Conditions: Malignant Neoplasm
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 690
Healthy volunteers: no

Brief summary:
This randomized phase III trial studies how well olanzapine with or without fosaprepitant work in preventing chemotherapy induced nausea and vomiting in cancer patients receiving chemotherapy that causes vomiting. Olanzapine and fosaprepitant dimeglumine may help control nausea and vomiting in patients during chemotherapy. Olanzapine is usually given in combination with other drugs, including fosaprepitant dimeglumine. It is not yet known if olanzapine when given with other drugs, is still effective without using fosaprepitant dimeglumine for controlling nausea and vomiting.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare between the two study arms the proportion of patients with no nausea for the overall (0-120 hours post-chemotherapy), acute (0-24 hours post-chemotherapy), and delayed periods (24-120 hours post-chemotherapy) for patients receiving highly emetogenic chemotherapy (HEC).

SECONDARY OBJECTIVES:

I. To compare between the two study arms the complete response (CR) rates (no emetic episodes and no use of rescue medication) in the acute, delayed, and overall periods.

II. To compare between the two study arms, the incidences of potential toxicities that have been ascribed to olanzapine.

III. To perform an economic evaluation of olanzapine and fosaprepitant dimeglumine (fosaprepitant) versus (vs.) olanzapine in patients receiving HEC (noting that all patients will also receive dexamethasone and a 5HT3 receptor antagonist).

IV. To explore the efficacy of olanzapine in chemotherapy cycles two to four, for patients who elect to continue on the same antiemetic regimen received in cycle one, in chemotherapy cycles two to four (continuation phase), by documenting nausea and complete response.

V. To explore the safety of olanzapine in chemotherapy cycles two to four, for patients who elect to continue on the same antiemetic regimen received in cycle one, in chemotherapy cycles two to four (continuation phase), by recording any adverse events or drug related toxicities.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive palonosetron hydrochloride intravenously (IV) over 30 seconds or ondansetron hydrochloride IV over 2-5 minutes or orally (PO) on day 1, dexamethasone PO on days 1-4, fosaprepitant dimeglumine IV over 20-30 minutes on day 1, and olanzapine PO on days 1-4. Treatment may repeat every 4 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive palonosetron hydrochloride IV over 30 seconds or ondansetron hydrochloride IV over 2-5 minutes or PO on day 1, dexamethasone PO on days 1-4, placebo IV over 20-30 minutes on day 1, and olanzapine PO on days 1-4. Treatment (with no placebo) may repeat every 4 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study, patients are followed up periodically.

Arms:
arm 1: Patients receive palonosetron hydrochloride IV over 30 seconds or ondansetron hydrochloride IV over 2-5 minutes or PO on day 1, dexamethasone PO on days 1-4, fosaprepitant dimeglumine IV over 20-30 minutes on day 1, and olanzapine PO on days 1-4. Treatment may repeat every 4 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive palonosetron hydrochloride IV over 30 seconds or ondansetron hydrochloride IV over 2-5 minutes or PO on day 1, dexamethasone PO on days 1-4, placebo IV over 20-30 minutes on day 1, and olanzapine PO on days 1-4. Treatment (with no placebo) may repeat every 4 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Palonosetron Hydrochloride intervention 2: Ondansetron Hydrochloride intervention 3: Dexamethasone intervention 4: Fosaprepitant Dimeglumine intervention 5: Olanzapine intervention 6: Placebo
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV or PO intervention 3: Given PO intervention 4: Given IV intervention 5: Given PO intervention 6: Given IV

Protocol document:
Prot_SAP_ICF_001.pdf: 
1 
 
Protocol Update #06 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO ALLIANCE A221602  
_________________________________________ 
 
OLANZAPINE WITH OR WITHOUT FOSAPREPITANT FOR THE PREVENTION OF 
CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV) IN PATIENTS RECEIVING 
HIGHLY EMETOGENIC CHEMOTHERAPY (HEC): A PHASE III RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED TRIAL 
Supplied agent(s): olanzapine (Alliance IND 120137; NSC 754829)  
 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
X Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other:  
 
 
 
 
If your site utilizes the CIRB as your IRB of record 
No recommended IRB level of review is provided by the Alliance since the CIRB is the IRB of record 
for this trial. 
The site has 30 days after the posting of this amendment to implement it at their site. Please refer to the 
amendment application and CIRB guidelines for further instructions. 
If your site utilizes a local IRB as your IRB of record 
IRB approval (or disapproval) is required within 90 days. Please follow your local IRB guidelines.  
Expedited IRB Approval is allowed. The proposed changes in this amendment are minor and do not 
affect the overall risk/benefit ratio. 
 
Re-consent is not required by the Alliance. Please follow the policy of your IRB of record regarding 
notifying patients of new information contained in this update. 
 
 


2 
 
 
UPDATES TO THE PROTOCOL: 
 
Cover Page (p. 1) 
• 
The email address for 
has been updated.  
• 
  
 
 
Protocol Contacts (p. 2) 
 
 
 
 
 
 
Section 3.2.20 Required Initial Laboratory Values (p. 18) 
“Serum Creatinine” has been updated to “Serum or Plasma Creatinine.” 
 
Section 13.9 Inclusion of Women and Minorities (pp. 67-68) 
The second sentence in the “Black or African American” definition has been removed. 
 
 
UPDATES TO THE MODEL CONSENT FORM:  
 
What extra exams, tests, and procedures are involved in this study? (pp. 82-83) 
Under “You will be asked to complete the surveys at the following time points,” in the last bullet point, 
“the University of Chicago” has been corrected to “Wayne State University.” 
 
Who will see my medical information? (pp. 86-87) 
The Certificate of Confidentiality language has been removed, and the first paragraph has been updated 
with the current NCI informed consent template language. 
 
Where can I get more information? (p. 87) 
The second paragraph has been updated with the current NCI informed consent template language. 
 
 
A replacement protocol document has been issued 
 
____________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 
 


 
NCI Version Date 07/01/2021 
Update #06 
 
 
 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
ALLIANCE A221602 
OLANZAPINE WITH OR WITHOUT FOSAPREPITANT FOR THE PREVENTION OF 
CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV) IN PATIENTS RECEIVING 
HIGHLY EMETOGENIC CHEMOTHERAPY (HEC): A PHASE III RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED TRIAL 
Supplied agent(s): olanzapine (Alliance IND 120137; NSC 754829)  
 
ClinicalTrials.gov Identifier: NCT03578081 
Study Chair 
 
 
 
 
 
 
 
Community Oncology Co-chair 
Pharmacogenetics Co-chair 
Clinical Economics Co-chair 
 
 
 
 
 
  
 
 
 
  
 
 
 
Health Outcomes Co-chair 
Symptom Intervention Committee Chair 
 
 
 
 
 
  
  
 
 
Primary Statistician 
Secondary Statistician 
 
  
 
 
 
 
 
Data Manager 
Protocol Coordinator 
 
 
 
 
 
 
 
 
Participating Organizations 
Alliance/Alliance for Clinical Trials in Oncology, ECOG-ACRIN/ ECOG ACRIN Cancer Research 
Group, NRG/NRG Oncology, SWOG/ SWOG


Alliance A221602 
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Study Resources: 
Expedited Adverse Event Reporting 
 
Medidata Rave iMedidata portal 
 
OPEN (Oncology Patient Enrollment Network) 
 
 Biospecimen Management System 
 
 
Protocol Contacts: 
A221602 Nursing Contacts 
 
A221602 Pharmacy Contact 
 
 
 
 
 
 
 
  
   
 
Alliance Biorepository at Mayo Clinic 
  
 
 
 
 
  
 
  
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and Data Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox  
 
Questions regarding specimens/specimen 
submissions: 
Roxann Neumann  
  
Questions regarding drug supply & 
administration 
Pharmacy Contact 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
 
 
 
  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 
 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). 
 
 
 
 
Contact the CTSU Help Desk 
with any OPEN related questions 
by phone or email : 
 
 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website 
). Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password.  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
Institutions will order the following supplies from the CTSU Operations Office: Questionnaire booklets. 
Supplies can be ordered by downloading and completing the CTSU Supply Request Form (available on 
the protocol-specific page on the CTSU website) and submitting it as instructed on the form. 
For clinical questions (i.e. patient eligibility or treatment-related): See Protocol Contacts (page 2) 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 
All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
 


Alliance A221602 
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OLANZAPINE WITH OR WITHOUT FOSAPREPITANT FOR THE PREVENTION OF 
CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV) IN PATIENTS RECEIVING 
HIGHLY EMETOGENIC CHEMOTHERAPY (HEC): A PHASE III RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED TRIAL 
Eligibility Criteria (see Section 3.2) 
Required Initial Laboratory Values 
• Diagnosis of malignant disease. 
Serum Creatinine 
≤2.0 mg/dL 
• No prior history of systemic chemotherapy for any malignancy  
• Scheduled to receive IV HEC (either cisplatin-containing  
AST or ALT 
≤3 x upper limit of 
normal (ULN) 
regimen or doxorubicin and cyclophosphamide [AC]). (See 
Section 3.2.3 for additional details) 
 
 
• 
No nausea or vomiting ≤24 hours prior to registration. 
• 
Negative pregnancy test (serum or urine) done ≤7 days prior to registration (See Section 3.2.5). 
• 
No known diagnosis of dementia. (See Section 3.2.6) 
• 
No known history of CNS disease (e.g. seizure disorder). 
• 
No treatment with another antipsychotic agent (see Section 3.2.8) 
• 
No chronic phenothiazine administration as an antipsychotic agent (see Section 3.2.9). 
• 
No use of amifostine within 7 days prior to registration. 
• 
No radiotherapy within 7 days prior to registration or planned for one week after the current dose of 
chemotherapy. 
• 
No use of quinolone antibiotic therapy within 7 days prior to registration. 
• 
No chronic alcoholism (as determined by the investigator). 
• 
No known hypersensitivity to olanzapine. 
• 
No known cardiac arrhythmia, uncontrolled congestive heart failure or acute myocardial infarction within the 
previous six months. 
• 
No history of uncontrolled diabetes, i.e., no diabetic ketoacidosis; (See Section 3.2.16)  
• 
Age ≥18 years. 
• 
ECOG Performance Status 0, 1 or 2 
• 
Patients must be able to read and comprehend English (See Section 3.2.19) 
Schema 
 
  
Initial Blinded Phase  
 
Optional Unblinded Continuation Phase  
R 
 
 
R  
3 additional cycles:  
A 
 
E  
Palonosetron/Ondansetron  
N 
 
 
R 
 
+ Dexamethasone  
D 
 
Palonosetron/Ondansetron  
E 
 
+ Olanzapine  
O 
+ Dexamethasone  
G  
+ Fosaprepitant IV* 
M 
 
+ Olanzapine 
I 
 
 
I 
 
+ Fosaprepitant*/placebo IV 
S 
 
3 additional cycles: 
Z 
 
 
T  
Palonosetron/Ondansetron 
E 
 
 
E 
 
+ Dexamethasone  
 
 
 
R 
 
+ Olanzapine  
 
 
 
 
No Placebo/Fosaprepitant* 
Nausea (Linear analogue visual scale) and response will be recorded. After the first cycle of chemotherapy, the 
patient will be given the option to continue on the same antiemetic regimen for a maximum of three additional 
cycles. If the patient agrees, he/she will be unblinded (See Section 8.2.2), re-registered (see Section 4.7.1), and 
allowed to continue for three additional cycles and evaluated for efficacy and any adverse events.  
* Aprepitant IV may be used in place of Fosaprepitant IV for sites that have adopted use of Aprepitant.  
Please refer to the full protocol text for a complete description of the eligibility criteria and 
treatment plan. 
 


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Table of Contents 
 
1.0 
Background ....................................................................................................................................... 8 
1.1. 
Introduction ................................................................................................................................... 8 
1.2 
Olanzapine Overview .................................................................................................................... 8 
1.3 
Olanzapine and chemotherapy-induced nausea and vomiting ...................................................... 8 
1.4 
NK-1 receptor antagonists .......................................................................................................... 11 
1.5 
Chemotherapy-induced nausea and vomiting guidelines in 2016/early 2017 ............................. 11 
1.6 
Rationale for current study .......................................................................................................... 12 
1.7 
Other olanzapine study details .................................................................................................... 13 
1.8 
Economic analysis of olanzapine and fosaprepitant vs. olanzapine............................................ 13 
1.9 
Study design ................................................................................................................................ 15 
2.0 
Objectives ....................................................................................................................................... 16 
2.1 
Primary objective ........................................................................................................................ 16 
2.2 
Secondary objective(s) ................................................................................................................ 16 
2.3 
Pharmacogenetics objectives (see also section 14.1.2) ............................................................... 16 
3.0 
Patient Selection .............................................................................................................................. 16 
3.1 
On-Study Guidelines ................................................................................................................... 16 
3.2 
Eligibility Criteria ....................................................................................................................... 17 
4.0 
Patient Registration ......................................................................................................................... 19 
4.1 
Investigator and Research Associate Registration with CTEP ................................................... 19 
4.2 
CTSU Site Registration Procedures ............................................................................................ 21 
4.3 
Patient Registration Requirements .............................................................................................. 22 
4.4 
Patient Enrollment (registration/randomization procedures (Step 1)) ........................................ 23 
4.5 
Registration to Correlative and Companion Studies ................................................................... 24 
4.6 
Stratification, Grouping Factors and Treatment Assignments .................................................... 24 
4.7 
Procedures for Double-Blinding the Treatment Assignment ...................................................... 25 
5.0 
Study Calendar ................................................................................................................................ 27 
6.0 
Data Collection and Submission ..................................................................................................... 28 
6.1 
Medidata patient cloud ePRO registration .................................................................................. 29 
6.2  
Medical bills/insurance claims .................................................................................................... 30 
6.3 
Specimen collection and submission .......................................................................................... 31 
7.0 
Treatment Plan/Intervention ........................................................................................................... 33 
7.1 
Fosaprepitant/Aprepitant /Placebo .............................................................................................. 33 
7.2 
Olanzapine .................................................................................................................................. 33 
7.3 
Palonosetron OR Ondansetron .................................................................................................... 33 


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7.4 
Dexamethasone ........................................................................................................................... 33 
7.5 
Continuation phase after first cycle of chemotherapy ................................................................. 34 
7.6 
Data Collection and Forms ......................................................................................................... 34 
8.0 
Dose and Treatment Modifications, Unblinding ............................................................................. 34 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care ......................................... 34 
8.2 
Unblinding Procedures ................................................................................................................ 35 
9.0 
Adverse Events ............................................................................................................................... 37 
9.1 
Routine Adverse Event Reporting .............................................................................................. 37 
9.2 
CTCAE Routine Reporting Requirements .................................................................................. 37 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) .................................................................. 37 
10.0 
Drug Information ............................................................................................................................ 42 
10.1 
General Considerations: .............................................................................................................. 42 
10.2 
Olanzapine (Zyprexa®) .............................................................................................................. 42 
10.3 
Fosaprepitant (Emend IV®) or placebo ...................................................................................... 46 
10.4 
Aprepitant (Cinvanti®) or Placebo ............................................................................................. 48 
10.5 
Palonosetron for IV Administration (Aloxi®) ............................................................................ 51 
10.6 
Ondansetron for Oral or IV Administration (Zofran®) .............................................................. 53 
10.7 
Dexamethasone for Oral Administration (DXM) ....................................................................... 54 
11.0 
Measures ......................................................................................................................................... 58 
11.1 
Baseline Nausea and Vomiting Questionnaire (Appendix II) ..................................................... 58 
11.2 
Nausea and Vomiting Daily Diary/Questionnaire (Appendix III) .............................................. 58 
11.3 
Daily Nurse Telephone Contact (Appendix IV) ......................................................................... 58 
11.4 
EQ-5D-3L Health Questionnaire (Appendix V) ......................................................................... 58 
12.0 
End of Treatment/Intervention ........................................................................................................ 58 
12.1 
Duration of Treatment ................................................................................................................. 58 
12.2 
Criteria for discontinuation of protocol treatment/intervention .................................................. 58 
12.3 
Follow-up .................................................................................................................................... 59 
12.4 
Extraordinary Medical Circumstances ........................................................................................ 59 
12.5 
Managing ineligible patients and registered patients who never receive protocol intervention . 59 
13.0 
Statistical Considerations ................................................................................................................ 60 
13.1 
Study Overview: ......................................................................................................................... 60 
13.2 
Sample Size, Accrual time and Study duration ........................................................................... 60 
13.3 
Statistical Design and Analysis of the Primary Endpoint ........................................................... 61 
13.4 
Analysis of Secondary Endpoints ............................................................................................... 62 
13.5 
Economic Data Analysis: ............................................................................................................ 64 
13.6 
Analysis plan for continuation phase: ......................................................................................... 65 


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13.7 
Study Monitoring ........................................................................................................................ 65 
13.8 
Study Reporting .......................................................................................................................... 66 
13.9 
Inclusion of Women and Minorities ........................................................................................... 67 
14.0 
Correlative And Companion Studies .............................................................................................. 68 
14.1 
Olanzapine Pharmacogenomics and Chemotherapy induced nausea and vomiting ................... 68 
15.0 
General Regulatory Considerations and Credentialing ................................................................... 73 
15.1 
Institutional Credentialing........................................................................................................... 73 
16.0 
References ....................................................................................................................................... 74 
17.0 
Model Consent Form ...................................................................................................................... 79 
Appendix I 
Patient Questionnaire .......................................................................................................... 92 
Appendix II 
Baseline Nausea and Vomiting Questionnaire .................................................................... 94 
Appendix III 
Nausea and Vomiting Daily Questionnaire ..................................................................... 95 
Appendix IV 
Daily Nurse Telephone Contact ...................................................................................... 96 
Appendix V 
EQ-5D-3L Health Questionnaire ...................................................................................... 111 
Appendix VI 
ePRO ............................................................................................................................. 113 
Appendix VII 
Patient Cloud ePRO patient information sheet ............................................................. 118 
Appendix VIII ePRO instruction flow chart for patients .......................................................................... 120 
 
 
 
 


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1.0 
BACKGROUND 
1.1. 
Introduction 
Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant 
deterioration in quality of life and is perceived by patients as a major adverse effect of the 
treatment [1]. The use of 5-hydroxytryptamine3 (5-HT3) receptor antagonists plus 
dexamethasone has significantly improved the control of acute CINV [1,2]. Studies have 
demonstrated additional improvement in the control of acute CINV and also delayed CINV with 
the use of palonosetron, a second generation 5-HT3 receptor antagonist [3], neurokinin-1 (NK-
1) receptor antagonists [4,5], and olanzapine, an antipsychotic which blocks multiple 
neurotransmitters in the central nervous system [6-11]. 
1.2 
Olanzapine Overview 
Olanzapine is an FDA-approved antipsychotic that blocks multiple neurotransmitters: dopamine 
at D1, D2, D3, D4 brain receptors, serotonin at 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, 
catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and 
histamine at H1 receptors [12,13]. Common side effects are sedation and weight gain [14, 15], 
as well as an association with the onset of diabetes mellitus [16]. Olanzapine’s activity at 
multiple receptors, particularly at the D2, 5-HT2c, and 5-HT3 receptors which appear to be 
involved in nausea and emesis, suggests that this drug may have significant anti-emetic 
properties. 
1.3 
Olanzapine and chemotherapy-induced nausea and vomiting 
1.3.1 
Olanzapine, when added to a 5HT3 receptor antagonist, an NK-1 receptor 
antagonist (NK1RA), and a corticosteroid, decreases nausea and improves complete 
response rates 
A recently-reported Alliance trial of olanzapine for chemotherapy-induced nausea and 
vomiting provided a positive result. This was presented at the ASCO Palliative Care 
Meeting in October 2015 [9]. The manuscript for this trial is now published [11]  
This trial demonstrated that olanzapine, when added to a 5-HT3 receptor antagonist, 
aprepitant/fosaprepitant and dexamethasone, did substantially improve the complete 
response (CR) rate (no vomiting and no use of rescue medications) and substantially 
improved the number of patients who had no nausea through the 5-day period of time 
following the single dose of chemotherapy, when compared to a placebo. The results from 
this trial, and other recently-reported ones, raise additional interesting questions regarding 
olanzapine for treating nausea and vomiting related to chemotherapy. These data are 
summarized in a recently published review manuscript [17]. 
1.3.2 
Pilot data support that olanzapine, when directly compared to an NK-1 receptor 
antagonist, decreases nausea and provides equivalent complete response rates 
A recent single institution phase III trial demonstrated that olanzapine, when combined 
with a single dose of dexamethasone and a single dose of palonosetron, was very effective 
in controlling acute and delayed CINV in patients receiving highly emetogenic 
chemotherapy (HEC) [6] as illustrated in Figures 1a and 1b. Compared to aprepitant, 
palonosetron, and dexamethasone, the olanzapine, palonosetron, and dexamethasone 
regimen resulted in equivalent complete responses (no vomiting and no rescue 
medications) to the aprepitant regime, but was significantly better in controlling nausea. 
There was excellent control of nausea without the use of multiple days of dexamethasone. 
These results were confirmed in a recently published randomized, double-blind, phase III, 
single institution study [10] comparing olanzapine to fosaprepitant in patients with 


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esophageal or head and neck cancer receiving concurrent chemotherapy and radiation 
therapy. 
 
In addition, another phase III study showed that the addition of olanzapine, to the 5-
HT3 receptor antagonist azasetron and dexamethasone, improved delayed CINV in 
patients receiving HEC (Figures 2a and 2b) or moderately emetogenic chemotherapy 
(MEC) (Figures 3a and 3b) [7]. 
 
 
Figure 1a. Complete response of patients receiving 
olanzapine, palonosetron, and dexamethasone or 
aprepitant, palonosetron, and dexamethasone prior 
to HEC. 
Figure 1b.  Percent of patients with no nausea after 
receiving olanzapine, palonosetron, and 
dexamethasone or aprepitant, palonosetron, and 
dexamethasone. 
 
 
Figure 2a. Complete response of patients receiving 
olanzapine, azasetron, and dexamethasone or 
azasetron and dexamethasone prior to HEC. 
Figure 2b.  Percent of patients with no nausea after 
receiving olanzapine, azasetron, and dexamethasone 
or azasetron, and dexamethasone. 
 


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1.3.3 
Randomized data support that olanzapine, when added to palonosetron and 
dexamethasone (without an NK1RA), markedly improves platinum-caused nausea 
and vomiting. 
A recent randomized controlled (but not patient blinded) trial, involving 100 patients 
receiving a variety of platinum-based treatments, reported that olanzapine, when added to 
palonosetron and dexamethasone (without an NK-1 receptor antagonist), led to a complete 
response rate of 96%, compared to 42% in a control group (p< 0.0001), with a 
corresponding improvement in nausea control (p< 0.0001) [32]. 
1.3.4 
Olanzapine appears to be effective for treating breakthrough chemotherapy-
induced nausea and vomiting (chemotherapy-induced nausea and vomiting despite 
previous prophylactic treatment). 
A recent study compared olanzapine to metoclopramide for the treatment of breakthrough 
emesis and nausea in patients receiving HEC and guideline-directed antiemetic prophylaxis 
[18]. Olanzapine was significantly better than metoclopramide for the treatment of 
breakthrough emesis and nausea. This was the first phase III study on the treatment of 
breakthrough emesis and nausea (Figure 4). 
 
Figure 3a. Complete response of patients receiving 
olanzapine, azasetron, and dexamethasone or 
azasetron and dexamethasone prior to MEC 
Figure 3b.  Percent of patients with no nausea after 
receiving olanzapine, azasetron, and dexamethasone 
or azasetron, and dexamethasone. 
 


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1.3.5 
Olanzapine may be effective in treating nausea and vomiting in cancer patients with 
advanced disease 
Olanzapine appears to be helpful for treating nausea and vomiting, unrelated to 
chemotherapy, in patients with advanced disease. 
Davis et al.[19] have reported a systematic review of the treatment of nausea and/or 
vomiting in cancer unrelated to chemotherapy or radiation. There have been case reports 
on the use of olanzapine as an anti-nausea agent for oncology conditions other than CINV 
[20-22]. These reports support that olanzapine was effective in treating patients with 
chronic nausea receiving palliative care, effective for intractable nausea due to opioids, 
neoplasm, and/or medications, and in controlling refractory nausea and vomiting in patients 
with advanced cancer [20-22]. An Alliance sponsored pilot placebo-controlled clinical trial 
is underway to study the use of olanzapine in this situation. 
1.4 
NK-1 receptor antagonists 
Information known about the use of NK-1 receptor antagonists (i.e., aprepitant, fosaprepitant, 
rolapitant, netupitant) for preventing chemotherapy-induced nausea and vomiting, without 
concurrent use of olanzapine: 
There are substantial data demonstrating the efficacy of NK-1 receptor antagonists (aprepitant, 
fosaprepitant, rolapitant, and netupitant) for decreasing vomiting in both the acute and delayed 
phases, with more benefit in the delayed phase. These drugs are virtually always given with the 
5-HT3 receptor antagonist and dexamethasone [17]. The literature also demonstrates that the 
available NK-1 receptor antagonists (aprepitant, netupitant, and rolapitant) are not effective in 
controlling nausea, suggesting that the NK-1 receptor may not play an important role in nausea 
control [17]. 
1.5 
Chemotherapy-induced nausea and vomiting guidelines in 2016/early 2017 
Information known about chemotherapy-induced nausea and vomiting guidelines in 2016/early 
2017: 
1.5.1 
NK-1 receptor antagonists, without the concurrent use of olanzapine, are still 
recommended as prophylaxis for patients receiving highly emetogenic 
chemotherapy 
All guidelines standardly recommend NK-1 receptor antagonists, without the concurrent 
use of olanzapine for patients receiving highly emetogenic chemotherapy [17, 23-25]. 
 
Figure 4. Percentage of patients with breakthrough 
CINV treated with olanzapine (OLN) or 
metoclopramide (METO) with no emesis or no 
nausea over a 72 hour observation period. 
 


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1.5.2 
Olanzapine, without the concurrent use of NK-1 receptor antagonists, are only 
recommended by NCCN guidelines [26] 
NCCN antiemetic guidelines are the only published antiemetic guidelines to recommend 
the use of olanzapine, in lieu of aprepitant, as an option for the prevention of chemotherapy-
induced nausea and vomiting. This recommendation was based on the randomized data 
discussed above [6], prior to the availability of the 2016 Alliance publication regarding 
olanzapine [11]. 
1.5.3 
Olanzapine, with the concurrent use of an NK-1 receptor antagonist, is not 
recommended as a regimen of choice in MASCC/ESMO antiemetic guidelines that 
were published in January 2017  
Despite the new information from the NCI-supported Alliance trial, that was publically 
available at the time that MASCC-ESMO guidelines were updated in 2016, the use of 
olanzapine, for preventing nausea and vomiting in patients receiving highly emetogenic 
chemotherapy, was not recommended in their most recent antiemetic recommendations 
published in 2017, noting that this drug could be considered in patients, ‘particularly when 
nausea is an issue’ [23]. 
1.5.4 
Olanzapine has been recommended for the treatment of established chemotherapy-
induced nausea and vomiting, occurring despite the use of prophylactic treatment 
NCCN guidelines do recommend the use of olanzapine for treatment of established 
chemotherapy-induced nausea and vomiting, occurring despite the use of prophylactic 
treatment [26]. 
1.6 
Rationale for current study 
1.6.1 
Introductory comments 
While it is clear that olanzapine has definite efficacy for the prevention of chemotherapy- 
induced nausea and vomiting, it is clear that the full utility of this drug in this situation has 
not been realized. The study of olanzapine, a generic agent in this clinical trial is very cost 
effective when compared to a number of other available antiemetic agents that have been 
the objects of pharmaceutical company-sponsored clinical trials.  
1.6.2 
Now that it has been established that olanzapine decreases nausea and vomiting in 
patients receiving highly emetogenic chemotherapy, when given with an expensive 
NK-1 receptor antagonist, how would it perform without the use of the expensive 
NK-1 receptor antagonist? 
We now have data from two different clinical trial designs that support that olanzapine-
containing regimens performed better than regimens that did not include olanzapine. The 
first of these is from our recent manuscript that demonstrated that olanzapine added to the 
previous standard NK-1 receptor antagonist-based regimen was more effective than 
placebo for the prevention of nausea and vomiting [11]. The second of these clinical trial 
designs consists of the above-noted randomized, controlled (but not definitive) trials that 
support that olanzapine is better than a standard NK-1 receptor antagonist-based regimen 
[6,10]. Additionally, as noted above, a recent randomized controlled (but not patient 
blinded) trial involving 100 patients receiving a variety of platinum-based treatments, 
reported that olanzapine, when added to palonosetron and dexamethasone (without an NK-
1 receptor antagonist), led to a complete response rate of 96%, compared to 42% in a 
control group (p< 0.0001), with a corresponding improvement in nausea control (p< 
0.0001) [32]. 


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Thus, it appears to be appropriate to compare two olanzapine-containing antiemetic 
regimens, one with the use of an NK-1 receptor antagonist and one without. This trial 
should help define how much benefit a relatively expensive NK-1 receptor antagonist (i.e., 
fosaprepitant) provides when given with an olanzapine-based three regimen arm. 
1.7 
Other olanzapine study details  
We propose 4 days of dexamethasone in this trial because standard practice is to use 4 days of 
dexamethasone, as per ASCO, NCCN, and MASCC guidelines [23-26]. We extensively 
discussed using a single day of dexamethasone or allowing this to be physician’s choice, but the 
4-day choice was chosen to be consistent with the current guidelines.  
A potential short-term toxicity of olanzapine is sedation [8,9]. The long-term toxicities include 
weight gain and hyperglycemia in some patients who take olanzapine for 3-6 months [12-16]. 
In the published phase II and phase III prophylactic CINV studies [6-11], there has been no 
evidence that weight gain and hyperglycemia occur when using olanzapine as a preventative 
agent for CINV during the few days post chemotherapy. In addition, there were no Grade III or 
IV toxicities reported and accrual did not appear to be impacted by potential toxicities in any of 
the phase II or phase III trials [6-11]. Sedation will be monitored with the treatment cycle 
similarly to the recently completed Alliance trial [9, 11]. We will not monitor weight gain or 
hyperglycemia, since patients will be treated with olanzapine for only 4 days. 
With regards to potential drug interactions, olanzapine has been given without any apparent 
clinical toxicities with other anti-emetics such as dexamethasone and 5-HT3 receptor 
antagonists [6-11]. While we are unaware of any studies that have monitored interactions 
between olanzapine and aprepitant, given that the various targeted receptors, mechanisms of 
action, and metabolism of each of these agents (aprepitant and olanzapine) are markedly 
different, significant interactions would not be anticipated. Supporting this contention, a 
Micromedex 2.0 search of interactions among all of these drugs (olanzapine, aprepitant, 
palonosetron, ondansetron, and dexamethasone) confirms that there are none, aside from the 
well-known phenomenon that increased systemic exposure to dexamethasone occurs with the 
concurrent use of aprepitant. 
It is particularly important for this to be conducted as a cooperative group study, as opposed to 
being conducted by a pharmaceutical company, since nausea control is not an on-label indication 
for olanzapine and the present study is designed to increase our knowledge concerning new 
mechanisms of nausea control, not to support a label extension for olanzapine. In addition, 
olanzapine is generic and quite inexpensive. 
1.8 
Economic analysis of olanzapine and fosaprepitant vs. olanzapine  
The objective of the economic analysis is to perform an economic evaluation of olanzapine and 
fosaprepitant vs. olanzapine in patients receiving HEC (noting that all patients will also receive 
dexamethasone and a 5HT3 receptor antagonist). We hypothesize that incremental costs of 
olanzapine and fosaprepitant over olanzapine will be substantial, but health gains will be 
minimal, and economic evaluation will demonstrate that olanzapine and fosaprepitant is not 
cost-effective relative to olanzapine at the standard thresholds of $50,000 and $100,000 per 
quality-adjusted life  -year gained[36]. Our approach will be to assess costs between treatment 
arms and determine cost-effectiveness and cost-utility ratios. 
1.8.1 
Estimated Drug Costs Per Course of Treatment 
Fosaprepitant (One 150mg injection on Day 1): $286.52 
Olanzapine (Four 10-mg tablets, 1 on each of Days 1-4): $0.81 


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Fosaprepitant+ Olanzapine (One 150mg injection on Day 1 + Four 10-mg tablets, Once on 
each of Days 1-4): $287.33 
1.8.2 
Study Measures 
Preference-based measures of health:  To construct cost-utility ratios, an economic 
measure of the value of a treatment relative to comparator treatments, it is necessary to 
measure the value of side effects such as nausea, emesis, and sedation and their degrees of 
severity. Value is measured on the utility scale, where 0 is assigned to health states as bad 
as death, and health states of 1 are equivalent to full health. The preferred approach in 
health economics has been to capture these values by asking respondents to make choices 
or state their preferences between various health states, and to base values on the 
preferences of community members rather than on those of patients themselves [37]. 
Generic preference-based measures of health (GPBM) that incorporate multiple attributes 
(domains or dimensions) of health status can be used in different patient groups and health 
conditions. These measures have two components in the context of our protocol: (1) a 
health status classification system, assessed on trial subjects; (2) a preference-based scoring 
system, assessed among members of the community. GPBMs allow for consistency and 
comparison between studies and are recommended for use in methodological guidelines 
[37]. 
Our economic evaluation uses the EuroQol EQ-5D-3L instrument (Appendix V; at the end 
of this current document), [38] as our GPBM. We use this instrument for a number of 
reasons. First, it has been validated for use in cancer patients, including patients receiving 
chemotherapy [39, 40]. Second, it is the most commonly used GPBM, used in 63% of 
economic evaluations, [41] thus representing a methodological standard. Third, in a context 
where different populations have different preferences over health states, it is one of the 
only GPBMs with a utility scoring system estimated using a representative sample of the 
US population [40]. Fourth, the questionnaire asks about patient’s health today, which 
matches our daily assessment of it. Finally, it is the simplest GPBM measure, taking 
approximately one minute to complete, and displays higher completion rates than other 
instruments among older adults [42]. Further details on the EQ-5D-3L measure are 
contained in Appendix V. 
The EQ-5D-3L will supplement the Nausea and Vomiting Daily Diary/Questionnaire and 
will be filled out by patients at baseline and on days 2-6. It will capture the health status 
decrements associated with nausea, emesis, and sedation related to the administered drugs. 
1.8.3 
Objective measures and Methods: 
Patient self-reported resource use will be tracked using the nurse/research coordinator’s 
daily telephone contact (Appendix IV) for the patient’s first chemotherapy cycle. This will 
capture use of protocol and any rescue medications, and any use of other pharmaceuticals 
and of health care services both at the trial site and at other providers during the 6-day 
study window of the cycle.  
Every two months, the Clinical Economics Co-chair will confer with medical coders and 
billing staff at Wayne State University to define typical sets of ICD-9, CPT, HCSPS and 
NDC codes used for billing for each drug and category of service used by patients on 
protocol during the previous two-month period. 
Certain patients treated during each two-month interval will receive more intense or 
complex services associated with significant health care costs, and self-reported resource 
use may not be sufficiently precise to confidently assess appropriate billing codes. For any 
such patient, the Clinical Economics Co-chair or his research assistant will contact the 


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nurse/research coordinator at the patient’s trial site and ask them to obtain all medical 
insurance claims for that patient during the 6-day study window and deliver them by mail 
to the co-chair.   
If the patient used the services of a provider outside of the enrolling institution, the research 
nurse will contact the billing department of that facility to obtain medical insurance claims 
from that provider as well. The provider will need to obtain a HIPAA release from the 
patient before providing any protected health information regarding the patient’s use of 
health care services to the Alliance study team.  
1.8.4 
Data Analysis: 
The economic data analysis is further described in Section 13.5. 
1.9 
Study design  
All patients eligible for the study receiving HEC in both arms will receive a 5-HT3 receptor 
antagonist (palonosetron 0.25 mg IV or ondansetron 8-16 mg IV or 16-24 mg PO, attending 
clinician choice) on day one and dexamethasone (12 mg PO, day one; 8 mg PO, days 2-4).  
Group 1:  
Patients will also receive the NK-1 receptor antagonist fosaprepitant (150 
mg IV), day one; plus olanzapine (10 mg/day PO, days 1 to 4, doses given approximately 
24 hours following the prior dose).  
Group 2:  
Patients will also receive a placebo (IV), day one; plus olanzapine (10 
mg/day PO, days 1 to 4, doses given approximately 24 hours following the prior dose). 
Intravenous fosaprepitant on day 1 is clinically equivalent to oral aprepitant for three days. 
Fosaprepitant is used in the current study in order to permit the use of an intravenous placebo in 
the study arms that do not contain an NK-1 receptor antagonist. 
The protocol doses of the 5-HT3 receptor antagonists, dexamethasone, and fosaprepitant listed 
above are standard doses recommended by various international anti-emetic guidelines [23-25]. 
One could argue that the effective dexamethasone dose will be a bit different in the arm getting 
fosaprepitant than the other arm, but there is not a lot of difference between the mildly different 
doses of dexamethasone [17] and we don’t think any small difference is worth the cost and 
complexity of trying to have different dexamethasone doses. We are requiring fosaprepitant on 
this trial so that we can use normal saline as a placebo, as opposed to having to obtain costly 
oral aprepitant placebos.  
The protocol dose of olanzapine was determined from the various studies in the literature [6-11, 
26]. In a phase I trial of olanzapine as a prophylactic antiemetic, Passik et al [28] determined 
that 10 mg/day for four days was a dose without much toxicity and minimal sedation. Navari et 
al [29] used a loading dose of olanzapine (daily for two days prior to chemotherapy), but 
subsequently determined that a loading dose was not necessary for efficacy and demonstrated 
that 10mg/day for four days beginning with the day of chemotherapy was highly efficacious in 
the prevention of nausea and emesis [6-11]. 
Due to the potential short-term toxicity of sedation with olanzapine, there has been extensive 
discussion of the use of a 5 mg/day dose for four days instead of the 10 mg daily dose. There 
have been no published phase III studies using the 5 mg dose to indicate whether this dose would 
have similar efficacy and/or less sedation than the 10 mg/day dose. A 2016 ASCO abstract [27] 
reported a phase II trial comparing 5 mg to 10 mg for emesis induced by highly emetogenic 
chemotherapy with cisplatin and suggested that efficacy and sedation were similar for the two 
doses. In order to study, additionally, a 5 mg dose in the current proposed trial, additional study 
arms would need to be added to the proposal and would require significantly more patients. We 


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have elected to use the 10 mg dose in this proposal given that this was the dose we used in the 
past trial and that it has been used more frequently. 
Patients will be stratified according to gender, their chemotherapy regimen, and the specific 5-
HT3 receptor antagonist used (i.e., palonosetron or ondansetron). Protocol therapy will be 
instituted for single day chemotherapy for one cycle only.  
2.0 
OBJECTIVES 
2.1 
Primary objective  
To compare between the two study arms the proportion of patients with no nausea for the overall 
(0-120 hours post-chemotherapy), acute (0-24 hours post-chemotherapy), and delayed periods 
(24-120 hours post-chemotherapy) for patients receiving HEC. The overall period is the efficacy 
period of primary interest and will be used as the primary endpoint to design the study.  
2.2 
Secondary objective(s) 
2.2.1 
To compare between the two study arms the complete response (CR) rates (no emetic 
episodes and no use of rescue medication) in the acute, delayed, and overall periods.  
2.2.2 
To compare between the two study arms, the incidences of potential toxicities that have 
been ascribed to olanzapine. 
2.2.3 
To perform an economic evaluation of olanzapine and fosaprepitant vs. olanzapine in 
patients receiving HEC (noting that all patients will also receive dexamethasone and a 
5HT3 receptor antagonist).  
2.2.4 
To explore the efficacy of olanzapine in chemotherapy cycles two to four, for patients 
who elect to continue on the same antiemetic regimen received in cycle one, in 
chemotherapy cycles two to four (continuation phase), by documenting nausea and 
complete response. 
2.2.5 
To explore the safety of olanzapine in chemotherapy cycles two to four, for patients who 
elect to continue on the same antiemetic regimen received in cycle one, in chemotherapy 
cycles two to four (continuation phase), by recording any adverse events or drug related 
toxicities. 
2.3 
Pharmacogenetics objectives (see also section 14.1.2) 
2.3.1 
To determine which polymorphisms in olanzapine-related and/or fosaprepitant-related 
genes are associated with nausea  
2.3.2 
To determine which polymorphisms in olanzapine-related and/or fosaprepitant-related 
genes are associated with complete response (see section 2.2.1) 
2.3.3 
To determine which polymorphisms in olanzapine-related genes are associated with 
toxicities related to olanzapine including sedation. 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 


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and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), which, in the opinion 
of the treating physician, would make this protocol unreasonably hazardous for the 
patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin 
cancers or cervical carcinoma in situ.  
• 
Patients who cannot swallow oral formulations of the agent(s). 
In addition: 
• 
Women and men of reproductive potential should agree to use an appropriate method 
of birth control throughout their participation in this study due to the teratogenic 
potential of the therapy utilized in this trial. Appropriate methods of birth control 
include abstinence, oral contraceptives, implantable hormonal contraceptives or double 
barrier method (diaphragm plus condom). 
• 
Concomitant treatment with Oral KCL, metoclopramide and anticholinergics is not 
allowed on this study. Patients taking these drugs should discontinue them prior to 
registration on the study. Treatment with intravenous KCL is allowed. See Section 8.1 
for more information.   
3.2 
Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
___ 
3.2.1 
Diagnosis of malignant disease of any stage. (Stage I through Stage IV)  
___ 
3.2.2 
No prior history of systemic chemotherapy for any malignancy. 
___ 
3.2.3 
Scheduled to receive intravenous HEC (Highly Emetogenic Chemotherapy) 
(either cisplatin-containing regimen or doxorubicin and cyclophosphamide 
[AC]). 
Cisplatin, given on a single day, at a dose of ≥ 70 mg/m2, with or without other 
chemotherapy agent(s)  
OR  
Doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2)   
___ 
3.2.4 
No nausea or vomiting ≤ 24 hours prior to registration. 
___ 
3.2.5 
Negative pregnancy test (serum or urine) done ≤ 7 days prior to registration, for 
women of childbearing potential only. 
A female of childbearing potential is a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 


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postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in 
the preceding 12 consecutive months). 
___ 
3.2.6 
No known diagnosis of dementia. Patients with stable treated brain metastases are 
eligible to participate. 
___ 
3.2.7 
No known history of CNS disease (e.g. seizure disorder). 
___ 
3.2.8 
No treatment with another antipsychotic agent such as olanzapine, risperidone, 
quetiapine, clozapine, phenothiazine or butyrophenone ≤ 30 days prior to registration.  
___ 
3.2.9 
No chronic phenothiazine administration as an antipsychotic agent (patients may 
receive prochloperazine and other phenothiazines as rescue anti-emetic therapy but not 
within 24 hours prior to registration). 
___ 
3.2.10 No use of amifostine within 7 days prior to registration. 
___ 
3.2.11  No radiotherapy within 7 days prior to registration or planned for one week after the 
current dose of chemotherapy.  
___ 
3.2.12 No use of quinolone antibiotic therapy within 7 days prior to registration.  
___ 
3.2.13 No chronic alcoholism (as determined by the investigator). 
___ 
3.2.14  No known hypersensitivity to olanzapine. 
___ 
3.2.15 No known uncontrolled cardiac arrhythmia, no known uncontrolled congestive 
heart failure, or no acute myocardial infarction within the previous six months. 
___ 
3.2.16 No history of uncontrolled diabetes mellitus, i.e., no diabetic ketoacidosis; within 6 
months prior to registration. Patients are eligible if they have controlled diabetes on 
diet, oral agents, and/or insulin. 
___ 
3.2.17 Age ≥18 years. 
___ 
3.2.18 ECOG Performance Status 0, 1 or 2 
___ 
3.2.19 Patients must be able to read and comprehend English. Local translation, 
including verbal translation of PROs is not permitted.  
___ 
3.2.20 Required Initial Laboratory Values ≤120 days prior to registration 
 Serum or Plasma Creatinine 
≤ 2.0 mg/dL 
AST or ALT 
≤ 3 x upper limit of normal (ULN) 
 
 


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4.0 
PATIENT REGISTRATION 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
    
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-
sponsored trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company 
employees) with limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 


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• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).  
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.2 
CTSU Site Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU Regulatory Support System 
(RSS). 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian 
sites only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 
in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
4.2.1 
Additional site registration requirements 
Additional requirements to obtain an approved site registration status include: 
An active Federal Wide Assurance (FWA) number; 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
Compliance with all protocol-specific requirements (PSRs). 
4.2.2 
Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a 


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Protocol Organization (PO) on the protocol. One way to search for a protocol is listed 
below.  
• 
Log in to the CTSU members’ website 
using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; 
or 
o Click on the By Lead Organization folder to expand, then select [Alliance], 
and protocol number [A221602]. 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.)  
4.2.3 
Submitting regulatory documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
4.2.4 
Checking your site’s registration status  
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
4.3 
Patient Registration Requirements 
Informed consent: the patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current 
human protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
 
 


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Patient-Reported Outcomes: This study includes the use of electronic patient-reported 
outcomes (ePRO). While it is expected that all patients will use ePRO, patients may refuse to 
use this option for this study if, for example, they do not own an appropriate device or are 
unwilling to download the patient cloud application. Booklets may be provided to patients who 
choose to decline ePRO for completion of questionnaires. 
Prior to registration, the patient should be asked about the availability of an electronic device 
and willingness to complete the patient-reported questionnaires on the device. The patient 
should be informed that the same method of completion must be used by the patient throughout 
the duration of the study for all time points. See Section 6.1 for further instructions on setting 
up ePRO.  
• 
Patient completed booklets: Patient questionnaire booklets are to be ordered prior to the 
registration of any patients. A limited number of patient completed booklets can be 
ordered by downloading and completing the CTSU Supply request form (located under 
site registration tab of the protocol specific page of the CTSU website) and submitting it 
through the CTSU regulatory portal. Samples of the booklets are found in Appendices II- 
V, which are to be used for reference and IRB submission only. They are not to be used 
for patient completion. 
Protected Health Information: Some patients treated on this study may receive additional 
health care services and incur associated health care costs. For these patients, medical bills, 
including hospital inpatient and outpatient as well as physician practice bills will be submitted 
to the clinical economics co-chair per Section 6.2. These patients must complete the institution’s 
own authorization for release of medical records. 
4.4 
Patient Enrollment (registration/randomization procedures (Step 1)) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer 
in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 


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Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To receive site reimbursement for bio-specimen submissions, completion dates must be 
entered in the OPEN Funding screen post registration. Please refer to the protocol-
specific funding page on the Alliance website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 
4.5 
Registration to Correlative and Companion Studies 
4.5.1 
Registration to Substudies described in Section 14.0  
There is one substudy within Alliance A221602. This correlative science study must be 
offered to all patients enrolled on Alliance A221602 (although patients may opt to not 
participate). This substudy does not require separate IRB approval. The substudy included 
within Alliance A221602 is: 
• 
Olanzapine Pharmacogenomics- chemotherapy induced nausea and vomiting, 
Alliance A221602-ST1 (Section 14.1) 
If a patient answers “yes” to “I agree to have my specimen collected and I agree that my 
specimen sample(s) and related information may be used for the laboratory study(ies) 
described above, “they have consented to participate in the substudy described in Section 
14. The patient should be registered to Alliance A221602-ST1 at the same time they are 
registered to the treatment trial (A221602). Samples should be submitted per Section 6.3. 
4.6 
Stratification, Grouping Factors and Treatment Assignments 
4.6.1 
Stratification Factors 
4.6.1.1 Gender:  Male vs. Female 
4.6.1.2 Chemotherapy Regimen: cisplatin-containing regimen vs. anthracycline + 
cyclophosphamide (AC) 
4.6.1.3 5-HT3 Receptor Antagonist: palonosetron vs. ondansetron  
4.6.2 
Grouping Factors  
4.6.2.1 Previous Protocol Treatment: Fosaprepitant/Aprepitant vs Placebo  
4.6.3 
Treatment Assignments  
The factors defined in 4.6.1 will be used as stratification factors. 
After the patient has been registered into the study, the values of the stratification factors 
will be recorded, and the patient will be assigned to one of the following treatment groups 
using the Pocock and Simon dynamic allocation procedure which balances the marginal 
distributions of the stratification factors between the treatment groups [36].  
• 
5-HT3 receptor antagonist (palonosetron or ondansetron) + dexamethasone + 
placebo + olanzapine  
• 
5-HT3 receptor antagonist (palonosetron or ondansetron) + dexamethasone + 
fosaprepitant + olanzapine 


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4.7 
Procedures for Double-Blinding the Treatment Assignment 
After the treatment assignment has been ascertained by randomization, the Registration 
Specialist will notify the designated data manager/nurse/pharmacist at the patient’s institution. 
The name of this contact person is to be indicated in the OPEN registration system at the time 
of registration. This contact person may not be involved in assessing adverse events or any other 
outcome measure and should not be the same person listed on page one of the OPEN registration 
Form as the person completing the form. The OPEN registration form should provide the source 
of communication, either fax or e-mail, and the appropriate contact information. The 
Registration Specialist will then communicate the treatment assignment “active or placebo” to 
designated contact at the patient’s institution. 
Once the treatment assignment has been communicated, the designated contact should prepare 
fosaprepitant, aprepitant or placebo for delivery to the patient.  
The dose will be prepared and labeled as “fosaprepitant 150 mg/aprepitant 130 mg or placebo” 
so that the contents are not discernible to the person administering the treatment. 
The pharmacist or designated contact person will maintain records that indicate the identity of 
the patient and their corresponding treatment assignment. The pharmacist or designated contact 
person at the treating site will maintain records that indicate the identity of the patient and their 
corresponding study medication code number. 
NOTE: If there is a possibility that patients will receive their medical bill prior to completing 
the initial phase, institutions should consider holding the bill for the patient for the 
fosaprepitant/aprepitant until 5 days after IV infusion, in order to preserve blinding. 
4.7.1 
Continuation Re-registration (step 2) Procedures  
Patients who choose to continue protocol treatment after the first cycle of chemotherapy 
will be unblinded per the unblinding procedures in Section 8.2.2. In order to unblind the 
patient, site staff must call the Alliance Registration Office (507-284-4130) during regular 
business hours to find out if the patient was receiving fosaprepitant or placebo (See also, 
Section 8.2.2). Site staff must ensure that the questionnaires associated with the initial cycle 
of treatment have been turned in by the patient before proceeding with unblinding, as these 
are related to the assessment of the primary endpoint of the study.  
If a patient is unblinded without following the process specified in Section 8.2.2, it will be 
treated as a major protocol deviation.  
Note: Patient must plan to be on the same chemotherapy cycle, and the same anti-emetic 
regimen in the continuation phase, to be eligible to participate in the continuation phase.  
If a patient potentially requires dose modification of the chemotherapy or anti-emetic 
regimen, he/she is not eligible for the continuation phase. Patient eligibility for 
continuation phase will not be affected if any AEs are not related to the chemotherapy or 
study treatment. 
If the patient was receiving fosaprepitant/aprepitant he/she will continue receiving the drug 
for 3 additional cycles. If the patient was receiving placebo, he/she will continue with 
protocol treatment without placebo (olanzapine, dexamethasone, and 5HT3 receptors 
only). 
Patients who choose to enter the continuation phase will be re-registered as follows:   
1. Site staff will log into the OPEN registration system and select the appropriate patient. 
2. Then select the next registration step. (Step 2) 


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3. Complete the OPEN Enrollment Form for the patient to be re-registered for the 
continuation phase. 
4. Verify the patient turned in their questionnaires for the initial cycle of treatment, 
yes/no. 
5. Confirm that patient does not require dose modifications of chemotherapy or the anti-
emetic regimen in the continuation phase yes/no.  
6. Once the re-registration to the continuation phase is successfully completed, a 
confirmation email will be sent to the CRP. 
If assistance is needed with this process, contact the Alliance Registration Office at 
 
Following re-registration, if the patient had been receiving fosaprepitant, the designated 
contact will be notified by the CRP so that s/he can prepare drug for delivery to the patient. 


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5.0 
STUDY CALENDAR 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial.  
Pre-Study Testing Intervals:  
To be completed ≤ 28 DAYS before registration: History and physical. 
 
Prior to 
Registration 
Prior to 
treatment on 
Day 1 
Days 2-6 
 
Continuation phase 
for three cycles 
Days 1-6 of each 
chemotherapy cycle 
Tests & Observations 
 
 
 
 
History and physical  
X 
 
 
 
Height, Weight, ECOG PS 
X 
 
 
 
Adverse Event Assessment 
 
X 
X (1)  
X (4) 
Baseline Nausea and Vomiting 
Questionnaire (Appendix II)* 
 
X 
 
 
Nausea and Vomiting Daily 
Questionnaire* 
 
 
X (2) 
X (2) 
Euro QOL(EQ-5D-3L) * 
 
X 
X (2) 
X (2) 
Daily Nurse Telephone Contact  
 
 
A 
 
Laboratory Studies 
 
 
 
 
Serum or Urine HCG 
X (3) 
 
 
 
Creatinine, AST or ALT 
X (5) 
 
 
 
Correlative Studies 
Blood sample 
To be collected at the time points described in Section 6.3 
* 
To be completed using ePRO. See Section 6.1 to register patients to the ePRO Patient Cloud and 
Appendix VI for other instructions. A copy of Appendix VII to be provided to the patient.  
A 
Nurse/Research Coordinator will contact the patient each day of Cycle 1 (Days 2-6, weekends & 
holidays included) to remind the patient to complete daily questionnaires, answer questions, and to 
query adverse events (see Appendices III-V). Daily Nurse Phone contact not required during 
continuation phase. At sites who don’t have research staff available on the weekends, please remind 
the patients the day before and ensure data collection on the next working day. 
1 
Adverse events experienced by patients on Day 1 and Day 2 will be collected during the nurse phone 
call on Day 2. Nurse/research coordinator will also contact the patient in person/ by phone 21 days 
after the initial phase of study treatment, to collect adverse events associated with the initial phase 
of treatment. This collection must occur prior to the start of treatment on the continuation phase.  For 
patients who start Cycle 2 prior to Day 21, the form will be completed according to the final contact 
with patient & AE assessment before continuation treatment begins.  
2 
Patient is to complete the Nausea and Vomiting Daily questionnaire (Appendix III) and EQ-5D-3L 
(Appendix V) on days 2-6. 
3 
For women of childbearing potential (see Section 3.2.5). Must be done ≤7 days prior to registration. 
4 
Adverse event assessments for continuation phase will be done during chemotherapy cycle visits 
5 
To be completed ≤120 days prior to registration. 
 
 


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6.0 
DATA COLLECTION AND SUBMISSION 
Data submission schedule: 
A Data Submission Schedule (DSS) is available on the Alliance study webpage, within the Case 
Report Forms section. The Data Submission Schedule is also available on the CTSU site within the 
study-specific Case Report Forms folder.  
Medidata Rave 
Medidata Rave is a clinical data management system being used for data collection for this trial/study. 
Access to the trial in Rave is controlled through the CTEP-IAM system and role assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus (AP) 
registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to 
 for registration types and 
documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site staff must log in to the Select Login 
using their CTEP-IAM username and password and click 
on the accept link in the upper right-corner of the iMedidata page. Site staff will not be able to access 
the study in Rave until all required Medidata and study specific trainings are completed. Trainings 
will be in the form of electronic learnings (eLearnings) and can be accessed by clicking on the link 
in the upper right pane of the iMedidata screen. If an eLearning is required and has not yet been taken, 
the link to the eLearning will appear under the study name in iMedidata instead of the Rave EDC 
link; once the successful completion of the eLearning has been recorded, access to the study in Rave 
will be granted, and a Rave EDC link will display under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to activate 
their account. Account activation instructions are located on the CTSU website in the Data 
Management section under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > 
 
 
• 
Patient-completed questionnaire booklets for this study are to be ordered prior to the 
registration of any patients (see Section 4.4). Samples of questionnaire booklets are available 
in Appendices II-V for reference and IRB submission only. They are not to be used for patient 
completion. Booklets must be given to patients to complete and patients should be instructed 


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to return the booklets to site staff either in person or by mail and site staff will enter patient 
and caregiver responses into Rave.  
• 
For electronic patient reported outcomes, the data from the patients’ responses are 
submitted directly from the device into the Rave database.  There are no documents to audit.  
The electronic responses are the source documentation. 
Data Quality Portal: 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered queries 
and form delinquencies, monitor data quality and timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, and timeliness reports. Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU website. 
Staff that have Rave study access can access the Rave study data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, DQP 
Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on the DQP. A 
protocol must have the Calendar functionality implemented in Rave by the Lead Protocol 
Organization for delinquent form details and reports to be available on the DQP. Site staff should 
contact the LPO Data Manager for their protocol regarding questions about Rave Calendaring 
functionality. 
6.1 
Medidata patient cloud ePRO registration  
This study includes the use of Medidata Patient Cloud electronic patient-reported outcomes 
(ePRO). After the patient is registered to the trial via OPEN and if the patient is willing to 
participate in electronic data collection, site staff will then complete a registration for the patient 
to the Patient Cloud ePRO through iMedidata. Note: Site staff must have already completed 
required eLearning for the Patient Cloud ePRO application to register a patient and information 
about the training is in the ePRO Appendix (Appendix VI). The registration to the Patient Cloud 
ePRO will create a unique patient registration code that site staff will provide to the patient. 
The patient (with assistance from site staff) should be instructed to download the Patient Cloud 
ePRO app onto his/her own device (IOS or Android, phone or tablet) and use the unique patient 
registration code to create an account. Once the patient's account is set up, the patient will be 
able to complete the submission of patient reported outcomes electronically for the trial. 
6.1.1 
CRP Patient Registration Instructions for ePRO 
Please visit the Medidata Learning Tool for reference information on Patient Cloud ePRO 
for CRPs. 
i. 
The subject registration process starts in iMedidata.  Begin by selecting the Patient 
Cloud ePRO Registration link for this study. 
ii. The patient management app will display, select your STUDY and SITE from the drop 
downs and click Launch. 
iii. Now the first patient can be registered. Create a subject ID and select a Country/ 
Language from the drop-down menu, (these are the only required data fields). The 


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subject initials are optional but are helpful in identifying which subject ID maps with 
which activation code. When finished, click Add. 
iv. The subject is added and will include the date, the subject ID, subject initials, (if 
included), and a unique auto-generated activation code. The activation code is unique 
for each patient and linked to the subject ID, it is not interchangeable. In addition, there 
is a status section, which indicates if the patient has registered to the app. When the 
patient has registered the status will change from "invited" to "registered." 
Note that site staff must have already completed the Medidata Patient Cloud training in 
order to register study participants. Please visit the Medidata Learning Tool for reference 
information on Patient Cloud ePRO for CRPs. 
  
  
For patients who are re-registered to the continuation phase according to Section 4.7.1, 
and who elected to use patient cloud ePRO for completion of questionnaires, site staff 
should instruct the patients to log in to the app following re-registration (so that it will 
automatically re-sync), for the forms related to the continuation phase to become available.  
6.2  
Medical bills/insurance claims  
Submission of medical bills, including hospital inpatient and outpatient as well as physician 
practice bills will be required for certain patients. These can be obtained from the trial site 
finance or billing department. Bills will include a list of services and billing codes performed 
and billed, insurance payments made for those services, as well as dates of visit, admission 
and/or discharge. Medical bills must be de-identified by institutional staff before mailing them 
to 
Site personnel MUST remove all protected health information (PHI) from 
the medical bills (including but not limited to):  
- 
Patient name  
- 
Patient initials  
- 
Date of birth  
- 
Phone numbers  
- 
Social security number  
- 
Medical record number or account number  
- 
Any unique identifying number, characteristic or code  
The Alliance patient ID number must be included on each page. De-identified medical bills 
should be mailed to: 
 
 
 
 
  
 
 
 
 
 
 


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6.3 
Specimen collection and submission  
• 
For patients registered to substudy A221602-ST1: All participating institutions must 
ask patients for their consent to participate in the correlative substudies planned for 
Alliance A221602- ST1, although patient participation is optional. Pharmacogenetic 
studies will be performed. Rationale and methods for the scientific components of these 
studies are described in Section 14.0. For patients who consent to participate, blood will 
be collected at the following time points for these studies: 
 
Prior to 
Treatment 
Storage/ Shipping conditions  
Submit 
to: 
 
For patients registered to A221602-ST1, submit the following: 
Number and volume of tubes to draw 
Whole Blood1 
(EDTA/lavender 
top) 
1 x 10 mL 
Cool pack/ship over night 
Mayo 
BAP 
Freezer  
1 
For patients who consent to A221602-ST1 (model consent question, “I agree to have 
my specimen collected and I agree that my specimen sample and related information 
may be used for the laboratory study described above”).Whole blood is to be used for 
pharmacogenomic analyses described in Section 14.1. 
6.3.1 
Specimen Submission Using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA 
THIS SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL:  
 using most standard web browsers 
(Safari, Firefox, Internet Explorer). For information on using the BioMS system, please 
refer to the ‘Help’ links on the BioMS webpage to access the on-line user manual, FAQs, 
and training videos.  To report technical problems, such as login issues or application 
errors, please contact: 
For assistance in 
using the application or questions or problems related to specific specimen logging, please 
contact: 
 
After logging collected specimens in BioMS, the system will create a shipping manifest.  
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All submitted specimens must be labeled with the protocol number (A221602 ST1), 
Alliance patient number, patient’s initials, date and type of specimen collected (i.e., whole 
blood). 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in 
the shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method 
of shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
Ship specimens on Monday through Friday. Shipping by overnight service to assure receipt 
is encouraged. Do not ship specimens on Saturdays.  


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All specimens should be sent to the following address: 
 
 
 
 
 
6.3.2 
Blood submission (for pharmacogenomic studies) 
For patients who consent to participate, (model consent question, “I agree to have my 
specimen collected and I agree that my specimen sample and related information may be 
used for the laboratory study described above”), whole blood samples will be used for the 
pharmacogenomic studies described in Section 14.1. This sample should be collected prior 
to the initiation of protocol treatment. 
Collect 10 mL of peripheral venous blood in an EDTA (lavender) tube. The tubes should 
be inverted several times to mix the EDTA and refrigerated until shipped on cool pack by 
overnight mail to the Alliance Biorepository. The samples should be shipped the same day 
that the blood is drawn per Section 6.3.1.  
Label samples with the following identification: 
1) Procurement date/time of collection 
2) Alliance patient number 
3)  Patient initials 
4) Alliance study number (i.e., A221602-ST1) 
5) Specimen type (i.e., whole blood) 
The 10 mL of blood can be collected in one 10 mL EDTA tube, or two 5 mL EDTA tubes 
or three 3 mL EDTA tubes, as long as the final volume is ~10 mL. 
 
 
 


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7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 14 days following registration. In the initial phase of the study, 
protocol therapy will be instituted with single day chemotherapy for one cycle only. Patients will be 
permitted to take rescue therapy of the treating investigator’s choice for nausea and/or 
emesis/retching, based on clinical circumstances. 
For questions regarding treatment, please see the study contacts page.  
NOTE: Chemotherapy is to be given on Day 1 of protocol treatment.  
 
Agent 
Day 1a 
Day 2 
Day 3 
Day 4 
1. 
Palonosetron OR 
0.25 mg IV 
- 
- 
- 
Ondansetron 
8- 16 mg IV 
OR  
16- 24 mg PO 
- 
- 
- 
2. 
Dexamethasone 
12 mg PO 
8 mg PO 
8 mg PO 
8 mg PO 
3. 
Fosaprepitant/ 
Aprepitant OR 
Placebo 
150 mg IV(Fosaprepitant) 
or  
130 mg IV (Aprepitant) 
- 
- 
- 
4. 
Olanzapine  
10 mg PO 
10 mg PO 
10 mg PO 
10 mg PO 
a) On Day 1, all agents are to be given prior to chemotherapy, with the exception that olanzapine 
may be taken prior to chemotherapy or at bedtime. If the patient did not take the olanzapine 
prior to chemotherapy and the patient develops nausea or vomiting prior to bedtime, the patient 
can take it prior to bedtime. 
7.1 
Fosaprepitant/Aprepitant /Placebo 
Intravenous fosaprepitant/ Intravenous aprepitant on day 1 is clinically equivalent to oral 
aprepitant for three days. Fosaprepitant is used in the current study in order to permit the use of 
an intravenous placebo in the study arms that do not contain an NK-1 receptor antagonist.  
Fosaprepitant/placebo or aprepitant/placebo should be administered intravenously over 20 to 30 
minutes prior to chemotherapy. If 2 minute IV push Cinvanti is used, a matching 2 minute IV 
push saline placebo should be used.  
7.2 
Olanzapine  
Olanzapine will be given as 10 mg /day for four days beginning on the day of chemotherapy. 
Olanzapine on the day of chemotherapy (day 1) may be taken prior to chemotherapy or at 
bedtime (after chemotherapy). Subsequent doses on day 2 to 4 may be taken at bedtime.  The 
patient should record the time of day in the patient diary (Appendix III). Missed doses should 
not be made up.  
7.3 
Palonosetron OR Ondansetron 
Palonosetron or ondansetron will only be given on Day 1 of chemotherapy.  
7.4 
Dexamethasone 
Dexamethasone will be given on all four days. On Day 1, dexamethasone will be given as 12 
mg PO. On Days 2-4, dexamethasone will be given as 8 mg PO. The patient may take it at about 
the same time of day that he/she received it on Day 1. 


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The study is designed and measured using dexamethasone PO.  If an institution typically gives 
IV dexamethasone, then the institution’s standing protocol must be changed for study 
participants to receive dexamethasone PO.  There is no exception to this study detail. 
7.5 
Continuation phase after first cycle of chemotherapy 
When patients come in for their clinic visit after Cycle 1, they will be encouraged to continue 
treatment with the study agents for an additional three cycles with chemotherapy. The treating 
physician and patient may decide to continue study treatment for up to three additional cycles. 
Patients who elect to continue with study treatment during the Continuation Phase will be 
unblinded as described in Section 8.2.2.  
• 
If the patient was receiving fosaprepitant/aprepitant, s/he will continue to receive 
fosaprepitant/aprepitant along with olanzapine, dexamethasone, and palonosetron or 
ondansetron for a maximum of three more cycles and will be evaluated for efficacy 
and adverse events. 
• 
If the patient was receiving placebo s/he will continue with olanzapine, 
dexamethasone, and palonosetron or ondansetron only (with no placebo) for a 
maximum of three more cycles and will be evaluated for efficacy and adverse events. 
7.6 
Data Collection and Forms 
The patient will complete the Baseline Nausea and Vomiting Questionnaire on day one, prior to 
the start of treatment. The patient will also complete the Nausea and Vomiting Daily 
Diary/Questionnaire on days 2-6 at the same time of day as the chemotherapy was given on day 
1 (+/- 1 hour).  Patients will also complete the EQ-5D-3L health questionnaire  to supplement 
the nausea and vomiting daily diary/questionnaire both at baseline and on Days 2-6. 
In addition, the nurse/research coordinator will contact the patient each day of Cycle 1 (Days 2-
6, weekends & holidays included) to record adverse events.  
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING  
No dose modifications will be allowed for olanzapine, if doses of olanzapine are modified per 
physician discretion during the continuation phase, patients must discontinue protocol treatment.  
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Concomitant medications 
Concomitant treatment with the following are not allowed while taking olanzapine. 
Patients are prohibited from receiving the following treatments while they are taking 
olanzapine, as they may interfere with the study drugs: 
• 
Treatment with another antipsychotic agent such as risperidone, quetiapine, 
clozapine, phenothiazine or butyrophenone.  
• 
Chronic phenothiazine administration as an antipsychotic agent (patients may 
receive prochloperazine and other phenothiazines as rescue anti-emetic therapy). 
• 
Amifostine.  
• 
Quinolone antibiotic therapy.  
In addition, because of drug interactions with Oral KCL, metoclopramide and 
anticholinergics, use of these drugs while taking olanzapine is not allowed. However, use 
of inhalers is allowed. Treatment with intravenous KCL is allowed.  


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Abdominal radiotherapy is also not allowed while taking olanzapine. 
8.1.2 
Supportive care 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent 
medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study treatment 
administration until 30 days after the final dose will be recorded in the medical records.  
Patients will be permitted to take rescue therapy of the treating investigator’s choice for 
nausea and/or emesis/retching, based on clinical circumstances. 
8.2 
Unblinding Procedures  
Unblinding can be done only in cases of an emergency or if the patient chooses to continue 
protocol treatment beyond Cycle 1 (see Section 8.2.2). Follow the directions below to unblind 
patient treatment. Please note that if a treatment assignment is unblinded during the initial phase 
of the study, the patient must discontinue protocol therapy. 
8.2.1 
Emergency Unblinding Procedures 
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at 
least possibly related to the investigational agent and for which unblinding would influence 
treatment decisions; or 2) medication error, such as accidental overdose. Expected adverse 
events are listed in the “Toxicities” section below.  
Contact the Alliance Executive Officer on call by calling 
 
  
The institution must provide the following information to the Alliance Executive Officer:  
• 
Alliance study ID (i.e., “A221602”)  
• 
Alliance patient ID number (e.g., “999999”)  
• 
Patient initials (e.g., “L,FM”)  
• 
Institution name  
• 
Name and telephone number of treating physician  
• 
Name and contact information of person requesting the unblinding procedure  
• 
Name and contact information of person to inform of treatment assignment  
• 
Reason for emergency unblinding  
Please remember that an emergency unblinding request may be authorized only by an 
Alliance Executive Officer, and emergency unblinding applies only if unblinding would 
influence management of the medical situation. After the Executive Officer deems 
unblinding is warranted, the treatment assignment will be provided to the contact person at 
the treating site. 
8.2.2 
Protocol-specified Unblinding 
Upon completion of one cycle of protocol treatment, trial participants will be asked 
whether they wish to participate in the continuation phase of the study (See Section 7.5). 
Participants who choose to participate in the continuation phase of the study will be 
unblinded. In order to unblind the patient, site staff must call the Alliance Registration 


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Office 
during regular business hours to find out if the patient was receiving 
fosaprepitant or placebo.  Site staff must ensure that the questionnaires associated with the 
initial cycle of treatment have been turned in by the patient before proceeding with 
unblinding, as these are related to the assessment of the primary endpoint of the study.  
Upon confirmation by the data manager that the criteria for one cycle of treatment have 
been met, the treatment assignment will be unblinded. No Alliance Executive Officer (or 
designee) approval is required. 
All patients who proceed with the continuation phase must be re-registered as described in 
Section 4.7.1. 
Participants who choose not to participate in the continuation phase of the study will 
not be re-registered to the study.  
However, upon completion of the initial cycle of protocol treatment, site staff may request 
unblinding of the treatment assignment in order to inform subsequent treatment decisions. 
This elective unblinding is only permitted after at least 120 hours following chemotherapy. 
Unblinding will be performed by the Registration Office during regular business hours, 
with confirmation from the data manager that the appropriate criteria have been met.  
In order to unblind the patient, site staff must call the Alliance Registration Office 
during regular business hours to find out if the patient was receiving 
fosaprepitant or placebo. Upon confirmation by the data manager that the criterion that one 
cycle of protocol treatment has been completed, the treatment assignment may be 
unblinded. No Alliance Executive Officer (or designee) approval is required. 
 
 


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9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 
 
Attribution 
to 
protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details 
on AE reporting procedures.  
9.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, the Adverse Events form is 
used for routine AE reporting in Rave. 
There are no solicited adverse events for this trial.  
9.2 
CTCAE Routine Reporting Requirements 
The following table outlines the combinations of time points, grades and attributions of AEs that 
require routine reporting to the Alliance Statistics and Data Center. Questions about routine 
reporting should be directed to the Data Manager. 
• 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data 
Submission on Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a 
a 
a 
Probable 
 
a 
a 
a 
a 
Definite 
 
a 
a 
a 
a 
a) 
Adverse Events: Other CRF - Applies to AEs occurring between registration and 
within 30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up 
Phase. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Investigational Drug Branch 
(IDB), the Alliance Central Protocol Operations Program, the Study Chair, and their Institutional 
Review Board if a patient has a reportable serious adverse event. 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.  The CTCAE is identified and located on the CTEP website 
at: 
 All appropriate 
treatment areas should have access to a copy of the CTCAE. All reactions determined to be 
“reportable” in an expedited manner must be reported using the Cancer Therapy Evaluation 
Program Adverse Event Reporting System (CTEP-AERS). 


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For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
9.3.1 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND ≤ 30 Days of the Last Dose of 
Treatment1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
• 
Grade 1 
Timeframes 
• 
Grade 2 
Timeframes 
• 
Grade 3 
Timeframes 
• 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 


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1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs  
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
9.3.2 
Expedited AE reporting timelines defined 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS ≤ 24 hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 
calendar days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 10 
calendar days of the investigator learning of the event.  
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND. 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
9.3.3 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or 
non-CTEP IND 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
Alliance A221602 uses a drug under a CTEP IND. The reporting requirements for 
investigational agents under a CTEP IND should be followed for all agents (any arm) in 
this trial. 
Reporting of cases of secondary AML/MDS is to be done using the NCI/CTEP Secondary 
AML/MDS Report Form. New primary malignancies should be reported using study Form, 
Notice of New Primary. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and administration site 
conditions.” Evidence that the death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 


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All new malignancies must be reported via CTEP-AERS whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be 
reported, i.e. solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. 
In CTCAE version 5.0, the new malignancies (both second and secondary) may be reported 
as one of the following: (1) Leukemia secondary to oncology chemotherapy, (2) 
Myelodysplastic syndrome, (3) Treatment-related secondary malignancy, or (4) 
Neoplasms benign, malignant and unspecified-other. Whenever possible, the CTEP-AERS 
reports for new malignancies should include tumor pathology, history or prior tumors, prior 
treatment/current treatment including duration, any associated risk factors or evidence 
regarding how long the new malignancy may have been present, when and how the new 
malignancy was detected, molecular characterization or cytogenetics of the original tumor 
(if available) and of any new tumor, and new malignancy treatment and outcome, if 
available. 
Treatment expected adverse events include those listed in Section 10.0 and in the package 
insert. 
• 
Grade 1-3 nausea or vomiting and hospitalization resulting from such do not require 
AERS reporting, but should be reported via routine AE reporting. 
• 
Grade 3 nausea or vomiting does not require AERS reporting, but should be reported 
via routine AE reporting 
• 
Grade 1-3 diarrhea and hospitalization resulting from such do not require AERS 
reporting, but should be reported via routine AE reporting 
• 
Grade 1-3 mucositis and hospitalization resulting from such do not require AERS 
reporting, but should be reported via routine AE reporting 
• 
Grade 1-3 dehydration and hospitalization resulting from such do not require AERS 
reporting, but should be reported via routine AE reporting 
• 
Grade 1-3 fatigue and hospitalization resulting from such do not require AERS 
reporting, but should be reported via routine AE reporting. 
• 
Grade 1-3 hematosuppression (leukopenia, neutropenia, lymphopenia, anemia, and 
thrombocytopenia) with hospitalization resulting from such do not require AERs 
reporting, but should be reported via routine AE reporting 
• 
Alliance A221602 uses a drug under an Alliance IND. These reporting requirements 
should be followed for either arm in this trial. 
• 
All new malignancies must be reported through CTEP-AERS whether or not they are 
thought to be related to previous or current treatment. This includes solid tumors 
(including 
non-melanoma 
skin 
malignancies), 
hematologic 
malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. In 
CTCAE version 5.0, new malignancies (both second and secondary) should be 
reported as one of the following: leukemia secondary to oncology chemotherapy; 
myelodysplastic syndrome; treatment-related secondary malignancy; or neoplasms 
benign, malignant and unspecified-other. Whenever possible, the CTEP-AERS reports 
for new malignancies should include tumor pathology, history of prior tumors, prior 
treatment/current including duration, any associated risk factors or evidence regarding 
how long the new malignancy may have been present, when and how the new 
malignancy was detected, molecular characterization or cytogenetics of the original 


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tumor (if available) and of any new tumor, and new malignancy treatment and 
outcome, if available. 
• 
All pregnancies and suspected pregnancies occurring in female patient during therapy 
or within 28 days after completion of treatment on A221602 must be reported via 
CTEP-AERS using the event term “pregnancy, puerperium and perinatal conditions – 
other, pregnancy (Grade 3) 
• 
CTEP-AERS reports should be amended upon completion of the pregnancy to report 
pregnancy outcome (e.g., normal, spontaneous abortion, therapeutic abortion, fetal 
death, congenital abnormalities) 
• 
The CTEP-AERS report should be amended for any neonatal deaths or complications 
occurring within 28 days of birth independent of attribution. Infant deaths occurring 
after 28 days considered to be related to in utero to the agent used in this trial should 
be reported via CTEP-AERS. 
CTEP-AERS reports should be submitted electronically. 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and submitted, along with any 
additional medical information (form is available on the CTEP website at 
The potential risk of exposure of the fetus to the investigational 
agent(s) or chemotherapy agent(s) should be documented in the “Description of Event” 
section of the CTEP-AERS report. 
Pregnancy loss  
• Pregnancy loss is defined in CTCAE as “Death in utero.”  
• Any Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy loss” under 
the Pregnancy, puerperium and perinatal conditions SOC.  
• A Pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, 
puerperium and perinatal conditions SOC, as currently CTEPAERS recognizes this event 
as a patient death. 
 
 


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10.0 DRUG INFORMATION 
10.1 
General Considerations: 
All study agents are to be administered at the registering institution.  
10.2 
Olanzapine (Zyprexa®) 
Procurement:   
Olanzapine 10 mg tablets will be provided to sites for use in this trial and will be supplied in 30 
count bottles.   
Sites may choose to repackage and label olanzapine at the time of dispense into a supply 
sufficient for the cycle or dispense a 30 count bottle to the patient to be used for Cycle 1 
and subsequent cycles if patients continue on olanzapine.  
If a 30 count bottle is dispensed in the original bottle to patients, sites are required to relabel 
the bottle before providing it to the patient in accordance with state pharmacy laws. A 
sample label template is provided below: 
 
Any remaining tablets the patient has after completion of the study are to be returned to the site 
and destroyed per each site’s drug destruction policy. 
Each participating institution will order a starter supply of olanzapine from McKesson Clinical 
Research Services.  Fax or email the Alliance A221602 Drug Order Request Form (downloaded 
from the protocol specific page of the Alliance website) to: 
 
 
 
Site personnel should reorder additional supplies of olanzapine based on their inventory levels, 
so that McKesson Clinical Research Services may send further supplies as needed.  
Within ninety days after the last patient is treated at the institution, any expired or remaining 
supplies should be destroyed according to institutional procedure. 
Formulation: 
Commercial olanzapine tablets used in this trial contain 10 mg of the drug.  Inactive ingredients 
are crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and 
microcrystalline cellulose.  The color coating contains hydromellose, polyethylene glycol 400 
and titanium dioxide.  
Storage and Stability: 
Olanzapine tablets are stored at controlled room temperature, 20º to 25ºC (68º to 77ºF). The USP 
defines controlled room temperature as a temperature maintained thermostatically that 


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encompasses the usual and customary working environment of 20º to 25ºC (68º to 77ºF) that 
results in a mean kinetic temperature calculated to be not more than 25ºC and that allows for 
excursions between 15º and 30ºC (59º and 86ºF) that are experienced in pharmacies, hospitals, 
and warehouses. Protect olanzapine tablets from light and moisture. 
Administration: 
Olanzapine will be taken as a single dose once daily Days 1 through 4 without regard to meals 
(prior to chemotherapy on day of chemotherapy administration or at bedtime and once daily at 
the same time as the initial dose thereafter).  
Drug Interactions:   
Olanzapine is a major substrate of CYP1A2 and a minor substrate of CYP2D6.  Carbamazepine, 
a potent inducer of CYP1A2 caused a 50% increase in the clearance of olanzapine.  Omeprazole 
and rifampin may cause an increase in olanzapine clearance.  The effects of olanzapine may be 
decreased by potent inducers of CYP1A2 and should be avoided if possible.  Fluvoxamine, an 
inhibitor of CYP1A2, decreases the clearance of olanzapine.  This results in a mean increase in 
olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male 
smokers.  The mean increase in olanzapine AUC is 52% and 108%, respectively.  Lower doses 
of olanzapine should be considered in patients receiving concomitant fluvoxamine.  Fluoxetine, 
an inhibitor of CYP2D6, causes a smaller increase (mean 16%) in the maximum concentration 
of olanzapine and a small decrease in the clearance of olanzapine (mean 16%).  The magnitude 
of impact of this factor is small in comparison to the overall variability between individuals, and 
therefore dose modification is not routinely recommended.  The co-administration of diazepam 
with olanzapine potentiated the orthostatic hypotension observed with olanzapine.  Olanzapine 
may potentiate the effects of antihypertensives, CNS acting medications and alcohol.  
Olanzapine may antagonize the effects of levodopa and dopamine agonists.  Olanzapine is an 
inhibitor of CYP1A2 (weak), CYP2C19 (weak), CYP2C9 (weak), CYP2D6 (weak), CYP3A4 
(weak).   
Pharmacokinetics:   
a) Absorption – Readily absorbed reaches peak concentrations in approximately 6 hours 
following an oral dose.  Food does not affect the rate or extent of olanzapine absorption. 
b) Distribution – Linear kinetics with half-life of 21 to 54 hours and apparent plasma clearance 
from 12 to 47 L/hr.  Olanzapine is extensively distributed throughout the body with a Vd of 
approximately 1000 L.  It is 93% bound to plasma proteins (primarily albumin and α1-acid 
glycoprotein. 
c) Metabolism – Direct glucuronidation and cytochrome P450 mediated oxidation via 
CYP1A2 (major) and CYP2D6 (minor) are the primary metabolic pathways for olanzapine.   
d) Excretion – Urine (57%, 7% as unchanged drug); feces (30%).  There is a 40% increase in 
olanzapine clearance in smokers, 30% decrease in females. 
Adverse Events 
All of the adverse events discussed below have been associated with olanzapine, but would be 
considered unexpected in the context of this trial. 
[U.S. Boxed Warning]:  Elderly patients with dementia-related psychosis treated with 
antipsychotics are at an increased risk of death compared to placebo.   
Other warnings and precautions:  suicide (particularly when used with fluoxetine), neuroleptic 
malignant syndrome, hyperglycemia, hyperlipidemia, weight gain, tardive dyskinesia, 


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orthostatic hypotension, leukopenia, neutropenia, agranulocytosis, seizures, cognitive or motor 
impairment, hyproprolactinemia. 
Common known potential toxicities >10%: 
Central nervous system:  somnolence, extrapyramidal symptoms, dizziness, headache, fatigue, 
insomnia 
Endocrine/metabolic:  prolactin increased 
Gastrointestinal:  weight gain, appetite increased, xerostomia, constipation 
Hepatic:  ALT increased 
Neuromuscular/skeletal:  weakness 
Miscellaneous:  accidental injury 
Less common known potential toxicities 1-10%: 
Cardiovascular:  chest pain, hypertension, peripheral edema, postural hypotension, tachycardia 
Central nervous system:  fever, personality changes, restlessness 
Dermatologic:  bruising 
Endocrine/metabolic: 
 
breast-related 
events 
(discharge, 
enlargement, 
galactorrhea, 
gynecomastia, lactation disorder), menstrual-related events (amenorrhea, hypomenorrhea, 
menstruation delayed, oligomenorrhea), sexual function-related events (anorgasmia, ejaculation 
delayed, erectile dysfunction, changes in libido, abnormal orgasm, sexual dysfunction) 
Gastrointestinal:  abdominal pain, diarrhea, flatulence, nausea, vomiting 
Genitourinary:  incontinence, UTI 
Hepatic:  hepatic enzymes increase 
Neuromuscular/skeletal:  abnormal gait, akathisia, articulation impairment, back pain, falling, 
hypertonia, joint/extremity pain, muscle stiffness, tremor 
Ocular:  amblyopia 
Respiratory:  cough, epistaxis, pharyngitis, respiratory tract infection, rhinitis, sinusitis 
Rare, less than 1% (limited to important or life threatening): 
Acidosis, agranulocytosis, anaphylactic reaction, angioedema, apnea, atelectasis, atrial 
fibrillation, cerebrovascular accident, congestive heart failure, deafness, diabetes mellitus, 
diabetic ketoacidosis, diabetic coma, dystonia, encephalopathy, facial paralysis, glaucoma, heart 
arrest, heart failure, hemorrhage, hepatitis, hypercholesterolemia, hyper/hypoglycemia, 
hyper/hypokalemia, hyperlipidemia, hyper/hyponatremia, hypertriglyceridemia, hyperuricemia, 
hyper/hypoventilation, hypoproteinemia, hypoxia, jaundice, ileus, ketosis, leukocytosis 
(eosinophilia), leukopenia, liver damage (cholestatic or mixed), liver fatty deposit, lung edema, 
lymphadenopathy, myasthenia, myopathy, neuralgia, neuroleptic malignant syndrome, 
neutropenia, pancreatitis, paralysis, pulmonary embolus, rash, rhabdomyolysis, seizure, sudden 
death, suicide attempt, syncope, tardive dyskinesia, thrombocythemia, thrombocytopenia, 
transient ischemic attack, venous thrombotic events. 
10.2.1 Nursing Guidelines 
1. Olanzapine has several drug to drug interactions, many of which can cause an increase 
in olanzapine clearance and increase the side effects of olanzapine. Assess patient’s 
medication list for any possible drug to drug interactions. Discuss with study doctor.  
2. Warn patients of the risk of suicide, especially for patients on fluoxetine. 


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3. Olanzapine can have significant CNS side effects, including somnolence, 
extrapyramidal symptoms, dizziness, headache, or insomnia.  Rarely patients may 
experience tardive dyskinesia, seizures, cognitive or motor impairment. Warn patients 
of these side effects and that they should not drive or do activities that require 
attentiveness until they know how agent affects them. 
4. Warn patient about possible GI side effects including increased appetite, xerostomia, 
constipation and weight gain. Less commonly nausea, vomiting, abdominal pain, and 
diarrhea. Treat symptomatically and monitor for effectiveness of intervention. 
5. Patients with diabetes should be monitored closely as olanzapine can increase blood 
sugar levels.  
6. Monitor CBC w/differential as agent may cause leukopenia, neutropenia and 
agranulocytosis.  Patients who are on cytotoxic chemotherapy may be at increased risk.  
7. Discuss possibility of sexually related side effects. 
 
 


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10.3 
Fosaprepitant (Emend IV®) or placebo 
Procurement:   
Fosaprepitant diemglumine 150 mg, lyophilized powder in single-dose vials for reconstitution 
will be obtained from commercial supplies at each member institution.  Pharmacies are 
instructed to use commercial supply fosaprepitant diemglumine  
Placebo will be not be supplied by this study and is the responsibility of the site.  Placebo will 
be 0.9% Sodium Chloride, USP 150 mL or 250 mL volume (per individual site reconstitution 
standard for fosaprepitant diemglumine).  
Outdated or remaining drug/product should be destroyed on-site per procedures in place at each 
institution. 
Formulation:   
Commercial fosaprepitant for injection contains 245.3 mg of fosaprepitant dimeglumine 
equivalent to 150 mg of fosaprepitant free acid and the following inactive ingredients:  edetate 
disodium (18.8 mg), polysorbate 80 (75 mg), lactose anhydrous (375 mg), sodium hydroxide 
and/or hydrochloric acid (for pH adjustment).   
Storage and Stability:   
Fosaprepitant for injection vials must be stored refrigerated at 2° to 8°C (36° to 46°F).  The 
reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below 
25°C (77°F)]. 
Preparation:  
Reconstitute the 150 mg vial with 5 mL 0.9% Sodium Chloride Injection, USP.  Add 
reconstituted fosaprepitant to an infusion bag containing 145 mL 0.9% Sodium Chloride for 
Injection, USP to yield a total volume of 150 mL and a final concentration of 1 mg/mL.  
Alternatively, if institutional preference is to administer fosaprepitant in 250 mL 0.9% Sodium 
Chloride for Injection, USP, sites may follow institutional preparation instructions. 
Note, fosaprepitant is incompatible with any solutions containing divalent cations (e.g., Ca2+, 
Mg2+), including Lactated Ringer’s Solution and Hartmann’s Solution. 
Administration: 
Fosaprepitant should be administered intravenously over 20 to 30 minutes prior to 
chemotherapy.    
Drug Interactions: 
Fosaprepitant is a prodrug of aprepitant and is a weak inhibitor of CYP3A4.  Aprepitant is a 
substrate, inhibitor and inducer of CYP3A4.   
Concurrent CYP3A4 Sensitive Substrates:  Use of fosaprepitant with drugs that are CYP3A4 
substrates (e.g. alfentanil, everolimus, ibrutinib, lovastatin, midazolam, simvastatin, sirolimus, 
tacrolimus, triazolam, vardenafil) may result in increased exposure and plasma concentration of 
the concomitant drug.  Concurrent use of pimozide is contraindicated with fosaprepitant due to 
the risk of significantly increased concentrations of pimozide, potentially resulting in QTc 
interval prolongation. 
Concurrent CYP3A4 strong or moderate inhibitors: Use of fosaprepitant with drugs that are 
strong or moderate CYP3A4 inhibitors (e.g. ketoconazole, diltiazem) may increase plasma 
concentrations of aprepitant and result in increased adverse reactions related to aprepitant. 
Concurrent CYP3A4 strong inducers:  Use of fosaprepitant with strong CYP3A4 inducers (e.g. 
rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy 
of fosaprepitant. 


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Pharmacokinetics:   
Distribution – Following administration of a single intravenous 150-mg dose of fosaprepitant, a 
prodrug of aprepitant, the mean AUC of aprepitant was 37.4 (+/- 14.8) mcg*hr/mL and the mean 
maximal aprepitant concentration (Cmax) was 4.2 (+/- 1.2) mcg/mL.  The mean volume of 
distribution at stead state (Vdss) is approximately 70L in humans. Aprepitant crosses the blood-
brain barrier. 
Metabolism – Conversion of fosaprepitant to aprepitant occurs in multiple exrahepatic tissues 
in addition to the liver.  Aprepitant undergoes extensive hepatic metabolism.  Aprepitant is 
metabolized primarily by CYP3A4 with minor contributions of CYP1A2 and CYP2C19.     
Excretion – Urine (57%), feces (45%).  Terminal half-life is 9 to 13 hours. 
Adverse Events 
Common known potential toxicities > 10%: 
Central nervous system:  fatigue 
Gastrointestinal:  diarrhea 
Less common known potential toxicities 1-10%: 
Central nervous system:  peripheral neuropathy, headache 
Gastrointestinal:  hiccups, anorexia, constipation, dyspepsia, eructation 
Genitourinary:  urinary tract infection 
Hematologic & oncologic:  neutropenia, anemia, leukopenia 
Hepatic:  increased serum ALT, increased serum AST 
Local:  infusion-site reaction 
Neuromuscular/skeletal:  weakness, limp pain 
Rare, less than 1% (limited to important or life threatening): 
Abdominal distention, abdominal pain, abnormal dreams, abnormal gait, acne vulgaris, 
anaphylaxis, anemia, angioedema, anxiety, bradycardia, candidiasis, cardiovascular signs and 
symptoms, chest discomfort, chills, cognitive dysfunction, colitis (neutropenic), conjunctivitis, 
cough, decreased visual acuity, diaphoresis, disorientation, dizziness, drowsiness, dysarthria, 
dysgeusia, dyspnea, dysuria, edema, epigastric distress, erythema, euphoria, febrile neutropenia, 
fecal impaction, flatulence, flushing, gastroesophageal reflux, gastroesophageal reflux disease, 
hallucination, hematuria (microscopic), hot flash, hyperglycemia, hypersensitivity reaction, 
hypertension, hypoesthesia, hyponatremia, impaired consciousness, increased serum alkaline 
phosphatase, insomnia, intestinal obstruction, lethargy, loss of consciousness, malaise, miosis, 
muscle cramps, myalgia, myasthenia, nausea, obstipation, oily skin, palpitations, paresthesia, 
perforated duodenal ulcer, pharyngitis, pollakiuria, polydipsia, polyuria, post nasal drip, 
pruritus, seizure, sensory disturbance, SIADH (syndrome of inappropriate antidiuretic hormone 
secretion), skin lesion, skin photosensitivity, skin rash, sneezing, staphylococcal infection, 
Stevens-Johnson syndrome, stomatitis, throat irritation, tinnitus, toxic epidermal necrolysis, 
urticaria, vomiting, weight changes (gain/loss), wheezing, xerostomia. 
10.3.1 Nursing Guidelines 
1. Use of fosaprepitant with other drugs that are CYP3A4 substrates, may result in 
increased plasma concentration of the concomitant drug.  
2. Use of fosaprepitant with strong or moderate CYP3A4 inhibitors (e.g., 
ketoconazole, diltiazem) may increase plasma concentrations of fosaprepitant and 
result in an increased risk of adverse reactions related to fosaprepitant. 


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3. Use of fosaprepitant with strong CYP3A4 inducers (e.g., rifampin) may result in a 
reduction in fosaprepitant plasma concentrations and decreased efficacy of 
fosaprepitant 
4. Co administration of Emend with warfarin, a CYP2C9 substrate, may result in a 
clinically significant decrease in International Normalized Ratio (INR) of 
prothrombin time. 
5. Upon coadministration with fosaprepitant, the efficacy of hormonal contraceptives 
may be reduced during administration of and for 28 days following the last dose 
of fosaprepitant 
6. Counsel patient for hypersensitivity, and drug interactions 
7. Monitor patient for headache and offer appropriate intervention 
8. Monitor patient for diarrhea and offer appropriate intervention 
9. Monitor patient for bradycardia and hypotension during administration 
10. Hiccups can occur with this drug 
11. Counsel patient to report systems to health care team 
10.4 
Aprepitant (Cinvanti®) or Placebo 
Procurement:   
Aprepitant 130 mg injectable emulsion will be obtained from commercial supplies at each 
member institution.  Pharmacies are instructed to use commercial supply intravenous aprepitant.  
Placebo will be not be supplied by this study and is the responsibility of the site.  Placebo will 
be either 0.9% Sodium Chloride, USP or 5% Dextrose Injection, USP.  The placebo should 
match the active drug in regard to preparation and administration.    
Outdated or remaining drug/product should be destroyed on-site per procedures in place at each 
institution. 
Formulation:   
Commercial intravenous aprepitant is a 130 mg/18 mL (7.2 mg/mL) opaque, off-white to amber 
emulsion in a single dose vial.   
Storage and Stability:   
Diluted aprepitant solution is stable at ambient room temperature for 6 hours in 0.9% Sodium 
Chloride Injection, USP or 12 hours in 5% Dextrose Injection, USP. 
Preparation:  
30-Minute IV Infusion: 
Aseptically withdraw 18 mL from the vial and transfer it into an infusion bag filled with 100 
mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose for Injection, USP to yield a total 
volume of 118 mL.  Gently invert the bag 4 to 5 times. Avoid shaking.  Before administration, 
inspect the bag for particulate matter and discoloration.  Discard the bag if particulate and/or 
discoloration are observed.  Use only non-DEHP tubing and non-PVC infusion bags.   
2-Minute IV Push: 
Aseptically withdraw 18 mL from the vial into a syringe. Do not dilute.  
Aprepitant can be prepared according to each site’s institutional practice ensuring that the 
placebo matches the preparation and administration. 


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Note, intravenous aprepitant is incompatible with any solutions containing divalent cations (e.g., 
Ca2+, Mg2+), including Lactated Ringer’s Solution and Hartmann’s Solution. 
Administration: 
30-Minute IV Infusion 
Intravenous aprepitant should be administered intravenously over 30 minutes approximately 30 
minutes prior to chemotherapy.     
2-Minute IV Push 
Administer aprepitant as a 2 minute IV push approximately 30 minutes prior to chemotherapy.  
Flush infusion line with normal saline before and after administration of aprepitant. 
Drug Interactions: 
Aprepitant is a substrate, weak-to-moderate (dose-dependent) inhibitor, and an inducer of 
CYP3A4.  Aprepitant is also an inducer of CYP2C9. 
Concurrent CYP3A4 Sensitive Substrates:  Use of aprepitant with drugs that are CYP3A4 
substrates may result in increased exposure and plasma concentration of the concomitant drug.  
Concurrent use of pimozide is contraindicated with aprepitant due to the risk of significantly 
increased concentrations of pimozide, potentially resulting in QTc interval prolongation. 
Concurrent CYP3A4 strong or moderate inhibitors: Use of aprepitant with drugs that are strong 
or moderate CYP3A4 inhibitors (e.g. ketoconazole, diltiazem) may increase plasma 
concentrations of aprepitant and result in increased adverse reactions related to aprepitant. 
Concurrent CYP3A4 strong inducers:  Use of aprepitant with strong CYP3A4 inducers (e.g. 
rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy 
of aprepitant. 
Concurrent warfarin use: Coadministration of aprepitant with warfarin, a CYP2C9 substrate, 
may result in a clinically significant decrease in the International Normalized Ratio (INR) of 
prothrombin time.  Monitor the INR in patients on chronic warfarin therapy in the 2-week period, 
particularly at 7 to 10 days, following initiation of aprepitant with each chemotherapy cycle. 
Risk of reduced efficacy of hormonal contraceptives: Upon coadministration with aprepitant, the 
efficacy of hormonal contraceptives may be reduced during administration and for 28 days 
following the last dose of aprepitant.  Advise patients to use effective alternative or back-up 
methods of non-hormonal contraception during treatment with aprepitant and for 1 month 
following administration of intravenous aprepitant.   
Pharmacokinetics:   
Distribution – Aprepitant is greater than 99% bound to plasma proteins. The mean apparent 
volume of distribution at steady state (Vdss) was approximately 70 L in humans.  Aprepitant 
crosses the blood brain barrier in humans  
Metabolism – Aprepitant undergoes extensive metabolism. In vitro studies using human liver 
microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor 
metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine 
ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected. 
Excretion – Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. 
The apparent terminal half-life ranged from approximately 9 to 13 hours. 
Adverse Events 
Common known potential toxicities > 10%: 
Central nervous system:  fatigue 
Hematologic & oncologic:  neutropenia 
Less common known potential toxicities 1-10%: 


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Cardiovascular: hypotension, bradycardia, flushing, palpitations, peripheral edema, syncope 
Central nervous system:  headache, dizziness, anxiety, hypoesthesia, hypothermia, malaise, 
peripheral neuropathy 
Dermatologic: pruritus, alopecia, hyperhidrosis, skin rash, urticarial 
Endocrine & metabolic: dehydration, decreased serum albumin, decreased serum potassium, 
decrease serum sodium, hot flash, hypokalemia, hypovolemia, increased serum glucose, weight 
loss 
Gastrointestinal:  constipation, diarrhea, dyspepsia, abdominal pain, hiccups, decreased appetite, 
dysgeusia, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting, 
xerostomia  
Genitourinary:  proteinuria 
Hematologic 
& 
oncologic: 
neutropenia, 
anemia, 
febrile 
neutropenia, 
hematoma, 
thrombocytopenia 
Hepatic:  increased serum ALT, increased serum AST, increased serum alkaline phosphatase, 
increased serum bilirubin 
Infection: candidiasis, postoperative infection 
Local:  infusion-site reaction, induration and inflammation at injection site 
Neuromuscular/skeletal:  weakness, musculoskeletal pain 
Renal: Increased blood urea nitrogen 
Respiratory: cough, dyspnea, hypoxia, oropharyngeal pain, pharyngitis, respiratory depression 
Rare, less than 1% (limited to important or life threatening): 
Abdominal distention, abnormal dreams, abnormal gait, acne vulgaris, anaphylaxis, 
angioedema, anxiety, cardiac disease, chest discomfort, chills, cognitive dysfunction, 
conjunctivitis, decreased neutrophils, disorientation, drowsiness, dysfunction, dysuria, edema, 
epigastric 
distress, 
euphoria, 
hematuria, 
hyperglycemia, 
hypersensitivity 
reaction, 
hyponatremia, increased thirst, lethargy, muscle cramps, myalgia, neutropenic enterocolitis, oily 
skin, perforated duodenal ulcer, pollakiuria, polyuria, polydipsia, post nasal drip, skin lesion, 
skin photosensitivity, sneezing, staphylococcal infection, Stevens-Johnson syndrome, 
stomatitis, throat irritation, tinnitus, toxic epidermal necrolysis, weight gain 
10.4.1 Nursing Guidelines 
1. Assess patient’s concomitant medications, including over the counter agents as 
there are many drug to drug interactions. 
2. Rarely hypersensitivity reactions can occur. Monitor patients during infusions and 
administer emergency medications as per facility policy. 
3. Gastrointestinal side effects may occur including diarrhea, constipation, taste 
changes, etc.  Treat symptomatically and monitor for effectiveness. 
4. Monitor patient for bradycardia and hypotension during administration 
5. Hiccups can occur with this drug 
6. Monitor CBC w/diff as cytopenia, most notably neutropenia can occur. Instruct 
patients to report any infectious symptoms to the team. 
7. Warn patients of fatigue. 
8. Monitor LFT’s.  
9. Injection site reaction can occur with induration. 
 
 


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10.5 
Palonosetron for IV Administration (Aloxi®) 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Outdated or remaining drug/product should be destroyed on-site per procedures in place at each 
institution. 
Formulation 
Solution, (Aloxi Intravenous):  0.25 mg/5 mL (5 mL) 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store 
intact vials at 20°C to 25°C (68°F to 77°F; excursions permitted to 15°C to 30°C (59°F 
to 86°F).  Do not freeze.  Protect from light.  Solutions of 5 mcg/mL and 30 mcg/mL in 
NS, D5W, D51/2NS and D5LR injection are stable for 48 hours at room temperature 
and 14 days under refrigeration.   
Administration 
Refer to the treatment section for specific administration instructions. Flush IV line with 0.9% 
sodium chloride prior to and following administration.  Infuse over 30 seconds beginning 
approximately 30 minutes prior to the start of chemotherapy.   
Drug Interactions 
Cytochrome P450 Effect: Substrate of CYP1A2 (minor), CYP2D6 (minor), CYP3A4 
(minor);  
Increased Effect/Toxicity: apomorphine, serotonin modulators.  
Decreased Effect: tapentadol; tramadol 
Pharmacokinetics 
Distribution Vd: Adults:  8.3 +  2.5 L/kg 
Protein binding: ~62% 
Metabolism: Hepatic (approximately 50% metabolized via CYP enzymes to inactive 
metabolites) 
Half-life elimination: Adults ~40 hours 
Excretion: Urine (80%; 40% as unchanged drug) 
Adverse Events 
Consult the package insert for the most current and complete information.  
Less common known potential toxicities 1-10%: 
Cardiovascular: Prolonged Q-T interval on ECG, bradycardia, sinus bradycardia, 
tachycardia, hypotension 
Central nervous system: Headache, anxiety, dizziness  
Dermatologic: Pruritus  
Endocrine & metabolic: Hyperkalemia  
Gastrointestinal: Constipation, diarrhea, flatulence 


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Genitourinary: Urinary retention 
Hepatic: Increased serum ALT, increased serum AST  
Neuromuscular & skeletal: Weakness  
Rare, less than 1% (limited to important or life threatening): 
Abdominal pain, allergic dermatitis, amblyopia, anaphylactic shock (very rare), anaphylaxis 
(very rare), anasarca, anemia, anorexia, arthralgia, cardiac arrhythmia, chills, decreased appetite, 
decreased blood pressure, decreased gastrointestinal motility, decreased platelet count, 
dermatological disease (infants, children, and adolescents), distended vein, drowsiness, 
dyskinesia (infants, children, and adolescents), dyspepsia, electrolyte disturbance, epistaxis, 
erythema, euphoria, extrasystoles, eye irritation, fatigue, fever, flattened T wave on ECG, flu-
like symptoms, glycosuria, hiccups, hot flash, hyperglycemia, hypersensitivity (very rare), 
hypersomnia, hypertension, hypokalemia, hypoventilation, increased bilirubin (transient), 
increased liver enzymes, infusion site pain (infants, children, and adolescents), injection site 
reaction (very rare; includes burning sensation at injection site, discomfort at injection site, 
induration at injection site, pain at injection site), insomnia, ischemic heart disease, 
laryngospasm, limb pain, metabolic acidosis, motion sickness, paresthesia, serotonin syndrome, 
sialorrhea, sinus arrhythmia, sinus tachycardia, skin rash, supraventricular extrasystole, tinnitus, 
vein discoloration, ventricular premature contractions, xerostomia  
10.5.1 Nursing Guidelines 
1. Headaches are the most common side effect. Rare episodes of tachycardia and 
arrhythmias have been observed. 
2. Rare hypersensitivity reactions have been observed. 
3. May exacerbate symptoms of lactose intolerance. 
 
 


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10.6 
Ondansetron for Oral or IV Administration (Zofran®) 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Outdated or remaining drug/product should be destroyed on-site per procedures in place at each 
institution. 
Formulation 
Tablets:  4 mg, 8 mg 
Tablets, orally-disintegrating:  4 mg, 8 mg 
Oral Solution, 4 mg/5 mL (50 mL) 
Solution (Ondansetron HCl Injection):  4 mg/2 mL (2 mL), 40 mg/20 mL (20 mL) 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store 
tablets between 2°C and 30°C (36°F to 84°F).  Store oral solution between 15°C and 
30°C (59°F and 86°F).  Protect from light.  Store vials between 2°C and 30°C (36°F to 
84°F).  Protect from light.  Stable when mixed in D5W or 0.9% Sodium Chloride for 48 
hours at room temperature.   
Administration 
Refer to the treatment section for specific administration instructions.  
Oral:  Oral dosage forms should be administered 30 minutes prior to chemotherapy.   
Oral disintegrating tablets:  Do not remove from the blister until needed.  Peel backing off the 
blister, do not attempt to push tablet through the foil.  Using dry hands, place tablet on the 
tongue and allow to dissolve.  Swallow with saliva (no need to administer other liquids).   
Intravenous:  May be administered IV Push per institutional guidelines undiluted over at least 
30 seconds but preferably over 2 to 5 minutes.  May administer via IV piggyback diluted over 
15 minutes.  Give approximately 30 minutes prior to chemotherapy. 
Drug Interactions 
Cytochrome P450 Effect: Substrate of CYP1A2 (minor), CYP2C9 (minor), CYP2D6 
(minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein; Inhibits:  CYP1A2 
(weak), CYP2C9 (weak) 
Increased Effect/Toxicity: QTc prolonging agents, metformin, panobinostat, serotonin 
modulators, tizanidine  
Decreased Effect: tapentadol; tramadol 
Pharmacokinetics 
Onset of action:  ~30 minutes 
Distribution Vd: Adults:  1.9 L/kg 
Protein binding: 70-76% 
Metabolism: Hepatic via hydroxylation, followed by glucuronide or sulfate conjugation 
Half-life elimination: Adults ~3-6 hours 
Excretion: Urine (44-60% as metabolites; ~5% as unchanged drug); feces (~25%) 


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Adverse Events 
Consult the package insert for the most current and complete information.  
Common known potential toxicities >10%: 
Central nervous system: Headache, fatigue, malaise  
Gastrointestinal: Constipation  
Less common known potential toxicities 1-10%: 
Central nervous system: Drowsiness, sedation, dizziness, agitation, anxiety, paresthesia, 
sensation of cold 
Dermatologic: Pruritus, skin rash 
Gastrointestinal: Diarrhea  
Genitourinary: Gynecologic disease, urinary retention 
Hepatic: Increased serum ALT, increased serum AST 
Local: Injection site reaction  
Respiratory: Hypoxia  
Miscellaneous: Fever  
Rare, less than 1% (limited to important or life threatening): 
Abdominal pain, accommodation disturbance, anaphylactoid reaction, anaphylaxis, 
angina pectoris, angioedema, atrial fibrillation, bradycardia, bronchospasm, bullous skin 
disease, cardiac arrhythmia, cardiorespiratory arrest (IV), chest pain, chills, depression 
of ST segment on ECG, dyspnea, dystonic reaction, ECG changes, extrapyramidal 
reaction (IV), flushing, hepatic failure (when used with other hepatotoxic medications), 
hiccups, hypersensitivity reaction, hypokalemia, hypotension, ischemic heart disease, 
laryngeal edema, laryngospasm (IV), liver enzyme disorder, mucosal tissue reaction, 
myocardial infarction, neuroleptic malignant syndrome, oculogyric crisis, palpitations, 
positive lymphocyte transformation test, prolonged Q-T interval on ECG (dose 
dependent), second-degree atrioventricular block, serotonin syndrome, shock (IV), 
Stevens-Johnson syndrome, stridor, supraventricular tachycardia, syncope, tachycardia, 
tonic-clonic seizures, torsades de pointes, toxic epidermal necrolysis, transient blindness 
(lasted ≤48 hours), transient blurred vision (following infusion), urticaria, vascular 
occlusive events, ventricular premature contractions, ventricular tachycardia, weakness, 
xerostomia 
10.6.1 Nursing Guidelines 
1. Headaches are the most common side effect. Rare episodes of tachycardia and 
arrhythmias have been observed. 
2. Rare hypersensitivity reactions have been observed. 
3. May exacerbate symptoms of lactose intolerance. 
10.7 
Dexamethasone for Oral Administration (DXM) 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 


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Outdated or remaining drug/product should be destroyed on-site per procedures in place at each 
institution. 
Formulation 
Commercially available for oral administration as:  
Tablets [scored]: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg 
Solution, oral: 0.5 mg/mL (500 mL) 
Solution, oral concentrate: Dexamethasone Intensol: 1 mg/mL (30 mL) 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store oral 
tablets at room temperature between 20ºC to 25ºC (68ºF to 77ºF). Protect from 
moisture. Dispense in a well-closed, light-resistant container as defined in the USP/NF. 
Store oral liquid at room temperature, do not freeze. Do not use if solution contains a 
precipitate. Refer to commercial package for drug expiration date. 
Administration 
Refer to the treatment section for specific administration instructions. May be taken with 
meals to decrease GI upset. 
Drug Interactions 
Cytochrome P450 Effect: Substrate of CYP3A4 (major); Induces CYP2A6 
(weak/moderate), 2C9 (weak/moderate), 3A4,  UGT1A1 Increased Effect/Toxicity: 
Aprepitant, azole antifungals, calcium channel blockers, cyclosporine, estrogens, and 
macrolides may increase the serum levels of corticosteroids. Corticosteroids may 
increase the hypokalemic effects of amphotericin B or potassium-wasting diuretics 
(loop or thiazide); monitor. Refer to the package insert for a listing of other drugs. 
Decreased Effect: Antacids and bile acid sequestrants may reduce the absorption of 
corticosteroids; may reduce the absorption of corticosteroids; separate administration by 
2 hours. Aminoglutethimide, barbiturates, and CYP3A4 inducers may reduce the serum 
levels/effects of dexamethasone and dexamethasone may decrease the levels/effects of 
other CYP3A4 substrates. Serum concentrations of isoniazid may be decreased by 
corticosteroids. Corticosteroids may lead to a reduction in warfarin effect. 
Corticosteroids may suppress the response to vaccinations. 
Ethanol/Nutrition/Herb Interactions:  
Ethanol: Avoid ethanol (may enhance gastric mucosal irritation). 
Food: Dexamethasone interferes with calcium absorption. Limit caffeine. 
Herb/Nutraceutical: Avoid cat’s claw, Echinacea (have immunostimulant properties) 
Pharmacokinetics 
Onset of action: Prompt 
Duration of metabolic effect: 72 hours 
Metabolism: Hepatic 
Half-life elimination: adults ~4 hours 
Time to peak, serum: Oral: 1-2 hours 
Excretion: Urine (~10%) 


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Adverse Events 
Consult the package insert for the most current and complete information.  
Common known potential toxicities, frequency not defined:   
Cardiovascular:  bradycardia, cardiac arrhythmia, cardiac failure, cardiomegaly, 
circulatory shock, edema, embolism (fat), hypertension, hypertrophic cardiomyopathy 
(premature infants), myocardial rupture (post-MI), syncope, tachycardia, 
thromboembolism, thrombophlebitis, vasculitis 
Central nervous system:  Depression, emotional lability, euphoria, headache, increased 
intracranial pressure, insomnia, malaise, myasthenia, neuritis, neuropathy, paresthesia, 
personality changes, pseudotumor cerebri (usually following discontinuation), psychic 
disorder, seizure, vertigo 
Dermatologic:  Acne vulgaris, allergic dermatitis, alopecia, atrophic striae, diaphoresis, 
ecchymoses, erythema, facial erythema, fragile skin, hyperpigmentation, hypertrichosis, 
hypopigmentation, perianal skin irritation (itching, burning, tingling; following IV 
injection), petechiae, skin atrophy, skin rash, subcutaneous atrophy, suppression of skin 
test reaction, urticaria, xeroderma 
Endocrine & metabolic: Adrenal suppression, carbohydrate intolerance, Cushing 
syndrome, decreased glucose tolerance, decreased serum potassium, diabetes mellitus, 
fluid retention, glycosuria, growth suppression (children), hirsutism, HPA-axis 
suppression, hyperglycemia, hypokalemic alkalosis, menstrual disease, moon face, 
negative nitrogen balance, protein catabolism, redistribution of body fat, sodium 
retention, weight gain 
Gastrointestinal: Abdominal distention, gastrointestinal hemorrhage, gastrointestinal 
perforation, hiccups, increased appetite, nausea, pancreatitis, peptic ulcer, pruritus ani 
(following IV injection), ulcerative esophagitis 
Genitourinary: Defective (increased or decreased) spermatogenesis 
Hematologic & oncologic: Kaposi sarcoma, petechial, tumor lysis syndrome 
Hepatic: Hepatomegaly, increased serum transaminases 
Hypersensitivity: Anaphylactoid reaction, anaphylaxis, angioedema, hypersensitivity 
Infection: Infection, sterile abscess 
Local: Postinjection flare (intra-articular use) 
Neuromuscular & skeletal: Amyotrophy, aseptic necrosis of bones (femoral and 
humoral heads), bone fractures, Charcot-like arthropathy, myasthenia, myopathy 
(particularly in conjunction with neuromuscular disease or neuromuscular-blocking 
agents), osteoporosis, rupture of tendon, steroid myopathy, vertebral compression 
fracture 
Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, subcapsular 
posterior cataract 
Respiratory: Pulmonary edema 
Miscellaneous: Wound healing impairment 
 
 


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10.7.1 Nursing Guidelines 
1. Monitor for hypertension, CHF and other evidence of fluid retention. 
2. Advise patient of possible mood or behavioral changes, i.e., depression, euphoria, 
insomnia, even psychosis.  Instruct patient to report any suspected changes to 
healthcare team. 
3. Assess for symptoms of gastric ulcer, heartburn, or gastritis.  Suggest antacids.  
Instruct patient to report symptoms to healthcare team if unable to control. 
4. Evaluate signs of infection, particularly local candidal infections and treat 
appropriately. 
5. Instruct patient to report frequent, unrelenting headaches or visual changes to 
healthcare team. 
 
 


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11.0 MEASURES 
Data from the patient questionnaires (Appendices II-V) will be used to measure treatment effect. The 
following measures will be used in this study: 
11.1 
Baseline Nausea and Vomiting Questionnaire (Appendix II) 
All patients will be asked to complete the baseline nausea and vomiting questionnaire prior to 
administering chemotherapy.  
11.2 
Nausea and Vomiting Daily Diary/Questionnaire (Appendix III) 
Patients will complete a daily diary on any experienced nausea and vomiting on days 2 to 6 post-
chemotherapy. 
11.3 
Daily Nurse Telephone Contact (Appendix IV) 
Nurse will contact patient daily on days 2-6 following Cycle 1 of chemotherapy (including 
holidays and weekends), in the initial phase only, to assess any adverse events and to remind 
them to take the study medication, the dexamethasone, and/or to complete the daily diary. Nurse 
will also record rescue medications and any additional new medications, as well as self-reported 
health care utilization for patients with adverse events. 
11.4 
EQ-5D-3L Health Questionnaire (Appendix V) 
Patients will complete the EQ-5D-3L questionnaire prior to administering chemotherapy and on 
days 2-6.  
12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment  
The treatment period for this study during the initial phase is a four day anti-emetic regimen, 
with chemotherapy being administered on Day 1.  
Continuation phase: If the patient has minimal or no nausea or emesis after the first cycle of 
chemotherapy and requests to continue on the same antiemetic regimen, the patient will be 
permitted to continue on the same antiemetic regimen (with the agreement of the patient’s 
physician) for a maximum of three additional cycles and will be evaluated for efficacy and any 
adverse events. 
12.2 
Criteria for discontinuation of protocol treatment/intervention 
12.2.1 Stopping study treatment due to toxicity: If the patient experiences a significant 
adverse event (per patient and physician discretion) felt to potentially be related to any of 
the study drugs, then the drug to which the adverse event is attributed should be 
discontinued. 
12.2.2 Disease progression or discontinuation of chemotherapy:  
If the patient progresses or discontinues chemotherapy, study treatment will be 
discontinued.  
 
 


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12.3 
Follow-up 
12.3.1 Duration of follow up for patients who continue study treatment 
Starting on the day that chemotherapy is given, patients will be followed from Day 1 
through Day 6.  For patients who elect to participate in the continuation phase, follow up 
will also continue through Day 6 of the fourth cycle of protocol therapy.  
12.3.2 Follow up for patients who discontinue study treatment early  
For patients who discontinue protocol therapy during Cycle 1 due to toxicity, disease 
progression, or discontinuation of chemotherapy, no follow-up will be required. 
Patients who discontinue protocol therapy due to toxicity, disease progression, or 
discontinuation of chemotherapy during the Continuation Phase, will be followed for 
toxicities but completion and submission of questionnaires and economic data will not be 
required.   
12.4 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or 
the patient no longer wishes to continue protocol therapy, protocol therapy shall be 
discontinued. In this event: 
Document the reason(s) for discontinuation of therapy on data forms. 
Follow the patient for protocol endpoints as required by the Study Calendar. 
12.5 
Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patient 
A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible.  
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, study chair, and executive officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), the follow-up requirements are specified below.  
Baseline and off treatment data submission required. See the Data Submission Schedule 
accompanying the All Forms Packet 


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13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Overview: 
This trial, following extensive discussion with multiple parties, is designed as a multi-center, 
randomized, double-blind, placebo-controlled study where patients will be randomly assigned 
at a ratio of 1:1 to receive either olanzapine + fosaprepitant (Group 1) or to olanzapine + placebo 
(Group 2). Both arms include a 5-HT3 receptor antagonist and dexamethasone.  
13.2 
Sample Size, Accrual time and Study duration 
13.2.1 Sample size 
The primary objective of the study is to compare the no nausea rate between the treatment 
arms. The study is powered using no nausea rate in the overall period (0-120 hours) as the 
primary endpoint.  
Our previous study [11] showed that the rate of no nausea in the overall period after 
treatment with olanzapine + fosaprepitant was 37%. We hypothesize that olanzapine + 
placebo is not inferior to olanzapine + fosaprepitant as a treatment for chemotherapy-
induced nausea. Based on our experience in clinical practice, we felt if the no nausea rate 
in the overall period after treatment with olanzapine + placebo is less than 10% lower than 
the no nausea rate after treatment with olanzapine + fosaprepitant then olanzapine + 
placebo could be considered non-inferior to olanzapine + fosaprepitant. That is, a non-
inferiority margin of 10% is considered to be clinical meaningful. To support that the 10% 
non-inferiority margin is reasonable, it is noted that in our preceding trial [11], we had 
noted that a 17.5 % superiority rate was clinically appropriate; in this current trial we are 
being a bit more stringent by decreasing 17.5% to 10%.  
The specific statistical hypotheses being considered are Ho: pc – pt ≥ .10 versus Ha: pc – pt 
< .10 where pc is the no nausea rate during the overall period after treatment with 
olanzapine  + fosaprepitant and pt is the no nausea rate after olanzapine + placebo. 
Assuming pc = 37% and using a one-sided Type I error rate of 0.05 with one planned 
interim analysis for efficacy and futility (non-binding) occurring after 50% of patients have 
enrolled and completed the Nausea and Vomiting Daily Diary/Questionnaire, 310 patients 
per arm will provide 80% likelihood (or power) to conclude that olanzapine + placebo is 
non-inferior to olanzapine + fosaprepitant if the no nausea rate with olanzapine + placebo 
is 37%. 
We anticipate that as much as 10% of patients will be lost due to cancellation or major 
violations, and thus the total target sample size will be inflated to 690 (345 per arm). 
13.2.2 Accrual Rate and Accrual Duration 
The proposed study is a standard antiemetic study for which patient accrual should be very 
timely and efficient. There are no complex accrual issues and no demands for extensive 
resources in the protocol. The investigators have extensive experience in conducting phase 
II and phase III antiemetic studies. The Alliance Symptom Intervention Committee 
expressed marked interest in participating in this trial. Considering the accrual rate in the 
previous Alliance olanzapine trial, the patient accrual is estimated to be 40 patients per 
month, supporting that the accrual will be completed within 18 months. 
13.2.3 Primary Endpoint Completion Date for ClinicalTrials.gov Reporting 
For purposes of ClinicalTrials.gov reporting, the Primary Endpoint Completion Date 
(PECD) for this study is the time the last patient registered has been followed for at least 5 
days. 


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13.3 
Statistical Design and Analysis of the Primary Endpoint  
13.3.1 Primary Endpoint 
No nausea is defined as a response of 0 in the nausea item of Nausea and Vomiting Daily 
Diary/Questionnaire in the overall (0-120 hours), acute (0-24 hours), and delayed (24-120 
hours) periods. 
13.3.2 Statistical Design 
Interim analysis decision rule: 
Interim analysis of non-inferiority and of inferiority of olanzapine + placebo as compared 
to olanzapine + fosaprepitant will be conducted when 50% of patients are enrolled and 
have completed the Nausea and Vomiting Daily Diary/Questionnaire. The Lan-DeMets 
family of alpha and beta spending functions corresponding to the O’Brien-Fleming 
boundary are used for controlling overall type I and type II error rates. Non-inferiority of 
olanzapine + placebo will be concluded if p-value <= 0.006 (corresponding to Z > 2.538) 
and inferiority of olanzapine + placebo will be concluded if p-value >= 0.370 
(corresponding to Z < 0.331). The second stage of this clinical trial shall continue if p-
value is in the interval of (0.006, 0.370). 
Final analysis decision rule: 
Final analysis will be conducted when all target patients are enrolled and have completed 
the Nausea and Vomiting Daily Diary/Questionnaire. Non-inferiority of olanzapine + 
placebo will be concluded if p-value < 0.048 (corresponding to Z > 1.662) and inferiority 
of olanzapine + placebo will be concluded if p-value >= 0.048 (corresponding to Z >= 
1.662). 
13.3.3 Study Operating Characteristics 
Simulation studies of 10,000 clinical trials are conducted for the proposed group sequential 
design.  The probabilities of early stopping (at the interim analysis) and empirical powers 
for various scenarios are summarized in the following table.  Of particular interest, 
assuming that the no nausea rate with olanzapine + fosaprepitant in the overall period is 
37% and the no nausea rate with olanzapine + placebo is 27% (that is, olanzapine + placebo 
is inferior to olanzapine + fosaprepitant), there is a 64.72% chance of stopping the trial 
early to conclude that olanzapine + placebo is inferior and there is a 4.63% chance of the 
trial concluding that olanzapine + placebo is non-inferior to olanzapine + fosaprepitant 
(type I error).  In another scenario where the no nausea rate with olanzapine + fosaprepitant 
is 37% and the no nausea rate with olanzapine + placebo is 37% (that is, olanzapine + 
placebo is truly non-inferior to olanzapine + fosaprepitant), the likelihood of stopping early 
to conclude inferiority is 7.13% and the likelihood of the trial concluding that olanzapine 
+ placebo is non-inferior to olanzapine + fosaprepitant is 80.38% (power).   
 
 


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Probability of no nausea 
Interim analysis 
conclusion 
Early 
stopping 
Final analysis conclusion 
Power 
olanzapine + 
fosaprepitant 
olanzapine 
+ placebo 
Noninferior 
Inferior 
Noninferior 
Inferior 
 
37% 
27% 
.54% 
64.72% 
65.26% 
4.09% 
30.65% 
4.63% 
32% 
5.18% 
28.51% 
33.69% 
29.74% 
36.57% 
34.92% 
37% 
23.15% 
7.13% 
30.28% 
57.23% 
12.49% 
80.38% 
40% 
42.52% 
2.24% 
44.76% 
51.69% 
3.55% 
94.21% 
 
13.3.4 Analysis Plan: 
A modified intent-to-treat principle [33] will be applied for statistical analysis of efficacy 
in evaluable patients.  Evaluable patients are defined as all patients meeting the eligibility 
criteria who did not cancel prior to receiving treatment and had no major violations. 
The proportions of patients with no nausea during the overall, the acute, and the delayed 
period will be summarized by treatment arm. They will be tested in a sequential manner, 
using a Simes gatekeeping procedure [34] to maintain the overall significance level at the 
specified by the Lan-DeMets family of alpha spending function [35].  The difference in no 
nausea proportions between arms will be estimated along with a one-sided 95% confidence 
interval.  The tests and the confidence intervals will be constructed using normal 
approximation of the binomial distribution adjusted for the non-inferiority margin.[35] 
 
H110: No nausea rate in the 
overall period with olanzapine 
+ placebo is inferior to the 
rate with olanzapine + 
fosaprepitant 
 
H210: No nausea rate in the acute period with 
olanzapine + placebo is inferior to the rate 
with olanzapine + fosaprepitant. 
H220: No nausea rate in the delayed period 
with olanzapine + placebo is inferior to the 
rate with olanzapine + fosaprepitant. 
Step 1. The null hypothesis of H110 serves as a gatekeeper; 
 
Step 2. The null hypotheses of H210 and H220 are tested only after H110 has been 
rejected. 
 
As the inference of H110 may depend on whether or not some hypotheses (H210 or H220) 
are rejected in the subsequent family, we will adopt the Simes gatekeeping procedure 
rather than Bonferroni gatekeeping procedure. A SAS macro %GateKeeper will be 
utilized to implement the decision matrix algorithm for adjusted p-values. 
13.4 
Analysis of Secondary Endpoints 
13.4.1 Secondary Endpoints 
a. Complete response (no emetic episodes and no use of rescue medication) during the 
acute, delayed and the overall periods as measured by the Nausea and Vomiting Daily 
Diary/Questionnaire. 


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b. Potential toxicities as ascribed to olanzapine as measured by the Nausea and Vomiting 
Daily Diary/Questionnaire. 
c. Nausea scores (0-10) repeatedly measured by the Nausea and Vomiting Daily 
Diary/Questionnaire. 
d. Frequency of rescue medication as measured by the Nausea and Vomiting Daily 
Diary/Questionnaire. 
13.4.2 Secondary Analysis  
The main objective of the secondary endpoints is to help us understand the full picture of 
patients’ experience on these two antiemetic regimens. Our main objective is to estimate 
difference in these endpoints between the two arms and superiority tests will be used for 
exploratory comparisons.  Analysis of secondary endpoints b. (toxicities) and d. (rescue 
medication) will only include patients who started their assigned treatment and patients 
will be analyzed based on the treatment they received (per protocol analysis population).  
Analysis of secondary endpoints a. (complete response) and c. (nausea score) will use the 
modified ITT analysis population as described for the primary endpoint.  If there is a high 
rate of drop-out or noncompliance, per protocol analysis of these endpoints will be 
conducted as a sensitivity analysis.  Multiplicity will not be adjusted for secondary 
analyses, hence, statistically significant findings from secondary analyses are exploratory 
in nature and therefore shall be interpreted as such.  
a) The CR rate for the overall, the acute, and the delayed period will be summarized by 
treatment arm and will be compared using a Chi-squared test.  The difference in CR 
rates between arms will be estimated along with a 95% confidence interval. Using the 
CR rates reported in our previous study59, a sample size of 620 evaluable patients will 
provide more than 80% power, at a two-sided Type I error rate of 0.05, to detect the 
following improvement in CR rates: 
Period 
CR rate 
Power (%) 
olanzapine + 
fosaprepitant 
olanzapine + 
placebo 
Acute (0 – 24 hours) 
.86 
.93 
82 
Delayed (25 – 120) 
.67 
.77 
80 
Overall (0 – 120) 
.64 
.76 
85 
 
a) b) Incidences of toxicities will be summarized by type and by treatment arm.  
Incidences of toxicities will be compared between arms using a Chi-squared test or the 
Fisher’s exact test as appropriate. Due to different types of toxicities and varying 
incidence rates, the power, at a two-sided Type I error rate of 0.05, to detect various 
differences in toxicity incidences between the arms with this sample size is given 
below. 
Toxicity level 
Toxicity incidence 
Power (%) 
olanzapine + 
fosaprepitant 
olanzapine + 
placebo 
Low 
.05 
.01 
84 


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Medium 
.20 
.11 
88 
High (most conservative) 
.50 
.38 
86 
 
In addition, undesired sedation and appetite increase as collected in the Nausea and 
Vomiting Daily Diary/Questionnaire will be analyzed by repeated measures analyses 
including descriptive statistics, graphical approaches, and growth curve models to 
account for the factor of day and time trend. 
c) 
In addition to the primary analysis described in Section 13.3.4, nausea scores (0-10) 
repeatedly measured by the Nausea and Vomiting Daily Diary/Questionnaire will be 
analyzed using the repeated measures analyses and growth curve models as described 
above for undesired sedation and increase in appetite. 
d) 
The proportion of patients taking any rescue medication as reported in the Nausea and 
Vomiting Daily Diary/Questionnaire will be summarized by treatment arm and will 
be compared between arms using a Chi-squared test or the Fisher’s exact test as 
appropriate. With this sample size, in the most conservative scenario where the 
proportion of patient taking rescue medication is 50%, there is an 86% power, at the 
two-sided Type I error of 0.05, to detect a 12% decrease in the proportion of patients 
taking rescue medication from 50% in the olanzapine + fosaprepitant arm compared 
to 38% in the olanzapine + placebo arm. 
In addition, the number of pills taken will be analyzed using the repeated measures 
analyses and growth curve models as described above. 
13.5 
Economic Data Analysis: 
Economic Evaluation Overview:  Analyses of costs (in $USD), cost-effectiveness (in $USD 
per averted nausea), and cost-utility (in $USD per Quality-Adjusted Life Year (QALY) gained) 
will be performed, will include direct medical costs and will use a 6-day time horizon. Costs 
will be calculated as quantities X unit costs for each type of health service or pharmaceutical 
used.  
Perspective: We adopt the healthcare sector perspective, which includes all direct medical costs 
in the cost analysis, including both medical costs borne by the payer and those borne by the 
patient. The healthcare sector perspective is the predominant perspective used in economic 
evaluations of drug therapy in oncology [43, 44]. We choose not to also conduct analysis from 
an exclusively patient perspective because in the trial, unlike in everyday medical practice, 
patient out-of-pocket costs for the anti-emetic agents are $0. We use Medicare unit prices for 
the total cost to the payer of these agents, and one might consider predicting what patient out-
of-pocket cost would be for Medicare patients off-protocol. However, only 19% of Medicare 
patients do not have some source of supplemental or alternative coverage to the standard 
Medicare benefit [45], and it is very difficult to predict out-of-pocket costs for the remaining 
81% of patients, which could range from $0 to 100% of the total cost of the drug, depending on 
the generosity of their insurance benefits. While patients incur other health care costs, past 
research and our expectations are that drug costs largely determine cost differences between 
anti-emetic regimens. Therefore, we do not feel we can provide a useful analysis of costs of anti-
emetics from the patient perspective; such a study is best conducted outside a clinical trial. 
Measurement: Health services and pharmaceuticals used will be assessed by patient self-report, 
as recorded by the nurse/research coordinator. Medical coders at Wayne State University will 
define typical sets of ICD-9, CPT, HCSPS and NDC codes used for billing for each drug and 
category of service. For health care services where the appropriate codes are ambiguous, medical 


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insurance claims with billing codes will be obtained, as described in the background Section 1.8 
of the protocol. Medicare unit costs will be used for consistency to price services and drugs 
defined by these billing codes for all patients, including for patients covered under other 
insurance plans.[46-48] EQ-5D-3L health status responses will be converted into utility weights 
using area-under-the-curve methods applied to the US population value set. [40] 
Analysis:  Due to the short time window of the intervention, all costs will be valued in 2017 
dollars with no adjustment for inflation or time discounting. 
Costs: Comparison of costs between treatment arms must account for the right-skewed 
distribution of costs. We will use nonparametric bootstrap to compare mean costs in a univariate 
analysis, and generalized linear models with log link and gamma family controlling for 
stratification factors, baseline fatigue/QOL and other patient characteristics, in a multivariate 
analysis.  
Utilities: We will estimate average health utilities for several patient health status subgroups: 
nausea vs. no-nausea, emesis vs. no-emesis, sedation vs. no-sedation, and combinations of these 
conditions. 
Cost-effectiveness and cost-utility ratios: The relative value of the olanzapine and 
fosaprepitant arm over the olanzapine arm is measured by incremental cost-effectiveness and 
cost-utility ratios: ratios of the difference in average costs over the difference in the proportion 
of patients with no nausea or in the average QALYs gained between patients in the 2 
comparative arms. Stochastic uncertainty around the estimates will be assessed with confidence 
intervals constructed using the bootstrap percentile method. [49] 
13.6 
Analysis plan for continuation phase: 
The proportion of patients participating in the optional continuation phase will be summarized 
separately by treatment arm.  The no nausea rates at the end of initial cycle will be compared 
between patients who select to continue vs. those who did not for each arm using a Chi-squared 
test.  The no nausea rates among patients who chose to continue will be compared between 
treatment arms using a Chi-squared test.  Logistic regression will be conducted to compare no 
nausea rates in the continuation phase between the treatment arms adjusting for patient response 
to their treatment in the first cycle.   
Complete response rates will be analyzed using the same approach. 
Adverse events occurring during this treatment phase will be summarized by treatment arm and 
will be compared between arms using a Chi-squared or a Fisher’s exact test as appropriate. 
Please note that due to the potential bias resulting from the optional and the unblinded nature of 
the continuation phase, this comparison is for exploratory purposes only. 
13.7 
Study Monitoring 
13.7.1 Adverse Event Stopping rule  
The stopping rule specified below is based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in the event 
of either (1) the study re-opening to accrual or (2) at any time during the conduct of the 
trial and in consideration of newly acquired information regarding the adverse event profile 
of the treatment(s) under investigation. The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified rule 
below. Accrual will be temporarily suspended to this study if at any time we observe events 
considered at least possibly related to study treatment (i.e., an adverse event with attribute 
specified as possible, probable, or definite) that satisfy the following criteria: 


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1. If 7 or more of the first 20 treated patients in either arm (or 35% of all patients after 20 
patients have been accrued) experience a grade 3 or higher non-hematologic adverse 
event. 
2. If 3 or more of the first 20 treated patients in either arm (or 15% of all patients after 20 
patients have been accrued) experience a grade 4 or higher non-hematologic adverse 
event. 
13.7.2 Accrual monitoring and stopping rule  
Slow Accrual: Patient accrual will be closely monitored by the investigators and secondary 
statistician on a monthly basis. If the accrual rate falls below 50% of expected accrual rate, 
investigators will carefully review feedback from sites and consider taking measures to 
encourage patient enrollment. 
13.8 
Study Reporting 
13.8.1 This study will be monitored by the Alliance Data and Safety Monitoring Board 
(DSMB), an NCI-approved functioning body. Reports containing efficacy, adverse event, 
and administrative information will be provided to the DSMB every month as per NCI 
guidelines. 
13.8.2 Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrials.gov” web site. The Primary and Secondary 
Endpoints (i.e., “Outcome Measures”) along with other required information for this 
study will be reported on ClinicalTrials.gov.  
 
 


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13.9 
Inclusion of Women and Minorities 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
2 
2 
1 
0 
5 
Asian 
8 
6 
0 
0 
14 
Native Hawaiian or 
Other Pacific 
Islander 
1 
0 
0 
0 
1 
Black or African 
American 
42 
37 
1 
0 
80 
White 
328 
238 
16 
8 
590 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
381 
283 
18 
8 
690 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
0 
0 
0 
0 
0 
White 
0 
0 
0 
0 
0 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
0 
0 
0 
0 
0 
 
• 
Ethnic Categories: 
- 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
- 
Not Hispanic or Latino 
• 
Racial Categories 
 
- 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains tribal 
affiliations or community attachment. 


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- 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, 
Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have 
been recorded as Pacific Islanders in previous data collection strategies.)  
- 
Black or African American – a person having origins in any of the black racial 
groups of Africa. 
- 
Native Hawaiian or other Pacific Islander – a person having origins in any of 
the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
- 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 
14.0 CORRELATIVE AND COMPANION STUDIES  
There will be one substudy, Alliance A221602-ST1 and all patients are encouraged to participate.  
14.1 
Olanzapine Pharmacogenomics and Chemotherapy induced nausea and vomiting  
14.1.1 Background 
Chemotherapy-induced nausea and vomiting (CINV) is a major severe side effect 
commonly observed in cancer patients undergoing treatment. This debilitating condition is 
associated with deterioration in life quality[50-53]CINV occurs in part from stimulation of 
a reflex pathway controlled by the brain and is triggered by impulses from the 
chemoreceptor trigger zone, gastrointestinal tract and possibly the cerebral cortex. 
Neurotransmitters notably dopamine, serotonin, substance P and their receptors have been 
reported to play critical roles in CINV. [54, 55] 
The introduction of 5-hydroxytryptamine3 (5-HT3) receptor antagonists revealed a central 
role of serotonin in the mechanism of acute emesis [56] with delayed emesis being 
attributed largely to the activation of neurokinin 1 (NK-1) receptors and substance P.  5-
hydroxytryptamine (5-HT3) receptor antagonists plus dexamethasone have significantly 
improved the control of acute CINV. [50,51] Studies have also demonstrated additional 
improvement in the control of acute and delayed CINV with the use of palonosetron, a 
second generation 5-HT3 receptor antagonist [51], aprepitant, a neurokinin-1 (NK-1) 
receptor antagonist [56], and olanzapine, which blocks multiple neurotransmitter receptors 
in the central nervous system notably serotonergic receptors.[57]  
Presently, many guidelines recommended for highly emetogenic chemotherapy regimens 
involve a 5-HT3 receptor antagonist, an NK-1 receptor antagonist, and dexamethasone. [58] 
Despite the use of multiple measures, CINV still persists in some patients, while others 
have minimal nausea or vomiting. A recent study reported that when olanzapine was added 
to a 5-HT3 receptor antagonist, aprepitant and dexamethasone there were patients who 
showed substantial improvements in complete response rate (no vomiting and no use of 
rescue medications) and patients who had no nausea (through the 5 day period following 
the single dose of chemotherapy), when compared to patients in a placebo study.[59] The 
substantial variations shown in improvements in vomiting and nausea could be due in part 
to individual differences in the function of the genes that metabolize, activate and/or are 
targets for the antiemetic drugs.  
This current proposal focuses on the use of olanzapine, an atypical antipsychotic drug and 
a multiple neurotransmitter receptor antagonist, in combination with palonosetron or 
ondansetron (5-HT3 receptor antagonists), dexamethasone and/or fosaprepitant (NK-1 
receptor antagonist). One arm of the study proposes to eliminate fosaprepitant, as a step 


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towards reducing the cost of expensive antiemetic drug treatments during chemotherapy 
while still maintaining similar levels of control over nausea and vomiting as observed in 
the olanzapine study. [59]  
Olanzapine is metabolized predominantly by oxidation mediated through CYP1A2 with 
CYP2D6 as a minor metabolizer and it also undergoes glucuronidation by UGT1A4, 
UGT2B10 and metabolized also by flavin monooxygenases (FMO1 and FMO3).[54,57] 
Olanzapine also binds strongly to dopaminergic (D1, D2, D3 and D4, Ki=11-31 nM), 
alpha-1-adrenergic, (α1, Ki=19nM), histamine H1(Ki=7nM), and muscarinic (M1, M2, 
M3, and M4, Ki=32-132nM) receptors.[57,61]  It also has high affinity for the serotonin 
receptor subtypes 5-hydroxytryptamine 2 subtypes (5-HT2A, 5-HT2C, Ki=4 and 11nM), 5-
hydroxytryptamine 3 (5-HT3, Ki= 57nM), and 5-hydroxytryptamine 6 (HT6, Ki=5nM) 
[61,62] Differences in olanzapine plasma concentrations in patients have been reported to 
contribute to risk of adverse effects and inadequate response to olanzapine.[60]  
Furthermore pharmacokinetics studies report that olanzapine clearance is lower in women 
than in men suggesting gender differences in olanzapine metabolism as well.[63] 
Aprepitant is the other antiemetic drug that will be eliminated in one arm of the parent 
study. It is administered intravenously as fosaprepitant, a prodrug of aprepitant and helps 
to prevent acute and delayed nausea and vomiting associated with chemotherapy. 
Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and 
CYP2C19.[64] CYP3A5 may also metabolize aprepitant as it accounts for about 50% of 
total hepatic CYP3A.[65] It is a selective high-affinity antagonist of human substance 
P/neurokinin 1 (NK1) receptors but has little or no affinity for serotonin (5-HT3), 
dopamine, and corticosteroid receptors, the targets of existing therapies for (CINV).[66] 
All of these enzymes are proteins and the genes encoding them are genetically polymorphic 
as such conferring variable activities to the proteins. Therefore, performing 
pharmacogenomic studies may offer some understanding of the genetic factors underlying 
these variations in CINV response.  
Genome wide association studies (GWAS) have been reported for some nausea and 
vomiting associated conditions such as migraines [67] motion sickness [68] and post-
operative nausea and vomiting (PONV). [69] To date, no GWAS studies have been done 
to determine the gene(s) that are highly linked to the CINV condition and reasons for this 
may be the cost associated with such studies.  
Only the candidate gene (single nucleotide polymorphism, SNP) approach has been 
reported for evaluating the genetic influence on CINV and a review summarizing those 
studies was reported recently.[70] Polymorphisms in genes such as CYP1A2, CYP2D6, 
CYP3A4, CYP3A5, HTR3A, HTR3B, HTR3C, HTR3D, ABCB1, and SLC22A1 have been 
evaluated in association with antiemetic efficacy of drugs including palonosetron, 
ondansetron, tropisetron, dexamethasone, aprepitant, and granisetron.[70] 
In this proposal, our focus is on the pharmacogenomics of olanzapine. Most studies have 
reported on olanzapine’s use in reducing and preventing CINV and on its metabolism and 
disposition as well as its target, however, there is little or no information on how variations 
in the genes that encode all those proteins affect CINV. The pharmacokinetics of 
olanzapine has been reported to be influenced by polymorphisms in GSTM3, and GRIN2B 
while CYP2C9, TPMT, UGT1A1 and ABCB1 polymorphisms have been reported to be 
related to the adverse effects of olanzapine.[71] Interestingly, a CYP1A2 SNP, rs762551 
(CYP1A2*F, C>A), with high basal enzyme activity, was reported to be associated with 
reduced olanzapine serum concentrations in Caucasian psychiatric patients[72] but other 
reports have indicated lack of correlation from this same polymorphism.[60,73,74]. In 


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another report, a SNP upstream of CYP1A1 and downstream of CYP1A2, rs2472297 was 
shown to influence olanzapine serum levels.[75]  As well, there are reports indicating lack 
of 
association 
between 
CYP2D6 
functional 
polymorphisms 
and 
olanzapine 
pharmacokinetics except when stratified for smoking[60]suggesting that smoking status 
may correlate with the variation in olanzapine metabolism and levels. Thus, several of these 
studies have been inconsistent in associating certain SNPs to the metabolism of and 
response to olanzapine. These inconsistencies could be due in part to the different 
populations studied (ethnic variation) and the specific SNPs chosen for genotyping. [76-
81]. A list of genes that have been associated with olanzapine and fosaprepitant/aprepitant 
in 
literature 
and 
in 
the 
drug 
bank 
is 
shown 
below: 
 
  
  
 
In view of the differences in such reports [70,76-79] and the paucity of any information 
relating to individual variations in olanzapine associated CINV, we will elucidate, the 
genetic determinants of CINV focusing primarily on olanzapine’s usage in the Alliance 
protocol A221602. We would systematically identify the polymorphisms in those genes 
responsible for the pharmacokinetics (metabolism) transport and pharmacodynamics 
(targets) of olanzapine. As well, as a secondary focus we will also identify the genetic 
polymorphisms associated with fosaprepitant/aprepitant and evaluate their association with 
CINV in the patients undergoing treatment. Thus, the two arms of the study could serve as 
ideal backgrounds for exploring possible associations of specific SNPs with variations in 
levels of CINV. 
14.1.2 Objectives: 
1.  To determine which polymorphisms in olanzapine and fosaprepitant related genes are 
associated with nausea in the acute, delayed, and overall periods.  
2. To determine which polymorphisms in olanzapine and fosaprepitant related genes are 
associated with complete response (CR) in the acute, delayed, and overall periods.  
3. To determine which polymorphisms in olanzapine-related genes are associated with 
toxicities ascribed to olanzapine. 
Approximately 620 patients will be evaluable for the primary outcome.  We anticipate 
obtaining samples for a total of 496 patients (80% of evaluable patients).   
Hypothesis: We hypothesize that SNPs in genes that metabolize (CYP1A1, CYP1A2, 
CYP2D6, UGT1A4, UGT2B10, FMO1 and FMO3), that transport (ABCB1) and are targets 
(HTR2A, HTR2C, HTR3A, HTR6 - serotonergic receptor subtypes; DRD1-4, dopaminergic 
receptors; ADR1A, alpha-1-adrenergic receptor; HRH1, histaminic receptor; CHRM1-5, 


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muscarinic receptors) for olanzapine will correlate with the severity of CINV in patients 
undergoing treatment. We further hypothesize that SNPs in TACR1 and in CYP1A2, 
CYP2C19, CYP3A4, CYP3A5, will also correlate with the severity of CINV in patients in 
the fosaprepitant treatment arm.   
We propose to achieve this hypothesis by genotyping patient DNA samples for tagSNPs in 
genes listed above responsible for the metabolism, transport and are targets for olanzapine 
and correlate these SNPs with the extent of nausea and vomiting.  SNPs which have 
previously been identified and been associated with olanzapine pharmacokinetics and/or 
pharmacodynamics as well as unique SNPs in genes listed in table under section 14.1.1 
will be evaluated or validated for the antiemetic efficacy of olanzapine [60, 61].  A partial 
list with some tagSNPs to be genotyped is shown below. 
 
 
14.1.3 Methods 
Blood collection: Whole blood sample will be collected in 1 x10 mL EDTA vacutainer 
tube (lavender top) from patients prior to treatment (See Section 6.3) for germline DNA 
isolation. Blood samples will be sent to the Mayo Clinic and DNA will be isolated in the 
Biospecimen Accessioning and Processing (BAP) lab. 
SNP selection and Genotyping:  
Genotype data from the National Center for Biotechnology Information (NCBI) dbSNP 
database will be used with programs in National Institute of environmental Health Sciences 
(https://snpinfo.niehs.nih.gov/), 
Genome 
variation 
server 
http://gvs.gs.washington.edu/GVS144/ ) to derive tagged SNPs from an initial list of 27 
genes namely ABCB1, ADRA1A, AHR, CHRM1, CHRM2, CHRM3, CHRM4, CHRM5, 
CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A43 , CYP3A5, DRD1, DRD2, DRD3, DRD4, 
FMO1, FMO3, HRH1, HTR2A, HTR2C, HTR3A, HTR6, TACR1, UGT1A4 and UGT2B10. 
SNPs with allele frequencies ≥ 20% and r2 ≥ 0.80 will be selected for genotyping. It is 
important to indicate here that there’s ethnic variation in specific SNPs and frequency of 
SNPs, therefore genotype information from the database should reflect the patient 
population on the trial. For example, tagSNPs will be derived from genotype data from 
both Caucasian and African-American databases. The acquired tagSNPs will be genotyped 
in the Genotyping Core of the Mayo Clinic Medical Genome Facility (MGF) or in any 


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Alliance associated genotyping core on either the Sequenom or the Illumina GoldenGate 
custom array. The tagSNPs to be genotyped will include the nine listed in Table 1. 
Genotyping:  The Agena iPLEX (previously called sequenom) genotyping protocol 
involves PCR amplification of DNA using SNP specific primers, followed by a base 
extension reaction using the iPLEX Gold chemistry (Agena Biosciences, San Diego, CA).  
The protocol has been used for years and will briefly be described here.  SNP-specific PCR 
and extension primers were designed and organized into pools with the Assay Design Suite 
(Agena). All primers were purchased from Integrated DNA Technologies (Coralville, IA). 
A QC run was performed with Coriell and CEPH controls, and results were tested for 
Mendelian inconsistencies. HotStar Taq Polymerase (Qiagen) was used for all PCRs. 15 
ng of DNA was added to each 5-ul PCR reaction mixture in a 384-well microtiter plate. 
The PCR condition was 94°C for 15 min for hot start, followed by 45 cycles of denaturing 
at 94°C for 20 sec, annealing at 56°C for 30 sec, extension at 72°C for 1 min for 45 cycles, 
and final incubation at 72°C for 3 min. The PCR products were then treated with SAP 
(shrimp alkaline phosphatase, Agena) for 40 min at 37°C then ramped to 85°C for 5 min 
to remove excess dNTPs. The final base extension products were diluted in double distilled 
water and then treated with 6mg of SpectroCLEAN (Agena) resin per well to remove 
contaminating salts. 10-18 nl of treated extension product was spotted to the appropriate 
location on a 384-pad SpectroCHIP II (Agena) using a RS1000 Nanodispenser (Agena, 
San Diego, CA).  A MassARRAY Analyzer Compact MALDI-TOF MS (Agena) was used 
for data acquisitions from the SpectroCHIP. All resultant genotyping calls were performed 
in real time by the MassARRAY Typer Analyzer v4.0.26.73 (Agena). 
14.1.4 Analyses 
SNP analysis: Results from genotyping will be sent to the bioinformatics/statisticians for 
analyses to correlate the SNPs to CINV and any other clinical outcome the end correlates 
indicated in protocol A221602 such as: (i) no nausea for the overall (0-120 hours post-
chemotherapy), acute (0-24 hours post- chemotherapy), and delayed periods (24-120 hours 
post-chemotherapy) for patients receiving highly emetogenic chemotherapy; (ii) complete 
response (CR) rates (no emetic episodes and no use of rescue medication) in the acute, 
delayed, and overall periods; (iii) incidence of potential toxicities ascribed to olanzapine 
including sedation. 
Statistical Analysis:  
The following analyses will be conducted separately for each SNP.  Bonferroni correction 
will be used to account for the number of SNPs considered in the analysis.  Due to the 
exploratory nature and the limited sample size, no multivariable models will be conducted 
for this aim. 
Patients will be classified by the status of their variant genotype (yes vs. no).  The no nausea 
rate and the complete response rate will be summarized separately by variant genotype 
status and will be compared between variant genotype groups using a Chi-square test for 
each time period across both treatment arms.  
The incidence of toxicities potentially ascribed olanzapine, including sedation, will be 
summarized by variant genotype status and will be compared between arms using a Chi-
squared test. 
Similar analyses will be conducted for polymorphism in fosaprepitant-related genes will 
be conducted among patients in the olanzapine + fosaprepitant arm only. 


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Additionally, we will explore the association between these polymorphisms with the 
outcomes described using the same methods treating the polymorphism as three groups 
(homozygous wild type vs. heterozygous vs. homozygous variant) 
15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
15.1 
Institutional Credentialing 
None  
 
 


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15115912. 
 
 
 


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17.0 MODEL CONSENT FORM 
 
Study Title for Study Participants: 
 
Testing the effectiveness of olanzapine with or without fosaprepitant in 
preventing nausea and vomiting in patients receiving chemotherapy 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
Olanzapine with or without fosaprepitant for the prevention of chemotherapy 
induced nausea and vomiting (CINV) in patients receiving highly emetogenic 
chemotherapy (HEC): A Phase III Randomized, Double Blind, Placebo-
Controlled Trial. 
 
This study is conducted by the Alliance for Clinical Trials in Oncology, a national clinical 
research group supported by the National Cancer Institute. The Alliance is made up of cancer 
doctors, health professionals, and laboratory researchers, whose goal is to develop better 
treatments for cancer, to prevent cancer, to reduce side effects from cancer, and to improve the 
quality of life of cancer patients. This study has public funding from the National Cancer 
Institute (NCI), part of the National Institutes of Health (NIH) in the United States Department of 
Health and Human Services. 
 
 
What is the usual approach to my diagnosis?  
You are being asked to participate in this study because treatments for cancer can cause the side 
effect of nausea and vomiting. People who do not take part in this study will receive standard 
medications that have been approved by the Food and Drug Administration for nausea and 
vomiting. 
 
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. For example: 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different study, if one is available. 
 
 
Why is this study being done? 
You have cancer and will be receiving chemotherapy that may cause nausea and vomiting. 
Olanzapine is a medication which has been approved by the Federal Drug Administration (FDA) 
for the treatment of specific mental illnesses and has been used in many patients over the past 15 
years, but it is not FDA approved to treat nausea and vomiting. Olanzapine has been shown to 
have anti-nausea and anti-vomiting effects in patients receiving chemotherapy. In previous 
studies, olanzapine was usually given in combination with other drugs, including a drug called 
fosaprepitant.  The purpose of this study is to see if olanzapine given in combination with these 


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other drugs, is still as effective without using the fosaprepitant. Information from this study will 
also be used by researchers at Wayne State University to evaluate health care costs when taking 
treatments used for nausea and vomiting. 
 
There will be about 690 people taking part in this study. 
 
 
What are the study groups? 
This study has 2 study groups. 
• Group 1 will get the usual chemotherapy drugs used for your type of cancer, either 
cisplatin or cyclophosphamide and doxorubicin, as well as following anti-
nausea/vomiting drugs: 
- 
Olanzapine by mouth on the day of chemotherapy and on days 2, 3, and 4 after 
chemotherapy  
-  Ondansetron (by mouth or through a vein in your arm) or palonosetron through 
a vein in your arm on the day of chemotherapy, plus 
-  Dexamethasone by mouth on the day of chemotherapy and on days 2, 3, and 4 
after chemotherapy, plus 
-  Fosaprepitant or Aprepitant through a vein in your arm on the day of 
chemotherapy 
 
• Group 2 will get the usual chemotherapy drugs used for your type of cancer, either 
cisplatin or cyclophosphamide and doxorubicin, as well as the following anti-
nausea/vomiting drugs: 
- 
Olanzapine by mouth on the day of chemotherapy and on days 2, 3, and 4 after 
chemotherapy  
-  Ondansetron (by mouth or through a vein in your arm) or palonosetron through 
a vein in your arm on the day of chemotherapy, plus 
-  Dexamethasone by mouth on the day of chemotherapy and on days 2, 3, and 4 
after chemotherapy, plus 
-  Placebo through a vein in your arm. The placebo looks like one of the IV study 
drugs but does not contain active medication. 
 
We will use a computer to assign you to one of the study groups (also called "randomization"). 
This means that you will be put into a group by chance, like flipping a coin.  We assign patients 
in this way because no one knows if one treatment is better or worse than the others.  
 


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Another way to find out what will happen to you during this study is to read the chart below. Start reading 
at the left side and read across to the right, following the lines and arrows. 
 
 
Initial Phase 
Optional Continuation 
 
 
 
 
 
Phase 
 
 
 
 
 
 
3 additional cycles:  
 
 
 
 
Palonosetron/Ondansetron  
 
Palonosetron/Ondansetron  
 
 
 
 
+ Dexamethasone  
 
+ Dexamethasone  
You agree  
 
Randomize 
 
+ Olanzapine 
 
+ Olanzapine  
to take part 
 
(The 
computer will  
 
+ Fosaprepitant/Aprepitant IV 
 
+ Fosaprepitant/Aprepitant IV 
in the study 
 
randomly put 
you in a study 
group) 
 
 
 
 
 
 
 
 
 
 
3 additional cycles: 
 
 
 
 
Palonosetron/Ondansetron  
 
Palonosetron/Ondansetron 
 
 
 
 
+ Dexamethasone  
 
+ Dexamethasone  
 
 
 
 
+ Olanzapine  
 
+ Olanzapine  
 
 
 
 
+ Placebo IV 
 
No Placebo/Fosaprepitant 
 
 
Initial Phase: On the first day of protocol treatment (Day 1), before you receive your 
chemotherapy, you will take all of the study drugs listed above in your group assignment.  
Olanzapine may be taken before you receive your chemotherapy or at bedtime. On Days 2, 3, 
and 4 after receiving chemotherapy, you will be asked to take olanzapine and dexamethasone 
tablets at about the same time of day as the time you received the study drugs on Day 1.  This 
four-day period of treatment is called “one cycle” of study treatment. 
 
 
Day 1 
Day 2 
Day 3 
Day 4 
Group 1 
Olanzapine  
Ondansetron or Palonosetron  
Dexamethasone 
Fosaprepitant/Aprepitant  
Olanzapine 
Dexamethasone 
Olanzapine 
Dexamethasone 
Olanzapine 
Dexamethasone 
Group 2 
Olanzapine  
Ondansetron or Palonosetron 
Dexamethasone 
Placebo   
Olanzapine 
Dexamethasone 
Olanzapine 
Dexamethasone 
Olanzapine 
Dexamethasone 
 
 
Continuation Phase: After you complete the first cycle of protocol treatment, you may choose 
to continue on the same anti- nausea regimen for an additional three cycles. This is called the 
“Continuation Phase” of the study. When you return to the clinic to receive your next cycle of 
chemotherapy, clinic staff will ask if you would like to continue on the same regimen. If you 
decide to participate in this three-cycle Continuation Phase, you will be told whether you were 


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receiving fosaprepitant or placebo.  If you were taking fosaprepitant or aprepitant, you will 
continue to receive it as part of your anti-nausea treatment, along with olanzapine, ondansetron 
or palonosetron, and dexamethasone. If you were getting placebo, you will not continue 
receiving placebo, but you will continue the treatment with the olanzapine, ondansetron or 
palonosetron, and dexamethasone. 
 
If you decide that you do not want to participate in the Continuation Phase, but would still like to 
know what treatment you were receiving, research staff at your clinic may contact the Alliance 
Registration Office during regular business hours to get this information.  
  
 
 
Day 1 
Day 2 
Day 3 
Day 4 
Group 1 
Olanzapine  
Ondansetron or Palonosetron  
Dexamethasone 
Fosaprepitant/ Aprepitant  
Olanzapine 
Dexamethasone 
Olanzapine 
Dexamethasone 
Olanzapine 
Dexamethasone 
Group 2 
Olanzapine  
Ondansetron or Palonosetron 
Dexamethasone 
Olanzapine 
Dexamethasone 
Olanzapine 
Dexamethasone 
Olanzapine 
Dexamethasone 
 
 
How long will I be in this study? 
You will be in the study for four days of anti-nausea medication plus two additional days to 
follow how you do with nausea and vomiting. If you choose to participate in the Continuation 
Phase, you will be in the study for an additional 3 cycles while you are still receiving 
chemotherapy. 
 
 
What extra exams, tests, and procedures are involved in this study? 
Before you begin the study, your doctor will review the results of your exams, tests and 
procedures including a urine pregnancy test if you are a woman of childbearing potential, to 
make sure it is safe for you to take part.  If you join the study, there will be exams, tests, and 
procedures that will be done to closely monitor your safety and health. Most of these are 
included in the usual care you would receive even if you were not in a study.  
 
You will be asked to complete questionnaires and telephone surveys as part of this study. The 
questionnaires will be used to find out more about how you are doing with any nausea or 
vomiting and how you feel during study treatment. In addition, you will be asked about any costs 
related to treatment for any nausea and vomiting. You don’t have to answer any question that 
makes you feel uncomfortable. 
 


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Electronic surveys: For this study, you will be asked to complete the questionnaires on your 
personal smartphone or electronic device, which can be used to enter your answers to the 
questions. If you need help installing and/or using the questionnaire application (or “app”) on 
your phone or tablet, ask for help at your study site. Someone may help you enter your answers 
in the device if you need. 
The use of your own electronic device on a cellular network may result in a small cost to your 
data plan.  Regardless of the device you use, your answers and personal information will not be 
stored on the device.  
 
Your survey answers will be sent to the research database and will be kept private as described in 
the section below called, “Who will see my medical information?”  Your e-mail address will 
only be used for this survey and will not be used for mail or marketing purposes. The Alliance 
will not keep your email address.  
If using your phone or a tablet is not possible or if you prefer to complete the questionnaires on 
paper, a paper survey will be provided. 
 
You will be asked to complete the surveys at the following time points: 
 
During the study: 
• You will be asked to complete questionnaires on day 1 prior to study treatment and 
each day for the next five days following the day of chemotherapy. You will be asked 
to complete a short questionnaire on the amount of nausea or vomiting you have 
experienced in the previous 24-hour period. You will also be asked complete a 
questionnaire about your general well-being and quality of life. These questionnaires 
should take about five minutes to complete.  
• Staff from your clinic will contact you by telephone on days 2-6 of your treatment, to 
remind you to take your medication and ask about any symptoms you are 
experiencing.  The staff will also ask you whether you made any additional visits to 
doctors or hospitals or began using other medications.  
• If you did make any additional visits to doctors or hospitals, staff from your clinic 
may collect information from your medical chart and/or from your medical insurance 
claims regarding the costs of these services or medications. You may be asked to sign 
a form to allow the release of your personal health information to the study 
researchers. This information will be used by researchers at Wayne State University 
to evaluate health care costs when taking treatments used for nausea and vomiting.  
 
What possible risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that: 
• You may spend more time in the hospital or doctor’s office than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
• The study drug(s)/study approach may not be better, and could possibly be worse, than 
the usual approach for your diagnosis. 
 
There is also a risk that you could have side effects from the study drugs or study approach. 


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Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
You can ask the study doctor questions about side effects at any time. Here are important points 
about how you and the study doctor can make side effects less of a problem: 
• Tell the study doctor if you notice or feel anything different, so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about. Keep in mind that there might be other side effects that researchers do not yet know about. 
If important new side effects are found, the study doctor will discuss these with you. 
 
Possible side effects of Olanzapine:  
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving olanzapine, between 20 and 100 may have: 
• Tiredness  
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving olanzapine, 4 to 20 may have: 
• Fever 
• Back Pain 
• Dry Mouth 
• Constipation 
• Vomiting 
• Discoloration of the skin resulting from bleeding underneath, usually caused by bruising 
• Indigestion 
• Difficulty sleeping 
• Joint Pain 
• Dizziness 
• Unsteady walking 
• Tremor 
• Stuffy nose 
• Increased cough 
• Difficulty swallowing 
• Weight gain 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving olanzapine, 4 to 20 may have: 
• Pain in the hands and feet 
 
RARE, AND SERIOUS 
In 100 people receiving olanzapine, 3 or fewer may have: 
• Chest pain 
• Severe muscle spasms  
• Lazy eye 
• Loss of bladder control  
• Urinary tract infection 
• Swelling of arms and legs  
 
Reproductive risks:  
You should not get pregnant, breastfeed, or father a baby while in this study. The drugs used in 
this study could be very harmful to an unborn or newborn baby. Check with the study doctor 
about what types of birth control to use and for how long. 
 
Tell your study doctor right away if you suspect that you or your partner have become pregnant 
during the study or within 6 months after your last dose of study drug. Your doctor will ask for 
health information about the pregnancy until the pregnancy is complete.  
 
What possible benefits can I expect from taking part in this study? 
Olanzapine has been shown to have anti-nausea and anti-vomiting effects in patients receiving 
chemotherapy, and in preventing delayed nausea that occurs following chemotherapy. It is not 
possible to know at this time if the study drug(s)/study approach is better than the usual 
approach. This study will help researchers learn things that will help people in the future. 
 
 
Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization running the study. 
 
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
In turn, the study doctor may remove you from the study, if: 
• Your health changes and the study is no longer in your best interest 
• New information becomes available 
• You do not follow the study rules 
• The study is stopped by the sponsor, Institutional Review Board, IRB, or FDA. 


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What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
 
For questions about your rights while in this study, call the ________________________ (insert 
name of center) Institutional Review Board at __________________ (insert telephone number).  
 
 
What are the costs of taking part in this study? 
The olanzapine will be supplied at no charge to you while you take part in this study. It is 
possible that the olanzapine may not continue to be supplied free while you are on the study. 
Although not likely, if this occurs, your study doctor will talk to you about your options.  
 
You or your healthcare plan will be charged for the dexamethasone and palonosetron or 
ondansetron. If you are randomized to the placebo arm, you will not be charged for the placebo. 
If you are randomized to the fosaprepitant or aprepitant arm, you or your insurance will be billed 
for fosaprepitant or aprepitant per usual care. The cost of getting the drugs ready and giving it to 
you is not paid by the study so you or your insurance company may have to pay for this. 
 
You and/or your health plan/insurance company will need to pay for all of the other costs of care. 
Before you decide to be in the study, you should check with your health plan or insurance 
company to find out exactly what they will pay for. 
 
You are responsible for all co-pays and deductibles according to your insurance plan. 
You will not be paid for taking part in this study. 
 
 
What happens if I am injured because I took part in this study? 
If you are injured as a result of taking part in this study and need medical treatment, please tell 
your study doctor. The study sponsors will not offer to pay for medical treatment for injury. Your 
insurance company may not be willing to pay for study-related injury. If you have no insurance, 
you would be responsible for any costs. 
 
If you feel this injury was a result of medical error, you have legal rights to receive payment for 
this injury even though you are in a study. 
 
 
Who will see my medical information? 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  


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Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used. 
 
There are organizations that may look at or receive copies of some of the information in your 
study records.   Your health information in the database may also be shared with these 
organizations. They are required to make sure your information is kept private, unless required 
by law to provide information. Some of these organizations are: 
 
• 
The Alliance for Clinical Trials in Oncology  
• 
The NCI Central IRB, which is a group of people who review the research with the goal of 
protecting the people who take part in the study. 
• 
The Food and Drug Administration and the National Cancer Institute in the U.S., and similar 
ones if other countries are involved in the study. 
• 
Researchers at Wayne State University 
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy. The goal of this data 
sharing is to make more research possible that may improve people’s health. Your study records 
may be stored and shared for future use in public databases.  However, your name and other 
personal information will not be used. 
 
 
Where can I get more information? 
You may visit the NCI web site at 
for more information about studies or 
general information about cancer. You may also call the 
 
 
 
A description of this clinical trial will be available on 
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. 
 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of 
study doctor[s]) at __________________ (insert telephone number). 


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Additional Studies Section: (Indicate clearly to participants that this is a 
separate section) 
This section is about optional studies you can choose to take part in 
 
This part of the consent form is about optional studies that you can choose to take part in. They 
are separate from the main study described above. These optional studies will not benefit your 
health. The researchers leading these optional studies hope the results will help other people with 
cancer in the future. 
 
The results will not be added to your medical records and you or your study doctor will not know 
the results. 
 
Neither you nor your insurance will be billed for these optional studies. You can still take part in 
the main study even if you say “no” to any or all of these studies. If you sign up for but cannot 
complete any of the optional studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
1. Optional sample collections for laboratory studies and/or biobanking for 
possible future studies 
Researchers are trying to learn more about cancer and other health problems using samples from 
people’s tissue, blood, urine, or other fluids. By conducting research on these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure health problems. 
 
Some of these studies may be about how genes affect health and disease and how people respond 
to treatment. Genes carry information about features that are found in you and your family, from 
the color of your eyes to health conditions for which you may be at risk. Research that studies 
your genes is known as genomics or genetics. 
 
If you choose to take part in this optional study, the study doctor for the main study would like to 
collect blood for research on whether your genes cause differences in how your body responds to 
treatments. 
 
In addition, the researchers ask your permission to store and use your samples and related health 
information (for example, your response to cancer treatment, results of study tests and medicines 
you are given) for medical research. The additional research that may be done is unknown at this 
time. Storing samples for future studies is called “bio banking”. The Biobank is being run by the 
Alliance and supported by the National Cancer Institute 
 
What is involved? 
If you agree to take part, here is what will happen next: 
1) About 2 teaspoons of blood will be collected from a vein in your arm, before you 
begin study treatment.  


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2) Your baseline blood sample and some related health information will be sent to an 
Alliance researcher at the Mayo Clinic for use in the study described above. 
Remaining baseline blood samples may be stored in the Biobank, along with samples 
from other people who take part. The samples will be kept until they are used up. 
3) Only qualified researchers can receive samples from the Biobank. There will be 
scientific and ethics reviews to ensure that the research is necessary and proper. 
Researchers will not be given your name or any other information that could directly 
identify you.  
4) Neither you nor your study doctor will be notified when research will be conducted. 
You will not receive reports or other information about any research that is done 
using your samples. 
5) Some of your genetic and health information may be placed in central databases that 
will be available to qualified researchers. Information that could directly identify you 
will not be included. 
 
What are the possible risks? 
1) The most common risks related to drawing blood from your arm are brief pain and 
maybe a bruise. 
2) Even without your name or other identifiers, your genetic information is unique to 
you. There is a risk that someone outside of the research could get access to your 
personal information in your medical records or trace information in a database back 
to you. The researchers believe the chance that someone could re-identify you is very 
small, but the risk may change in the future as people come up with new ways of 
tracing information.  
3) In some cases, this information could be used to make it harder for you to get or keep 
a job or insurance. There are laws against the misuse of genetic information, but they 
may not give full protection. There can also be a risk in knowing genetic information. 
New health information about inherited traits that might affect you or your blood 
relatives could be found during a study. The researchers believe the chance these 
things will happen is very small, but cannot promise that they will not occur. 
 
How will information about me be kept private? 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1) When your samples are sent by the biobank to the qualified researchers, no 
information identifying you (such as your name) will be sent. Samples will be 
identified by a unique code only.  
2) The list that links the unique code to your name will be kept separate from your 
sample and health information. Any biobank and Alliance staff with access to the list 
must sign an agreement to keep your identity confidential. 
3) Researchers to whom the Alliance sends your sample and information will not know 
who you are. They must also sign an agreement that they will not try to find out who 
you are. 
4) Information that identifies you will not be given to anyone, unless required by law. 


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5) If research results are published, your name and other personal information will not 
be used. 
 
What are the possible benefits? 
You will not benefit from taking part. The researchers, using the samples from you and others, 
might make discoveries that could help people in the future. 
 
Are there any costs or payments? 
There are no costs to you or your insurance. You will not be paid for taking part. If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any 
profits. 
 
What if I change my mind? 
If you decide you no longer want your samples to be used, you can call the study doctor, 
_________________, (insert name of study doctor for main trial) at 
________________________ (insert telephone number of study doctor for main trial) who will 
let the researchers know. Then, any sample that remains in the biobank will no longer be used 
and related health information will no longer be collected. This will not apply to those samples 
or related information that have already been given to or used by qualified researchers. 
 
What if I have questions? 
If you have questions about the use of your samples for research, contact the study doctor, 
________________, (insert name of study doctor for main trial), at _____________________ 
(insert telephone number of study doctor for main trial). 
 
Please circle your answer to show whether or not you would like to take part in each option: 
 
Samples for the laboratory studies: 
I agree to have my specimen collected and I agree that my specimen sample(s) and 
related information may be used for the laboratory study(ies) described above. 
 
 
YES 
 
NO 
 
 
Samples for future research studies: 
My samples and related information may be kept in a biobank for use in future health 
research. 
 
 
YES 
 
NO 
 


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I agree that my study doctor, or their representative, may contact me or my physician to 
see if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
My signature agreeing to take part in the main study 
 
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions have been answered. I will be given a signed copy of this form. I agree to take part 
in the main study and any additional studies where I circled ‘yes’.  
 
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 
 
 
Signature of person(s) conducting the informed consent 
discussion___________________________________ 
Date of signature_____________________________________ 
 


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APPENDIX I 
PATIENT QUESTIONNAIRE 
 
PATIENT INFORMATION SHEET 
TREATMENT 
Patient Completed Quality of Life Booklet (Baseline) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
1. This booklet is to be completed day 1 during your clinic visit prior to treatment. 
 
2. The booklet contains 2 set of questions: 
a. Baseline Nausea and Vomiting Questionnaire 
b. EQ-5D-3L Health Questionnaire 
 
3. Directions on how to complete this set of questions are written on the top of the page. 
 
4. Please return your booklet when you are finished. 
 
 
Thank you for taking the time to help 
 
 


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PATIENT INFORMATION SHEET 
TREATMENT 
Patient Completed Quality of Life Booklet (days 2-6) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
 
1. This booklet is to be completed days 2-6 (the 5 days following your chemotherapy), ideally, at 
about the same time your chemotherapy was given (1 hour before to 1 hour after your 
chemotherapy time). 
 
2. The booklet contains 2 set of questions: 
a. Nausea and Vomiting Daily Diary/Questionnaire  
b. EQ-5D-3L Health Questionnaire  
 
3. Directions on how to complete this set of questions are written on the top of the page. 
 
4. You may call a member of the study team to answer any questions you might have.  You will be 
given a name and telephone number.  You can call anytime with any concerns or questions. A 
nurse/research coordinator will also call you days 2-6 and they can answer questions you might 
have.  
 
5. It is very important that you return the booklet to us, whether you finish the study or not. 
 
6. When the booklet is complete, return it in the provided envelope. 
 
 
Thank you for taking the time to help 
 
 


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APPENDIX II 
BASELINE NAUSEA AND VOMITING 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 
at all 
 
Nausea as 
bad as it can 
be 
 
 
 
2. Please rate any undesired sedation trouble that you had over the past 24 hours 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
undesired 
sedation 
at all 
 
Undesired 
sedation as 
bad as it can 
be 
 
 
 
 
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 
appetite 
increase 
at all 
 
Undesired 
appetite 
increase as 
bad as it can 
be 
 
 
 


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APPENDIX III NAUSEA AND VOMITING DAILY QUESTIONNAIRE 
 
Date: ____/____/________ 
 
Please take Olanzapine at the same time that you took it on Day 1 of the study. Record the time that 
you took the Olanzapine here:  
________________ 
 
Check one option in each box, then continue and answer questions 1-3 below. 
 
 
Nausea (check one) 
*Vomiting (check one) 
Number of extra nausea/vomiting pills taken 
because you developed nausea/vomiting 
Last 
24 
hours 
__None 
__Mild 
__Moderate 
__Severe 
__None 
__Once 
__Twice 
__More than twice 
__None 
__One 
__Two 
__More than two 
 
*A single vomiting episode is defined as: 
• 
a single vomit of solid 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 vomiting 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 
at all 
 
Nausea as 
bad as it can 
be 
 
 
 
2. Please rate any undesired sedation trouble that you had over the past 24 hours 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
undesired 
sedation 
at all 
 
Undesired 
sedation as 
bad as it can 
be 
 
 
 
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 
appetite 
increase 
at all 
 
Undesired 
appetite 
increase as 
bad as it can 
be 
 
 


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APPENDIX IV DAILY NURSE TELEPHONE CONTACT 
Nurse/Research Coordinator Contact  
Days 2, 3 and 4 
 
Daily Telephone contact (check one) 
Day 2 
 
 
Day 3 
 
 
Day 4 
 
 
 
Date of telephone contact or date of attempt to contact was made (dd MMM yyyy) _ _-_ _ _-_ _ _ _ 
 
Were you able to contact the patient?  
Yes    
No (If no, then end form) 
If contacted, list the Time of day: HH:MM  ___:___ 
 
Verify the following with the subject: 
Dexamethasone 8 mg PO QD taken today (check one) 
Yes     
No 
 
If “No”, provide reason 
________________________________________________________________________ 
Olanzapine 10 mg PO QD taken today? (check one) 
Yes     
No 
 
If “No”, provide reason 
________________________________________________________________________ 
 
 
Number of vomiting episodes over the past 24 hours __________ 
Symptom Assessment: (Where 0 is none and 10 is as bad as it can be.) 
 
    Worst nausea over the past 24 hours (circle one) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
    Undesired sedation trouble over the past 24 hours (circle one)  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
    Undesired appetite increase over the past 24 hours (circle one) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 


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Rescue Medication taken? (check one) 
Yes     
No 
(if yes): 
Drug Name (check one or more): 
 Anticholinergics: Scopolamine transdermal patch (Transderm Scop) 
 Diphenhydramine (Benadryl) 
 Lorazepam (Ativan) 
 Haloperidol (Haldol) 
 Dronabinol (Marinol, Syndros) 
 Prochlorperazine (Compazine) 
 Metoclopramide (Reglan) 
 Ondansetron (Zofran) 
 Other (list): _________________________________________ 
 
 
 
Dose (check one or more. If more than one rescue medication, list drug to which that dose refers): 
 1 pill  ______________________ 
 2 pills  ______________________ 
 3 pills  ______________________ 
 4 pills  ______________________ 
 1 patch  ______________________ 
 1 infusion  ______________________ 
 Other (please specify):  ______________________ 
 
 
Number of doses the past 24 hours (check one or more. If more than one rescue medication, list drug to 
which that number of doses refers): 
 1  _____________________ 
 2  _____________________ 
 3  _____________________ 
 4  _____________________ 
 5  _____________________ 
 Other (please specify):  _____________________ 


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Did you start taking any other new medications today, other than rescue medications, that you were not 
taking before Day 1 of the protocol? 
(if yes): 
Drug Name (list one or more): ___________________________________________________ 
 
Dose (check one or more. If more than one medication, list drug to which that dose refers): 
 1 pill  ______________________ 
 2 pills  ______________________ 
 3 pills  ______________________ 
 4 pills  ______________________ 
 1 patch  ______________________ 
 1 infusion  ______________________ 
 Other (please specify):  ______________________ 
 
Number of doses the past 24 hours (check one or more. If more than one medication, list drug to which 
that number of doses refers): 
 1  _____________________ 
 2  _____________________ 
 3  _____________________ 
 4  _____________________ 
 5  _____________________ 
 Other (please specify):  _____________________ 
 
 
Did patient have any adverse events? (check one) 
Yes     
No 
 
If yes, fill out AE form: Record all adverse events that meet the following criteria: grade 2 with 
attribution of possible, probable or definite and all grade 3, 4 and 5 regardless of attribution.  
 
 
 


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Health Care Use: 
 
If the patient experienced an adverse event(s) of grades 2, 3, 4, or 5, including grade 2 adverse event(s) 
unlikely related or unrelated to the intervention, ask the patient if they used any health care for the 
treatment of the adverse event. Health care use includes any interaction with a health care provider 
regarding the adverse event(s). Some examples include visiting your oncologist at the hospital or in their 
office and receiving a prescription for a rescue therapy, calling or emailing the nurse or your primary care 
physician, visiting the emergency department or being hospitalized. Do not record visits to the pharmacy 
to fill a prescription for one of the reported medications. 
 
Did you use any health care associated with adverse events in the past 24 hours? (check one) 
Yes     
No 
 
 
(Complete the form on the next page if you checked the “Yes” box above.) 
 
 
 
 
 
Comments 
 ____________________________________________________________________________________________ 
 ____________________________________________________________________________________________ 
Please remind the patient to complete the patient diary. If possible, have the patient complete their 
questionnaire form while on the phone call. Please explain the rescue nausea medication information 
specifically “Number of extra (PRN) nausea/vomiting pills taken.” 
 


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Health care use associated with adverse events in past 24 hours 
 
Site of care and Provider types (check as many Sites of care as apply, and for each one, which Providers 
were used there): 
 Hospital Outpatient Department 
 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Emergency Department 
 
 Emergency Medicine Physician  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Provider’s office 
 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Phone call to provider 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Email to provider 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Telemedicine 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 


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 Hospital Inpatient Department 
 Hematologist/oncologist 
 Internal Medicine/Hospital Medicine Physician 
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Intensive Care Unit (ICU) Hospital Inpatient Department 
 Hematologist/oncologist 
 Internal/Hospital Medicine Physician 
 Critical/Intensive Care Physician  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Other (please specify): _______________________________ 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
If hospitalized, date of admission: ___________________________ 
 
Name(s) of provider(s) (record as accurately as patient can recall):  
_____________________________________________________________________________________________ 
Address(es) of provider(s) (record as accurately as patient can recall): 
 _____________________________________________________________________________________________ 
 
Reasons for use of health care (check one or more. If more than one Site of Care was used, list Site(s) of 
Care in which each adverse event was treated): 
 Nausea/Vomiting Reasons for use ___________________________________________________________ 
 Sedation __________________________________________________________________________________ 
 Fatigue ___________________________________________________________________________________ 
 Anemia ___________________________________________________________________________________ 
 Appetite changes __________________________________________________________________________ 
 Constipation ______________________________________________________________________________ 
 Diarrhea __________________________________________________________________________________ 


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 Bleeding __________________________________________________________________________________ 
 Blurred vision _____________________________________________________________________________ 
 Arm or leg swelling ________________________________________________________________________ 
 Peripheral neuropathy ______________________________________________________________________ 
 Mental status change _______________________________________________________________________ 
 Severe headache ___________________________________________________________________________ 
 Fever / Chills / Febrile neutropenia ___________________________________________________________ 
 Urine and bladder changes / Proteinuria / Kidney problems ______________________________________ 
 Hypertension ______________________________________________________________________________ 
 Blood clot / Venous thromboembolic event ___________________________________________________ 
 Thrombocytopenia _________________________________________________________________________ 
 Other adverse event (please specify): ____________________________________________________ 
 
 
Laboratory tests (check one): 
Yes      
No  
(if yes, check one or more): 
Blood        
Urine        
Other (please specify):____________________ 
 
 
 
Imaging tests (check one): 
Yes      
No  
(if yes, check one or more and indicate part of body):  
X-Ray        
CT        
MRI        
Ultrasound          
Other (please specify):_________________ 
Of which part of body: _________________ 
 
 
 
 


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Nurse/Research Coordinator Contact  
Days 5 and 6 
 
Daily Telephone contact (check one) 
 
 
 
 
Day 5 
 
 
 
 
Day 6 
 
Date of telephone contact or date of attempt to contact was made: (dd MMM yyyy) _ _-_ _ _-_ _ _ _ 
 
Were you able to contact the patient?  
Yes    
No (If no, then end form) 
If contacted, list the Time of day HH:MM  ___:___ 
 
Number of vomiting episodes over the past 24 hours __________ 
Symptom Assessment: (Where 0 is none and 10 is as bad as it can be.) 
 
    Worst nausea over the past 24 hours (circle one) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
    Undesired sedation trouble over the past 24 hours (circle one)  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
    Undesired appetite increase over the past 24 hours (circle one) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 


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Rescue Medication taken? (check one) 
Yes     
No 
(if yes): 
Drug Name (check one or more): 
 Anticholinergics: Scopolamine transdermal patch (Transderm Scop) 
 Diphenhydramine (Benadryl) 
 Lorazepam (Ativan) 
 Haloperidol (Haldol) 
 Dronabinol (Marinol, Syndros) 
 Prochlorperazine (Compazine) 
 Metoclopramide (Reglan) 
 Ondansetron (Zofran) 
 Other (list): _________________________________________ 
 
 
 
Dose (check one or more. If more than one rescue medication, list drug to which that dose refers): 
 1 pill  ______________________ 
 2 pills  ______________________ 
 3 pills  ______________________ 
 4 pills  ______________________ 
 1 patch  ______________________ 
 1 infusion  ______________________ 
 Other (please specify):  ______________________ 
 
 
Number of doses the past 24 hours (check one or more. If more than one rescue medication, list drug to 
which that number of doses refers): 
 1  _____________________ 
 2  _____________________ 
 3  _____________________ 
 4  _____________________ 
 5  _____________________ 
 Other (please specify):  _____________________ 
 


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Did you start taking any other new medications today, other than rescue medications, that you were not 
taking before Day 1 of the protocol? 
(if yes): 
Drug Name (list one or more): ___________________________________________________ 
 
Dose (check one or more. If more than one medication, list drug to which that dose refers): 
 1 pill  ______________________ 
 2 pills  ______________________ 
 3 pills  ______________________ 
 4 pills  ______________________ 
 1 patch  ______________________ 
 1 infusion  ______________________ 
 Other (please specify):  ______________________ 
 
Number of doses the past 24 hours (check one or more. If more than one medication, list drug to which 
that number of doses refers): 
 1  _____________________ 
 2  _____________________ 
 3  _____________________ 
 4  _____________________ 
 5  _____________________ 
 Other (please specify):  _____________________ 
 
Ask patient the following question (on Day 6 only) : Have you received your medical bill for your recent 
dose of chemotherapy and nausea medications? 
Yes     
No 
 
 
 
Did patient have any adverse events? (check one) 
Yes     
No 
 
If yes, fill out AE form: Record all adverse events that meet the following criteria: grade 2 with 
attribution of possible, probable or definite and all grade 3, 4 and 5 regardless of attribution.  
 
 
 


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Health Care Use: 
 
If the patient experienced an adverse event(s) of grades 2, 3, 4, or 5, including grade 2 adverse event(s) 
unlikely related or unrelated to the intervention, ask the patient if they used any health care for the 
treatment of the adverse event. Health care use includes any interaction with a health care provider 
regarding the adverse event(s). Some examples include visiting your oncologist at the hospital or in their 
office and receiving a prescription for a rescue therapy, calling or emailing the nurse or your primary care 
physician, visiting the emergency department or being hospitalized. Do not record visits to the pharmacy 
to fill a prescription for one of the reported medications. 
 
Did you use any health care associated with adverse events in the past 24 hours? (check one) 
Yes     
No 
 
 
(Complete the form on the next page if you checked the “Yes” box above.) 
 
 
 
 
 
Comments 
 ____________________________________________________________________________________________ 
 ____________________________________________________________________________________________ 
Please remind the patient to complete the patient diary. If possible, have the patient complete their 
questionnaire form while on the phone call. Please explain the rescue nausea medication information 
specifically “Number of extra (PRN) nausea/vomiting pills taken.” 
 


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Health care use associated with adverse events in past 24 hours 
 
Site of care and Provider types (check as many Sites of care as apply, and for each one, which Providers 
were used there): 
 Hospital Outpatient Department 
 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Emergency Department 
 
 Emergency Medicine Physician  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Provider’s office 
 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Phone call to provider 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Email to provider 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Telemedicine 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 


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 Hospital Inpatient Department 
 Hematologist/oncologist 
 Internal Medicine/Hospital Medicine Physician 
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Intensive Care Unit (ICU) Hospital Inpatient Department 
 Hematologist/oncologist 
 Internal/Hospital Medicine Physician 
 Critical/Intensive Care Physician  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
 Other (please specify): _______________________________ 
 Hematologist/oncologist 
 Internal Medicine/Family Medicine/General Practitioner  
 Advanced Practice Nurse 
 Physician Assistant 
 Other (please specify): ______________________ 
 
If hospitalized, date of admission: ___________________________ 
 
Name(s) of provider(s) (record as accurately as patient can recall):  
_____________________________________________________________________________________________ 
Address(es) of provider(s) (record as accurately as patient can recall): 
 _____________________________________________________________________________________________ 
 
Reasons for use of health care (check one or more. If more than one Site of Care was used, list Site(s) of 
Care in which each adverse event was treated): 
 Nausea/Vomiting Reasons for use ___________________________________________________________ 
 Sedation __________________________________________________________________________________ 
 Fatigue ___________________________________________________________________________________ 
 Anemia ___________________________________________________________________________________ 
 Appetite changes __________________________________________________________________________ 
 Constipation ______________________________________________________________________________ 
 Diarrhea __________________________________________________________________________________ 


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 Bleeding __________________________________________________________________________________ 
 Blurred vision _____________________________________________________________________________ 
 Arm or leg swelling ________________________________________________________________________ 
 Peripheral neuropathy ______________________________________________________________________ 
 Mental status change _______________________________________________________________________ 
 Severe headache ___________________________________________________________________________ 
 Fever / Chills / Febrile neutropenia ___________________________________________________________ 
 Urine and bladder changes / Proteinuria / Kidney problems ______________________________________ 
 Hypertension ______________________________________________________________________________ 
 Blood clot / Venous thromboembolic event ___________________________________________________ 
 Thrombocytopenia _________________________________________________________________________ 
 Other adverse event (please specify): ____________________________________________________ 
 
 
Laboratory tests (check one): 
Yes      
No  
(if yes, check one or more): 
Blood        
Urine        
Other (please specify):____________________ 
 
 
 
Imaging tests (check one): 
Yes      
No  
(if yes, check one or more and indicate part of body):  
X-Ray        
CT        
MRI        
Ultrasound          
Other (please specify):_________________ 
Of which part of body: _________________


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Nurse/Research Coordinator Contact (Day 21) 
 
Date of telephone contact or date of attempt to contact: (dd MMM yyyy) _ _-_ _ _-_ _ _ _ 
 
Were you able to contact the patient?  
Yes    
No (If no, then end form) 
(If contacted), contact time: (HH:MM AM or PM)  ___:___ 
 
Did patient have any adverse events (new or continuing grade 2+ adverse events since day 7 of the initial 
treatment)?   
Yes     
No 
 
If yes, fill out AE form: Record all adverse events that meet the following criteria: grade 2 with 
attribution of possible, probable or definite and all grade 3, 4 and 5 regardless of attribution. And 
update the Date of most recent contact on Patient Status: Treatment (Intervention) form accordingly. 
 
Comments 
 ___________________________________________________________________________________  
 ___________________________________________________________________________________  
 ___________________________________________________________________________________  
 
 
 


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APPENDIX V 
EQ-5D-3L HEALTH QUESTIONNAIRE 
By placing a checkmark in one box in each group below, please indicate which statements best 
describe your own health state today. 
 
 
Mobility 
 
I have no problems in walking about 
❑ 
I have some problems in walking about 
❑ 
I am confined to bed 
❑ 
 
 
Self-Care 
 
I have no problems with self-care 
❑ 
I have some problems washing or dressing myself 
❑ 
I am unable to wash or dress myself 
❑ 
 
 
Usual Activities (e.g. work, study, housework, family or leisure 
activities) 
 
I have no problems with performing my usual activities 
❑ 
I have some problems with performing my usual activities 
❑ 
I am unable to perform my usual activities 
❑ 
 
 
Pain / Discomfort 
 
I have no pain or discomfort 
❑ 
I have moderate pain or discomfort 
❑ 
I have extreme pain or discomfort 
❑ 
 
 
Anxiety / Depression 
 
I am not anxious or depressed 
❑ 
I am moderately anxious or depressed 
❑ 
I am extremely anxious or depressed 
❑ 
USA (English) © 1998 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 


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9 0 
8 0 
7 0 
6 0 
5 0 
4 0 
3 0 
2 0 
1 0 
100 
0 
 
 
 
 
To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which 
the best state you can imagine is marked 100 and the 
worst state you can imagine is marked 0. 
 
We would like you to indicate on this scale how good or 
bad your own health is today, in your opinion. Please do 
this by drawing a line from the box below to whichever 
point on the scale indicates how good or bad your health 
state is today. 
 
 
 
 
 
 
USA (English) © 1998 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
Best imaginable 
health state 
Worst imaginable 
health state 
Your own health 
state today 


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APPENDIX VI EPRO 
1.0 Introduction 
Electronic collection of patient-reported outcomes is preferred but not mandatory.  Patients will 
need to use their own device (IOS or Android phone or tablet).  Short term data will only appear 
on the patient’s device until responses are completed.  The patient data will import directly into the 
database once the patient clicks the submit button and will no longer be on the patient's device.  
Site staff access 
Site users of ePRO and the Patient Cloud require the same access as those using Rave. Access to 
the trial in the Patient Cloud is granted through the iMedidata application to all persons with the 
appropriate roles assigned in Regulatory Support System (RSS). To access the Patient Cloud via 
iMedidata, the site user must have an active CTEP-IAM account and the appropriate Rave role 
(Rave CRA, Read-Only, Site Investigator) on either the LPO or participating organization roster at 
the enrolling site. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, 
site users must log into the Select Login using their CTEP-IAM user name and password, and click 
on the “accept” link in the upper right-corner of the iMedidata page. Please note, site users will not 
be able to access the study in the Patient Cloud until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and can 
be accessed by clicking on the link in the upper right pane of the iMedidata screen.  
Users who have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). 
Additional information on iMedidata/Rave is available on the CTSU members’ website under the 
Rave tab at 
or
 
   
2.0 
Security 
All data are encrypted on the device (128 bit on file +https transfer) and the app requires a user to 
have a username and password.  If the user is idle for too long (5 minutes inactivity time), the app 
will time out and the user will need to log in again. 
The data will only reside on the device for a short period of time.  Once the user clicks “submit,” 
the data is securely transferred over https between the device and internal relay.  No identifying 
information is stored in iMedidata (only email address is stored). 
The Patient information (email/password) does not reside in Medidata Rave EDC and the patient 
accounts are hidden in iMedidata from sites and sponsors in the Patient Cloud Relay. 
The ePRO application is Part 11 compliant and acts as a gateway between device and Medidata 
Clinical Cloud (MCC).   
Messages and information communicated to and from the Patient Cloud are encrypted and therefore 
this information cannot be read if intercepted while in transit. 
 
 


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3.0 
CRP Training for ePRO 
Please visit the Medidata Learning Tool for reference information on Patient Cloud ePRO for 
CRAs. 
4.0 
Checklist for activities prior to consenting a patient 
• 
Site staff must have already completed required eLearning for the Patient Cloud ePRO 
application. See last bullet with hyperlink to training video library. Contact the Study data 
manager to request appropriate Rave access to register patients in Patient Cloud ePRO 
• 
Accept study invitation at iMedidata.com 
Note: you must be rostered in RSS and have received an invitation to Patient Cloud ePRO 
• 
Verify the IOS or Android operating system is using the most current version 
• 
Verify Patient Cloud ePRO app is using the most current version 
• 
Refer to 
to review Quick reference guides  
5.0 
Instructions for ePRO patient registration 
Please visit the Medidata Learning Tool for additional screen shots and video tutorials on how to 
register participants to the study. 
i. 
The patient registration process starts in iMedidata.  Begin by clicking on the Patient Cloud 
Registration link for this study 
ii. The patient management app will display, select your STUDY and SITE from the drop downs 
and click Launch. 
iii. Now the first patient can be registered. Create a subject ID and select a Country / Language 
from the drop down, (these are the only required data fields). The patient initials are optional, 
but may help in identifying which subject ID maps with which activation code. When finished, 
click Add. 
iv. The patient added will appear at the top of the table and will include the date the patient was 
added, the subject ID, initials, (if included) and a unique auto-generated activation code. The 
activation code is unique for each patient and linked to the subject ID, it is not interchangeable. 
In addition, there is a status section, which determines if the patient has registered. When the 
patient has registered the status will change from invited to registered. 
 
 


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6.0 
Patient Users 
To use the Patient Cloud ePRO, patients will need to use their own device (IOS, Android phone or 
tablet).  Short term data will only appear on the patient’s device until responses are completed and 
submitted.  The patient data will import directly into the database once the patient selects the 
“Submit” button and will no longer be visible on the patient's device. 
Patient compliance: The patient data imports directly from her/his device into the Rave database.  
There are no documents to audit.  The electronic responses are the source documentation. 
6.1 
Patient Instructions for Accessing the Patient Cloud App using their personal device 
Downloading the Patient Cloud ePRO App: 
If you are using your personal device, and you do not have the Patient Cloud ePRO app, 
use the following instructions. When downloading the app, you must use the Apple ID or 
Google account associated with the device. If the Patient Cloud ePRO app is already on 
the device, or if you are using a provider's device, you can skip this section. 
You will need an email address that you agree to use for this purpose. The e-mail address 
is needed to identify you on the Patient Cloud Application and for you to receive 
notifications to let you know when forms are due. Your e-mail address will only be used 
for this survey study, and will not be used for mail or marketing purposes. 
If you decide to use the electronic method to complete the questionnaires, and do not have 
an e- mail address, you may sign up for one at no charge at many different websites. A few 
sites that are commonly used and will allow you to create an email address very easily are 
Yahoo, Gmail, and Outlook. 
For iOS: 
1. An Apple ID is required for downloading the Patient Cloud ePRO app. 
2. Tap the App Store icon. 
3. Search for Medidata Patient Cloud and follow the installation instructions. 
Note: Patient Cloud ePRO is listed as an iPhone App in the App store. When using an iPad, 
please view the search results under iPhone apps. 
For Android: 
1. A Google account is required for downloading the Patient Cloud ePRO app 
2. Tap the Play Store icon. 
3. Search for Medidata Patient Cloud and follow the installation instructions. 
Registering on the App: 
You must register in order to complete and submit your study forms. When you register, 
you will create a username, which is your email address, and a password that allows you 
to log in to the Patient Cloud ePRO app. 
Note: You must have an activation code to begin this process. If you do not have an 
activation code, please contact your provider. 
There are two possible ways to register. Your provider may have sent you a link to a web 
address where you may register from any web browser, including the one on your device. 
The other way to register is on the Patient Cloud ePRO app. 


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1. If registering from the Patient Cloud app, tap Register on the bottom of the log in page. 
If registering on the web, open the URL shield.imedidata.com on a web browser. 
2. Enter your activation code and tap Activate. 
3. On the next page, read the instructions and tap Next. 
4. Read the privacy notice and tap I agree. Then tap OK to confirm. 
5. Enter and confirm your email address. Tap Next. 
6. Enter and confirm your password. Tap Next. 
7. Choose a security question by scrolling through the dropdown menu to display the 
question of your choice. 
8. Enter your security question response. 
9. Tap Create my account to complete your registration. 
If you registered on the Patient Cloud ePRO app, it automatically logs you out. If you 
registered on the web, you are presented with the option to download the Patient Cloud 
ePRO app. You can then proceed to log in with the credentials you created. 
Logging in to the App after registration: 
1. Enter your Email and Password that you created during the registration process. (If you 
previously set a PIN code, just enter your four-digit PIN.) 
2. Tap Log in. 
Note: If you do not remember your password, tap Forgot Password, and follow the 
instructions provided. 
Setting a PIN Code: 
The first time you log in to the Patient Cloud ePRO app, you are given the option to create 
a PIN code. A PIN code allows you to bypass the step of entering your email and password 
every time you need to log in to the Patient Cloud ePRO app. Instead, you can enter a four-
digit PIN. 
1. If you wish to set a PIN code the first time you log in, tap Yes when prompted. 
2. Note: You can also set your PIN at a later time by tapping the options menu on the top 
left of most pages and selecting Set PIN. 
3. Enter a four-digit PIN. 
4. Re-enter the four-digit PIN to confirm. 
If you forget your PIN code, tap Forgot PIN and you can access the app using your email 
and password. You may reset your PIN by tapping the options menu on the top left of most 
pages and selecting Set PIN. 
Resetting Your Password: 
You can reset your password by using the options menu at the top left of most pages. 
1. Tap the options menu icon. 
2. Tap Reset Password. 
3. Follow the instructions to reset your password. 


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Completing and Submitting Forms: 
Once logged in, forms related to your study display on the Tasks page. If you are enrolled 
in multiple studies, select the appropriate study first, and then select a form. New forms 
can appear on the Tasks page at any time, depending on how the study is designed. 
There are two types of forms displayed on the Task List page: 
• 
Scheduled Forms (with a 
 icon): These forms have a "Due Date" indicator in them 
so you are aware of the last day by which you will need to complete the form. If the 
form is due in less than one day, you will see the due time in hours. 
• 
Anytime Forms (with a 
 icon): These forms have "Last Completed Time" indicator 
on them which tells the most recent date or time when you completed the form. If 
you start a form, but do not complete it, you will see an 'Incomplete" status beneath 
the form name, along with a half-moon icon 
1. Select the appropriate form. 
2. Follow the on-screen instructions until you reach the end of the form where you are 
given the opportunity to review and change your responses prior to submitting. 
3. Review your responses by scrolling down the list. 
4. If you need to change an answer, tap the question to go back and change the answer. 
5. When you are ready to submit, tap Submit Your Data. 
Note: Once a form is submitted, you will be unable to edit any of your responses. In some 
cases, you may be asked to acknowledge your submission by entering your password 
 
 


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APPENDIX VII PATIENT CLOUD EPRO PATIENT INFORMATION SHEET  
(Sites: Please print and provide this appendix to the patient who will be using Patient Cloud 
for completion of questionnaires). 
This document will guide you on how to access the research questionnaires and help you know 
when you need to fill out each questionnaire via the Patient Cloud app. 
Questionnaire schedule during each chemotherapy treatment cycle: 
BEFORE you receive chemotherapy treatment today: 
1. Confirm you are connected to Wi-Fi or data. 
2. Open the Patient Cloud app on your personal device (E.g. smartphone or tablet) and 
login with your email and password or your PIN. 
3. Please fill out the following questionnaires on your device BEFORE study treatment. 
• Electronic Questionnaire 1: Electronic Nausea and Vomiting 
Questionnaire (Baseline)  
• Electronic Questionnaire 2: Electronic EQ-5D-3L (Baseline) 
Once data is submitted for baseline, the forms will disappear from patient cloud app.  
 
Each day for the next 5 days after receiving chemotherapy treatment, complete below 
questionnaires for Initial treatment cycle for Day 2 through Day 6.  
• Electronic Questionnaire 1: Electronic Nausea and Vomiting Questionnaire 
(Initial Treatment)  
• Electronic Questionnaire 2: Electronic EQ-5D-3L (Initial Treatment)  
Each form is available to you for days 2 through 6 (5 times).  
Initial Treatment (1) = Day 2  
Initial Treatment (2) = Day 3 
Initial Treatment (3) = Day 4 
Initial Treatment (4) = Day 5 
Initial Treatment (5) = Day 6 
Once you submit the above forms, the forms will disappear from the patient cloud 
app.  
 
Questionnaire schedule for Continuation Phase (Cycles 2-4 if you elect to continue): 
Once you are enrolled to continue in the study,  
Each day for the next 5 days after receiving chemotherapy treatment for Cycles 2, 3 and 4,  
Please complete below questionnaires for Continuation treatment cycle for Day 2 through 
Day 6.  
• Electronic Questionnaire 1: Nausea and Vomiting (Continuation Treatment 
Cycle 2) 
• Electronic Questionnaire 2: EQ-5D-3L (Continuation Treatment Cycle 2) 


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• Electronic Questionnaire 1: Nausea and Vomiting (Continuation Treatment 
Cycle 3) 
• Electronic Questionnaire 2: EQ-5D-3L (Continuation Treatment Cycle 3) 
• Electronic Questionnaire 1: Nausea and Vomiting (Continuation Treatment 
Cycle 4) 
• Electronic Questionnaire 2: EQ-5D-3L (Continuation Treatment Cycle 4) 
 
Once data is submitted, the forms will disappear from the patient cloud app.  
 
 
 


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APPENDIX VIII EPRO INSTRUCTION FLOW CHART FOR PATIENTS  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Download the Patient Cloud ePRO app 
 
Create a username and password for the Patient 
Cloud app by selecting the ‘Register’ option on the 
login screen. Use the activation code from your clinic. 
Log in to the Patient Cloud app 
See your forms on the main screen 
Complete, review, and submit your 
forms 
Tip: When a form is due, 
you will see the alarm clock 
with the date and time the 
form will close. 
 
For help with the Patient Cloud ePRO app, please ask 
your study team! 
 
Tip: Your username must be in email 
format (for example, 
jodiesmith20@email.com).