A involves administration of ondansetron alone for 3 weeks followed by the use of 1 dose of 
rolapitant plus daily doses of ondansetron for 3 weeks.  Sequence B involves the use of 1 dose of 
rolapitant plus daily doses of ondansetron for 3 weeks followed by 3 weeks of ondansetron alone.  For 
the rolapitant plus ondansetron weeks (1 or 4), patients will self-administer the single oral dose of 
rolapitant 1-2 hours before the first fraction of radiation on the planned week. Subjects will be given a 
prescription for ondansetron 8 mg pills to be taken 30 minutes before their daily TMZ dose.  After the 
start of radiation therapy, the type of additional rescue antiemetic medication, if needed will be left up 
to the investigator’s discretion.  Subjects will be informed that they are allowed to take rescue 
antiemetic medication in either arm of the study.  If the subject experiences nausea and vomiting and 
does take a rescue antiemetic, the subject will be asked to record the use of an additional antiemetic in 
the medication log provided to them. Subjects will complete weekly medication logs and surveys (see 
appendices) to capture study outcomes. Subjects will be told that the study is voluntary and that they 
may exit at any time if they wish.  
 
9.4.2 
Missed Doses 
Patients will be reminded by the study team via a weekly phone call to take daily ondansetron and the 
rolapitant prior to weeks 1 or 4 of radiation depending on the assigned sequence (A vs. B).  The time 
and date of ondansetron and rolapitant administration will be recorded in the patient medication log 
(see appendices). Subjects will be required to contact their treating physician for instructions if they 
forget to take rolapitant before the scheduled week of radiation or ondansetron before their daily 
chemotherapy. Rescue medication (e.g. ondansetron 8 mg p.o.) will be used to make up a missed dose. 
9.4.3 
Concomitant Medications 
Prophylactic medication for the prevention of nausea and vomiting 24 hours prior to the start of 
radiation therapy through the full course of radiation therapy is prohibited, with the exception of the 
study drugs. Corticosteroids will be allowed for treatment of cerebral swelling. Rescue medication for 
treatment of nausea and vomiting is permitted while receiving radiation therapy at the discretion of the 
investigator. The date(s) of the rescue medication administration will be recorded in the patient 
medication log (see appendices). 
 


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9.5 Study Drug Blinding 
Not applicable 
9.6 Randomization 
A permuted block randomization will be used to assign patients, in an unblinded fashion, to one of two 
treatment sequences as described in Section 9.1.  A 1:1 allocation ratio will be used. 
9.7 Rationale for Selection of Dose, Regimen, and Treatment Duration 
Rolapitant is an FDA-approved, novel long-acting new highly selective NK1 receptor antagonist (RA) that 
is designed to be given in combination with a 5HT3-RA (i.e. ondansetron) to prevent CINV. Based on 
preclinical data and the half- life (170 hrs.) described previously and below, one oral rolapitant dose of 
180 mg will be administered in combination with oral daily ondansetron at 8 mg/day to provided 
antiemetic coverage for 3 weeks of radiation (3-half-lives for rolapitant). Sequence A involves 
administration of ondansetron alone for 3 weeks followed by the use of rolapitant X 1 dose plus 
ondansetron for 3 weeks; whereas sequence B involves the use of rolapitant X 1 dose plus ondansetron 
for 3 weeks followed by 3 weeks of ondansetron alone.  For the rolapitant plus ondansetron weeks (1 or 
4), patients will self-administer the oral rolapitant pill 1-2 hours before the first fraction of radiation on 
the planned week (see schema). The rolapitant doses will be supplied by TerSera. 
9.8 Definition of Evaluable Subjects, On Study, and End of Study 
An evaluable subject is defined as a patient who meets eligibility criteria and completes at least two 
weeks of radiation for first CR and ~ 6 weeks of radiation for additional secondary outcomes. 
9.9 Early Study Termination 
This study can be terminated at any time for any reason by the PI-sponsor.  If this occurs, all subjects on 
study should be notified as soon as possible.  Additional procedures and/or follow up should occur in 
accordance with Section 12.6, which describes procedures and process for prematurely withdrawn 
patients. 
10 STUDY DRUG 
10.1 Names, Classification, and Mechanism of Action 
Rolapitant or Varubi® (formerly referred to as SCH 619734) is an FDA-approved potent, selective, competitive 
neurokinin-1 (NK1) receptor antagonist with no known activity at other pharmacologic targets.  It binds with 
high affinity to the human NK1 receptor (Ki = 0.66 nM) and competitively antagonizes functional effects 
mediated by activation of the NK1 receptor in cultured cells (Kb = 0.45 nM). The endogenous activator of 
NK1 receptors is the neuropeptide Substance P. Rolapitant does not have significant affinity for NK2 or 
NK3 receptors or for a battery of other receptors, transporters, enzymes, and ion channels. The compound 
is active in animal models of chemotherapy-induced nausea and vomiting (CINV) and has demonstrated 
efficacy in phase 2 studies in patients receiving highly emetogenic chemotherapy (HEC). Because NK1 RA is 
known to be effective in CINV have also been shown to be effective in postoperative nausea and vomiting 
(PONV), rolapitant has also been investigated and shown to be effective in a phase 2 study in the prevention 
of PONV. 
 
The first indication for which rolapitant is being developed is the prevention of CINV. CINV has both an acute 
(0 to 24 hrs.) and delayed (>24 to 120 hrs.) phase and it was expected that rolapitant will be very effective in 
preventing CINV both phases in patients receiving either HEC or MEC agents. Cisplatin doses >60 mg/m2 
represent the standard chemotherapy agent used in many clinical trials to determine effectiveness of anti-
CINV therapies against a HEC regimen. MEC includes chemotherapy agents that are categorized as Hesketh 3 
or 4 and include carboplatin, cisplatin (<50 mg/m2) and cyclophosphamide regimens such as 
cyclophosphamide 750 – 1500 mg/m2 IV alone or combined with other chemotherapy agents and 


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cyclophosphamide 500 – 750mg/m2 administered with other emetogenic chemotherapy (Hesketh level 3, 
other than cyclophosphamide). MEC clinical trials often include breast cancer patients receiving a combination 
of intravenous cyclophosphamide plus an anthracycline drug such as doxorubicin or epirubicin. There are both 
acute (0 to 24 hrs.) and delayed (>24 to 120 hrs.) phases of CINV which are distinct after HEC but less 
differentiated after MEC. 
10.2 Packaging and Labeling 
The drug product will be supplied in blister packs containing two (2) 90 mg tablets provided by TerSera.   
10.3 Supply, Receipt, and Storage 
Study drug supplies must be stored in a secure, limited-access location under the storage conditions specified 
on the drug supply label.  Rolapitant tablets are stored at controlled Room temperature, 20-25°C (68-77°F); 
excursions permitted to 15-30°C (59-86°F).   
10.4 Dispensing and Preparation 
There is no preparation as each 90 mg pill is packaged in a separate sealed blister pack.  The study pharmacist 
will dispense 2-90 mg pills (for a total dose of 180mg) to the patients to be administered either on week 1 or 4 
depending on assigned sequence as directed by the study team.  
10.5 Compliance and Accountability 
Patients will be reminded by the study team to begin rolapitant during week 1 or 4 of radiation depending on 
assigned sequence.  Patients will also be reminded to take daily ondansetron. Compliance will be recorded by 
study coordinator through weekly patient questioning and patient recording in medication log (see 
appendices).  Of note compliance is a secondary objective (see Section 15.5). 
10.6 Disposal and Destruction 
The ICS will either destroy or return the unused study drug at the discretion of TerSera. The investigational 
pharmacist will be responsible for performing and documenting such activities.  
10.7 Other Study Drugs (Ondansetron) 
10.7.1 
Description 
Ondansetron is a first generation 5-HT3-RA (serotonin-3). 
10.7.2 
Source 
Ondansetron (Zofran) is commercially available and will not be provided in this study. 
10.7.3 
Dosage and Administration 
Ondansetron will be administered on both arms of the protocol at 8 mg p.o, daily on Days 1- 42 days, 
30-60 minutes prior to each dose of chemotherapy. A prescription for Ondansetron 8 mg p.o. daily 30-
60 minutes before temozolomide X 7 days (with 6 refills) will be provided by provider. 
10.7.4 
Drug Ordering 
Ondansetron is commercially available and will not be provided in this study.  A prescription for 
Ondansetron will be given to the patient on both arms of the study. 


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11 SUBJECT ELIGIBILITY 
11.1 Inclusion Criteria 
Selection of Subjects: Patients with a malignant glioma who plan to undergo standard RT with concomitant 
daily temozolomide (TMZ) therapy. 
 
Please refer to section 5.4 for a complete listing of the Inclusion Criteria.  
 
  
11.2 Exclusion Criteria 
 
Please refer to section 5.4 for a complete listing of the Exclusion Criteria.  
  
12 SCREENING AND ON-STUDY TESTS AND PROCEDURES 
Patients will be initially screened during the -28 to 0  days prior to study initiation. During this time period, the 
following will be recorded: physical examination; vital signs and weight; laboratory studies (complete blood count 
with differential, platelet, blood chemistries, liver function tests and urinalysis); past medical history; concomitant 
medications (steroids and anticonvulsants); and predictors of RINV (e.g. irradiation site, planned dose, treatment 
field, alcohol intake, gender, age). Prior to study enrollment, patient's medications should be reviewed by the 
clinical pharmacist to prevent concerns with drug interactions.  The patient’s medications will be evaluated by the 
PI, the patient’s study physician, and/or the study pharmacist on a case by case basis for safety. Laboratory 
evaluations, performance status, concomitant medications, and adverse events for final eligibility should be 
confirmed within 2 weeks of initiating radiation with concomitant TMZ. 
 
Patients will be filling out data collection tools (i.e. MAT and TSMQ-9) day 0 (baseline) and days 1, 2, 4, and 7 (for 
days 7, 1, 2-3, and 4- 6, respectively) of each week of radiation therapy.  In addition, they will be recording their 
medication and the use of rescue medication in a medication log as noted below (See Section 12.7 and appendices 
for study tools). 
 
The CRC will be collecting data from the tools listed below and placing data in an electronic database that is 21CFR 
Part 11 compliant (e.g. Medidata Rave).  Monthly meetings between the CRC and primary investigators will occur 
to review data.  Patient Surveys and follow up phone calls will be conducted weekly to obtain and validate data.  
The CRC is required to monitor protocol patients weekly or as many times as necessary to obtain toxicities.  
Toxicities are obtained via clinical notes or telephone conversations with the local oncology office and/or patient.  
The National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 4 is to be used to score the adverse 
advents. All graded toxicities are then entered in the database and reviewed together with the Primary 
Investigator (PI) and CRC and confirmed by source documents. Attributions are approved by primary investigators. 
 
 
 
 
 
 
 
 


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Table 7: Screening and Study-related Tests and Procedures 
Phase 
Screen 
Start 
Study Period 
End 
 
Week of radiation 
-4 to 0 
1 
2 
3 
4 
5 
6 
Days of radiation 
-28 to 0 
1-7 
8- 14 
15-21 
22-28 
29-35 
36-42 
General Evaluations 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Eligibility Criteria 
X5 
 
 
 
 
 
Past Medical History 
(RINV predictors) 
     
X 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
Height, Weight, BSA 
X 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
Performance Status 
X2 
 
 
 
 
 
Concomitant Medications 
X2 
X 
 
 
 
 
 
Adverse Events 
X2 
Continuous1 
Laboratory Evaluations 
 
 
 
 
 
 
CBC with Platelets 
X2 
 
 
 
 
 
 
Serum Chemistry tests 
X2 
 
 
 
 
 
 
Liver Function tests 
X2 
 
 
 
 
 
 
Serum Pregnancy Test 
X2 
      
 
    
 
           
Urinalysis 
X2 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
Sequence A: Rolapitant  (Day) 
 
 
 
 
   X(22) 
 
 
Sequence B: Rolapitant  (Day) 
 
X(1) 
 
 
 
 
 
Sequence A/B: Daily Ondansetron  
 
X(1-
7) 
X (8-
14) 
X(15-
21) 
X(22-28) 
X(29-
35) 
X(36-
42) 
Concomitant Temozolomide 
 
X 
X 
X 
X 
X 
X 
Surveys/Medication log 
 
 
 
 
 
 
Medication Log 
 
X 
X 
X 
X 
X 
X 
MAT Survey (Day 0 (baseline) and Days 
1,2,4,7/week)3 
X 
X 
X 
X 
X 
X 
X 
TSQM9 Sequence A for wks1-3; 4-6 
  
  
  
  
X(22)4 
  
X(43)4 
TSQM9 Sequence B for wks1-3; 4-6 
 
 
 
 
X(22)4 
 
X(43)4 
1. Adverse events will be monitored until at least 30 days after the dose of Rolapitant (or 2 weeks after the end of radiation) 
2. Laboratory evaluations, performance status, concomitant medications, and adverse events for final eligibility should be confirmed 
within 2 weeks of initiating radiation with concomitant TMZ.  
3. MASCC questionnaire on Day 0 (baseline), and Days 1, 2, 4, and 7 (for days 7, 1, 2-3, 4-6, respectively) 
                    4. TSMQ-9 administered after week 3 (Day 22) and after week 6 of radiation (Day 43) 
5. Eligibility criteria should be checked after informed consent (-4 to 0 weeks) and should be confirmed within 2 weeks of initiating 
radiation and concomitant TMZ. 
12.1 Screening Examination 
The screening examination will take place between Day -28 and 0. Laboratory evaluations, performance 
status, concomitant medications, and adverse events  will be confirmed within 2 weeks of initiating radiation 
and concomitant TMZ.  An informed consent will be signed by the patient before any screening procedure 
takes place.  Subject data to be collected at the Screening Examination as listed above in Table 7 includes the 
following: physical examination; vital signs and weight; laboratory studies (complete blood count with 
differential, platelet, blood chemistries, liver function tests, urinalysis, and Beta-HG); past medical history; 
concomitant medications (steroids and anticonvulsants); and predictors of RINV (e.g. irradiation site, planned 
dose, treatment field, alcohol intake, gender, age).   
 
If a subject is found to be ineligible to participate in the study, minimal records regarding the subject and the 
reason for screen failure will be retained in the study database. 
12.2 Treatment Period 
The treatment period will consist of six weeks of radiation and concomitant temozolomide as previously 
described above. Sequence A involves administration of ondansetron alone for 3 weeks followed by the use of 


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rolapitant X 1 dose plus daily ondansetron for 3 weeks; whereas, sequence B involves the use of rolapitant X 1 
dose plus daily ondansetron for 3 weeks followed by 3 weeks of daily ondansetron alone.  For the rolapitant 
plus ondansetron weeks (1 or 4), patients will self-administer the oral rolapitant pill 1-2 hours before the first 
radiation fraction on the planned week (see schema). Subjects will be given a prescription for ondansetron 
8mg pills to be taken 30 minutes before their TMZ dose.  After the start of radiation therapy, the type of 
additional rescue antiemetic medication, if needed, will be up to the investigator’s discretion.  Subjects will be 
informed that they are allowed to take rescue antiemetic medication in either arm.  If the subject experiences 
nausea and vomiting and does take a rescue antiemetic, the subject will be asked to record the use of 
additional antiemetic in a medication log provided to them. Subjects will complete weekly medication logs and 
surveys (see appendices) to capture study outcomes. Subjects will be told that the study is voluntary and that 
they may exit at any time if they wish.  
12.3 End of Treatment 
The end of treatment will occur at the last day of radiation therapy and will include the weekly study 
assessments outlined above (see appendices). 
12.4 Follow-up Period 
The follow-up period will consist of a two-week period following chemoradiation treatment (or at least 30 
days from the last dose of rolapitant in Sequence A) in order to identify and collect any additional toxicity 
during this time.  
12.5 End of Study 
The study will be considered complete once enrollment has been met, follow-up procedures on all subjects 
have been conducted, and data analysis is concluded.  The study may also be terminated early for any reason 
by the PI-sponsor.  In order to terminate the study with the Duke IRB, all data extraction and analysis must be 
complete.  Therefore, if any articles for publication are derived from the current study, they must be 
submitted and accepted with no further need for additional data review prior to termination with the IRB. 
 
Subjects that are lost to follow-up will be documented in the patient record and in the 21 CFR Part 11 
compliant database (e.g. Medidata Rave). In the eCRF, the subject will be marked at “Patient Status 
Unknown,” along with a corresponding explanation, if any.  This status may also be documented on an “Off 
Study Form” in the eCRF. 
12.6 Early Withdrawal of Subject(s) 
12.6.1 
Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time.  The PI may also withdraw a subject from 
the study at any time based on his/her discretion.  Reasons for PI-initiated withdrawal may include, but 
are not limited to the following: 
- 
Adverse events or intolerable symptoms 
- 
Abnormal laboratory values 
- 
Abnormal test procedure results 
- 
Protocol deviation 
- 
Administrative issues 
- 
Pregnancy 
- 
Non-compliance of the subject 
12.6.2 
Follow-up Requirements for Early Withdrawal 
Subjects who prematurely withdraw due to toxicity will be followed for two weeks after a subject is 
removed from the study. End of study requirements outlined above will be conducted. 


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12.6.3 
Replacement of Early Withdrawal(s) 
Not applicable 
12.7 Study Assessments 
12.7.1 
Medical History 
Standard medical history assessments will be conducted and recorded per institutional guidelines. Past 
medical history will include predictors of RINV (e.g. irradiation site, planned dose, treatment field, 
alcohol intake, gender, age etc.). The MAT survey will capture known patient reported predictors (see 
appendices). 
12.7.2 
Physical Exam 
Standard physical exam and neurological assessment will be conducted and documented per 
institutional and PRTBTC guidelines. 
12.7.3 
 MASCC Antiemesis Tool (MAT)  
The MAT is a validated, reliable and easy-to-use clinical tool consisting of an eight-item assessment of 
acute and delayed CINVCR rates.18 It was developed by the Multinational Association of Supportive Care 
in Cancer (MASCC) members to assist patients and oncology professionals in communicating accurately 
about the prevention and control of nausea and vomiting that may occur with chemotherapy.  The 
concept of the MAT is to provide an easy-to-use and easy-to-evaluate tool to assist in providing the best 
individual care to patients.  Additionally, the tool was designed to aid treatment centers in 
understanding the effectiveness of their antiemetic strategies. The internal consistency reliability of the 
scale was high, with Cronbach alphas of 0.77 (patient sample) and 0.82 (care-giver sample). Responses 
were similar between the UK and U.S. samples in terms of nausea and vomiting, and both samples 
found the scale easy to use. Contrasted-groups validity (using age as a grouping variable) and 
concurrent validity (MAT compared with Rhodes Index for nausea, vomiting and retching -INVR) 
suggested that the scale is sensitive to detect the different dimensions of CINV and performed well 
against a daily assessment of nausea/vomiting (total score correlation r=0.86, P<0.001). Recall of events 
was high even three weeks after chemotherapy (correlations with INVR of 0.44-0.99, all P<0.01). Factor 
analysis clearly identified three factors, namely vomiting, acute nausea, and delayed nausea. Proxy 
assessments by caregivers were congruent with the patients' responses, especially in relation to 
vomiting. The MAT facilitates discussion between clinicians and patients about their nausea and 
vomiting experience, thereby potentially aiding treatment decisions.  Assessments of CINV CR rates are 
conducted at baseline and weekly on days 1, 2, 4 and 7, and ultimately will capture data for all days a 
patient is in the study (See Section 12 and appendices). 
12.7.4 
Treatment Satisfaction Questionnaire for Medication (TSMQ-9)  
To evaluate patient preference for the combination of rolapitant plus ondansetron vs. ondansetron 
alone, the patients will fill out the valid TSMQ-9 questionnaire for weeks 1-3 and weeks 4-6 (see 
schema).  Analysis of the patient satisfaction or preference endpoint can be found in Section 15.5.2. 
 
The 14-item Treatment Satisfaction Questionnaire for Medication (TSQM) Version 1.4 is a reliable and 
valid instrument to assess patients' satisfaction with medication, providing scores on four scales – side 
effects, effectiveness, convenience and global satisfaction.16 In naturalistic studies, administering the 
TSQM with the side effects domain was thought to provoke the physician to assess the presence or 
absence of adverse events in a way that is clinically atypical, carrying the potential to interfere with 
routine medical care.  As a result, an abbreviated 9-item TSQM (TSQM-9), derived from the TSQM 
Version 1.4 but without the five items of the side effects domain was created.16 In a study using an 
interactive voice response system (IVRS)-administered TSQM-9, it was psychometrically evaluated 


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among patients taking antihypertensive medication. TSQM-9 domains had high internal consistency as 
evident from Cronbach's alpha values of 0.84 and greater.16  TSQM-9 domains also demonstrated good 
test-retest reliability with high intraclass correlation coefficients exceeding 0.70.16 As expected, the 
TSQM-9 domains were able to differentiate between individuals who were low, medium and high 
compliers of medication, with moderate to high effect sizes.16  There was evidence of convergent 
validity with significant correlations with the medication adherence scale.16  The TSQM-9 was found to 
be a reliable, valid tool to assess treatment satisfaction in naturalistic study designs, in which there is 
potential that the administration of the side effects domain of the TSQM would interfere with routine 
clinical care. 
13 SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse events, as 
defined below.  At each study visit, the PI or designee must assess, through non-suggestive inquiries of the subject 
or evaluation of study assessments, whether an AE or SAE has occurred. 
13.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study drug and which does 
not necessarily have a causal relationship with this treatment.  For this protocol, the definition of AE also 
includes worsening of any pre-existing medical condition and the onset of new illness.  An AE can therefore be 
any unfavorable and unintended or worsening sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of rolapitant plus ondansetron vs ondansetron alone whether or 
not related to use of the rolapitant plus ondansetron vs ondansetron alone.  But laboratory value changes that 
require therapy or adjustment in prior therapy are considered adverse events. 
 
From the time the subject signs the informed consent form through the End of Study visit (as defined in 
Section 12.5), all AEs must be recorded in the subject medical record and adverse events case report form. 
 
AEs will be assessed according to the CTCAE version 4.  If CTCAE grading does not exist for an AE, the severity 
of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or fatal (5). 
 
Attribution of AEs will be indicated as follows: 
- 
Definite:  The AE is clearly related to the study drug 
- 
Probably:  The AE is likely related to the study drug 
- 
Possible:  The AE may be related to the study drug 
- 
Unlikely:  The AE is doubtfully related to the study drug 
- 
Unrelated:  The AE is clearly NOT related to the study drug 
13.1.1 
Reporting of AEs 
Not required by sponsor 
13.2 Serious Adverse Events 
An AE is considered “serious” if, in the opinion of the investigator,  it is one of the following outcomes*: 
- 
Fatal 
- 
Life-threatening 
- 
Constitutes a congenital anomaly or birth defect 
- 
A medically significant condition (defined as an event that compromises subject safety or may 
require medical or surgical intervention to prevent one of the three outcomes above). 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant incapacity or substantial disruption to conduct normal life 
functions. 
 


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*Exception: Preplanned (at time of informed consent) hospitalization for elective procedures, for protocol 
compliance or social reasons, or for observation will not be considered criteria for an SAE. The reason for the 
planned hospitalization should be documented. Complications experienced during these hospitalizations must 
be reported as SAEs if hospitalization is prolonged due to AE, or if the complication meets other serious 
criteria. 
13.2.1 
Reporting of SAEs 
Only adverse events that the Duke Sponsor-Investigator determines to be serious, unanticipated, and 
related or possibly/probably (i.e. more likely than not) related to the research must be reported to the 
Duke IRB.  Those adverse events will be submitted in the electronic IRB system, according to the 
following guidelines: 
• 
Report within 24 hours of learning about any subject’s death that was unanticipated and 
more likely related to the research than unrelated; 
• 
Report within 5 business days of learning about any serious, unanticipated, and related or 
possibly/probably related adverse event; 
• 
Report within 10 business day of learning about any other unanticipated problem or event 
that was more likely related to the research than unrelated. 
13.2.1.1 
   Reporting to TerSera 
Serious adverse events that the Duke Sponsor-Investigator determines to be serious 
and related to rolapitant is to be shared with TerSera via MedWatch or CIOMS I form 
within 3 working days of Investigator awareness. If supporting documentation is 
included in the submission to TerSera (e.g., hospital reports, consultant reports, death 
certificates, autopsy reports, etc.), please redact any patient identifiers (including 
Medical Record number). 
 
TerSera SAE Contact Details 
• 
Email: TESAROPV@UBC.com 
• 
Fax: 1.866.750.6823 
13.2.2 
Reporting Product Complaints for TerSera Products 
Any written, electronic or oral communication that alleges dissatisfaction related to manufactured 
clinical drug product with regards to its manufacturing, testing, labeling, packaging, or shipping, must 
be reported by the Sponsor Institution or qualified designee to TerSera Call Center (US Call center: 
TerSera@medinfodept.com) within 1 working day of first becoming aware of the possible defect.  This 
report to TerSera may also be made by telephone to the designated TerSera representative (1-844-483-
7276) or by fax to the Call Center (1-913-451-6409).  The product and packaging components in 
question, if available, must be stored in a secure area under specified storage conditions until it is 
determined whether the product is required to be returned for investigation of the defect.  If the 
product complaint is associated with an SAE, the SAE must be reported separately in accordance with 
the protocol, and the SAE report should mention the product quality complaint. 
 
13.3 Special Warnings and Precautions 
Not Applicable 
13.4 Safety Oversight Committee (SOC) 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-
investigator phase I and II, therapeutic interventional studies that do not have an independent Data Safety 
Monitoring Board (DSMB). The primary focus of the SOC is review of safety data, toxicities and new 
information that may affect subject safety or efficacy. Annual safety reviews include, but may not be limited 


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to, review of safety data, enrollment status, stopping rules if applicable, accrual, toxicities, reference 
literature, and interim analyses as provided by the sponsor-investigator.  The SOC in concert with the DCI 
Monitoring Team (see Section 14.1 for Monitoring Team description) oversees the conduct of DUHS cancer-
related, sponsor-investigator greater-than-minimal-risk intervention studies that do not have an external 
monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and reported in 
accordance with the protocol, standing operating procedures (SOPs), Good Clinical Practice (GCP), and 
applicable regulatory requirements. 
14 QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 Monitoring 
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject safety and to 
ensure that the protocol is conducted, recorded, and reported in accordance with the protocol, standard 
operating procedures, good clinical practice, and applicable regulatory requirements.  As specified in the DCI 
Data and Safety Monitoring Plan, the DCI Monitoring Team will conduct routine monitoring after the third 
subject is enrolled, followed by annual monitoring of 1 – 3 subjects until the study is closed to enrollment and 
subjects are no longer receiving study interventions that are more than minimal risk.   
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious 
and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and DCI 
leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the sponsor, the 
Principal Investigator, or the IRB.  All study documents must be made available upon request to the DCI 
Monitoring Team and other authorized regulatory authorities, including but not limited to the National 
Institute of Health, National Cancer Institute, and the FDA.  Every reasonable effort will be made to maintain 
confidentiality during study monitoring. 
14.2 Audits 
The Duke Office of Audit, Risk and Compliance (OARC) office may conduct confidential audits to evaluate 
compliance with the protocol and the principles of GCP.  The PI agrees to allow the OARC auditor(s) direct 
access to all relevant documents and to allocate his/her time and the time of the study team to the OARC 
auditor(s) in order to discuss findings and any relevant issues. 
 
OARC audits are designed to protect the rights and well-being of human research subjects. OARCA audits may 
be routine or directed (for cause). Routine audits are selected based upon risk metrics generally geared 
towards high subject enrollment, studies with limited oversight or monitoring, Investigator initiated 
Investigational Drugs or Devices, federally-funded studies, high degree of risk (based upon adverse events, 
type of study, or vulnerable populations), phase 1 studies, or studies that involve Medicare populations. 
Directed audits occur at the directive of the IRB or an authorized Institutional Official. 
 
OARC audits examine research studies/clinical trials methodology, processes and systems to assess whether 
the research is conducted according to the protocol approved by the DUHS IRB. The primary purpose of the 
audit/review is to verify that the standards for safety of human subjects in clinical trials and the quality of data 
produced by the clinical trial research are met. The audit/review will serve as a quality assurance measure, 
internal to the institution. Additional goals of such audits are to detect both random and systemic errors 
occurring during the conduct of clinical research and to emphasize “best practices” in the research/clinical 
trials environment. 


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14.3 Data Management and Processing 
14.3.1 
Case Report Forms (CRFs) 
The electronic CRF will be the primary data collection document for the study.  The CRFs will be 
updated in a timely manner following acquisition of new source data.  Only approved study staff (the PI, 
the research coordinators, the research nurses, the data management team, and the clinical trials 
manager), are permitted to make entries, changes, or corrections in the CRF. 
 
An audit trail will be maintained automatically by the electronic CRF management system, which will be 
a 21 CFR Part 11 compliant database (e.g. Medidata Rave).  Designated personnel will complete user 
training, as required or appropriate per regulations. 
14.3.2 
Data Management Procedures and Data Verification 
Designated personnel (e.g. the data management team and the clinical trials manager) using the 
electronic CRF will have access based on their specific roles in the protocol.   
 
Completeness of entered data will be checked automatically by the eCRF system, and users will be 
alerted to the presence of data inconsistencies.  Additionally, the data management team and the 
statistical team will cross-reference the data to verify accuracy.  Missing or implausible data will be 
highlighted for the PI requiring appropriate responses (i.e. confirmation of data, correction of data, 
completion or confirmation that data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
14.3.3 
Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the following activities: 
- 
Data clarification and/or resolution 
- 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
- 
Review of site study records for completeness 
- 
Shipment of all remaining laboratory samples to the designated laboratories 
15 STATISTICAL METHODS AND DATA ANALYSIS 
All statistical analysis will be performed under the direction of the statistician designated in key personnel.  Any 
data analysis carried out independently by the investigator must be approved by the statistician before publication 
or presentation. 
15.1 Analysis Sets 
The analysis of the complete response endpoint will focus on all patients randomized to sequence A or B.  
However, the analysis of the patient preference endpoint will focus on those patients who have experienced 
both regimens and provided a preference assessment.  Safety analyses will include all patients who receive 
protocol treatment. 
15.2 Patient Demographics and Other Baseline Characteristics 
The socio-demographic and clinical characteristics of all randomized patients will be summarized by sequence 
assignment using means/SD, medians, percentiles, frequencies/proportions. 


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15.3 Treatments 
Within each sequence assignment, a frequency distribution will be generated for the number of weeks of anti-
emetic therapy received when ondansetron was administered alone, and when ondansetron was 
administered with rolapitant. 
15.4 Primary Objective 
The primary objective of this study is to compare the efficacy of rolapitant plus ondansetron vs. ondansetron 
alone in the prevention of nausea and vomiting, as measured by the overall complete response rate, among 
malignant glioma patients during RT and concomitant TMZ (see Section 8). 
 
As described in Sections 15.6 and 15.7, the study was originally designed to enroll 170 glioma patients with the 
expectation that 160 patients would be randomized to receive one of two treatment sequences of anti-emetic 
therapy for the prevention of nausea and vomiting associated with RT and concomitant TMZ.   A formal 
interim analysis was planned after 80 patients had been randomized (i.e. 40 patients to each treatment 
sequence).  As of mid-January 2022, 53 patients had been randomized.  On January 18, 2022, TerSera, the 
study’s funding source, requested that accrual to the study be terminated in the next few months. 
 
Given this request from TerSera, the accrual target for this study is reduced to 57 patients.  The decision to 
terminate early has not been influenced by the data collected to date, as no interim analyses have been 
conducted.  The analyses as described below will be conducted; however, they may no longer have the power 
to detect the hypothesized effect size. 
15.4.1 
Variable 
Complete response (CR) rate associated with rolapitant plus ondansetron and that associated with 
ondansetron during the first two weeks of RT and concomitant TMZ is defined as the proportion of 
patients with no emetic episode or use of rescue medication while receiving radiation and 
concomitant TMZ. The CR rate will be assessed via the modified MASCC Antiemesis Tool (MAT).17  
15.4.2 
Statistical Hypothesis, Model, and Method of Analysis 
As the primary analysis, a chi-square test will compare treatment regimens (ondansetron alone vs 
rolapitant + ondansetron) with respect to the proportion of patients who experience a CR during 
the first 2 weeks of RT and TMZ treatment.  As an additional analysis, logistic regression will assess 
the effect of potential confounders on this relationship.  Among the covariates that will be 
considered is the dose of decadron administered during the 2 weeks of RT and TMZ treatment. 
 
As an exploratory analysis, a generalized linear model with a logit link that accounts for correlation 
between the CR status observed during the first and second treatment period within the same 
patient will be used to assess the impact of period, treatment, and their interaction.  The purpose 
of this latter analysis is to assess whether the incremental effect of combination treatment relative 
to ondansetron alone is the same whether rolapitant is administered during the first period (i.e. 
first 3 weeks) or the second period (i.e. the second 3-week treatment regimen).  It should be noted 
that this test will have low power to detect a clinically meaningful interaction effect. Within the 
context of the generalized linear model described above, the impact of covariates on CR rate will 
be explored. Included among these covariates will be the dose of decadron administer during that 
segment of the treatment regimen. 
15.5 Secondary Objectives 
 
Please refer to Section 8 for the secondary objectives and endpoints.  The key secondary objective is to assess 
whether malignant glioma patients receiving RT and concomitant TMZ are more satisfied with rolapitant plus 
ondansetron vs. ondansetron for the prevention of RINV.  Other secondary objectives include: (1) To describe 


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the rationale behind a patient’s satisfaction with antiemetic preference based upon effectiveness, 
convenience, and global satisfaction, (2) To evaluate patient compliance with rolapitant plus ondansetron and 
ondansetron alone, and (3) To assess the safety of rolapitant plus ondansetron in the prevention of RINV in 
primary glioma patients receiving RT and concomitant TMZ. 
15.5.1 
Key Secondary Objective 
The percentage of patients who prefer rolapitant plus ondansetron over ondansetron, as 
determined by response to the question with “Which nausea medication regimen was I most 
satisfied with?” will be calculated, with a 95% confidence interval.  An exact binomial test assessing 
whether the proportion preferring the treatment regimen that includes rolapitant is 0.5 will be 
conducted.  Logistic regression will explore the potential that sequence influences patient 
preference. 
15.5.2 
Other Secondary Objectives 
Mean patient satisfaction scores for effectiveness, convenience and global satisfaction, will be 
computed based upon responses to the TSQM-9 treatment satisfaction survey16  that patients 
complete at the end of week 3 after treatment with ondansetron alone or  combination treatment.  
Three subscales will be computed:  effectiveness (3 items), convenience (3 items), and global 
satisfaction (3 items).  Assuming there is no evidence of a carry-over effect, a paired t-test will be 
conducted comparing satisfaction with combination treatment and with ondansetron treatment 
alone. 
 
The efficacy of rolapitant plus ondansetron vs. ondansetron monotherapy in the prevention of 
nausea and vomiting will be separately assessed, as measured by the respective CIN, CIV CR rates, 
among malignant glioma patients during RT and concomitant TMZ. The CR outcome for nausea will 
be defined as no use of rescue medication for nausea, while the CR outcome for vomiting will be 
defined as no use of rescue medication for vomiting. The CIN and CIV CR rates will be assessed via 
the modified MASCC Antiemesis Tool (MAT). 
 
For each 3-week treatment regimen, compliance is defined as the percentage of days that pills 
were appropriately used. The distribution of compliance during treatment with ondansetron alone 
and with combination treatment will be described with a frequency distribution.  A nonparametric 
paired test (e.g. Wilcoxon) may be used to compare compliance within the two regimens (as 
documented on the medication logs). 
 
For the manuscript, adverse events that are possibly, probably, and definitely treatment related 
that are reported during the ~ 6 weeks of treatment will be summarized.  For each type of adverse 
event experienced by a patient during rolapitant plus ondansetron and during ondansetron 
treatment, the maximum grade experienced by each patient will be tabulated by treatment group 
(i.e. rolapitant plus ondansetron or ondansetron treatment).  Given the cross-over design of this 
study, patients will contribute data to both treatment groups. Two tabulations of toxicity data will 
be generated for review by the Safety Oversight Committee including one that includes all toxicities 
regardless of attribution, and another that includes only toxicities that are possibly, probably, and 
definitely related to protocol treatment.  For each of these tabulations, the maximum grade of 
each type of toxicity experienced by each patient will be summarized with frequency distributions 
within each treatment (rolapitant plus ondansetron vs. ondansetron).  For ClinicalTrials.gov, serious 
adverse events and other adverse events will be summarized separately. These tabulations will 
reflect the number of patients who experience each type of toxicity regardless of grade or 
attribution. 
 


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15.6 Interim Analysis 
Original Study Design:  An interim efficacy analysis will be conducted after 40 patients are randomized to each 
sequence (a total of 80 patients).  Given that the interim analysis will primarily focus on the complete 
response endpoint, study accrual will be suspended for approximately 2 weeks while the initial outcome data 
from all patients is collected.  This interim analysis will allow early accrual termination for efficacy or for 
futility.   
 
The O’Brien-Fleming analogue will define the alpha and beta spending function.  The group sequential 
procedure for proportions within PASS has been used to simulate the following boundaries for comparing the 
CR rate in the two groups using a large-sample Z-test.19,20 
 
 
Significance Boundary 
Futility Boundary 
Look 
Z-Value Scale 
P-value Scale 
Z-Value Scale 
P-Value Scale 
1 (after 80 patients) 
2.505 
0.006 
0.325 
0.373 
2 (after 160 patients) 
1.657 
0.049 
1.657 
0.049 
 
At the time of the interim analysis, the combination would be considered superior to ondansetron 
monotherapy if the p-value was less than 0.006 and accrual terminated.  If, on the other hand, the p-value 
associated with this comparison was 0.373 or larger, there would be a recommendation that accrual be 
terminated early due to futility.   
 
These boundaries will be used as guidance in determining whether patient accrual should be terminated early.  
Other issues may also factor into that decision-making. 
 
Modified Study Design: With the reduction in the study’s accrual target as described in Section 15.4, no 
interim analyses are planned. 
15.7 Sample Size Calculation 
15.7.1 
Original Study Design 
One hundred seventy (170) glioma patients will be enrolled with the expectation that 160 patients 
will be randomized to receive one of two treatment sequences of anti-emetic therapy for the 
prevention of nausea and vomiting associated with RT and concomitant TMZ.   A permutated block 
randomization with an allocation ratio of 1:1 will be used to assign patients to sequence A or B.  
Sequence A involves a 3-week regimen of daily ondansetron followed by a 3-week regimen 
consisting of rolapitant (day 22 only) and daily ondansetron; whereas Sequence B involves a 3-
week regimen of rolapitant (day 1 only) and daily ondansetron followed by a 3-week regimen of 
daily ondansetron.   The study has one primary and one KEY secondary endpoint:  CR rate and 
patient overall preference for ondansetron treatment with or without rolapitant.  Though the 
primary CR rate endpoint will focus on treatment during the first 2 weeks of RT and TMZ, a cross-
over design is proposed so that a patient will experience both modes of treatment, and be 
equipped to make a comparative assessment of preference.   
 
Power Calculations for Complete Response, Primary Endpoint:  The power of the comparison of 
ondansetron and the combination of ondansetron and rolapitant relative to the CR rate during the 
initial 2 weeks of treatment with RT and TMZ will be considered here.  This comparison will focus 
on the anti-emetic experience during the first regimen of the two treatment regimens that the 
patient will receive.  Let  
 
p1 = overall complete response rate for the first 2 weeks of treatment with the combination 
antiemetic regimen, and 
 


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p0 = overall complete response rate during the first 2 weeks of treatment with ondansetron alone.   
 
The hypothesis that will be assessed is whether the CR rate with combination treatment is greater 
than that with ondansetron alone.  Specifically, the hypothesis that will be tested is as follows:       
 
H0: p1 ≤ p0 versus H1: p1 > p0 
 
Temozolomide prescribing information reports a vomiting rate of 20% with concomitant RT + TMZ.  
Anti-emetic treatment failure includes the occurrence of vomiting or the use of an anti-emetic for 
nausea and/or vomiting.  Therefore, we anticipate that approximately 25% of patients receiving 
ondansetron alone to either vomit or receive an anti-emetic.  Equivalently, a CR rate of 75% is 
anticipated with ondansetron alone. 
 
One hundred sixty (160) patients will be randomized to either sequence A or B with the expectation 
that 152 patients will provide an assessment of their experience during the first 2 weeks of 
treatment with the first regimen.  With 152 patients, there is 80% power to detect an increase in 
the CR rate from 75% with ondansetron to 90% with the combination of ondansetron and 
rolapitant (α=0.05; one-tailed). 
 
Power Calculations for Patient Preference, KEY Secondary Endpoint: The hypothesis of this study is 
that patients will prefer the combination of ondansetron and rolapitant over ondansetron alone for 
the prevention of nausea and vomiting.  If no overall preference exists, then the percentage of 
patients who choose combination treatment is expected to be approximately 50%.  The hypothesis 
that will be tested is whether the proportion of patients who prefer combination treatment is 
greater than 50%.  Statistically, the hypothesis that will be tested is: 
 
H0: p ≤ 0.5 vs H1: p > 0.5 
 
where p is the proportion of patients who prefer combination treatment over ondansetron alone.  
Under the assumption that approximately 140 patients will have experienced both regimens and 
provided a preference assessment, the study has 93% power to detect a preference rate of 65% or 
greater with a two-tailed test conducted at the 0.05 level of significance. 
15.7.2 
Modified Study Design 
As described in Section 15.4, the sample size goal for this study is reduced to 57 patients.  With 57 
patients, there is 80% power to detect an increase in the CR rate from 75% with ondansetron to 
97% with the combination of ondansetron and rolapitant (α=0.05; one-tailed).  Alternatively, there 
is 80% power to detect an increase in CR rate from 63% to 90%. 
 
Relative to patient preference, with 57 patients, the study has 83% power to detect a preference 
rate of 69% or greater with a two-tailed test conducted at the 0.05 level of significance. 
16 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
16.1 Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 


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16.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee 
The protocol, informed consent form, advertising material, and additional protocol-related documents must 
be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) for 
review.  The study may be initiated only after the Principal Investigator has received written and dated 
approval from the CPC and IRB. 
 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form.  The CPC should be informed about any protocol 
amendments that potentially affect research design or data analysis (i.e. amendments affecting subject 
population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.). 
 
The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most recent IRB 
approval.  The Principal Investigator must also obtain protocol re-approval from the CPC within 1 year of the 
most recent IRB approval, for as long as the protocol remains open to subject enrollment. 
16.3 Informed Consent 
The informed consent form must be written in a manner that is understandable to the subject population.  
Prior to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of 
the research, methods, potential risks and benefits, subject concerns, and other study-related matters.  This 
discussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility 
of coercion.  Appropriate accommodations will be made available for potential subjects who cannot read or 
understand English or are visually impaired.  Potential subjects will have the opportunity to contact the 
Principal investigator or authorized key personnel with questions, and will be given as much time as needed to 
make an informed decision about participation in the study. 
 
Before conducting any study-specific procedures, the Principal Investigator must obtain written informed 
consent from the subject or a legally acceptable representative.  The original informed consent form will be 
stored with the subject’s study records, and a copy of the informed consent form will be provided to the 
subject.  The Principal Investigator is responsible for asking the subject whether the subject wishes to notify 
his/her primary care physician about participation in the study.  If the subject agrees to such notification, the 
Principal Investigator will inform the subject’s primary care physician about the subject’s participation in the 
clinical study. 
16.4 Study Documentation 
Study documentation includes but is not limited to source documents, case report forms (CRFs), monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, 
and regulatory documents that can be found in the DCI-mandated “Regulatory Binder”, which includes but is 
not limited to signed protocol and amendments, approved and signed informed consent forms, FDA Form 
1572, and CAP and CLIA laboratory certifications. 
 
Source documents are original records that contain source data, which is all information in original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial.  Source documents include but are not limited to hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical 
trial.  DUHS utilizes Epic Maestro Care as an electronic health record.  When possible, the original record 
should be retained as the source document.  However, a photocopy is acceptable provided that it is a clear, 
legible, and an exact duplication of the original document. 


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16.5 Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be 
maintained.  Research Data Security Plans (RDSPs) will be approved by the appropriate institutional Site Based 
Research group. 
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course 
of the study.  Prospective participants will be consented in an exam room where it is just the research staff, 
the patient and his family, if desired. For all future visits, interactions with research staff (study doctor and 
study coordinators) regarding research activities will take place in a private exam room. All research related 
interactions with the participant will be conducted by qualified research staff who are directly involved in the 
conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key 
accessible only by the research staff. Subjects will be identified only by a unique study number and subject 
initials.  Electronic records of subject data will be maintained using a dedicated 21 CFR Part 11 compliant 
database (e.g. Medidata Rave), which is housed in an encrypted and password-protected secure network 
drive.  Access to electronic databases (without edit rights) will be limited to the PI, the study coordinator, and 
the statistical team.  The only personnel with both access and edit rights to the electronic databases are the 
data management team, including the clinical trials manager.  The security and viability of the IT infrastructure 
will be managed by the DCI and/or Duke Medicine.   
 
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.     
 
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or publications in 
scientific journals. 
16.6 Data and Safety Monitoring 
Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring Plan.  
For a more detailed description of the DSMP for this protocol, refer to Section 13.5 and 14.1. 
16.7 Protocol Amendments 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to 
implementation.  IRB approval is not required for protocol changes that occur to protect the safety of a 
subject from an immediate hazard.  However, the Principal Investigator must inform the IRB and all other 
applicable regulatory agencies of such action immediately. 
 
Though not yet required, the CPC should be informed about any protocol amendments that potentially affect 
research design or data analysis (i.e. amendments affecting subject population, inclusion/exclusion criteria, 
agent administration, etc.). 
16.8 Records Retention 
The Principal Investigator will maintain study-related records for the longer of a period of: 
- at least two years after the date on which a New Drug Application is approved by the FDA (if an IND is 
involved) 
- at least two years after formal withdrawal of the IND associated with this protocol (if an IND is involved) 
- at least six years after study completion (Duke policy) 
 


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17 REFERENCES 
 
 
1. 
Feyer PC, Maranzano E, Molassiotis A, et al: Radiotherapy-induced nausea and vomiting (RINV): 
MASCC/ESMO guideline for antiemetics in radiotherapy: update 2009. Support Care Cancer 19 Suppl 1:S5-14, 
2011 
 
2. 
Maranzano E, De Angelis V, Pergolizzi S, et al: A prospective observational trial on emesis in 
radiotherapy: analysis of 1020 patients recruited in 45 Italian radiation oncology centres. Radiother Oncol 94:36-41, 
2010 
 
3. 
Ramlov A, Tietze A, Khalil AA, et al: Prophylactic cranial irradiation in patients with small cell 
lung cancer. A retrospective study of recurrence, survival and morbidity. Lung Cancer 77:561-6, 2012 
 
4. 
Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant 
temozolomide for glioblastoma. New England Journal of Medicine 352:987-96, 2005 
 
5. 
Gralla RJ, Osoba D, Kris MG, et al: Recommendations for the use of antiemetics: evidence-based, 
clinical practice guidelines. American Society of Clinical Oncology. Journal of Clinical Oncology 17:2971-94, 1999 
 
6. 
(NCCN): National Comprehensive Cancers Network: Clinical practice guidelines in oncology. , 
2011, 2012 
 
7. 
Corp. MSD: Highlights of prescribing information.Temodar® (temozolomide) Capsules, 
Temodar® (temozolomide) for injection, 2013 
 
8. 
Bae SH, Park MJ, Lee MM, et al: Toxicity profile of temozolomide in the treatment of 300 
malignant glioma patients in Korea. J Korean Med Sci 29:980-4, 2014 
 
9. 
Gralla RJ RF, Tonato M, Herrstedt J: MASCC/ESMO Antiemetic Guideline 2013. Multinational 
Association of Supportive Care in Cancer [MASCC], Multinational Association of Supportive Care in Cancer 
[MASCC], 2013 
 
10. 
Basch E, Prestrud AA, Hesketh PJ, et al: Antiemetics: American Society of Clinical Oncology 
clinical practice guideline update. Journal of Clinical Oncology 29:4189-98, 2011 
 
11. 
Stupp R, Hegi ME, Mason WP, et al: Effects of radiotherapy with concomitant and adjuvant 
temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis 
of the EORTC-NCIC trial. Lancet Oncol 10:459-66, 2009 
 
12. 
Affronti ML, Woodring S, Allen K, et al: Phase II study to evaluate the safety and efficacy of 
intravenous palonosetron (PAL) in primary malignant glioma (MG) patients receiving standard radiotherapy (RT) 
and concomitant temozolomide (TMZ). Support Care Cancer, 2016 
 
13. 
Feyer P, Jahn F, Jordan K: Prophylactic Management of Radiation-Induced Nausea and Vomiting. 
Biomed Res Int 2015:893013, 2015 
 
14. 
Rapoport BL, Chasen MR, Gridelli C, et al: Safety and efficacy of rolapitant for prevention of 
chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy 
in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol 16:1079-89, 
2015 
 
15. 
Schwartzberg LS, Modiano MR, Rapoport BL, et al: Safety and efficacy of rolapitant for 
prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic 
chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-
controlled, double-blind, phase 3 trial. Lancet Oncol 16:1071-8, 2015 
 
16. 
Bharmal M, Payne K, Atkinson MJ, et al: Validation of an abbreviated Treatment Satisfaction 
Questionnaire for Medication (TSQM-9) among patients on antihypertensive medications. Health Qual Life 
Outcomes 7:36, 2009 
 
17. 
Brearley SG, Clements CV, Molassiotis A: A review of patient self-report tools for chemotherapy-
induced nausea and vomiting. Supportive Care in Cancer 16:1213-29, 2008 
 
18. 
Molassiotis A, Coventry PA, Stricker CT, et al: Validation and psychometric assessment of a short 
clinical scale to measure chemotherapy-induced nausea and vomiting: the MASCC antiemesis tool. J Pain Symptom 
Manage 34:148-59, 2007 
19.  
O’Brien PC and Fleming TR:  A multiple testing procedure for clinical trials.  Biometrics 35:549-
556, 1979 
              20.      PASS 14 Power Analysis and Sample Size Software (2015). NCSS, LLC. Kaysville, Utah, USA, 
ncss.com/software/pass. 
 


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18 APPENDICES 
18.1 Appendix 1: Sequence A-TSQM9/MAT Questionnaire 
Please see attached 
 
18.2 Appendix 2: Sequence B-TSQM9/MAT Questionnaire 
Please see attached        
 
18.3 Appendix 3: Medication Log:   Sequence A 
Please see attached 
 
18.4 Appendix 4: Medication Log:   Sequence B 
Please see attached 
18.5 Appendix 5: Birth Control Recommendations 
Please see attached