Conditions: Chemotherapy Induced Nausea Vomiting
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
Prevention and control of Chemotherapy-Induced Nausea and Vomiting (CINV) are most important in treatment of cancer patients. CINV is one of the most distressing severe side effects of cancer treatment and can have a significant impact on a patient's quality of life. The chemotherapy agents that cause the worst degree of nausea and vomiting are categorized into two groups: moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC). Nausea and vomiting that occurs within the first day of the administration of chemotherapy agents is considered acute CINV, while nausea and vomiting following 24 hours of the administration of chemotherapy agents is considered delayed CINV. Refractory CINV occurs when patients develop CINV during subsequent cycles of chemotherapy when drugs preventing vomiting and nausea (antiemetic prophylaxis) has not been successful in controlling CINV in earlier cycles. The purpose of this study is to assess the efficacy of Akynzeo in the treatment of refractory CINV

Detailed description:
This is a Phase II, single-center, single-arm, open-label, feasibility trial using a fixed dose combination of netupitant and palonosetron (Akynzeo®) in the treatment of refractory CINV. The primary aim of this study is feasibility, defined as 70% completion rate of all study procedures over 7 days.

Eligible subjects will be identified in weekly palliative care patient triage meetings. Patients who are 18 years of age or older, have histologically confirmed cancer, and confirmed refractory CINV will be eligible. After obtaining written informed consent and verifying that the study subject meets all eligibility criteria, the subject will be enrolled in the study through the University California San Diego (UCSD) Moores Cancer Center Clinical Trials Office. Subjects will be allowed to participate only once in the study. Study Day 1 will be the day of Akynzeo® dosing. Subjects will receive a single capsule of Akynzeo® (300 mg of netupitant and 0.5 mg of palonosetron) on Study 1. Study drug may be taken with or without food. Subjects will complete a study drug diary to document date and time of Akynzeo® administration. On Study Day 1, the study coordinator will educate the subject on how to complete the Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool, and Functional Living Index Emesis (FLIE) scale, and medication diary and each of these documents will be completed for that day. An adequate number of copies of each subject questionnaire and diary will be provided to the subject on Study Day 1 for completion at home during the post-treatment observation portion of the study (Study Days 2-7) as needed.

Arms:
arm 1: Subjects will be allowed to participate only once in the study. Study Day 1 will be the day of Akynzeo® dosing. Subjects will receive a single capsule of Akynzeo® (300 mg of netupitant and 0.5 mg of palonosetron) on Study 1.

Interventions: intervention 1: Netupitant and Palonosetron
Intervention descriptions: intervention 1: 300 mg of netupitant and 0.5 mg of palonosetron

Protocol document:
Prot_SAP_000.pdf: 
UCSD Moores Cancer Center 
 
 
 
 
            CONFIDENTIAL 
Combination of Netupitant and Palonosetron (Akynzeo®) in  
the Treatment of Refractory CIN and Vomiting 
Protocol Version 5.0 
 
 
 
 
 
Page 1 of 37 
Protocol Date 08/04/2017 
 
 
 
 
Fixed-Dose Combination of Netupitant and Palonosetron (Akynzeo®) in the Treatment of 
Refractory Chemotherapy-Induced Nausea and Vomiting 
 
Principal Investigator 
Eric Roeland, MD 
Assistant Clinical Professor 
Department of Medicine 
Oncology & Palliative Care 
University of California, San Diego 
Moores Cancer Center 
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Phone: 858-534-3361 
Fax: 858-822-5380 
E-mail:  eroeland@ucsd.edu 
 
 
Study Agent:  
Netupitant/Palonosetron (Akynzeo®) 
 
 
 
Protocol 
Date 
Original (v 1.0) 
10/03/2016 
Amendment 1 (V 2.0) 
01/25/2017 
Amendment 2 (V 3.0) 
04/14/2017 
Amendment 3 (V 4.0) 
06/26/2017 
Amendment 4 (V 5.0) 
08/04/2017 
 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
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Combination of Netupitant and Palonosetron (Akynzeo®) in  
the Treatment of Refractory CIN and Vomiting 
Protocol Version 5.0 
 
 
 
 
 
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Protocol Date 08/04/2017 
 
LIST OF INVESTIGATORS 
 
PRINCIPAL INVESTIGATOR 
Eric Roeland, MD 
University of California, San Diego 
Moores Cancer Center  
3855 Health Sciences Drive #0987 
La Jolla, CA 92093 
Ph: 858-534-3361 
F: 858-822-5380 
eroeland@ucsd.edu 
 
SUB-INVESTIGATORS 
Joseph Ma, PharmD 
Associate Professor  
Skaggs School of Pharmacy & Pharmaceutical Sciences  
University of California, San Diego 
9500 Gilman Drive, MC 0714 
San Diego, CA 92093 
Phone: 858-822-3485 
Fax: 858-822-6857 
Email: jdma@ucsd.edu 
 
BIOSTATISTICIANS 
Jiayi Hou, Ph.D. 
Clinical and Translational Research Institute (CTRI) 
University of California, San Diego  
9500 Gillman Drive #0990  
La Jolla, CA 92093-0990 
jhou@ucsd.edu 
 
Gordon Honerkamp-Smith, C.Phil.  
Clinical and Translational Research Institute (CTRI) 
University of California, San Diego  
9500 Gillman Drive #0990  
La Jolla, CA 92093-0990  
ghonerka@ucsd.edu 
 
 
 
 
 
Acknowledgements: 
The CTRI is partially supported by the National Institutes of Health, Grant UL1TR001442 of 
CTSA funding, as well as by Helsinn Therapeutics (U.S.), Inc (funding and study drug) 
 
 


UCSD Moores Cancer Center 
 
 
 
 
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Combination of Netupitant and Palonosetron (Akynzeo®) in  
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Protocol Version 5.0 
 
 
 
 
 
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Protocol Date 08/04/2017 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
UCSD Principal Investigator 
 
 
_____________________________ 
Printed Name 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
 
 
 
 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
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Combination of Netupitant and Palonosetron (Akynzeo®) in  
the Treatment of Refractory CIN and Vomiting 
Protocol Version 5.0 
 
 
 
 
 
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TABLE OF CONTENTS 
STUDY SCHEMA ......................................................................................................................................... 7 
STUDY SUMMARY ...................................................................................................................................... 8 
1.0 
BACKGROUND AND RATIONALE ........................................................................................... 13 
1.1 
Treatment Guidelines for Chemotherapy-Induced Nausea & Vomiting (CINV) ......................... 13 
1.2 
Defining Breakthrough Versus Refractory CINV ......................................................................... 13 
1.3 
Fixed Dose Combination of NK1 Receptor Antagonist and 5-HT3 Receptor Antagonist ........... 13 
2.0 
STUDY OBJECTIVES ................................................................................................................ 14 
2.1 
Primary ........................................................................................................................................ 14 
2.2 
Secondary: .................................................................................................................................. 14 
2.3 
Exploratory: ................................................................................................................................. 14 
3.0 
PATIENT ELIGIBILITY ............................................................................................................... 15 
3.1 
Inclusion Criteria ......................................................................................................................... 15 
3.2 
Exclusion Criteria ........................................................................................................................ 15 
4.0 
TREATMENT PLAN ................................................................................................................... 16 
4.1 
Subjects and Centers .................................................................................................................. 16 
4.2 
Study Design ............................................................................................................................... 16 
5.0 
DESCRIPTION OF PROCEDURES ........................................................................................... 16 
5.1 
Patient CINV Risk Factors .......................................................................................................... 16 
5.2 
Removal of Subjects from Study/Study Treatment: .................................................................... 17 
5.3 
Future Directions ......................................................................................................................... 17 
5.4 
Other Therapy ............................................................................................................................. 17 
5.5 
Efficacy Measures: ...................................................................................................................... 18 
5.5.1 
Patient Medication Diary 
18 
5.5.2 
Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool© 
(MAT) 
18 
5.5.3 
Functional Living Index Emesis (FLIE) Scale 19 
5.5.4 
Healthcare Utilization 
19 
5.5.5 
Patient Preference 
19 
6.0 
STUDY DRUG REGIMENS ........................................................................................................ 19 
6.1 
Study Drug Requested Per Patient ............................................................................................. 20 
7.0 
SAFETY MEASURES ................................................................................................................ 20 
8.0 
ADVERSE EVENTS ................................................................................................................... 20 
8.1 
Adverse Event Monitoring ........................................................................................................... 21 
8.2 
Severity ....................................................................................................................................... 21 
8.3 
Seriousness ................................................................................................................................ 22 
8.4 
Relationship ................................................................................................................................ 22 
8.5 
Prior experience .......................................................................................................................... 22 
8.6 
Reporting Requirements for Adverse Events ............................................................................. 22 
8.6.1 
Expedited Reporting 22 
8.6.2 
Routine Reporting Requirements 
23 
8.6.3 
Pregnancy Reporting Requirements 23 


UCSD Moores Cancer Center 
 
 
 
 
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9.0 
STATISTICAL ANALYSIS ......................................................................................................... 24 
9.1 
Study Design ............................................................................................................................... 24 
9.2 
Primary outcome measures and sample size ............................................................................. 24 
9.3 
Secondary aims .......................................................................................................................... 24 
9.4 
Data and Safety Collection and Monitoring ................................................................................ 25 
10.0 
REFERENCES ........................................................................................................................... 26 
11.0 
APPENDICES ............................................................................................................................. 28 
11.1 
Appendix 1- MASCC Antiemesis Tool ........................................................................................ 28 
Appendix 2- List of Strong CYP3A4 Inducers and Strong and Moderate CYP3A4 Inhibitors ................ 32 
11.2 
Appendix 3- Patient Medication Diary ......................................................................................... 33 
Appendix 4- five point Likert scale questionnaire .................................................................................... 34 
11.3 
Appendix 5 - Functional Living Index for Emesis (FLIE) scale ................................................... 35 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine transaminase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Transaminase 
CINV 
Chemotherapy-Induced Nausea & Vomiting 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTRI 
Clinical and Translational Research Institute 
CYP3A4 
Cytochrome P450 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FLIE 
Functional Living Index for Emesis 
HEC 
Highly Emetogenic Chemotherapy 
HIPAA 
Health Insurance Portability and Accountability Act 
HRPP 
Human Research Protections Program 
ICH 
International Conference on Harmonization 
IDS 
Investigational Drug Services 
IQR 
Interquartile Range 
IRB 
Institutional Review Board 
MASCC 
Multinational Association of Supportive Care in Cancer 
MEC 
Moderately Emetogenic Chemotherapy 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NK1 
Neurokinin-1 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
5-HT3 
5-hydroxytryptamine-3 
 
 
 
 
 
 
 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
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the Treatment of Refractory CIN and Vomiting 
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STUDY SCHEMA 
 
 
 
 
 
 


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STUDY SUMMARY 
Title 
Fixed-Dose Combination of Netupitant and Palonosetron 
(Akynzeo®) in the Treatment of Refractory Chemotherapy-Induced 
Nausea and Vomiting 
Short Title 
Akynzeo® in the Treatment of Refractory CINV 
Phase 
II 
Methodology 
Single-arm, single-center, open-label study 
Study Duration 
The anticipated total study duration is 24 months from fully-
executed contract and IRB approval. 
Individual subject participation is limited to approximately 1 week. 
Study Center(s) 
UC San Diego (UCSD) Moores Cancer Center 
UCSD Medical Center - La Jolla 
Objectives 
Primary: To determine the feasibility of using a fixed-dose 
combination of netupitant and palonosetron (Akynzeo®) in the 
treatment of refractory CINV.  For this study, refractory CINV is 
defined as nausea and/or vomiting that occurs after the first cycle 
of cancer targeted therapy despite guideline-based prophylaxis 
and after first-line rescue medication with either a dopamine 
receptor antagonist, steroid, and/or benzodiazepine. 
 
Hypothesis: Feasibility, defined as more than 70% of selected 
study subjects completing all study related procedures, will be 
achieved. 
 
Secondary:  
• To evaluate the occurrence of adverse events using the 
National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.10 
• To evaluate complete response defined as no emesis and no 
use of rescue medication for 5 days after Akynzeo® 
administration.   
• To characterize 24-hour intervals of CINV using the MASCC 
Antiemesis Tool (MAT).11 
• To evaluate 5-day health related quality of life recall using the 
Functional Living Index for Emesis (FLIE) scale.12 
• To evaluate healthcare resource utilization as defined by the 
number of emergency room visits, hospitalizations, and infusion 
center visits encounters regarding signs/symptoms associated 
with CINV over the seven-day study period. 
• To evaluate the occurrence of refractory CINV using CINV risk 
assessment at follow up day 7 compared to treatment day 1. 
 
Exploratory: To determine patient preference for use of Akynzeo® 
for future planned chemotherapy utilizing a five-point Likert scale 
Number of Subjects 
50 
Diagnosis and Main 
Patients who have histologically-confirmed cancer, and confirmed 
refractory CINV will be eligible  


UCSD Moores Cancer Center 
 
 
 
 
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Protocol Version 5.0 
 
 
 
 
 
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Inclusion Criteria 
 
Inclusion Criteria:  
1. Adults greater than or equal to 18 years old. 
2. Must have a histologically-confirmed cancer diagnosis. 
3. Must have refractory CINV defined as nausea and/or vomiting 
that occurs after the first cycle of cancer targeted therapy 
despite guideline-based prophylaxis and after first-line rescue 
medication with either a dopamine receptor antagonist, 
steroid, and/or benzodiazepine.   
4. Eastern Cooperative Oncology Group (ECOG) performance 
status less than or equal to 2. 
5. Life expectancy greater than 3 months. 
6. Corrected serum calcium level less than or equal to 10.5 
mg/dL. 
7. Women of child-bearing potential must agree to use adequate 
contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study 
participation, and for 14 days following completion of therapy.  
A) A woman of child-bearing potential is any female 
(regardless of sexual orientation, having undergone a tubal 
ligation, or remaining celibate by choice) who meets the 
following criteria: 
i) Has not undergone a hysterectomy or bilateral 
oophorectomy; or 
ii) Has not been naturally postmenopausal for at least 12 
consecutive months (i.e., has not had menses at any 
time in the preceding 12 consecutive months) 
8. Women of child-bearing potential must have a negative 
pregnancy test prior to initiating study treatment. 
9. Ability to understand and willingness to sign a written informed 
consent. 
 
Exclusion Criteria: 
1. Patients with QTc interval greater than 450 ms.   
2. Patients with a known hypersensitivity reaction to 5-HT3 
receptor antagonists or NK1 receptor antagonists. 
3. Patients who have taken any medication classified as a strong 
CYP3A4 inducer within one week of Study Day 1 or 5 half-
lives (whichever is longer) or use of a strong or moderate 
CYP3A4 inhibitor within one week of Study Day 1 or 5 half-
lives (whichever is longer) (see Appendix 2). 
4. Patients with severe hepatic impairment as defined as 
AST/ALT greater than three times the upper limit of normal, 
and/or total bilirubin greater than 3 mg/dL, and/or Child-Pugh 
score >9. 
5. Patients with severe renal impairment defined as creatinine 
clearance of 15-29 mL/min and/or diagnosed with Stage 4 
chronic kidney disease.  
6. Patients with end-stage renal disease defined as creatinine 
clearance of <15mL/min and/or diagnosed with Stage 5 
chronic kidney disease. 


UCSD Moores Cancer Center 
 
 
 
 
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7. Pregnant or lactating females are excluded from enrollment on 
this trial.  
8. Patients unable to swallow oral medications. 
9. Any other condition that, in the opinion of the investigator, may 
impact the absorption of oral medications. 
 
Study Product(s), 
Dose, Route, Regimen 
Subjects will be allowed to participate only once in the study.  
Study Day 1 will be the day of Akynzeo® dosing.  Subjects will 
receive a single capsule of Akynzeo® (300 mg of netupitant and 
0.5 mg of palonosetron) on Study 1 
Duration of 
administration 
Study drug (Akynzeo®) is an oral fixed-dose combination of 300 
mg of netupitant and 0.5 mg of palonosetron.  Akynzeo® will be 
administered once as an oral capsule and will be supplied as 300 
mg netupitant/0.5 mg palonosetron hard gelatin capsules with a 
white body and caramel cap with “HE1” printed on the body.   
Statistical 
Methodology 
Ideally, a phase III placebo controlled trial would be completed to 
demonstrate the efficacy of Akynzeo® in the refractory CINV.  
However, data regarding pharmacologic interventions for refractory 
CINV are lacking.  Furthermore, it is not established if intervening 
in the refractory CINV setting is practically feasible.  Consequently, 
we believe a feasibility study is the necessary first step followed by 
a larger randomized trial.   
 
Primary outcome measures and sample size 
The proposed study is a prospective, single-center, feasibility trial.   
The primary aim of this study is feasibility – specifically feasibility 
will be defined as completion of all study procedures over seven 
days.  For the primary aim, we assume an acceptable completion 
rate from strata of MEC/HEC or tumor types of all study-related 
procedures would be at least 70%. Assuming a true completion 
rate of 85%, a sample size of 50 patients would have an 80% 
power to detect an absolute difference of 15% at Type I error 0.05.   
 
Secondary aims 
Secondary outcome measures including (1) the evaluation of 
adverse events utilizing the NCI CTCATE v4.03,10 (2) complete 
response (no emesis and no rescue medication use), (3) 
characterization of 24-hour CINV using the MAT,11 (4) five-day 
health related quality of life utilizing the FLIE,12 and (5) healthcare 
resource utilization (emergency room visits, hospitalizations, and 
infusion center visits over seven days).   
(1) Adverse events will recorded in detail and the number of 
events will be described using n and percent. The severity 
will be described using means (SD) and medians (IQR) of 
the adverse event grade (which ranges 0-5). 
(2) The proportion of patients experiencing complete response 
will be described with descriptive statistics (n and percent) 
as well as by using a one-sample confidence interval for 
proportions, applying the normal approximation to the 
binomial distribution. In addition, a one-sample z test for 
proportions will be used to determine if the complete 


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response rate in this sample is significantly different then 
the 90% seen in previous studies.17 
(3) CINV will be analyzed using the MAT. The MAT consists of 
8 distinct items, 4 of these items are binary and will be 
described using n and percents the other 4 items are 
continuous (ranging from 0-10) and will be described using 
mean and SD. Binary variables will also be described using 
one-sample confidence intervals for proportions (as 
described in #2 above) and continuous variables will be 
described using one-sample confidence intervals for 
means. 
(4) Quality of life will be analyzed as a binary response, impact 
on quality of life vs no impact, a score of less than 54 on 
the FLIE domain scores and a score of less than 108 on 
the total score indicates an impact on quality of life. Each 
domain score, and the total score, will be analyzed 
separately using a 95% confidence interval to describe the 
proportion of participants with impacted QoL.  
(5) Healthcare resource utilization will be assessed by 
recording the number of emergency room visits, 
hospitalizations (with length of stay), and infusion center 
visits. Each healthcare utilization will be categorized with 
respect to whether it was specifically related to nausea and 
vomiting during the seven-day follow up period.  A table 
summarizing the number of each type of utilization related 
to nausea and vomiting will be provided.   
(6) The occurrence of refractory CINV will be analyzed using 
CINV risk assessment at follow up day 7 compared to 
treatment day 1. 
 
 
Patient demographic characteristics (age, sex, and patient 
reported race/ethnicity) will be described using standard 
descriptive statistics (n/% or mean/SD). 
 
As an exploratory aim, regression analysis will be used to develop 
a predictive model for CINV, based on age, sex, history of >1 
alcoholic beverage per day, history of motion sickness, history of 
hyperemesis gravidarum, and history of anxiety. 
 
 
 


UCSD Moores Cancer Center 
 
 
 
 
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SCHEDULE OF EVENTS 
 
Screening 
 
Treatment 
(Study 
Day 1) 
Follow-Up 
(Study 
Day 2-3) 2,5 
Follow-Up 
(Study 
Day 4-7) 2, 5 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Demographics 
X 
 
 
 
Medical and surgical history 
X 
 
 
 
ECOG Performance Status 
X 
 
 
 
Confirmed presence of refractory CINV  
X 
 
 
 
Serum pregnancy test1  
X 
 
 
 
Physical exam with vitals, weight7 
X 
per routine frequency 
Complete metabolic profile7 
X 
per routine frequency 
Complete blood count with differential, platelets7 
                      per routine frequency 
EKG QTc evaluation 
X7 
 
X3 
 
Patient CINV risk factors  
 
X 
 
X 
Akynzeo® dispensing and administration 
 
X 
 
 
Patient medication diary 
 
X 
 
 
Collect hospitalization and emergency room visit data 
 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
Adverse event monitoring 
 
X 
X 
X 
MASCC Antiemesis Tool8 (MAT) 
X 
X 
X 
X 
Functional Living Index for Emesis (FLIE) scale9 
X  
X 
 
X4 
Patient preference Likert-scale 
 
 
 
X6 
 
  1 Women of childbearing potential only 
   2 Subjects will be monitored for a total of 6 days following Akynzeo® dosing 
   3 QTc evaluation on Day 3±3 days with single EKG.  If patient experiences worsening cardiac 
symptoms during the study, additional EKG(s) will be performed as clinically indicated  
   4 Complete on Day 5 only 
  5 Daily unless otherwise indicated.  Daily safety assessment and hospitalization/ER visit information on 
Days 2-7 may occur via in-person visit or telephone call from a study team member.  Subjects will 
also receive a daily reminder (via in-person visit or telephone call) to complete required 
questionnaires/diaries.   
   6 Complete on Day 7 only  
    7 EKG, laboratory and physical exam results obtained within 4 weeks prior to the informed consent 
date may be used to fulfill study requirements.  EKG results may be obtained after screening 
processes yield positive refractory CINV. 
8 To be completed daily for 4 days after CINV prophylaxis or Akynzeo® dosing.  
9 To be completed on the 5th day after CINV prophylaxis or  Akynzeo® dosing 
 
 
 
 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Treatment Guidelines for Chemotherapy-Induced Nausea & Vomiting (CINV) 
 
 
Current treatment guidelines by the Multinational Association of Supportive Care in Cancer 
(MASCC), National Comprehensive Cancer Network (NCCN), and the American Society of 
Clinical Oncology (ASCO), have focused efforts on the prevention and treatment of 
chemotherapy-induced nausea and vomiting (CINV).  A standard approach for highly 
emetogenic chemotherapy (HEC) is to pretreat with a three-drug regimen, including a 
neurokinin-1 (NK1) receptor antagonist, a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, 
and glucocorticoid.  In contrast, moderately emetogenic chemotherapy (MEC) pretreatment 
usually includes a 5-HT3 receptor antagonist and a glucocorticoid.  These treatment modalities 
have focused on the acute (<24 hours) and delayed (>24 hours) phases of CINV.  As an NCCN 
designated and ASCO QOPI cancer center, we follow guideline based recommendations for 
CINV prophylaxis.   
 
1.2 
Defining Breakthrough Versus Refractory CINV 
Little is known about appropriate evidenced-based treatment of refractory CINV.  Refractory 
CINV is distinct from breakthrough CINV.  Breakthrough nausea and/or emesis can been 
defined as nausea and/or vomiting that occurs while on prophylactic antiemetics and/or 
requiring the use of rescue antiemetics.1  Breakthrough CINV has also been described as 
nausea and/or vomiting occurring within 5 days of initial  chemotherapy and after completion of 
appropriate prophylactic antiemetic agents.2  In contrast, refractory CINV has been described as 
occurring during subsequent treatment cycles when prophylactic and rescue antiemetics are not 
effective.1,2   
 
Evidence-based literature regarding treatment of refractory CINV is sparse and represents an 
unmet medical need.  A case report has suggested potential palliation with an NK1 receptor 
antagonist, but in the non-CINV setting.  A 27-year-old patient with breast cancer and meningeal 
metastases had an 18-month history of poorly controlled nausea/vomiting despite treatment of 
numerous antiemetics.  After two doses of aprepitant 80 mg once daily, there was no recurrence 
of nausea/vomiting and no observed side effects.3  In a retrospective study of cancer patients 
(n=33), olanzapine 5-10 mg daily was studied for the treatment of refractory nausea/vomiting 
regardless of the chemotherapy emetogenicity.4  Refractory nausea and vomiting was defined 
as presence of symptoms after administration of both guideline-recommended CINV antiemetic 
prophylaxis and after first-line rescue medication.4  The addition of olanzapine resulted in a 70% 
overall success rate, which did not differ between HEC and MEC regimens.4   
 
1.3 
Fixed Dose Combination of NK1 Receptor Antagonist and 5-HT3 Receptor 
Antagonist   
Akynzeo® is an oral capsule containing a fixed-dose combination of 300 mg of netupitant and 
0.5 mg of palonosetron.  Netupitant is a highly selective NK1 receptor antagonist and 
palonosetron is a long acting 5-HT3 receptor antagonist.  Palonosetron prevents nausea and 
vomiting during the acute phase and netupitant prevents nausea and vomiting during both the 
acute and delayed phase after cancer chemotherapy.  Single-dose administration of Akynzeo® 


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in healthy subjects, results in peak plasma concentrations in about 5 hours.  Mean elimination 
half-life in cancer patients was 80±29 hours for netupitant and 48±19 hours for palonosetron.5   
Three phase III clinical trials in over 2,500 chemotherapy-naïve patients evaluating Akynzeo® 
have recently been published for prevention of CINV over repeated cycles of both HEC and 
MEC regimens.6-8  Akynzeo® was safe, well tolerated, and showed superiority in preventing 
CINV from HEC and MEC regimens.  However, there is no published literature regarding the 
use of Akynzeo® for the treatment of refractory CINV.   
 
The overwhelming majority of CINV studies have focused on prevention of nausea and/or 
emesis.  However, 15-30% of patients continue to experience CINV despite receiving guideline-
based CINV prophylaxis.7,8 Refractory CINV represents a an unmet medical need and 
controlling refractory CINV has the potential to maximize cancer therapy, improve quality of life, 
and minimize costs associated with healthcare utilization.   
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary 
To determine the feasibility of using a fixed dose combination of netupitant and 
palonosetron (Akynzeo®) in the treatment of refractory CINV.  For this study, refractory 
CINV is defined as nausea and/or vomiting that occurs after the first cycle of cancer 
targeted therapy despite guideline-based prophylaxis and after first-line rescue 
medication with either a dopamine receptor antagonist, steroid, and/or benzodiazepine. 
 
Hypothesis: Feasibility, defined as more than 70% of selected study subjects completing 
all study related procedures, will be achieved. 
2.2 
Secondary:  
o To evaluate the occurrence of adverse events using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.10 
o To evaluate complete response defined as no emesis and no use of rescue 
medication for 5 days after Akynzeo® administration.   
o To characterize 24-hour CINV using a modified MASCC Antiemesis Tool 
(MAT).11 (Appendix 1) 
o To evaluate 5-day health related quality of life recall using the Functional Living 
Index for Emesis (FLIE) scale.12 
o To evaluate healthcare resource utilization as defined by the number of 
emergency room visits, hospitalizations, and infusion center visits encounters 
regarding signs/symptoms associated with CINV over the seven-day study 
period. 
o To evaluate the occurrence of refractory CINV using CINV risk assessment at 
follow up day 7 compared to treatment day 1. 
 
2.3 
Exploratory:  
To determine patient preference for use of Akynzeo® for future planned chemotherapy 
utilizing a five-point Likert scale. 
 


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3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
1. Adults greater than or equal to 18 years old. 
2. Must have a histologically confirmed cancer diagnosis. 
3. Must have refractory CINV defined as nausea and/or vomiting that occurs after the first 
cycle of cancer targeted therapy despite guideline-based prophylaxis and after first-line 
rescue medication with either a dopamine receptor antagonist, steroid, and/or 
benzodiazepine.   
4. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 
2. 
5. Life expectancy greater than 3 months. 
6. Corrected serum calcium level less than or equal to 10.5 mg/dL. 
7. Women of child-bearing potential must agree to use adequate contraception (hormonal 
or barrier method of birth control; abstinence) prior to study entry, for the duration of 
study participation, and for 14 days following completion of therapy.  
A woman of child-bearing potential is any female (regardless of sexual orientation, 
having undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria: 
a. Has not undergone a hysterectomy or bilateral oophorectomy; or 
b. Has not been naturally postmenopausal for at least 12 consecutive months (i.e., 
has not had menses at any time in the preceding 12 consecutive months) 
8. Women of child-bearing potential must have a negative pregnancy test prior to initiating 
study treatment. 
9. Ability to understand and willingness to sign a written informed consent. 
 
3.2 
Exclusion Criteria  
1. Patients with QTc interval greater than 450 ms.   
2. Patients with a known hypersensitivity reaction to 5-HT3 receptor antagonists or NK1 
receptor antagonists. 
3. Patients who have taken any medication classified as a strong CYP3A4 inducer within 
one week of Study Day 1 or 5 half-lives (whichever is longer) or use of a strong or 
moderate CYP3A4 inhibitor within one week of Study Day 1 or 5 half-lives (whichever is 
longer) (see Appendix 2). 
4. Patients with severe hepatic impairment as defined as AST/ALT greater than three times 
the upper limit of normal and/or, total bilirubin greater than 3 mg/dL, and/or Child-Pugh 
score >9. 
5. Patients with severe renal impairment defined as creatinine clearance of 15-29 mL/min 
and/or diagnosed with Stage 4 chronic kidney disease.  
6. Patients with end-stage renal disease defined as creatinine clearance of <15mL/min 
and/or diagnosed with Stage 5 chronic kidney disease. 
7. Pregnant or lactating females are excluded from enrollment on this trial.  
8. Patients unable to swallow oral medications. 
9. Any other condition that, in the opinion of the investigator, may impact the absorption of 
oral medications. 
 
 
 
 


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4.0 
TREATMENT PLAN 
4.1 
Subjects and Centers 
A total of 50 subjects, who are 18 years of age or older, have histologically confirmed cancer, 
confirmed refractory CINV as defined above, an ECOG performance status 0-2, and normal 
calcium level will be enrolled on this single-center, single-arm study. 
4.2 
Study Design 
This is a Phase II, single-center, single-arm, open-label, feasibility trial using a fixed dose 
combination of netupitant and palonsetron (Akynzeo®) in the treatment of refractory CINV.   The 
primary aim of this study is feasibility, defined as 70% completion rate of all study procedures 
over 7 days 
5.0 
Description of Procedures 
 
Eligible subjects will be identified in weekly palliative care patient triage meetings.  Patients who 
are 18 years of age or older, have histologically confirmed cancer, and confirmed refractory 
CINV will be eligible.  
 
After obtaining written informed consent and verifying that the study subject meets all eligibility 
criteria, the subject will be enrolled in the study through the UCSD Moores Cancer Center 
Clinical Trials Office. The study coordinator will educate the subject on how to complete the 
MASCC Antiemesis Tool (MAT), and FLIE scale after CINV prophylaxis. Subjects will be asked 
to complete the MAT on a daily basis for 4 days and then the FLIE on the 5th day after cancer 
treatment. Subjects will be allowed to participate only once in the study.  Study Day 1 will be the 
day of Akynzeo® dosing.  Subjects will receive a single capsule of Akynzeo® (300 mg of 
netupitant and 0.5 mg of palonosetron) on Study 1. Study drug may be taken with or without 
food.  Subjects will complete a study drug diary to document date and time of Akynzeo® 
administration.  On Study Day 1, the study coordinator will educate the subject on how to 
complete the written MASCC Antiemesis Tool, and FLIE scale, and medication diary for each 
day following the Study Day 1..  An adequate number of copies of each subject questionnaire 
and diary will be provided to the subject on Study Day 1 for completion at home during the post-
treatment observation portion of the study (Study Days 2-7) as needed.    
5.1 
Patient CINV Risk Factors 
Classifying CINV risk by chemotherapy type has provided a valuable framework for the 
development of international prophylactic antiemetic guidelines. However, considerable work 
has revealed a number of patient specific variables that may contribute to emetic risk.  
Therefore, antiemetic guidelines relying solely on emetogenicity of chemotherapy may 
potentially undertreat patients at higher individual emetic risk than what the chemotherapy alone 
suggests. CINV patient-related risk prediction models have been developed.13-15  Based on data 
from these models, several key patient risk factors will be collected on Study Day 1 prior to 
Akynzeo® dosing including: age, sex, alcohol consumption, history and severity of previous 
CINV, history of morning sickness with pregnancy, history of motion sickness, less sleep the 
night before chemotherapy, and pre-chemotherapy anxiety.  
 
During the post-treatment observation portion of the study, subjects will receive a daily phone 
call from a member of the study team to inquire about any adverse event that the subject may 


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be experiencing and whether they have had any hospitalizations or emergency room visits since 
the last contact.  During these calls, the study team member will also remind the subject to 
complete the MASCC Antiemesis Tool and medication diary.  On Study Day 5 only, the subject 
will also be instructed to complete the FLIE scale.  The subject will be asked to return to clinic 
on Study Day 3 (+3 days) for a single EKG.  Additional clinic visits, physical exams, or 
laboratory tests performed during the 7-day treatment and follow-up periods will be scheduled 
according to routine care and according to the subject’s treating physician. 
 
Subjects will be asked to return all completed and unused study materials, including subject 
diaries and questionnaires to a member of the study team at their next routine clinic visit. 
 
A more detailed description of selected assessments is included in the Efficacy Measures and 
Safety Measures sections. 
5.2 
Removal of Subjects from Study/Study Treatment: 
 
Study subjects may be removed from study treatment or follow-up at any time at their own 
request or at the discretion of the investigator for any of the following reasons: 
 
• 
The subject’s medical condition worsens or if rescue therapy for subject’s CINV fails 
secondary interventions. 
• 
The investigator believes that study participation is jeopardizing subject’s safety. 
• 
The investigator believes that other treatment options may be more beneficial. 
• 
Helsinn or the FDA stops the research due to safety concerns. 
• 
Subject non-compliance with study procedures and requirements.   
 
 
If a study subject is withdrawn from study participation, the subject will be asked to complete 
the following study requirements: 
• Return unused study materials, including subject diaries and questionnaires. 
 
Discuss future medical care with the investigator 
5.3 
Future Directions 
 
If feasibility is achieved on this study, then future plans would include analysis of secondary and 
exploratory objectives to determine if there are any trends towards a clinically-meaningful and 
plausible study endpoint, which would be further developed in a larger Phase II study.  We have 
several key palliative care oncology collaborators, and ultimately plan to propose the Phase II 
concept through a cooperative group such as the Palliative Care Research Cooperative Group 
or the Alliance in Clinical Oncology Trials Symptom Intervention Committee, both of which Dr. 
Roeland is an active member. 
5.4 
Other Therapy 
 
Akynzeo® should be used with caution in patients receiving concomitant medications that are 
primarily metabolized through CYP3A4. The plasma concentrations of CYP3A4 substrates can 
increase when co-administered with AKYNZEO. The inhibitory effect on CYP3A4 can last for 
multiple days.  


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Length of washout period will be one week prior to Day 1 and/or 5 half-lives whichever is longer 
for any drug that is a known strong CYP3A4 inducer and/or strong or moderate CYP3A4 
inhibitor.  A list of known in vivo strong CYP3A4 inducers and inhibitors is available from the 
U.S. Food and Drug Administration.16  Strong CYP3A4 inducers include, but are not limited to, 
rifampin, St. John’s wort, phenytoin, and efavirenz.  Strong CYP3A4 inhibitors include, but are 
not limited to, ketoconazole, grapefruit juice, clarithromycin, and erythromycin.  Use of any drug 
that is a known weak CYP3A4 inhibitor and/or a known CYP3A4 substrate is permitted.  See 
Appendix 2 for a more comprehensive list of strong and moderate CYP3A4 inhibitors and strong 
CYP3A4 inducers.  
Standard of care for routine CINV prophylaxis at the UCSD Moores Cancer Center follows 
NCCN guidelines.  Routine CINV prophylaxis may be administered concomitantly throughout 
the 1-week treatment and follow-up period of this study.  Patients receiving HEC are pretreated 
with a three-drug regimen, including an NK1 antagonist, 5-HT3 receptor antagonist, and 
glucocorticoid.  Patients receiving MEC receive a 5-HT3 receptor antagonist and a 
glucocorticoid.  Lastly, patients receiving low emetogenic chemotherapy do not receive any 
standard CINV prophylaxis.  For all types of chemotherapy, use of routine breakthrough 
medication at UCSD, which includes a dopamine antagonist (i.e. prochlorperazine) and/or a 
benzodiazepine (i.e. lorazepam) will be permitted.   
 
Unless there is a need for urgent intervention, additional medication for refractory CINV will be 
prohibited.  This includes over-the-counter medications, medical marijuana, herbal supplements, 
and investigational agents for CINV.  Other medications, which are considered necessary for 
the patient’s safety and wellbeing, may be given at the discretion of the investigator. 
 
5.5 
Efficacy Measures: 
5.5.1 Patient Medication Diary 
Subjects will be asked to record all oral and self-administered medications received while on 
study.  This will include any rescue medications used to treat their CINV each day, as well as 
any vitamins, homeopathic/herbal remedies, nutritional supplements, over-the-counter analgesic 
medication use, and all other over-the-counter “as needed” medications. Subjects will complete 
this diary (Appendix 3) on the day of Akynzeo® treatment (Study Day 1) and daily during the 
post-treatment observation portion of the study (Study Days 2-7).  
 
5.5.2 Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool© 
(MAT) 
The MAT is a validated tool to measure CINV in 24-hour intervals developed by members of 
Multinational Association for Supportive Care in Cancer (MASCC) to assist patients and 
oncology professionals in communicating accurately about the prevention and control of nausea 
and vomiting that may occur with chemotherapy.11  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 will aid treatment centers in understanding the effectiveness of 
their antiemetic strategies. The MAT was first created and posted in 2004.  It is now available in 
eleven languages, obtained by the standard forward/backward translation process.  The MAT 
consists of eight items. Four of these items refer to the occurrence, duration, and frequency of 
acute nausea and vomiting, and four refer to the occurrence, duration, and frequency of delayed 


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nausea and vomiting.  Dichotomous items are scored ‘‘0’’ (‘‘No’’) or ‘‘1’’ (‘‘Yes’’) and continuous 
variables as marked on the 0-10 scale. In total, there are 4 dichotomous variable items and 4 
continuous variable items.  There is no summing of items; instead, items are evaluated on their 
own in clinical practice.  Each subject will complete a written form of the MAT at approximately 
the same time each day during the study.  The MAT will be completed daily for 4 days after 
CINV prophylaxis and after Akynzeo® treatment (Study Day 1).  Thereafter, it will be completed 
daily during the post-treatment observation portion of the study at the same time each day 
starting 24 hours from the time of previous questionnaire completion.  English and Spanish 
versions of the MAT will be made available at study activation.  Additional foreign translations 
will be performed as needed. 
 
5.5.3 Functional Living Index Emesis (FLIE) Scale 
The FLIE is a validated patient-reported measure of the impact of CINV on daily life, which 
measures a 5-day recall.  The FLIE is a short, self-administered instrument containing two 
domains, one for nausea (nine items) and one for vomiting (nine items).  Responses to each 
question are rated on a 100mm visual analog scale that is scored on a one to seven-point scale 
as described in the FLIE scoring manual. A higher score indicates a better quality of life.  
Minimal or no impact of CINV on daily life will be defined as an average score of more than six 
on the seven-point scale (i.e. 108 total score or greater than 54 domain score).12 The FLIE will 
be completed on the 5th day after CINV prophylaxis, and on the day of Akynzeo® treatment 
(Study Day 1.  During the post-treatment observation portion of the study, the FLIE will be 
completed on Day 5 only.  English and Spanish versions of the MAT will be made available at 
study activation.  Additional foreign translations will be performed as needed. 
 
5.5.4 Healthcare Utilization  
CINV healthcare utilization data including information on the number and location of any 
emergency room visits, hospitalizations, and infusion center visits will be obtained via phone 
interview assessment on a daily basis over the seven-day treatment and follow-up periods.  
Phone calls will reference time since last phone interview and review prior responses. Study 
subjects will be asked to report all symptoms and problems leading up to the health care 
contact. All non-UCSD emergency room visits, hospitalizations, or infusion center visits will be 
followed-up with a medical request to verify the symptoms and reasons for such contacts.  
Records will be reviewed by study staff, and PI will be consulted for any clarifications. The 
primary and multiple secondary reasons for emergency room visits, hospitalizations, or infusion 
center visits will be recorded. 
 
5.5.5 Patient Preference  
On Study Day 7, subjects will be asked to complete a five-point Likert scale containing the 
question “On a scale of 1-5, how likely are you to ask your doctor for Akynzeo® to treat your 
refractory CINV in the future?”  Questionnaire results will be used to determine patient 
preference for future use of Akynzeo® for refractory CINV.   
 
6.0 
Study Drug Regimens  
 
Study drug (Akynzeo®) is an oral fixed-dose combination of 300 mg of netupitant and 0.5 mg of 
palonosetron.  Akynzeo® will be administered once as an oral capsule and will be supplied as 
300 mg netupitant/0.5 mg palonosetron hard gelatin capsules with a white body and caramel 


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cap with “HE1” printed on the body.  All study drug will be supplied by Helsinn, using the current 
marketed product..IDS will label the study drug with the drug name, study reference number and 
storage conditions.  Study drug will be dispensed to the subject by UCSD Investigational Drug 
Services (IDS).  IDS will be responsible for all study drug shipments and accountability. After 
refractory CINV is confirmed and all study-related procedures completed on Day 1, subjects will 
be instructed to take one Akynzeo® capsule.  Subjects will be administered a single, oral fixed-
dose combination of 300 mg of netupitant and 0.5 mg of palonosetron.  Akynzeo® must be kept 
in a secure place under appropriate storage conditions, as specified on the label and in the 
Investigator’s Brochure.  All study drug will be stored in original containers until dispensed to the 
study patients. 
 
If a patient vomits after taking their Akynzeo® dose within 12 hours and the capsule is expelled 
from the body intact, it will be considered a missed dose. The patient will be instructed to take a 
picture of the capsule (if possible) and contact the PI who  will determine if the patient should 
repeat up to one additional dose of Akynzeo®. Any changes from the dosing schedule including 
missed doses should be recorded in a CRF. 
 
6.1 
Study Drug Requested Per Patient 
 
1 capsule (300 mg of netupitant and 0.5 mg of palonosetron) per patient 
 
7.0 
Safety Measures 
 
A physical examination and complete metabolic profile will be assessed at screening to evaluate 
for the presence of any pre-treatment abnormalities and to confirm eligibility.  Physical 
examination and laboratory testing to evaluate adverse effects that develop during the seven-
day treatment and follow-up periods will be performed according to routine frequency for 
monitoring of the subject’s cancer according to the treating oncologist.   
 
Subjects will also be monitored for evidence of QTc interval changes at screening (an EKG will 
be required prior to Akynzeo® treatment on C2D1) and during the study treatment period on 
Study Day 3±3 days with a single EKG.  If the patient experiences any worsening cardiac 
symptoms, including, but not limited to dizziness, shortness of breath, or chest pain, during the 
study period, additional EKG(s) will be performed as clinically indicated. 
 
Daily safety assessments will be performed on the day of Akynzeo® treatment (Study Day 1), 
and daily during the post-treatment observation portion of the study (Study Days 2-7).  All 
adverse events will be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.10 
8.0 
Adverse events 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.  
 
Progression of the cancer under study or events that are unequivocally due to disease 


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progression should not be reported as an AE during the study (unless it is considered to be drug 
related by the investigator). 
8.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of patient safety and care.  
 
As far as possible, each adverse event should be evaluated to determine: 
• 
duration (start and end dates) 
• 
severity (grade) 
• 
seriousness 
• 
relationship to study agent 
• 
action taken (i.e., none, study agent modification, medical intervention) 
• 
outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
Adverse events monitoring begins at the time of informed consent signature and ends within 30 
days of the last administration of the study drug. 
 
All patients experiencing an adverse event, at least possibly related to the drug, will be 
monitored until:  
• 
the adverse event resolves or the symptoms or signs that constitute the adverse event 
return to baseline;  
• 
any clinically significant abnormal laboratory values have returned to baseline;  
• 
there is a satisfactory explanation other than the study drug for the changes observed; or 
• 
death. 
8.2 
Severity 
All adverse events will be graded according to the NCI CTCAE version 4.0310. The CTCAE 
v4.0310 is available at http://ctep.cancer.gov/reporting/ctc.html 
 
Per CTCAE v 4.03 when no predefined grading is available, the severity of an AE is graded as 
follows: 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 Death related to AE. 
• 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
• 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 


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8.3 
Seriousness 
A “serious” adverse event (SAE) is defined in regulatory terminology as any untoward medical 
occurrence that: 
1. Results in death. If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
2. Is life-threatening. The patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe. 
3. Requires in-patient hospitalization or prolongation of existing hospitalization.  
Note: Hospitalization (including hospitalization for an elective procedure) for a pre-
existing condition that has not worsened does not constitute a serious adverse event. 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event.  
• 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as SAE. 
The event may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.  
8.4 
Relationship 
The relationship to the IP of each AE/SAE will be evaluated by the investigator using the 
following levels: 
 
• 
Not related: The temporal relationship of the clinical event to the administration 
of IP makes a casual relationship unlikely; and other drugs, therapeutic 
intervention or underlying conditions provide a sufficient explanation for the 
observed event. 
• 
Related: The temporal relationship of the clinical event to the administration of 
the IP makes a casual relationship possible; and other drugs, therapeutic 
interventions or underlying conditions do not provide sufficient explanation for the 
observed event. A clear-cut temporal association with improvement on cessation 
of the study drug or recurrence upon re-challenge may also be observed 
8.5 
Prior experience 
Expected events are those that have been previously identified as resulting from administration 
of the agent. An adverse event is considered unexpected, for expedited reporting purposes 
only, when either the type of event or the severity of the event is not listed in the current known 
adverse events listed in the agent clinical experience section of this protocol and Akynzeo 
prescribing information. 
8.6 
Reporting Requirements for Adverse Events 
8.6.1 Expedited Reporting 
A. The Principal Investigator must be notified within 24 hours of learning of any serious 
adverse events, regardless of attribution, occurring during the study or within 30 days of the 
last administration of the study drug.  
B. The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR). 
The following events meet the definition of UPR: 


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1. Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to subjects or 
others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated sponsor 
safety report), interim result or other finding that indicates an unexpected change 
to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator. 
C. The FDA must be notified according to the following timelines: 
• 
within 7 calendar days of any unexpected fatal or life-threatening adverse event with 
possible relationship to study drug, and  
• 
within 15 calendar days of any event that is considered: 1) serious, 2) unexpected, and 
3) at least possibly related to study participation. 
D. A copy of all SAEs will be submitted to Helsinn’s safety designee using the approved local 
regulatory form within 24 hours of the Principal Investigator’s awareness by email (Drug-
Safety@Helsinn.com) or fax (732-744-1089). 
 
8.6.2 Routine Reporting Requirements 
A. The UCSD HRPP must be notified of any adverse events that are not unanticipated 
problems involving risk to subjects or others (non-UPRs) at the time of the annual 
Continuing Review.  
 
B. The FDA must be notified of all non-serious adverse events annually at the time of the 
annual report. 
 
C. Helsinn will be notified of all non-serious adverse events in summary or line-item form upon 
Helsinn’s request and at the conclusion of the study.    
 
8.6.3 Pregnancy Reporting Requirements 
 
The Principal Investigator must be notified within 24 hours of any pregnancies occurring in a 
female patient or a female partner of a male patient along with pregnancy outcomes. Elective 
abortions without complications should not be considered adverse events unless they were 
therapeutic abortions. Hospitalization for normal delivery of a healthy newborn should not be 
considered a significant adverse event. Spontaneous abortions should always be reported as 
significant adverse events. 
 
The Investigator should follow-up with the study patient or the female partner of the study 
patient until delivery or termination of pregnancy, even if the patient was withdrawn from the 
clinical study or the clinical study was completed. Helsinn will be informed of all pregnancy 
outcomes using the contact information provided above. 


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9.0 
Statistical Analysis 
9.1 
Study Design 
Ideally, a phase III placebo controlled trial would be completed to demonstrate the efficacy of 
Akynzeo® in the refractory CINV.  However, data regarding pharmacologic interventions for 
refractory CINV are lacking.  Furthermore, it is not established if intervening in the refractory 
CINV setting is practically feasible.  Consequently, we believe a feasibility study is the 
necessary first step followed by a larger randomized trial.   
 
9.2 
Primary outcome measures and sample size 
The proposed study is a prospective, single-center, feasibility trial.   The primary aim of this 
study is feasibility – specifically feasibility will be defined as completion of all study procedures 
over seven days.  For the primary aim, we assume an acceptable completion rate from strata of 
MEC/HEC or tumor types of all study-related procedures would be at least 70%. Assuming a 
true completion rate of 85%, a sample size of 50 patients would have an 80% power to detect 
an absolute difference of 15% at Type I error 0.05.   
9.3 
Secondary aims 
Secondary outcome measures including (1) the evaluation of adverse events utilizing the NCI 
CTCATE v4.03,10 (2) complete response (no emesis and no rescue medication use), (3) 
characterization of 24-hour CINV using the MAT,11 (4) five-day health related quality of life 
utilizing the FLIE,12 and (5) healthcare resource utilization (emergency room visits, 
hospitalizations, and infusion center visits over seven days).   
(1) Adverse events will recorded in detail and the number of events will be described using 
n and percent. The severity will be described using means (SD) and medians (IQR) of 
the adverse event grade (which ranges 0-5). 
(2) The proportion of patients experiencing complete response will be described with 
descriptive statistics (n and percent) as well as by using a one-sample confidence 
interval for proportions, applying the normal approximation to the binomial distribution. In 
addition, a one-sample z test for proportions will be used to determine if the complete 
response rate in this sample is significantly different then the 90% seen in previous 
studies.17 
(3) CINV will be analyzed using the MAT. The MAT consists of 8 distinct items, 4 of these 
items are binary and will be described using n and percents the other 4 items are 
continuous (ranging from 0-10) and will be described using mean and SD. Binary 
variables will also be described using one-sample confidence intervals for proportions 
(as described in #2 above) and continuous variables will be described using one-sample 
confidence intervals for means. 
(4) Quality of life will be analyzed as a binary response, impact on quality of life vs no 
impact, a score of less than 54 on the FLIE domain scores and a score of less then 108 
on the total score indicates an impact on quality of life. Each domain score, and the total 
score, will be analyzed separately using a 95% confidence interval to describe the 
proportion of participants with impacted QoL.  
(5) Healthcare resource utilization will be assessed by recording the number of emergency 
room visits, hospitalizations (with length of stay), and infusion center visits. Each 
healthcare utilization will be categorized with respect to whether it was specifically 
related to nausea and vomiting during the seven-day follow up period.  A table 
summarizing the number of each type of utilization related to nausea and vomiting will 
be provided.   


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(6) The occurrence of refractory CINV will be analyzed using CINV risk assessment at 
follow up day 7 compared to treatment day 1. 
 
 
Patient demographic characteristics (age, sex, and patient reported race/ethnicity) will be 
described using standard descriptive statistics (n/% or mean/SD). 
 
As an exploratory aim, regression analysis will be used to develop a predictive model for CINV, 
based on age, sex, history of >1 alcoholic beverage per day, history of motion sickness, history 
of hyperemesis gravidarum, and history of anxiety. 
9.4 
Data and Safety Collection and Monitoring 
All analyses will be conducted using the latest version of R (R Foundation for Statistical 
Computing, Vienna, Austria. http://www.R-project.org/) or SAS (SAS Institute, Cary, NC). The 
study team will provide support for data monitoring and cleaning. 
 
Records and data to be obtained from the study subjects are detailed above in the Schedule of 
Events. Subject outcome information will be documented in the electronic medical record and 
subject’s research record.  Data for this study will be entered into a password-protected set of 
electronic case report forms via the Velos eResearch web-based system.  Velos eResearch is 
an integrated software system for managing clinical trials.  This system supports several clinical 
trial functions, including electronic case report forms, tracking and scheduling of subject visits 
and events, and study reporting.  The software links to the UCSD Health System’s Epic 
Electronic Medical Record System to provide improved information and integration for clinical 
research projects. A robust support team assists investigators in implementing protocols and 
calendars and building electronic case report forms.  Velos provides automated data export 
procedures for designated users into Excel, and then transferred into SAS and R.  Access to the 
Velos database for this study will be limited to those users required to perform study-specific 
functions such as data entry and monitoring.  A designated study coordinator from the UCSD 
Moores Cancer Center Clinical Trials Office will be responsible for entering all study data.   
 
In addition to adverse event monitoring and clinical oversight by the principal investigator and 
co-investigators, the clinical trials office internal monitor and/or a study team member will 
perform quality assurance of the study.  Monitoring will occur once every 3-6 months based 
upon rate of subject enrollment.  
 
This study will use the UCSD Moores Cancer Center Data Safety and Monitoring Board (DSMB) 
to provide oversight in the event that this treatment approach leads to unforeseen toxicities.  It 
will be left to the Investigator’s clinical judgment whether or not an adverse event is related and 
of sufficient severity to require the subject’s removal from treatment.  A subject may also 
voluntarily withdraw from treatment due to what he or she perceives as an intolerable adverse 
event.  
 
If the subject was permanently withdrawn from the study or investigational product due to a 
serious adverse event, the Investigator will notify the IRB of serious adverse events occurring at 
the site and other adverse event reports received, in accordance with local procedures. 
Subsequent review of serious, unexpected and related adverse events by the PI, DSMB, IRB, 
and/or Helsinn may also result in suspension of further trial interventions/administration of study 
agent at a site. The PI and/or Helsinn retains the authority to suspend additional enrollment for 
the entire study as applicable.  All serious adverse events must be reported within 1 working 
day of discovery or notification of the event.  Serious adverse events will be collected 


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throughout the study period, beginning with the signing of the informed consent through study 
completion.  For all collected AEs, the clinician who examines and evaluates the subject will 
determine the adverse event’s causality based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories of 
definitely related, probably related, possibly related, unlikely and unrelated.  
 
10.0 
REFERENCES 
1. NCCN Clinical Practice Antiemesis Guidelines in Oncology (NCCN Guidelines). Version 
1.2015, 2015. 
2. Navari RM: Treatment of Breakthrough and Refractory Chemotherapy-Induced Nausea 
and Vomiting. BioMed Research International, 2015. 
3. Lowery L, Andrew I, Gill S, et al: The use of aprepitant in a case of refractory nausea 
and vomiting. Palliative medicine:0269216314530180, 2014. 
4. Vig S, Seibert L, Green MR: Olanzapine is effective for refractory chemotherapy-induced 
nausea and vomiting irrespective of chemotherapy emetogenicity. Journal of cancer 
research and clinical oncology 140:77-82, 2014. 
5. Akynzeo® Prescribing information. APIP, 2014. 
6. Gralla R, Bosnjak S, Hontsa A, et al: A phase III study evaluating the safety and efficacy 
of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of 
chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. 
Annals of Oncology:mdu096, 2014. 
7. Hesketh P, Rossi G, Rizzi G, et al: Efficacy and safety of NEPA, an oral combination of 
netupitant and palonosetron, for prevention of chemotherapy-induced nausea and 
vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal 
study. Annals of Oncology 25:1340-1346, 2014. 
8. Aapro M, Rugo H, Rossi G, et al: A randomized phase III study evaluating the efficacy 
and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for 
prevention of chemotherapy-induced nausea and vomiting following moderately 
emetogenic chemotherapy. Annals of Oncology 25:1328-1333, 2014. 
9. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with 
metastatic non–small-cell lung cancer. New England Journal of Medicine 363:733-742, 
2010. 
10. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03. 
http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CB4QFjAA
&url=http%3A%2F%2Fwww.hrc.govt.nz%2Fsites%2Fdefault%2Ffiles%2FCTCAE 
manual - DMCC.pdf&ei=2ptfVa-
tKpGuogTbo4HoCg&usg=AFQjCNG4OnSycmuS6wqwm2C0zVI8pT4qyA&sig2=K7D0s5
d5nOMk0CEi6X0rEw&bvm=bv.93990622,d.cGU.  Accessed May 22, 2015. 
11. 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. Journal of pain and symptom management 34:148-159, 2007. 
12. Martin A, Pearson J, Cai B, et al: Assessing the impact of chemotherapy-induced 
nausea and vomiting on patients' daily lives: a modified version of the Functional Living 
Index—Emesis (FLIE) with 5-day recall. Supportive care in cancer 11:522-527, 2003. 
13. Molassiotis A, Aapro M, Dicato M, et al: Evaluation of risk factors predicting 
chemotherapy-related nausea and vomiting: results from a European prospective 
observational study. Journal of pain and symptom management 47:839-848. e4, 2014. 


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14. Dranitsaris G, Bouganim N, Milano C, et al: Prospective validation of a prediction tool for 
identifying patients at high risk for chemotherapy-induced nausea and vomiting. J 
Support Oncol 11:14-21, 2013. 
15. Pirri C, Katris P, Trotter J, et al: Risk factors at pretreatment predicting treatment-
induced nausea and vomiting in Australian cancer patients: a prospective, longitudinal, 
observational study. Supportive Care in Cancer 19:1549-1563, 2011. 
16.  U.S. Food and Drug Administration.  Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers. 
.http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm. [Accessed 28 August 2015]. 
17. Hesketh PJ, Rossi G, Rizzi G, et al:  Efficacy and safety of NEPA, an oral combination of 
netupitant and palonosetron, for prevention of chemotherapy-induced nausea and 
vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal 
study. Annals of Oncology 25:1340-1346, 2014. 
 
 
 


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11.0 
Appendices  
11.1 
Appendix 1- MASCC Antiemesis Tool 
 
 
 


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Appendix 2- List of Strong CYP3A4 Inducers and Strong and Moderate CYP3A4 Inhibitors 
 
 
Strong CYP3A4 inhibitors include the following: 
• 
Boceprevir 
• 
Clarithromycin 
• 
Conivaptan 
• 
Grapefruit juice 
• 
Indinavir 
• 
Itraconazole  
• 
Ketoconazole  
• 
Lopinavir/ritonavir 
• 
Mibefradil 
• 
Nefazodone  
• 
Nelfinavir 
• 
Posaconazole  
• 
Ritonavir, 
• 
Saquinavir  
• 
Telaprevir 
• 
Telithromycin 
• 
Voriconazole 
 
Moderate CYP3A4 inhibitors are the following: 
• 
Amprenavir 
• 
Aprepitant 
• 
Atazanavir 
• 
Ciprofloxacin 
• 
Darunavir/ritonavir  
• 
Diltiazem  
• 
Erythromycin  
• 
Fluconazole  
• 
Fosamprenavir  
• 
Grapefruit juice 
• 
Imatinib 
• 
verapamil 
Strong CYP3A4 inducers include the following:  
• 
Avasimibe 
• 
Carbamazepine 
• 
Phenytoin  
• 
Rifampin  
• 
St. John’s wort 
 
 
 
 


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11.2 
Appendix 3- Patient Medication Diary  
 
 
 
 
Herbal supplement use? 
 No  
 Yes, which one? Dose? Frequency? _________________________________________ 
 
Marijuana use? 
 No  
 Yes, which one? Dose? Frequency? _________________________________________ 
 
 


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Appendix 4- five point Likert scale questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.3 
Appendix 5 - Functional Living Index for Emesis (FLIE) scale 
 
 
 
 
 


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