Phase II Trial Testing the Antiemetic Efficacy of a Single-day Low Dose Aprepitant (or Fosaprepitant) Added to a 5-HT3 Receptor Antagonist Plus Dexamethasone in Patients Receiving Carboplatin
Phase: PHASE2
Conditions: Chemotherapy-induced Nausea and Vomiting
Sponsor: Albert Einstein College of Medicine

Phase II Trial Testing the Antiemetic Efficacy of a Single-Day Low Dose of 
Aprepitant (or Fosaprepitant) added to a 5-HT3 Receptor Antagonist plus 
Dexamethasone in Patients Receiving Carboplatin  
 
Principal investigator:  Richard J. Gralla
Professor of Medicine
Albert Einstein College of Medicine
Jacobi Medical Center
Room 3N20, Building 1
1400 Pelham Parkway South
Bronx, New York 10461
 
Phone: (718) 918-6235 - office
Fax: (718) 918-5578
Email: rgralla@gmail.com
 
Co-investigators:  Karine Darbinyan, Balazs Halmos, Haiying Cheng
Research coordinator: Walter Vazquez, MS
Assistant Director
Regulatory Affairs
Research Center
Jacobi Medical Center
1400 Pelham Parkway South 
Building One 6W4
Bronx, NY 10461
 
Phone: (718) 918-3568 - office
Fax: (718) 918-4308
Email: Walter.Vazquez@nbhn.net
 
Statistician
Shankar Viswanathan, Dr.P.H.
Albert Einstein College of Medicine
Jack and Pearls Resnick Campus
1300 Morris Park Avenue
Block, Room 315
Bronx, NY 10461
Phone: 718-430-3762
Email: Shankar.viswanathan@einstein.yu.edu
IRB NUMBER: 2015-5109
IRB APPROVAL DATE: 09/28/2018

Background 
Chemotherapy-induced nausea and vomiting (CINV) is consistently listed as one of the greatest 
concerns of patients with cancer, negatively affects quality of life (QOL) and is a leading cause 
of increasing use of health care resources including urgent care visits (1). 
 
Major risk factors increasing the likelihood of emesis with chemotherapy include:  female 
gender, young age, and low chronic alcohol use.  It should be noted; however, that the main 
predictive factor for the development of CINV is the emetic potential of a given 
chemotherapeutic agent (1). 
 
Carboplatin causes both acute and delayed emesis.  Results from 4 recent randomized clinical 
trials (as in table 1) have shown that the rate of emesis, even with two agent antiemetic 
regimens, with carboplatin is higher than was previously recognized.  Guideline groups have 
typically classified this agent as moderately emetic (MEC); however, its risk of inducing vomiting 
is at the upper range of this classification, and borders on highly emetic (2,3). The 
recommendation for prevention has been the use of a two-drug regimen (a 
5hydroxytryptamine receptor antagonist (5-HT3RA) plus dexamethasone).  Based on the 
evidence from the 4 recent trials mentioned below, guideline groups are considering 
recommending the addition of a neurokinin-1 receptor antagonist (NK1RA) in all patients 
receiving carboplatin, using traditional NK1RA dosing and schedules.
 
The recent randomized studies have shown that patients given only a 2-drug regimen have 
about a 50% likelihood of emesis if they are women, and about a 30% likelihood of emesis if 
they are men.  Major improvements were reported when a neurokinin-1 receptor antagonist 
(NK1RA) aprepitant was added (4,5,6,7), as seen in table 1.  This improvement is of a similar 
magnitude to that seen in patients receiving cisplatin (a chemotherapeutic agent for which a 3 
drug regimen containing an NK1RA is universally guideline-recommended).  Similar 
improvements were also seen in a trial in which the NK1RA antiemetic was rolapitant rather 
than aprepitant (8).  The Tanioka and Yahata studies were conducted entirely in patients with 
GYN malignancies, and it is not surprising that the control rates are lower in these all female 
groups; nonetheless, the magnitude of benefit with the addition of the 3rd agent is similar in 
both genders.
 
 
IRB NUMBER: 2015-5109
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Table 1. Complete Emetic Control rate of 3-drug NK1RA-containing regimen over 2-drug 
regimen in randomized trials in patients receiving carboplatin (4,5,6,7)
 
Overall (0-120 
hours)
Complete response
NK1RA + 5-HT3RA 
+DEX
5-HT3RA +DEX
Absolute 
difference
Tanioka ( N=91) *
62%
52%
10%
Ito (N=134)
80%
67%
13%
Yahata (N=324) *
62%
47%
15%
Gralla (N=192)
84%
70%
14%
* Studies conducted in women only
 
The most commonly used neurokinin-1 receptor antagonist, aprepitant, is generally given over 
3 days.  Interestingly, most studies indicate that this class of agent gives similar results when 
given in just one day, or over multiple days (9). Typically the 1 day regimens use higher NK1RA 
doses (such as 150 mg of IV fosaprepitant or 165 mg of oral aprepitant), although a dose 
response relationship has not been clearly established for this purpose.  Recent studies 
conducted by Roila compared the efficacy of aprepitant on one day at a low dose (125 mg) 
versus the full three day regimen totaling 285 mg (10, 11) in patients receiving either cisplatin 
or the combination of anthracyclines plus сyclophosphamide (AC). In both double-blind studies, 
those patients randomly assigned to just one day of lower dose aprepitant had control of 
emesis equal to those receiving multiple days and higher total doses.  In both of these trials, 
patients assigned to the single day aprepitant arm also received additional antiemetics on days 
2 and 3.  However, recent studies have failed to show an advantage for continuing 
dexamethasone after day 1 in patients receiving AC (14) or in those receiving cisplatin (15).  
Additionally, a meta-analysis (16) indicated that as long as dexamethasone is given on day 1, 
there is no advantage to adding a serotonin antagonist (such as ondansetron) after day 1, and 
ondansetron has been shown to be similar to metoclopramide in the delayed emesis phase.  
Similarly to studies conducted by Roila (10, 11), Grunberg and colleagues showed noninferiority 
of single-dose intravenous (IV) fosaprepitant (a phosphorylated analog of aprepitant that is 
rapidly converted to aprepitant after IV administration) in a randomized study involving over 
2000 patients receiving cisplatin chemotherapy (12). Fosaprepitant 115 mg IV has been 
approved as an alternative to the 125-mg oral aprepitant dose on day 1 of a 3-day regimen (13).
The role of continued steroids after day 1 in patients receiving carboplatin has only been 
recently tested, and this has been part of the trials using a variety of chemotherapeutic agents. 
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Although current guidelines often recommend the use of dexamethasone on 3 consecutive 
days after MEC, there are several newer considerations that call this into question: 1) a recently 
published meta-analysis of RCTs comparing 1-day versus 3-day duration of dexamethasone for 
the CINV prophylaxis, showed that 1-day therapy provides similar efficacy in control (18). Many 
of these patients received carboplatin. Of note also, a Japanese study conducted in 402 patients 
receiving either AC or Cisplatin (HEC) showed no difference in antiemetic efficacy (non-
inferiority) of a single day dexamethasone regimen when prospectively compared with a 3 day 
dexamethasone regimen. Importantly, the 1 day regimen found significant reductions in steroid 
induced side effects (15). Additionally, a large multinational trial in patients receiving AC 
chemotherapy showed that a single dose of dexamethasone on day 1 along with a single day of 
NEPA (combination of 5-HT3RA palonosetron with NK1RA netupitant) offers convenient single-
day prophylaxis for both acute and delayed CINV (17), with competitive antiemetic efficacy 
when compared with historical experiences. 2) Carboplatin is no longer considered to be “MEC” 
by some guideline groups (MASCC / ESMO).
Lower dose regimens and those of a shorter duration, not only are less expensive, but also are 
the easiest possible regimen for the patient to adhere to, making antiemetic regimens very 
easy.  These shorter regimens are also easier to order, making compliance with evidence-based 
guidelines more likely. Additionally, with a shorter administration schedule, there is less chance 
of drug-drug interactions and side effects. All studies indicate that oral and IV antiemetics of 
these classes are equally efficacious (12).
All three classes of agents used in this trial have been commercially available for more than a 
decade and have been used many million times.  The serotonin antagonist ondansetron was 
approved more than 2 decades ago.  Its major side effects are mild headache and mild 
constipation, both of which are easily treated, if desired by common laxatives or 
acetaminophen.  While intravenous ondansetron is associated with mild QTc prolongation, 
when given orally at the dose in this study, QTc prolongation is trivial, and the FDA has not 
asked for any additional warnings for such oral dosing.  Agents of this class also can give mild 
increases in transaminases, of no known clinical significance.  Other agents in this class, such as 
palonosetron have similar side effects to ondansetron.  Aprepitant has few recognizable side 
effects in comparative clinical trials.  It may be associated with increased hiccoughs, although 
this effect is seen only in men.  The intravenous pro-drug form of aprepitant, fosaprepitant, has 
similar efficacy, pharmacokinetics, and side effects when compared with aprepitant (12).  
However, fosaprepitant is associated with an increased risk of venous irritation, when 
compared with the oral agent; this effect is greatest when given with AC chemotherapy and 
least when given with platinum agents (as in this protocol).  Both these NK1RAs have a mild 
effect on CYP 3A4.  This effect prolongs the half-life of dexamethasone, which is seen as an 
advantage in this trial, perhaps prolonging its beneficial effects.  The side effects of 
dexamethasone are well known and include hyperglycemia and mood changes.  As this protocol 
decreases the exposure to dexamethasone over some guidelines, it is expected that there may 
IRB NUMBER: 2015-5109
IRB APPROVAL DATE: 09/28/2018

be fewer corticosteroid adverse effects for patients on this protocol than for those who are 
placed on NCCN guideline recommended regimens.
Guideline groups are now starting to recommend a 3-agent preventive antiemetic regimen for 
patients receiving carboplatin, based on the evidence from the studies presented in table 1; 
however, not all guideline groups have yet made this recommendation.  If it can be shown that 
a less expensive, more convenient (1-time administration), and potentially safer regimen 
performs in the same way for patients receiving carboplatin as it did for those receiving 
cisplatin or AC chemotherapy, and similarly to those receiving 3 days of aprepitant with 
carboplatin in the recent randomized trials, a new standard may be established.
Objectives 
 
•
Primary:  To determine in patients receiving their first cycle of carboplatin-based 
chemotherapy, the complete control rate of emesis (acute and delayed; no vomiting and 
no use of rescue medications) with the addition of one dose of the oral aprepitant or 
intravenous fosaprepitant to a combination of oral dexamethasone + an oral 5-HT3RA 
(ondansetron).  
•
Secondary:  To estimate the control rate on the second cycle of this chemotherapy in 
those patients agreeing to be assessed in the subsequent chemotherapy cycle.
 
Methods
 
Assessment
CINV will be assessed by using the validated MASCC Antiemesis Tool (MAT) (19), which 
efficiently and accurately evaluates the incidence of vomiting and the severity of nausea and 
vomiting in the acute and delayed emesis periods. 
 
Patients will be enrolled at Jacobi Medical Center and Montefiore Medical Center. Patients will 
be asked to sign an informed consent form.  Patients will be called on day 2 and 5 to remind 
about form completion and will return the MAT form on their next outpatient visit (or 
immediately after completion if the patient is an inpatient). 
Consent forms then will be kept at a clinical trial center in a file. Case report forms were 
developed to capture data relevant to research.
Patient selection Inclusion criteria
 
•
Age 18 and above
•
No prior chemotherapy
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•
Confirmed malignancy, scheduled to receive carboplatin monotherapy, or carboplatin in 
combination with agents of minimal, low, or moderate emetic potential 
•
Laboratory parameters adequate for chemotherapy
 
Exclusion criteria
•
Patients with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 3 or 
4
•
Presence of nausea and vomiting or use of major antiemetic agents during the 24 hours 
before chemotherapy administration
•
Patients receiving radiotherapy within 5 days prior to the carboplatin
•
Pregnancy or lactation
•
Known allergy to any of the 3 antiemetics
Antiemetic Medication administration
All medications that will be used in this study are commercially available. NK1RA have been 
used for over 12 years and 5-HT3RA and dexamethasone have been used even longer than that. 
All common side effects of these medications were mentioned above and have also been 
captured in consent form. We are not expecting serious adverse events since these are 
commonly used agents that are almost never associated with SAEs, and we are giving a lower 
dose and frequency of these FDA approved medications. They may be obtained or dispensed 
either by the Jacobi Medical Center, or the Montefiore Medical Center pharmacies, or 
aprepitant may be obtained by prescription from an outside pharmacy.  If aprepitant is 
obtained at an outside pharmacy, the patient will bring the agent to their chemotherapy 
appointment; all NK1RA drug administration will be directly observed. The use of either 
aprepitant or fosaprepitant will be entirely the choice of the ordering oncologist, as both agents 
are equivalent (12). 
 
Ideally all drugs will be given immediately before (within 5 minutes) chemotherapy; however if 
a delay occurs up to 2 hours between the antiemetics and chemotherapy, this will be allowable 
and no additional dosing will be needed.  The time of administration of the NK1RA in relation to 
the chemotherapy will be recorded.  
 
All patients will be given 125 mg of aprepitant orally or 115 mg IV of fosaprepitant prior to the 
first cycle of carboplatin-based chemotherapy. 
 
Antiemetic drug doses and schedules (same doses in all age and gender groups). Please see 
medication package inserts attached separately. 
Aprepitant or Fosaprepitant:
- 125 mg of Aprepitant orally immediately prior to chemotherapy
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- If fosaprepitant given instead, it will be administered immediately prior to chemotherapy at 
115mg IV (over 20 minutes). The administration site of the fosaprepitant will be noted and 
will be evaluated for possible venous irritation.
Dexamethasone:
- 20 mg of dexamethasone orally immediately prior to chemotherapy 
Ondansetron:
- 16 mg orally, immediately prior to the chemotherapy.  
 
Table 2.  Antiemetic Dosing and Schedule
Day 1 (immediately prior to chemotherapy, only)
- aprepitant 125mg po or fosaprepitant 115mg IV 
- ondansetron 16 mg po 
- dexamethasone 20mg po
CYCLE 2:
Patients agreeing to be followed on the second cycle with be assessed in the same way.  During 
the follow-up visit after the first cycle, patients on study will be asked if they wish to continue 
participation during their second chemotherapy cycle (given that they are still eligible).  
Patients will not need to sign a separate consent, but will need to give their verbal affirmation, 
which will be noted in the case report form.
The dosing and timing of the antiemetics may change according to the results in the first cycle, 
and other demographic characteristics, as follows:
Female patients:
- If there was no vomiting on the first cycle and the antiemetics were well tolerated, all 
antiemetics will be given identically to cycle 1.
 
- If any vomiting was experienced on the first cycle, patients will instead receive the typical 
3day aprepitant (125 mg po day 1, and 80 mg po days 2 and 3), or fosaprepitant 150 mg IV 
(given over 30 minutes) on day 1 only. (The choice of the aprepitant or fosaprepitant regimen 
will be at the discretion of the ordering oncologist).   Ondansetron and dexamethasone on 
day 1 will be given as on cycle 1. In addition, 12mg of dexamethasone will be given on day 3. 
 
 Male patients:
- For those aged 50 or older, if there was no vomiting with the first cycle and the antiemetics 
were well tolerated, all antiemetics will be given identically to cycle 1 EXCEPT that the 
aprepitant dose will be reduced to one 80 mg oral administration on day 1.  If fosaprepitant 
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is used, it will be given at a total dose of 75 mg over 15 minutes.  All will be given 
immediately prior to chemotherapy.  Ondansetron and dexamethasone will be given as with 
cycle 1.     
 
- For those under age 50, if there was no vomiting on the first cycle and the antiemetics were 
well tolerated, all antiemetics will be given identically to cycle 1.
 
- Male patients of any age, if they experienced any vomiting on the first cycle, will instead 
receive the typical 3-day aprepitant (125 mg po day 1, and 80 mg po days 2 and 3), or 
fosaprepitant 150 mg IV (given over 30 minutes) on day 1 only.  (The choice of the aprepitant 
or fosaprepitant regimen will be at the discretion of the ordering oncologist).  Ondansetron 
and dexamethasone on day 1 will be given as on cycle 1. In addition, 12mg of 
dexamethasone will be given on day 3.      
Statistics and Analysis:
The primary goal of the study is to estimate the complete control rate of emesis with the 
addition of one dose of the oral NK1RA aprepitant or the IV NK1RA fosaprepitant to a 
combination of oral dexamethasone + an oral 5-HT3RA (ondansetron). We will compute the 
relevant proportions and corresponding 95% confidence interval. The association of emesis 
control rate by gender and other socio-demographic and clinical covariates will be examined 
using Chi-square test, in case of small sample size Fisher's exact test will be used.  Similar 
analysis will be performed to examine the secondary endpoints of complete control, complete 
emesis control and complete nausea control in the acute emesis period (the initial 24 hours 
after chemotherapy), delayed emesis period (the 24 - 120 hour period after chemotherapy) and 
in the control in the second cycle of chemotherapy.
 
Justification of sample size:
We anticipate to recruit a total of 50 patients for this study over one year after protocol 
approval, from prior experience with usage of carboplatin, we expect approximately 60% will 
be females. We project conservatively a 70% complete control rate based on prior literature 
(i.e. a 62% complete control rate in women and an 82% complete control rate in men). To 
evaluate the adequacy of the sample size (i.e. number of emesis control observed), we 
computed the precision, as measured by the width of the 95% CI, with which the proportion of 
emesis control rate can be estimated. The width of the 95% CI will be no greater than 26.7% 
(i.e. +/-the lower and upper limit of complete control rate will be 55.4% to 82.1%) with the 
proposed sample size based on exact Clopper-Pearson formula. 
Review Bodies.  The primary data monitoring and safety group will be the Data and Safety 
Monitoring Board (DSMB).  This body will be constituted for this phase II trial.  Information 
required in reports by this committee will include 1) summaries of accrual rates and patterns; 2) 
information on all adverse events and protocol violations; and 3) efficacy results at the time of 
each DSMB meeting, which will not be available to the investigators.  Note, there is no interim 
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analysis specified for this trial.  This committee will meet at least annually.  The majority of the 
members will not be from any of the study institutions, and no member will be involved in any 
way with the study.  Membership will include as a minimum:  a statistician, a medical 
oncologist, and a research oncology nurse.  Members of the DSMB are: Gregory Bizette, MD 
(Medical Oncologist, Ochsner Cancer Institute), James Symanowski, PhD (Biostatistician, Levine 
Cancer Institute), Patricia J. Hollen, RN, PhD, FAAN (Oncology Research Nurse; University of 
Virginia). 
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