Conditions: Gynecologic Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 62
Healthy volunteers: no

Brief summary:
The objective of this study is to investigate the efficacy of olanzapine as compared to neurokinin-1 receptor antagonists (NK1-RAs) in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with gynecologic malignancies receiving single day outpatient chemotherapy (carboplatin and paclitaxel) every 3 weeks.

Detailed description:

Arms:
arm 1: Nk1-RA will be given on day 1 of each 3-week chemotherapy cycle, for up to 6 cycles. arm 2: Olanzapine will be given on days 1-4 of each 3-week chemotherapy cycle, for up to 6 cycles.

Interventions: intervention 1: Ondansetron intervention 2: Dexamethasone intervention 3: Neurokinin-1 Receptor Antagonist (NK1-RA) intervention 4: Olanzapine intervention 5: Compazine
Intervention descriptions: intervention 1: 8 mg IV or 16 mg by mouth on day 1 pre-chemotherapy; then 8 mg by mouth twice a day on days 2-4 of chemotherapy intervention 2: 20 mg IV on day 1 pre-chemotherapy intervention 3: 150 mg IV on day 1 pre-chemotherapy intervention 4: 5 mg by mouth on days 1-4 of chemotherapy (taken at night) intervention 5: 5-10 mg by mouth, available as needed, every 6 hours, days 1-5

Protocol document:
Prot_SAP_000.pdf: 
ID: UMCC 2019.173    
Olanzapine for the Prevention of Chemotherapy Induced Nausea and 
Vomiting in Gynecologic Oncology Patients    
NCT04503668


 
 
 
PROTOCOL UMCC NUMBER 2019.173 
 
Phase III randomized control trial investigating olanzapine for the prevention of 
chemotherapy induced nausea and vomiting in patients with gynecologic malignancies 
receiving every 3-week carboplatin and paclitaxel chemotherapy 
 
Principal Investigator: 
Shitanshu Uppal, MBBS 
 
 
 
 
Michigan Medicine, Department of Obstetrics and Gynecology  
 
 
 
 
Division of Gynecologic Oncology 
 
 
 
 
1500 E Medical Center Dr SPC 5902 
 
 
 
 
Ann Arbor, MI 48109-5902 
 
 
 
 
Phone: 734-647-8906; Fax: 734-936-9269 
 
 
 
 
uppal@med.umich.edu 
 
Sub-Investigator(s):  
Aimee Rolston, MD MS 
 
 
 
 
Department of Obstetrics and Gynecology 
 
 
 
 
Division of Gynecologic Oncology 
 
 
 
 
 
 
 
R Kevin Reynolds, MD 
 
 
 
 
Department of Obstetrics and Gynecology 
 
 
 
 
Division of Gynecologic Oncology 
 
 
 
 
 
Karen McLean, MD PhD 
 
 
 
 
Department of Obstetrics and Gynecology 
 
 
 
 
Division of Gynecologic Oncology 
 
 
 
 
 
Jean Hansen, DO 
 
 
 
 
Department of Obstetrics and Gynecology 
 
 
 
 
Division of Gynecologic Oncology 
 
Biostatistician: 
 
Sarah Bell 
 
 
 
 
Michigan Medicine, Department of Obstetrics and Gynecology 
 
 
 
 
scasin@med.umich.edu 
 
Study Drug:  
 
Olanzapine, Zyprexa 
 
Initial version: 
 
1/16/2020 
Updated version: 
 
8/04/2020 


 
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Page ii of iv 
 
 
TABLE OF CONTENTS 
ABBREVIATIONS ..................................................................................................................... 1 
STUDY SCHEMA....................................................................................................................... 2 
STUDY SYNOPSIS .................................................................................................................... 3 
1.0 BACKGROUND AND RATIONALE ............................................................................. 5 
1.1 
Disease Background .............................................................................................5 
1.2 
Study Agent(s) Background and Associated Known Toxicities ..........................7 
1.3 
Other Agents .........................................................................................................8 
1.4 
Rationale ...............................................................................................................8 
2.0 STUDY OBJECTIVES ........................................................................................................ 9 
2.1 
Primary Objectives ...............................................................................................9 
2.2 
Secondary Objectives ...........................................................................................9 
 
    2.3       Exploratory Objectives…………………………………………………………..9 
2.4 
Endpoints ..............................................................................................................9 
3.0 PATIENT ELIGIBILITY ................................................................................................. 10 
3.1 
Inclusion Criteria ................................................................................................10 
3.2 
Exclusion Criteria ...............................................................................................11 
4.0 SUBJECT SCREENING AND REGISTRATION PROCEDURES ...................... 11 
5.0 TREATMENT PLAN ........................................................................................................ 11 
5.1 
Treatment Dosage and Administration ...............................................................11 
5.2 
Toxicities and Dosing Delays/Dose Modifications ............................................12 
5.3 
Concomitant Medications/Treatments ................................................................12 
5.4 
Duration of Therapy ...........................................................................................13 


 
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5.5 
Off Treatment Criteria ........................................................................................13 
5.6 
Duration of Follow-Up .......................................................................................13 
5.7 
Off Study Criteria ...............................................................................................13 
5.8 
Patient Replacement ...........................................................................................14 
6.0 STUDY PROCEDURES ................................................................................................... 14 
6.1 
Time and Events Table .......................................................................................14 
7.0 MEASUREMENT OF EFFECT ..................................................................................... 15 
7.1 
Safety/Tolerability ..............................................................................................15 
8.0 ADVERSE EVENTS .......................................................................................................... 15 
8.1 
Experimental Therapy ........................................................................................15 
8.2 
Adverse Event Reporting Requirements.............................................................16 
8.3 
Definitions ..........................................................................................................16 
8.4 
Adverse Event Characteristics ............................................................................18 
8.5 
Serious Adverse Event Reporting Guidelines ....................................................18 
8.6 
Routine Reporting ...............................................................................................19 
8.7 
Reporting of Unanticipated Problems ................................................................19 
8.8 
Stopping Rules ....................................................................................................19 
9.0 DRUG INFORMATION ................................................................................................... 19 
9.1 
Olanzapine ..........................................................................................................19 
10.0 STATISTICAL CONSIDERATIONS ......................................................................... 21 
10.1 
Study Design/Study Endpoints ...........................................................................21 
10.2 
Sample Size and Accrual ....................................................................................21 
10.3 
Data Analyses Plans ...........................................................................................21 


 
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Page iv of iv 
 
 
11.0 DATA AND SAFETY MONITORING ....................................................................... 22 
12.0 REFERENCES .................................................................................................................. 23 
13.0 APPENDICES ................................................................................................................... 25 
 


 
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Page 1 of 31 
 
ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSU 
Clinical Trials Support Unit 
DSMB 
Data and Safety Monitoring Board 
H&P 
History & Physical Exam 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
NCI 
National Cancer Institute 
PI 
Principal Investigator 
p.o. 
per os/by mouth/orally 
SAE 
Serious Adverse Event 
UaP 
Unanticipated Problem 
 


 
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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Page 3 of 31 
 
STUDY SYNOPSIS 
 
Title 
Phase III randomized control trial investigating olanzapine for the 
prevention of chemotherapy induced nausea and vomiting in 
patients with gynecologic malignancies receiving every 3-week 
carboplatin and paclitaxel chemotherapy 
Phase 
Phase III 
Methodology 
Randomized 
Study Duration 
24 months 
Study Center(s) 
Single center 
Objectives 
Primary: To compare complete response (CR - no emetic episodes 
and no use of rescue medications) between the two arms for the 
overall (0-120 hours post-chemotherapy) period for patients with 
gynecologic malignancies receiving every three-week carboplatin / 
paclitaxel chemotherapy.  
 
Secondary:  
1) To compare complete response between the two arms for 
the acute (0-24 hours post-chemotherapy) and delayed (24-
120 hours post-chemotherapy) periods.  
2) To compare rates of no nausea between the two arms for the 
acute, delayed, and overall periods.  
3) To compare average levels of undesired sedation between 
the two arms on days 1-5 of chemotherapy. 
4) To compare average levels of undesired increased appetite 
between the two arms on days 1-5 of chemotherapy. 
Number of Subjects 
170 (85 per arm) 
 


 
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Page 4 of 31 
 
Inclusion Criteria 
1. Diagnosis of gynecologic malignancy 
2. No chemotherapy in the last 12 months 
3. Scheduled to receive Carboplatin (AUC>=4) and Paclitaxel 
every three weeks 
4. Age >= 18 years and <90 
5. ECOG performance status 0 or 1 
6. English speaking 
7. Appropriate laboratory parameters: 
a. Serum creatinine <= 2.0mg/dL 
b. AST and ALT <= 3x upper limit of normal 
c. Absolute neutrophil count (ANC) >= 1000/mm3 
8. No vomiting in the 24hours prior to initiating chemotherapy 
9. If childbearing potential exists, negative pregnancy test 
within 7 days prior to registration 
Exclusion Criteria 
1. Significant cognitive compromise 
2. History of CNS disease (e.g. brain metastases, seizure 
disorder, dementia) 
3. Current or recent (within 30 days) treatment with another 
antipsychotic agent (antidepressant medications are OK) 
4. Concurrent radiotherapy treatment 
5. Known hypersensitivity to olanzapine 
6. Known cardiac arrhythmia, uncontrolled congestive heart 
failure or acute myocardial infarction within the last six 
months 
7. History of diabetes mellitus on medication (insulin or oral 
glycemic agent) 
8. Alcohol abuse / chronic alcoholism 
9. History of closed angle glaucoma 
10. Current enrollment in other clinical trials 
Study Product(s), Dose, 
Route, Regimen 
Olanzapine: 5mg per day orally at bedtime for days 1-4 of 
chemotherapy  
Duration of 
Administration 
4 days (with each of six chemotherapy cycles) 
Reference Therapy 
Nk1 inhibitor (Aprepitant, Fosaprepitant) 
Statistical Methodology 
Outcomes will be compared between the two arms using chi-
square and paired sample t tests. All statistical analyses will be 
performed using STATA.  
 
 
 
 
 
 
 
 


 
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Page 5 of 31 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 Disease Background 
Chemotherapy induced nausea and vomiting (CINV) is one of the most feared and 
distressing side effects of cytotoxic chemotherapy.1,2 It has significant quality of 
life (QoL) implications and may interfere with treatment adherence / response.3–5 
CINV is typically classified as either acute (hours 0-24 after chemotherapy 
administration) or delayed (hours 24-120 after chemotherapy administration). 
Prophylactic antiemetic regimens are prescribed based on the emetogenic 
potential of the chemotherapy agent(s). When studying control of CINV, 
outcomes of interest typically include 1) complete response (CR - no emesis and 
no use of rescue medications) during the time period(s) of interest and 2) no 
nausea during the same time period(s).6 
 
Improvement in the control of CINV was initially achieved with the use of 5-
hydroxytryptamine3 receptor antagonists (5HT3- RA) and dexamethasone. More 
recently, the addition of neurokinin-1 receptor antagonists (NK1-RA) and/or 
olanzapine, an antipsychotic which blocks several neurotransmitters, have shown 
promise in improving control of CINV in highly and/or moderately emetogenic 
chemotherapy regimens.6  
 
In patients with gynecologic malignancies, namely cancer of the ovary (including 
fallopian tube/primary peritoneal) and uterus, first line chemotherapy typically 
consists of carboplatin (AUC 5-7) and paclitaxel. Historically, carboplatin fell 
under the moderately emetogenic classification for which a two-drug antiemetic 
prophylactic combination was recommended (5HT3-RA and dexamethasone). 
More recently, it has been recognized that carboplatin doses of AUC >=4 
typically result in higher levels of nausea and vomiting than other drugs in the 
moderate category. As such, the most recent clinical practice update published in 
2017 from the American Society of Clinical Oncology (ASCO) made specific 
recommendations for a three-drug antiemetic prophylactic combination (NK1-
RA, 5HT3-RA, and dexamethasone) for chemotherapy regimens including 
carboplatin AUC >=4. The most recent National Comprehensive Cancer Network 
(NCCN) guidelines are in agreement with this – despite re-classifying carboplatin 
AUC >=4 into the highly emetogenic category, they specifically state that the 
above three-drug regimen is preferred with carboplatin.7 These recommendations 
are based on several studies that showed improved complete response with the 
addition of a NK1-RA to the previously used two drug (5HT3-RA and 
dexamethasone) regimen for carboplatin AUC >=4.8-10 This triple-drug antiemetic 
prophylactic combination is what our institution currently uses as standard of care 
for the prevention of CINV in gynecologic oncology patients receiving 
carboplatin and paclitaxel chemotherapy.  
 
 
NK1-RAs are expensive and despite some improvement in the control of CINV in 
the gynecologic oncology population, it remains a significant issue (with high 


 
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cost) for many patients. Previous studies investigating the prevention of CINV 
using a triple drug regimen (NK1-RA, 5HT3-RA and dexamethasone) in 
gynecologic oncology patients receiving carboplatin-based chemotherapy show a 
wide range of complete response from 62-90% that is, on average, lower than 
what is reported in other populations. Additionally, investigators note worse 
control in the delayed versus acute period as well as for nausea specifically, 
suggesting a need for improvement in this area.8,9 Unique factors about our 
patient population that may contribute to these findings include: 1) female 
patients are at higher risk for CINV, as compared to their male counterparts; and, 
2) our population is one of the few intra-peritoneal malignancies that is treated 
with carboplatin (or another highly emetogenic chemotherapy) in the upfront 
setting. 
 
The use of olanzapine has been studied primarily in other, non-carboplatin based 
HEC regimens and has shown improvement in not only CR but also nausea 
control when compared to non-olanzapine prophylactic regimens.11–13 A 
randomized, phase III trial comparing olanzapine to aprepitant (a NK1-RA) for 
the prevention of CINV in selected HEC regimens (cisplatin or cyclophosphamide 
and doxorubicin) showed a statistically significant improvement in rates of no 
nausea (both delayed and overall) in the olanzapine group (69% vs 38%).14 Given 
the aforementioned guidelines, olanzapine is not considered standard of care in 
the gynecologic oncology population and few studies have investigated the use of 
olanzapine in this context. However, evidence suggests that it could be of 
substantial benefit and may even be superior to NK1-RAs.   
 
Additionally, few studies have focused on whether the efficacy of antiemetic 
prophylactic regimens is sustained or varies with subsequent chemotherapy 
cycles. Limited evidence suggests that both olanzapine and NK1-RAs sustain 
their effect over subsequent chemotherapy cycles.14 However, because the 
sustained response to antiemetic prophylactic regimens is multifactorial -- 
including, but not limited to, chemotherapy agents used -- it is important to 
investigate these trends for specific populations of interest. One study evaluating 
the response to an NK1-RA in the ovarian cancer population found that rates of 
complete response and no nausea were sustained over six cycles but with a 
decreasing trend, suggesting the need for more data in this area.  
 
In summary, CINV, and particularly delayed nausea, remains a major issue for 
many patients with gynecologic malignancies despite the addition of NK1-RAs.15 
Olanzapine has been shown to be effective in controlling CINV in other HEC 
regimens and may even be superior to NK1-RAs, particularly in nausea control. 
These data suggest that olanzapine has the potential to provide benefit in our 
patient population that is 1) more vulnerable to CINV and 2) has a multifactorial 
etiology of nausea and vomiting, including both burden of intra-abdominal 
disease as well as chemotherapy. But, few studies have focused on the efficacy of 
olanzapine within the gynecologic oncology and/or carboplatin based 
chemotherapy population.11,16 As such, the purpose of this study is to compare the 


 
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Page 7 of 31 
 
efficacy of olanzapine versus an NK1-RA in patients with gynecologic 
malignancies receiving carboplatin and paclitaxel chemotherapy.  
 
1.2 Study Agent(s) Background and Associated Known Toxicities 
Olanzapine is an antipsychotic agent approved by the Food and Drug 
Administration (FDA) for schizophrenia. It inhibits several neurotransmitter 
receptors including: dopamine at D1 - D4 receptors; serotonin at 5-HT2a, 5-HT2c, 
5-HT3, and 5-HT6 receptors; catecholamines at alpha 1-adrenergic receptors; 
acetylcholine at muscarinic receptors; and histamine at H1 receptors.11,12,14 It is 
thought that olanzapine’s activity at multiple receptors, some of which may play a 
role in nausea and vomiting (namely D2, 5-HT2c, and 5-HT3), results in its 
antiemetic effects.11,12,14 Several studies have demonstrated it efficacy in 
improving control of emesis and nausea in CINV involving HEC and MEC 
regimens.11  
 
The most common side effects of olanzapine include short-term mild sedation as 
well as increased appetite with associated weight gain and increased risk of 
diabetes mellitus (with prolonged use >6 months).12 Other known potential 
toxicities include: dizziness, headache, fatigue, increased prolactin, increased 
ALT, and weakness. Most of these side effects/toxicities are for chronic, daily 
use. Given the short term, intermittent nature of olanzapine’s use, most of these 
side effects are not applicable in the context of this study. The major exceptions 
are its sedation potential and effects on appetite.  
 
The majority of previous studies investigating the use of olanzapine in 
prophylaxis of CINV used a dose of 10mg with one of the main side effects being 
increased sedation / somnolence. A recent randomized phase II study compared 
5mg and 10mg doses of olanzapine for prophylaxis of CINV in HEC regimens 
and found that the 5mg dose resulted in higher rates of CR and lower somnolence 
rates.17 It was thus recommended that the 5mg dose be used for further phase III 
studies and is the basis upon which 5mg was chosen for this study. These prior 
studies also supported the safety of using olanzapine on a short term, intermittent 
basis in the context of CINV. There were no observed grade 3 or 4 toxicities that 
were thought to be attributable to olanzapine.12,14,16  
 
 
 
Pharmacokinetics: 
- 
Absorption: Readily absorbed. Peak concentrations are reached approximately 
6 hours after oral dose. Food does not affect absorption. 
- 
Distribution: Half-life is ~21-54 hours. Half-life is 1.5 times longer in elderly 
patients.   
- 
Metabolism: Significant first pass metabolism (~40% of the dose is 
metabolized before reaching systemic circulation). Direct glucuronidation and 
cytochrome P450 mediated oxidation via CYP1A2 (major) and CYP2D6 
(minor) are primary metabolic pathways.  


 
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Page 8 of 31 
 
- 
Elimination: Primarily eliminated through the urine. Smoking increases 
clearance by ~40%. Female sex decreases clearance by 30%.  
1.3 Other Agents 
 
 
Ondansetron 
Ondansetron is a 5HT3-RA FDA approved for the prevention of CINV. Recent 
guidelines from both ASCO and NCCN recommend the use of a 5HT3-RA in 
prophylactic combination regimens for CINV in both MEC and HEC.9,10  
 
 
Dexamethasone 
Dexamethasone is a synthetic glucocorticoid most often used as an anti-
inflammatory or immunosuppressive agent. It has also been shown to be effective 
in preventing both acute and delayed CINV.18 Similar to ondansetron, recent 
guidelines from both ASCO and NCCN recommend the use of dexamethasone in 
prophylactic combination regimens for CINV in both MEC and HEC.9,10 Given 
significant side effects associated with dexamethasone, including insomnia, 
hyperglycemia, indigestion/epigastric discomfort, agitation, increased appetite, 
weight gain, and acne, effort has been made to try to limit dose and duration of 
dexamethasone use in CINV by combining it with other effective agents.10,14 The 
most recent NCCN and ASCO guidelines suggest that dexamethasone should be 
limited to day 1 only in patients receiving carboplatin.9,10  
 
The dose chosen for this study is also influenced by concomitant use of paclitaxel 
chemotherapy. In this context, dexamethasone is also used to prevent infusion-
related hypersensitivity reactions, for which intravenous and oral regimens exist.19 
Given the oral regimen requires taking multiple doses of dexamethasone prior to 
chemotherapy, our institution typically gives dexamethasone 20mg IV prior to 
chemotherapy infusion to avoid compliance issues.   
 
 
Neurokinin-1 Receptor Antagonists 
Fosaprepitant and aprepitant are highly selective substance P neurokinin-1 
receptor antagonists which are approved for prevention of acute and delayed 
CINV. Several studies have supported the efficacy of NK1-RAs in combination 
with dexamethasone and a 5HT3-RA for prevention of CINV in carboplatin based 
chemotherapy.7,8,20 These data are reflected in the most recent ASCO and NCCN 
guidelines as described above.9,10 
1.4 Rationale 
CINV, and particularly delayed nausea, remains a significant issue for many 
patients with gynecologic malignancies, despite the costly addition of NK1-RAs 
as recommended by ASCO and NCCN.9,15 Olanzapine is recommended for 
prophylaxis of CINV in other HEC regimens but is not currently standard of care 
in the gynecologic oncology population. Previous studies comparing olanzapine 
to an NK1-RA in other HEC regimens show that it may be superior.10,14 These 
data suggest that olanzapine has the potential to provide substantial benefit to our 


 
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Page 9 of 31 
 
patient population that is 1) more vulnerable to CINV and 2) has a multifactorial 
etiology of nausea and vomiting including both chemotherapy and burden of 
intraperitoneal disease. As such, the purpose of this study is to compare the 
efficacy of olanzapine versus an NK1-RA in patients with gynecologic 
malignancies receiving every three-week carboplatin and paclitaxel 
chemotherapy. Additionally, we seek to investigate sustained response of 
prophylactic regimens over multiple chemotherapy cycles. If an olanzapine triple-
drug regimen is superior to a NK-1 RA triple-drug regimen as predicted, there are 
significant cost-saving implications of this finding. We believe olanzapine has the 
potential to not only improve the care of our patients but provide a cost-effective 
alternative to the current standard of care.  
 
2.0 
STUDY OBJECTIVES 
2.1 Primary Objectives 
1. To compare complete response (CR - no emetic episodes and no use of 
rescue medications) between the two arms for the overall (0-120 hours 
post-chemotherapy) period for patients with gynecologic malignancies 
receiving every three-week carboplatin / paclitaxel chemotherapy. 
2.2 Secondary Objectives  
1. To compare complete response between the two arms for the acute (0-24 
hours post-chemotherapy) and delayed (24-120 hours post-chemotherapy) 
periods.  
2. To compare rates of no nausea between the two arms for the acute, 
delayed, and overall periods.  
3. To compare average levels of undesired sedation between the two arms on 
days 1-5 of chemotherapy. 
4. To compare average levels of undesired increased appetite between the 
two arms on days 1-5 of chemotherapy. 
 
2.3 Exploratory Objectives 
1. To investigate differences in sustained efficacy between the regimens over 
six cycles of treatment.  
2. To investigate the efficacy of adding a fourth agent (whichever drug – 
olanzapine or NK1-RA – that the patient is not already receiving) to the 
regimen for those patients that have poor control of CINV with the 
regimen to which they were randomized. 
2.4 Endpoints 
Primary Endpoint 
Complete response (CR) in the overall time period. CR is defined as no episodes 
of emesis and no use of rescue medications. Patient reported diaries for days 1-5 


 
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of chemotherapy will be used to measure this outcome (patients will complete 
diaries on days 2-6 about the preceding 24 hours, please see Appendix C - E). 
Secondary Endpoints 
 
1. Complete response in the acute and delayed periods. Outcome will be 
measured using patient reported diaries. 
2. No nausea in the acute, delayed and overall time periods. Patients will 
record daily levels of nausea on days 1-5 of chemotherapy using a Likert 
scale ranging from 0 to 10 with 0 indicating no nausea and 10 indicating 
maximum level of nausea.21 This will be recorded in the patient diaries 
cited in 2.4.1. 
3. Undesired sedation during days 1-5 of chemotherapy. Patients will record 
levels of undesired sedation each day for days 1-5 of chemotherapy using 
a Likert scale ranging from 0 to 10 with 0 indicating no undesired sedation 
and 10 being maximum amount of undesired sedation. This will be 
recorded in the patient diaries cited in 2.4.1. 
4. Undesired increase in appetite during days 1-5 of chemotherapy. Patients 
will record levels of undesired increase in appetite each day for days 1-5 
of chemotherapy using a Likert scale ranging from 0 to 10 with 0 
indicating no undesired increase in appetite and 10 being maximum 
amount of undesired increase in appetite. This will be recorded in the 
patient diaries cited in 2.4.1. 
 
 
 
Exploratory Endpoint 
 
1. Sustained efficacy of each regimen over six cycles of treatment, as defined 
by maintaining rates of complete response and no nausea 
2. Rates of complete response and no nausea in those patients for whom a 
fourth agent is added in the setting of poorly controlled CINV with the 
regiment to which they were randomized. 
  
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. 
3.1 Inclusion Criteria 
1. 
Diagnosis of gynecologic malignancy 
2. 
No chemotherapy in the last 12 months 
3. 
Scheduled to receive Carboplatin (AUC>=4) and Paclitaxel every three 
weeks 
4. 
Age >= 18 years and <90 
5. 
ECOG performance status 0 or 1 
6. 
English speaking 
7. 
Willing and able to provide informed consent 


 
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8. 
Appropriate laboratory parameters: 
 
Serum Creatinine 
<= 2.0 mg/dL 
AST and ALT 
<= 3x upper limit of normal 
Absolute neutrophil count (ANC) 
>= 1000/mm3 
 
9. 
No vomiting in the 24 hours prior to initiating chemotherapy 
10. 
If childbearing potential exists (premenopausal with reproductive organs 
intact), negative pregnancy test within 7 days prior to registration 
3.2 Exclusion Criteria 
10. 
Significant cognitive compromise 
11. 
History of CNS disease (e.g. brain metastases, seizure disorder, dementia) 
12. 
Current or recent (within 30 days) treatment with another antipsychotic 
agent (antidepressant medications are OK) 
13. 
Concurrent radiotherapy treatment 
14. 
Known hypersensitivity to olanzapine 
15. 
Known cardiac arrhythmia, uncontrolled congestive heart failure or acute 
myocardial infarction within the last six months 
16. 
History of diabetes mellitus on medication (insulin or oral glycemic agent) 
17. 
Alcohol abuse / chronic alcoholism 
18. 
History of closed angle glaucoma 
19. 
Current enrollment in other clinical trials 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
 
After informed consent is obtained and PRIOR to the initiation of protocol 
therapy all patients satisfying the inclusion/exclusion criteria must have eligibility confirmed. 
Once informed consent is obtained and eligibility confirmed, patients will be randomized using a 
web-based tool, the University of Michigan computerized randomization system (TATUM – 
“Treatment Assignment Tool – UM”). Subjects will be randomized to either the NK1-RA or 
Olanzapine arm at a 1:1 allocation ratio.  Blocked randomization with random block sizes will be 
used to ensure group balance.  The randomization code will be generated by an independent 
statistician. 
5.0 
TREATMENT PLAN 
5.1 Treatment Dosage and Administration 
Protocol treatment must start within 7 business days of enrollment to the study. 
Protocol therapy will be administered in relation to single day outpatient 
chemotherapy for each of six cycles. Patients will be permitted to take rescue 
antiemetic medication as needed based on clinical circumstances.  
 
 
 
REGIMEN DESCRIPTION 


 
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Page 12 of 31 
 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Ondansetron 
None 
8mg IV 
OR 16mg 
PO 
IV OR PO Day 1 pre-chemo 
3 weeks 
(21 days) 
 
8mg BID 
PO 
Days 2-4 
Dexamethasone 
None 
20mg 
IV 
Day 1 pre-chemo 
NK1-RA on formulary 
Fosaprepitant 
 
None 
 
150mg  
 
 
IV 
 
 
 
Day 1 pre-chemo 
 
 
Olanzapine 
Take at night  
5mg 
PO 
Days 1-4 
Compazine 
None 
5-10mg  
PO 
Available as prn 
rescue medication 
days 1-5 
 
 
5.2 Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. 
Each patient will be assessed for the development of toxicity according to the 
Time and Events Table (Section 6.1). Toxicity will be assessed according to the 
NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
Dose adjustments should be made according to the system showing the greatest 
degree of toxicity.  
 
Toxicity Dose Reductions 
 CTCAE Grade 
Olanzapine 
0-2 
No change from original starting dose 
3  
Hold until resolved to < Grade 2, then resume 5mg dose 
Second episode of grade 3 or 1st 
episode 4 toxicity 
Hold until resolved to < Grade 2, then resume 5mg dose 
Third episode of grade 3 or 2nd 
episode 4 toxicity 
Remove subject from treatment 
5.3 Concomitant Medications/Treatments 
The following concomitant drugs and/or treatments are prohibited: 
1. Any antipsychotic agent (anti-depressant medications are OK) 
 
The following concomitant drugs and/or treatments may be used, but only with 
caution: 
1. Fluvoxamine - decreases clearance of olanzapine. Dose reductions should be 
considered 
2. Diazepam - may potentiate orthostatic hypotension that can be observed with 
olanzapine 


 
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Page 13 of 31 
 
3. Antihypertensives, CNS acting medications, alcohol - olanzapine may 
potentiate the effects of these medications 
4. Levodopa and dopamine agonists- olanzapine may antagonize the effects 
5. Carbamazepine: increased olanzapine clearance 
5.4 Duration of Therapy 
Olanzapine will be given for 4 days with each chemotherapy cycle. In the absence 
of treatment delays due to adverse events, treatment may continue for 6 cycles or 
until one of the following criteria apply: 
● Inter-current illness that prevents further administration of treatment 
● Unacceptable adverse event(s) 
● Patient voluntarily withdraws from treatment OR 
● General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
5.5 Off Treatment Criteria  
Patients will be removed from protocol therapy when any of the criteria listed in 
Section 5.4 apply. Document in the source the reason for ending protocol therapy 
and the date the patient was removed from treatment. All patients who 
discontinue treatment should comply with protocol specific follow-up procedures 
as outlined in Section 5.6. The only exception to this requirement is when a 
subject withdraws consent for all study procedures or loses the ability to consent 
freely. 
5.6 Duration of Follow-Up 
Patients will not be followed after removal from treatment. Patients removed from 
treatment for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
5.7 Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation from study will be 
documented and may include: 
 
1. Patient withdraws consent (termination of treatment and follow-up); 
 
2. Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
 
3. Patient is unable to comply with protocol requirements; 
 
4. Treating physician judges continuation on the study would not be in the 
patients’ best interest; 
 


 
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Page 14 of 31 
 
5. Patient becomes pregnant (pregnancy to be reported per institutional 
guidelines); 
 
6. Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
 
7. Termination of the study by The University of Michigan, Sponsor, or the 
FDA; 
 
8. Patient completes protocol treatment and follow-up criteria. 
5.8 Patient Replacement 
Patients will not be replaced.  
6.0 
STUDY PROCEDURES 
6.1 Time and Events Table 
Pre-study Pre-Chemo3 
Day 13  
Days 2-4 
Days 5-6 
Follow-Up 
Assessment 
X 
Informed Consent 
X 
History and PE 
Height & Weight 
X 
 
 
 
 
 
Performance Status 
X 
Toxicity Evaluations 
 
X5 
 
X6 
X6 
X3 
Baseline patient 
questionnaire 
X 
 
 
 
 
 
Pre chemo 
questionnaire 
X 
Patient Diaries 
X3 
X3 
CBC1 
X 
X 
Randomization 
X 
Concomitant 
Medication Review 
X 
X 
Contraceptive 
Counseling4 
X 
Differential1 
X 
X 
CMP1 
X 
X 
 
 
 
 
Pregnancy Test2 
X 
X 
Study Drug 
Administration 
X 
X3 
 
1Routinely ordered prior to chemotherapy. Will not be ordered separately for the study.  
 
2For all women of childbearing potential, as defined above 
 
3For each of six cycles 


 
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Page 15 of 31 
 
4For women of childbearing potential (premenopausal with reproductive organs intact), 
contraceptive counseling will occur at time of informed consent and pregnancy testing.  
5Cycles 2-6 
6Cycle 1 only (patient phone calls only scheduled for cycle 1)   
7.0 
MEASUREMENT OF EFFECT 
Protocol therapy will be administered in relation to single day outpatient 
chemotherapy for each of six cycles. Patient demographic information (age, 
height, weight, BMI, race/ethnicity), relevant co-morbid diseases, and malignancy 
related factors (primary site of disease, whether they have had prior chemotherapy 
and when, whether current chemotherapy is neoadjuvant or adjuvant therapy, 
current burden of disease, ECOG performance status) will be obtained through a 
combination of baseline patient questionnaires (see Appendix A) and extraction 
from the electronic medical record. Data for primary and secondary outcomes will 
be collected through patient diaries, which contain questionnaires that ask about 
daily episodes of emesis, use of rescue medications, and daily levels of nausea, 
undesired sedation, and undesired increase in appetite (see Appendix C - E). 
Patients will be given a booklet with each chemotherapy cycle to complete and 
bring with them to their next visit for the subsequent chemotherapy cycle. The 
baseline questionnaire (Appendix B) will be completed on the day of 
chemotherapy, prior to treatment for every cycle. They will then receive daily text 
reminders to complete the questionnaire for each of five days after chemotherapy. 
Because our analyses of primary and secondary outcomes will focus mainly on 
data from cycle one, a study team member will also call the patients daily to 
remind them to complete their questionnaires (in addition to sending text 
reminders, see Appendix F). Patients will receive text reminders only for cycles 2-
6.  
 
Our analyses of primary and secondary outcomes will focus on data from cycle 1.  
Data will be collected through all 6 cycles to allow for identification of variation 
over time. Additionally, for patients that have poor control of CINV (>=2 
episodes of emesis in 1 day and/or use of >2 rescue medications/day for >=2 days 
for emesis or nausea and/or any emergency room/urgent care visits for 
nausea/vomiting), the agent they are not receiving (olanzapine or NK1-RA) will 
be added so that they receive a four drug regimen for their next cycle (also an 
NCCN approved prophylactic regimen). We will then assess for improved control 
of CINV in subsequent cycles.  
7.1 Safety/Tolerability 
Analyses will be performed for all patients having received at least one cycle of 
study drug. The study will use the CTCAE version 5.0 for reporting of adverse 
events.  
8.0 
ADVERSE EVENTS 


 
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Page 16 of 31 
 
8.1 
Experimental Therapy 
Not applicable.  
 
8.2 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial 
and is done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Data on adverse events will be 
collected from the time of the initial study treatment through 30 days after the last 
cycle. Any serious adverse event that occurs more than 30 days after the last study 
treatment and is considered related to the study treatment must also be reported. 
Serious Adverse Events (SAEs) will continue to be followed until: 
● Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
● There is satisfactory explanation other than the study treatment for the changes 
observed; or  
● Death. 
The investigator is responsible for the detection, documentation, grading and 
assignment of attribution of events meeting the criteria and definition of an AE or 
SAE. The definitions of AEs and SAEs are given below. It is the responsibility of the 
principal investigator to ensure that all staff involved in the trial is familiar with the 
content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial 
study treatment is considered to be pre-existing in nature. Any known pre-existing 
conditions that are ongoing at time of study entry should be considered medical 
history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 
8.2, occurring from the initial study treatment administration through 30 days 
following the last cycle of the study treatment must be recorded as an adverse event 
in the patient’s source documents and on the CRF regardless of frequency, severity 
(grade) or assessed relationship to the study treatment. 
In addition to new events, any increase in the frequency or severity (i.e., toxicity 
grade) of a pre-existing condition that occurs after the patient begins study treatment 
is also considered an adverse event. 
8.3 Definitions 
1. 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient 
receiving study treatment and which does not necessarily have a causal 
relationship with this treatment. An AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or 


 
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disease temporally associated with the use of an experimental intervention, 
whether or not related to the intervention.  
1. 
Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the investigator, 
it results in any of the following outcomes: 
 
o Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
o A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of 
either the investigator [or sponsor], its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event 
that, had it occurred in a more severe form, might have caused death.  
 
o Inpatient hospitalization or prolongation of existing hospitalization for 
> 24 hours. 
 
o A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
 
o A congenital anomaly/birth defect 
 
o Important medical event 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition of “Serious Adverse Event”. 
Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; 
convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries 
should not be reported as SAEs unless the underlying medical condition 
has worsened during the course of the study. Preplanned hospitalizations 
or procedures for preexisting conditions that are already recorded in the 
patient’s medical history at the time of study enrollment should not be 
considered SAEs. Hospitalization or prolongation of hospitalization 
without a precipitating clinical AE (for example, for the administration of 
study therapy or other protocol-required procedure) should not be 


 
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Page 18 of 31 
 
considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
2. 
Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
 For approved and marketed drugs or devices, those adverse events 
are described in the approved Package Insert (Label).  
 For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure.  
 In clinical research studies, information on expected adverse 
events is also summarized in the protocol and in the consent 
document.  See section 9.1 for the list of expected adverse events 
related to the drug under study. 
3. 
Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in 
the Package Insert, Investigator’s Brochure, in published medical 
literature, in the protocol, or in the informed consent document.  
8.4 
Adverse Event Characteristics 
1. CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of 
the CTCAE version 5.0 can be downloaded from the CTEP web site. 
(http://ctep.cancer.gov) 
2. Attribution of the AE 
The investigator or co-investigator is responsible for assignment of 
attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.5 
Serious Adverse Event Reporting Guidelines 
1. The Principal Investigator must be notified within 1 business day of study 
team’s knowledge of any event meeting the criteria and definition of a 
serious adverse event, regardless of attribution, occurring during the study 
or within 30 days of the last administration of the study related treatment.  


 
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Page 19 of 31 
 
2. The investigator must report all events meeting the criteria and definition 
of a serious adverse event as per the local IRB reporting requirements.  
8.6 Routine Reporting 
All other adverse events are to be reported annually as part of regular data 
submission as per institutional guidelines. 
8.7 Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the 
conduct of human subjects research that represent unanticipated problems but are 
not considered adverse events. For example, some unanticipated problems involve 
social or economic harm instead of the physical or psychological harm associated 
with adverse events. In other cases, unanticipated problems place subjects or 
others at increased risk of harm, but no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an 
adverse event) that may represent an unanticipated problem, the investigator 
should assess whether the incident, experience, or outcome represents an 
unanticipated problem. The incident, experience or outcomes is considered 
unanticipated if it meets all of the following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of 
harm than was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents 
an unanticipated problem, the investigator must report it to the IRB according to 
the local IRB policies. 
8.8 Stopping Rules  
Given overall moderate risk of this study as well as non-safety endpoints, we do 
not anticipate needing to interrupt or stop this study.  
9.0 
DRUG INFORMATION 
9.1 Olanzapine 
● Other names for the drug: Zyprexa 
 
● Description: 5mg tablets, 12 tablets per bottle  
 
● Classification - type of agent: Atypical antipsychotic 
 
● Mode of action: Neurotransmitter receptor antagonist with action against 
several neurotransmitters including: dopamine at D1 - D4 receptors; serotonin 
at 5-HT2a, 5-HT2c, 5-HT3, and 5-HT6 receptors; catecholamines at alpha 1-


 
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Page 20 of 31 
 
adrenergic receptors; acetylcholine at muscarinic receptors; and histamine at 
H1 receptors 
 
● Pharmacokinetics: 
- 
Absorption: Readily absorbed. Peak concentrations are reached 
approximately 6 hours after oral dose. Food does not affect absorption. 
- 
Distribution: Half-life is ~21-54 hours. Half-life is 1.5 times longer in 
elderly patients.   
- 
Metabolism: Significant first pass metabolism (~40% of the dose is 
metabolized before reaching systemic circulation). Direct glucuronidation 
and cytochrome P450 mediated oxidation via CYP1A2 (major) and 
CYP2D6 (minor) are primary metabolic pathways.  
- 
Elimination: Primarily eliminated through the urine. Smoking increases 
clearance by ~40%. Female sex decreases clearance by 30%.  
 
● Contraindications: There are no absolute contraindications. See exclusion 
criteria and restricted concomitant medications/treatments above.  
 
● Warnings and Precautions: 
- 
Significant cognitive compromise  
- 
Elderly patients with dementia: increased risk of death and 
cerebrovascular disease 
- 
Metabolic changes: prolonged use associated with increased risk of 
diabetes mellitus 
- 
Orthostatic hypotension: use with caution in patients with diseases that 
could affect hemodynamic compromise  
- 
History of seizures: use with caution as may lower seizure threshold 
- 
Hyperprolactinemia: may increase prolactin level 
 
● Side effects: Please see a complete list of potential side effects in FDA 
package insert for olanzapine. Side effects most likely to occur in the context 
of short-term, intermittent use in this study include somnolence and increased 
appetite.   
 
● Drug Interactions:  
- 
Diazepam: may potentiate orthostatic hypotension 
- 
Alcohol: may potentiate orthostatic hypotension 
- 
Carbamazepine: increased olanzapine clearance  
- 
Fluvoxamine: may increase olanzapine levels 
- 
CNS acting drugs: caution should be used with other centrally acting 
drugs  
- 
Antihypertensives: may potentiate orthostatic hypotension 
- 
Levodopa and dopamine agonists: olanzapine may antagonize their effects 
- 
Other antipsychotics: based on specific antipsychotic agent (see package 
insert for specific drug) 
 


 
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Page 21 of 31 
 
● Storage and Stability: Store at room temperature (20-25o C)  
 
● Preparation and Dispensing: Olanzapine will be prescribed and provided by 
the patient's pharmacy per their standard preparation and dispensing protocols. 
 
● Availability: commercially available 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 Study Design/Study Endpoints 
Study Design: Randomized controlled trial 
Study Endpoints: 
  
Primary Endpoint: Complete response in the overall time period.  
Secondary Endpoints: 1) Complete response in the acute and delayed time 
periods; 2) No nausea in the acute, delayed, and overall time periods; 3) 
Undesired sedation during days 1-5 of chemotherapy; and 4) Undesired 
increase in appetite during days 1-5 of chemotherapy.  
10.2 Sample Size and Accrual 
A prior study investigating the use of an NK1-RA in carboplatin-based 
chemotherapy found a complete response rate of 80% in those that received the 
NK1-RA in combination with a 5HT3-RA and dexamethasone. We considered a 
15% change in this proportion to be clinically meaningful. Using nQuery 8.4.1.0, 
we calculated that we would need a sample size of 152 patients (76 per arm) to 
obtain 80% power with a Type 1 error level of 0.05. We then increased the total 
number of patients to account for a 10% dropout rate.  
 
A subject is considered evaluable if they complete cycle 1 of carboplatin and 
paclitaxel chemotherapy. Dose reductions in chemotherapy agents are allowed per 
standard clinical protocols.  
10.3 Data Analyses Plans 
The proportion of patients with complete response and no nausea will be 
calculated for the acute, delayed and overall periods in both arms. Proportions 
will be compared using a chi-square test using a significance level of 0.05%.  
 
Baseline rates of somnolence and increased appetite will be assessed prior to each 
cycle of chemotherapy (Appendix B). Mean somnolence and increased appetite 
scores for each day of chemotherapy will be compared to baseline means using 
paired t-tests.  
 
The proportion of patients with complete response and no nausea in each arm will 
be calculated for six cycles. To investigate the sustained efficacy of each regimen, 
the proportions will be compared within each arm over six cycles using repeated 
measures of variance.  
 


 
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Page 22 of 31 
 
For patients with uncontrolled CINV, as defined above, and for whom a fourth 
prophylactic agent is added in a subsequent cycle, complete response and rates of 
no nausea will be compared before and after the addition of the fourth agent using 
McNemar’s test.  
11.0 
DATA AND SAFETY MONITORING 
The study team will meet every 3 months or more frequently depending on the activity of 
the protocol. The discussion will include matters related to the safety of study 
participants, validity and integrity of the data, enrollment rate relative to expectations, 
characteristics of the participants, retention of participants, adherence to protocol, and 
data completeness. At these meetings, a report will be drafted with this information and 
submitted to an independent Data and Safety Monitoring Board (DSMB).  
The data, safety and quality of the trial will be monitored through an independent, 
external DSMB. The DSMB will include experts in oncology, biostatistics, and safety 
who are not participating in this trial and do not have affiliation with the Sponsor or other 
significant conflicts of interest.  
The DSMB will consist of the following members: 
Michael Frumovitz, MD MPH, Gynecologic Oncologist, MD Anderson Cancer Center 
Ritu Salani, MD MBA, Gynecologic Oncologist, OSU Cancer Center 
Rebecca Stone, MD MS, Gynecologic Oncologist, Johns Hopkins  
Colleen Rivard, MD, Gynecologic Oncologist, University of Minnesota 
Leslie Clark, MD, Gynecologic Oncologist, University of North Carolina 
 
 
Sarah Monsell, Biostastician, University of Washington 
 
DSMB meetings will be held approximately every 3 months. Ad hoc meetings will take 
place if needed. DSMB recommendations will be provided to the PI and submitted to 
IRBMED per institutional guidelines. 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
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Page 23 of 31 
 
 
12.0 
REFERENCES 
1.     Nausea C-I. Chemotherapy-Induced Nausea and Vomiting in Women With Gynecological 
Cancer. Available from: https://cdn.journals.lww.com/cancernursingonline 
2.  Ng TL, Hutton B, Clemons M. Chemotherapy-Induced Nausea and Vomiting: Time for 
More Emphasis on Nausea? Oncologist 2015;20(6):576–83. 
3.  Bloechl-Daum B, Deuson RR, Mavros P, Hansen M, Herrstedt J. Delayed nausea and 
vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic 
chemotherapy despite antiemetic treatment. J Clin Oncol 2006;24(27):4472–8. 
4.  Osoba D, Zee B, Warr D, Latreille J, Kaizer L, Pater J. Effect of postchemotherapy nausea 
and vomiting on health-related quality of life. The Quality of Life and Symptom Control 
Committees of the National Cancer Institute of Canada Clinical Trials Group. Support Care 
Cancer 1997;5(4):307–13. 
5.  Razvi Y, Chan S, McFarlane T, et al. ASCO, NCCN, MASCC/ESMO: a comparison of 
antiemetic guidelines for the treatment of chemotherapy-induced nausea and vomiting in 
adult patients. Support Care Cancer 2019;27(1):87–95. 
6.  Navari RM. Management of Chemotherapy-Induced Nausea and Vomiting: New Agents 
and New Uses of Current Agents. Springer; 2016. 
7.  Antiemesis NCCN 2017.pdf. 
8.     Yahata H, Kobayashi H, Sonoda K, et al. Efficacy of aprepitant for the prevention of 
chemotherapy-induced nausea and vomiting with a moderately emetogenic chemotherapy 
regimen: a multicenter, placebo-controlled, double-blind, randomized study in patients with 
gynecologic cancer receiving paclitaxel and carboplatin. Int J Clin Oncol 2016;21(3):491–7. 
9.    Choi CH, Kim MK, Park J-Y, et al. Safety and efficacy of aprepitant, ramosetron, and 
dexamethasone for chemotherapy-induced nausea and vomiting in patients with ovarian 
cancer treated with paclitaxel/carboplatin. Support Care Cancer 2014;22(5):1181–7. 
10. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology 
Clinical Practice Guideline Update. J Clin Oncol 2017;35(28):3240–61. 
11.  Chiu L, Chow R, Popovic M, et al. Efficacy of olanzapine for the prophylaxis and rescue of 
chemotherapy-induced nausea and vomiting (CINV): a systematic review and meta-analysis. 
Support Care Cancer 2016;24(5):2381–92. 
12.  Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the Prevention of Chemotherapy-
Induced Nausea and Vomiting. N Engl J Med 2016;375(2):134–42. 
13.  Tan L, Liu J, Liu X, et al. Clinical research of Olanzapine for prevention of chemotherapy-
induced nausea and vomiting. J Exp Clin Cancer Res 2009;28:131. 


 
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14.  Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of 
chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol 
2011;9(5):188–95. 
15.  Komatsu H, Oishi T, Sato S, et al. Evaluating Chemotherapy-induced Nausea and Vomiting 
and Food Intake in Patients With Gynecologic Cancer. Anticancer Res 2019;39(8):4555–60. 
16.  Tanaka K, Inui N, Karayama M, et al. Olanzapine-containing antiemetic therapy for the 
prevention of carboplatin-induced nausea and vomiting. Cancer Chemother Pharmacol 
2019;84(1):147–53. 
17.  Yanai T, Iwasa S, Hashimoto H, et al. A double-blind randomized phase II dose-finding 
study of olanzapine 10 mg or 5 mg for the prophylaxis of emesis induced by highly 
emetogenic cisplatin-based chemotherapy. Int J Clin Oncol 2018;23(2):382–8. 
18.  Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-
induced nausea and vomiting: a meta-analysis of randomized evidence. J Clin Oncol 
2000;18(19):3409–22. 
19.  O’Cathail SM, Shaboodien R, Mahmoud S, et al. Intravenous versus oral dexamethasone 
premedication in preventing Paclitaxel infusion hypersensitivity reactions in gynecological 
malignancies. Int J Gynecol Cancer 2013;23(7):1318–25. 
20.  Hesketh PJ, Schnadig ID, Schwartzberg LS, et al. Efficacy of the neurokinin-1 receptor 
antagonist rolapitant in preventing nausea and vomiting in patients receiving carboplatin-
based chemotherapy. Cancer 2016;122(15):2418–25. 
21.  Börjeson S, Hursti TJ, Peterson C, et al. Similarities and differences in assessing nausea on a 
verbal category scale and a visual analogue scale. Cancer Nurs 1997;20(4):260–6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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13.0 
APPENDICES 
 
Appendix A. Baseline patient questionnaire 
 
Date: _____/_____/_____ 
Age: ______ 
 
Race/Ethnicity: 
 
▢ White 
  
▢ Black 
 
▢ Asian 
 
▢ American Indian or Alaska Native 
 
▢ Other: ___________ 
 
Health history (please indicate whether you have any of the following conditions): 
 
▢ Gastric ulcers 
 
▢ Gastroparesis (delayed stomach emptying) 
 
▢ Irritable bowel syndrome 
 
▢ Cyclical vomiting syndrome 
 
▢ History of prolonged nausea/vomiting with pregnancy (e.g. hyperemesis gravidarum) 
 
Social history: 
 
Do you currently smoke tobacco? ▢ Yes   ▢ No 
 
If “yes”, how many cigarettes per day: ______________________________________ 
 
 
Do you currently smoke marijuana? ▢ Yes   ▢ No 
 
If “yes”, how much per day: ______________________________________ 
 
 
 
 


 
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Page 26 of 31 
 
 
Appendix B. Pre-chemotherapy patient questionnaire 
 
Date: _____/_____/_____ 
 
For the following 3 questions, please circle the one number (0-10) that best describes the 
way you felt over the past 24 hours.  
 
1. Please rate your worst nausea over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No nausea 
 
 
 
 
 
 
 
 
            Nausea as bad 
                at all 
 
 
 
 
 
 
 
 
               as it can be 
 
2. Please rate any undesired sedation that you had over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No undesired 
 
 
 
 
 
 
 
 
      Undesired sedation 
             sedation 
 
 
 
 
 
 
 
 
       as bad as it can be             
                at all 
 
 
 
 
 
 
 
 
                
 
3. Please rate any undesired appetite increase that you had over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No undesired  
 
 
 
 
 
 
 
      Undesired appetite 
       appetite increase  
 
 
 
 
 
 
 
         increase as bad             
                at all 
 
 
 
 
 
 
 
 
              as it can be 
 
 
 


 
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Page 27 of 31 
 
Appendix C. Daily patient questionnaire (day 2) 
 
Date: _____/_____/_____ 
 
Please verify that you took the following medications as prescribed in the preceding 24 hours: 
 
If in Olanzapine arm: 
Olanzapine 5mg at night: ▢ Yes   ▢ No 
 
If “no”, please provide reason: _______________________________________________ 
 
Check one option in each box, then continue and answer questions 1-3 below.  
 
*Vomiting (check one) 
#of EXTRA nausea/vomiting pills 
(Compazine) taken because you 
developed nausea/vomiting 
Last 24 
hours 
__None 
__Once 
__Twice 
__More than twice, please indicate 
amount: ___ 
__None 
__One 
__Two 
__More than two, please indicate 
amount: ___ 
*A single episode of vomiting is defined as:  
● a single vomit of sold or liquid stomach contents 
● a single retch, or ‘dry heave’, that did not produce solid or liquid stomach 
contents 
● any episode of continuous vomiting or retching 
 
Note: episodes separated from each other by the absence of retching or vomiting for at least 1 
minute should be considered separate emetic episodes 
 
For the following 3 questions, please circle the one number (0-10) that best describes the 
way you felt over the past 24 hours.  
 
1. Please rate your worst nausea over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No nausea 
 
 
 
 
 
 
 
 
            Nausea as bad 
                at all 
 
 
 
 
 
 
 
 
               as it can be 
 
2. Please rate any undesired sedation that you had over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No undesired  
 
 
 
 
 
 
 
      Undesired sedation 
             sedation 
 
 
 
 
 
 
 
 
       as bad as it can be             
                at all 
 
 
 
 
 
 
 
 
                
 
3. Please rate any undesired appetite increase that you had over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No undesired  
 
 
 
 
 
 
 
      Undesired appetite 
       appetite increase  
 
 
 
 
 
 
 
         increase as bad             
                at all 
 
 
 
 
 
 
 
 
              as it can be 
 


 
________________________________________________________________________ 
Page 28 of 31 
 
Appendix D. Daily patient questionnaire (days 3-5) 
 
Date: _____/_____/_____ 
 
Please verify that you took the following medications as prescribed in the preceding 24 hours: 
 
Ondansetron 8mg twice a day: ▢ Yes   ▢ No 
 
If “no”, please provide reason: _______________________________________________ 
 
If in Olanzapine arm: 
Olanzapine 5mg at night: ▢ Yes   ▢ No 
 
If “no”, please provide reason: _______________________________________________ 
 
Check one option in each box, then continue and answer questions 1-3 below.  
 
*Vomiting (check one) 
#of EXTRA nausea/vomiting pills 
(Compazine) taken because you 
developed nausea/vomiting 
Last 24 
hours 
__None 
__Once 
__Twice 
__More than twice, please indicate 
amount: ___ 
__None 
__One 
__Two 
__More than two, please indicate 
amount: ___ 
*A single episode of vomiting is defined as:  
● a single vomit of sold or liquid stomach contents 
● a single retch, or ‘dry heave’, that did not produce solid or liquid stomach 
contents 
● any episode of continuous vomiting or retching 
 
Note: episodes separated from each other by the absence of retching or vomiting for at least 1 
minute should be considered separate emetic episodes 
 
For the following 3 questions, please circle the one number (0-10) that best describes the 
way you felt over the past 24 hours.  
 
1. Please rate your worst nausea over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No nausea 
 
 
 
 
 
 
 
 
            Nausea as bad 
                at all 
 
 
 
 
 
 
 
 
               as it can be 
 
2. Please rate any undesired sedation that you had over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No undesired  
 
 
 
 
 
 
 
      Undesired sedation 
             sedation 
 
 
 
 
 
 
 
 
       as bad as it can be             
                at all 
 
 
 
 
 
 
 
 
                
 
3. Please rate any undesired appetite increase that you had over the past 24 hours 


 
________________________________________________________________________ 
Page 29 of 31 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No undesired  
 
 
 
 
 
 
 
      Undesired appetite 
       appetite increase  
 
 
 
 
 
 
 
         increase as bad             
                at all 
 
 
 
 
 
 
 
 
              as it can be 
 
 


 
________________________________________________________________________ 
Page 30 of 31 
 
Appendix E. Daily patient questionnaire (day 6) 
 
Date: _____/_____/_____ 
 
Check one option in each box, then continue and answer questions 1-3 below.  
 
*Vomiting (check one) 
#of EXTRA nausea/vomiting pills 
(Compazine) taken because you 
developed nausea/vomiting 
Last 24 
hours 
__None 
__Once 
__Twice 
__More than twice, please indicate 
amount: ___ 
__None 
__One 
__Two 
__More than two, please indicate 
amount: ___ 
*A single episode of vomiting is defined as:  
● a single vomit of sold or liquid stomach contents 
● a single retch, or ‘dry heave’, that did not produce solid or liquid stomach 
contents 
● any episode of continuous vomiting or retching 
 
Note: episodes separated from each other by the absence of retching or vomiting for at least 1 
minute should be considered separate emetic episodes 
 
For the following 3 questions, please circle the one number (0-10) that best describes the 
way you felt over the past 24 hours.  
 
1. Please rate your worst nausea over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No nausea 
 
 
 
 
 
 
 
 
            Nausea as bad 
                at all 
 
 
 
 
 
 
 
 
               as it can be 
 
2. Please rate any undesired sedation that you had over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No undesired  
 
 
 
 
 
 
 
      Undesired sedation 
             sedation 
 
 
 
 
 
 
 
 
       as bad as it can be             
                at all 
 
 
 
 
 
 
 
 
                
 
1. Please rate any undesired appetite increase that you had over the past 24 hours 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
       No undesired  
 
 
 
 
 
 
 
      Undesired appetite 
       appetite increase  
 
 
 
 
 
 
 
         increase as bad             
                at all 
 
 
 
 
 
 
 
 
              as it can be 
 
 


 
________________________________________________________________________ 
Page 31 of 31 
 
 
Appendix F. Research Coordinator Contact Form 
 
Day of Telephone Contact (check one): 
 ▢ Day 2   ▢ Day 3 ▢ Day 4  ▢ Day 5  ▢ Day 6   
 
Date of telephone contact or date of attempted contact: _____/_____/_____ 
 
Were you able to contact the patient? ▢ Yes   ▢ No 
If yes, list time of day contacted: ___:___ 
 
Please remind the patient to complete their questionnaire. Offer to go through the questionnaire 
with them over the phone and have them fill it out at the same time. Please explain the rescue 
nausea medication information specifically “number of extra (PRN) nausea and vomiting pills 
taken.” 
 
Please also ask about adverse events and answer the following: 
 
Did patient have any adverse events? (check one)  ▢ Yes   ▢ No 
 
If yes, fill out AE: Record all adverse events, including event, grade, and attribution. 
 
Comments: 
______________________________________________________________________________
______________________________________________________________________________ 
 
 

ICF_001.pdf: 
ID: UMCC 2019.173    
Olanzapine for the Prevention of Chemotherapy Induced Nausea and 
Vomiting in Gynecologic Oncology Patients    
NCT04503668


Page 1 of 14
Consent Version: ______4/5/2023______
UNIVERSITY OF MICHIGAN
CONSENT TO BE PART OF A RESEARCH STUDY
 
1.  KEY INFORMATION ABOUT THE RESEARCHERS AND THIS STUDY  
Study title: Phase III randomized controlled trial investigating olanzapine for the prevention of 
chemotherapy induced nausea and vomiting in patients with gynecologic malignancies receiving every 
3-week carboplatin and paclitaxel chemotherapy (UMCC Number 2019.173)
Company or agency sponsoring the study: None
Names, degrees, and affiliations of the principal investigator and study coordinator (if applicable):
Principal Investigator: 
Aimee Rolston, MD MS
Michigan Medicine, Department of Obstetrics and Gynecology
Study Coordinator:
Daniela Martin
Michigan Medicine, Department of Obstetrics and Gynecology
1.1 Key Study Information
You may be eligible to take part in a research study.  This form contains important information that will 
help you decide whether to join the study.  Take the time to carefully review this information.  You 
should talk to the researchers about the study and ask them any questions you have.  You may also wish 
to talk to others such as your family, friends, or other doctors about joining this study.  If you decide to 
join the study, you will be asked to sign this form before you can start study-related activities.  Before 
you do, be sure you understand what the research study is about.
A research study is different from the regular medical care you receive from your doctor.  Research 
studies hope to make discoveries and learn new information about diseases and how to treat them.  You 
should consider the reasons why you might want to join a research study or why it is not the best 
decision for you at this time.  
Research studies do not always offer the possibility of treating your disease or condition.  Research 
studies also have different kinds of risks and risk levels, depending on the type of the study.  You may 
also need to think about other requirements for being in the study.  For example, some studies require 
you to travel to scheduled visits at the study site in Ann Arbor or elsewhere. This may require you to 
arrange travel, change work schedules, find childcare, or make other plans.  In your decision to 
participate in this study, consider all of these matters carefully.  
This research is studying a drug, Olanzapine, in a large group of people to learn how well it works to 
prevent nausea and vomiting related to chemotherapy.  This research will find out if Olanzapine, when 
given with other standard medications, will improve our ability to prevent nausea and vomiting in 
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patients with gynecologic cancers receiving carboplatin and paclitaxel chemotherapy.  Olanzapine will 
be compared to the current standard of care drug, a neurokinin-1 receptor antagonist. Your health-
related information will be collected for this research study.   
This study involves a process called randomization.  This means that the drug you receive in the study 
(Olanzapine versus neurokinin-1 receptor antagonist) is not chosen by you or the researcher.  The study 
design divides study participants into separate groups, based on chance (like the flip of a coin), to 
compare different treatments or procedures.  If you decide to be in the study, you need to be 
comfortable not being able to decide which treatment you will receive. You will know the treatment you 
are receiving once assigned to a certain group. 
There can be risks associated with joining any research study.  The type of risk may impact whether you 
decide to join the study.  For this study, some of these risks may include increased sedation and 
increased appetite.  More detailed information will be provided later in this document.
This study may offer some benefit to you now or others in the future by decreasing the amount of 
nausea and vomiting you experience with chemotherapy.  More information will be provided later in 
this document.
We expect the amount of time you will participate in the study will be approximately 5 months.
You can decide not to be in this study.  Alternatives to joining this study include standard of care 
management for nausea and vomiting related to chemotherapy or choosing not to take medications for 
this reason during chemotherapy.  
Even if you decide to join the study now, you are free to leave at any time if you change your mind.
More information about this study continues in Section 2 of this document.
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2. PURPOSE OF THIS STUDY
2.1 Study purpose: 
The purpose of this study is to find more effective medications for the prevention of nausea and 
vomiting caused by chemotherapy. This study is being performed to find out whether Olanzapine, when 
given with other standard anti-nausea medications, improves our ability to control nausea and vomiting 
related to chemotherapy in patients receiving carboplatin and paclitaxel for a gynecologic cancer. 
Current standard of care involves the use of a neurokinin-1 receptor antagonist (NK1-RA), along with 
other anti-nausea medications, to prevent nausea and vomiting related to chemotherapy. Olanzapine is 
an alternative drug that has been shown to prevent nausea and vomiting related to chemotherapy in 
other patient populations. It’s use in patients with gynecologic cancers receiving carboplatin and 
paclitaxel chemotherapy is not well studied. 
Our objective is to compare the use of Olanzapine to NK1-RAs in patients with gynecologic cancers 
receiving standard chemotherapy. The results of our proposed work have the potential to significantly 
improve patients’ experiences related to chemotherapy. 
3. WHO MAY PARTICIPATE IN THE STUDY
Taking part in this study is completely voluntary.  You do not have to participate if you don't want to.  
You may also leave the study at any time.  If you leave the study before it is finished, there will be no 
penalty to you, and you will not lose any benefits to which you are otherwise entitled. 
3.1 Who can take part in this study?
You are invited to take part in this study because you have a gynecologic cancer for which you are 
receiving carboplatin and paclitaxel chemotherapy at The University of Michigan and are between the 
ages of 18 and 89. You also are not receiving any radiation treatments, have not been treated with any 
chemotherapy in the last 12 months, have no history of adverse reactions to Olanzapine, have no history 
of significant heart disease, are not on any medications for diabetes, ls, and have not had 5 or more 
episodes of vomiting within 1 week prior to initiation of chemotherapy.
Every study has strict guidelines for determining which people may participate.  These are called 
eligibility criteria.  You will need to meet all of these criteria before you can participate in this study.  If 
you agree to consider participating in this study, you will undergo evaluations to see if you meet the 
eligibility criteria for this study.  Even though you may meet all the criteria for participation, it is possible 
that you may not be enrolled in this study for other reasons.
3.2 How many people are expected to take part in this study?
The research study is planned to include approximately 170 patients receiving carboplatin and paclitaxel 
chemotherapy for a gynecologic cancer. We expect to enroll all of these patients at the University of 
Michigan. 
4.  INFORMATION ABOUT STUDY PARTICIPATION
4.1 What will happen to me in this study?  
The study team will explain the research study and answer any questions you may have about the study. 
If you are interested in participating in the study, the study team will look through your medical chart 
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and ask you questions to determine whether you are eligible for the study. Any labs/studies required to 
evaluate your eligibility for this study are already collected as part of standard of care for receiving 
chemotherapy. No additional labs or studies need to be performed solely for the purpose of this study. 
Once eligibility is confirmed and you decide to participate, you will be asked to sign the informed 
consent form at the end of this document. 
If you are currently participating in any other study, you should let the study team know and they will 
determine if it is safe for you to also take part in this study. If you do not meet the requirements for 
participation, the study doctor will explain why and will discuss with you other options.
Participation in the study will start with your first standard of care cycle of chemotherapy. In addition to 
coming to the hospital for your standard of care visits, lab work, and chemotherapy infusion, as part of 
the study, we will ask that you complete short (less than 10 question) surveys regarding your symptoms 
on days 1-6 of chemotherapy. More details regarding these surveys can be found below. 
As a subject participating in this research study, you have certain responsibilities that may apply to this 
study, such as ensuring that you arrive at all of your scheduled appointments, take your medications as 
directed, and report any adverse reactions you may have during the study.
Screening Period
Screening for this study will take place prior to your first cycle of chemotherapy / during your 
chemotherapy education visit. Your labs and medical history will be reviewed to determine eligibility. If 
you are able to have children, a pregnancy test will also be required.  
Study Intervention Period
If you meet all criteria to participate in the study, you will enter the intervention period. 
As for this study, you will be randomly assigned to receive either Olanzapine (taken at night by mouth on 
days 1-4 of chemotherapy) or a neurokinin 1 receptor antagonist (given by IV on day of chemotherapy). 
You have an equal chance of receiving either medication. Which treatment you receive is decided at 
random by a computer (purely by chance, like tossing of a coin). 
We will ask that you complete short (less than 10 question) surveys regarding your symptoms on days 1-
6 of chemotherapy. You will be given a booklet with these questionnaires to complete. You will be sent 
text reminders to complete the questionnaires. In addition, for cycle 1, a study team member will be 
calling you to remind you to complete the questionnaires. We ask that you bring the booklet with you to 
your next doctor’s visit prior to your next cycle of chemotherapy. We ask that you complete these 
questionnaires for all planned cycles of chemotherapy. 
The schedule for study procedures is as follows:
-
Pre study/consent visit: consent, history and physical, baseline questionnaires, standard of care 
labs, contraceptive counseling 
-
Before chemo treatments: pre-chemo study questionnaire and standard of care labs. The labs 
can be completed the day of chemo or before. 
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-
On chemo days: standard of care labs if not completed prior, study drug administration
-
Post Chemo Treatment: patient diary filled out for days 1-6, study drug administration if 
randomized to Olanzapine arm. 
If your nausea and vomiting is not well controlled by the medications you are assigned to receive, it is 
possible your doctor may change or add to the prescriptions for your next cycle of chemotherapy. This 
will be determined based on your symptoms. 
Study Completion and Follow Up Period
After completion of the study, a final assessment of side effects will be performed during your routine 
post chemotherapy office visit by a member of our study team. There will be no additional follow up. 
4.2 How much of my time will be needed to take part in this study?  
Your study visits will all coincide with standard of care clinic visits prior to scheduled chemotherapy. We 
anticipate additional time for study purposes as follows:

Screening/Enrollment Period: additional 30 minutes to allow for consent process, randomization 
and education

Study Intervention Period: additional 10 minutes each visit to allow study team member to 
retrieve prior questionnaires, answer questions, and discuss any side effects/concerns

Study Completion and Follow up Period: additional 10 minutes at final follow up visit to allow 
study team member to retrieve complete questionnaires, answer questions, and discuss any 
side effects/concerns
In addition to the above, you will be asked to complete a short questionnaire on days 1-6 of 
chemotherapy. We expect that this will take you ~5 minutes each day. 
4.3 When will my participation in the study be over? 
The expected duration for your participation depends on the study treatment and your health condition. 
All patients will continue participation in the study until the end of chemotherapy, cancer progression 
necessitating a different therapy, or if you, the study team, or your provider decides that you should not 
continue to be in the study. 
4.4 What will happen with my information and/or biospecimens used in this study?
Your collected information may be shared with other researchers: 

With appropriate permissions, your identifiable collected information may be shared, and/or,

Without your additional consent, your identifiable private information may be stripped of 
identifiers and used for future research studies or distributed to another researcher for future 
research studies. 
5.  INFORMATION ABOUT STUDY RISKS AND BENEFITS
5.1 What risks will I face by taking part in the study?  What will the researchers do to protect me 
against these risks?
Your provider and the study team will monitor you closely for side effects. Even with frequent 
monitoring, enrolling in this study involves risks, and some side effects of the medications cannot be 
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predicted. Side effects can range from mild to severe to life threatening. Most side effects will get better 
when you stop taking the study drug, but some may be long lasting or may never go away. Side effects 
may even cause death. You should tell your provider or the study team immediately about any side 
effects that you have or any change in how you feel while on this study. If you have side effects, your 
dose may have to be reduced, or you may have to stop taking the drugs and wait until you feel better 
before you start again. Your study team may give you medicines or lower your dose of drugs to help 
lessen side effects.  If any side effect is intolerable, you may have to permanently stop taking the drugs.
The known or expected risks are:
Risks associated with Olanzapine:
Common side effects:

Sedation

Increased appetite
Less common side effects

Dizziness

Headache

Hypotension

Constipation

Fatigue

Increased prolactin

Increased liver enzymes

Weakness

Increased risk of diabetes mellitus
Risks or other discomforts associated with study procedures
Questionnaires
As part of the study, you will be asked to complete questionnaires about your symptoms during 
chemotherapy. Some of the questions may seem very personal or embarrassing. They may make you 
uncomfortable. You may refuse to answer any of the questions that you do not wish to answer. If the 
questions make you uncomfortable, we can help you to find a counselor.
The researchers will try to minimize these risks by monitoring you closely. The study will give the lowest 
effective dose of Olanzapine. Additionally, the study design is one where Olanzapine is used 
intermittently for short periods which minimizes side effects when compared to chronic, daily use. If you 
have side effects, we will make appropriate adjustments as defined by the study protocol. You may need 
to discontinue Olanzapine if side effects are too serious. Your risks are further minimized by using the 
results of blood tests you are already having for your clinical care. There are no additional tests or 
studies required specifically for this research study. 
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Additionally, there may be a risk of loss to confidentiality or privacy.  For example, if your identity as a 
participant in this research or your identifiable genetic or health information were disclosed to 
unauthorized persons, there is the possible risk of discrimination by employers or insurance providers.  
The researchers believe that the risks of such improper disclosure are very small because strict privacy 
and confidentiality procedures for this research have been adopted.  See Section 9 of this document for 
more information on how the study team will protect your confidentiality and privacy.
There could be risks to a fetus in this study. If you are pregnant or become pregnant during the study, 
these risks could affect you or your fetus. Women must agree to either abstain from sexual activities 
that could result in pregnancy or use at least one acceptable method of birth control (i.e. condom, IUD, 
pill) while taking part in this study.
As with any research study, there may be additional risks that are unknown or unexpected.
5.2 What happens if I get hurt, become sick, or have other problems as a result of this research?
The researchers have taken steps to minimize the risks of this study.  Even so, you may still have 
problems or side effects, even when the researchers are careful to avoid them. Please tell the 
researchers listed in Section 10 about any injuries, side effects, or other problems that you have during 
this study.  You should also tell your regular doctors.
5.3 If I take part in this study, can I also participate in other studies?
Being in more than one research study at the same time, or even at different times, may increase the 
risks to you.  It may also affect the results of the studies.  You should not take part in more than one 
study without approval from the researchers involved in each study.  
5.4 How could I benefit if I take part in this study?  How could others benefit?  
You may not receive any personal benefits from being in this study. Some of the possible benefits to you 
as a participant in this study are reduction in the nausea and vomiting you experience with 
chemotherapy, or elimination of those symptoms all together. Less nausea and vomiting with 
chemotherapy improves your ability to get your treatments on time. Others may also benefit from the 
knowledge gained from this study.
5.5 Will the researchers tell me if they learn of new information that could change my willingness to 
stay in this study?
Yes, the researchers will tell you if they learn of important new information that may change your 
willingness to stay in this study. If new information is provided to you after you have joined the study, it 
is possible that you may be asked to sign a new consent form that includes the new information.
6.  ALTERNATIVES TO PARTICIPATING IN THE STUDY
6.1 If I decide not to take part in this study, what other options do I have?
If you decide not to take part in this study, you will be provided with current standard of care 
medications for the prevention of nausea and vomiting related to chemotherapy. 
7.  ENDING THE STUDY
7.1 If I want to stop participating in the study, what should I do?
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You are free to leave the study at any time.  If you leave the study before it is finished, there will be no 
penalty to you. You will not lose any benefits to which you may otherwise be entitled.  If you choose to 
tell the researchers why you are leaving the study, your reasons for leaving may be kept as part of the 
study record. If you decide to leave the study before it is finished, please tell one of the persons listed in 
Section 10 “Contact Information”.
If you withdraw full consent from the study, your data will be destroyed at that time. If you withdraw 
from study treatment, the data that has been collected up until that point in the study will be used.
7.2 Could there be any harm to me if I decide to leave the study before it is finished? 
Tell the study doctor if you are thinking about stopping or decide to stop.  It is important to tell the 
study doctor if you are thinking about stopping so any risks can be evaluated by your doctor. If you 
decide to leave the study before it is finished, please tell your study doctor or one of the researchers 
listed in Section 10 “Contact Information” (below).
7.3 Could the researchers take me out of the study even if I want to continue to participate?
Yes. There are many reasons why the researchers may need to end your participation in the study.  
Some examples are:

The researcher believes that it is not in your best interest to stay in the study.

You become ineligible to participate.

Your condition changes and you need treatment that is not allowed while you are taking part in 
the study.

You do not follow instructions from the researchers.

The study is suspended or canceled.
8.  FINANCIAL INFORMATION
8.1 Who will pay for the costs of the study?  Will I or my health plan be billed for any costs of the 
study?  
You or your health plan will pay for all the things you would have paid for even if you were not in the 
study, like:

Health care given during the study as part of your regular care

Items or services needed to give you study drugs or devices

Monitoring for side effects or other problems

Deductibles or co-pays for these items or services.
If you are injured or in the event of a medical emergency, dial 911 or visit your nearest Emergency 
Room. If you believe the study has made you sick or caused you injury, contact one of the people listed 
in section 10 of this document (Contact Information). If taking part in the study makes you sick or causes 
you injury, you or your insurance provider will be billed for all costs of treatment as the study does not 
provide compensation for sickness or injury caused by the study. It is possible that your insurance will 
not cover these costs.
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If you do not have a health plan, or if you think your health plan may not cover these costs during the 
study, please talk to the researchers listed in Section 10 below or call your health plan’s medical 
reviewer.
By signing this form, you do not give up your right to seek payment if you are harmed as a result of 
being in this study.
8.2 Will I be paid or given anything for taking part in this study?
No, you will not be paid for taking part in this study. 
8.3 Who could profit or financially benefit from the study results?
No person or organization has a financial interest in the outcome of this study.
Even so, research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their 
organizations, and other entities, including companies, may potentially benefit from the use of the data 
or discoveries. You will not have rights to these discoveries or any proceeds from them.
9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED 
HEALTH INFORMATION
The information below describes how the confidentiality of your research records will be protected in 
this study, and any sub-studies described in this document.  
9.1 How will the researchers protect my information? 
Your participatin will occur at the University of Michigan. Your data will be kept confidential, to the 
extent permitted by applicable laws, in the following manner:

Your name will not be used in any reports about the study

Your will be identified only by a study code (subject ID number)

Your identifying information will be kept secure
The study team will assign a code number to your study data. Some study data may contain information 
that could be used (perhaps in combination with other information) to identify you (e.g. date of birth). 
The study team will use the study data for research purposes to support the scientific objectives of the 
study. Study data (that does not directly identify you) may be published in medical journals or shared 
with others as part of scientific discussions. 
Your research information will be stored entered into a secure database and stored in a locked cabinet. 
It will not be made part of your regular medical record. Your stored research information will be labeled 
with your study code and will not include any identifying information. Only the study team will have 
access to the document linking your study code with your name/other identifiyng information. This 
document will be locked with restricted access.  
A description of this clinical trial will be available on http://www.clinicaltrials.gov/, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time.
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9.2 What protected health information (PHI) about me could be seen by the researchers or by other 
people?  Why?  Who might see it?
Signing this form gives the researchers your permission to obtain, use, and share information about you 
for this study, and is required in order for you to take part in the study.  
Medical information and billing records are protected by the privacy regulations of the federal Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  This type of information is called 
protected health information (PHI).  PHI about you may be obtained from any hospital, doctor, and 
other health care provider involved in your care, including:

Hospital/doctor's office records, including test results (X-rays, blood tests, urine tests, etc.)

Mental health care records (except psychotherapy notes not kept with your medical records)

Alcohol/substance abuse treatment records

Health plan/health insurance records

All records relating to your condition, the treatment you have received, and your response to 
the treatment

Billing information

Demographic information

Personal identifiers
There are many reasons why information about you may be used or seen by the researchers or others 
during or after this study.  Examples include:

The researchers may need the information to make sure you can take part in the study.  

The researchers may need the information to check your test results or look for side effects.  

University, Food and Drug Administration (FDA) and/or other government officials, auditors, 
and/or the IRB may need the information to make sure that the study is done in a safe and 
proper manner.   

Study sponsors or funders, or safety monitors or committees, may need the information to: 
o
Make sure the study is done safely and properly
o
Learn more about side effects 
o
Analyze the results of the study 

Insurance companies or other organizations may need the information in order to pay your 
medical bills or other costs of your participation in the study.

The researchers may need to use the information to create a databank of information about 
your condition or its treatment.

Information about your study participation may be included in your regular UMHS medical 
record.

Federal or State law may require the study team to give information to government agencies. 
For example, to prevent harm to you or others, or for public health reasons. 
The results of this study could be published in an article, but would not include any information that 
would let others know who you are. 
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9.3 What happens to information about me after the study is over or if I cancel my permission to use 
my PHI?
As a rule, the researchers will not continue to use or disclose information about you, but will keep it 
secure until it is destroyed.  Sometimes, it may be necessary for information about you to continue to be 
used or disclosed, even after you have canceled your permission or the study is over.  
Examples of reasons for this include:

To avoid losing study results that have already included your information 

To provide limited information for research, education, or other activities. (This information 
would not include your name, social security number, or anything else that could let others 
know who you are.) 

To help University and government officials make sure that the study was conducted properly
As long as your information is kept within the University of Michigan Health System, it is protected by 
the Health System’s privacy policies.  For more information about these policies, ask for a copy of the 
University of Michigan “Notice of Privacy Practices”.  This information is also available on the web at 
http://www.uofmhealth.org/patient+and+visitor+guide/hipaa.  Note that once your information has 
been shared with others as described under Question 9.2, it may no longer be protected by the privacy 
regulations of the federal Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
9.4 When does my permission to use my PHI expire?  
Your permission expires at the end of the study, unless you cancel it sooner. You may cancel your 
permission at any time by writing to the researchers listed in Section 10 "Contact Information" (below).  
If you withdraw your permission, you may no longer be eligible to participate in this study.
10. CONTACT INFORMATION
10.1 Who can I contact about this study?
Please contact the researchers listed below to:

Obtain more information about the study

Ask a question about the study procedures or treatments

Talk about study-related costs to you or your health plan 

Report an illness, injury, or other problem (you may also need to tell your regular doctors)

Leave the study before it is finished

Express a concern about the study
Principal Investigator: Aimee Rolston, MD MS
Mailing Address: University of Michigan
         
         1500 East Medical Center Drive
Telephone: 734-647-8906
                     734-936-4000 Hospital Operator – 24-hr paging
Study ID: HUM00175458   IRB: IRBMED   Date Approved: 5/18/2023   Expiration Date: 5/17/2024


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Consent Version: ______4/5/2023______
Study Coordinator:  Daniela Martin
Mailing Address: 1500 East Medical Center Drive
Telephone: 734-232-1846
You may also express a question or concern about a study by contacting the Institutional Review 
Board listed below:
University of Michigan Medical School Institutional Review Board (IRBMED)
2800 Plymouth Road
Building 520, Room 3214
Ann Arbor, MI 48109-2800
Telephone: 734-763-4768  (For International Studies, include the appropriate calling codes.)
Fax: 734-763-1234
e-mail: irbmed@umich.edu 
If you are concerned about a possible violation of your privacy or concerned about a study you may 
contact the University of Michigan Health System Compliance Help Line at 1-866-990-0111.
When you call or write about a concern, please provide as much information as possible, including the 
name of the researcher, the IRBMED number (at the top of this form), and details about the problem.  
This will help University officials to look into your concern.  When reporting a concern, you do not have to 
give your name unless you want to.
11.  RECORD OF INFORMATION PROVIDED
11.1 What documents will be given to me?
Your signature in the next section means that you have received copies of all of the following 
documents:

This "Consent to be Part of a Research Study" document (you will receive a copy of the signed 
and dated informed consent) (Note: In addition to the copy you receive, copies of this document 
will be stored in a separate confidential research file and may be entered into your regular 
University of Michigan medical record.)

Questionnaire packet
12.  SIGNATURES
Study ID: HUM00175458   IRB: IRBMED   Date Approved: 5/18/2023   Expiration Date: 5/17/2024


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Consent Version: ______4/5/2023______
Sig-A
Consent/Assent to Participate in the Research Study
I understand the information printed on this form.  I have discussed this study, its risks and potential benefits, 
and my other choices with [NAME OF STUDY TEAM MEMBER OBTAINING CONSENT] ______________________.  
My questions so far have been answered.  I understand that if I have more questions or concerns about the 
study or my participation as a research subject, I may contact one of the people listed in Section 10 (above).  I 
understand that I will receive a copy of this form at the time I sign it and later upon request.  I understand that if 
my ability to consent or assent for myself changes, either I or my legal representative may be asked to re-
consent prior to my continued participation in this study.
Print Legal Name: ___________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Sig-D
Consent/Assent to Collect for Unspecified Future Research
This project involves the option to allow the study team to keep your identifiable specimens/data for use in 
future research.  I understand that it is my choice whether or not to allow future use of my specimens.  I 
understand that if my ability to consent or assent for myself changes, either I or my legal representative may be 
asked to re-consent prior to my continued participation in this study.
_____ Yes, I agree to let the study team keep my specimens for future research.
_____ No, I do not agree to let the study team keep my specimens for future research.
Print Legal Name: ___________________________________________________________________
Signature: _________________________________________________________________________
f Si
(
/dd/
)
Study ID: HUM00175458   IRB: IRBMED   Date Approved: 5/18/2023   Expiration Date: 5/17/2024


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Consent Version: ______4/5/2023______
Sig-G
Principal Investigator or Designee
I have provided this participant and/or his/her legally authorized representative(s) with information about this 
study that I believe to be accurate and complete.  The participant and/or his/her legally authorized 
representative(s) indicated that he or she understands the nature of the study, including risks and benefits of 
participating.
Printed Legal Name: __________________________________________________________________
Title: ______________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Study ID: HUM00175458   IRB: IRBMED   Date Approved: 5/18/2023   Expiration Date: 5/17/2024