Netupitant/Palonosetron Hydrochloride and Dexamethasone With or Without Prochlorperazine or Olanzapine in Improving Chemotherapy-Induced Nausea and Vomiting in Patients With Breast Cancer
Phase: PHASE3
Conditions: Breast Carcinoma
Sponsor: University of Rochester NCORP Research Base

URCC16070 Protocol Version Date 01/04/2023 
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TREATMENT OF REFRACTORY NAUSEA 
URCC16070 
NCT03367572 
 
URCC NCORP Research Base: 
Saunders Research Building 
265 Crittenden Blvd, Room 2.235 
CU 420658 
Rochester, NY  14642 
 
 
Phone:  585-275-1364 
email:  urcc_ncorp@urmc.rochester.edu 
website:  http://urcc-ncorp.org/ 
Study Chair: 
 
  
Luke Peppone, Ph.D., M.P.H. 
URCC NCORP Research Base  
 
Study Co-Chairs: 
 
 
 
Gary R. Morrow Ph.D., M.S. 
URCC NCORP Research Base  
 
Sarah L. Kerns, Ph.D., M.P.H 
Medical College of Wisconsin 
 
 
NCORP Co-Chair: 
 
Kathleen Yost, M.D. 
Cancer Research Consortium of Western 
Michigan NCORP 
 
Medical Monitor: 
 
 
Chunkit Fung, M.D. 
URCC NCORP Research Base  
 
Biostatisticians: 
 
Eva Culakova, Ph.D., M.S. 
URCC NCORP Research Base 
 
Participating Institutions:   
NCORP community sites affiliated with the 
URCC NCORP Research Base 
 
IND: 
 
NA 
 
Agent(s)/Supplier:  Prochlorperazine (Compazine®), olanzapine (Zyprexa®), and dexamethasone will 
be supplied by the University of Rochester Investigational Drug Service (IDS).  Netupitant/palonosetron 
(Akynzeo®) will be supplied by Helsinn Therapeutics (U.S.) Inc., of Iselin, New Jersey 
 
Packaged and distributed by:  
University of Rochester Investigational Drug Service    
 
Document History 
Version Date  
Initial 
6-27-17 
Amendment 1 
10-12-17 
Amendment 2 
1-11-18 
Amendment 3 
2-12-18 
Amendment 4 
10-10-18 
Amendment 5 
01-25-19 
Amendment 6 
05-15-19 
Amendment 7 
06-26-20 
Amendment 8 
07-17-20 
Amendment 9 
01-04-23 

URCC16070 Protocol Version Date 01/04/2023 
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Protocol Contact Information 
 
Study Chair:  
 
 
 
 
 
Luke Peppone, PhD, MPH  
 
 
 
 
 
 
 
 
luke_peppone@urmc.rochester.edu 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
(Sign in at https://www.ctsu.org, 
and select the Regulatory > 
Regulatory Submission.) 
 
Institutions with patients waiting 
that are unable to use the 
Portal should alert the CTSU 
Regulatory Office immediately 
at 1-866-651-CTSU (2878) to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory 
assistance. 
Refer to the patient 
enrollment section of the 
protocol for detailed 
instructions.  
Data collection for this study will be 
done through REDCap. All data and 
REDCap questions should be 
directed to: 
 
URCC NCORP Research Base 
Protocol Coordinator: 
URCC 16070@urmc.rochester.edu 
 
URCC NCORP Research Base 
Saunders Research Building 
265 Crittenden Blvd 
Box 658 
Rochester, NY 14642 
 
Do not submit study data or forms to 
the CTSU. Do not copy the CTSU 
on data submissions. 
 
Refer to the data submission section 
of the protocol for further 
instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (https://www.ctsu.org). Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program – 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password. 
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS). 
 
For URCC Research Base regulatory questions, contact URCC Regulatory@urmc.rochester.edu. 
For adverse event reporting contact URCC 16070@urmc.rochester.edu. 
 
All study supplies will be distributed from URCC. Supplies can be ordered by contacting the Protocol 
Coordinator at URCC 16070@urmc.rochester.edu. 
 
For questions regarding the URCC NCORP website, contact 
URCC Techsupport@urmc.rochester.edu. 
 
For clinical questions (i.e. patient eligibility or treatment-related): 
URCC 16070@urmc.rochester.edu 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) 
Contact the CTSU Help Desk by phone or email: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 

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TABLE OF CONTENTS 
 
 
INSIDE COVER PAGE............................................................................. Error! Bookmark not defined. 
SCHEMA ..................................................................................................................................................... 3 
1. 
INTRODUCTION AND BACKGROUND ................................................................................... 6 
1.1  Rationale ....................................................................................................................................................... 6 
1.2 
Literature Review and Preliminary Studies .............................................................................................. 8 
1.3 
Study Medications ........................................................................................................................................ 9 
1.4 
Feasibility ....................................................................................................................................................... 9 
2. 
AIMS/OBJECTIVES ...................................................................................................................... 9 
3. 
CHARACTERISTICS OF STUDY POPULATION ................................................................. 10 
3.1 
Inclusion Criteria for Participation in the Cycle 1 Portion of the Study ............................................... 10 
3.2 
Additional Inclusion Criteria for Participants Advancing to the Cycle 2 Portion of the Study .......... 11 
3.3 
Exclusion Criteria for Participation in the Cycle 1 Portion of the Study .............................................. 11 
3.4 
Additional Exclusion Criteria for Participants Advancing to the Cycle 2 Portion of the Study ........ 12 
3.5 
Source of Study Participants .................................................................................................................... 12 
3.6 
Process of Consent .................................................................................................................................... 13 
3.7 
Recruitment and Retention Plan .............................................................................................................. 13 
4. 
REGISTRATION AND RANDOMIZATION ............................................................................. 14 
4.1 
CTEP Requirements .................................................................................................................................. 14 
4.2 
CTSU Registration Procedures ................................................................................................................ 15 
4.3 
Enrolling Participants (Cycle 1) ................................................................................................................ 16 
4.4 
Randomization/Stratification (Cycle 2) .................................................................................................... 17 
5. 
RESEARCH PROTOCOL/STUDY PROCEDURES .............................................................. 18 
5.1 
Summary of Study Plan ............................................................................................................................. 18 
5.2 
Schedule of Activities................................................................................................................................. 20 
5.3 
Screening, Baseline and Cycle 1 Assessments .................................................................................... 20 
5.4 
Intervention/Study Agent ........................................................................................................................... 21 
5.5 
Evaluation During the Study Intervention – Cycle 2 Assessments ..................................................... 23 
5.6  Blood Draw .................................................................................................................................................. 24 
5.7 
There Will Be No Follow-up Assessments ............................................................................................. 25 
5.8 
Reported Adverse Events and Potential Risks ...................................................................................... 26 
5.9 
 Participant Withdrawal .............................................................................................................................. 26 
5.10 Emergency Study Agent Disclosure ........................................................................................................ 26 
5.11 Data & Specimen Banking for Future Research Use ........................................................................... 26 
5.12 Genetic/Genomic Research Activities ..................................................................................................... 26 
5.13 Costs to the Participant ............................................................................................................................. 27 
5.14 Payment for Participation .......................................................................................................................... 27 
6. 
intervention/study agent ADMINISTRATION and information ............................................. 27 
6.1 
Contraindications ........................................................................................................................................ 27 
6.2 
Concomitant Medications .......................................................................................................................... 27 
6.3 
Dose Modification ....................................................................................................................................... 27 
6.4 
Adherence/Compliance ............................................................................................................................. 27 
7.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION .......................................... 27 
7.1 
Primary Endpoint ........................................................................................................................................ 28 
7.2 
Secondary Endpoints................................................................................................................................. 28 
7.3 
Off-Agent Criteria ....................................................................................................................................... 28 
7.4 
Off-Study Criteria ........................................................................................................................................ 28 
8.  
Study Agent/ Distribution ........................................................................................................... 28 
8.1 
Availability ................................................................................................................................................... 28 
8.2 
Distribution .................................................................................................................................................. 28 
8.3  Agent Accountability .................................................................................................................................. 29 
8.4 
Packaging, Labeling and Shipping of Study Medication ...................................................................... 29 
8.5 
Storage ........................................................................................................................................................ 30 
8.6 
Blinding and Unblinding Methods ............................................................................................................ 30 

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8.7 
 Drug Information - Olanzapine (Zyprexa®) ........................................................................................... 30 
8.8 
Drug Information - Prochlorperazine (Compazine®) ............................................................................ 33 
8.9 
 Drug Information - Akynzeo® .................................................................................................................. 37 
8.10 Drug Information - Dexamethasone ........................................................................................................ 40 
9. 
CORRELATIVE/SPECIAL STUDIES ....................................................................................... 43 
10. 
SPECIMEN MANAGEMENT ..................................................................................................... 43 
10.1 Laboratories ................................................................................................................................................ 43 
10.2 Specimen Banking ..................................................................................................................................... 43 
10.3 Shipping Instructions ................................................................................................................................. 43 
10.4 Tissue Banking ........................................................................................................................................... 43 
11.0 
REPORTING ADVERSE EVENTS FOR THE FIRST PART OF THE STUDY, I.E., THE SURVEY 
AT CHEMOTHERAPY CYCLE 1. .......................................................................................................... 43 
11.1 AE guidelines .............................................................................................................................................. 44 
11.2 Definitions .................................................................................................................................................... 44 
11.3 Reporting Adverse Events ........................................................................................................................ 45 
11.4 Responsibilities for Expedited Reporting ................................................................................................ 45 
12.0 
REPORTING ADVERSE EVENTS FOR THE SECOND PART OF THE STUDY, I.E., THE 
RANDOMIZED INTERVENTION AT CHEMOTHERAPY CYCLE 2. ............................................... 46 
12.1 Adverse Event (AE) Definition. ................................................................................................................. 46 
12.2 Serious Adverse Event (SAE) Definition................................................................................................. 47 
12.3 Reporting Adverse Events ........................................................................................................................ 47 
12.4 Responsibilities for Expedited Reporting ................................................................................................ 48 
13. 
STUDY MONITORING ............................................................................................................... 49 
13.1 Data Management Summary.................................................................................................................... 49 
13.2 On-site Audits. ............................................................................................................................................ 50 
13.3 Records To Be Kept................................................................................................................................... 51 
13.4 Data and Safety Monitoring Plan ............................................................................................................. 51 
13.5 Record Retention ....................................................................................................................................... 52 
14. 
STATISTICAL CONSIDERATIONS ......................................................................................... 52 
14.1 Study Design/Description .......................................................................................................................... 52 
14.2 Data Handling ............................................................................................................................................. 53 
14.3 Sample Size and Power ............................................................................................................................ 53 
14.4 Calculation of the Primary Outcome Variable ........................................................................................ 54 
14.5 Primary Objectives and Analysis Plans .................................................................................................. 54 
14.6 Secondary Objectives, Endpoints, Analysis Plans ................................................................................ 54 
14.7 Exploratory Analyses: ................................................................................................................................ 55 
14.8 Interim Analysis .......................................................................................................................................... 55 
14.9 Ancillary Studies ......................................................................................................................................... 55 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................................... 56 
15.1 Institutional Review Board Approval ........................................................................................................ 56 
15.2 Submission of Regulatory Documents .................................................................................................... 56 
15.3 Other ............................................................................................................................................................ 56 
16. 
FINANCING, EXPENSES, AND/OR INSURANCE ............................................................... 56 
17. 
REFERENCES ............................................................................................................................ 56 
  

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1. 
INTRODUCTION AND BACKGROUND  
 
1.1  
Rationale 
 
 
Chemotherapy-Induced Nausea Remains a Significant Problem:  Despite the provision of 
antiemetic regimens in accordance with the American Society of Clinical Oncology (ASCO) 
guidelines,(1)  chemotherapy-related nausea remains a significant issue and is rated by patients 
as a greater problem than vomiting.(2-8)  Nausea following chemotherapy is also three times 
more likely to occur than vomiting.(9) The three major antiemetic guidelines focus almost 
exclusively on vomiting or on nausea and vomiting combined.(1,10,11)  There is little information 
provided specifically for nausea control and an absence of clear guidelines on which antiemetic 
regimen to give patients who have already experienced nausea at a prior chemotherapy cycle. 
 
Nausea remains one of the most troublesome and frequent side effects associated with cancer 
treatment.(2-5,12-17)  It is a widespread problem that causes extreme discomfort and seriously 
impairs QOL,(18,19) and it negatively affects patients’ nutritional habits, ability to work, and 
motivation to follow recommended treatment regimens.(18-21)  The introduction of the 5-HT3 RA 
class of antiemetics (e.g., granisetron) more than 15 years ago reduced treatment-related 
vomiting, but not treatment-related nausea.(2,3,13-15)  More recently, the use of palonosetron 
(Aloxi), a second-generation 5-HT3 RA, and aprepitant (Emend®), a neurokinin-1 receptor 
antagonist), have further increased control of emesis; treatment-related nausea, however, 
remains a significant problem.(4,6,7,17,22,23)  Our recently completed multi-center antiemetic 
study on optimal treatment for nausea conducted by the URCC CCOP (now NCORP) Research 
Base showed that nausea remains a significant problem and that more effective regimens for 
controlling nausea are needed.(9)  Over half the patients studied experienced nausea, and 
control afforded by all of the antiemetic regimens examined was inadequate.    
 
 
Current ASCO guidelines for refractory chemotherapy-induced nausea and vomiting (CINV) 
suggest that oncologists consider adding olanzapine (Zyprexa®) or a dopamine antagonist such 
as prochlorperazine (Compazine®) to the antiemetic regimen, but these are only two of many 
possible strategies for control of refractory CINV.(1)  We chose to examine the efficacy of 
prochlorperazine in the present proposal because it is suggested for control of refractory CINV in 
both the ASCO(1) and National Comprehensive Cancer Network (NCCN)(11) antiemetic 
guidelines and because of our very positive experience with it in Preliminary Studies 1 and 2, 
described later.  We chose to study olanzapine because it too is suggested for control of 
refractory CINV in both the ASCO and NCCN antiemetic guidelines and also because of the 
positive findings from the recently closed Alliance Group study of olanzapine for the prevention of 
CINV(24) and also the very positive systematic review of six randomized clinical trials evaluating 
olanzapine for CINV.(25) 
 
 
Current Multinational Association for Supportive Care in Cancer (MASCC) guidelines do not 
discuss optimal treatments for nausea in patients with nausea following a previous cycle and do 
not recommend any specific treatment for recurrent emesis, although they do say that “rotation of 
antiemetics within a given family of antiemetic agents would be unlikely to lead to additional 
benefit.”(10) ASCO guidelines for refractory vomiting suggest that clinicians should consider 
adding lorazepam, alprazolam, a dopamine antagonist or olanzapine to the regimen or 
substituting high-dose intravenous metoclopramide for the 5-HT3 antagonist.(1)  The current 
protocol represents a rigorous examination of the benefits of incorporating either olanzapine or a 
dopamine antagonist (i.e., prochlorperazine) to the Cycle 2 antiemetic regimen of patients who 
experienced emesis or nausea despite optimal prophylaxis at Cycle 1.  
 
 
In addition, this study will provide important data on factors related to the occurrence of nausea 
and on optimal control of nausea in breast cancer patients receiving moderately or highly 
emetogenic chemotherapy.  As we move to an age of more patient-centered medicine, it is easy 

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to see how individualized treatment regimens based on patient characteristics will enable 
oncologists to pick the appropriate antiemetic regimen for their individual patients, and the 
nausea algorithm we seek to develop could lead to a more personalized medicine by providing 
the information necessary for modifying antiemetic regimens based upon individual risk factors. 
This algorithm could lead to an empirically based personalized medical approach for control of 
chemotherapy-induced nausea.   
 
 
Approach:  The study consists of two parts with screening and some assessments occurring at 
baseline and chemotherapy Cycle 1 and the randomized portion of the study (N = 333) occurring 
at Cycle 2.  During Cycle 1, we will screen and consent chemotherapy naïve breast cancer 
patients about to begin a chemotherapy regimen that contains doxorubicin, and/or 
cyclophosphamide, and/or carboplatin.  All three of the drugs are commonly given and all have at 
least moderate emetogenic potential.  A key inclusion criterion will be that all patients must be 
scheduled to receive antiemetic drugs recommended in the ASCO guidelines.(1)  We anticipate 
needing to screen approximately  1600 patients, or more if necessary, to meet our Cycle 2 target 
number.  The Cycle 2 portion will be conducted in those participants who experience moderate or 
greater nausea at Cycle 1 despite the recommended antiemics prescribed at Cycle 1.  It will be a 
Phase III randomized, double-blinded, placebo-controlled, 3-arm study (N = 333) that builds upon 
our prior CINV studies and investigates optimal control of CINV in patients who experienced 
CINV following initial chemotherapy.  At Cycle 1, all rescue medications will be allowed for 
uncontrolled chemotherapy-induced nausea and vomiting (CINV).  At Cycle 2, only the study 
agents can be taken for CINV.  For breakthrough nausea and vomiting at Cycle 2 all rescue 
medications with the exception of metoclopramide and lorazepam will be allowed.  We note that 
these two antiemetics are not allowed because benzodiazepines and anticholinergics are 
excluded from the protocol.  We will document the type and days when prescribed rescue 
medications were taken.   
 
Design Considerations  
 
• 
We include a CINV assessment, but no intervention at Cycle 1, to provide baseline 
information on CINV for patients who are randomized at Cycle 2.  It will also allow us to assess 
the actual levels of CINV in breast cancer patients from moderately and highly emetogenic 
chemotherapy when ASCO guideline antiemetics are provided.(1) 
 
• 
Arm 1 will be the control condition.  In this study arm, participants will receive Akynzeo® with 
dexamethasone along with appropriate placebos.  We note that Akynzeo® is an oral, fixed 
combination of an NK1 receptor antagonist (netupitant) and a 5-HT3 receptor antagonist 
(palonosetron) in a single capsule.  It was approved by the U.S. Food and Drug Administration to 
treat nausea and vomiting in patients undergoing cancer chemotherapy in October 2014 and 
added to the ASCO antiemetic treatment guidelines in January 2015.   
 
• 
An important consideration in choosing Akynzeo® for the control condition rather than 
continuing with the combination of aprepitant and palonosetron that most participants would have 
received at Cycle 1 was to ensure that no patient would be randomized to the same medication at 
Cycle 2 that failed to control their CINV at Cycle 1.  To ensure this, we have excluded patients 
receiving Akynzeo® at Cycle 1 from participating in the study.  We note that while aprepitant and 
netupitant are both NK1 receptor antagonists, they differ significantly in that netupitant has a 
substantially longer half-life at approximately 80 hours than aprepitant at 9-13 hours.  
 
• 
We chose to study olanzapine because it is suggested for control of refractory CINV in both 
the ASCO and NCCN antiemetic guidelines and also because of a recent very positive systematic 
review of six randomized clinical trials evaluating olanzapine for CINV(25) as well as the positive 
findings from the recently closed Alliance Group study of olanzapine for the prevention of 

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CINV.(24)  We note that the latter study examined prevention of CINV at Cycle 1 of 
chemotherapy and not treatment of refractory CINV as we propose.   
 
• 
We chose to examine the efficacy of prochlorperazine in the present proposal for four 
reasons: 1) because of our very positive experience with it in Preliminary Studies 1 and 2, 
described in Section 1.2,  2) the fact that as a dopamine antagonist, prochlorperazine employs a 
method of action for control of nausea that is different from those of the netupitant, palonosetron 
and dexamethasone, and that may be additive to those agents, 3) its more than five-decade 
history as a widely used and very effective antiemetic in the cancer environment, and 4) its 
inclusion in the current ASCO guidelines as a suggestion for treating refractory vomiting(1).  
 
• 
We chose to prescribe prochlorperazine q8h rather than prn because the q8h dosing was 
more effective than prn dosing in preliminary study 1, and also because the NCCN antiemetic 
Guidelines recommend routine around-the-clock administration of antiemetics rather than PRN 
for refractory nausea.(11)  
 
• 
We chose to extend the study medication (i.e., olanzapine/prochlorperazine), as well as 
dexamethasone, to include Day 4 at Cycle 2 because our data in Preliminary study 2 showed that 
38.3% of breast cancer patients who experienced peak nausea of > 3 (scale = 1-7) during any of 
days 1-3 of chemotherapy also experienced nausea at a level > 3 on Day 4.  We note that having 
a peak nausea level > 3 at Cycle 1 is a key eligibility criterion for the randomized portion of the 
current study. 
 
• 
We chose to limit eligibility to breast cancer patients to make the sample as homogeneous 
as possible while still keeping the study clinically meaningful.  This patient group has greater 
nausea than most if not all other large patient groups.(26) 
 
• 
We chose to collect blood at baseline on participants for exploratory analyses to further 
elucidate the possible relationship between glutathione metabolism and CINV(27) as well as to 
bank blood for exploratory analyses examining germline genetic markers that might help identify 
subgroups of patients at high risk for development of cancer-related or treatment-related side 
effects as well as subgroups most likely (or least likely) to respond to a particular antiemetic 
regimen.(28)  We note that we are not specifying any specific genetic markers at this time, but will 
monitor the field closely over the next several years as we collect the samples in order to target 
the most relevant genetic markers when we do the analyses several years from now. 
  
• 
We originally predicted 1) that approximately 40% of subjects from Cycle 1 would meet all 
the eligibility criteria for Cycle 2 and 2) that 90% of eligible subjects would participate in Cycle 2. 
While our first prediction was accurate, our second prediction was not. Our assumption was that 
100% of subjects eligible for Cycle 2 would participate, but the participation rate was only 
approximately 63% among the first 500 subjects enrolled to Cycle 1 and meeting the Cycle 2 
eligibility. Therefore, it is necessary to increase our originally planned accrual for Cycle 1 from 
800 subjects to 1,200 subjects. This is necessary to meet our accrual goal of 333 subjects 
completing Cycle 2. 
 
1.2 
Literature Review and Preliminary Studies  
 
Preliminary Study 1 was conducted between 2001 and 2004 in 671 chemotherapy-naïve patients 
receiving chemotherapy containing doxorubicin.(29)  All patients were given a first generation 5-
HT3 RA antiemetic plus dexamethasone on the day of treatment (Day 1) and randomized to one 
of three regimens for Days 2 and 3: Group 1 – prochlorperazine 10 mg p.o. every 8 hours; Group 
2 – any first generation 5-HT3 RA using standard dosage; or Group 3 – prochlorperazine 10 mg 
p.o. as needed.  No corticosteroids were given on Days 2 and 3 of treatment.  The study was 

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designed to determine if a 5-HT3 RA antiemetic was more effective than prochlorperazine in 
controlling DN.  There was no difference between the groups in mean or maximum delayed 
nausea (DN) severity.  Patients taking prochlorperazine regularly were least likely to report DN 
(71% vs. 79% [Group 2] and 82% [Group 3], p<0.05).   
 
Preliminary Study 2 tested four antiemetic regimens for control of DN following chemotherapy 
containing a platinum-based drug or an anthracycline in 1021 chemotherapy-naïve patients and 
was conducted from 2007 to 2010.(9) Group 1 of the prior study was included as a comparator 
group, and new groups to examine regimens containing palonosetron, aprepitant, and/or 
dexamethasone were added.  We found that the addition of dexamethasone on Days 2 and 3 
reduced DN and the beneficial effect of adding aprepitant for control of DN was the same as 
adding prochlorperazine. 
 
1.3 
Study Medications  
 
The following two antiemetic medications are provided to some randomized participants during 
Cycle 2: Prochlorperazine (Compazine®), Olanzapine (Zyprexa®).  Details on the medications 
are provided in Sections 5.4 and 8.    
 
1.4 
Feasibility 
 
A key advantage to conducting this study within the NCORP network is the demonstrated track 
record of this group in recruiting patients prior to initial chemotherapy as evidenced by both 
Preliminary Studies 1 and 2 meeting their accrual goals.  Other relevant factors related to 
NCORP are: 1) NCORP Community Sites and Minority/Underserved Community Sites have been 
involved in developing this protocol, 2) Interest was high with our NCORP affiliates as determined 
by discussion at our annual NCORP Research Base meeting in September 2015, 3) all accrual 
will take place at NCORP sites, and 4) the University of Rochester NCORP (previously URCC 
CCOP) Research Base has conducted five previous chemotherapy-induced nausea and vomiting 
(CINV) studies (total N = 3,365), all of which met their accrual targets.  
 
2. 
AIMS/OBJECTIVES  
 
2.1  
Primary Aim is to determine if control of nausea at Cycle 2 in participants who 
experienced CINV at Cycle 1 is improved by the addition of either prochlorperazine or olanzapine 
to the control arm of netupitant, palonosetron and dexamethasone. 
 
2.1.1 Hypothesis 1:  Control of nausea at Cycle 2 in participants who experienced CINV 
at Cycle 1 despite receiving an ASCO-recommended antiemetics(1) can be improved by 
the addition of either prochlorperazine or olanzapine to the standard antiemetic 
combination of netupitant, palonosetron and dexamethasone.   
 
2.2  
Secondary Aim 1 is to determine if olanzapine is more effective than prochlorperazine in 
controlling nausea at Cycle 2 in participants who experienced CINV at Cycle 1 when used in 
combination with netupitant, palonosetron and dexamethasone. 
 
2.2.1 Hypothesis 2:  Olanzapine, which is a newer antiemetic drug with a more 
problematic side-effect profile than prochlorperazine, is more effective than 
prochlorperazine in controlling nausea when used in combination with netupitant, 
palonosetron and dexamethasone. 
 
2.3  
Secondary Aim 2 is to determine if control of vomiting at Cycle 2 in participants who 
experienced CINV at Cycle 1 is improved by the addition of either prochlorperazine or olanzapine 
to the control arm of netupitant, palonosetron and dexamethasone. 

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2.3.1 Hypothesis 3:  Control of vomiting at Cycle 2 in participants who experienced 
CINV at Cycle 1 despite receiving an ASCO-recommended antiemetic regimen(1) can be 
improved by the addition of either prochlorperazine or olanzapine to the standard 
antiemetic combination of netupitant, palonosetron and dexamethasone.   
 
2.4  
Secondary Aim 3 is to determine if olanzapine is more effective than prochlorperazine in 
controlling vomiting at Cycle 2 in participants who experienced CINV at Cycle 1 when used in 
combination with netupitant, palonosetron and dexamethasone.  
 
2.4.1 Hypothesis 4:  Olanzapine, which is a newer antiemetic drug with a more 
problematic side-effect profile than prochlorperazine, is more effective than 
prochlorperazine in controlling vomiting when used in combination with netupitant, 
palonosetron and dexamethasone. 
 
2.5 
Exploratory Aim 1 is to create an empirically-based algorithm predicting nausea from 
breast cancer chemotherapy regimens that takes into account not only state-of-the-art antiemetic 
regimens but also participant factors such as age, race, education, ethnicity, QOL, alcohol 
consumption, susceptibility to nausea, expectancy, anxiety, level of nausea on the day prior to 
treatment, and prior history of nausea.   
 
2.6 
Exploratory Aim 2 is to compare the effects of the interventions on QOL, as assessed by 
the FACT-G, by following the same procedures described under the Primary Aim and the first 
Secondary Aim, using change in the FACT-G scores as the response.  
 
2.7 
Exploratory Aim 3 is to provide preliminary data on the frequency and severity of sleep 
disturbance, fatigue, anxiety, and dizziness, across treatment conditions.  
 
2.8 
Exploratory Aim 4 is to provide preliminary data on biological factors (e.g. GSH 
recycling, genetic markers) that may help identify a subgroup of participants at high risk for 
development of cancer-related or treatment-related side effects, or response to treatment. 
 
3. 
CHARACTERISTICS OF STUDY POPULATION  
 
3.1 
Inclusion Criteria for Participation in the Cycle 1 Portion of the Study 
 
Participants must: 
3.1.1 Have a diagnosis of breast cancer and be chemotherapy naïve. Note: Prior 
methotrexate for non-cancerous conditions is allowed.    
  
3.1.2 Be scheduled to receive a single-day chemotherapy regimen that contains 
doxorubicin, and/or cyclophosphamide, and/or carboplatin. Single-day chemotherapy is 
defined  as only one infusion or injection per cycle.  Herceptin® (trastuzumab) and 
other chemotherapy agents will be allowed with any of these regimens.   
 
3.1.3 Be scheduled to receive an antiemetic regimen that does not contain Akynzeo®.   
• 
For chemotherapy regimens with a high emetic risk, the antiemetic regimen must 
include an NK-1 antagonist receptor, a 5HT3 receptor antagonist and 
dexamethasone. Other antiemetics, including additional dexamethasone and 
olanzapine, may also be included at cycle one. 
• 
For chemotherapy regimens with a moderate emetic risk, the antiemetic regimen 
must include a 5HT3 receptor antagonist and dexamethasone. Other antiemetics, 
including additional dexamethasone and olanzapine, may also be included at cycle 
one. 

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3.1.4 Be able to read English. Materials will not be provided in Spanish because 
validated translations of most of the study measures are not available in Spanish, and 
Spanish translating capacity is not available at all affiliate sites.  
 
3.1.5 Be at least 18 years of age.   
 
3.1.6 Be female. 
 
3.1.7 Have the ability to give written informed consent. 
 
3.1.8 Have ECOG performance status of 0, 1, or 2   
 
3.1.9 Note: Because the NCCN antiemetic guidelines (11) state that olanzapine should 
be used with caution in elderly patients, patients 80 years of age or older must have 
approval from an oncologist or their designee to participate in this study.  
 
3.1.10 Note: Because aprepitant can lower International Normalized Ratio (INR) levels if 
taken concurrently with warfarin, patients currently receiving warfarin must have approval 
from an oncologist or their designee to participate in this study.  
 
3.1.11 Women of child-bearing potential must agree to use adequate contraception 
(hormonal or barrier method of birth control, or abstinence) for the duration of the study 
and have a negative pregnancy test within 10 days prior to the initiation of chemotherapy.  
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform her study physician immediately.  
 
3.2 
Additional Inclusion Criteria only for the Participants Advancing to the Cycle 2 
Portion of the Study 
 
Participants must: 
3.2.1  Only participants with a nausea score > 3 at least once on the 4-day home record 
from Cycle 1 can be randomized for Cycle 2. 
 
3.2.2  Participants must be scheduled to receive the same chemotherapy regimen as 
received at Cycle 1. 
 
3.2.3 Because quinolone antibiotic therapy can increase the level or effect of olanzapine 
by altering drug metabolism and thereby potentially increase risk of side effects, patients 
currently receiving quinolone antibiotic therapy must have approval from an oncologist or 
their designee to participate in the Cycle 2 portion of the study.  (A partial list of quinolone 
antibiotics is included in the supporting documents section of the protocol webpage.) 
 
3.3 
Exclusion Criteria for Participation in the Cycle 1 Portion of the Study 
 
Participants must not: 
3.3.1 Have clinical evidence of current or impending bowel obstruction. 
 
3.3.2  Have a known history of central nervous system disease (e.g., brain metastases or 
a seizure disorder.) 
 
3.3.3 Have dementia. 
 
3.3.4 Have uncontrolled diabetes mellitus or uncontrolled hyperglycemia. 

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3.3.5 Have severe hepatic impairment, severe renal impairment, or end-stage 
renal disease as determined by the treating physician. 
 
3.3.6 Have had long-term treatment (> 5 days within the past 30 days) with an 
antipsychotic agent such as risperidone, quetiapine, clozapine, a phenothiazine, or a 
butyrophenone within 30 days before enrollment or plans for such treatment during the 
study period.  Note: Participants could have received prochlorperazine and other 
phenothiazines as antiemetic therapy on a short term basis (i.e., < 5 days).  (A partial list 
of antipsychotic agents is included in the supporting documents section of the protocol 
webpage.)  
 
3.3.7 Have a known cardiac arrhythmia, uncontrolled congestive heart failure, or acute 
myocardial infarction within the previous 6 months. 
 
3.3.8 Be taking benzodiazepines regularly (> 5 days within the past 30 days).  PRN use 
(≤ 5 days) for the short-term relief of the symptoms of anxiety, anxiety associated with 
depressive symptoms, or as a rescue medication for breakthrough CINV is allowed.  (A 
partial list of benzodiazepines is included in the supporting documents section of the 
protocol webpage.) 
 
3.3.9 Be taking anticholinergic medications.  (A partial list of anticholinergic medications 
is included in the supporting documents section of the protocol webpage.) 
 
3.3.10 Be taking amifostine (Ethiofos). 
 
3.3.11 Have a known hypersensitivity to olanzapine or to phenothiazines. 
 
3.4 
Additional Exclusion Criteria only for the Participants Advancing to the Cycle 2 
Portion of the Study 
 
Participants: 
3.4.1 Must not have received Akynzeo® at Cycle 1. 
 
3.4.2 Must still meet all the exclusion criteria for Cycle 1. 
 
3.5 
Source of Study Participants 
 
3.5.1 Sample Population:  Participants will be recruited at the NCORP affiliates within 
the URCC Research Base network.  Based upon the demographics of Preliminary Study 
2, which had similar eligibility requirements and was run in many of the same locations as 
this study is, we expect 2% of the study population to be Hispanic, and 10% to be a racial 
minority, mostly African-American.  Since having a diagnosis of breast cancer is an 
eligibility criterion, we will exclude men from participating in the study because it is unlikely 
we could recruit enough men to conduct meaningful analyses on that participant sub-
group.  
 
3.5.2 Participants must be 18 years of age or older.  Women under 18 seldom have 
breast cancer and it is unlikely we could recruit enough of that age group with breast 
cancer to conduct meaningful analyses on that participant sub-group.   
 
Anticipated Participant Breakdown 
 

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Racial Categories 
Not 
Hispanic or 
Latino: 
Female 
Not 
Hispanic 
or Latino: 
Male 
Hispanic 
or Latino: 
 
Female 
Hispanic 
or Latino: 
 
Male 
Unknown 
or Not 
Reported  
Female 
Unknown 
or Not 
Reported  
Male 
 
Total 
American 
Indian/Alaska Native 
9 
0 
0 
0 
0 
0 
9 
Asian 
49 
0 
0 
0 
2 
0 
51 
Native Hawaiian or 
Other Pacific 
Islander 
12 
0 
0 
0 
0 
0 
12 
Black or African 
American 
182 
0 
3 
0 
19 
0 
204 
White  
1,199 
0 
32 
0 
55 
0 
1,286 
More Than One 
Race 
13 
0 
0 
0 
1 
0 
14 
Unknown or Not 
Reported 
7 
0 
5 
0 
12 
0 
24 
Total 
1,471 
0 
40 
0 
89 
0 
1,600 
 
3.6 
Process of Consent 
 
3.6.1  Prior to study initiation, the informed consent document will be reviewed and 
approved by the Central IRB (CIRB). Any subsequent changes to the informed consent 
will be approved by the CIRB prior to initiation.  NCORP sites will use the CIRB-approved 
consent form, which can include any local boilerplate language previously approved by 
the CIRB. 
 
3.6.2 All potential study participants will be given a copy of the CIRB-approved Informed 
consent to review.  The site investigator/investigator’s designee will explain all aspects of 
the study in lay language and answer all questions regarding the study. If the patient 
decides to participate in the study, she will be asked to sign and date the informed 
consent document.  The study agents will not be released to a patient who has not signed 
the informed consent document.  Patients who refuse to participate or who withdraw from 
the study will be treated without prejudice. 
 
3.6.3 The site investigator/investigator’s designee will also sign the consent form.  The 
date of this signature should correspond with the date the participant signs. 
 
3.6.4 The eligibility checklist must be signed and dated by a physician prior to 
registration and the initiation of any study procedures.  
 
3.7 
Recruitment and Retention Plan 
 
3.7.1 Study personnel at participating NCORP sites with appropriate human subject 

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• 
Addition to a site roster 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
In addition, all investigators acting as the Site-Protocol PI investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must be rostered 
at the enrolling site with a participating organization. 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov 
 
4.2 
Cancer Trials Support Unit Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
4.2.1 IRB Approval:   
 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if the 
study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU 
Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval and on at least one participating 
roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 

URCC16070 Protocol Version Date 01/04/2023 
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• 
Compliance with all protocol-specific requirements (PSRs). 
 
4.2.2 Checking Your Site’s Registration Status: 
 
Site’s registration status may be verified on the CTSU members’ website.   
 
Click on Regulatory tab at the top of the screen 
 
Click on Site Registration; and  
 
Enter the site’s 5-character CTEP Institution Code and click on Go 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
 
Note:  The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
4.3 
Enrolling Participants (Cycle 1) 
 
 
 
NOTE:  Coordinators must complete REDCap training prior to enrolling participants. 
 
4.3.1 This study consists of two parts with screening and some assessments occurring 
at baseline and Cycle 1 and the randomized portion of the study (N = 333) occurring at 
Cycle 2.  At Cycle 1, we will consent chemotherapy naïve breast cancer patients about to 
begin a chemotherapy regimen that contains doxorubicin and/or cyclophosphamide and/or 
carboplatin and are scheduled to receive antiemetics that are recommended in the ASCO 
Clinical Practice Guidelines.  We anticipate needing to consent approximately 1600 
participants at Cycle 1 to meet our Cycle 2 target number.  It should take three to four 
years to meet our targeted enrollment.  
 
4.3.2 To enroll a participant who meets the eligibility criteria and who has signed the 
informed consent document, log on to the URCC NCORP Research Base website at 
http://www.urcc-ncorp.org/, enter your NCORP’s username and password, choose 
“Register a Subject”, and enter the information outlined in the next section.  If you are 
unable to log on, contact the study email at URCC_16070@urmc.rochester.edu. 
 
The following information will be requested: 
 
a. NCORP name  
b. NCORP component CTEP ID 
c. Enrolling physician name 
d. Enrolling physician CTEP Investigator ID 
e. Name and telephone number of person performing assessments 
f. Verification that participant has met all inclusion and exclusion criteria in Sections 
3.1 and 3.3. 
g. Verification that consent form has been signed 
h. Participant’s identification 
• 
First and last initials 
• 
Birth date (MM/DD/YYYY) 
• 
Gender 
• 
Race and Ethnicity 
• 
Five-digit zip code 
• 
Payment code 
i. 
Date of first chemotherapy 

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A confirmation of registration will be emailed to the registering NCORP’s administrator, and if 
requested, a confirmation email will be sent to the NCORP’s coordinating center  
 
NOTE:  Immediately following registration, study staff must use the participant registration ID 
number to create a record in REDCap and complete the REDCap Participant Information form.  
 
 
4.4 
Randomization/Stratification (Cycle 2) 
 
4.4.1 Randomization.  Participants will not be randomized at Cycle 1. Randomization 
will occur following the assessment of CINV after Cycle 1, and a participant will be 
randomized for Cycle 2 only if the reported nausea at Cycle 1 was ≥ 3 (on a 1-7 scale).  A 
computer-generated randomization schedule will be used to assign participants in equal 
numbers to the three study arms, with a random (50/50) block of 3 or 6.  The schedule is 
prepared by and maintained by the URCC NCORP Research Base biostatistician.   
 
4.4.2 Stratification.  The three study arms are stratified by  
• 
NCORP 
• 
Presence of vomiting 
• 
Whether the participant received doxorubicin at Cycle 1   
• 
Chemotherapy setting (neo-adjuvant, adjuvant or metastatic) 
 
4.4.3 
Randomization is done exclusively through REDCap. Randomization occurs when both the 
Four Day Home Record and the Case Summary are entered and marked as complete iniREDCap.  
The following information will be requested: 
• 
NCORP name  
• 
Participant’s study ID 
• 
Did the participant report vomiting on the 4-Day Home Record Diary? 
• 
Did the participant receive doxorubicin at Cycle 1? 
• 
Chemotherapy setting (neo-adjuvant, adjuvant, or metastatic) 
 
The three treatment arms for Cycle 2 are: 
 
Arm 1 
Agent 
Day 1 
Day 2 
Day 3 
Day 4 
netupitant/palonosetron One 300mg capsule 
approximately one 
hour prior to 
chemotherapy 
 
 
 
Dexamethasone 
12mg PO 30 
minutes prior to 
chemotherapy 
8mg PO in 
the morning 
8mg PO in 
the morning 
8mg PO in the 
morning 
Placebo to match 
prochlorperazine 
One capsule with 
chemotherapy then 
q8h 
One capsule 
q8h 
One capsule 
q8h 
One capsule 
q8h 
Placebo to match 
olanzapine 
One capsule with 
chemotherapy 
One capsule 
in the 
morning 
One capsule 
in the 
morning 
One capsule 
in the morning 
 
 
 

URCC16070 Protocol Version Date 01/04/2023 
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Arm 2 
Agent 
Day 1 
Day 2 
Day 3 
Day 4 
netupitant/palonosetron One 300mg capsule 
approximately one 
hour prior to 
chemotherapy 
 
 
 
Dexamethasone 
12mg PO 30 
minutes prior to 
chemotherapy 
8mg PO in 
the morning 
8mg PO in 
the morning 
8mg PO in the 
morning 
Prochlorperazine 
10mg PO with 
chemotherapy then 
q8h 
10mg PO 
q8h 
10mg PO 
q8h 
10mg PO q8h 
Placebo to match 
olanzapine 
One capsule with 
chemotherapy 
One capsule 
in the 
morning 
One capsule 
in the 
morning 
One capsule 
in the morning 
 
 
Arm 3 
Agent 
Day 1 
Day 2 
Day 3 
Day 4 
netupitant/palonosetron One 300mg capsule 
approximately one 
hour prior to 
chemotherapy 
 
 
 
Dexamethasone 
12mg PO 30 
minutes prior to 
chemotherapy 
8mg PO in 
the morning 
8mg PO in the 
morning 
8mg PO in 
the morning 
Placebo to match 
prochlorperazine 
One capsule with 
chemotherapy then 
q8h 
One capsule 
q8h 
One capsule 
q8h 
One capsule 
q8h 
Olanzapine 
 
10mg PO with 
chemotherapy 
10mg PO in 
the morning 
10mg PO in 
the morning 
10mg PO in 
the morning 
 
5. 
RESEARCH PROTOCOL/STUDY PROCEDURES 
 
5.1 
Summary of Study Plan 
 
The study consists of two parts with screening and assessments occurring at baseline and 
chemotherapy Cycle 1 and the randomized portion of the study (N = 333) occurring prior to Cycle 
2.  During Cycle 1, we will screen and consent chemotherapy naïve breast cancer patients about 
to begin a chemotherapy regimen that contains doxorubicin, and/or cyclophosphamide, and/or 
carboplatin.  All three of the drugs are commonly given and all have at least moderate 
emetogenic potential.  A key inclusion criterion will be that all patients must be scheduled to 
receive antiemetic drugs recommended in the ASCO guidelines.(1).(1)  We will screen 
approximately  1600 patients, or more if necessary, to meet our Cycle 2 target number.  The 
Cycle 2 portion is conducted in those participants who experience moderate or greater nausea at 
Cycle 1.  This is a Phase III randomized, double-blinded, placebo-controlled, 3-arm study (N = 
333) that builds upon our prior CINV studies and investigates optimal control of CINV in patients 
who experienced CINV following initial chemotherapy.  A blood draw is done prior to Cycle 1 to 
assess biomarkers.   
 
At Cycle 1, all rescue medications with the following exceptions will be allowed for uncontrolled 
chemotherapy-induced nausea and vomiting (CINV).  Use of lorazepam at Cycle 1 only for the 
short-term relief of the symptoms of anxiety, anxiety associated with depressive symptoms, or as 

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a rescue medication for breakthrough CINV is allowed for a maximum of 4 days.  At Cycle 1, use 
of metoclopramide as a rescue medication is not allowed.  At Cycle 2, all rescue medications with 
the exception of metoclopramide and lorazepam will be allowed for uncontrolled chemotherapy-
induced nausea and vomiting (CINV).  We note that these two antiemetics are not allowed 
because benzodiazepines and anticholinergics are excluded from the protocol.  We will document 
the type and days when prescribed rescue medications were taken.   
 
Study Measures  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 

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5.2 
Schedule of Activities 
 
Evaluation/ Procedure 
Registration 
Prior to 
beginning 
chemo-
therapy 
Cycle 1 
chemo-
therapy 
evaluation 
Randomization 
For Eligible 
Participants 
Cycle 2 
chemo-
therapy 
evaluationa 
Informed Consent 
X 
 
 
 
 
Assess Eligibility 
X 
 
 
 
 
Participant Information 
(REDCap new pt record) 
X 
 
 
 
 
Current Prescription 
Medications 
 
X 
 
 
 
Blood Draw for 
Biomarkers 
 
X 
 
 
 
Study Assessments  
 
X 
X 
 
X 
Telephone Contact/AE 
Assessmentb 
 
 
Xc 
 
X 
 
a Cycle 2 assessments are for randomized participants only 
b Telephone calls are made on or close to Day 4 of Cycles 1 and 2 
c Eligibility for randomization at Cycle 2 will be assessed during the Cycle 1 telephone contact. 
 
5.3 
Screening, Baseline and Cycle 1 Assessments 
 
5.3.1 Screening:  Participants will be screened, consented for study participation, 
registered through the URCC NCORP Research Base online participant registration 
system, and entered into REDCap Participant Information.  Participants must be 
registered prior to completing any study procedures or completing any questionnaires. 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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questionnaires to take home as well as a postage-paid envelope.  The participants will 
need to mail the Four-day Home Record as well as any other paper questionnaires that 
were used back to each site in the provided postage-paid envelopes.   
 
5.3.4. The REDCap online survey system is licensed to the University of Rochester.  
The quality of psychological and behavioral data is enhanced through use of REDCap 
because data entry errors due to skip patterns are removed. All participants are given an 
ID code that is linked to their registration ID.  That ID will be used when the final dataset 
is de-identified. This de-identified dataset will be downloaded from the REDCap server 
space onto a password protected server.  REDCap uses encryption algorithms to protect 
participant data.   
 
5.3.5 Phone contact between participant and research team during Cycle 1.   
 
5.3.5.1 Participants will be told that it is very important that they speak to the 
designated member of the research team on or about Day 4 and should expect a 
call from them on Day 4, or just after if Day 4 is a non-work day.  
 
5.3.5.2  The designated member of the research team will initiate a phone call to 
participants on Day 4, or just after if Day 4 is a non-work day.  All reasonable 
efforts must be made to speak to the participant, including making multiple calls if 
necessary.   Note: While leaving a message for the participant to call back is 
permissible, continued attempts to reach the participant must be made even after 
leaving the message. (Permission will be obtained to leave messages on a 
participant’s voicemail before any messages are left.) 
 
5.3.6 The call consists of the following elements:  
 
5.3.6.1 To remind participants to complete the questionnaires and mail back the 
paper forms.  
 
5.3.6.2 To ask the participant if she experienced any adverse events, and if so, to 
obtain relevant details regarding that event(s).  Adverse events must be recorded 
on the Telephone Contact Sheet and reported on the Adverse Event form if 
required as outlined in Sections 11 & 12. 
 
 
5.3.6.3 To determine if the participant is eligible for randomization at Cycle 2 by 
assessing the eligibility criteria in Sections 3.2 and 3.4.   
 
5.3.6.4 If the participant is eligible, to ask the participant if she wishes to 
participate in the randomized portion of the study at Cycle 2.  The participant’s 
response must be recorded on the Telephone Contact Sheet. 
 
5.4 
Intervention/Study Agent 
 
 
 
 
 
 
 
 
) 

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5.4.4. Obtaining Study Agent (Additional Study Drug Information in Section 8) 
 
Study agent will be shipped from the URCC NCORP Research Base to each participating 
NCORP.  In order for the sites to have interventions available upon enrollment, the URCC 
NCORP Research Base will ship study drug for each arm to each site.  Kits will be 
shipped to the designated pharmacy, investigator, or designee, who will be responsible for 
the receipt of the study drug from the research base, storage, and distribution to 
participants.  Distribution and supply will be monitored and recorded using a modified 
version of the standard NCI Investigational Agent Accountability Record. Study drug can 
be requested by emailing the study mailbox at urcc_16070@urmc.rochester.edu. 
 
When ordering, the number of kits of each arm and the study protocol number are 
required. Orders will be express mailed from the research base within 2 working days 
unless notified otherwise.  
 
5.4.5. Agent Disposal 
 
Any study agent returned by participants must be recorded on the Study Agent Return 
REDCap form and destroyed at the NCORP site per their institution’s guidelines.  At the 
completion of this investigation, any study drug left in stock (i.e., not dispensed to a study 
participant) will be destroyed at the NCORP site per their institution’s guidelines and 
recorded on the DARF.  
 
5.5 
Evaluation During the Study Intervention – Cycle 2 Assessments 
 
The same assessments that were used following Cycle 1 will be repeated following Cycle 2.  The 
study ends with the completion of these assessments. 
 
5.5.1 Phone contact between participant and research team during Cycle 2.   
 
5.5.1.1 Participants will be told to expect a call from the designated member of 
the research team on Day 4, or just after if Day 4 is a non-work day.   
 
5.5.1.2  In order to maximize the likelihood of phone contact with the participant, if 
the research team has not heard from the participant by mid-afternoon of Day 4, 
a member of the research team will initiate a phone call to participants on Day 4, 
or just after if Day 4 is a non-work day.  All reasonable efforts must be made to 
speak to the participant, including making multiple calls if necessary.   
 
5.5.2 The call has the following elements,  
 

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5.5.2.1 To remind participants to complete the questionnaires and mail back the 
paper forms.  
 
5.5.2.2 To ask about adverse events.  Adverse events must be recorded on the 
Telephone Contact Sheet and on the Adverse Event form if required as outlined 
in Sections 11 & 12. 
 
5.5.2.3 To record when and how much of the study medication was taken. 
 
5.6  
Blood Draw 
 
 
 
 
   
 
5.6.2 All requisitions, blood tubes, microfuge tubes, freezer boxes, pipettes, and labels 
for blood draws are provided by the URCC NCORP Research Base in the form of 
barcoded and pre-labeled participant kits. All participant kits are study specific.   
 
DO NOT MIX REQUISITIONS, BLOOD TUBES, MICROFUGE TUBES OR PIPETTES 
ACROSS PARTICIPANT BLOOD DRAW KITS EVEN IN THE SAME STUDY BECAUSE 
THE BARCODES AND LABELS ARE KIT SPECIFIC. 
 
DO NOT MIX THE FREEZER BOXES, LABELS OR EXTRA SUPPLIES PROVIDED 
ACROSS STUDIES EVEN URCC NCORP RESEARCH BASE STUDIES BECAUSE 
THEY ARE STUDY SPECIFIC. 
 
5.6.3 All study coordinators will fill in the appropriate participant information on the 
requisition form in each kit when it is assigned to the participant.  Each NCORP is 
responsible for designating an individual that is certified by URCC and a lab or facility that 
meets the biosafety level II criteria to perform the blood draws and to handle, dispose, 
store and ship the blood samples appropriately.   
 
5.6.4 Serum will be extracted from the red top tube for future studies of protein levels 
assessed using Multiplex and ELISA methods as appropriate. To extract the serum, the 
tube will first sit upright for 30 minutes at room temperature after blood collection.  The 
tube will then be put into a centrifuge (4°C if available) and spun for 15 minutes at 1600 x 
g.  After 15 minutes, there should be a clear separation of the serum (yellowish liquid on 
top) from the other cells.  If this is not evident, then centrifuge for 15 additional minutes.  
The upper layer of serum is then gently aliquotted into the pre-labeled pink 2.0ml 
microfuge tubes provided in each URCC NCORP participant blood draw kit. All microfuge 
tubes are then placed in the pre-labeled freezer boxes provided by the URCC NCORP 
Research Base and the freezer box is then placed in either a -20°C freezer or a -80° C 
degree freezer (-80°C is preferred if available but not required) for storage until shipped to 
URCC NCORP Research Base. All blood samples must be shipped to URCC within 3 
months of being drawn.  The serum will be stored and banked for use in future research if 
participants have given permission. 
 
5.6.5 One purple top EDTA tube will be prepared and stored for measurement of GSH 

URCC16070 Protocol Version Date 01/04/2023 
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metabolism. The other purple top EDTA tube and the Paxgene tube will be prepared and 
stored for future DNA and RNA extraction, respectively. The EDTA tubes will be rocked 10 
times and then placed upright in a -20° C freezer for a minimum of 24 hours.  After 24 
hours, the EDTA tubes can then be transferred to a -20° or -80° C freezer if available.  
The Paxgene tube will be rocked 10 times, stored upright for minimum of 2 hours and a 
maximum of 24 hours at room temp and then placed upright in a -20° C freezer for a 
minimum of 72 hours.  After 72 hours, the Paxgene tube can be transferred to a -80° C 
freezer if available.  After the tubes have been frozen upright for their designated time 
above, they can then be placed on their side in the pre-labeled freezer boxes provided by 
the URCC NCORP Research Base.  (Storage in a -80° C freezer after 4 days is preferred 
if available but not required.)  
 
5.6.6 Shipping Supplies to NCORPs and Inventory Tracking:  The participating NCORP 
must notify the URCC NCORP Research Base that they have IRB approval and plan to 
participate. A starter blood drawing package, operations manual, and an initial supply of 
barcoded and pre-labeled blood draw kits will be shipped to the NCORP for distribution 
and use.  
 
Each NCORP site will be responsible for designating someone on the research staff to be 
responsible for receiving the blood draw supplies and kits.  The staff member will verify 
that the shipment contains the correct number of supplies and kits and that the supplies 
and kits are in good condition.  The identification numbers must be verified for accuracy 
and recorded.  The Investigational Device Accountability Record (DARF) will be used to 
track supplies and kits arriving from the URCC NCORP Research Base, kits given to 
participants, samples stored, and samples shipped to the URCC NCORP Research Base. 
 
5.6.7 Shipping Frozen Blood Samples to URCC NCORP Research Base: 
 
THE URCC NCORP RESEARCH BASE MUST BE NOTIFIED AND ARRANGEMENTS 
MADE TO RECEIVE SAMPLES AT THE URCC NCORP RESEARCH BASE 24 HOURS 
IN ADVANCE PRIOR TO SHIPPING ANY SAMPLES 
 
WE WILL NOT ACCEPT PACKAGES TO BE RECEIVED ON A FRIDAY. 
 
To arrange shipping samples, please submit a request to our lab via REDCap survey 
(https://redcap.urmc.rochester.edu/redcap/surveys/?s=3A3TM83ERD). Our lab will 
approve of a shipping date based upon availability. 
 
Ship Samples To: 
ATTN: Cancer Control 
University of Rochester Medical Center 
CCPL Laboratory (2-3155) 
601 Elmwood Avenue 
Rochester, NY 14642 
 
Samples must be stored frozen and shipped within 3 months.  Samples can be shipped 
sooner if storage space is limited.   
 
The NCORPs are responsible for shipping all samples to the URCC NCORP Research 
Base.  All samples must be shipped priority overnight and frozen on dry ice.  Each 
NCORP is responsible for adhering to the Code of Federal Regulations guidelines when 
packing and shipping the frozen blood samples to the research base.         
 
5.7 
There Will Be No Follow-up Assessments 

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5.8 
Reported Adverse Events and Potential Risks 
 
5.8.1 The risks related to the study medication are described in Sections 8.7 – 8.10. 
 
5.8.2 There is a chance of bruising and a very slight chance of infection with blood 
collection.  This will be minimized through the use of standardized hospital procedures for 
blood collection, use of a trained phlebotomist, and sterile materials. 
 
5.8.3 For any clinically adverse event, the toxicity grading scale established by the FDA 
will be used.  It is as follows:  
• 
Grade 1 toxicity (Mild): No interference with activity 
• 
Grade 2 toxicity (Moderate): Some interference with activity not requiring 
medical intervention. 
• 
Grade 3 toxicity (Severe): Prevents daily activity and requires medical 
intervention. 
• 
Grade 4 toxicity (Potentially Life Threatening): ER visit or hospitalization. 
 
5.8.4  Adverse events will be reported as per Sections 11 and 12. 
 
5.9 
 Participant Withdrawal  
 
If a study participant decides to voluntarily withdraw from the study, the study staff should ask her 
to clarify whether she wishes to withdraw from all components of the study or only from a single 
component of the study. If she requests to be withdrawn from a component of the study (e.g., 
study agent), research activities involving other components of the clinical trial, such as data 
collection activities, for which the participant previously gave consent, may continue. Any 
withdrawals or partial withdrawals are documented on the REDCap Withdrawal Form.  Note: 
Completing this form is not required for participants who completed Cycle 1 of the study but did 
not meet the eligibility requirements to advance to the randomized portion of the study at Cycle 2.  
 
5.10 
Emergency Study Agent Disclosure 
 
The research pharmacist at each NCORP will not know what medications each participant 
received. Unblinding of the study agent is ONLY permitted in the case of serious and unexpected 
adverse events that are definitely, probably or possibly associated with the use of the study agent 
AND if knowledge of the study treatment arm received is necessary for interpreting the medical 
event and related treatment of that medical event.  Participants will not be withdrawn from the 
analyses should drug disclosure occur. Refer to section 8.6 for further information regarding the 
unblinding process. 
 
5.11 
Data & Specimen Banking for Future Research Use 
 
 
 
 
 
5.12 
Genetic/Genomic Research Activities 
 
 
 

 
 
 
 
 
 
5.13 
Costs to the Participant 
 
There will be no extra cost to participants for participating in the study. All study medications will 
be provided at no cost to participants. 
  
5.14 
Payment for Participation 
 
Participants will not receive remuneration for taking part in the study. 
 
6. 
INTERVENTION/STUDY AGENT ADMINISTRATION AND INFORMATION 
 
6.1 
Contraindications 
 
Because the co-administration of benzodiazepines (CNS depression) or anticholinergic 
medications (delirium) may cause clinically significant interactions with olanzapine(25), patients 
taking those medications regularly will be ineligible for the study.  PRN use is allowed.  The 
NCCN antiemetic guidelines(11) state that olanzapine should be used with caution in elderly 
patients, patients with dementia-related psychosis and patients with type II diabetes and 
hyperglycemia.  As a precaution, we will therefore exclude patients with dementia-related 
psychosis, uncontrolled diabetes mellitus or uncontrolled hyperglycemia from participating in the 
study, and use caution when putting elderly patients on the study. 
 
6.2 
Current Prescription Medications 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
6.3 
Dose Modification 
 
There will be no dose modifications in this study. 
 
6.4 
Adherence/Compliance 
 
6.4.1 All participants who provide evaluable data will be included in the analyses. 
 
6.4.2 Compliance with taking the study medication will be assessed at the Cycle 2 
phone contact.  
 
7.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 

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7.1 
Primary Endpoint 
 
The primary outcome variable will be Average Nausea (measured on a 7-point scale anchored by 
“Not at all Nauseated” and “Extremely Nauseated”) defined as the average nausea rating across 
15 assessment points (i.e., the afternoon, evening, and night reporting periods on Day 1 and the 
morning, afternoon, evening, and night reporting periods on Days 2 – 4.  In the event that data 
are missing from eleven or more of the fifteen nausea assessment points, we will set the score to 
missing. 
 
7.2 
Secondary Endpoints 
 
The outcome variable for secondary aim 1 will be average nausea as described above. The 
outcome variable for secondary aims 2 and 3 will be Any Vomiting (yes/no). 
 
7.3 
Off-Agent Criteria  
 
Participants may stop taking study agent for the following reasons: completed the protocol-
prescribed intervention, adverse event or serious adverse event, inadequate agent supply, 
noncompliance, concomitant medications, or medical contraindication. Participants will continue 
to be followed, if possible, for safety reasons and in order to collect endpoint data according to 
the schedule of events.  
 
7.4 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any 
protocol-required follow-up period is completed, adverse event/serious adverse event, lost to 
follow-up, non-compliance, concomitant medication, medical contraindication, withdrawal of 
consent, death, determination of ineligibility - does not require withdrawal (including screen 
failure), physician request, or pregnancy. 
 
8.  
STUDY AGENT/ DISTRIBUTION 
 
8.1 
Availability 
 
All study medications provided to participants in Cycle 2 are FDA approved or commonly used for 
the treatment and prevention of chemotherapy-related nausea and vomiting.   There are no 
investigational agents, but two of the medications. i.e., prochlorperazine and olanzapine will be 
placebo-controlled and receipt of them will be randomized.  Two additional medications, i.e., 
Akynzeo® and dexamethasone, will be provided unblinded to all participants at Cycle 2.  No 
medications are provided at Cycle 1.   
 
Akynzeo® is distributed and marketed by Helsinn Therapeutics (U.S.) Inc., of Iselin, New Jersey, 
under license from Lugano, Switzerland-based Helsinn Healthcare S.A.  Helsinn Therapeutics will 
provide the Investigational Drug Service (IDS) within the Department of Pharmacy at the 
University of Rochester Medical Center sufficient quantity of Akynzeo® to run the study.  The IDS 
will procure the remaining study medications and will, in turn, provide all four of the study 
medications and matching placebo as described below to the affiliate NCORP sites.    
 
8.2 
Distribution 
 
The study medication will only be released by the research base after IRB approval of the 
protocol and consent documents are received and the NCORP is approved to participate.  
 

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URCC-supplied agents must be requested by the Pharmacist, Investigator (or their authorized 
designees) at each NCORP.  The URCC does not automatically ship agents; the site must make 
a request. Study drug can be requested by emailing the study mailbox at 
urcc_16070@urmc.rochester.edu and should include complete shipping and contact information.  
 
8.3  
Agent Accountability 
 
The NCORP site, and responsible party designated at the site, must maintain a careful record of 
the inventory and disposition of all agents received from the URCC NCORP Research Base using 
the Investigational Agent Accountability Record (DARF). The NCORP site is required to maintain 
accurate records of receipt, dispensing and final disposition of study agent. Included on the DARF 
should be a record from whom the agent was received and to whom study agent was shipped, 
date, quantity and batch or lot number. 
 
8.4 
Packaging, Labeling and Shipping of Study Medication 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 

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8.5 
Storage 
 
All of the study agents should be stored at room temperature, between 68°F and 77°F (20°C and 
25°C), away from heat, moisture, and light.  
 
8.6 
Blinding and Unblinding Methods 
 
Participants, study coordinators, and investigators will be blinded to prochlorperazine/placebo 
group and the olanzapine/placebo group assignments.  Study agents supplied to NCORPs will be 
labeled with a letter code that will be used to identify the assigned treatment arm for unblinding 
purposes. An unblinding key will be kept by IDS. 
 
Unblinding of the study agent is ONLY permitted in the case of serious and unexpected adverse 
events that are definitely, probably or possibly associated with the use of the study agent AND if 
knowledge of the study treatment arm received is necessary for interpreting the medical event 
and related treatment of that medical event. In such cases, the treating M.D. or their designee 
can be given the treatment group assignment from the University of Rochester Investigational 
Drug Service. Documentation should be sent to the email address below and include participant 
ID number, site investigator, and reason for unblinding in the message: 
 
Kari Gilliland  
kari_gilliland@urmc.rochester.edu 
585-275-1364 
 
Participants that require emergency study agent disclosure will discontinue the study agent. The 
research team may continue to follow the study participant for assessment data with participant 
and treating physician approval.   
 
8.7 
 
 

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8.9.6 Warnings and Precautions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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about 30% of patients. 
 
 
 
 
). 
 

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9. 
CORRELATIVE/SPECIAL STUDIES 
NA 
 
10.0 
SPECIMEN MANAGEMENT  
 
10.1 
Laboratories 
 
All samples will be stored at the URMC Cancer Control and Psychoneuroimmunology Laboratory 
in a URCC NCORP Research Base secure and alarmed -80C freezer. 
 
10.2 
Specimen Banking 
 
Blood samples will be stored for use in future research at the URMC Cancer Control and 
Psychoneuroimmunology laboratory.   
 
10.3 
Shipping Instructions 
See Sections 5.6.6 and 5.6.7 
 
10.4 
Tissue Banking 
 
NA 
 
11.0 CYCLE 1 AE REPORTING - REPORTING ADVERSE EVENTS FOR BASELINE AND 
CHEMOTHERAPY CYCLE 1 PORTION OF THE STUDY.   
 
Note: The reporting of adverse events for the Cycle 2 portion of the study, i.e., the 

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randomized phase at chemotherapy cycle 2 is described in Section 12 below. 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized.  All appropriate treatment areas should have access to the CTCAE version 5.0.  The 
CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
The relationship to the study agent and the severity of each adverse event as judged by the 
investigator must be recorded.  Attribution to protocol treatment for each adverse event must be 
determined by the investigator and reported on the required forms, using the codes provided. 
 
11.1 
Any adverse event (AE) that is possibly, probably, or definitely related to the study 
questionnaires or to the study blood draw will be reported according to the guidelines below:   
 
11.1.1 As this portion of the study is a survey with no intervention, any AE that occurs 
during baseline or the first chemotherapy cycle that is not possibly, probably, or definitely 
related to the study questionnaires or to the study blood draw, with the exception of 
death within 30 days, will not be reported.  
 
11.2 
Definitions 
 
Adverse event (AE) is any untoward medical occurrence associated with the use of a medical 
product, which does not necessarily have a causal relationship with its use.  An adverse event 
can be any unfavorable and unintended sign (including abnormal laboratory test results), 
symptom, or disease temporally associated with the use of the study product or not considered 
related to the study product.  The relationship of each adverse event to the study interventions 
must be recorded as one of the choices on the scale described below. 
 
Attribution:  An assessment of the relationship between the adverse event and study 
agent/intervention, using the following categories. 
 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to the study  questionnaires or 
blood draw 
Unlikely  
The AE is doubtfully related to study questionnaires or blood 
draw 
Possible 
The AE may be related to study questionnaires or blood draw 
Probable 
The AE is likely related to study questionnaires or blood draw 
Definite 
The AE is clearly related to study questionnaires or blood 
draw 
 
Serious Adverse Event (SAE):  A serious adverse event is defined as any adverse medical 
event (experience) that results in at least one of the outcomes listed below: 
1) Death 
2) Life-threatening 
3) Requires inpatient hospitalization or prolongation of existing hospitalization. 
4) Results in persistent or significant disability/incapacity with substantial disruption of the 
ability to conduct normal life functions. 
5) Congenital anomaly/birth defect. 
6) A medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon medical judgment, it may 

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jeopardize the patient or participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
 
Hospitalization (or prolongation of hospitalization):  For AE reporting purposes, a 
hospitalization is defined as an inpatient hospital stay equal to or greater than 24 hours. 
 
11.3 
Reporting Adverse Events for Baseline and Chemotherapy Cycle 1 
 
Note: The reporting of adverse events for the Cycle 2 portion of the study, i.e., the 
randomized phase at chemotherapy cycle 2 is described in Section 12 below. 
 
All adverse events, whether observed by study staff or investigator, elicited from or volunteered 
by the participant that is possibly, probably, or definitely related to the study questionnaires or 
to the study blood draw should be documented.  Each adverse event will include the date of 
onset, date of resolution, severity, and any action taken. 
 
Recording of the adverse events will occur once the participant signs the consent form.  
 
Adverse events will be reported to the URCC NCORP Research Base using REDCap.  The 
following table will be utilized to report adverse events at baseline and the Cycle 1 portion of the 
study: 
 
Adverse Event – for Baseline and Cycle 1 portion of the study 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
 
 
 
Unlikely 
       
 
       
       
Possible 
URCC 
URCC 
URCC 
URCC 
URCC 
Probable 
URCC 
URCC 
URCC 
URCC 
URCC 
Definite 
URCC 
URCC 
URCC 
URCC 
URCC 
 
All adverse events will be reported to the URCC NCORP Research Base via REDCap. Serious 
adverse events requiring expedited reporting via CTEP-AERS are described below in Section 
11.4.  Serious adverse events (described in section 11.2) not requiring expedited reporting 
through CTEP-AERS should be entered into REDCap within 10 calendar days of learning of the 
event. 
 
11.4 
Responsibilities for Expedited Reporting  
 
URCC NCORP Research Base affiliates are required to notify the URCC Research Base if a 
participant has an adverse event requiring expedited reporting.  All SAEs that meet expedited 
reporting criteria defined in the reporting table below will be reported via CTEP-AERS, the 
Adverse Event Expedited Reporting System, accessed via the CTEP web site, https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task  
 
Attribution 
Grade 4 
Grade 5b 
 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or Unlikely  
 
 
CTEP-AERSa 
CTEP-AERSa 
Possible, Probable, 
Definite 
CTEP-AERSa 
CTEP-AERSa 
CTEP-AERSa 
CTEP-AERSa 
a Indicates an expedited report is to be submitted via CTEP-AERS within 10 calendar days of learning of 
the event. 
b Includes all deaths within 30 days of the blood draw or completing the  questionnaires, regardless of 
attribution.  Any death that occurs more than 30 days after the blood draw or completing the questionnaires 

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and is attributed (possibly, probably or definitely) to them and is not due to cancer recurrence must be 
reported according to the instructions above. 
 
Submission of the on-line CTEP-AERS report plus any necessary amendments generally 
completes the reporting requirements.  You may, however, be asked to submit supporting clinical 
data to the Research Base in order to complete the evaluation of the event.   
For more information see: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
 
Contact Information for NCI Safety Reporting: 
Website for submitting 
expedited reports 
http://eapps-ctep.nci.nih.gov/ctepaers  
AEMD Help Desk (for CTEP)* 
301-897-7497 Monday through Friday, 7:00 AM to 7:00 PM 
(US Eastern Time) 
Fax for expedited report 
supporting Medical 
Documentation for CTEP Trials 
301-230-0159  
(Back-up FAX: 301-897-7404) 
AEMD Help Email: 
aemd@tech-res.com 
Technical (E.G., IT or 
computer issues ONLY) Help 
Phone * 
1-888-283-7457 or 301-840-8202 
CTEP-AERS Technical Help 
Email 
ncictephelp@ctep.nci.nih.gov 
CTCAE v 5 Help/Questions 
Email 
ncicctcaehelp@mail.nih.gov 
CTEP-AERS FAQs link 
https://ctepcore.nci.nih.gov/ctepaers/help/webhelp/help%20-
%20frequently%20asked%20questions.htm 
CTEP-AERS Computer based 
training link 
https://ctep.cancer.gov/protocolDevelopment/ 
electronic_applications/adverse_events.htm 
Office phone and fax are accessible 24 hours per day 7 days a week (The AEMD phone line is 
staffed from Monday through Friday, 7:00 AM to 7:00 PM ET. Any phone call after these hours 
will go to voicemail. Please leave contact information and the phone call will be returned the 
following business day.) 
 
12.0 
CYCLE 2 AE REPORTING - REPORTING ADVERSE EVENTS FOR THE CYCLE 2 
PORTION OF THE STUDY.   
 
Note: The reporting of adverse events for the Cycle 1 portion of the study, i.e., the survey 
at chemotherapy cycle 1 is described in Section 11 above. 
 
CTCAE term (AE description) and grade:  CTCAE version 5.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to the CTCAE version 5.0.  The CTCAE version 
5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
The relationship to the study agent and the severity of each adverse event as judged by the 
investigator must be recorded.  Attribution to protocol treatment for each adverse event must be 
determined by the investigator and reported on the required forms, using the codes provided. 
 
12.1 
Adverse event (AE) is any untoward medical occurrence associated with the use of a 
medical product, which does not necessarily have a causal relationship with its use.  An adverse 
event can be any unfavorable and unintended sign (including abnormal laboratory test results), 
symptom, or disease temporally associated with the use of the study product or not considered 

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related to the study product.  The relationship of each adverse event to the study interventions 
must be recorded as one of the choices on the scale described below. 
 
Attribution:  An assessment of the relationship between the adverse event and study 
agent/intervention, using the following categories. 
 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to the study agent (or 
product)/intervention 
Unlikely  
The AE is doubtfully related to study agent /intervention 
Possible 
The AE may be related to study agent/intervention 
Probable 
The AE is likely related to study agent/intervention 
Definite 
The AE is clearly related to study agent/intervention 
 
12.2 
Serious Adverse Event (SAE):  A serious adverse event is defined as any adverse 
medical event (experience) that results in at least one of the outcomes listed below: 
1) 
Death 
2) 
Life-threatening 
3) 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
4) 
Results in persistent or significant disability/incapacity with substantial disruption of 
the ability to conduct normal life functions. 
5) 
Congenital anomaly/birth defect. 
6) 
A medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon medical judgment, it 
may jeopardize the patient or participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
Hospitalization (or prolongation of hospitalization):  For AE reporting purposes, a 
hospitalization is defined as an inpatient hospital stay equal to or greater than 24 hours. 
 
12.3 
Reporting Adverse Events 
 
Note: The reporting of adverse events for the Cycle 1 portion of the study, i.e., the survey 
at chemotherapy cycle 1 is described in Section 11 above. 
 
All adverse events, whether observed by study staff or investigator, elicited from or volunteered 
by the participant, should be documented.  Each adverse event will include the date of onset, 
date of resolution, severity, and the relationship to the study agent or intervention, and any 
action taken with respect to the study agent or intervention. 
 
Adverse events will be reported to the URCC NCORP Research Base using REDCap.  The 
following table will be utilized to report adverse events: 
 
Adverse Event – for Cycle 2 portion of the study 
 
Grade 
1 
Grade 
2 
Grade 
3 
Grade 
4 
Grade 
5 
Unrelated 
 
 
URCC 
URCC 
URCC 
Unlikely 
       
 
URCC 
URCC 
URCC 
Possible 
URCC 
URCC 
URCC 
URCC 
URCC 
Probable 
URCC 
URCC 
URCC 
URCC 
URCC 
Definite 
URCC 
URCC 
URCC 
URCC 
URCC 
 
All adverse events will be reported to the URCC NCORP Research Base on the Adverse Event 

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Report Form in REDCap. Serious adverse events requiring expedited reporting via CTEP-AERS 
are described below in Section 12.4.  Serious adverse events (described in section 12.2) not 
requiring expedited reporting through CTEP-AERS should be entered into REDCap within 10 
calendar days of learning of the event. 
 
**Any rash, regardless of attribution should be reported.** See section 8.7.5 
 
All adverse events reported to the URCC Research Base will be reported to the Data Safety 
Monitoring Committee. 
 
12.4 
Responsibilities for Expedited Reporting  
 
URCC NCORP Research Base affiliates are required to notify the URCC Research Base if a 
participant has an adverse event requiring expedited reporting.  All SAEs that meet expedited 
reporting criteria defined in the reporting table below will be reported via CTEP-AERS, the 
Adverse Event Expedited Reporting System, accessed via the CTEP web site, https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task  
 
Commercial reporting requirements are provided in the table below.  The commercial agents 
used in this study are netupitant/palonosetron, olanzapine, prochlorperazine and dexamethasone.  
 
Expedited reporting requirements for adverse events experienced by participants who 
have received study agent/intervention within 30 days of the last administration of 
commercial study agent/intervention should be reported as follow:   
 
Attribution 
Grade 4 
Grade 5b 
 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or Unlikely 
 
 
CTEP-AERSa 
CTEP-AERSa 
Possible, Probable, 
Definite 
CTEP-AERSa 
CTEP-
AERSa 
CTEP-AERSa 
CTEP-AERSa 
a Indicates an expedited report is to be submitted via CTEP-AERS within 10 calendar days of learning of 
the event. 
b This includes all deaths within 30 days of the last dose of study agent with a commercial 
agent/intervention, regardless of attribution.  Any death that occurs more than 30 days after the last dose of 
study commercial agent/intervention and is attributed (possibly, probably or definitely) to the 
agent/intervention and is not due to cancer recurrence must be reported according to the instructions 
above. 
 
Submission of the on-line CTEP-AERS report plus any necessary amendments generally 
completes the reporting requirements.  You may, however, be asked to submit supporting clinical 
data to the Research Base in order to complete the evaluation of the event.   
For more information see: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
 
Contact Information for NCI Safety Reporting: 
Website for submitting expedited 
reports 
http://eapps-ctep.nci.nih.gov/ctepaers  
AEMD Help Desk (for CTEP)* 
301-897-7497 Monday through Friday, 7:00 AM to 7:00 PM 
(US Eastern Time) 
Fax for expedited report supporting 
Medical Documentation for CTEP 
Trials 
301-230-0159  
(Back-up FAX: 301-897-7404) 
AEMD Help Email: 
aemd@tech-res.com 

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Technical (E.G., IT or computer 
issues ONLY) Help Phone * 
1-888-283-7457 or 301-840-8202 
CTEP-AERS Technical Help Email 
ncictephelp@ctep.nci.nih.gov 
CTCAE v 5 Help/Questions Email 
ncicctcaehelp@mail.nih.gov 
CTEP-AERS FAQs link 
https://ctepcore.nci.nih.gov/ctepaers/help/webhelp/help%20-
%20frequently%20asked%20questions.htm 
CTEP-AERS Computer based 
training link 
https://ctep.cancer.gov/protocolDevelopment/ 
electronic_applications/adverse_events.htm 
Office phone and fax are accessible 24 hours per day 7 days a week (The AEMD phone line is 
staffed from Monday through Friday, 7:00 AM to 7:00 PM ET. Any phone call after these hours 
will go to voicemail. Please leave contact information and the phone call will be returned the 
following business day.) 
 
Additional Instructions: 
• 
Rash, regardless of grade or attribution should be reported.  
• 
All pregnancies occurring in female participants during therapy or within 28 days after 
completion of treatment on URCC 16070  must be reported via CTEP-AERS using the 
event term “pregnancy, puerperium and perinatal conditions – other, pregnancy (grade 3). 
• 
CTEP-AERS reports should be amended upon completion of the pregnancy to report 
pregnancy outcome (e.g., normal, spontaneous abortion, therapeutic abortion, fetal death, 
congenital abnormalities). 
• 
The CTEP-AERS report should be amended for any neonatal deaths or complications 
occurring within 28 days of birth independent of attribution.  Infant deaths occurring after 
28 days considered to be related to in utero to the agent used in this trial should be 
reported via CTEP-AERS. 
 
13. 
STUDY MONITORING 
 
13.1 
Data Management Summary 
This project will collect data in the following formats: paper documents, REDCap electronic 
questionnaires, and biospecimens (blood). 
 
13.1.1 Paper data are entered electronically at the NCORP site as soon as they are 
collected by the study coordinator through the secure REDCap system, following the 
URCC16070 REDCap Manual available on the protocol page of the URCC NCORP 
Research Base website and processed as follows: 
 
1. 
Paper data are visually checked by the site coordinator line by line for missing, 
duplicate, ambiguous or unreasonable responses and if found, they will be corrected 
prior to electronic data entry. 
2. 
The coordinator will log in to the REDCap system with their uniquely assigned 
credentials, open the participant’s record and enter the data. 
3. 
All paper forms will be uploaded electronically to the URCC NCORP Research Base 
through REDCap and a copy kept on site. 
4. 
All data entered in REDCap will be double-checked against the corresponding paper 
form for inconsistencies and checked for missing, ambiguous or unreasonable 
responses by the research base. If found, the originating site will be queried for such 
data.  
5. 
One copy of the amended paper form stays on site and an electronic copy must be 
included in the query response sent to the URCC. Data are amended per GCP on the 
paper form and in REDCap, and the change is documented at the research base.  
6. 
Queries are also generated if data are not received per the protocol timeline. 
7. 
When all data have been received on any given case, a chart audit is performed at 

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the research base to ensure receipt and accuracy of all required data. 
8. 
All paper documents are stored in locked file cabinets or in locked, limited access file 
rooms. The REDCap database of those documents is stored on protected servers 
located behind University of Rochester firewalls, with limited access. 
 
13.1.2 REDCap data are entered electronically and processed as follows: 
 
1. 
All REDCap questionnaires are directly filled out electronically by either the 
participant at home or the coordinator at the site. 
2. 
Data are visually checked in the REDCap system at the URCC NCORP Research 
Base for ambiguous or unreasonable responses, and if found, the originating site is 
queried for such data.  
3. 
When a query response is received, REDCap data are amended per GCP, and the 
change is documented.  
4. 
Queries are also generated if data are not received per the protocol timeline. 
5. 
When all data have been received on any given case, a REDCap database audit is 
performed to ensure receipt and accuracy of all required data. 
6. 
The REDCap database of those electronic questionnaires is stored on protected 
servers located behind University of Rochester firewalls, with limited access. 
 
13.1.3 Biospecimens:  Blood kits sent from URCC have bar-coded tubes for collecting 
samples.  One kit is used for one data collection time point of one participant.  Samples 
are frozen on site and shipped frozen to URCC on dry ice where they are stored in locked 
-80o freezers in a research base lab with limited access.  
 
13.2 
On-site audits are conducted at least every three years in accordance with NIH/NCI 
CTMB Guidelines.  The primary objective of an on-site audit is to document compliance of the 
NCORP site with protocol and regulatory requirements, to verify accuracy of data by comparing 
submitted data to source documents at the NCORP site, and to provide information on good 
clinical practices in study conduct and data management.  The equivalent of 10% of cases 
accrued at each component site is audited.  The on-site pharmacy is also audited at that time.  
 
 
 

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13.3 
Records To Be Kept 
 
 
 
SCHEDULE OF DATA 
COLLECTION 
FORMS 
Baseline(Pre-
chemotherapy  
After 
Chemotherapy 
Cycle 1 
After 
Chemotherapy 
Cycle 2 for 
Randomized 
Participants 
Only 
COMPLETED BY PARTICIPANT 
On-Study Form1 
X 
 
 
Functional Assessment of Cancer Therapy 
Scale-General (FACT-G)1 
X 
X 
X 
Medical Symptom Checklist1 
X 
X 
X 
MASCC Antiemesis Tool (MAT)1 
 
X 
X 
Four-Day Home Record (nausea, vomiting, 
rescue medication use, fatigue, anxiety, 
dizziness, and sleep disturbance)2 
 
X 
X 
Medication Diary 
 
 
X 
COVID Effects 
X 
 
X 
COMPLETED BY COORDINATOR 
Consent Form3  
X 
 
 
REDCap Participant Information4 (must be 
completed immediately following 
registration) 
X 
 
 
Eligibility Checklist3 
X 
X(for Cycle 2) 
 
Blood Requisition Form3 
X 
 
 
REDCap Current Prescription Medications4 
X 
 
 
REDCap Case Summary Form4 
X 
X 
X 
 
 
 
 
Randomization 
 
X 
 
Chemotherapy and Supportive Care Records 
(copy from medical record)3 
 
X 
X 
Telephone Contact Sheet3 
 
X 
X 
REDCap Adverse Event4 
X 
X 
X 
REDCap Investigational Agent Return Form4 
 
 
X 
1 Paper versions of these forms are available for those participants opting out of using REDCap. 
2 Paper version only, coordinator will enter data into REDCap at the NCORP site. 
3 Paper version only, to be submitted to URCC via scanned PDF or US mail.  
4 REDCAP version only, no paper version.  SAEs will be reported through CTEP-AERs per 
Section 11 and 12. 
 
13.4 
Data and Safety Monitoring Plan 
 
All adverse events reported to URCC are per Sections 11 and 12.   

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The James P Wilmot Cancer Center Data Safety Monitoring Committee (DSMC) will serve as the 
DSMC of record for this study. The DSMC provides oversight of study progress and safety by 
review of accrual and events at regularly scheduled meetings.   
 
Study investigators conduct continuous review of data and patient safety. The Wilmot Cancer 
Center Peer Review Committee has determined that progress reports of these data will be 
submitted annually to the DSMC for review. These reports will include: the number of participants 
enrolled, withdrawals, any significant toxicities, and serious adverse events both expected and 
unexpected. The research base maintains a database of all adverse events with toxicity grade 
and information regarding treatment required, complications, or sequelae.  A copy of the AE 
spreadsheet is submitted with the annual progress report to the DSMC for review.  
 
• 
Any adverse event that is serious, related AND unexpected must be reported within 10 
calendar days from notification to the DSMC safety coordinator and DSMC chair.  The 
NCORP sites will report to the URCC NCORP Research Base and if applicable CTEP AERS 
per Sections 11 and 12 of the protocol.  The NCORP Research Base will be responsible for 
reporting to the DSMC. The DSMC Chair will determine whether further action is required, 
and when patient safety is of concern, may call an interim meeting. 
 
• 
Serious adverse events that are related AND expected or unrelated AND unexpected will be 
reported to the Committee for review at the annual meeting. SAE reports are expected to 
include sufficient detail so that the DSMC can determine the severity, toxicity grade, 
expectedness, treatment required, and a follow up report documenting resolution or if there 
are sequelae. Unless otherwise specified in the protocol, serious adverse events that require 
reporting (but not necessarily expedited) are expected, related, non-hematologic toxicities of 
grades 3, 4 or 5. See Sections 11 and 12 for specific reporting requirements for this protocol.  
 
The Data Safety Monitoring Committee provides oversight of study progress and safety by review 
of accrual and events at regularly scheduled meetings. The DSMC will monitor all adverse event 
rates utilizing a cumulative spreadsheet listing of events submitted along with progress reports by 
the PI.  All serious adverse events that have occurred in the prior 3 months will be reviewed at  
the DSMC’s regularly scheduled quarterly meeting in order to confirm toxicity grade, 
expectedness, relatedness, sequelae, follow up required, and risk to current or future subjects. 
 
The URCC will notify the NCORP sites immediately of any serious safety concerns identified by 
the DSMC.  DSMC reports will be available for download on the research base website. 
 
13.5 
Record Retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing 
evidence to study eligibility, history and physical findings, laboratory data, results of consultations, 
etc.), as well as IRB records and other regulatory documentation will be retained by the 
Investigator in a secure storage facility in compliance with Health Insurance Portability and 
Accountability Act (HIPAA), Office of Human Research Protections (OHRP), Food and Drug 
Administration (FDA) regulations and guidances, and NCI/DCP requirements, unless the 
standard at the site is more stringent. For NCI/DCP, records will be retained for at least five years 
after the completion of the research. The records must be accessible for inspection and copying 
by authorized persons of the Food and Drug Administration and the URCC Research Base. 
 
14. 
STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design/Description 
 

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The Cycle 2 portion will be conducted in those participants who experienced moderate or greater 
nausea at Cycle 1.  It will be a Phase III randomized, double-blinded, placebo-controlled clinical 
trial of an intervention examining the efficacy of the three treatment arms for control of CINV.  
 
14.2 
Data Handling 
 
Data will be analyzed as intent-to-treat. The assumptions underlying all statistical analyses will be 
thoroughly checked using appropriate graphical and numerical methods.(42,43)  In the case of 
serious violations of the assumptions, appropriate nonparametric methods or transformations will 
be attempted.(44,45)  In the event of outlying observations, we will carefully check the data and 
make corrections if necessary.  If no errors are found, we will conduct analyses both with and 
without the outlying data and report both results to assess the sensitivity.  All hypothesis testing 
will be performed at the two-sided 0.05 level, with the exception of the Primary Analysis, which 
will use the 0.05/2=0.025 level.  SAS, JMP and R will be used for the analyses as appropriate. 
 
14.3 
Sample Size and Power 
 
Sample Size: The number of participants needed for the randomized portion of the study will be 
111 participants per arm, or 333 total.  The accrual necessary at Cycle 1 to have 333 eligible 
participants for the randomized portion of the trial at Cycle 2 will be1600.  These numbers are 
derived based upon data from Preliminary Study 2.  In that study, 46.1% of the randomized 
participants reported Peak Nausea of ≥ 3, the nausea eligibility criterion for this study.  Using that 
number, in order to have 333 eligible participants at Cycle 2, we will need to accrue 724 
participants at Cycle 1.  We conservatively assume that 10% of the Cycle 1 participants who 
would be eligible for the randomized portion of the study at Cycle 2 will decide not to continue 
with the study, so we will increase our targeted accrual at Cycle 1 by 10% to 796 participants.  
We rounded this number to 800 for our projected recruitment at Cycle 1 and will recruit additional 
participants beyond the projected 800, if necessary, to reach our Cycle 2 target of 333 
randomized participants. In summary, we anticipate approximately 28% of patients screened 
during Cycle 1 to enroll for the randomized portion of the study. Eligible patients willing to 
continue on the study, will be immediately following the assessment of CINV after Cycle 1 of 
chemotherapy randomized to continue on the study. Randomized portion of the study starts at 
Cycle 2 of chemotherapy. Following URCC Research Base standard operation procedures, data 
are evaluated for quality immediately upon its receipt. Moreover, the statistical group routinely 
performs data quality checks to identify problems so corrective action can be taken early. 
Therefore, we anticipate the data analysis to begin 4-6 weeks after full enrollment is completed 
and data has matured. 
 
Update 04/29/2020: Based on the first 517 subject, 214 were eligible for Cycle 2 for 41.4%, falling 
slightly below of our preliminary estimate of 46.1%. Of the 214 subjects eligible for Cycle 2, only 
135 (63%) decided to continue with the study. We had assumed a maximum of 10% would not 
continue with the study, while in reality 37% of subjects did not continue the study. Therefore, it is 
necessary to increase our Cycle 1 accrual to 1,200 subjects in order to meet our Cycle 2 target of 
333 randomized participants, as the majority of our statistical assumptions are based on that 
sample size. 
 
Update 08/01/2022: Based on the first 1,084 subjects, 413 were eligible for Cycle 2 for 39.0%, 
falling slightly below of our preliminary estimate of 41.1%. Of the 413 subjects eligible for Cycle 2, 
only 241 (58%) decided to continue with the study. We had assumed a maximum of 10% would 
not continue with the study, while in reality 42% of subjects did not continue the study. Therefore, 
with recruiting 1500 patients for Cycle 1, it is expected on average (probability 50%) that =333 will 
enroll for Cycle 2. To ensure high probability to reach the targeted goal n=333 for Cycle 2, we 
propose to recruit n=1600 for Cycle 1. Recruiting n=1600 patients for Cycle 1 provides 90% 
probability to meet our Cycle 2 target of 333 randomized participants, as the majority of our 

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statistical assumptions are based on that sample size. 
 
Power:  Our target accrual of evaluable participants for the randomized portion of the study is 
100 participants per arm.  We conservatively assume that 10% of randomized participants will fail 
to provide evaluable data so we will recruit 111 participants per arm, or 333 total.  The standard 
deviation and pre-post correlation for average nausea at cycle 2 for 35 participants in an ongoing 
R01 examining acupressure bands in addition to standard antiemetics in breast cancer patients 
beginning chemotherapy who had nausea of >= 3 at cycle 1 and provided data at cycle 2 and did 
not use acupressure bands were 0.953 and 0.5, respectively.   
 
For the Primary aim, we will use a one-way analysis of variance on Post – Pre change scores. 
We have Arms 1 (control), 2, and 3. Two tests will be done using contrasts: 1 vs. 2 and 1 vs. 3, 
and a significance level of 0.05 / 2 = 0.025. Using the numbers above, we estimate the SD of the 
change scores to be 0.953, conservatively assuming a pre-post correlation of 0.5. When the 
sample size in each of the 3 groups is 100, we calculate that our planned one-way analysis of 
variance will have 90% power to detect a difference in means of 0.48, or a half standard 
deviation. In light of the fact that there are no minimum clinically important difference (MCID) 
guidelines for changes in our average nausea measure, this can be considered to be a clinically 
relevant change.(46) 
 
14.4 
Calculation of the Primary Outcome Variable 
 
The primary outcome variable will be Average Nausea (measured on a 7-point scale anchored by 
“Not at all Nauseated” and “Extremely Nauseated”) defined as the average nausea rating across 
15 assessment points (i.e., the afternoon, evening, and night reporting periods on Day 1 and the 
morning, afternoon, evening, and night reporting periods on Days 2 – 4.  In the event that data 
are missing from eleven or more of the fifteen nausea assessment points, we will set the score to 
missing. 
 
14.5 
Primary Objectives and Analysis Plans  
 
14.5.1 The Primary Aim is to determine if control of nausea at Cycle 2 in participants 
who experienced CINV at Cycle 1 is improved by the addition of either prochlorperazine or 
olanzapine to the control arm of netupitant, palonosetron and dexamethasone. 
 
14.5.2 Primary Hypothesis:  Control of nausea at Cycle 2 in participants who 
experienced CINV at Cycle 1 despite receiving  ASCO-recommended antiemetics(1) can 
be improved by the addition of either prochlorperazine or olanzapine to the standard 
antiemetic combination of netupitant, palonosetron and dexamethasone.   
 
14.5.3 Primary Analysis:  We will use a one-way analysis of variance on Post – Pre 
change scores.  We have Arms 1 (control), 2, and 3.  Two tests will be done using 
contrasts: 1 vs. 2 and 1 vs. 3, using a significance level of 0.05 / 2 = 0.025.   
 
14.6 
Secondary Objectives, Endpoints, Analysis Plans 
 
14.6.1 Secondary Aim 1 is to determine if olanzapine is more effective than 
prochlorperazine in controlling nausea at Cycle 2 in participants who experienced CINV at 
Cycle 1 when used in combination with netupitant, palonosetron and dexamethasone.  
This will be assessed by estimating the contrast D = (3 – 1) – (2 – 1), where 3 is the Arm 3 
mean, 2 is the Arm 2 mean, and 1 is the Control mean, and testing whether D = 0 versus 
the one-sided alternative hypothesis that D > 0. 
 
14.6.2 Secondary Aims 2 and 3 will compare the effects of the interventions on vomiting 

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by fitting a generalized linear model.  The response will be Any Vomiting (yes/no) after 
Cycle 2, treatment arm as the main factor, and Any Vomiting after Cycle 1 as a covariate.  
Estimation will be performed using maximum likelihood assuming a binomial distribution 
and logit link.  The same group of contrasts described in the Primary Aim analysis will be 
estimated and tested, with a significance level of 0.025 to adjust for multiple tests. 
 
14.7 
Exploratory Analyses: 
 
14.7.1 We will create an empirically-based algorithm predicting nausea from breast 
cancer chemotherapy regimens. To do so, we will use the Cycle 1 diary data (total N = 
approximately 1600 overall) to develop a predictive model for the risk of developing 
nausea, using age, race, ethnicity, QOL, alcohol consumption, susceptibility to nausea, 
expectancy, anxiety, level of nausea on the day prior to treatment, and prior history of 
nausea as potential predictors.  For this analysis, the outcome will be binary, with 
Nausea=YES if Peak Nausea > 3 and NO otherwise.  We will apply two modeling 
paradigms: 1) Classification Trees, and 2) logistic regression.   
 
14.7.1.1 
Classification trees consist of finding a series of binary rules with which 
to base classifications, e.g., if Age is under 65, Race is Caucasian, and highly 
emetogenic chemotherapy agents are used, there is a X% risk of CINV.  These 
models are very easy to apply in practice and have been shown to be especially 
effective if there are interactions between the predictors in the model.(47)  We will 
use Conditional Tree methodology for the computations.(48)   
 
14.7.1.2 
Logistic regression will also be performed.  This method can be 
superior to classification trees if there are few, if any, interactions among the 
predictor variables.  The best model will be chosen using leave-one-out cross 
validation, where an observation is set aside; the model is fit to the remaining 
ones, and the fitted model is used to predict the set-aside observation.  This is 
repeated for each observation.  The resultant set of predictions is compared to the 
observed data in terms of misclassification rate, sensitivity, specificity and area 
under the curve.  
 
14.7.2 We will compare the effects of the interventions on QOL, as assessed by the 
FACT-G, by following the same procedures described under the Primary Aim and the first 
Secondary Aim, using change in the FACT-G scores as the response.  
 
14.7.3 Descriptive analyses will be conducted on the frequency and severity of side-
effects, i.e., sleep disturbance, fatigue, anxiety, and dizziness, across treatment 
conditions.  
 
14.7.4 Assessment of biological factors (e.g. GSH recycling, genetic markers) may help 
identify a subgroup of patients at high risk for development of cancer-related or treatment-
related side effects, or response to treatment. Assays to investigate these factors may 
include, for example, measurement of GSH metabolism, assessment of genetic variants 
such as SNPs, measurement of cytokines, or measurement of proteins associated with 
drug absorption, distribution, metabolism, and excretion. The most promising assay(s) will 
be selected at the time of analysis based on the current state of the science. 
 
14.8 
Interim Analysis 
 
There will be no interim analysis for this protocol.  
 
14.9 
Ancillary Studies 

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Ancillary studies could include secondary data analyses and use of blood samples for future 
research.   
 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS  
 
15.1 
Institutional Review Board Approval 
 
Prior to initiating the study and receiving agent, the NCORPs must obtain written approval to 
conduct the study from the NCI Central IRB. Should changes to the study become necessary, 
protocol amendments will be submitted to the DCP PIO according to DCP Amendment 
Guidelines. The DCP-approved amended protocol must be approved by the CIRB prior to 
implementation of any changes. 
 
After the study is closed to accrual, it should not be permanently closed at the community sites 
until notified to do so by the URCC NCORP Research Base. 
 
15.2 
Submission of Regulatory Documents 
 
All regulatory documents are reviewed at the NCORP for completeness and accuracy prior to 
submission to URCC. Once review is completed by the NCORP, the original regulatory 
documents are forwarded to the URCC Regulatory Compliance Specialist as follows: 
 
URCC_Regulatory@urmc.rochester.edu 
 
15.3 
Other 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice, and the 
applicable regulatory requirements. 
 
16. 
FINANCING, EXPENSES, AND/OR INSURANCE 
 
This study is supported by the URCC NCORP Research Base grant UG1CA189961 and R01 
CA200579. There are no expenses to the participant for participating in this study and they will 
not be paid for their participation. 
 
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