Prevention of Nausea and Vomiting Secondary to FOLFIRINOX Chemotherapy in Gastrointestinal Cancer Patients
Phase: NA
Conditions: Gastrointestinal Cancer, Nausea Post Chemotherapy
Sponsor: Philip Philip

 
 
                                                                                                                                                      1 
2011-116 Prevention of Nausea and Vomiting Secondary to  
FOLFIRINOX Chemotherapy in Gastrointestinal Cancer Patients 
 
Principal Investigator: 
Philip A. Philip, MD, PhD 
 
Wayne State University 
 
Barbara Ann Karmanos Cancer Institute 
 
4100 John R, HW04HO 
 
Detroit, MI, 48201 
 
Telephone:  313-576-8746 
 
Fax:  313-576-8767 
 
E-mail: philipp@karmanos.org 
 
Co-Investigators:   
Anthony Shields, MD, PhD 
 
 
 
 
 
 
 
 
 
 
 
Statistician:   
 
Greg Dyson, PhD 
Mid-Med Bldg 
87 E. Canfield 
Detroit MI 48201 
dysong@karmanos.org 
 
Data Manager:  
 
Colette Zack, BS, CCRP 
Mid-Med Bldg 
87 E. Canfield, MM03CT 
Detroit, MI 48201 
Tel # 313-576-9835 
Fax # 313-576-8368 
 
 
 
 
 
 

 
 
2
 
Table of Contents 
 
 
1) 
Objectives 
 
 
 
 
 
 
 
3 
2) 
Background and Rationale 
 
 
 
 
 
3 
3) 
Drug Information 
 
 
 
 
 
 
5 
4) 
Patient Selection 
 
 
 
 
 
 
8 
 
 
 
5) 
Pre-study Evaluation 
 
 
 
 
 
 
9 
6) 
Treatment 
                         
 
 
 
 
9 
7) 
Dose Adjustment 
 
 
 
 
 
 
10 
8) 
Criteria for Evaluation and Endpoint Assessment 
 
 
10 
 
9) 
Reason for Removal From Study 
 
 
 
 
10 
 
10) Statistical Considerations 
 
 
 
 
 
10 
 
11) Study Administration and Investigator Obligations 
 
 
12 
 
Appendix 1: SWOG Performance Scale 
 
 
 
 
14 
Appendix 2: Data Safety Monitoring Board  
 
 
 
15 
Appendix 3: Baseline Nausea Form  
 
 
 
 
16 
Appendix 4: FOLFIRINOX chemotherapy  
 
 
 
17 
Appendix 5: Study Calendar  
 
 
 
 
 
18 
Appendix 6: Daily Diary 
 
 
 
 
 
 
19 
References 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
 
Protocol Version 1: November 21, 2011 
Protocol Version 2: July 20, 2012 
Protocol Version 3: December 4, 2012 
Protocol Version 4: July 29, 2013 
Protocol Version 5: July 17, 2014 
Protocol Version 6: November 17, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
3
 
 
 
 
1) Objectives: 
Primary:  
To evaluate efficacy of the addition of fosaprepitant in controlling acute and delayed vomiting 
with the standard prophylactic anti-emetic combination of 5-HT3 receptor antagonist and 
dexamethasone for gastrointestinal cancer patients receiving FOLFIRINOX (5-FU, oxaliplatin 
and irinotecan) chemotherapy. The primary objective is to determine the rate of complete 
response (no emetic episode and no rescue medication) in the combined acute and delayed phase 
from 0-120 hours after chemotherapy.  
 
Secondary:  
To determine the incidence of nausea and vomiting in both acute (<24 hours) and delayed (24-
120 hours) setting in patients receiving FOLFIRINOX chemotherapy. 
   
Tertiary: 
Follow overall survival in patients receiving FOLFIRINOX chemotherapy.  
 
2) Background and Rationale: 
 
          Nausea and vomiting are symptomatic side effects of chemotherapy that are both 
physically and psychologically burdensome.  Until the advent of the serotonin receptor 
antagonists, control of nausea and vomiting for patient receiving high-dose chemotherapy was 
inadequate. According to the American Society of Clinical Oncology guidelines, the current 
approach for prophylaxis of nausea and vomiting caused by chemotherapy deemed highly 
emetogenic is 5-HT3 antagonists (ondansetron or granisetron) combined with corticosteroids and 
aprepitant.1 At Karmanos Cancer Institute, ondansetron is the preferred 5-HT3 antagonist used 
for chemotherapy associated nausea and vomiting.  Neurokinin 1 receptor antagonists (NK1RA) 
are a class of anti-emetic compounds that can block NK1 receptor in the gastrointestinal fibers 
and the brainstem and is thought to play a key role in emesis induction when these receptors are 
stimulated by radiation and/or chemotherapy.2 Mechanism of action for NK1RA appears distinct 
from the 5-HT3’s, which act mainly at peripheral sites. Aprepitant (an antagonist at this receptor) 
was first tested in animal models including ferrets and displayed potent and long-acting anti-
emetic activity.3  NK1RA’s antagonize a much broader range of emetic stimuli than the 5-HT3’s 
in animal models.4 
 
 
The benefit of combining aprepitant with 5-HT3 receptor antagonists and corticosteroids 
for the prevention of chemotherapy induced nausea and vomiting (CINV) was initially shown in 
two phase III trials that included 1099 patients receiving cisplatin-containing chemotherapy (≥70 
mg/m2 per cycle).5 6  In both trials, patients were randomly assigned to ondansetron (day 1) plus 
dexamethasone (days 1 to 4) with either aprepitant (125 mg by mouth on day 1, followed by 80 
mg orally on days 2 and 3) or placebo. The end point of both studies was complete protection 
from emesis with no need for any rescue antiemetic. Acute emesis was blocked more effectively 
in patients receiving aprepitant (overall 86 percent versus 73 percent with placebo). The 
aprepitant-containing regimen maintained its advantage in controlling CINV over multiple 
treatment cycles. Similar results were seen in a third phase III trial, in which patients were 
randomly assigned to a three-drug regimen including aprepitant, ondansetron, and 
dexamethasone or to ondansetron plus dexamethasone only. The overall, acute, and delayed 
complete response rates were significantly better with the aprepitant regimen (72 versus 61, 88 

 
 
4
versus 79, and 74 versus 63 percent, respectively) compared to ondansetron plus dexamethasone 
alone.7   
 
 
 
Fosaprepitant is the prodrug of aprepitant that is converted to aprepitant in vivo after 
intravenous (IV) administration. It is approved in 41 countries as an alternative to the 125 mg 
oral dose on day 1 of the three-day regimen, with oral aprepitant administered on Days 2 and 3 in 
combination with a 5HT3 antagonist and dexamethasone for the prevention of acute and delayed 
nausea and vomiting associated with initial and repeat courses of highly emetogenic 
chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC). A Phase III study was 
recently conducted utilizing fosaprepitant, at a dose of 150 mg as a single dose alternative to the 
3-day regimens in cancer patients for the prevention of chemotherapy induced nausea and 
vomiting. The study enrolled 2,322 patients, 1,147 in the fosaprepitant regimen and 1,175 in the 
aprepitant regimen. The treatment regimens were similar with regard to baseline demographics. 
Patients ranged in age from 19-86 years. The most common primary tumor types were 
respiratory, gastrointestinal cancer, reproductive cancer, and genitourinary cancer. The primary 
endpoint was the proportion of patients with Complete Response in the overall phase (0 to 120 
hours following initiation of cisplatin chemotherapy). Complete Response is defined as the 
absence of vomiting episodes, retching or dry heaves (no vomiting) and no use of rescue 
medication. The fosaprepitant group had a complete response of 72% as compared to 72% in 
patient receiving aprepitant for 3 days.  Acute and delayed phase had similar outcome 89% vs. 
88% and 74% vs. 74%. No vomiting was noted in 73% treated with fosaprepitant while 75% had 
no vomiting in the aprepitant group.8 
 
 
Adverse events were reported for 1,389 (60.1%) patients, 671 (58.7%) in the 
fosaprepitant regimen group and 718 (61.4%) in the aprepitant regimen group. The adverse 
events were generally comparable between the fosaprepitant and aprepitant groups. In general, 
the adverse event profile observed was typical of a patient population with cancer receiving 
highly emetogenic chemotherapy. The most frequently reported clinical adverse events reported 
in both the fosaprepitant regimen group and the aprepitant regimen group were asthenia (10%), 
constipation (10%), anorexia (7.9%), diarrhea (8.3%), and nausea (6.5%).8 These adverse events 
occurred at a similar incidence between patients receiving the fosaprepitant regimen and patients 
receiving the aprepitant regimen with the exception of asthenia and anorexia, which occurred at a 
slightly higher incidence in the aprepitant regimen group. Overall, the adverse events observed in 
these studies were comparable to the types of adverse events observed in patients with cancer 
receiving highly emetogenic chemotherapy.  
 
          Pancreatic adenocarcinoma is one of the most lethal cancers with a 1-year and 5-year 
survival rates of at best 20%, and 5%, respectively.9 Palliative cytotoxic therapy remains a 
frequently used treatment modality in patients with pancreas cancer. The pivotal trial by Burris 
et. al in 1997 made single agent gemcitabine as a standard of care for the past decade.10  This 
was a prospectively designed study that compared 5-fluorouracil to gemcitabine therapy in 126 
patients.  5-FU was given as a bolus at 600mg/m2 weekly and gemcitabine was given at 
1000mg/m2 for 30 minutes weekly for seven weeks followed by one week of rest, then it was 
given weekly for 3 weeks followed by one week of rest.  The results showed statistically 
significant improvement in the primary endpoint of clinical benefit response (CBR: defined as 
composite of measurements of pain, performance status and weight) and 5 weeks improvement 
in median survival.  However the median survival for gemcitabine arm was still a dismal 5.65 
months with 1 year survival rate of 18%. More than 10 large randomized clinical trials were 
conducted to improve the clinical outcome in pancreas cancer but the results were all 
disappointing. 

 
 
5
      
          In 2010 American Society of Clinical Oncology meeting, a randomized phase 3 trial 
comparing the FOLFIRINOX regimen (oxaliplatin and irinotecan plus fluorouracil and 
leucovorin) to gemcitabine in advanced pancreatic cancer was presented.11  Results showed an 
overall survival increased from 6·8 months to 11·1 months (p<0·0001). More interestingly, 
almost half the patients in the FOLFIRINOX group were alive after 1 year, and response rate 
was 31·6%—the highest rate seen in phase 3 pancreatic cancer trials. However the side effects of 
treatment was worse in the FOLFIRINOX group.  Patients had 61% vomiting with grade III 
nausea and vomiting in 15%.  In another FOLFIRINOX study in advanced colorectal cancer, up 
to 79.4% had vomiting and 91% had nausea.12 Based on the above data, FOLFIRINOX is 
considered highly emetogenic chemotherapy since most of the above studies have utilized 5HT3 
antagonist as anti-emetic drugs and still experienced major nausea and vomiting episodes. 
Although the toxicity of FOLFIRINOX regimen is higher than single agent, such superior 
outcome has led many clinicians to use this regimen in advanced pancreatic cancer patients.  
Since quality of life is important in palliative setting, improving nausea and vomiting in 
gastrointestinal cancer would be important.  Many clinical trials have demonstrated that 
aprepitant can improve the nausea and vomiting in both highly and moderately emetogenic 
population.13 14  
 
In this open labeled study, the goal is to improve complete response to nausea and 
vomiting from about 30% in historical control to about 60% with addition of fosaprepitant in 
patients receiving FOLFIRINOX chemotherapy.  Hopefully this study could elucidate the impact 
of fosaprepitant in the GI cancer patients receiving FOLFIRINOX chemotherapy. 
 
 
3. Drug Information: 
A. Description: 
Fosaprepitant Dimeglumine, (EMEND™ for Injection) is a phosphoryl prodrug of 
aprepitant (EMEND™2) that can be administered intravenously (IV). Fosaprepitant 
is rapidly (within 30 minutes) converted to aprepitant after IV administration. Aprepitant 
is a selective high affinity antagonist of substance P/neurokinin 1 (NK1) receptors. It has 
little or no affinity for serotonin, dopamine and corticosteroid receptors.   
 
Fosaprepitant is an off-white, odorless powder that is highly soluble in water or 0.9% 
solution of sodium chloride (about 55 mg/mL as free acid equivalent). It is prepared 
by a multistep chemical synthesis as the bis-meglumine salt, which has a molecular 
formula of C23H22F7N4O6P•(C7H17NO5)2 and a molecular weight of 1004.83 (61.1% 
of which is attributable to the free acid). The neat solid is thermally unstable and 
degrades at about 155°C to aprepitant by loss of the phosphate group. It is also 
unstable in aqueous solutions and it must be formulated as a lyophilized powder in 
order to prevent its degradation during storage. 
 
Fosaprepitant will be supplied for clinical use in 10-mL vials as a sterile, lyophilized 
preparation; each vial contains an overage of 5% to account for non-withdrawable loss 
after reconstitution of the lyophilized product in order to deliver appropriate dose. The 
lyophilized product per 115 mg vial contains 120.8 mg free acid equivalent of active drug 
substance, 60.4 mg polysorbate 80, 302.0 mg lactose, as well as 15.1 mg of edetate 
disodium and nitrogen as an inert gas. The lyophilized product per 150 mg vial contains 
157.5 mg free acid equivalent (150 mg label claim) of active drug substance, 78.8 mg 
polysorbate 80, 393.8 mg lactose, as well as 19.7 mg of edetate disodium and nitrogen as 
an inert gas. Sodium hydroxide or hydrochloric acid may be added to the pre-
lyophilization drug solution in the amount sufficient to obtain pH 9.2 during 

 
 
6
manufacturing. The lyophilized product must be stored at 2 to 8°C. Prior to use, the 
preparation will be reconstituted with 0.9% Sodium Chloride Injection, USP to a final 
concentration of 1 mg/mL. The final drug solution is stable for 24 hours at ambient room 
temperature. This product allows for reconstitution in normal saline taken from any 
package including PVC bags and do not require specialized IV infusion equipment. 
Fosaprepitant is incompatible with Lactated Ringer’s Solution (LRS) or any other 
solutions containing divalent cations. Fosaprepitant should be reconstituted or mixed 
with solutions for which physical and chemical compatibility has been established. 
    
B. Pharmacology: 
 
1. Pharmacokinetics:  
 
Following a single intravenous dose of fosaprepitant administered as a 15-minute 
infusion to healthy volunteers the mean AUC of aprepitant was 31.7 (± 14.3) mcg•hr/mL 
and the mean maximal aprepitant concentration (Cmax) was 3.27 (± 1.16) mcg/mL. The 
mean aprepitant plasma concentration at 24 hours post dose was similar between the 125-
mg oral aprepitant dose and the 115-mg intravenous fosaprepitant dose. 
 
2.  Distribution: 
Fosaprepitant is rapidly converted to aprepitant. Aprepitant is greater than 95% bound to 
plasma proteins. The mean apparent volume of distribution at steady state (Vdss) is 
approximately 70 L in humans. Aprepitant crosses the placenta in rats and rabbits and 
crosses the blood brain barrier in humans. 
 
3. Metabolism:   
Fosaprepitant was rapidly converted to aprepitant in vitro incubations with liver 
preparations from nonclinical species (rat and dog) and humans. Furthermore, 
fosaprepitant underwent rapid and nearly complete conversion to aprepitant in S9 
preparations from multiple other human tissues including kidney, lung and ileum. Thus, it 
appears that the conversion of fosaprepitant to aprepitant can occur in multiple extra 
hepatic tissues in addition to the liver. In humans, fosaprepitant administered 
intravenously was rapidly converted to aprepitant within 30 minutes following the end of 
infusion. 
Aprepitant undergoes extensive metabolism. In vitro studies using human liver 
microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor 
metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the 
morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 
was detected. In healthy young adults, aprepitant accounts for approximately 24% of the 
radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-
aprepitant, indicating a substantial presence of metabolites in the plasma. Seven 
metabolites of aprepitant, which are only weakly active, have been identified in human 
plasma. 
4. Excretion: 

 
 
7
Following administration of a single I.V. 100-mg dose of [14C]-fosaprepitant to healthy 
subjects, 57% of the radioactivity was recovered in urine and 45% in feces.  Aprepitant is 
eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent 
terminal half-life of aprepitant ranged from approximately 9 to 13 hours. 
      
  C. Drug Interactions 
Drug interaction studies with oral midazolam have shown that IV fosaprepitant has a 
dose-dependent weak to moderate inhibitory effect on CYP3A4. In addition, in a  
study of diltiazem, there was a moderate increase in plasma diltiazem concentrations 
when co administered with a single IV dose of fosaprepitant consistent with an  
inhibitory effect of aprepitant on CYP3A4-mediated metabolism of diltiazem. 
 
 D. Toxicology 
Clinical studies of various formulations of fosaprepitant including fosaprepitant PS80 
have indicated that fosaprepitant is generally safe and well tolerated, with an adverse 
event profile comparable to both the oral aprepitant (EMEND™) 3-day regimen, as well 
as the comparator therapies used in the clinical trials. Infusion-related adverse events that 
have been reported with the use of the market formulation of fosaprepitant include 
infusion site pain, infusion site redness, infusion site itching, and induration.  Isolated 
reports of immediate hypersensitivity reactions including flushing, erythema, and 
dyspnea have occurred during infusion of fosaprepitant. These hypersensitivity reactions 
have generally responded to discontinuation of the infusion and administration of 
appropriate therapy. It is not recommended to reinitiate the infusion in patients who 
experience hypersensitivity reactions. The overall safety of aprepitant was evaluated in 
approximately 6,500 individuals. Since fosaprepitant is converted to aprepitant, those 
adverse events associated with aprepitant might also be expected to occur with 
fosaprepitant. The most common drug-related adverse events in patients that were treated 
with aprepitant in combination with ondansetron and dexamethasone include: hiccups, 
asthenia/fatigue, ALT increased, constipation, headache and anorexia. The adverse event 
profile was typical of cancer patients receiving cisplatin based chemotherapy. Other 
symptoms in patient receiving chemotherapy included fatigue. The incidence of clinical 
and laboratory adverse events were generally similar to the Standard therapy regimen 
(ondansetron and dexamethasone) for both groups.  Overall, EMEND™ is safe and well-
tolerated. 
    
E. Special Population 
 
1. Gender 
Following oral administration of a single 125-mg dose of aprepitant, no difference in AUC0-24hr 
was observed between males and females. The Cmax for aprepitant is 16% higher in females as 
compared with males. The half-life of aprepitant is 25% lower in females as compared with 
males and Tmax occurs at approximately the same time. These differences are not considered 
clinically meaningful. No dosage adjustment is necessary based on gender. 
2. Geriatric 
Following oral administration of a single 125-mg dose of aprepitant on Day 1 and 80 mg once 
daily on Days 2 through 5, the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% 
higher on Day 5 in elderly (≥65 years) relative to younger adults. The Cmax was 10% higher on 

 
 
8
Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not 
considered clinically meaningful. No dosage adjustment is necessary in elderly patients. 
3. Pediatric 
Fosaprepitant has not been evaluated in patients below 18 years of age. 
4. Race 
Following oral administration of a single 125-mg dose of aprepitant, the AUC0-24hr is 
approximately 25% and 29% higher in Hispanics as compared with Whites and Blacks, 
respectively. The Cmax is 22% and 31% higher in Hispanics as compared with Whites and 
Blacks, respectively. These differences are not considered clinically meaningful. There was no 
difference in AUC0-24hr or Cmax between Whites and Blacks. No dosage adjustment is 
necessary based on race. 
5. Hepatic Insufficiency 
Fosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic insufficiency is not 
expected to alter the conversion of fosaprepitant to aprepitant. Oral aprepitant was well tolerated 
in patients with mild to moderate hepatic insufficiency. Following administration of a single 125-
mg dose of oral aprepitant on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild 
hepatic insufficiency (Child-Pugh score 5 to 6), the AUC0-24hr of aprepitant was 11% lower on 
Day 1 and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In 
patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), the AUC0-24hr of 
aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy 
subjects given the same regimen. These differences in AUC0-24hr are not considered clinically 
meaningful; therefore, no dosage adjustment is necessary in patients with mild to moderate 
hepatic insufficiency. There are no clinical or pharmacokinetic data in patients with severe 
hepatic insufficiency (Child-Pugh score >9)  
6. Renal Insufficiency 
A single 240-mg dose of oral aprepitant was administered to patients with severe renal 
insufficiency (CrCl<30 mL/min) and to patients with end stage renal disease (ESRD) requiring 
hemodialysis. In patients with severe renal insufficiency, the AUC0-∞ of total aprepitant 
(unbound and protein bound) decreased by 21% and Cmax decreased by 32%, relative to healthy 
subjects. In patients with ESRD undergoing hemodialysis, the AUC0-∞ of total aprepitant 
decreased by 42% and Cmax decreased by 32%. Due to modest decreases in protein binding of 
aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was 
not significantly affected in patients with renal insufficiency compared with healthy subjects. 
Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the 
pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate. No 
dosage adjustment is necessary for patients with renal insufficiency or for patients with ESRD 
undergoing hemodialysis. 
 
4. Patient Selection 
A. Inclusion Criteria 
1. Patient receiving FOLFIRINOX chemotherapy 
2. SWOG Performance status 0 or 1 (See appendix 1) 

 
 
9
3. Age > 18 
4. Ability of patient or guardian to understand and to provide voluntary 
written informed consent 
 
 
B. Exclusion Criteria 
 
1. Patient with current illness requiring chronic systemic steroids use or requiring     
chronic use of anti emetics  
2. Patients with GI obstruction who cannot take oral medication 
3. Active peptic ulcer disease. 
4. Known Hypersensitivity to any component of the study regimen 
5. Patients taking any of the following medications: Oral Contraceptives (except for 
the administration of stopping menses), tolbutamide, phenytoin, midazolam, 
ketoconazole, rifampin, paroxetine, and Diltiazem  
6. Pregnant or nursing women 
7. Patients using illegal drugs 
 
Protocol Registration 
The attending physician will consider the patient for the study.  All patient information will 
be forwarded to the Data Management office (313-576-9385) for determination of eligibility.  
Upon informed consent and eligibility confirmation, the patient will be registered to the 
study.   
 
 
5. Pre-Study Evaluation 
 
1. 
Patients will undergo evaluation for chemotherapy treatment for advanced 
gastrointestinal cancer and planned for FOLFIRINOX chemotherapy. 
2. History and physical exam, weight, performance status would be documented 
3. Following labs are required 
a. BUN, creatinine  
b. electrolytes  
c. alkaline phosphatase, AST, ALT  
d. albumin  
e. bilirubin 
f. CBC+D 
g. Female patients must have a pregnancy test unless they have had a 
hysterectomy or menopause 
 
4. Patients will fill out a form on baseline nausea state including number of emetic 
episodes that day 
 
6. Treatment 
 
Patients will be treated with FOLFIRINOX chemotherapy every 2 weeks as standard of care for 
gastrointestinal cancer. The acceptable regimen for the clinical trial is shown in appendix 4.The 
premedication would include ondansetron (zofran) 16mg IVPB, dexamethasone 12 mg orally 
and the study drug which is fosaprepitant 150mg given intravenously 30 min prior to treatment. 
Dexamethasone 8mg orally will be given twice daily on days 2-4. Patients are to keep a diary 
daily from days 1-5 (5 days). They will record following information: 
 

 
 
10
1. Number of emetic episodes per day 
2. Date and time of each episode 
3. Use of any rescue nausea medication 
 
Patients will return on D3 for 5-FU pump removal and will be asked to bring in their diary for 
assessment of the nausea and vomiting.  On day 5 of the chemotherapy, patients will be 
contacted by phone for toxicity assessment by the study coordinator for the first cycle. In the 
subsequent cycles (cycle 2), diary would be used to collect the episode of nausea and vomiting 
and use of rescue nausea medications. The patient may continue on treatment and to take IV 
fosaprepitant with chemotherapy after cycle 2 if there is clinical benefit noted by the 
investigator.  After cycle 2 only survival data will be collected.    
        
 
7.  Dose Adjustments 
 
      Fosaprepitant will be held at the discretion of the PI with any of the Grade II toxicities that 
is likely related to use of the study medication.  Fosaprepitant will be discontinued if 
patient develops Grade IV toxicity following administration.  Investigator can use NCI 
common toxicity criteria for any toxicity encountered that is not specifically listed here and 
use instructions above. Patients will be considered treatment failure if more then two 
vomiting occurs within an hour and will be treated using other antiemetics.  
 
 
8. Criteria for evaluation and Endpoint assessment 
 
Nausea and vomiting will be assessed in two different time periods 
1. 0-24 hours will be defined as the acute phase 
2. 25-120 hours will be defined as the delayed phase 
Emesis Response 
1. Complete: Defined as no emetic episodes and no rescue medications 
2. Partial Response:  0-2 emetic episodes and no use of rescue medications 
3. Failed Response: >2 emetic episodes and/or use of rescue medications 
 
Patient will fill a diary from Days 1-5 (5 days), documenting detailed account of 
vomiting episodes. Patient will be assessed for delayed vomiting on a follow up visit with 
the study investigators or coordinator on Days 3.  
 
9. Reasons for removal from study 
a. Death 
b. Participant withdrawal 
c. Grade 3-5 toxicity from fosaprepitant (probably or definitely attributed to 
treatment) as judged by primary investigator 
d. Non- compliance to study drug during cycle 1 or cycle 2 
 
10. Statistical Considerations 
 
 
10.1 Objectives 
The primary objective of this study is to determine whether fosaprepitant has 
sufficient efficacy in controlling nausea and vomiting in patients receiving 
FOLFIRINOX chemotherapy as defined as complete response (no emetic episode 

 
 
11
and no rescue medication) in the combined acute and delayed phase from 0-120 
hours after first cycle of chemotherapy.  
 
The secondary objectives are to estimate the rates of control of a) acute and delayed 
vomiting and b) nausea..  
 
The tertiary objective is to estimate overall survival of enrolled patients.  
This endpoint will be assessed every 6 months from the start of cycle 1 using 
medical record data. 
 
10.2 Endpoints 
 
The primary endpoint is control of vomiting in the first cycle of chemotherapy. This 
endpoint will have been achieved if a patient has no episodes of vomiting and 
requires no rescue medication during the first 120 hours after fosaprepitant 
administration.  
 
The secondary endpoints are a) control of acute and delayed vomiting following 
fosaprepitant administration; b) control of acute and delayed nausea  during the first 
five days following fosaprepitant administration.  
 
The tertiary endpoints is overall survival defined as time of initiation of treatment 
until death or censor.  
 
10.3 Design 
 
A single stage optimal design was used for testing the null response (defined in the 
first paragraph in Section 10.1) rate (0.30) versus the alternative response rate 
(0.60). A sample size of 25 patients and a critical value of 12 responses results in a 
0.038 probability of concluding that the new treatment is effective, if the new 
treatment is actually not effective (Type I error). If the new treatment is actually 
effective, there is 0.922 power of concluding that it is effective. If the total number 
of patients who respond is 12 or more, then the response rate hypothesis under the 
null (0.30) is rejected in favor of the alternative (0.60). If the total number of 
patients who respond is 11 or less, then we fail to reject that the response rate 
hypothesis is 0.30.  
 
10.4 Statistical Analysis of the Primary Endpoint 
 
If the total number of patients who respond is 12 or more, then the response rate 
hypothesis under the null (0.30) is rejected in favor of the alternative (0.60). If the 
total number of patients who respond is 11 or less, then we fail to reject that the 
response rate hypothesis is 0.30.  
 
 
10.5 Statistical Analyses of the Secondary Endpoints 
 
The secondary endpoints (control of acute and delayed vomiting, control of nausea 
and toxicity) will be described with a point estimate and a Wilson’s two-sided 90% 
confidence interval.  
 
10.6 Statistical Analyses of the Tertiary Endpoint 

 
 
12
 
The response rate will be described with a point estimate and a Wilson’s two-sided 
90% confidence interval.  The Kaplan-Meier method will be used to estimate the 
survival curve for overall survival. 
 
10.7 Accural and study duration 
At this institution we see approximately 20-24 patients annually who would be 
eligible for this trial. To account for patients who may not be able to complete the 
treatment due to toxicity of chemotherapy, we propose to accrue an additional 5 
patients, resulting in a total of 30 patients. Thus, we expect that the study will require 
approximately 15 to 18 months to complete accrual. Allowing for 2 months of 
follow-up to obtain all endpoint information on the last patient enrolled and 2 months 
to assemble, analyze and interpret the data the total study duration is projected to be 
at most 22 months for all endpoints excluding overall survival. We will assess the 
overall survival endpoint every 6 months when the administrative database is 
updated. 
10.8 Toxicity Monitoring 
We have chosen a safety threshold of 0.25 to monitor toxic side effects. All enrolled 
patients will be evaluated for toxicity. We would recommend reconsidering the study 
for safety reasons if there were X many occurrences of grade 3 or higher toxicity 
(using the CTCAE guidelines) among the first N (or fewer) patients treated, as it 
would result in an upper confidence limit greater than 0.25: 
 
N 
X 
p 
UCL 
8 
1 
0.125 
0.255 
13 
2 
0.154 
0.256 
18 
3 
0.167 
0.253 
22 
4 
0.182 
0.261 
27 
5 
0.185 
0.256 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the above table, N = the number of patients treated; X = the cumulative number of 
patients with a grade 3 or higher toxicity currently observed; p = the observed toxicity 
rate; and UCL = the exact 1-sided upper 80% confidence limit for p, using Wilson's 
method without a continuity correction. 
 
 
11. Study Administration and Investigator Obligations 
a. Review Boards  
The study must have the approval of the Protocol Review and Monitoring 
Committee of the Clinical Trials Office at the Karmanos Cancer Institute 
and of the Wayne State University Institutional Review Board (IRB). 
b.  Informed Consent 
It is the responsibility of the investigator to design the Informed Consent 
form.  The consent form has been designed using appropriate National or 
Regional guidelines (equivalent to the American Federal Guidelines 
(Federal Register July 27, 1981 or 21 CFR Part 50) 
c. Adverse Events  

 
 
13
Definitions:  A serious adverse event is any experience that suggests 
significant hazard, contraindication, side effect, or precaution.  A serious 
adverse event includes any experience that: 
1. Is fatal or immediately life threatening 
2. Is severely or permanently disabling 
3. Requires or prolongs hospitalization 
All adverse effects will be noted in the patient’s medical record.  The 
adverse reactions must be reported to the data manager’s office, principal 
investigator and the local IRB using the following procedures: 
1.Unexpected and/or severe toxicities: any unexpected Grade 2 or 3 
toxicity (not previously reported in the literature or package insert) 
must be reported in writing on an Adverse Drug Reaction Form to the 
data manager’s office.  Any Grade 4 or 5 toxicity must be reported by 
phone to the data managers’ office within 24 hours of the event.  An 
Adverse Drug Reaction Form must be sent to the data manager’s 
office. 
2. Deaths:  within 30 days of study medication should be reported 
except if cause is secondary to cancer progression. 
3. Adverse Event reporting to the FDA: 
FDA shall be notified by telephone or by facsimile transmission of any 
unexpected fatal or life-threatening experience associated with the use of 
the drug as soon as possible but in no event later than 7 calendar days after 
the sponsor’s initial receipt of the information.  Each telephone call or 
facsimile transmission to FDA shall be transmitted to the FDA review 
division that has responsibility for review of the IND.  Principal 
investigator shall notify FDA and all participating investigators in a 
written IND safety report of any adverse experience associated with the 
use of the drug that is both serious and unexpected.  Each notification shall 
be made as soon as possible and in no event later than 15 calendar days 
after initial report of the information.  Each written notification may be 
submitted on FDA Form 3500A or in a narrative format and shall bear 
prominent identification of its contents, i.e., “IND Safety Report.”  Each 
written notification to FDA shall be transmitted along with a FDA Form 
1571 to the FDA division that has responsibility for review of the IND.  If 
FDA determines that additional data are needed, the agency may require 
further data to be submitted.  In each written IND safety report, the 
investigator shall identify all safety reports previously filed with the IND 
concerning a similar adverse experience, and shall analyze the significance 
of the adverse experience in light of the previous, similar reports. 
d. Termination of Study 
Specific instances that may precipitate termination are:  The incidence 
and/or severity of adverse drug experiences in this or other studies 
indicating a potential health hazard caused by the treatment. 
e. Study Amendments 
If the protocol requires an amendment, the amendment must be submitted to 
the IRB for approval together with a revised consent form, if applicable. 
f. Data Safety and Monitoring: Appendix 2 
 

 
 
14
Appendix 1: SWOG Performance Scale 
 
 
 
Grade  
 
 
 
 
Scale 
0 
Fully active; able to carry on all pre-disease activities without restriction 
(Karnofsky 90-100) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work 
(Karnofsky 70-80) 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours (Karnofsky 50-60) 
3 
Capable of only limited self-care; confined to bed or chair  (Karnofsky 30-40) 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair (Karnofsky 10-20) 
5 
Dead 
 
 
 

 
 
15
APPENDIX 2: DATA SAFETY AND MONITORING PLAN 
 
Adverse Event Reporting: 
Unexpected Grade 4 or 5 toxicities are to be reported to the Karmanos Clinical Trial Data 
Management Office by telephone (313-576-9385) within 24 hours of the event.  Unexpected 
Grade 2 and 3 toxicities are to be submitted in writing to 87 E. Canfield MM03CT, Detroit, MI 
48201.  Proper documentation will be submitted to the Wayne State University Institutional 
Review Board if it meets reporting requirements.  
 
Patient safety will be monitored by the PI and protocol data manager(s) on a monthly basis. At 
this time the safety of protocol participants, i.e., adverse event reporting will be reviewed.   
Merck Sharp & Dohme Corp. (Attn: Worldwide Product Safety; FAX 215 993-1220) will be 
provided with copies of all serious adverse experiences, regardless of causality, within two 
working days. Additionally, any pregnancy occurring in association with use of a Merck Product 
will be reported to Merck Sharp & Dohme Corp. (Attn: Worldwide Product Safety; FAX 215 
993-1220). A copy of all 15 Day Reports and Annual Progress Reports is submitted as required 
by FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other 
local regulators by the investigator. This submission will be cross referenced according to local 
regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of 
submission. Additionally, a copy of these reports will be submitted to Merck Sharp & Dohme 
Corp. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
In studies involving human subjects, serious adverse experience means any experience that 
suggest a significant hazard, contraindication, side effect or precaution. A serious adverse 
experience includes any experience that is fatal or immediately life threatening, results in a 
persistent or significant disability/incapacity, requires or prolongs in-patient hospitalization, or is 
a congenital anomaly, cancer, or overdose. Other important medical events that may not result in 
death, not be life-threatening, or not require hospitalization may be considered a serious adverse 
experience when, based upon appropriate medical judgment, the event may jeopardize the 
subject/patient and may require medical or surgical intervention to prevent one of the outcomes 
listed previously. 
 
Quarterly reporting of summary data will be provided to the Data and Safety Monitoring 
Committee for oversight of monitoring. Overall assessment of accrual, toxicities and responses 
will be done at this time to determine whether significant benefits or risks are occurring that 
would warrant study closure. Adherence to the protocol, i.e., protocol violations, and data 
completeness and integrity will also be reviewed at this time. 
 
One month prior to anniversary date of the IRB original approval, a yearly summary report of 
trial activities will be made to all participating co-investigators and the Data and Safety 
Monitoring Committee. This report will include the number of patients on the trial, the number 
of patients treated, a summary of all adverse events reported to date using CTC 3.0 grading 
(http://ctep.cancer.gov/forms/CTCAEv3.pdf), a specific list of serious adverse events requiring 
immediate reporting and any significant developments that may affect the safety of the 
participants or ethics of the study.

 
 
16
 
Appendix 3:  Baseline Nausea and Vomiting Form 
 
 
Patient Initials        -      -          Accrual Number                      . 
 
 
Date of assessment ___/___/____ 
 
Number of emetic episodes within the last 24 hours __________. 
 
An emetic episode is defined as: 
1. A single vomit or retch 
2. Continuous vomiting or retching separated by one minute. 
 
 
Number of nausea episodes within the last 24 hours __________. 
 
 
 
    Day 0:     /       / 
 
 
            0mm 
 
 
 
 
 
 
100mm 
 
 
 
 
 
 
                  Mild Nausea 
 
   No Nausea  
 
 
 
 
  Severe Nausea 
 
 
 
 
 
 
 

 
                                                                                                                                                      17 
Appendix 4: FOLFIRINOX chemotherapy 
 
 
The regimen is comprised of oxaliplatin 85 mg/m(2) and irinotecan 180 mg/m(2) plus 
leucovorin 400 mg/m(2) followed by bolus 5-FU 400 mg/m(2) on day 1, then 5- FU 2,400 
mg/m(2) as a 46-hour continuous infusion given every two weeks. The key components are 
oxaliplatin, irinotecan and infusional 5-FU. Bolus 5-FU and leucovorin doses can be modified or 
dropped per investigator’s discretion at any time. Oxaliplatin and irinotecan dose can be 
modified or dropped secondary to toxicity issues as per standard of care.  Use of biologic agents 
like bevacizumab and cetuximab that does not affect nausea and vomiting is also allowed per 
investigator.  

 
 
18
Appendix 5; Study Calendar 
 
 
 
 
 
 
Cycle 1 
 
 
Cycle 2 
Baseline 
PreStudy 
D1 
D2 
D3 
D4 
D5 
D1 
D2 
D3 
D4 
D5 
FU 
H& P 
X 
 
 
 
 
 
X 
 
 
 
 
 
PS 
X 
 
 
 
 
 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
X 
 
 
 
 
 
Cbc w/diff 
X 
 
 
 
 
 
X 
 
 
 
 
 
Multi phasic 
X 
 
 
 
 
 
X 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
Nausea/vomiting 
evaluation Form Baseline 
X 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
 
X 
 
 
 
 
X 
 
 
 
 
 
FOLFIRINOX 
 
X 
 
 
 
 
X 
 
 
 
 
 
Diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Nurse/Study 
coordinator Evaluation 
 
 
 
X 
 
 
 
 
 
 
 
 
Phone contact by 
Research nurse or study 
coordinator 
 
 
 
 
 
X 
 
 
  
 
 
 
FU every 6 mos from start 
of cycle 1 using medical 
records 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
The patient may continue to take IV fosaprepitant with chemotherapy after cycle 2 
if there is clinical benefit noted by the investigator.  

 
 
19
Appendix 6: Daily Diary 
(Day 1- 5)  
 
Patient Initials        -      -          Accrual Number                      . 
Please mark on the rulers below at what level your nausea is each morning.  
 
 
    Day 1:     /       / 
 
 
            0mm 
 
 
 
 
 
 
100mm 
 
 
 
 
 
 
                  Mild Nausea 
 
   No Nausea  
 
 
 
 
  Severe Nausea 
 
    
    Day 2:     /       / 
 
 
            0mm 
 
 
 
 
 
 
100mm 
 
 
 
 
 
 
                  Mild Nausea 
 
     No Nausea  
 
 
 
 
  Severe Nausea 
 
     
    Day 3:     /       / 
 
 
            0mm 
 
 
 
 
 
 
100mm 
 
 
 
 
 
 
                  Mild Nausea 
 
      No Nausea 
 
 
 
 
  Severe Nausea 
 
     
    Day 4:     /       / 
 
 
            0mm 
 
 
 
 
 
 
100mm 
 
 
 
 
 
 
                  Mild Nausea 
 
      No Nausea 
 
 
 
 
  Severe Nausea 
 
     
    Day 5:     /       / 
 
 
            0mm 
 
 
 
 
 
 
100mm 
 
 
 
 
 
 
                  Mild Nausea 
 
      No Nausea 
 
 
 
 
  Severe Nausea 
 
Emesis diary 
Episode 
Number 
Date 
Time 
Rescue Medication Used 
1 
  
  
  
2 
  
  
  
3 
  
  
  
4 
  
  
  
5 
  
  
  
6 
  
  
  
 
  

 
 
20
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