Clinical trial NCT03097588
Conditions: Malignant Neoplasm
Sponsor: OHSU Knight Cancer Institute
Start date: 2017-04-27; Completion date: 2020-03-20
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well netupitant and palonosetron hydrochloride work in preventing chemotherapy induced nausea and vomiting in patients with cancer undergoing BEAM conditioning regimen before stem cell transplant. Chemotherapy, such as carmustine, cytarabine, etoposide, and melphalan (BEAM), makes people feel sick to their stomach and causes vomiting. Netupitant and palonosetron hydrochloride may reduce the nausea and vomiting caused by the BEAM treatment.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the efficacy of netupitant and palonosetron hydrochloride (NEPA) to prevent nausea and vomiting both during and after a highly emetogenic (BEAM) conditioning regimen for hematopoietic stem cell transplantation (HSCT).

SECONDARY OBJECTIVES:

I. To differentiate response to NEPA over different phases of chemotherapy-induced nausea.

OUTLINE:

Within 60 minutes before standard of care BEAM treatment, patients receive netupitant and palonosetron hydrochloride orally (PO) on days 1, 3, and 6.

After completion of study treatment, patients are followed up at 14 days.

Arms: arm 1: Within 60 minutes before standard of care BEAM treatment, patients receive netupitant and palonosetron hydrochloride PO on days 1, 3, and 6.

Netupitant: 300 mg, QD, Given PO Palonosetron Hydrochloride: 0.5 mg, QD, Given PO Questionnaire Administration: Ancillary studies
Interventions: intervention 1: Netupitant intervention 2: Palonosetron Hydrochloride intervention 3: Questionnaire Administration
Intervention descriptions: intervention 1: 300 mg, Given PO, QD intervention 2: 0.5 mg, Given PO, QD intervention 3: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version 5.1: November 27, 2018 
Page 1 of 38 
 
Oregon Health & Science University 
OHSU Knight Cancer Institute 
IRB Protocol #:  16288 
Other Protocol #:  NCT03097588 
 
TITLE: A Phase II Clinical Trial of NEPA (Netupitant/Palonosetron) for Prevention of 
Chemotherapy Induced Nausea and Vomiting (CINV) in Patient Receiving the BEAM Conditioning 
Regimen Prior to Hematopoietic Cell Transplantation (HSCT) 
 
Coordinating Center: 
Oregon Health and Science University Hospital and Clinics 
 
Principal Investigator: 
Joseph Bubalo PharmD, BCPS, BCOP 
Pharmacy Services, CR 9-4 
3181 SW Sam Jackson Park Road 
Portland, OR 97239 
503-494-8007 
Fax 503-494-5094 
bubaloj@ohsu.edu 
 
Co-Investigators: 
Richard T. Maziarz, MD  
 
Andy Chen, MD, PhD 
 
Sarah Nagle, MD 
 
 
 
Biostatistician: 
Jeong Youn Lim, PhD 
Biostatistics Shared Resource, CR-145 
Knight Cancer Institute 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road 
Portland, OR 97239 
503-418-1555 
limje@ohsu.edu 
 
 
Supplied Agent: 
Netupitant/Palonosetron (NEPA)  
 
IND# 132440 
 
 
Original Protocol Date: 
December 23, 2016 
 
Protocol Revision Dates: 
October 12, 2017 


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Protocol Version 5.1: November 27, 2018 
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Contents 
1.0 
OBJECTIVES ........................................................................................................6 
1.1 
Primary Objective ...................................................................................................6 
1.2 
Secondary Objectives ..............................................................................................6 
2.0 
BACKGROUND ...................................................................................................6 
2.1 
Chemotherapy-induced nausea and vomiting (CINV) ...............................................6 
2.2 
Study Agents...........................................................................................................8 
2.3 
Other Agents ......................................................................................................... 11 
2.4 
Study and Dose Rationale ...................................................................................... 11 
3.0 
STUDY POPULATION ....................................................................................... 13 
3.1 
Inclusion Criteria................................................................................................... 13 
3.2 
Exclusion Criteria.................................................................................................. 13 
4.0 
REGISTRATION PROCEDURES ....................................................................... 14 
4.1 
Subject Registration .............................................................................................. 14 
4.2 
Local Registration ................................................................................................. 15 
5.0 
TREATMENT PLAN .......................................................................................... 15 
5.1 
Agent Administration ............................................................................................ 15 
5.2 
Distribution........................................................................................................... 16 
5.3 
General Concomitant Medication and Supportive Care Guidelines .......................... 16 
5.3 
Duration of Treatment ........................................................................................... 16 
5.4 
Duration of Follow-up ........................................................................................... 17 
5.5 
Criteria for Evaluation ........................................................................................... 17 
5.6 
Criteria for Removal from Study ............................................................................ 18 
5.7 
Study Discontinuation ........................................................................................... 18 
6.0 
DOSING DELAYS/DOSE MODIFICATIONS..................................................... 19 
7.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS..................... 19 
7.1 
Adverse Events ..................................................................................................... 19 
7.2 
DRUG INTERACTIONS ...................................................................................... 19 
7.3 
Adverse Event Characteristics................................................................................ 21 
7.4 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events.................... 21 
7.5 
Central Reporting of Adverse Events for Multicenter Studies.................................. 21 
7.6 
Regulatory Reporting ............................................................................................ 22 
7.7 
Sponsor or additional reporting requirements ......................................................... 22 
8.0 
PHARMACEUTICAL INFORMATION .............................................................. 22 
8.1 
Agent Accountability............................................................................................. 22 


Protocol Version 5.1: November 27, 2018 
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8.2 
Study Agent (Commercially available product) ...................................................... 23 
9.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................... 24 
10.0 
STUDY PROCEDURES AND SCHEDULE OF EVENTS.................................... 24 
10.1 Screening/Baseline Visit........................................................................................ 24 
10.2 Study Treatment Visits .......................................................................................... 25 
10.3 End of Study/Early Termination ............................................................................ 25 
10.4 Study Assessments and Procedures ........................................................................ 25 
10.5 Schedule of Events ................................................................................................ 27 
11.1 Definitions (assessed via a daily CINV Questionnaire) ........................................... 29 
11.1.1 No Nausea = no nausea and < 1 on the 0-10 numerical scale. .................................. 29 
11.1.2 Mild Nausea = reported nausea and 1-3 on the 0-10 numerical scale........................ 29 
11.1.3 Moderate Nausea = reported nausea and 4-6 on the 0-10 numerical scale. ............... 29 
11.1.4 Severe nausea = reported nausea and 7-10 on the 0-10 numerical scale.................... 29 
11.2 Response Definitions:............................................................................................ 29 
11.2.1 Complete Response (CR): The complete absence of emesis, mild to moderate nausea, 
and no rescue therapy in subjects who have received all 6 days of chemotherapy and 
4 days of observation. Patients who do not complete days 1-6 will not be included in 
calculation of CR.................................................................................................. 29 
11.2.2 Complete Protection (CP): CR plus no nausea ........................................................ 29 
11.2.3 Major Response (MR): One or two episodes of emesis on only one day with any level 
of nausea or no emesis with severe nausea............................................................. 29 
11.2.6 Treatment Failure (TF): More than 2 episodes of emesis on any one day of the 
conditioning regimen or 2 emetic episodes on > 3 days of the conditioning regimen. 
Note: Emesis occurring within 2 hours of infusing DMSO containing stem cells will 
not be considered an antiemetic failure. ................................................................. 29 
12.0 
DATA REPORTING/REGULATORY REQUIREMENTS ................................... 29 
12.1 Data Collection and Storage................................................................................... 29 
12.2 
Privacy, Confidentiality, and Data Security (required) .......................................... 30 
12.3 Protocol Review .................................................................................................... 30 
12.4 Informed Consent.................................................................................................. 30 
12.5 Changes to Protocol .............................................................................................. 30 
12.6 Maintenance of Records ........................................................................................ 31 
12.7 OHSU IRB Reporting of Unanticipated Problems and Adverse Events.................... 31 
12.8 OHSU Knight Cancer Institute Data and Safety Monitoring Plan ............................ 31 
12.9 Inclusion of Women, Minorities and Children ........................................................ 31 
13. 
STATISTICAL CONSIDERATIONS................................................................... 32 
13.1 Study Design......................................................................................................... 32 


Protocol Version 5.1: November 27, 2018 
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13.2 Primary and Secondary Endpoints.......................................................................... 33 
13.3 Analysis Populations ............................................................................................. 33 
13.4 Statistical Analysis Plan ........................................................................................ 33 
13.4.1 Analysis of Primary Endpoint............................................................................. 33 
13.4.2 Analysis of Secondary Endpoints ....................................................................... 33 
13.4.3 Interim Analyses and Stopping Rules ................................................................. 33 
13.5 Sample Size and Power ......................................................................................... 34 
13.6 Randomization Method ......................................................................................... 34 
13.7 Handling of Missing Data ...................................................................................... 34 
REFERENCES....................................................................................................................... 35 
APPENDIX A ........................................................................................................................ 36 
ECOG Performance Status Criteria .................................................................................. 36 
Appendix B: NEPA Prescribing Information ........................................................................... 37 
APPENDIX C: CINV Questionnaire ....................................................................................... 38 


Protocol Version 5.1: November 27, 2018 
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1.0 
OBJECTIVES 
1.1 
Primary Objective 
To assess the efficacy of NEPA to prevent nausea and vomiting both during and after a highly emetogenic 
(BEAM) conditioning regimen for hematopoietic stem cell transplantation (HSCT). The efficacy is 
measured by Complete Response (CR) defined as no emesis and no rescue therapy for hours 0-264 (6 days 
of chemotherapy and 5 days post-chemotherapy). 
 
1.2 
Secondary Objectives 
To differentiate response to NEPA over different phases of chemotherapy-induced nausea. Specifically, CR 
is assessed for hours 0-144 (Acute phase) and hours 145-264 (delayed phase), and Complete Protection 
(CP) defined as CR plus no nausea is assessed for hours 0-144, 145-264, and the whole period. 
 
 
2.0 
BACKGROUND 
2.1 
Chemotherapy-induced nausea and vomiting (CINV) 
Abstract 
The management of chemotherapy-induced nausea and vomiting (CINV) during preparative regimens for 
Hematopoietic Stem Cell Transplant (HSCT) continues to be a poorly studied area and an unmet patient 
need. Still unaddressed in the most recent evidence based guidelines such as American Society of Clinical 
Oncology (ASCO) and Multinational Association Of Supportive Care In Cancer (MASCC), patients 
undergoing high dose antineoplastics as they prepare for autologous or allogeneic stem cell rescues have a 
high risk for emesis. Preparative regimens are generally multiple days of high dose chemotherapy, which 
result in the risk for a combination of acute and delayed emesis. NEPA with the combination of neurokinin 
1 antagonist and serotonin antagonist represents a unique product to address both types of CINV in a single 
agent. Thus we propose to use it to prevent CINV in patients receiving the BEAM (carmustine, etoposide, 
cytarabine, and melphalan) preparative regimen. This regimen is a 6-day therapy course with high dose 
(and highly emetogenic) chemotherapy on day 1 and 6 with lower risk chemotherapy for acute emesis on 
days 2 through 5. Our plan is to dose NEPA on days 1, 3, and 6 to cover the complete course of therapy 
and continue to monitor for 5 days after to assess for control of delayed CINV as well as acute. Given the 
current poor levels of control with previously available agents and scant experience with multiday dosing 
of NEPA we propose a phase II trial to gain baseline safety and efficacy data without a placebo arm. 
Advancement in management of CINV has been critical in administering highly emetogenic agents required 
for myeloablative conditioning regimens in HSCT. However, there remains a need for safe, effective, and 
reliable agents to eradicate CINV. Furthermore, delayed-onset CINV is increasingly recognized as more 
difficult to treat than acute-phase CINV. 


Protocol Version 5.1: November 27, 2018 
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NEPA is a recently approved combination antiemetic, containing fixed doses of netupitant (an NK1 receptor 
antagonist) and palonosetron (a 5HT3 receptor antagonist). Having pharmacologically distinct mechanisms, 
combined NEPA offers synergistic reduction and potential elimination of CINV. NEPA has previously 
been shown to be superior to palonosetron in single and multiple cycles of both highly1 and moderately1,2 
emetogenic chemotherapy regimens. 
 
Mechanism and Clinical Importance 
From the earliest use of cytotoxic chemotherapies, nausea and vomiting have been a limiting factor in 
treatment. Significant advancements have been made in understanding the underlying cause of 
chemotherapy-induced nausea and vomiting (CINV) as well as in managing it. CINV has three distinct 
subtypes – acute, delayed and anticipatory. While there have been improvements in the prevention of all 
three areas, CINV remains problematic especially with highly emetogenic chemotherapies (HEC) and in 
the delayed-onset setting (occurring over 24 hours after chemotherapy administration). 
Several areas of the brain and their associated neurotransmitters have been implicated in the development 
of nausea and vomiting. Specifically, the chemoreceptor trigger zone (CTZ) at the caudal end of the fourth 
ventricle in the area postrema lacks an effective blood brain barrier, permitting chemical stimuli from blood 
and cerebrospinal fluid (CSF) to activate the CTZ and induce the sensation of nausea and the emesis 
response. Four major neurotransmitter systems, the dopaminergic (D2), histaminic (H1), serotonergic (5- 
HT3), and cholinergic (muscarinic), have been implicated in inducing this response and blockade of these 
receptors have been effective in managing nausea and emesis. 
The subnucleus gelatinosus at the nucleus tractus solitarius (NTS), a convergence of afferent neurons from 
the vagal and vestibulary systems and efferents from the area postrema, has also been identified as critical 
for initiating emesis. In this area, the neurokinin 1 receptor agonist Substance P acts as a common chemical 
signal for neuronal communication.3 Blockade with NK1 receptor antagonists has demonstrated additive 
antiemetic efficacy. 
Delayed onset nausea and emesis have been largely associated with the activation of tachykinin family 
neurokinin 1 (NK1) receptors (broadly distributed in the central and peripheral nervous systems) by 
substance P 4,5. As shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses. 
In vitro administration of both netupitant and palonosetron demonstrated an additive internalization of the 
NK1 receptor.6 
While not directly life threatening, impaired quality of life and morbidity from poorly controlled CINV 
continues to be a problem. Sequelae of CINV include poor adherence to chemotherapy regimens, anxiety, 
impaired nutrition and risk of dehydration, and mucosal damage with exacerbation of mucositis, which is 
already an adverse effect of many chemotherapies. Further, in a recent review of 67 studies, Sommariva et 
al.  highlight the  effect  on health-related quality of life  and  the  additional  health-care cost  of    poorly 


Protocol Version 5.1: November 27, 2018 
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controlled CINV. In this study, specific costs were highly variable, but reviewed studies agreed that CINV 
led to increased medication expenditure and inpatient, outpatient, and emergency department visits; 
however, the addition of palonosetron, a 5-HT3 receptor antagonist, reduced use of rescue medications and 
the further addition of aprepitant, an NK1 receptor antagonist, provided benefit in certain populations 
receiving HEC.7 
 
Current Therapy 
Current treatment recommendations for management of CINV in highly emetic chemotherapy (HEC) are 
for triple therapy with an NK1 receptor antagonist (NK1RA), 5-HT3 receptor antagonist (5-HT3RA), and 
dexamethasone. Four 5-HT3RAs - ondansetron, granisetron, dolasetron, and palonosetron are available as 
antiemetics in the United States. Palonosetron has demonstrated superiority over the other 5-HT3RAs 
because it helps to control delayed CINV in addition to acute CINV, whereas the other 5-HT3RAs 
(ondansetron, granisetron, dolasetron) are primarily active only in acute CINV. Further, the addition of an 
NK1RA, such as aprepitant and fosaprepitant, to antiemetic chemotherapy regimens has improved 
management of acute nausea/vomiting. Currently available NK1RAs include aprepitant, fosaprepitant, 
netupitant, and rolapitant. Most prophylaxis regimens with 5-HT3 antagonists also contain dexamethasone 
10-20 mg IV daily, as dexamethasone further enhances its efficacy of antiemetic control, and is now 
considered the standard of therapy in HEC 8,9.  
In a study combining aprepitant, palonosetron, and low-dose dexamethasone prior to conditioning regimens 
for autologous hematopoietic stem cell transplant, none of 18 analyzed patients had emetic failure and 
complete control was achieved in 78 % in the acute phase, 33% in delayed, and 17% in extended phases.10 
Yet, nausea continued to occur in 78%, albeit not to a significant degree in 61%.10 This study helped 
establish the triple regimen as standard of care over the prior standard of ondansetron and dexamethasone 
where emesis is prevented in only 4-20% of patients.10 While demonstrating a significant improvement, 
CINV continues to be inadequately managed (78% with some nausea), especially in delayed-onset nausea 
and vomiting (77% with delayed emesis). 
Inadequate nausea control contributes to the morbidity of HSCT with persistence of common side effects 
of conditioning regimens for bone marrow or stem cell transplant. CINV can impair nutrition, exacerbate 
mucositis, and overall negatively impact upon patients’ quality of life and functional capacity. 
 
2.2 
Study Agents 
NEPA (300 mg netupitant/0.5 mg palonosetron), commercially available as Akynzeo®11, is an oral fixed 
dose combination product of netupitant, a substance P/neurokinin 1 (NK1) receptor antagonist, and 
palonosetron hydrochloride, a serotonin-3 (5-hydroxytryptamine 3; 5HT3) receptor antagonist (RA). Both 
netupitant and palonosetron hydrochloride are anti-nausea and antiemetic agents. 


Protocol Version 5.1: November 27, 2018 
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Each NEPA (Akynzeo®; 300 mg netupitant/0.5 mg palonosetron) capsule is composed of one white- 
caramel hard gelatin capsule which contains three tablets each containing 100 mg netupitant and one gelatin 
capsule containing 0.56 mg palonosetron hydrochloride (equivalent to 0.50 mg palonosetron). The inactive 
ingredients are microcrystalline cellulose, sucrose fatty acid esters, povidone K-30, croscarmellose sodium, 
purified water, silicon dioxide, sodium stearyl fumarate, magnesium stearate, mono-and di-glycerides of 
capryl/capric acid, glycerin, polyglyceryl oleate, butylated hydroxyanisole (BHA), gelatin, sorbitol, 
titanium dioxide, yellow iron oxide, and red iron oxide. It may contain traces of medium-chain triglycerides, 
lecithin, and denatured ethanol. 
 
NEPA Pharmacology 
Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors, and palonosetron 
is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for 
other receptors. 
The receptor occupancy for the CINV dosing regimen of netupitant was measured in a human Positron 
Emission Tomography (PET) study. Netupitant was shown to cross the blood brain barrier with a NK1 
receptor occupancy of 92.5%, 86.5%, 85.0%, 78.0%, and 76.0% in striatum at 6, 24, 48, 72, and 96 hours, 
respectively, after administration of 300 mg netupitant. Co-administration of single dose netupitant 600 mg 
and palonosetron 1.5 mg had no significant effects on the QTc interval. 
 
NEPA Pharmacokinetics 
After single dose administration of NEPA (Akynzeo) in healthy subjects, the peak plasma concentrations 
for netupitant and palonosetron were reached in about 5 hours. When administered under fed condition, the 
systemic exposure to netupitant and palonosetron was similar to those obtained under fasting condition. In 
cancer patients who received a single dose of NEPA (Akynzeo®) 1 hour prior to chemotherapy (docetaxel, 
etoposide, or cyclophosphamide), the Cmax and AUC of netupitant and its metabolites were similar to those 
in healthy subjects. The mean Cmax and AUC of palonosetron in cancer patients were similar to those in 
healthy subjects. No significant changes in pharmacokinetics of netupitant and palonosetron were observed 
when 450 mg oral netupitant and 0.75 mg oral palonosetron were co-administered. 
 
NEPA Elimination 
Following administration of a single oral 0.75 mg dose of [14C]-palonosetron to six healthy subjects, 85% 
to 93% of the total radioactivity was excreted in urine, and 5% to 8% was eliminated in feces. The amount 
of unchanged palonosetron excreted in the urine represented approximately 40% of the administered dose. 
In cancer patients, t½ was 48 ± 19 hours. After a single-dose of approximately 0.75 mg intravenous 


Protocol Version 5.1: November 27, 2018 
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palonosetron, the total body clearance of palonosetron in healthy subjects was 160 ± 35 mL/h/kg (mean ± 
SD) and renal clearance was 66.5 ± 18.2 mL/h/kg. 
Netupitant inhibits CYP3A4, thus caution with co-administration of CYP3A4 inducers/inhibitors/substrates 
should be followed.12 However, there was no significant interaction observed between netupitant and 
palonosetron, thus the primary effect of NEPA on CYP3A4 inducers/inhibitors/substrates was similar to 
what is seen with netupitant alone 12. 
 
Netupitant 
Netupitant is chemically described: 2-[3,5-bis(trifluoromethyl)phenyl]-N, 2 dimethyl-N-[4- 
(2methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl] propanamide. The empirical formula is 
C30H32F6N4O, with a molecular weight of 578.61. Netupitant exists as a single isomer, is white to off- 
white crystalline powder, and is freely soluble in toluene and acetone, soluble in isopropanol and ethanol, 
and very slightly soluble in water. 
Netupitant Absorption 
Upon oral administration of a single dose of netupitant, netupitant started to be measurable in plasma 
between 15 minutes and 3 hours after dosing. Plasma concentrations reached Cmax in approximately 5 hours. 
There was a greater than dose-proportional increase in the systemic exposure with the dose increase from 
10 mg to 300 mg and a dose-proportional increase in systemic exposure with a dose increase from 300 mg 
to 450 mg. 
Netupitant Distribution 
In cancer patients netupitant disposition was characterized by a large apparent volume of distribution (Vz/F: 
1982 ± 906 L) (mean ± SD). Human plasma protein binding of netupitant is greater than 99.5% at drug 
concentrations ranging from 10-1300 ng/mL and protein binding of its major metabolites (M1, M2 and M3) 
is greater than 97% at drug concentrations ranging from 100 to 2000 ng/mL. 
Netupitant Metabolism 
Once absorbed, netupitant is extensively metabolized to form three major metabolites: desmethyl 
derivative, M1; N-oxide derivative, M2; and OH-methyl derivative, M3. Metabolism is mediated primarily 
by CYP3A4 and to a lesser extent by CYP2C9 and CYP2D6. Metabolites M1, M2 and M3 were shown to 
bind to the substance P/neurokinin 1 (NK1) receptor. 
Mean Cmax was approximately 11%, 47% and 16% of netupitant for metabolites M1, M2 and M3, 
respectively. Mean AUC for metabolites M1, M2 and M3 was 29%, 14% and 33% of netupitant, 
respectively. The median Tmax for metabolite M2 was 5 hours and was about 17-32 hours for metabolites 
M1 and M3. 
 
Palonosetron 


Protocol Version 5.1: November 27, 2018 
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Palonosetron hydrochloride is chemically described: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3- 
yl]2,3,3a,4,5,6-hexahydro-1-oxo-1H-benz[de]isoquinoline hydrochloride. The empirical formula is 
C19H24N2O.HCl, with a molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer, 
is a white to off-white crystalline powder, and is freely soluble in water, soluble in propylene glycol, and 
slightly soluble in ethanol and 2-propanol. 
Palonosetron Absorption 
Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching 97%. 
After single oral doses using buffered solution mean maximum palonosetron concentrations (Cmax) and 
area under the concentration-time curve (AUC0-∞) were dose proportional over the dose range of 3.0 to 80 
μg/kg in healthy subjects. 
Palonosetron Distribution 
Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of 
palonosetron is bound to plasma proteins. 
Palonosetron Metabolism 
Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary 
metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites each have less than 
1% of the 5-HT3 RA activity of palonosetron. In vitro metabolism studies have suggested that CYP2D6 and 
to a lesser extent CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron. However, clinical 
pharmacokinetic parameters are not significantly different between poor and extensive metabolizers of 
CYP2D6 substrates. 
 
2.3 
Other Agents 
Dexamethasone 12 mg 1 hour prior (+/- 30 minutes) to chemotherapy on Day 1, then 8 mg PO daily on 
days 2 through 6. Dexamethasone will not continue on day 7 (SCT Day 0), as our subjects will receive 
hydrocortisone with stem cell infusions as per our institutional standard. Additionally, with use of other 
NK1 antagonists during stem cell conditioning, our institutional protocols do not include dexamethasone 
on the day of stem cell infusion. Patients on strong CYP 3A4 inducers or inhibitors would need to have 
those agents replaced with clinical alternatives prior to beginning the study. Length of washout period will 
be 7 days. Benzodiazepines will not be allowed as hypnotics. Additional antiemetics will be allowed for 
rescue but not for prophylaxis. 
 
2.4 
Study and Dose Rationale 
NEPA has been evaluated in other chemotherapy regimens, but has yet to be evaluated in HSCT 
conditioning regimens. Combined use of netupitant and palonosetron (NEPA) has been effective in 
managing CINV in single dose administration of both highly and moderate emetogenic chemotherapies. To 
determine the optimal netupitant dose for future fixed-dose administration, a phase II study randomized 


Protocol Version 5.1: November 27, 2018 
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694 chemotherapy naïve patients to one of 5 antiemetic groups prior to receiving highly emetogenic 
chemotherapy (cisplatin): one of 3 doses of netupitant (100, 200 and 300 mg) with single dose palonosetron 
(0.5 mg), oral palonosetron alone (0.5 mg; PALO), and standard 3-day aprepitant (APR) and ondansetron; 
all in combination with dexamethasone.13 The 300 mg netupitant dose with PALO was superior to lower 
NEPA doses and to PALO alone. Furthermore, all three NEPA arms were well tolerated and had similar 
safety profiles to PALO and APR. 
5- HT3 RAs were effective at reducing acute nausea and emesis, but palonosetron has been identified as the 
only 5HT3-antagonist to reduce both acute and delayed-onset nausea and vomiting.14 Similarly, growing 
data suggests delayed nausea and vomiting are due to activation of the NK1 pathway; furthermore, the long 
half-life of netupitant positions it well to remain effective during delayed phase nausea and vomiting.4 The 
combination of netupitant and palonosetron was shown in vitro to induce a synergistic inhibition of the 
Substance P response in NG108-5 cells, which express both 5-HT3 and NK1 receptors.14 Another in vitro 
study showed additive NK1 receptor internalization in NG108-5 cells with combined administration of 
netupitant and palonosetron, potentially identifying the mechanism belying this synergistic inhibition of 
Substance P response.6 
NEPA has been evaluated in its current formulation in a number of settings, including its phase II trial for 
dosage as noted above. NEPA has been evaluated in phase III trials for both singly dosed chemotherapy 
and over repeated cycles for highly and moderately emetogenic chemotherapies.1 However, it has not yet 
been evaluated specifically in moderately and highly emetogenic conditioning regimens for hematopoietic 
stem cell transplant (HSCT). 
In a randomized phase III study, NEPA had a significantly higher complete response (no emesis and no 
rescue medication) compared with Palonosetron (PALO) alone following a moderately emetogenic 
chemotherapy (anthracycline-cyclophosphamide). Complete response was seen in 76.9% of NEPA patients 
compared with 69.5% given palonosetron. Importantly, this study included primarily women (98.2% 
NEPA; 97.9% PALO).2 This study excluded those receiving highly emetogenic chemotherapy (HEC), 
radiation therapy, or bone marrow or stem-cell transplant. 
While previously shown to be effective in single dose chemotherapy regimens, a multinational, double- 
blind study randomized 413 patients to receive either a single dose of NEPA and dexamethasone or a three- 
day dosing of aprepitant, palonosetron and dexamethasone in multiple (at least six) cycles of both MEC 
and HEC1. Again, patients were ineligible if preparing for HSCT. NEPA showed a small but consistent 
improvement in complete response (from 2-7%) compared with aprepitant/palonosetron over 6 
chemotherapy cycles.1 
In high-dose, highly-emetogenic chemotherapy, palonosetron needs to be dosed more frequently than 
netupitant due to palonosetron’s approximate 40 hour half-life, in contrast with netupitant’s approximate 
90 hour half-life. As Einhorn et al. showed, palonosetron along with dexamethasone is effective in alternate- 


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day dosing in multi-day highly emetogenic cisplatin-containing regimen (BEP), where cisplatin is given 
over 5 days and palonosetron is given on days 1, 3, and 5.15 The majority of patients had no emesis, 
moderate-to-severe nausea, or need for rescue medications. Similarly, the present study will dose NEPA on 
days 1, 3 and 6. Notably, NEPA will be redosed on day 6 instead of day 5 because day 6 of the BEAM 
regimen includes melphalan, the drug of greatest emetogenic potential in the regimen. 
 
3.0 
STUDY POPULATION 
3.1 
Inclusion Criteria 
1. 
Subjects must be undergoing autologous or allogeneic Hematopoietic Stem Cell Transplant 
(HSCT) with the BEAM conditioning regimen prior to HSCT; 
 
2. 
Age ≥ 18 years. Both men and women and members of all races and ethnic groups will be included; 
 
3. 
ECOG performance status ≤ 2 or Karnofsky Performance Score >60% (see Appendix A, Appendix 
A2 for Karnofsky Performance Score (KPS) conversion); 
4. 
Able to swallow oral medications; 
 
5. 
Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
1. 
Subjects with known hypersensitivity or other allergic reactions attributed to compounds of similar 
biologic composition to netupitant, palonosetron, dexamethasone, or other agents used in the study. 
 
2. 
Subjects who are receiving any other investigational agents or have received another investigational 
drug in the last 30 days. 
 
3. 
Subjects who have had emesis or required antiemetics in the 48 hours prior to starting the BEAM 
conditioning regimen. Patients required to take antipsychotics, appetite stimulants, or other 
medications with antiemetic effects will also be excluded if those medications cannot be replaced 
by therapeutic equivalents. 
 
4. 
Female subjects who are pregnant, have a positive serum hCG, or are lactating and intend to 
breastfeed a child. Pregnant women are excluded from this study because hematopoietic stem cell 
transplant conditioning regimens including the BEAM regimen have the potential for teratogenic 
or abortifacient effects. NEPA itself is Pregnancy Class C. Because there is an unknown but  
 
potential risk for adverse events in nursing infants secondary to treatment of the mother with NEPA, 
breastfeeding should be discontinued if the mother is treated with NEPA. These potential risks may 


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also apply to other agents used in this study. 
 
5. 
HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential 
for pharmacokinetic interactions with NEPA. In addition, these subjects are at increased risk of 
lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be 
undertaken in subjects receiving combination antiretroviral therapy when indicated. 
 
6. 
Subjects who have taken a neurokinin antagonist within 14 days prior to beginning the BEAM 
regimen. 
 
7. 
Subjects who have a serum creatinine > 2 x ULN. 
 
8. 
Subjects with severe renal failure or End stage renal disease (estimated GFR (glomerular filtration 
rate) of < 30 mL/min) as estimated by the Cockcroft-Gault formula. 
Formula (Men): GFR [mL/min] = {((l40 – age[y]) x body weight [kg]) / (72 * SCr [mg/dL)} 
Formula (Women): GFR [mL/min] = 0.85 * {((l40 – age[y]) x body weight [kg]) / (72 * SCr 
[mg/dL)} 
9. 
Subjects with severe hepatic insufficiency (Child-Pugh  Score > 9). 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin [mg/dL] 
<34 
(<2) 
34–50 (2–3) 
>50 (>3) 
Serum albumin [g/dL] 
>3.5 
2.8–3.5 
<2.8 
Prothrombin time, 
prolongation [s] 
<4.0 
4.0–6.0 
> 6.0 
Ascites 
None 
Mild (or suppressed with 
medication) 
Moderate to severe (or 
refractory) 
Hepatic encephalopathy 
None 
Grade I–II 
Grade III–IV 
 
10. Subjects who have reported drinking > 5 alcoholic drinks daily for the last year. 
 
11. Subjects who have concurrent illness requiring systemic corticosteroid use other than the planned 
dexamethasone during conditioning therapy. 
 
12. Subjects with gastrointestinal conditions that might result in malabsorption of the study drug. 
 
13. Subjects with a history of anxiety-induced (“anticipatory”) nausea and vomiting. 
 
14. Subjects on strong CYP 3A4 inducers or inhibitors who are unable to have those agents replaced 


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with clinical alternatives prior to beginning the study. Length of washout period will be 7 days. 
Notably, in the case of allogeneic transplant recipients requiring cyclosporine or tacrolimus, no 
empiric dose adjustments will be required due to close level monitoring and adjustments that are 
standard in OHSU protocols. 
 
15. Subjects unable to discontinue benzodiazepines as antiemetics will not be allowed. Additional 
antiemetics will be allowed for rescue but not for prophylaxis. 
 
16. Subjects with personal or family history of QT prolongation, uncorrected electrolyte abnormalities, 
congestive heart failure, bradyarrhythmia, conduction disturbances, and those taking anti- 
arrhythmic medicinal products or other medicinal products that lead to QT prolongation or 
electrolyte abnormalities. Relevant information will be collected as part of subject medical 
history. 
 
 


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4.0 
REGISTRATION PROCEDURES 
4.1 
Subject Registration 
 Participants will be required to give written informed consent to participate in the study before any 
screening tests or evaluations are conducted that are not part of standard care.There is no randomization 
for treatment. This is a phase II trial with an intention-to-treat all patients who are enrolled in this clinical 
trial. Potential subjects will be seen by investigators of this study as a new patient or consult visit or as a 
follow-up visit.  
 
4.2 
Local Registration 
Registrations from all consented subjects must be entered into the electronic Clinical Research Information 
System (eCRIS). This trial is  registered with ClinicalTrials.gov and the Clinical Trials Reporting 


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Program (CRTP) of the National Cancer Institute (NCI). This study will use using an electronic data 
capture (EDC) system on OHSU secure servers [electronic case report form (eCRF)], and patient 
information will be entered into the eCRF in real time. Registration of OHSU patients will include the 
minimum of the following: 
• 
A completed Eligibility Checklist signed by the investigator 
• 
Signed copies of the most recent IRB-approved, informed consent form including HIPAA 
authorization.  
 
 
 
5.0 
TREATMENT PLAN 
5.1 
Agent Administration 
Treatment will be administered either inpatient or outpatient. Reported adverse events and potential risks 
associated with NEPA (netupitant/palonosetron) and dexamethasone are described in Section 7. No dose 
modifications for NEPA and dexamethasone are planned in this protocol. No investigational or commercial 
antiemetic agents or therapies other than those described below may be administered with the intent to treat 
the subject's malignancy. The study regimen is described below: 
NEPA 300 mg/0.5 mg PO will be administered 60 minutes (+/-30 minutes) prior to chemotherapy on Day 
1, Day 3, and Day 6. 
Dexamethasone 12 mg PO will be given 60 minutes (+/-30 minutes) prior to chemotherapy on Day 1 and 8 
mg PO will be given on each additional day of conditioning chemotherapy (Days 2 through 6). Due to 
netupitant interaction with dexamethasone, see section 7.2.1, this dose is equivalent to the standard 
dexamethasone dose of 20 mg/day. Dexamethasone will only be given on days that chemotherapy is 
received. 
HSCT Conditioning Regimen 
BEAM HSCT chemotherapy conditioning regimen: 
• Carmustine* 300 mg/m2 IV on Day 1 
• Etoposide 200 mg/m2/day IV days 2 through 5 
• Cytarabine 400 mg.m2/day IV on days 2 through 5 
• Melphalan 140 mg/m2 IV on day 6 
 
*In patients with BMI 30 or higher, BEAM dosing will be per standard of care and the ASBMT guidelines 
for obese patients. Dosing for Carmustine is based on a 40% adjusted body weight. 
 
5.2 
Distribution 
A study investigator’s order will be entered into BEACON and sent to the investigational drug pharmacy. 
The pharmacy will supply the nursing floor with unit dose capsules. 
The doses are to be administered on the nursing floor by a research nurse and documented in the patient’s 


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medical record. If the dose is unused, the medication will be returned to the investigational pharmacy.


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5.3 
General Concomitant Medication and Supportive Care Guidelines 
• All previously ordered scheduled antiemetics will be discontinued. 
• Benzodiazepines will not be allowed as hypnotics. 
• Drugs interacting with NEPA are not allowed on study. Patients previously taking drugs that interact 
with NEPA, such as those metabolized through the cytochrome P450 system, may participate after a 
minimum washout period of 7 days. 
• In individuals with personal or family history of long QT syndrome, anti-arrhythmic medications and 
or other medicinal products that lead to QT prolongation or electrolyte abnormalities will be minimized 
as discussed in exclusion criteria. 
 
All patients will receive rescue antiemetics per normal procedures and number of doses of each agent will 
be charted on the medication administration record and tracked by type and quantity. If needed for patient 
comfort or safety, rescue medications may be administered on a regularly scheduled basis at the physician’s 
discretion. The choice of rescue medications will be left to the health care provider’s discretion but dose 
and efficacy will be tracked. The actual time of first rescue medication from the start of conditioning 
therapy will be noted. Because there is a potential for interaction of NEPA with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture the concurrent 
use of all other drugs, over-the-counter medications, or alternative therapies. The principal investigator 
should be alerted if the subject is taking any agent known to affect or with the potential to affect selected 
CYP450 isoenzymes. 
 
5.3 
Duration of Treatment 
Patients will be hospitalized per standard of care for bone marrow and peripheral stem cell transplantation. 
Once discharged from the hospital, patients will continue with the recommended follow-up care post 
transplantation in the outpatient bone marrow transplant/hematology clinic. Patients will be followed 14 
days (+/- 72 hours of day 20 as in Section 5.4) after receiving their last dose of NEPA for potential adverse 
events. This follow up visit may occur in the clinic or in the hospital if the patient is still admitted. 
 
5.4 
Duration of Follow-up 
Subjects will be monitored on study for a maximum of 20 days (11 days of initial evaluation plus end of 
study evaluation 14 days after receiving the final dose of NEPA). End of study corresponds with HSCT 
Day +13; however, for clarity all study documentation will refer to study days 1-20. End of study 
assessment must be performed within ±72 hours of the true day 20 (i.e. Between days 17-23). The End of 


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study evaluation will be completed at either the end of the study or at early termination. In the event that 
therapy is stopped for a life-threatening allergy, or some other unreasonable toxicity, then patients will be 
followed for one month from the date therapy is stopped or until the resolution of the toxicity. If the 
toxicity is expected to continue the patient will be followed until the stabilization of that toxicity. 
 
5.5 
Criteria for Evaluation 
Nausea will be assessed daily using a self-reported QOL/nausea assessment form (CINV Questionnaire; 
Appendix C) beginning on admission and continuing through Study Day 10. Patients will complete a 
daily CINV questionnaire, noting number of episodes of emesis as well as whether they experienced 
nausea and to what degree (0-10). Emetic episodes will also be noted by the patient’s nurse, recorded on 
the daily medical record, and verified for number each day with the patient. If patient reporting is 
discordant with nursing records and this discordance cannot be reconciled, the maximal number of 
episodes for a given day will be used. Either retching (visceral contraction without the expulsion of stomach 
contents) or emesis (visceral contraction with the expulsion of stomach contents) will be considered an 
emetic episode for study purposes. The actual time of first emesis from the start of conditioning therapy 
will be noted. The percentage of total food eaten and days of parenteral nutrition during the study period 
will be monitored for each patient through the patient self-reported questionnaire. Meals are ad libitum 
and percentage is based on each patient’s desired meal. Patients will record their own number and 
percentage of meals eaten in the daily CINV questionnaire (Appendix C). 
 
 
 
Definitions (assessed via daily CINV Questionnaire - Appendix C) 
 No Nausea = no reported nausea and <1 on the 0-10 numerical scale. 
 Mild Nausea = reported nausea and 1-3 on the 0-10 numerical scale. 
 Moderate Nausea = reported nausea and 4-6 on the 0-10 numerical scale. 
 Severe nausea = reported nausea and 7-10 on the 0-10 numerical scale. 
 
 
Response Definitions: 
 Complete Response (CR): The complete absence of emesis, mild to moderate nausea, and no rescue 
therapy in subjects who have received all 6 days of chemotherapy and 4 days of observation. 
Patients who do not complete days 1-6 will not be included in calculation of CR. 
 Complete Protection (CP): CR plus no nausea 
 Major Response (MR): One or two episodes of emesis on only one day with any level of nausea 
or no emesis with severe nausea 


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 Minor Response (mR): One to two episodes of emesis on > 1 day but less than 3 days with any 
level of nausea. 
 Partial Response (PR): Emesis with 2 or fewer episodes of emesis on any one day of the 
conditioning regimen or fewer than 2 emetic episodes on > 3 days of the conditioning regimen. 
 Treatment Failure (TF): More than 2 episodes of emesis on any one day of the conditioning 
regimen or 2 emetic episodes on > 3 days of the conditioning regimen. Note: Emesis occurring 
within 2 hours of infusing DMSO containing stem cells will not be considered an antiemetic 
failure. 
 
5.6 
Criteria for Removal from Study 
Subjects may choose to withdraw from the study at any time without penalty of jeopardizing their health 
care or loss of benefits to which the subject is otherwise entitled. Every reasonable effort should be made 
to determine the reason a subject withdraws prematurely, and this information should be recorded in the 
eCRF. Should a subject or the subject’s legally authorized guardian/representative decide to withdraw 
themselves or the subject from the study, all efforts will be made to complete and report the End of 
Treatment evaluations as thoroughly as possible. 
A subject may be withdrawn from the study, if, in the investigator’s expert medical judgment, the subject 
is non-compliant with the study requirements. Subjects may be withdrawn at the discretion of the Food and 
Drug Administration (FDA) or the investigator. A subject may also be discontinued from the study for the 
following reasons: 
• If a patient experiences a grade 3 toxicity that is attributed to NEPA the patient will be discontinued 
from the study and followed until resolution of the toxicity as described in section 10.2. 
• If the patient is suspicious for hepatic insufficiency as defined by having bilirubin > 2.0 mg/dL a 
Child-Pugh Score should be calculated. If a patient develops hepatic insufficiency (Child-Pugh score 
> 9) then NEPA will be discontinued and they will be followed through Study Day 20 or until their 
score falls below 5 whichever period is longer. 
 
5.7 
Study Discontinuation 
If a subject is withdrawn from the study: 
• 
The reason(s) for withdrawal must be documented in the subject’s medical record and eCRF. 
• 
The End-of-treatment or Early Termination visit should be performed within 14 days (+/-72 hours of 
true day 20) of last dose. 
• 
All subjects must be followed for safety until the time of the follow-up evaluation, until study drug 
related toxicities resolution , or until stabilization of the adverse event, whichever is longer. 
If the sponsor investigator or regulatory authority discovers conditions during the study that indicate that 
the study or study site should be terminated, this action may be taken after appropriate consultation with 


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the investigators. The sponsor-investigator has the right to terminate the study at any time. Reasons for 
terminating the study may include the following: 
• 
Incidence or severity of adverse events in this or other studies indicates a potential health hazard to 
subjects. 
• 
Subject enrollment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete. 
• 
Investigator(s) do not adhere to the protocol or applicable regulatory guidelines in study conduction. 
 
 
 
6.0        DOSING DELAYS/DOSE MODIFICATIONS 
NEPA dose adjustments or delays are prohibited. NEPA will be dosed under usual standard of care, 
including those with BMI >30 per guidance from the oncology pharmacist. NEPA does not require dose 
adjustment for diminished renal function. In the event of toxicity judged by the investigators to be related 
to the study drug, patients may be withdrawn from the study as noted in Section 5.6 and alternative 
antiemetics instituted for patient safety. Note that other agents which may potentially require dose 
adjustments due to an interaction with NEPA (see section 7.2) will be reviewed and adjusted 
appropriately by the oncology pharmacist. 
 
 
7.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
7.1 
Adverse Events 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. Sections 5 and 6 of the 
Prescribing Information for NEPA (Appendix B) identify known reported and theoretical potential adverse 
events. Occurrence of hypersensitivity reactions or serotonin syndrome as described in section 5 of the 
Prescribing Information would warrant expedited reporting. 
 
7.2 
DRUG INTERACTIONS 
Effects of NEPA on Other Drugs 
Interaction with CYP3A4 Substrates 
Netupitant, a component of NEPA, is a moderate inhibitor of CYP3A4. 
AKYNZEO should be used with caution in patients receiving concomitant medications that are primarily 
metabolized through CYP3A4. The plasma concentrations of CYP3A4 substrates can increase when co- 
administered with NEPA. The inhibitory effect on CYP3A4 can last for multiple days. 
Dexamethasone 


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A two-fold increase in the systemic exposure of dexamethasone was observed 4 days after single dose of 
netupitant. The duration of the effect was not studied beyond 4 days. Administer a reduced dose of 
dexamethasone with NEPA. 
Midazolam 
When administered with netupitant, the systemic exposure to midazolam was significantly increased. 
Consider the potential effects of increased plasma concentrations of midazolam or other benzodiazepines 
metabolized via CYP3A4 (alprazolam, triazolam) when administering these drugs with NEPA. 
Interaction with chemotherapeutic agents 
The systemic exposure of chemotherapy agents metabolized by CYP3A4 can increase when administered 
with NEPA. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, 
paclitaxel, etoposide, irinotecan, cyclophosphamide, ifosfamide, imatinib, vinorelbine, vinblastine, and 
vincristine. Caution and monitoring for chemotherapeutic related adverse events are advised in patients 
receiving chemotherapy agents metabolized primarily by CYP3A4. 
Interaction with oral contraceptives 
Clinically significant effect of NEPA on the efficacy of oral contraceptives containing levonorgestrel and 
ethinyl estradiol is unlikely. 
 
Effects of Other Drugs on NEPA 
Netupitant, a component of NEPA, is mainly metabolized by CYP3A4. 
In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent CYP3A4 and CYP1A2 are 
involved in the metabolism of palonosetron. 
CYP3A4 Inducers 
Avoid concomitant use of NEPA in patients who are chronically using a strong CYP3A4 inducer such as 
rifampin. A strong CYP3A inducer can decrease the efficacy of NEPA by substantially reducing plasma 
concentrations of the netupitant component. 
CYP3A4 Inhibitors 
Concomitant use of NEPA with a strong CYP3A4 inhibitor (e.g., ketoconazole) can significantly increase 
the systemic exposure to the netupitant component of NEPA. However, no dosage adjustment is necessary 
for single dose administration of NEPA. 
Serotoninergic Drugs 
Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) 
has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic 
drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake 
inhibitors (SNRIs). 


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7.3 
Adverse Event Characteristics 
CTCAE term (AE severity description and grade): The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for 
AE reporting. A copy of the CTCAE version 4.03 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Expectedness: Adverse Events can be ‘Unexpected’ or ‘Expected’ (see sections 5 and 6 of the current 
Prescribing Information attached to this document as Appendix B for known warnings and AEs). 
Causality of the AE: 
• Definite: the AE is clearly related to the study treatment; 
• Probable: the AE is likely related to the study treatment; 
• Possible: the AE may be related to the study treatment; 
• Unlikely: the AE is unlikely related to the study treatment; 
• Unrelated: the AE is clearly NOT related to the study treatment. 
 
 
7.4 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
Unanticipated Problems (UPs) and Adverse Events (AEs) will be reported to OHSU IRB according to the 
policies, procedures and guidelines posted on the OHSU IRB web site: 
http://www.ohsu.edu/xd/about/services/integrity/policies/all-irb-documents.cfm.  
Unanticipated Problems and Serious Adverse Events as defined below must be reported to OHSU IRB 
within 5 business days after the PI learns of the event. If any of these require a change (as determined by 
the PI or the IRB) to the protocol or consent form, the PI will make those changes promptly and submit 
the revised documents to the OHSU IRB. 
This study will use the Office for Human Research Protections (OHRP) definition of unanticipated 
problems (UPs). UPs are defined as any incident, experience, or outcome that meets all of the following 
criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 An adverse event or suspected adverse reaction is considered “serious” if it results in any of the 


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following outcomes: 
• 
Death; 
• 
A life-threatening adverse event; 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions; or 
• 
A congenital anomaly or birth defect. 
 
 
7.5 
Central Reporting of Adverse Events for Multicenter Studies 
N/A 
 
 
7.6 
Regulatory Reporting 
For this investigator-initiated study, the OHSU Principal Investigator is the study sponsor. The sponsor- 
investigator is required to report SAEs to the FDA through the MedWatch reporting program, even if the 
trial involves a commercially available agent. SAEs to be reported include any unexpected (not included in 


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the prescribing information). SAEs occurring during clinical studies will be reported to FDA as MedWatch 
form (specified in the investigational new drug/biologic regulations using the FDA 3500 Voluntary 
Reporting form, which is available for submission online at (and also available as a pdf): 
http://www.fda.gov/Safety/MedWatch/HowToReport/ucm085568.htm). 
Sponsor will report to FDA any identified and validated signal originated from the study and the final study 
report. 
 
7.7 
Sponsor or Additional Reporting Requirements. 
Sponsor (i.e. Principal Investigator) will send to Helsinn Corporate Drug Safety (drug- 
safety@helsinn.com) all the available information regarding any SAE (i.e. considered at least possibly 
related to NEPA), within 15 calendar days from when the Investigator first became aware of it in 
MedWatch format for events not considered life-threatening. Any possibly related SAE that is life-
threatening or results in subject death will be reported to Helsinn within 7 calendar days, in alignment 
with FDA guidelines for IND Safety Reporting. Sponsor is responsible for performing signal detection as 
required by US regulations (Safety Assessment for IND Safety Reporting- Guidance for the Industry) and 
will report to Helsinn Corporate Drug Safety any signals it might identify within 3 working days from 
identifying them. The notification will include a report explaining which is the evidence and reason that 
has led sponsor to identify a signal. 
Helsinn Corporate Drug Safety may ask additional information to Investigator or Sponsor regarding the 
received serious adverse event or safety signal to better assess it, but will not in any why try to influence 
Investigator’s or Sponsor’s causality assessment. 
Sponsor will send to Helsinn the final draft of the study report and or of any publication prior to submitting 
it to an Authority or to a publisher. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational or commercial agents 
administered in this study can be found in Section 7.1. 
 
8.1 
Agent Accountability 
The sponsor-investigator, or a responsible party designated by the sponsor-investigator, must maintain a 
careful record of the inventory and disposition of the study agent. Medication accountability for this study 
will be maintained by OHSU Research Pharmacy Services (See the NCI Investigator’s Handbook for 
Procedures for Drug Accountability and Storage  
(See http://ctep.cancer.gov/investigatorResources/investigators_handbook.htm). 
Responsibility for drug accountability at the study site rests with the sponsor-investigator; however, the 


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sponsor-investigator may assign some of the drug accountability duties to an appropriate pharmacist or 
designee. Inventory and accountability records must be maintained and readily available for inspection by 


Protocol Version 5.1: November 27, 2018 
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the study monitor and are open to inspection at any time by any applicable regulatory authorities. 
The sponsor-investigator or designee will be expected to collect and retain all used, unused, and partially 
used containers of study medication until the end of the study. The sponsor-investigator or designee must 
maintain records that document: 
• 
Investigational product delivery to the study site 
• 
The inventory at the site 
• 
Use by each subject including pill/unit counts from each supply dispensed 
• 
Return to the sponsor-investigator or designee 
 
These records should include dates, quantities, batch/serial numbers (if available), and the unique code 
numbers (if available) assigned to the investigational product and study subjects. The investigational 
product must be used only in accordance with the protocol. The Investigator will also maintain records 
adequately documenting that the subjects were provided the correct study medication specified. 
Completed accountability records will be archived by the site. At the completion of the study, the 
Investigator or designee will oversee shipment of any remaining study drug back to Helsinn for destruction 
according to institutional standard operating procedures. If local procedures mandate site destruction of 
investigational supply, prior written approval must be obtained from Helsinn or Helsinn’s study drug 
distributor. 
 
8.2 
Study Agent (Commercially available product) 
Availability: NEPA (Akynzeo®) is supplied to investigators by Helsinn. 
Product description: AKYNZEO® (300 mg netupitant/0.5 mg palonosetron) is an oral fixed combination 
product of netupitant, a substance P/neurokinin 1 (NK1) receptor antagonist, and palonosetron 
hydrochloride, a serotonin-3 (5HT3) receptor antagonist. Both netupitant and palonosetron hydrochloride 
are anti-nausea and anti-emetic agents. 
Netupitant is chemically described: 2-[3,5-bis(trifluoromethyl)phenyl]-N, 2 dimethyl-N-[4- 
(2methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl] propanamide. The empirical formula is 
C30H32F6N4O, with a molecular weight of 578.61. Netupitant exists as a single isomer. Netupitant is white 
to off-white crystalline powder. It is freely soluble in toluene and acetone, soluble in isopropanol and 
ethanol, and very slightly soluble in water. 
Palonosetron hydrochloride is chemically described: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3- 
yl]2,3,3a,4,5,6-hexahydro-1-oxo-1H-benz[de]isoquinoline hydrochloride. The empirical formula is 
C19H24N2O.HCl, with a molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer. 
Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, soluble 
in propylene glycol, and slightly soluble in ethanol and 2-propanol. 


Protocol Version 5.1: November 27, 2018 
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Each AKYNZEO® (300 mg netupitant/0.5 mg palonosetron) capsule is composed of one white-caramel 
hard gelatin capsule which contains three tablets each containing 100 mg netupitant and one gelatin capsule 
containing 0.56 mg palonosetron hydrochloride (equivalent to 0.50 mg palonosetron). The inactive 
ingredients are microcrystalline cellulose, sucrose fatty acid esters, povidone K-30, croscarmellose sodium, 
purified water, silicon dioxide, sodium stearyl fumarate, magnesium stearate, mono-and di-glycerides of 
capryl/capric acid, glycerin, polyglyceryl oleate, butylated hydroxyanisole (BHA), gelatin, sorbitol, 
titanium dioxide, yellow iron oxide, and red iron oxide. It may contain traces of medium-chain triglycerides, 
lecithin, and denatured ethanol. 
AKYNZEO® (300 mg netupitant/0.5 mg palonosetron) capsules: hard gelatin capsules with white body and 
caramel cap with “HE1” printed on the body. They are supplied as follows: 
 NDC # 62856-796-01: pack of one capsule in one blister 
 NDC # 62856-796-04: pack of four capsules (two capsules per blister strip). 
Solution preparation: Not applicable 
Storage requirements: Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted from 15 °C to 30 °C 
(59 °F to 86 °F). 
Route of administration: Oral administration. 
 
 
 
9.0        BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
None planned 
 
 
 
10.0 
STUDY PROCEDURES AND SCHEDULE OF EVENTS 
10.1 
Screening/Baseline Visit 
Investigator will obtain written informed consent from the patient prior to any study-driven tests or 
procedures. However, any tests or procedures done as part of standard care and within window per 
protocol may be used. All procedures must be performed prior to the first day of conditioning therapy. 
Screening will occur within thirty days of enrollment. This time frame is needed to facilitate pre-study 
screening of potential subjects, who may come from all areas of the state. Investigator will ensure that 
subject satisfies all inclusion and exclusion criteria prior to enrollment. 
 
10.2 
Study Treatment Visits 
Each subject will be followed for a maximum of 20 days (+/-72 hours). The schedule of events in section 
10.5 indicates mandatory data collected at each time point for the trial, but it is expected that additional 
tests/procedures or visits may occurs as standard of care, which is entirely at the discretion of the 


Protocol Version 5.1: November 27, 2018 
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investigator. Most subjects 


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will have laboratory studies and clinical evaluations outside of this schedule as part of their standard care. 
 
 
10.3 
End of Study/Early Termination 
End of study will be at Study Day 20 (equivalent to HSCT Day +13).This assessment must be performed 
within ±72 hours. The End of study evaluation will be completed at either the end of study or at early 
termination. In the event that therapy is stopped for a life-threatening allergy, or some other unreasonable 
toxicity, then patients will be followed for one month or until the resolution of the toxicity. If the toxicity 
is expected to continue the patient will be followed until the stabilization of that toxicity. 
 
10.4 
Study Assessments and Procedures 
Demographics and Medical History: Demographic data and a complete medical history will be collected 
during the screening periodto starting study treatment. Medical history in between visits should be 
documented at each study visit once study treatment has started. All transfusions including date, product 
transfused, number of units, and reason for transfusion should also be collected as part of the interval 
medical history. 
Concomitant Medications: All concomitant medications and treatments must be recorded in the electronic 
case report form (eCRF). Any prior medication received up to 15 days prior to the Baseline visit will be 
recorded in the eCRF. Concomitant treatments that are required to manage a subject’s medical condition 
during the study will also be recorded in the eCRF. Prior and/ or ongoing medications will be reviewed 
during screening to determine subject eligibility. The medication record will be maintained following 
enrollment including any changes to the dose or regimen. Prior and concomitant medication including any 
prescription, over the counter or natural/herbal/multivitamin preparations taken will be recorded. 
Physical Exam: Physical exams must be performed by a medically qualified individual such as a licensed 
physician, Physician’s Assistant or advanced Registered Nurse Practitioner as local law permits. The 
physical exam at baseline should be performed per institutional standards and standard care physical 
exams done prior to patient consent may be used. All other physical exams will include an evaluation of 
any AEs or any previously reported symptoms or prior physical examination findings. 
Performance Status: ECOG or Karnofsky Performance Score will be determined and performed at 
screening as indicated in the schedule of events in section 10.5. Refer to Appendix A for ECOG scale and 
Karnofsky Performance Score conversion. 
Weight: Must be collected prior to treatment with NEPA and as indicated in section 10.5 Schedule of 
events 
Vital Signs: Resting vital sign measurements must be performed ±24 hours of target days noted in the 
schedule of events. Vital sign measurements must include: blood pressure, pulse, respiration rate and 
temperature. 


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Complete Blood Count: Local hematology will be collected per institutional standards and must include 


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at minimum a white cell count, differential, hemoglobin, hematocrit, and platelet count. Note: it is 
allowable to use labs from prior day for care of these patients, as daily labs are often performed 
immediately prior to midnight.  
Chemistry: Local chemistry will be collected per institutional standards and must include at minimum the 
following: sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, glucose, calcium, alanine 
transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, albumin, total bilirubin. Note: it 
is allowable to use labs from prior day for care of these patients, s daily labs are often performed 
immediately prior to midnight.  
Pregnancy Test: A urine pregnancy test is required for all female subjects during screening for women of 
childbearing potential. If the urine pregnancy test is positive, serum pregnancy tests must be performed per 
institutional standards. 
Adverse Event assessments: Toxicities and adverse experiences will be assessed at each visit using the 
NCI Common Toxicity Criteria for Adverse Events 4.03 (CTCAE). Adverse event collection will begin 
when subject takes their first dose of study drug and continues until the subject completes the End of Study 
visit or until one month following toxicity on trial, whichever comes later 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
All AEs at CTCAE grade 3 or 4 and All AEs related to gastrointestinal symptoms of any CTCAE 
grade for AEs should be recorded in the eCRF. 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this general guideline: 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated; 
• 
Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental ADL; 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL; 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated; 
• 
Grade 5 Death related to AE. 
Adverse events are collected and summarized after the completion of each patient’s study period. As noted 
previously, SAEs are assessed immediately and reported within 24 hours. Non-SAE adverse events will be 
closely evaluated after the initial 13 patients, and the results will be included in the determination of study 
continuation. If not previously reported product-related, treatment-emergent, adverse events are prominent 
in this patient group, the clinical trial medical personnel (MDs) will determine if they are sufficient to 
require study cessation in the event that study efficacy end points are being met, which would otherwise 
allow study progression to the full patient complement. If such events are present and the decision is made 


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to proceed, additional information will be provided to the CRRC and IRB for their examination and review. 
 
CINV Questionnaire: Nausea will be assessed daily using the patient self-reported CINV Questionnaire; 
Appendix C) beginning on Day 1 and continuing through Day 11 (HSCT Day 


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+4). 
 
 
10.5 
Schedule of Events 
 
Visit 
Screening 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
11 
End of Study/ 
Early Term 
Day 
-30 
1 
2 
3 
4 
5 
6 
7 
HSCT 8 
9 
10 
 
11 
20 
Countdown to HSCT 
-6 
-5 
-4 
-3 
-2 
-1 
0 
HSCT 
+1 
+2 
+3 
+4 
+13 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
 
X------------------------------------------------------------------------ 
--X 
X 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
NEPA 
(Study 
Agent) 
Administration1 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Dexamethasone 
Administration2 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
HSCT Conditioning3 
X 
X 
X 
X 
X 
X 
Carmustine 
X 
 
 
 
 
Etoposide 
 
X 
X 
X 
X 
Cytarabine 
 
X 
X 
X 
X 
Melphalan 
 
 
 
 
 
X 
Adverse event evaluation 
X --------------------------------------------------------------------------------------X 
CINV Questionnaire 
X4 
X4 
X ------------------------------------------------------------- X 
X 
β-hCG (female pts only) X 
 
1300mg/0.5mg 
212mg on Day -6, 8mg on Days -5, -4, -3, -2, and -1 
3HSCT Conditioning: Carmustine (300mg/m2), Etoposide (200 mg/m2), Cytarabine (400 mg/m2), Melphalan (140 mg/m2) 
4The baseline CINV Questionnaire can be administered at either Screening or Visit 1 


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11.0 
MEASUREMENT OF EFFECT 
Nausea will be assessed daily using the patient self-reported CINV Questionnaire (Appendix C) 
beginning on admission and continuing through Study Day 11. Emetic episodes will be noted by 
the patient’s nurse and recorded on the daily medical record. They will be verified for number 
each designated visit day with the patient. Either retching (visceral contraction without the 
expulsion of stomach contents) or emesis (visceral contraction with the expulsion of stomach 
contents) will be considered an emetic episode for study purposes. The actual time of first emesis 
from the start of conditioning therapy will be noted. 
 
The percentage of each meal eaten and days of parenteral nutrition during the study period will be 
monitored for each patient. Meals are ad libitum and percentage is based on each patient’s desired 
meal. Patients will record their own number and percentage of meals eaten in the CINV 
Questionnaire (Appendix C). 
 
11.1 Definitions (assessed via a daily CINV Questionnaire) 
11.1.1 No Nausea = no nausea and < 1 on the 0-10 numerical scale. 
11.1.2 Mild Nausea = reported nausea and 1-3 on the 0-10 numerical scale. 
11.1.3 Moderate Nausea = reported nausea and 4-6 on the 0-10 numerical scale. 
11.1.4 Severe nausea = reported nausea and 7-10 on the 0-10 numerical scale. 
 
11.2 Response Definitions: 
11.2.1 Complete Response (CR): The complete absence of emesis, mild to moderate nausea, and 
no rescue therapy in subjects who have received all 6 days of chemotherapy and 4 days of 
observation. Patients who do not complete days 1-6 will not be included in calculation of 
CR. Any use of rescue medications in any subject without emesis and minor to moderate 
nausea will reclassify the patient from CR to MR. 
11.2.2 Complete Protection (CP): CR plus no nausea 
11.2.3 Major Response (MR): One or two episodes of emesis on only one day with any level of 
nausea or no emesis with severe nausea 
11.2.4 Minor Response (mR): One to two episodes of emesis on > 1 day but less than 3 days 
with any level of nausea. 
11.2.5 Partial Response (PR): Emesis with 2 or fewer episodes of emesis on any one day of the 
conditioning regimen or fewer than 2 emetic episodes on > 3 days of the conditioning 
regimen. 
11.2.6 Treatment Failure (TF): More than 2 episodes of emesis on any one day of the conditioning 


Protocol Version 5.1: November 27, 2018 
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regimen or 2 emetic episodes on > 3 days of the conditioning regimen. Note: Emesis 
occurring within 2 hours of infusing DMSO containing stem cells will not be considered 
an antiemetic failure. 
 
12.0 
DATA REPORTING/REGULATORY REQUIREMENTS 
 
12.1 Data Collection and Storage 
Study outcome data will be captured in electronic case report forms (eCRFs) using an 
electronic data capture (EDC) system stored and maintained on OHSU secure servers, 
which facilitates information being stored in a unified format and location. To further 
preserve confidentiality, PHI in the EDC system will be limited to just birth date and visit 
dates. The web-accessible EDC system is password protected and encrypted with role-
based security, and administered by designated informatics staff within OHSU or Knight 
Cancer Institute. All users of the database are assigned a unique ID, username, and 
password and must complete training appropriate to their role before they are authorized 
to enter, access, and store data in the database. 
 
Basic accrual tracking information (demographic, consent, visit information) will be 
captured in OHSU’s electronic clinical information research system (eCRIS), hosted on 
OHSU secure servers and managed by OHSU’s information technology group at their 
data center in downtown Portland, Oregon. Any additional printed documents containing 
participant identifiers, such as those from the medical record to confirm eligibility, will 
be filed in binders and kept in a locked, secure location. 
 
Quality assurance will be conducted as outlined in section 12.8 under data safety and 
monitoring. 
 
12.2 
Privacy, Confidentiality, and Data Security (required) 
Original data collection sheets will be maintained as noted above. Only research staff will 
have access to the patient database for data entry and subsequent data analysis. All 
computers have locking workstations including the most recent versions of the PGP 
desktop which prevents access by unauthorized staff. No data will be saved to a flash drive. 
All data will be de-identified once data collection is complete and no identifiable patient 
information will be used for subsequent publications or presentations 
 


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12.3 
Protocol Review 
The protocol and informed consent form for this study must be reviewed and approved in 
writing by the OHSU Knight Cancer Institute (CI) Clinical Research Review Committee 
(CRRC) and the appropriate Institutional Review Board (IRB) prior to any subject being 
consented on this study. 
 
12.4 
Informed Consent 
Written informed consent will be obtained from all subjects or the legally authorized 
representative of the subject participating in this trial, as stated in the Informed Consent 
section of the Case of Federal Regulations, Title 21, Part 50. If a subject’s signature cannot 
be obtained, and for all subjects under the age of 18, the investigator must ensure that the 
informed consent is signed by the subject’s legally authorized representative. If a patient 
is not primary English-speaking, a translator and witness will be present and the subject 
may sign OHSU’s respective primary language consent short form after the full consent 
has been translated.  
 
A documented telephone consent may be obtained in cases where a subject may be 
unavailable for onsite consent due to subject resources or distance from site and where 
primary investigator considers telephone consent appropriate. Subject will undergo 
identity verification by full name and date of birth and confirmation they will need to 
sign consent form at their next site visit. Patient will not undergo any study-driven labs or 
procedures outside standard of care prior to signing physical consent form.  
 
For both onsite and telephone initial consent, the consent process will be documented. At 
the time of onsite consent, subject will receive a copy of their signed consent form, a 
copy of the signed consent will be maintained in the subject’s medical record, and the 
original signed consent form will be maintained in the subject study binder. 
 
12.5 
Changes to Protocol 
Any modification of this protocol must be documented in the form of a protocol revision 
or amendment signed by the principal investigator and approved by the CRRC and IRB, 
before the revision or amendment may be implemented. The only circumstance in which 
the amendment may be initiated without regulatory approval is for a change necessary to 
eliminate an apparent and immediate hazard to the subject.  In that event, the investigator 


Protocol Version 5.1: November 27, 2018 
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must notify the CRRC and IRB in writing within 10 working days after the implementation. 
Investigators holding the IND must notify FDA of substantive changes to the protocol. 
 
12.6 
Maintenance of Records 
If the investigator relocates or for any reason withdraws from the study, the study records 
must be transferred to an agreed upon designee, such as another institution, another 
investigator, or to OHSU Knight Cancer Institute Clinical Trials Office. Records must be 
maintained according to sponsor or FDA requirements. 
12.7 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
12.8 
OHSU Knight Cancer Institute Data and Safety Monitoring Plan 
In addition to complete study and pharmacy files, complete records must be maintained on 
each subject treated on this protocol. OHSU Knight Cancer Institute, through the auditing 
function of the Knight Clinical Trials Office, is responsible for ensuring that all member 
investigators and affiliate investigators conduct clinical research studies in compliance 
with local IRB standards, FDA regulations and NIH policies and in accordance with the 
Data and Safety Monitoring Plan policies and procedures here. 
 
Locally initiated studies will be audited by OHSU Knight CI Auditor. Newly approved 
studies may be audited any time after enrollment has been initiated. Each OHSU Knight 
approved treatment protocol will be audited on an annual basis in accordance with the 
Knight Data and Safety Monitoring Plan. 
 
12.9 
Inclusion of Women, Minorities and Children 
12.9.1 Inclusion of Women and Minorities 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or 
ethnic subset. No subject will be excluded from the study on the basis of gender, racial or 
ethnic origin. Male, female and minority volunteers will be recruited for this study from 
the general population and approximately 50% men and 50% women will be studied. 
The projected gender, racial, and ethnic composition of the study will represent that of the 
state of Oregon 
Table 1: Population Demographics - Oregon (%) 
 


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Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
11.7 
Not Hispanic or Latino 
88.3 
Ethnic Category: Total of all subjects* 
100* 
Racial Category 
American Indian or Alaskan Native 
1.4 
Asian 
3.7 
Black or African American 
1.8 
Native Hawaiian or other Pacific Islander 
0.3 
White 
83.6 
More than one race 
3.8 


Protocol Version 5.1: November 27, 2018 
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Unknown/Other 
5.3 
Racial Category: Total of all subjects* 
100* 
TOTALS 
50.4 
49.6 
100* 
Source: Adapted from U.S. Census Bureau, 2010 *Totals may not equal 100 due to rounding 
 
 
Table 2: Projected Accrual for the Present Study 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
2-3 
2-3 
5 
Not Hispanic or Latino 
19 
19 
38 
Unknown 
0-1 
0-1 
Ethnic Category: Total of all subjects* 
21-22 
21-22 
43* 
Racial Category 
American Indian or Alaskan Native 
0-1 
0-1 
0-1 
Asian 
0-1 
0-1 
1-2 
Black or African American 
0-1 
0-1 
0-1 
Native Hawaiian or other Pacific Islander 
0-1 
0-1 
0-1 
White 
18 
18 
36 
More than one race 
0-1 
0-1 
1-2 
Unknown 
0-1 
0-1 
1-2 
Racial Category: Total of all subjects* 
18-24 
18-24 
43* 
Source: Adapted from U.S. Census Bureau, 2010 
*Totals may not equal 43 due to rounding 
 
12.9.2 
Inclusion of Children 
In accordance with NIH guidelines on the inclusion of children as participants in research 
involving human subjects, children under the age of 18 years must be included in all human 
subjects’ research, conducted or supported by the NIH, unless there are clear and compelling 
reasons not to include them. Therefore, proposals for research involving human subjects must 
include a description of plans for the inclusion of children. 
This protocol does not include children for the following reason: 1. The number of children 
with this type of cancer is limited. 2. Additionally, no dosing or adverse event data are 
currently available on the use of this study agent in this way in subjects <18 years of age, 
therefore, children are excluded from this study but will be eligible for future pediatric 
trials with this study agent. 
13. STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
This is a Phase II clinical trial designed according to Simon’s two-stage optimum design. 
The initial stage will enroll 13 subjects. If 3 or fewer subjects obtain a complete response 


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(defined as no emesis or rescue therapy during 0-264 hours), the trial will be stopped due 
to futility. If 4 or more subjects show a complete response, an additional 30 patients will 
be enrolled for a total planned enrollment of 43 subjects. This design has 80% power and 
one-sided 5% significance level to detect a complete response rate of 20% (historical 
rate) vs. 40% (desired rate). 


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13.2 
Primary and Secondary Endpoints 
A primary endpoint is Complete Response (CR) defined as no emesis and no rescue 
therapy for hours 0-264, 6 days of chemotherapy and 5 days post chemotherapy. 
 
A secondary endpoint is CR for hours 0-144 (Acute phase), CR for hours 145-264 
(delayed phase), and Complete Protection (CP) rate defined as CR plus no nausea for 
hours 0-144, 145-264, and the whole period. 
 
13.3 
Analysis Populations 
An intent to treat (IIT) analysis set consists of all patients consented and enrolled regardless 
of the receipt of the study drug or completion of CINV assessments. The IIT analysis set 
is used to report the trial accrual. A safety analysis set consists of IIT patients who receive 
at least one dose of the study drug. The safety analysis set is used for safety evaluation. An 
efficacy analysis set consists of any patient who completes 4 or more days of this trial (i.e., 
receives 2 doses of NEPA), and the efficacy analysis set is used for the assessment of 
efficacy. 
13.4 
Statistical Analysis Plan 
13.4.1 Analysis of Primary Endpoint 
We will provide an estimate of CR and 95% confidence interval. Where appropriate, data 
visualization techniques will be used to graphically present the CR and CP rates over time. 
13.4.2 Analysis of Secondary Endpoints 
The proportion of patients with CR and CP for each time period will be provided along 
with 95% confidence interval. As exploratory analyses, the number of emetic episodes and 
rescue agents taken per patient for 264 hours from start of therapy and as well as the number 
occurring in 0-24 hours and 0-144 hours (acute phase) vs. those which occur between 145- 
264 hours (delayed phase) from chemotherapy administration will be reported 
descriptively. Mean levels of nausea per day and median time to worse level of nausea via 
the CINV Questionnaire will be computed and reported descriptively. Time to first emesis 
and time to first rescue will be depicted via Kaplan-Meier curves showing the percentage 
of patients who had no emesis or rescue medication use for the acute and delayed time 
periods. Ability to take in oral nutrition and fluids and changes over the 5 day period will 
be calculated via reports from the CINV Questionnaire and reported descriptively. 
13.4.3 Interim Analyses and Stopping Rules 
The trial will enroll 13 patients in Stage I. If the number of patients with CR is 3 or fewer, 
the trial will be closed due to futility (i.e., CR rate is unlikely to be 40%, the desired CR 


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rate). Otherwise, the trial will continue until a total of 43 patients are enrolled. NEPA is 
considered promising and worth further investigation if there are 13 or more CRs among 
43 patients (i.e., CR rate significantly better than the standard of care). 
Safety and tolerability will be assessed via review of adverse events (AEs), vital signs, and 
laboratory values. Incidence of Grade 3 or higher NEPA related toxicity will be estimated 
along with 95% confidence interval for each major organ system defined in NCI CTCAE 
v4.03. 
13.5 
Sample Size and Power 
The complete planned study set is of 43 total patients. As above, 13 initial patients in Stage 
I will identify utility vs futility of this study, with a plan to proceed to the full 43 patient 
population (additional 30 subjects) if CR is 4 or more in Stage I. With a historical CR rate 
of 20% with standard of care compared with the desired NEPA response rate of 40% with 
5% significance level and 80% power, 43 total subjects would adequately power this study. 


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13.6 
Randomization Method 
N/A; non-randomized 
 
13.7 
Handling of Missing Data 
If a patient is unavailable for prompt evaluation we would accept an evaluation within a 24 
hour period due to medical necessity or patient inability to complete the CINV 
Questionnaire form. Days missed will be reported and evaluated separately at the end of 
the study. If a patient is unable to complete the form due to illness, we will attempt to 
support form completion with minimal assistance from study personnel or caregivers (e.g. 
verbal instructions to circle their selection). For any patient who is unable to complete the 
CINV Questionnaire on the first 6 days of chemotherapy, those patients will be censored 
and replaced with another study subject for complete enrollment, as those days are 
considered vital for efficacy assessment. For patients who are unable to complete the form 
on days 7-10, study results will be noted separately in the final manuscript but will not be 
censored from the trial. Patients who complete 7 but fewer than 10 days of the CINV 
Questionnaire for any reason will be assessed in a secondary analysis. However if these 
occur in stage I the PI will assess the reason for non-completion and determine whether 
they are considered non-responders (e.g. too nauseated to fill out the form) vs. unable to 
complete the form for medical, scheduling, or other reasons outside of study controls. The 
latter patients would be replaced to support the stage I analysis, as it is crucial to ongoing 
study procedures but would not be replaced in stage II. 


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REFERENCES 
 
1. Gralla, R. J. et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose 
combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and 
vomiting over repeated cycles of chemotherapy. Ann. Oncol. 25, 1333–1339 (2014). 
2. Aapro, M. et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed- 
dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea 
and vomiting following moderately emetogenic chemotherapy. Ann. Oncol. 25, 1328–1333 (2014). 
3. Diemunsch, D. P. & Grélot, L. Potential of Substance P Antagonists as Antiemetics. Drugs 60, 533– 
546 (2000). 
4. Janelsins, M. C. et al. Current pharmacotherapy for chemotherapy-induced nausea and vomiting in 
cancer patients. Expert Opin. Pharmacother. 14, 757–766 (2013). 
5. Hesketh, P. J. et al. Differential involvement of neurotransmitters through the time course of 
cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur. J. Cancer 39, 
1074–1080 (2003). 
6. Thomas, A. G., Stathis, M., Rojas, C. & Slusher, B. S. Netupitant and palonosetron trigger NK1 
receptor internalization in NG108-15 cells. Exp. Brain Res. 232, 2637–2644 (2014). 
7. Sommariva, S., Pongiglione, B. & Tarricone, R. Impact of chemotherapy-induced nausea and 
vomiting on health-related quality of life and resource utilization: A systematic review. Crit. Rev. 
Oncol. Hematol. doi:10.1016/j.critrevonc.2015.12.001 
8. Abbott, B. et al. Granisetron (Kytril) plus dexamethasone for antiemetic control in bone marrow 
transplant patients receiving highly emetogenic chemotherapy with or without total body irradiation. 
Publ. Online 19 June 2000 Doi101038sjbmt1702424 25, (2000). 
9. Ballen, K. Prospective evaluation of antiemetic outcome following high-dose chemotherapy with 
hematopoietic stem cell support. Publ. Online 10 Dec. 2001 Doi101038sjbmt1703280 28, (2001). 
10. Deauna-Limayo, D. et al. Combined use of multiday palonosetron with aprepitant and low-dose 
dexamethasone in prevention of nausea and emesis among patients with multiple myeloma and 
lymphoma undergoing autologous hematopoietic stem cell transplant: A pilot study. J. Oncol. Pharm. 
Pract. 20, 263–269 (2014). 
11. Eisai, Inc. Akynzeo Prescribing Information. (2015). Available at: 
https://www.akynzeo.com/media/Prescribing_Information.pdf. (Accessed: 9th January 2016) 
12. Natale, J. J. et al. Drug–drug interaction profile of components of a fixed combination of netupitant 
and palonosetron: Review of clinical data. J. Oncol. Pharm. Pract. 1078155215586824 (2015). 
doi:10.1177/1078155215586824 
13. Hesketh, P. J. et al. Efficacy and safety of NEPA, an oral combination of netupitant and 
palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly 


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emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann. Oncol. 25, 1340–1346 
(2014). 
14. Stathis, M., Pietra, C., Rojas, C. & Slusher, B. S. Inhibition of substance P-mediated responses in 
NG108-15 cells by netupitant and palonosetron exhibit synergistic effects. Eur. J. Pharmacol. 689, 
25–30 (2012). 
15. Einhorn, L. H. et al. Palonosetron plus dexamethasone for prevention of chemotherapy-induced 
nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. 
Support. Care Cancer 15, 1293–1300 (2007). 
. 


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APPENDIX A 
Karnofsky Status  
Karnofsky 
Grade  
ECOG 
Grade  
ECOG Status  
Normal, no complaints  
100  
0  
Fully active, able to carry on all pre-disease 
performance without restriction  
Able to carry on normal 
activities. Minor signs or 
symptoms of disease  
90  
1  
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, 
office work  
Normal activity with effort  
80  
1  
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, 
office work  
Care for self. Unable to carry 
on normal activity or to do 
active work  
70  
2  
Ambulatory and capable of all selfcare but 
unable to carry out any work activities. Up and 
about more than 50% of waking hours  
Requires occasional 
assistance, but able to care for 
most of his needs  
60  
2  
Ambulatory and capable of all selfcare but 
unable to carry out any work activities. Up and 
about more than 50% of waking hours  
Requires considerable 
assistance and frequent 
medical care  
50  
3  
Capable of only limited selfcare, confined to 
bed or chair more than 50% of waking hours  
Disabled. Requires special 
care and assistance  
40  
3  
Capable of only limited selfcare, confined to 
bed or chair more than 50% of waking hours  
Severly disabled. 
Hospitalisation indicated 
though death nonimminent  
30  
4  
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair  
Very sick. Hospitalisation 
necessary. Active supportive 
20  
4  
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair  


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Karnofsky Status  
Karnofsky 
Grade  
ECOG 
Grade  
ECOG Status  
treatment necessary  
Moribund  
10  
4  
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair  
Dead  
0  
5  
Dead  
As published in Am. J Clin. Oncol.:  
Oken MM, Creech RH, Tormey DC et. al. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
 


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Appendix B: NEPA Prescribing Information 
https://www.akynzeo.com/media/Prescribing_Information.pdf 


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APPENDIX C: CINV Questionnaire 
CINV Questionnaire 
 
Study ID:   
 
  
 
Date:   
/  
/  
 
VISIT 
□Screening/V
1 
□V2 (-5) 
□V3 (-4) 
□V4 (-3) 
□V5 (-2) 
□V6 (-1) 
□V7 
(HSCT) 
□V8 (+1) 
□V9 (+2) 
□V10 (+3) □V11 (+4)   
 
 
Please answer all of the questions. There are no right or wrong answers. We will ask you to complete 
this form every day for the first 10 days of treatment. 
 
The following terms are used in the questionnaire:  
 
Vomiting: the bringing up of stomach contents  
 
Nausea: the feeling that you might vomit 
 
1. How much difficulty did you have falling asleep last? 
Please circle the number that best answers the question. 
 
0 = no difficulty 
10 = didn’t fall asleep 
 
Please write the number that you circled 
     ________________ 
 
2. How many meals do you eat on a typical day? 
  
 
 
 
3. In the past 24 hours, how many meals did you eat? 
  
 
 
 
4. Of the meals you ate, what percent of the total food did you eat? 
Please circle the number that best answers the question. 
 
0 = none 
100 = all of my food 
 
              Please write the number that you circled.           ________________ 
 
5. If you vomited in the past 24 hours, how many times did it happen? 
  
 
 
6. In the past 24 hours, did you have any nausea? 
Yes 
No 


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7. If you had any nausea, how much nausea did you have in the last 24 hours? 
Please circle the number that best answers the question. 
 
 
 
                                        0 = none                               10 = as much as possible 
 
              Please write the number that you circled.              ________________ 


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APPENDIX D: Eligibility & Registration Checklists 
 
 
 
ELIGIBILITY CHECKLIST #1 
 
SUBJECT INFORMATION 
Subject #: 
Initials: 
 
 
 
 
Preparer’s Signature:                                                               Date: 
 
 
 
 
SUBJECT INFORMATION 
INCLUSION CRITERIA 
Each subject must meet all of the following inclusion criteria to be enrolled: 
# 
CRITERIA 
YES 
NO 
COMMENTS/VALUES 
1 
Subject is undergoing autologous or allogeneic 
Hematopoietic Cell Transplant (HSCT) with the BEAM 
conditioning regimen prior to HSCT 
 
 
 
2 
Age ≥ 18 years 
 
 
3 
ECOG performance status ≤ 2 or Karnofsky 
Performance Score >60% 
 
 
4 
Able to swallow oral medications 
 
 
5 
Ability to understand and the willingness to sign a 
written informed consent document  
 
 
39
SUBJECT REGISTRATION & ELIGIBILITY 
STUDY ID: 16288 
PI: JOSEPH BUBALO 
SUBJECT REGISTRATION & ELIGIBILITY 
STUDY ID: 16288 
PI: JOSEPH BUBALO 


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Subject #: 
Initials: 
 
EXCLUSION CRITERIA 
Each subject must not meet any of the following exclusion criteria: 
# 
CRITERIA 
YES 
NO 
COMMENTS/VALUES 
1 
Subject has known hypersensitivity or other 
allergic reactions attributed to compounds of 
similar biologic composition to netupitant, 
palonosetron, dexamethasone, or other agents used 
in the study   
 
 
 
2 
Subject is receiving any other investigational 
agents or has received another investigational 
drug in the last 30 days 
 
 
 
4 
Female who is pregnant, has a positive serum 
hCG, or is lactating and intends to breast feed a 
child. Pregnant women are excluded from this 
study.  
 
 
 
 
 N/A – Male 
 
5 
HIV-positive on combination antiretroviral therapy  
 
 
7 
Subject has a serum creatinine > 2 x ULN 
 
 
 
8 
Subject has severe renal failure or end stage renal 
disease (estimated GFR of <30 mL/min using the 
Cockcroft-Gault formula) 
 
 
 
9 
Subject has severe hepatic insufficiency (Child 
Pugh score > 9) 
 
 
 
10 
Subject has been drinking > 5 alcoholic drinks 
daily for the last year 
 
 
 
11 
Subject has concurrent illness requiring systemic 
corticosteroid use other than the planned 
dexamethasone during conditioning therapy 
 
 
 
12 
Subject has gastrointestinal condition which might 
result in malabsorption of the study drug  
 
 
 
13 
Subject has a history of anxiety-induced 
(“anticipatory”) nausea and vomiting 
 
 
 
15 
Subjects unable to discontinue 
benzodiazepines as antiemetics will not be 
allowed. Additional antiemetics will be 
allowed for rescue but not for prophylaxis. 
 
 
 


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16 
Subject has a personal or family history of QT 
prolongation, uncorrected electrolyte 
abnormalities, congestive heart failure, 
bradyarrhythmia, conduction disturbances or is 
taking anti-arrhythmic medicinal products or other 
medicinal products that lead to QT prolongation or 
electrolyte abnormalities.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preparer’s Signature:                                                               Date: 
 
 
REGISTRATION 
 
SUBJECT REGISTRATION & ELIGIBILITY 
STUDY ID: 16288 
PI: JOSEPH BUBALO 


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(Source documentation must accompany Eligibility checklist, completed Registration and Demographics 
forms in order to confirm eligibility) 
 
Date Consent Signed 
 
Subject Meets Eligibility 
Inclusion/Exclusion 
 Yes        
 No 
Eligibility Determination 
Date Screening/Baseline Assessment Collection: _____/_____/______ 
 
Done 
Not Done 
Comments 
• 
Comment if “not done” selected 
• 
Enter date if different from 
Screening/Baseline 
Medical History 
 
 
 
Concomitant Medications 
 
 
 
Physical Exam 
 
 
 
ECOG or Karnosky Performance 
Score  
 
 
 
Weight 
 
 
 
Vital Signs 
 
 
 
Pregnancy Test  
 
 
 
Complete Blood Count (CBC) 
 
 
 
Chemistry Panel (CMP) 
 
 
 
 
 
 
 
 
 
Preparer’s Signature:                                                               Date: 
 
 
 
 
Demographics 
42
SUBJECT REGISTRATION & ELIGIBILITY 
STUDY ID: 16288 
PI: JOSEPH BUBALO 


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Date of Birth 
___ 
Age at time of study 
entry  
_____ 
Sex 
 Female            
 Male 
Race (Check One) 
 American Indian or Alaska Native 
 Asian 
 Black or African American 
 Caucasian or White 
 More than one race 
 Native Hawaiian or Other Pacific Islander 
 Other Specify________________ 
Ethnicity 
 Hispanic or Latino 
 Non-Hispanic 
 
 
Subject entered into OHSU Clinical Research 
Information System? 
 Yes    
 No     
 
 
 
INVESTIGATOR NAME 
 
INVESTIGATOR SIGNATURE  
 
DATE  
 
 
 
 
Preparer’s Signature:                                                               Date: 
 
 
 
 
SUBJECT REGISTRATION & ELIGIBILITY 
STUDY ID: 16288 
PI: JOSEPH BUBALO 


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ELIGIBILITY SUMMARY #1 
 ELIGIBLE 
 
 INELIGIBLE; subject is a screen fail 
 
 INELIGIBLE; waiver granted. Criteria and rationale: ________________________________________ 
________________________________________________________________________________________________
________________________________________________________________________________________________
________ 
 
 
SPONSOR-INVESTIGATOR NAME 
Joseph Bubalo 
SPONSOR-INVESTIGATOR SIGNATURE  
 
DATE  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preparer’s Signature:                                                               Date: 
 
 
ELIGIBILITY CHECKLIST #2 
SUBJECT INFORMATION 
Subject #:  
Initials:  
 
SUBJECT REGISTRATION & ELIGIBILITY 
STUDY ID: 16288 
PI: JOSEPH BUBALO 


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EXCLUSION CRITERIA 
Each subject must not meet any of the following exclusion criteria: 
# 
CRITERIA 
YES 
NO 
COMMENTS/VALUES 
3 
Subject has had emesis or required anti-emetics in the 48 
hours prior to starting the BEAM conditioning regimen. 
Also, patient required to take antipsychotics, appetite 
stimulants, or other medications with anti-emetic effects 
will be excluded if those medications cannot be replaced 
by therapeutic equivalents   
 
 
 
6 
Subject has taken a neurokinin antagonist within 14 
days prior to beginning BEAM regimen  
 
 
 
14 
Subject is on strong CYP3A4 inducers or inhibitors and 
is unable to have those agents replaced with clinical 
alternatives prior to the beginning of the study. Length 
of washout period will be 7 days. In the case of 
allogeneic transplant recipients requiring cyclosporine 
or tacrolimus, no empiric dose adjustments will be 
required due to close level monitoring and adjustments, 
which are standard OHSU protocols. 
 
 
 
 
 
 
 
 
 
 
Preparer’s Signature:                                                               Date: 


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INVESTIGATOR NAME 
 
INVESTIGATOR SIGNATURE  
 
DATE  
 
 
 
ELIGIBILITY SUMMARY #2 
 ELIGIBLE 
 
 INELIGIBLE; subject is a screen fail 
 
 INELIGIBLE; waiver granted. Criteria and rationale: ________________________________________ 
________________________________________________________________________________________________
________________________________________________________________________________________________
________ 
 
 
 
SPONSOR-INVESTIGATOR NAME 
Joseph Bubalo 
SPONSOR-INVESTIGATOR SIGNATURE  
 
DATE  
 
 
 
 
 
 
 
 
 
 
 
 
 
Preparer’s Signature:                                                               Date: 
 
SUBJECT REGISTRATION & ELIGIBILITY 
STUDY ID: 16288 
PI: JOSEPH BUBALO