A Randomized Open Label Phase II Trial of Aprepitant (Emend) in Combination With Ondansetron Compared to Standard 5HT3 Serotonin Antagonist (Ondansetron) in the Prevention of Acute and Delayed Chemotherapy Induced Nausea and Vomiting (CINV) in Glioma Patients Receiving a Temozolomide Based Regimen
Phase: PHASE2
Conditions: Nausea, Vomiting, Glioma
Sponsor: Katy Peters

Protocol No.: 11.0 
 
CONFIDENTIAL 
 
 
Protocol Date: 10/20/14 
 
 
Clinical Protocol 
 
A Randomized Open Label Phase II Trial of Aprepitant (Emend) in 
Combination with Ondansetron Compared to Standard 5HT3 
Serotonin Antagonist (Ondansetron) in the Prevention of Acute and 
Delayed Chemotherapy Induced Nausea and Vomiting (CINV) in 
Glioma Patients receiving a Temozolomide Based Regimen  
 
 
 
 
PRINCIPAL INVESTIGATOR:  Mary Lou Affronti, DNP, RN, MSN, ANP, MHSc 
 
 
 
CO-PRINCIPAL INVESTIGATOR and IND SPONSOR:  Katherine B. Peters, MD, 
PhD 
 
 
 
STUDY COORDINATOR:  Sarah Woodring CRC 
 
 
 
 
 
 
 
 
VERSION NO. 11.0 
 
 
 
 
 
STUDY DRUG: APREPITANT 
 
 
SUPPORT PROVIDED BY:  MERCK 
 
 
 
 
 
 
 
DATE OF PROTOCOL: 
10/20/14  
 
 
 

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Table of Contents 
1 
INTRODUCTION .................................................................................................. 4 
 
Chemotherapy-Induced Nausea and Vomiting (CINV) .......................................... 4 
 
Aprepitant ................................................................................................................ 4 
1.2.1 Chemical properties of aprepitant ........................................................................... 4 
1.2.2 Aprepitant mechanism of action ............................................................................. 5 
1.2.3 Aprepitant in chemotherapy induced nausea and vomiting .................................... 5 
2 
BACKGROUND AND RATIONALE: .................................................................. 6 
3 
STUDY OBJECTIVES ........................................................................................... 9 
 
Primary Objective ................................................................................................... 9 
 
Secondary Objectives .............................................................................................. 9 
 
Exploratory Objectives.......................................................................................... 10 
 
Efficacy ................................................................................................................. 10 
4 
INVESTIGATIONAL PLAN ............................................................................... 11 
 
Summary of Study Design and Treatment Regimen............................................. 11 
 
Aprepitant/Ondansetron: ....................................................................................... 11 
 
Ondansetron: ......................................................................................................... 12 
 
Pharmacokinetic Sampling.................................................................................... 12 
 
Chemotherapy treatment plan ............................................................................... 12 
 
Study Location ...................................................................................................... 13 
 
Study Population ................................................................................................... 13 
 
Criteria for enrollment........................................................................................... 13 
4.8.1 Inclusion criteria.................................................................................................... 13 
4.8.2 Exclusion criteria .................................................................................................. 14 
 
Study Procedures and Study Flow Chart .............................................................. 14 
4.9.1 Screening/baseline procedures, study day -14 to study day 1. .............................. 15 
4.9.2 Administrative plan and daily procedures............................................................. 15 
4.9.3 Subject withdrawal ................................................................................................ 16 
5 
STUDY MEDICATION ....................................................................................... 16 
 
Aprepitant .............................................................................................................. 16 
5.1.1 Description ............................................................................................................ 16 
5.1.2 Source .................................................................................................................... 16 
5.1.3 Dosage and Administration ................................................................................... 16 
5.1.4 Packaging .............................................................................................................. 16 
5.1.5 Labeling ................................................................................................................ 17 
5.1.6 Storage and Handling ............................................................................................ 17 
5.1.7 Disposal ................................................................................................................. 17 
5.1.8 Drug Ordering ....................................................................................................... 17 
 
Ondansetron .......................................................................................................... 17 
5.2.1 Description ............................................................................................................ 17 
5.2.2 Source .................................................................................................................... 17 
5.2.3 Dosage and Administration ................................................................................... 17 
5.2.4 Drug Ordering ....................................................................................................... 17 
6 
DEFINITION of Adverse Event ........................................................................... 17 
 
Adverse Event (AE) .............................................................................................. 17 

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7 
INSTITUTIONAL REPORTING REQUIREMENTS ......................................... 20 
 
Safety Reporting of Adverse Events and Serious Adverse 
Events 20 
 
Reporting of Serious Treatment Emergent Adverse Events ................................. 21 
8 
STATISTICAL METHODS ................................................................................. 23 
 
Overview and Sample Size Justification ............................................................... 23 
 
Analytic Methods .................................................................................................. 24 
 
Toxicity Monitoring .............................................................................................. 24 
9 
STUDY MANAGEMENT: DATA SAFETY AND 
MONITORING PLAN ......................................................................................... 24 
 
Audits and Inspections .......................................................................................... 24 
 
Study Monitoring Requirements ........................................................................... 25 
 
Monitoring ............................................................................................................ 25 
 
Audits .................................................................................................................... 26 
 
Data Collection ..................................................................................................... 26 
10 
REFERENCES ...................................................................................................... 28 
11 
APPENDICES ...................................................................................................... 34 
 
CINV Patient Survey (MAT/Osoba) ..................................................................... 34 
 
Cytochrome P450 Drug Interaction Table ............................................................ 34 
 
PK Sample Collection/Processing and Plasma Storage for 
Temozolomide and AIC Metabolite Analysis................................................................... 34 
 
Stupp Regimen (2005) .......................................................................................... 34 
 
NCI CTC Toxicity Grading (Version 4.0) ............................................................ 35 
 
The Preston Robert Tisch Brain Tumor Center Clinical 
Research Team Standard Operating Procedure for Randomization of 
Aprepitant (Emend) Study ................................................................................................ 35 
 
 
 

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1 INTRODUCTION 
 Chemotherapy-Induced Nausea and Vomiting (CINV) 
While the incidence of CINV has been significantly reduced since the advent of 
dexamethasone and first generation selective serotonin subtype 3 (5HT3) receptor antagonists 
(RA), nausea and emesis continue to rank among the most distressing side effects of 
chemotherapy and are reported in up to 50% and 76% of chemotherapy-treated patients 
respectively. CINV can be classified into phases which include; 1) acute CINV (A-CINV), 
occurring within the 24 hours post treatment; 2) delayed (D-CINV), occurring after 24 hours 
and up to 120 hours or 2 days after a multi-dose regimen. Although all first generation 5HT3 -
RA demonstrate efficacy in preventing A-CINV, effective prevention of D-CINV has not 
been achieved. Even with strict adherence to ASCO/NCCN antiemetic evidence based 
guidelines, D-CINV occurs in 50% of patients. While physicians and nurses are fairly 
accurate in predicting A-CINV, they dramatically underestimate rates of D-CINV. Poorly 
controlled CINV can also lead to numerous medical conditions such has dehydration, 
electrolyte imbalance, and Mallory-Weiss tears resulting in re-hospitalization (increased 
medical costs), reduced efficacy and impairment of psychological, social, emotional as well as 
physical well-being; all which may affect QOL. Thus, challenges remain in the prevention of 
CINV, which include assessing the efficacy substance P/neurokinin 1(NK1) receptor 
antagonist. 
 
 Aprepitant  
There are three selective first generation 5-HT3-RA (serotonin-3) available for the prevention 
of acute CINV including ondansetron, dolasetron, and granisetron. Although these agents 
have some pharmacological differences in 5-HT3 receptor binding affinity, selectivity and 
metabolism, these minor variations have not resulted in clinically meaningful differences in 
efficacy among them. According to current evidence-based and NCCN guidelines, these 5-
HT3–RA are equivalent with regard to efficacy and are therapeutically interchangeable when 
used at equipotent doses. All first-generation 5-HT3-RA demonstrate considerable efficacy in 
preventing acute CINV with acute response rates as single agents ranging from 50% to 70%.  
 
Emend (Aprepitant) is a substance P/neurokinin 1(NK1) receptor antagonist. It has little or no 
affinity for 5-HT3, corticosteroid or dopamine receptor, the targets of existing antiemetic 
therapies for CINV, but has selective high affinity of human substance P neurokinin 1 (NK1). 
It is usually given as a one-time dose of 125 mg pre-chemotherapy followed by a 2 day 80 mg 
regimen to control CINV. Aprepitant undergoes extensive liver metabolism that primarily 
involves the CYP3A4 gene with minor involvement of the CYP1A2 and CYP2C19 genes. 
Enzyme inducing anticonvulsant drugs (EIAED) and other chemotherapy agents such as 
temozolomide may be affected by the use of this antiemetic agent.   
 
1.2.1 Chemical properties of aprepitant 
Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist and is the first and only 
member of this new therapeutic class of antiemetic medications. 
 
Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) 
receptors.  Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and 

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corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea 
and vomiting and postoperative nausea and vomiting. 
 
Aprepitant has been show in animal models to inhibit emesis induced by cytotoxic 
chemotherapeutic agents, such as cisplatin, via central actions.  Animal and human Positron 
Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood 
brain barrier and occupies brain NK1 receptors.  Animal and human studies show that 
aprepitant augments the antiemetic activity of the 5-HT3 receptor antagonist, ondansetron, and 
the corticosteroid, dexamethasone, and inhibits both the acute and delayed phases of cisplatin-
induced emesis. 
 
A computerized search of the published medical literature identified references that described 
the pharmacology and mechanism of action of aprepitant.  These references are summarized 
below. 
 
1.2.2 Aprepitant mechanism of action 
Aprepitant has a novel antiemetic mechanism of action as a brain penetrant, competitive 
reversible and selective high-affinity antagonist at human substance P/NK1 receptors.  
Preclinical studies involving PET imaging of the healthy human brain have demonstrated that 
substance P/NK1 receptors are located centrally in the brain stem. Substance P has been 
shown in animals to cross the blood-brain barrier Tattersall and colleagues demonstrated that 
central nervous system penetration of an NK1 receptor antagonist was required for antiemetic 
activity.  The NK1 receptor antagonists are required to penetrate and enter into the CNS to 
exert their antiemetic effect at the centrally located NK1 receptors.  Tattersall and colleagues 
also demonstrated that a nonbrain penetrant NK1 receptor antagonist was ineffective. 
 
1.2.3 Aprepitant in chemotherapy induced nausea and vomiting 
Cisplatin is one of the most emetogenic cancer chemotherapeutic agents administered in 
clinical practice.  The vomiting induced by cisplatin follows a biphasic pattern.  During the 
first phase, the peak frequency of vomiting occurs in 6 to 8 hours post-chemotherapy and 
diminishes in approximately 12 hours.  During the second phase, vomiting begins at 
approximately 16 hours post-chemotherapy and peaks between 24 and 72 hours. 
 
Hesketh P.J. et al. (2003) conducted a post hoc analysis of the two Phase IIa CINV clinical 
studies of aprepitant, to compare the time course of the anti-emetic effect of the NK1 receptor 
antagonist, aprepitant, a 5HT3 antagonist or the combination of both drugs.  It is important to 
note that the dose and the dosing regimen in the Phase IIa CINV clinical studies were not the 
final aprepitant regimen that was used in the Phase III CINV clinical studies.  In the first 
study, over the entire period of 7 days post-cisplatin therapy, 31% of patients treated with 
aprepitant had no emetic episodes compared to 21.7% of patients treated with ondansetron.  
However, in the first 8 hours post-cisplatin treatment, 82.6% of patients treated with 
ondansetron had no emesis compared to 36.7% of patients treated with aprepitant.  No emesis 
rates in the ondansetron group declined to 69.6% and 52.2% in the 0 to 16 hour and 0 to 24 
hour periods post-cisplatin, respectively, whereas the no-emesis rate for aprepitant group 
remained unchanged during the 8 to 24 hour period.  In the second study, 36% of patients in 

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the aprepitant treatment group had no emesis compared to 23% of patients in the granisetron 
treatment group over the 0 to 120 hour period post-cisplatin treatment.  Dexamethasone was 
administered to patients in this study.  In the 0 to 8 hour period, 92.2% of patients in the 
granisetron treatment group had no emesis compared to 49.4 in the aprepitant treatment 
group.  During the 0 to 16 hour and the 0 to 24 hour period, the percent of patients with no 
emetic episodes continued to decline to 81.1% and 56.7% respectively, in the granisetron 
treatment group, whereas the percent of patients with no emetic episodes remain unchanged in 
the aprepitant treatment group.  When aprepitant was combined with granisetron, only 20% of 
the patients experienced emesis during the first 24 hours. 
 
The analysis of the studies for the time course of anti-emetic effect concluded that 5HT3 
receptor antagonists have a better control of emesis during the 8 to 12 hours post-cisplatin in 
the pathogenesis of CINV associated with highly emetogenic chemotherapy since the 
serotonin-dependent mechanism appears to be predominate, whereas NK1 receptor 
antagonists have better emetic control thereafter, as NK1-dependant mechanism appears to 
predominate. 
 
In the two highly emetogenic CINV Phase III studies (Study 1 and Study 2), the estimated 
time to first emesis after initiation of cisplatin treatment was longer with the aprepitant 
regimen, and the incidence of first emesis was reduced in the aprepitant regimen group 
(aprepitant 125 MG on Day 1 and 80 mg on Days 2 and 3, ondansetron 32 mg IV on Day 1 
and dexamethasone 12 mg PO on Day 1 and 8 mg PO on Days 2 to 4) compared with 
standard therapy group (ondansetron 32 mg intravenously and dexamethasone 20 mg orally 
on Day 1 and dexamethasone 8 mg twice daily on Days 2-4) as depicted in the Kaplan-Meyer 
curve.  The curves in both Study 1 and Study 2 appear to be similar up to approximately 16 
hours after the administration if cisplatin, but the curves then diverge after that time as the 
statistical significance with the aprepitant regimen becomes evident.  (P-Value <0.001 based 
on a log rank test for Study 1 AND Study 2; nominal p-values not adjusted for multiplicity.)   
 
In a moderately emetogenic chemotherapy study, the time to first emesis after the initiation of 
moderately emetogenic chemotherapy was longer for patients in the aprepitant regimen 
compared with a standard therapy regimen (ondansetron 8 mg BID on Days 1 through 3 and 
dexamethasone 20 mg on Day 1 only), as depicted in the Kaplan-Meier curve.  The aprepitant 
regimen showed superiority versus the standard therapy regimen at approximately 6 hours, 
and the gap between the two regimens continued to diverge and widen over the 120 hour (5-
day) period. 
2 BACKGROUND AND RATIONALE:  
Primary glioblastoma multiforme (GBM) is the most lethal type of brain tumor with a median 
survival rate of approximately 15 months. Unfortunately, the median survival rate for GBM 
patients has not significantly changed despite over 25 years of research involving a variety of 
agents and delivery systems. In a recently published population-based study the overall 
survival of patients with newly diagnosed GBM was 42.6% at 6 months, 17.7% at one year 
and 3.3% at 2 years. The outlook is somewhat better for less common tumors, such as 
anaplastic astrocytoma with a 38-50% 2 year survival rate. Despite decades of intensive 

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investigation, the prognosis for most patients with malignant gliomas remains very poor 
primarily due to the high resistant to current available therapy. The role of adjuvant 
chemotherapy in glioma treatment has been controversial. A meta-analysis of 12 randomized 
trials comparing additional adjuvant chemotherapy to radiation demonstrated only a 5 percent 
increase (from 15 to 20%) in two-year survival rate. Occasional responses (15%) to single or 
multiple agent chemotherapy are observed in the setting of recurrent tumor, but these 
responses are generally of short duration, and cures are rare. Thus, the general consensus in 
2002 was that the use of chemotherapy following surgery and radiotherapy produced a 
marginal benefit over that seen with surgery and radiotherapy alone.  However, in 2005, 
Stupp et al. reported the results of a multi-institutional phase III EORTC trial in which 
patients with primary glioblastoma multiforme were randomized after surgery to receive 
either radiation alone or radiation with concurrent temozolomide followed by six cycles of 
adjuvant temozolomide. The two-year survival was significantly higher (26.4%) for patients 
receiving radiation and adjuvant temozolomide than for patients receiving radiation therapy 
alone (10.4%). Recently, Stupp reported an updated overall survival of  27.2% (95% CI 22.2-
32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-
14.0) at 5 years with single agent temozolomide. When compared to the 12 trial meta-analysis 
conducted by Stewart et al mean increased survival time is improved but remains poor. To 
date, standard therapy for glioma patients currently consists of surgical resection followed by 
temozolomide and concurrent radiotherapy followed by at least 6 cycles of adjuvant 
temozolomide. One limitation in the use of this effective regimen in adjuvant temozolomide is 
its high level of chemotherapy induced nausea and vomiting (CINV) which occurs at a rate of 
56%. Thus, it is important to ameliorate toxicities, such as chemotherapy induced nausea and 
vomiting (CINV) to prevent dose reductions and early termination that lead to poorer overall 
tumor response rates and decreased quality of life.  
 
Glioma CINV: Currently, we use the standard of care first generation antiemetic, oral 
ondansetron 8 mg p.o. with each oral temozolomide dose. Several phase II studies have been 
conducted within the Duke Brain Tumor Center that has examined the CINV in the treatment 
of patients with malignant glioma.  In these studies patients were treated with ondansetron and 
dexamethasone with intravenous chemotherapy with the hope of preventing CINV.  These 
phase II studies demonstrated that 55% of patients experienced CINV (45% CR: patients did 
not experience CINV) as defined by the NCI (National Cancer Institute) Common Toxicity 
Criteria (CTC) version 3.0. These studies measured CINV frequency and did not utilize the 
standard and acceptable efficacy CR endpoint used in multiple phase III pivotal CINV trials 
(Aapro 2006; Gralla 2003). Thus a pilot and feasibility study to determine the use of 
"Ondansetron and Palonosetron (PALO) in the prevention of acute and delayed CINV in forty 
malignant glioma patients receiving irinotecan in combination with bevacizumab" utilizing 
the standard efficacy CR endpoint was conducted. The pilot study assessed this primary 
dichotomous outcome defined as the proportion of patients achieving a complete response 
(CR) for individual days 1-5 after receiving chemotherapy. A patient was deemed a CR if (1) 
no emesis or retching was reported on that day; and/or (2) no rescue medication for nausea or 
vomiting/retching was used on that day. Overall we concluded that 65% of PALO patients 
had CR versus 60% of ondansetron patients. However, these data did not provide evidence 
that a difference in CR rate existed between the two treatment groups. Due to the small 

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sample size, there was inadequate power to conclude that the two treatments had equivalent 
efficacy. Furthermore, a higher proportion of patients in the ondansetron group who received 
concomitant oral dexamethasone, a known antiemetic, which could have contributed to the 
overall ondansetron CR rate. It has been demonstrated that adding dexamethasone to an 
antiemetic regimen improves overall acute efficacy and prevention of CINV by 20%. Thus, 
dexamethasone is routinely admixed with 5HT3-RA and administered prior to chemotherapy 
to enhance efficacy. However, most patients in the pivotal PALO phase III randomized 
controlled, non-inferiority trials did not receive standard of care intravenous (i.v) 
dexamethasone. The seminal paper published by in the New England Journal of Medicine 
established the Stupp regimen as the gold standard therapy for glioblastoma patients. This 
trial documented a 20% CINV rate for adjuvant temozolomide (Stupp, 2005, Supplemental 
table 1) using 5HT3 RAs as the antiemetic of choice. This CINV rate translates into an 80% 
CR rate. Oral chemotherapy does not require decadron as a standard antiemetic. We believe 
that the CINV CR rate of 80% can be improved with adding the substance P/neurokinin 
1(NK1) receptor antagonist Aprepitant. Thus, it was recommended that a larger Phase II trial 
be conducted to determine if improved efficacy exists between Aprepitant in combination 
with Ondansetron vs. ondansetron alone(standard of care) in glioma patients receiving 
temozolomide.  
 
CINV risk factors: Characteristics of both the patient and chemotherapeutic agent contribute 
to the risk of developing CINV. Overall, patients who are under 50 years of age, female and 
who receive prior treatment with chemotherapy are at increased risk. Chemotherapy in glioma 
can range in emetogenicity, with moderately and high emetogenic agents causing CINV in > 
30% and >90%, respectively, of patients treated. The gold standard Stupp regimen (see 
Appendix 11.4) has documented a 20% CINV rate for adjuvant temozolomide (Stupp, 2005). 
This fact places temozolomide in the moderate emetic risk category due to the brain 
pathology (intracranial edema). It has also been noted that aprepitant may alleviate delayed 
CINV but may interact with EIAEDS (enzyme- inducing anti-epileptic drugs) causing 
unacceptable toxicity.  
 
EIAED Interactions:  Alterations in the activity of cytochrome P450 enzymes can affect the 
clearance of chemotherapeutic drugs. Aprepitant, a moderate inhibitor and inducer of 
cytochrome P450 3A4, is now increasingly used for the prevention of chemotherapy induced 
nausea and vomiting. However, there is little published data on the potential interaction 
between enzyme inducing antiepileptic drugs (EIAED) and aprepitant. Thus, in this proposed 
(study we would like to exclude patients receiving EIAED’s due to its unknown interaction 
with Aprepitant).  
 
Safety of Administration:  Three recently published articles describe the administration of 
aprepitant beyond the currently approved 3 days.   Albany et al. (2012) performed a 
randomized, placebo-controlled Phase 3 study of aprepitant in combination with a 5HT3 
receptor antagonist and dexamethasone in patients with testicular cancer that were on a 5-day 
cisplatin combination chemotherapy treatment.  In this study, patients receiving 2 consecutive 
identical courses of 5-day cisplatin-based chemotherapy were randomly assigned to either 
aprepitant at 125 mg on Day 3 and 80 mg on Days 4-7 or to placebo in their first course of 

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treatment.  They then crossed over to the opposite treatment with their second course. The 
study found significant improvement in complete response of both acute and delayed CINV 
with aprepitant, which they defined as “no emetic episodes with no use of rescue medication,” 
in comparison to placebo.  The study also found no increase in observed toxicity in 
comparison to placebo. 
 
Stiff et al. (2012) performed a randomized, placebo-controlled Phase 3 study of aprepitant in 
combination with ondansetron and dexamethasone in “patients treated with ablative 
preparative regimens,” i.e. patients preparing for stem cell transplant.  Patients were 
randomized to receive either 1) dexamethasone and ondansetron every day of the preparative 
regimen plus 1 additional day combined with aprepitant 125 mg on Day 1 of the preparative 
regimen followed by 80 mg on each remaining day of the regimen plus 3 additional days or 2) 
dexamethasone and ondansetron on every day of the preparative regimen plus 1 additional 
day and a placebo for aprepitant.  The study found that patients who received aprepitant had 
significantly higher rates of complete response, i.e. better control of vomiting, compared to 
the regimen with placebo. Aprepitant was well tolerated in the study, with only heartburn and 
asthenia occurring more frequently in the aprepitant arm than the placebo arm. 
 
Lastly, Gralla (2012) offers a review of the Albany et al. (2012) study.  Gralla concludes that 
the Albany et al. trial “provides evidence for a new approach for controlling emesis in 
multiple-day chemotherapy and highlights many unmet needs in the complete control of 
emesis for all patients on each cycle of chemotherapy.” 
 
In our trial, we are comparing the use of aprepitant in combination with ondansetron with 
standard administration of ondansetron alone during the first 5 days of every 28-day cycle of 
oral temozolomide for patients with malignant glioma (125mg on Day 1 followed by 80 mg 
on Days 2 -5).   
3 STUDY OBJECTIVES 
 Primary Objective  
To assess CINV efficacy of Aprepitant in combination with Ondansetron vs. Ondansetron 
alone in preventing acute and delayed CINV (Complete Control (CC): days 1-7) in brain 
tumor patients during adjuvant temozolomide therapy. 
 
 Secondary Objectives  
To assess the efficacy of Aprepitant in combination with Ondansetron  vs. Ondansetron alone 
in preventing acute CINV in brain tumor patients during the acute period (first 24 hours) of 
receiving adjuvant temozolomide therapy. 
 
To assess the efficacy of Aprepitant in combination with Ondansetron vs. Ondansetron alone 
in preventing delayed CINV (days 2-7). 
 
To assess the safety and tolerability of Aprepitant administered concomitantly with 
Ondansetron. 

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 Exploratory Objectives 
To assess the time to treatment failure of Ondansetron treatment with and without Aprepitant. 
 
To explore the effects of age, gender, chemotherapy history, and concomitant glucocorticoid 
on the efficacy of Ondansetron treatment with and without Aprepitant. 
 
To explore the impact of Aprepitant on quality of life and daily function.  
 
 Efficacy 
 
Primary CINV Efficacy Endpoint: Primary efficacy endpoint is the proportion of patients 
achieving an acute and delayed complete response (CR: proportion of patients with no emetic 
episode and no rescue medication). 
 
Complete control (CC): Study days 1–7 (acute and delayed CINV) the proportion of patients 
achieving complete control (CC); defined as no emetic episode, no need for rescue medication 
during days 1-7; number of emetic episodes daily; time to first emetic episode; as captured by 
the MAT (MASCC Antiemesis Tool)/Osoba survey (MASCC refers to Multinational 
Association for Supportive Care in Cancer™). Severity of nausea and other toxicities 
measured daily by the NCI Common Toxicity Criteria (version 4.0) (see Appendix 11.5). This 
tool is used in previous Duke University Medical Center Studies to evaluate toxicity and 
patient perceptions of cancer treatment-related side effects. 
 
Secondary endpoints of the study include: 
 
Complete response (CR): (1) Assessed from the beginning of study day 1, CR is defined for 
acute CINV as no emetic episode and no use of rescue anti-nausea medication during the first 
24 h following chemotherapy administration. An emetic episode is defined as one episode of 
vomiting or a sequence of episodes in very close succession not relieved by a period of 
relaxation of at least 1 min, any number of unproductive emetic episodes (retches) in any 
given 5 min period, or an episode of retching lasting <5 min combined with vomiting not 
relieved by a period of relaxation of at least 1 min; (2) Complete response (CR) on study days 
2–7 (delayed CINV) is defined as the proportion of patients achieving a CR during the 
delayed time period. The data will be captured by the validated MAT/Osoba survey. 
 
Operational definitions of other secondary outcome are as follows: (a) CINV CR:  Absence of 
nausea/vomiting defined as no emetic episode or use of rescue medication; (b) CIV 
CR:  Absence of vomiting episode or the use of vomit medication; (c) CIN CR: Absence of 
the use of medication to help nausea, or due to concern about the possibility of experiencing 
nausea.    
 
Time to treatment failure (first emetic episode or first need of rescue medication, whichever 
occurred first): as measured by the MAT/Osoba survey which indicates time of first emetic 
episode or rescue medication. 

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Quality of life (QOL): patient's global satisfaction with the antiemetic regimen as measured 
by the Osoba survey.  This survey will be administered at baseline and for day 1 (acute 
period) and for days 2-7 (delayed period) to determine overall global satisfaction (Acute and 
delayed combined to determine overall CC, days 1-7).  
4 INVESTIGATIONAL PLAN  
 Summary of Study Design and Treatment Regimen  
One hundred and thirty-six (136) malignant glioma patients receiving temozolomide will be 
accrued in this open labeled phase II randomized single institution trial of Aprepitant in 
combination with Ondansetron vs. Ondansetron alone for the prevention of acute and delayed 
CINV.  Sixty-eight (68) patients will be randomized to each arm of the study. 
 
OPEN LABEL PHASE II RANDOMIZED 
STUDY DESIGN SCHEMA
CINV Efficacy (N=136)
Temozolomide at 150 
mg/m2 or 200mg/m2 po
daily; 
Day 1-5
NO EIAEDs
N=136
APREPITANT ONDANSETRON REGIMEN
Day 1:      Aprepitant:125 mg po X1 
Ondansetron 8 mg po X1
Day 2-5:   Aprepitant 80 mg daily X 4
Ondansetron 8 mg po X 4               
N= 68
ONDANSETRON REGIMEN
Day 1-5:   Ondansetron  8mg po daily 
X5
N= 68
R*
 
* R= randomization 
 
 Aprepitant/Ondansetron: 
On day 1, eligible patients will receive a single oral dose of Aprepitant 125 mg p.o, 1 hour 
before first dose of the 5-day oral temozolomide regimen. This will be followed by Aprepitant 
80 mg p.o. on days 2 -5 (1 hour prior to temozolomide). In addition, on days 1-5, eligible 
patients will receive a single oral dose of Ondansetron, 30 minutes before the first dose of the 
5–day oral temozolomide regimen.  After the start of chemotherapy, additional rescue anti-
emetic medication will be at the investigator’s discretion.   
 

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 Ondansetron: 
On days 1-5, eligible patients will receive a single oral dose of Ondansetron, 30 minutes 
before first dose of the 5–day oral temozolomide regimen. After the start of chemotherapy, 
additional rescue anti-emetic medication will be at the investigator’s discretion.  
 
Patients will be initially screened for eligibility within 14 days prior to study initiation. 
During this time period, the following will be recorded: physical examination; vital signs and 
weight; laboratory tests [complete blood count (CBC) with differential, complete metabolic 
panel (CMP)]: past medical history; concomitant medications; and history of nausea and 
vomiting.  All women of child bearing potential will have pregnancy excluded as standard of 
care prior to initiation of temozolomide. CINV will be assessed at baseline and for Days 1-7. 
Follow-up telephone assessment will occur for day 1 and days 2-7, day 15, and 30 (for serious 
toxicity only) after beginning the study drug(s).  All subjects will be followed for a total of 30 
days. Patient surveys will be collected to record the following: emetic episodes; use of rescue 
medication; patient global satisfaction; and severity of nausea, which will be evaluated daily 
until day 7 via the CINV Patient Survey (MAT/Osoba) (see Section 11.1).  
 
Toxicity will be assessed through adverse event (AE) reporting for a period of 15 days (30 
days for serious AEs). After the investigator learns of a serious adverse event (SAE), every 
attempt will be made to obtain vital sign measurements, laboratory tests at 24 h and 1 week 
(+/- 2 days) after the SAE (including hematology, blood chemistry, liver function tests and 
urine analysis), physical examination at 24 h and 1 week (+/- 2 days) after the SAE.  
 
 Pharmacokinetic Sampling 
Every attempt will be made to obtain pharmacokinetic (PK) sampling as soon as possible after 
the investigator learns of a serious adverse event (i.e. NCI CTC Version 4.0, grade 4 non-
hematologic toxicity that is probably or definitely related to aprepitant) in relationship to 
when the study drugs were administered, in order to measure drug (temozolomide and its 
metabolite, 5-aminoimidazole-4-carboximide (AIC)) concentrations.  A PK kit containing 
collection tubes with stabilizing agent will be sent to the appropriate laboratory drawing and 
processing the PK blood sample.  These samples will be collected and run at the 
pharmacokinetic lab at Duke University Medical Center (please see Appendix 11.3).  Results 
of the PK sampling would be reported to both the FDA and Merck via adverse event reporting 
(see section 7). Merck will support the set-up, collection and running of the assay. 
 
 Chemotherapy treatment plan  
Glioma patients eligible for the study will receive temozolomide orally according to the 
standard 5-day schedule every 28 days. The temozolomide will be dosed at either 150 mg or 
200 mg per square meter beginning with the first cycle. Patients will receive Aprepitant at 125 
mg p.o. on Day 1 and 80mg p.o. qd on days 2 -5 and Ondansetron 8 mg p.o. qd days 1-5 or 
Ondansetron only 8 mg p.o. qd days 1-5, depending upon the arm of the study to which they 
have been randomized. 

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Protocol Date: 10/20/14 
 
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 Study Location 
This study will be conducted at The Preston Robert Tisch Brain Tumor Center Clinic at Duke 
University Medical Center and at the local oncologist’s office. 
 
 Study Population 
It is expected that 136 patients with gliomas who attend the Preston Robert Tisch Brain 
Tumor Center Clinic at Duke University Medical Center will be enrolled onto this open- 
label, randomized, Phase II, 2-Arm Trial in a 12-month period. Approximately 170 patients 
will be screened for patient eligibility assuming 20% will either not be eligible or not agree to 
participate in the study. We plan to begin enrollment in the spring of 2013 and enrollment 
should be completed by summer of 2014.  
 
 Criteria for enrollment   
4.8.1 Inclusion criteria 
In order to be included in the study, patients must meet all of the following criteria: 
 
1. 
Patients must have histologically confirmed diagnosis of glioma (either low or high 
grade) and be either chemotherapy naïve or non-naïve and scheduled to receive 
temozolomide-based +/- Bevacizumab- based chemotherapy. Patients with recurrent 
disease whose diagnostic pathology confirmed glioma (either low or high grade) will 
not need re-biopsy. 
2. 
Age ≥ 18 years 
3. 
≤  2 prior chemotherapeutic regimens 
4. 
Patient is scheduled to receive adjuvant temozolomide at either 150mg/m2 or  
200mg/m2 po X 5 days out of a 28 day cycle +/- Bevacizumab  
5. 
Study participation will occur during the first cycle of the 5 day temozolomide course. 
6. 
An interval of at least 6 weeks between prior surgical resection and study enrollment 
7. 
Karnofsky ≥ 60%. 
8. 
Hematocrit > 29%, ANC > 1,000 cells/µl, platelets > 100,000 cells/µl 
9. 
Serum creatinine < 1.5 mg/dl, serum SGOT and bilirubin < 1.5 times upper limit of 
normal 
10. 
For patients on oral corticosteroids, they must be stable clinically on corticosteroids or 
tapered off prior to starting the study drug. For patients taking dexamethasone, the 
dose should not exceed 8 mg qd (or 4 mg BID), if clinically stable, and the dose 
should not be escalated over entry dose level, if clinically possible.  The patient’s dose 
of dexamethasone will be evaluated by the PI, the patient’s study physician, and/or the 
study pharmacist on a case by case basis for safety.  All doses of oral corticosteroids 
will be reduced by 50% to avoid drug to drug interactions with Aprepitant, unless oral 
corticosteroids are at physiologic dose (e.g. dexamethasone 1mg, prednisone 10 mg, or 
cortisone 30 mg). It is recommended that oral corticosteroid doses be escalated back to 
full dose on Day 7 (2 days after Aprepitant is discontinued) based on Aprepitant half-
life pharmacokinetic data, and expert clinical opinion.  

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11. 
Signed informed consent approved by the Institutional Review Board prior to patient 
entry 
12. 
If sexually active, patients will take contraceptive measures for the duration of 
protocol treatment and continue until one month after treatment.  The efficacy of 
hormonal contraceptives during and for 28 days following the last dose of Aprepitant 
may be reduced.  Alternative or back-up methods of contraception must be used. 
13. 
Approved rescue medication for the treatment of nausea and vomiting is permitted at 
the discretion of the investigator.  The rescue antiemetics allowed will include: 
ondansetron, granisetron and lorazepam.  
 
4.8.2 Exclusion criteria  
In order to be included in the study, patients must meet all of the following criteria: 
 
1. 
Pregnant or breast-feeding (While both aprepitant and ondansetron are classified as 
Category B drugs, an eligibility criteria for this study is that the patient be scheduled 
to receive a temozolomide-based chemotherapy regimen +/- bevacizumab, which are 
Category D and C drugs respectively.  Therefore, while not considered necessary for 
the administration of the current study drugs, a pregnancy test should be a part of 
normal clinical care for the patients in this study, if the patient is determined to be of 
child-bearing potential.)  
2. 
No prior nitrosourea (e.g. lomustine, carmustine) 
3. 
Inability or unwillingness to understand or cooperate with study procedures 
4. 
Concurrent administration of CYP3A4 enzyme-inducing anti-epileptic drugs 
(EIAEDs) including phenytoin, phenobarbitol, carbamazepine, oxcarbazepine or 
primidone (see Appendix 11.2).  
5. 
Prohibited medications:  
Patients taking CYP3A4 enzyme inducers and moderate or strong inhibitors will be 
excluded from this trial.  Please refer to the website listed in Appendix 11.2 of the full 
protocol for updates to this list of medications.  
6. 
Received any drug with potential anti-emetic effect within 24 hours prior to the start 
of study-designated chemotherapeutic agent: HT3 receptor or substance P/neurokinin 
1(NK1) receptor antagonists; Dopamine receptor antagonists (metoclopramide); 
Phenothiazine anti-emetics (prochlorperazine, thiethylperazine and perphenazine); 
Diphenhydramine, scopolamine, chlorpheniramine maleate, trimethobenzamide; 
Haloperidol, droperidol, tetrahydrocannabinol, or nabilone  
7. 
Any vomiting, retching or NCI Common Toxicity Criteria version 4.0 grade 2-4 
nausea 24 hours preceding chemotherapy 
8. 
Ongoing vomiting from any organic etiology 
9. 
Will receive radiotherapy of cranium within one week prior to or during the study 
 
  
  Study Procedures and Study Flow Chart 
 
DAY 
-14 
to 1 
1 
2 
3 
4 
5 
6 & 7 

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Protocol Date: 10/20/14 
 
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SCREENING 
X 
 
 
 
 
 
 
MAT Survey  
X 
X 
X 
X 
X 
X 
X 
Osoba Survey 
 
X 
X 
X 
X 
X 
X 
Toxicity 
Assessment a 
 
Continuous 
Arm               1 
Aprepitant in 
combination 
with 
Ondansetron 
 
 
 
 
125 mg 
PO 
 
 
8 mg PO 
 80 mg PO 
  
 
 
8 mg PO 
80 mg PO 
 
 
 
8 mg PO 
80 mg PO 
 
 
8 mg PO 
80 mg PO 
 
 
 
8 mg PO 
 
Arm 
2 
Ondansetron 
 
8 mg PO 
8 mg PO 
8 mg PO 
8 mg PO 
8 mg PO 
 
Temozolomide 
 
 
      X  
150mg/m2  
or 
200mg/m2 
PO 
     X  
150mg/m2  
or 
200mg/m2 
PO 
      X  
150mg/m2  
or 
200mg/m2 
PO 
         X  
150mg/m2  
or 
200mg/m2 
PO 
X  
150mg/m2  
or 
200mg/m2 
PO 
 
a If a serious adverse event occurs, toxicity will be assessed for 30 days. 
 
4.9.1 Screening/baseline procedures, study day -14 to study day 1. 
Screening procedures may be performed up to the day of chemotherapy just prior to 
administration of the oral Aprepitant or Ondansetron. 
 
The following procedures are to be completed before admission into the study: 
• Signing of the approved informed consent form prior to conducting study required 
procedures. 
• Determination that the patient meets all study inclusion/exclusion criteria.  
• Physical examination, including medical history and neurological examination 
• Vital signs 
• CBC 
• CMP 
• MAT survey 
• Randomization will be conducted after eligibility criteria are met. The randomization will 
be overseen by the statistical team designated in key personnel as noted in the BTC SOP 
(see Appendix 11.6).  
 
4.9.2 Administrative plan and daily procedures 
The study team will be collecting data from the tools listed below.Data will be housed in 
Oracle Clinical (OC).  Regular meetings between the study team and primary investigators 
will occur to review data.  The clinical research coordinator (CRC) is required to monitor 
protocol patients weekly or as many times necessary to obtain toxicities. Toxicities will be 
obtained via clinical notes or telephone conversations with the local oncology office and /or 
patient. The National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 4.0 
will be used to score the adverse advents.  All graded toxicities will be entered in the OC 

Protocol No.: 11.0 
 
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Protocol Date: 10/20/14 
 
Page 16 of 36 
 
database and reviewed together with the Primary Investigator (PI), the data management 
team, and CRC and confirmed by source documents. Attributions are approved by the primary 
investigators. 
 
4.9.2.1 Evaluation tools 
As stated in “Study design and treatment regimen” the evaluation tools   include the 
following: 
• 
NCI Common Toxicity Criteria (CTC) (version 4.0) (see Section 11.5) 
• 
MAT/Osoba CINV Patient Survey  (see Section 11.1) 
 
4.9.3 Subject withdrawal 
Patients may be discontinued from the study for any of the following reasons: 
• A serious adverse event or a significant change in laboratory value occurs that, in the 
opinion of the investigator, makes it unsafe for the patient to continue in the study.  In this 
case, the appropriate measures will be taken. 
• The patient dies. 
• The patient is lost to follow-up.  Lost to follow-up in this study identifies a patient with 
whom no contact of any kind can be established.  When a patient is thought to be lost to 
follow-up, a reasonable effort shall be made to contact the patient. 
• The patient requests to be withdrawn from the study.  
• The investigator, for any reason, terminates the entire study or terminates the study for 
that patient or the attending physician requests that the patient be withdrawn for any other 
medical reason. 
5 STUDY MEDICATION 
 Aprepitant 
5.1.1 Description   
Aprepitant is a substance P/neurokinin 1(NK1) receptor antagonist. 
 
5.1.2 Source 
Aprepitant is manufactured by Merck Inc. 
 
5.1.3 Dosage and Administration 
Subjects will receive a single oral dose of Aprepitant 125 mg p.o, 1 hour before their first 
dose of the 5-day oral temozolomide regimen. This will be followed by Aprepitant 80 mg 
p.o.q.d. on days 2 -5, 1 hour before their chemotherapy. 
 
5.1.4 Packaging 
No. 3854 — 80 mg capsules: White, opaque, hard gelatin capsule with “461” and “80 mg” 
printed radially in black ink on the body. They are supplied as follows: 
NDC 0006-0461-02 unit-of-use BiPack of 2 
 
NDC 0006-0461-06 unit-dose package of 6. 

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No. 3855 — 125 mg capsules: Opaque, hard gelatin capsule with  white body and pink cap 
with “462” and “125 mg” printed radially in black ink on the body. They are supplied as 
follows: 
 
NDC 0006-0462-06 unit-dose package of 6. 
 
5.1.5 Labeling 
EMEND (Aprepitant) Capsules 
 
5.1.6 Storage and Handling 
Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. 
 
5.1.7 Disposal 
Study drug allocated for the above referenced study, upon completion of the study or upon 
notice of the drug’s expiration, should be disposed of at the site, pursuant to the Good Clinical 
Practice (GCP) Guidelines and the Investigator’s Institutional policies. Therefore, unused 
study drug allocated for the study referenced above should not be returned to Merck.  
 
5.1.8 Drug Ordering 
Aprepitant will be provided free of charge by Merck Inc. 
 
 Ondansetron 
5.2.1 Description 
Ondansetron is a first generation 5-HT3-RA (serotonin-3). 
 
5.2.2 Source 
Ondansetron (Zofran) is commercially available and will not be provided in this study. 
 
5.2.3 Dosage and Administration 
Ondansetron will be administered on both arms of the protocol at 8 mg p.o. qd on Days 1- 5 
days, 30 minutes prior to each dose of chemotherapy. 
 
5.2.4 Drug Ordering 
Ondansetron is commercially available and will not be provided in this study.  A prescription 
for Ondansetron will be given to the patient on both arms of the study. 
6 DEFINITION of Adverse Event 
 Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product/biologic (at any dose) or device and which does not necessarily have 
to have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example) a symptom or 

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disease temporally associated with the use of a medicinal product whether or not considered 
related to the medicinal product: 
• occurring in the course of the use of a drug, biological product, or device, 
• associated with, or observed in conjunction with product overdose, whether accidental or 
intentional, 
• associated with, or observed in conjunction with product abuse, and/or 
• associated with, or observed in conjunction with product withdrawal. 
 
An adverse event is also any failure of expected pharmacological or biologic therapeutic 
action (with the exception of such failure occurring in a clinical trial). 
 
Serious - Any adverse drug, biologic or device experience occurring at any dose that results 
in any of the following outcomes:  death, a life threatening adverse drug experience, requires 
or prolongs in-patient hospitalization, a persistent or significant disability/incapacity or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
life threatening or require hospitalization may be considered a serious adverse experience 
when, based upon appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or a home, blood dyscrasias or convulsions that do 
not result in in-patient hospitalization, or the development of drug dependency or drug abuse. 
 
Non-serious - Any AE which does not meet the criteria for a serious adverse event. 
 
Life-threatening - the patient/subject was at immediate risk of death from the AE as it 
occurred. 
 
In addition, the Principal Investigator will have all reports of the following forwarded to 
him/her: 
 
• Pregnancy (patient or partner) – We acknowledge that these are not serious, unless a serious 
outcome occurs (e.g. miscarriage, congenital anomaly). 
• Overdose – we acknowledge that these are not serious, unless a serious outcome occurs. 
 
Attribution 
The Principal Investigator or his designee will document his/her opinion and any supporting 
laboratory and clinical information of the potential attribution of the study drug to any grade 3 
or greater toxicity based on the following guidelines:  
 
Unrelated 
This category applies to those toxicities that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc.) 
 
Unlikely (must have any two criteria) 

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In general, this category can be considered applicable to those toxicities that are judged to be 
unrelated to the test drug.  A toxicity may be considered unlikely if or when: 
 
1. It does not follow a reasonable temporal sequence from administration of the test drug; 
2. It could readily have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; 
3. It does not follow a known pattern of response to the test drug; 
4. It does not reappear or worsen when the drug is re-administered. 
 
Possible (must have any two criteria) 
This category applies to those toxicities for which a connection with the test drug 
administration appears unlikely but cannot be ruled out with certainty.  A toxicity may be 
considered possibly related if and when: 
 
1. It follows a reasonable temporal sequence from administration of the test drug; 
2. It could not readily have been produced by the subject’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the subject; 
3. It does follow a known pattern of response to the test drug. 
 
Probable (must have any two criteria) 
This category applies to those toxicities that are felt with a high degree of certainty to be 
related to the test drug.  A toxicity may be considered probably related if and when: 
 
1. It follows a reasonable temporal sequence from administration of the test drug; 
2. It could not reasonably be explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the 
subject; 
3. It disappears or decreases on cessation or reduction in dose.  There are important 
exceptions when a toxicity does not disappear upon discontinuation of the drug, yet drug-
relatedness clearly exists (e.g. bone marrow depression, fixed drug eruptions, tardive 
dyskinesia); 
4. It follows a known pattern of response to the test drug. 
 
Definite (must have all four criteria) 
This category applies to those toxicities that are felt to be incontrovertibly related to the test 
drug.  A toxicity may be considered definitely related if and when: 
 
1. It follows a reasonable temporal sequence from administration of the test drug; 
2. It could not reasonably be explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the 
subject; 
3. It disappears or decreases on cessation or reduction in dose with re-exposure to drug. 
(Note: this is not to be construed as requiring re-exposure of the subject; however, a 
category of definitely related can only be used when a recurrence is observed.) 
4. It follows a known pattern of response to the test drug. 

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7 INSTITUTIONAL REPORTING REQUIREMENTS 
 Safety Reporting of Adverse Events and Serious Adverse Events 
Adverse event reporting and definitions: 
The NCI CTC Version 4.0 will be used.  In the event of an adverse event the first concern will 
be for the safety of the subject.   
 
Only adverse events that the Duke Sponsor-Investigator determines to be serious, unexpected, 
and related or possibly (i.e., more likely than not) related to the research must be reported to 
the Duke IRB.  Those adverse events will be submitted in the electronic (eIRB) system, 
according the following guidelines: 
• Report within 24 hours of learning about any subject’s death that was 
unanticipated and more likely related to the research than unrelated; 
• Report within 5 business days of learning about any serious, 
unanticipated, and related or possibly/probably related adverse event; 
• Report within 10 business day of learning about any other unanticipated 
problem or event that was more likely related to the research than 
unrelated. 
 
The Sponsor-Investigator must report to the FDA, in an IND safety report, any suspected 
adverse reaction that is both serious and unexpected. Before submitting this report, the 
sponsor needs to ensure that the event meets all three of the definitions contained in the 
requirement:  
• Suspected adverse reaction (i.e. there is a reasonable possibility that the 
drug caused the adverse event) 
• Serious  
• Unexpected  
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
 
The Sponsor-Investigator is required to report to the FDA all IND Safety reports in writing 
within 15 days (7 days for unexpected fatal or life-threatening suspected adverse reaction).  
The FDA Form 3500A can be found on the FDA website, www.fda.gov.  All other adverse 
events will be reported to the FDA in the Annual Report. 
 
Investigators are required to report to The Merck Drug Safety ANY serious treatment 
emergent adverse event (STEAE) that is study related as soon as possible. 
   
A STEAE is any sign, symptom or medical condition that emerges during Aprepitant or 
Ondansetron treatment or during a post-treatment follow-up period that (1) was not present at 
the start of treatment and it is not a chronic condition that is part of the patient’s medical 
history, OR (2) was present at the start of treatment or as part of the patient’s medical history 

Protocol No.: 11.0 
 
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Protocol Date: 10/20/14 
 
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but worsened in severity and/or frequency during therapy, AND that meets any of the 
following regulatory serious criteria: 
• 
Results in death  
• 
Is life-threatening  
• 
Requires or prolongs inpatient hospitalization  
• 
Is disabling  
• 
Is a congenital anomaly/birth defect  
• 
Is medically significant or requires medical or surgical intervention to  prevent one of the 
outcomes listed above. 
 
 Reporting of Serious Treatment Emergent Adverse Events  
Information about all serious adverse events will be collected and recorded on the FDA 
Medwatch 3500A form.  To ensure patient safety each serious adverse event that is study 
related will also be reported to MERCK Drug Safety, preferably in writing by fax, within 24 
hours of discovery by the Principal Investigator and sent to: Merck (Attn: Worldwide Product 
Safety; FAX 215 993-1220) with copies of all serious adverse experiences, within two 
working days regardless of drug relationship.  Additionally, any pregnancy occurring in 
association with use of a Merck Product will be reported to Merck (Attn: Worldwide Product 
Safety; FAX 215 993-1220). 
 
A copy of all 15 Day Reports and Annual Progress Reports will be submitted as required by 
FDA, if applicable, or other local regulators by the sponsor-investigator. Cross reference this 
submission according to local regulations, will be submitted to the Merck Investigational 
Compound number (IND, CSA, etc.) at the time of submission. Submitted copy of these 
reports will be sent to Merck (Attn: Worldwide Product Safety; FAX 215 993-1220) at the 
time of submission to the appropriate regulatory agency. 
 
Merck Drug Safety 
Fax: 215-993-1220 
(Please use the safety reporting fax cover sheet for your fax transmission) 
 
AND: 
 
Study Coordination Center/Principal Investigator 
Contact Information and fax #:  
Katherine B. Peters, MD, PhD 
919-684-6173-phone 
Mary Lou Affronti RN, MSN, ANP, MHSc 
919-684-6239 phone 
919-684-6674-fax 
 
AND: 
 
The Duke IRB 
(eIRB system) 

Protocol No.: 11.0 
 
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Mandatory MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event Description 
(section 5) of the MedWatch 3500A form: 
 
• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Follow-up information:   
 
Additional information may be added to a previously submitted report by any of the following 
methods: 
 
• 
Adding to the original Mandatory MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• 
Summarizing new information and faxing it with a cover letter including subject 
identifiers (i.e. D.O.B. initial, subject number), protocol description and number, if 
assigned, suspect drug, brief adverse event description, and notation that additional or 
follow-up information is being submitted  (The subject identifiers are important so that the 
new information is added to the correct initial report) 
 
Occasionally MERCK may contact the reporter for additional information, clarification, or 
current status of the subject for whom and adverse event was reported. 
 
Assessing Causality: 
 
Investigators are required to assess whether there is a reasonable possibility that Aprepitant 
and/or Ondansetron caused or contributed to an adverse event.  The following general 
guidance may be used. 
 
Attribution of AEs will be indicated as follows: 
- 
Definite:  The AE is clearly related to the study drug 
- 
Probably:  The AE is likely related to the study drug 
- 
Possible:  The AE may be related to the study drug 
- 
Unlikely:  The AE is doubtfully related to the study drug 
- 
Unrelated:  The AE is clearly NOT related to the study drug 

Protocol No.: 11.0 
 
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8 STATISTICAL METHODS  
 Overview and Sample Size Justification 
The objective of this study is to assess the efficacy of Aprepitant vs. Ondansetron in the 
prevention of chemotherapy induced nausea and vomiting in brain tumor patients treated with 
temozolomide +/- Avastin.  The primary basis for this assessment will be the complete control 
rate (CC), defined as the proportion of patients with no emetic episode and no rescue 
medication during days 1-7. 
 
A two-arm open-labeled randomized phase II screening trial is proposed in which 136 patients 
are randomized with equal probability to receive Ondansetron with or without Aprepitant. 
Patient randomization will be stratified by grade (I/II vs. III/IV) and the number of prior 
regimens (0/1 versus 2).  Within each of the 4 strata defined by these factors, a permuted 
block randomization scheme will be used to assign patients to receive either Ondansetron with 
or without Aprepitant.   
 
Though the study is comparative, the goal of the study is to determine whether Aprepitant is 
worthy of further investigation in this setting, and not to make definitive statements about the 
comparative effectiveness of Ondansetron treatment with or without Aprepitant.  A control 
arm is included in this study design in lieu of historical controls to ensure that an appropriate 
comparison can be made without concern that the patients receiving standard treatment differ 
in some manner (Rubinstein, 2009; Ratain, 2009; Ratain, 2008) 
 
Stupp (2005) reports that 19% of patients treated with temozolomide experience grade 2-4 
vomiting.  Given that the focus of this study is on the occurrence of such toxicity during days 
1-7, it is reasonable to assume for sample size calculations that rate of CINV is approximately 
14%, or CC rate of 86%.  If the true CC rate associated with Aprepitant were comparable, 
there would be limited interest in further investigating the use of Aprepitant as a prophylactic 
treatment for CINV.  However, if the true CC rate associated with Aprepitant were 96% or 
greater, there would be interest in pursuing further research with Aprepitant to determine the 
merits of integrating it use into standard treatment of glioma patients undergoing 
temozolomide treatment.  The statistical hypothesis that will be assessed is as follows: 
 
H0:  P1 ≤ P2  versus H1:  P1 > P2 
 
where P1 is the proportion of patients treated with Aprepitant who do not experience CINV 
(i.e. CC rate) and P2 is the same proportion among patients not treated with Aprepitant.   
 
As a phase II study, there is a need to constrain the sample size requirements at the expense of 
either an increased false negative or false positive rate.  As proposed by Ratain and Sargent, a 
false-positive rate of 0.2 will be used to test this hypothesis.  With 68 randomized patients per 
arm (total=136 patients) in this screening study, the power of a test conducted at the 0.2 level 
of significance is 0.9.  This power was computed assuming that the CC rate in the two arms is 
86% under the null hypothesis, and 86% and 96% under the alternative hypothesis.   
 

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An interim efficacy analysis will be conducted after 68 patients have been enrolled onto the 
study.  If the observed proportion of patients treated with Aprepitant who do not experience 
CINV is less than that observed among patients not treated with Aprepitant, patient accrual 
will be terminated.  With this interim analysis, simulation studies show that the type I and II 
error rates are 0.19 and 0.11, respectively.  The probability that the study will be terminated 
early under the null hypothesis is 0.43, while the probability of early termination under the 
alternative hypothesis is 0.04. 
 
 Analytic Methods 
Primary Analysis:  The proportion of patients with no emetic episode or rescue medication 
during days 1-7, also referenced as the CC rate, will be estimated with a 95% confidence 
interval within each treatment arm.  Logistic regression will be used to compare treatment 
arms with respect to the CC rate assuming a 0.2 level of significance. 
 
Secondary Analyses: The acute CINV CR rate (i.e. for day 1) will be calculated, and a logistic 
regression model will compare treatment arms.  The delayed CR rate (i.e. for days 2-7) will 
also be calculated with a logistic regression model comparing treatment arms. 
 
The Cochran-Armitage Trend Test will be used to compare treatment arms with respect to the 
day of treatment failure of the antiemetic therapy. 
 
Logistic regression will be used to examine the effect of treatment arm, age, gender, 
chemotherapy history, the use of glucocorticoids on the  CCCR rate. Statistical interactions 
with arm will also be explored in this analysis.  
 
The frequency of toxicity will be summarized by treatment arm, type and most severe grade 
experienced. 
 
A generalized linear model for repeated measures will compare treatment arms with respect to 
the pattern over time for global satisfaction with antiemetic treatment and quality of life. 
 
 Toxicity Monitoring 
If the percentage of patients with treatment-related grade 4 or 5 non-hematologic toxicity in 
the Aprepitant arm is greater than 5%, and that observed proportion is double the percentage 
of patients without Aprepitant with treatment-related grade 4 or 5 non-hematologic toxicity, 
then accrual will be suspended and the data carefully reviewed to determine if accrual should 
be permanently terminated. 
9 STUDY MANAGEMENT: DATA SAFETY AND MONITORING PLAN 
 Audits and Inspections 
Authorized representatives of the Institutional Review Board (IRB) or Duke Cancer Institute 
(DCI) may visit the center to perform audits or inspections, including source data verification. 
The purpose of such an audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, 

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Page 25 of 36 
 
and data were recorded, analyzed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), guidelines of the International Conference on Harmonization (ICH), 
and any applicable regulatory requirements. 
 
 Study Monitoring Requirements 
The DCI Safety Oversight Committee (SOC) conducts annual data and safety monitoring for 
DUHS sponsor-investigator phase I and II, therapeutic interventional studies that do not have 
an independent DSMB. Annual safety reviews include review of safety data, enrollment 
status, stopping rules if applicable, accrual, toxicities, reference literature, and interim 
analyses as provided by the sponsor-investigator.  Studies are rated satisfactory when 
adequate accrual with lack of excessive toxicity is present. 
 
The sponsor-investigator provides the DCI Safety Oversight Committee (SOC) – Safety 
Report to the SOC annually, upon request, or the data may be submitted simultaneously with 
required reporting, e.g., FDA annual report. Attachments (e.g., accrual tables, toxicities and 
reference literature) are also acceptable for SOC review. The sponsor-investigator is notified 
in writing if additional information is needed and if protocol or operational changes are 
required. The SOC will notify the sponsor-investigator and DUHS IRB when significant 
safety concerns are identified. The SOC Chair has the authority to temporarily suspend 
accrual to the study pending acceptable changes. Any recommendation for temporary or 
permanent suspension of an NIH-funded clinical protocol will be reported by the sponsor-
investigator via written communication to the responsible NCI grant program director. 
 
 Monitoring  
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits as defined 
by DCI Cancer Protocol Committee (CPC), on DUHS sponsor-investigator therapeutic 
intervention and prevention intervention studies that do not have an external monitoring plan, 
ensuring subject safety and that the protocol is conducted, recorded and reported in 
accordance with the protocol, standing operating procedures (SOPs), Good Clinical Practice 
(GCP), and applicable regulatory requirements. The Monitoring Team also provides ongoing 
education and resources to investigators and study teams to enhance the quality. 
 
As specified in the DCI Data and Safety Monitoring Plan, the DCI Monitoring team will 
conduct  routine monitoring after the third subject is enrolled, followed by annual monitoring 
of 1-3 subjects until the study is closed to enrollment and subjects are no longer receiving 
study interventions that are more than minimal risk. The frequency of monitoring may also be 
tailored as defined by the CPC. Additional monitoring may be prompted by findings from 
monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other 
concerns and may be initiated upon request of DUHS and DCI Leadership, the DCI CPC, the 
Safety Oversight Committee (SOC), the study supporter, the Principal Investigator, or the 
IRB. All study documents must be made available upon request to the DCI Monitoring Team 
and other authorized regulatory authorities, including but not limited to the National Institute 
of Health, National Cancer Institute, and the FDA.  Every reasonable effort will be made to 
maintain confidentiality during study monitoring. 

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Page 26 of 36 
 
 
This phase II study is limited to Duke University Medical Center. Routine monitoring by 
study investigators will review toxicity data including all SAEs and other issues relevant to 
the study such as interim assessment of accrual, outcome and compliance with study 
guidelines. 
 
 Audits 
The Duke School of Medicine Clinical Trials Quality Assurance (CTQA) office may conduct 
audits to evaluate compliance with the protocol and the principles of GCP.  The PI agrees to 
allow the CTQA auditor(s) direct access to all relevant documents and to allocate his/her time 
and the time of the study team to the CTQA auditor(s) in order to discuss findings and any 
relevant issues. 
 
CTQA audits are designed to protect the rights and well-being of human research subjects. 
CTQA audits may be routine or directed (for cause). Routine audits are selected based upon 
risk metrics generally geared towards high subject enrollment, studies with limited oversight 
or monitoring, Investigator initiated Investigational Drugs or Devices, federally-funded 
studies, high degree of risk (based upon adverse events, type of study, or vulnerable 
populations), Phase I studies, or studies that involve Medicare populations. Directed audits 
occur at the directive of the IRB or an authorized Institutional Official. 
 
CTQA audits examine research studies/clinical trials methodology, processes and systems to 
assess whether the research is conducted according to the protocol approved by the DUHS 
IRB. The primary purpose of the audit/review is to verify that the standards for safety of 
human subjects in clinical trials and the quality of data produced by the clinical trial research 
are met. The audit/review will serve as a quality assurance measure, internal to the institution. 
Additional goals of such audits are to detect both random and systemic errors occurring 
during the conduct of clinical research and to emphasize “best practices” in the 
research/clinical trials environment. 
 
 Data Collection 
The PIs will be responsible for accurate, consistent, timely, complete and reliable data 
collection. 
 
The study coordinator and PIs are responsible for ensuring that the following forms are 
completed in a legible and timely manner for every patient enrolled on study. These forms are 
an integral part of the study data and will be maintained in the patient’s clinical chart at the 
Brain Tumor Center at Duke (BTC). Errors on the forms should be lined through, but not 
obliterated, with the correction inserted, initialed and dated by the study coordinator or PIs.  
All source documents will be available for inspection by the FDA, DUHS IRB, and the 
Duke Cancer Institute Safety Oversight Committee.  All source documents will be available at 
all times for inspection by the FDA, DUHS IRB, and the DCI SOC.  
 
Patient data will be entered into an Oracle Clinical database created and maintained by Duke 
CCIS. The data are backed up daily and stored on a secure medical center server. The PIs, 

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Page 27 of 36 
 
study investigators, study statisticians, clinical research coordinator, and data coordinators for 
the study are the only individuals who will have access to the web-based Oracle application. 
 
 

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Page 28 of 36 
 
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66. Walker, M. D., Green, S. B., Byar, D. P., Alexander, E., Jr., Batzdorf, U., Brooks, 
W. H., . . . Strike, T. A. (1980). Randomized comparisons of radiotherapy and 
nitrosoureas for the treatment of malignant glioma after surgery. New England 
Journal of Medicine, 303(23), 1323-1329. doi: 10.1056/NEJM198012043032303 
67. Wickham, R. (2010). Best practice management of CINV in oncology patients: II. 
Antiemetic guidelines and rationale for use. J Support Oncol, 8(2 Suppl 1), 10-15.  
 
 
 
 

Protocol No.: 11.0 
 
CONFIDENTIAL 
 
 
Protocol Date: 10/20/14 
 
Page 34 of 36 
 
11 APPENDICES 
 
CINV Patient Survey (MAT/Osoba) 
Please see attached. 
 
 
 
Cytochrome P450 Drug Interaction Table 
Please see the following website, which is updated frequently as new information becomes 
available (Flockhart, 2007): 
 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
 
 
 
PK Sample Collection/Processing and Plasma Storage for 
Temozolomide and AIC Metabolite Analysis 
 
Materials to be ready and ICE-COLD or REFRIGERATED ahead of time of sample 
collection: 
1. 4-mL sodium heparin “green top” Vacutainer® tubes, ref# 367871 (1 ea.)  
2. 2-mL polypropylene screw-cap tube containing 0.06 mL of 8.5% phosphoric acid (1 
ea.) This tube will be clearly labeled “A.” 
3. 1-mL polypropylene transfer pipettes (1 ea.) 
4. 2-mL cryo-vials labeled “TEMO/AIC,” study #, patient study #, date and time of 
blood draw, as well as date and time of doses of aprepitant, ondansetron and 
temozolomide (2ea.).  These tubes will be clearly labeled “B.” 
5.  
 
For temozolomide/AIC measurement, blood sample will be collected in pre-chilled (wet ice 
or refrigerated at 4 oC) sodium heparin “green top” Vacutainer® tube and immediately placed 
back on wet ice or refrigerated at 4 oC. The sample will be processed as soon as possible 
(within 60 minutes) by centrifugation (4ºC, 1200 g, 10 min). The plasma will be transferred in 
tube labeled “A” (2 mL polypropylene (PP) screw-cap tube containing 0.06 mL of 8.5% 
phosphoric acid), mixed well, and content transferred into two equal (~1-mL ea.) aliquots 
using two tubes labeled “B” (“TEMO/AIC”-labeled 2-mL PP tubes), and immediately stored 
at -20ºC (or lower) until the time of analysis. 
 
 
Stupp Regimen (2005) 
Radiation therapy administered as fractionated focal irradiation in daily fractions of 2Gy 
given 5 days a week for 6 weeks for a total of 60 Gy, or 1.8 Gy given 5 days a week for 33 
treatments for a total of 59.4 Gy,  and concomitant temozolomide 75 mg/m2 daily (7 days per 
week) during radiotherapy. 
 
External beam radiation (XRT) will begin 2-6 weeks after surgery and temozolomide 75 
mg/m2 daily will be started within the first 5 days of XRT.  Beginning, a minimum of 2 weeks 
after the last radiation treatment, temozolomide will be given at 150 to 200 mg/m2 daily the 
first 5 days of each 28-day cycle. 

Protocol No.: 11.0 
 
CONFIDENTIAL 
 
 
Protocol Date: 10/20/14 
 
Page 35 of 36 
 
 
 
NCI CTC Toxicity Grading (Version 4.0) 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 
The Preston Robert Tisch Brain Tumor Center Clinical Research 
Team Standard Operating Procedure for Randomization of Aprepitant 
(Emend) Study 
 
eIRB# Pro00031206: A Randomized Open Label Phase II Trial of Aprepitant (Emend) 
in Combination with Ondansetron Compared to Standard 5HT3 Serotonin Antagonist 
(Ondansetron) in the Prevention of Acute and Delayed Chemotherapy Induced Nausea 
and Vomiting (CINV) in Glioma Patients receiving a Temozolomide Based Regimen   
 
Purpose: To provide standard operating procedures for randomizing subjects to the above 
clinical trial.   
Scope: Statistical Team, Principal Investigator, Study Coordinator, DCI IT and ICS  
Process:  
As per the protocol, a permuted block randomization schema will be developed by team 
statistician and provided to DCI IT for REDcap development   
• REDcap (via SAS) will randomize subjects to one of two treatment arms based on the 
following 2 factors that create 4 strata:   
1. Number of regimens  
• 0 or 1 regimens  
• 2 regimens  
2. Histologic grade  
• Grade 1 or 2 
• Grade 3 or 4 
• Randomization date  (the date that the randomization information is being entered ) 
• Subject is randomized to 1 of 2 Arms 
1. Arm A: Emend + Zofran 
2. Arm B: Zofran alone 
• Data Management team and/or Statistical team will access treatment assignment 
information in REDcap and Oracle Clinical on a monthly basis to assess data quality 
and consistency  
• A second research team member will verify that each subject has been randomized 
correctly when checking eligibility 
 
Procedures: 
1. CRC or designate assigns a subject ID Number on DOCR enrollment log when subject 
deemed protocol eligible 
• Study ID numbers to start with #101 and continues sequentially 
2. CRC or designee enters the required stratification factors in Redcap to randomize 
subject and uses the assigned numbers sequentially per DOCR enrollment log  
• Number of regimens 

Protocol No.: 11.0 
 
CONFIDENTIAL 
 
 
Protocol Date: 10/20/14 
 
Page 36 of 36 
 
• Histologic grade  
• Date of randomization 
3. Arm A orders are processed and approved in DUHS electronic ordering system by 
BTC physician  ( EMEND only ) and prescription  provided to subject for Zofran  
4. Arm B Zofran prescription is provided by physician 
5. EMEND is dispensed from ICS if randomized to Arm A 
6. Randomization assignments sheets will be printed from REDcap to verify eligibility to 
Arm A or Arm B  
 
Access to randomization data in Redcap is issued by DCI IT after the Investigator/designee 
approval: 
1. CRC 
2. CRC identified backup 
3. Clinical Trials Manager 
4. Data Manager 
5. Statisticians – view only 
6. DCI IT 
* Refer to REDcap Randomization Project document for further information.