Conditions: Recurrent Nasopharynx Carcinoma
Keywords: Recurrent nasopharynx carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This is a pilot study to evaluate the response rates for patients undergoing high dose conditioning chemotherapy using Etoposide, Carboplatin and Ifosfamide followed by autologous stem cell transplantation for the treatment of recurrent Nasopharyngeal Cancer (NPC) in children, adolescents, and young adults.

Detailed description:
The use of high dose chemotherapy followed by autologous peripheral blood stem cell (PBSC) transplantation in recurrent nasopharyngeal carcinoma has shown promise when compared with standard chemotherapy. This study has been designed to evaluate response rates and toxicities associated with undergoing high dose conditioning with Etoposide, Carboplatin and Ifosfamide followed by autologous stem cell transplantation support in the treatment of recurrent nasopharyngeal carcinoma in children, adolescents, and young adults.

Arms:
arm 1: Single arm - receives high dose Etoposide phosphate, Ifosfamide, and Carboplatin followed by Autologous Stem Cell Transplantation

Interventions: intervention 1: Etoposide phosphate intervention 2: Carboplatin intervention 3: Ifosfamide intervention 4: Autologous Stem Cell Transplantation
Intervention descriptions: intervention 1: Etoposide is one of three drugs used in the high-dose conditioning phase intervention 2: Carboplatin is one of the drugs used in the high-dose conditioning phase. intervention 3: Ifosfamide is one of the drugs used in the high-dose conditioning phase intervention 4: Autologous Stem Cell Transplantation follows the high-dose chemotherapy phase of the arm.

Protocol document:
Prot_SAP_000.pdf: 
High Dose Conditioning With Ifosfamide, Carboplatin, and Etoposide With Autologous Stem Cell 
Transplantation for Patients With Recurrent Nasopharyngeal Carcinoma   
NCT02137096 
03/23/2017 


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HIGH DOSE CONDITIONING WITH IFOSFAMIDE, CARBOPLATIN AND ETOPOSIDE 
WITH AUTOLOGOUS STEM CELL TRANSPLANTATION FOR PATIENTS WITH 
RECURRENT NASOPHARYNGEAL CARCINOMA 
 
Investigator(s): 
           John Fort, MD 
Paul Castillo, MD 
John Wingard, MD 
 
1. ABSTRACT / PURPOSE:  
Nasopharyngeal carcinoma (NPC) is a rare disease in children and adolescents in the 
United States.  There is no current standard treatment for recurrent disease.  Treatment is 
individualized based on previous treatment (usually combined modality radiation and 
chemotherapy), sites of disease recurrence, and the patient’s overall health status and 
anticipated tolerance of additional chemotherapy and radiotherapy. NPC is a highly 
chemosensitive disease, however, maintaining long-term remission is challenging. The 
role of consolidation with high dose chemotherapy has been investigated in number of 
pilot studies and shown to be tolerated. In this study, based on prior experience, the 
combination of high dose ifosfamide, carboplatin and etoposide followed by autologous 
stem cell rescue will be investigated as a consolidation therapy for locally advanced and 
metastatic NPC to increase disease remission rate and long term survival.  
 
2. BACKGROUND:  
Nasopharyngeal carcinoma (NPC) is a rare tumor in children accounting for 
approximately 1% of all childhood tumors, it also accounts for 20 – 50% of all primary 
nasopharyngeal tumors in this age group1,2.  It arises from the surface epithelial cells of 
the nasopharynx and has been associated with Epstein-Barr virus (EBV) infection2.  Most 
patients with childhood NPC have undifferentiated histology (WHO type III) and present 
with locoregionally advanced disease2. Pediatric and adolescent patients are treated 
based on adult regimens with radiotherapy as the principal mode of treatment3.  The 
addition of chemotherapy has been shown to improve survival in patients with locally 
advanced NPC4.   Despite standard combined modality therapy, 20 – 30% of patients 
with NPC will present with recurrent or metastatic disease4.  Most recurrences occur 
within the first two years of diagnosis and repeat radiation therapy is often not an option.  
Various combinations of chemotherapy have been tried in adults and in children with 
varying results, but overall response and survival have remained dismal.   
The use of high dose chemotherapy followed by autologous peripheral blood stem cell 
(PBSC) transplantation in recurrent NPC has shown promise when compared with 
standard chemotherapy.  Airoldi and colleagues5 reported long-term results of high dose 
chemotherapy as late intensification with autologous PBSC support in 6 patients. After 
conventional chemotherapy, there was 1 CR (16%), 3 PR (50%), and 2 NC (34%). After 
high dose chemotherapy, 4 patients achieved CR (66%), 1 PR (17%), and 1 MR (17%). 
Toxicity was manageable. After a median follow-up of 30 months (range, 14-50), two 


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patients were alive without disease (34%), one was alive with bone disease (16%), and 
three (50%) died of disease at 16, 18, and 24 months5. 
Chen T-Y et al also reported that high dose chemotherapy followed by autologous stem 
cell transplantation is feasible with acceptable toxicity and can convert partial remission 
into complete remission6.     
3. SPECIFIC AIMS: 
3.1. To evaluate the response rates for patients undergoing high dose conditioning 
using Etoposide, Carboplatin and Ifsofamide followed by autologous stem cell 
transplantation for the treatment of recurrent NPC in children, adolescents, and 
young adults. 
3.2. To evaluate the toxicities associated with undergoing high dose conditioning using 
Etoposide, Carboplatin and Ifsofamide followed by autologous stem cell 
transplantation for the treatment of recurrent NPC in children, adolescents, and 
young adults.  
4. RESEARCH PLAN: 
4.1. Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonisation (ICH) and in 
accordance with the ethical principles underlying European Union Directive 
2001/20/EC and the United States Code of Federal Regulations, Title 21, Part 50 
(21CRF50).  
The study will be conducted in compliance with the protocol.  The protocol, any 
amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion before 
initiation of the study. 
All potential serious breaches must be reported to University of Florida IRB-01.  A 
serious breach is a breach of the conditions and principles of GCP in connection 
with the study or the protocol, which is likely to affect, to a significant degree, the 
safety or physical or mental integrity of the subjects of the study or the scientific 
value of the study.  
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective tasks.  This study will not use 
the services of study personnel where sanctions have been evoked or where 
there has been scientific misconduct or fraud (eg. loss of medical licensure, 
debarment).  Systems with procedures that ensure the quality of every aspect of 
the study will be implemented.  
4.2. Institutional Review Board/Independent Ethics Committee 
Investigators must ensure that subjects (or, in those situations where consent 
cannot be given by subjects, the legally acceptable representative) are clearly and 
fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which they volunteer to participate.  Freely given 


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written informed consent must be obtained from every subject (or, in those 
situations where consent cannot be given by subjects, the legally acceptable 
representative) before clinical study participation including informed consent for 
any screening procedures conducted to establish subject eligibility for the study. 
The rights, safety, and well being of the study subjects are the most important 
considerations and should prevail over interests of science and society. 
Subjects unable to give their written consent (eg. children less than 18 years of 
age, stroke patients, or those with sever dementia) may be enrolled in the study 
only with the consent of a legally acceptable representative.  The subject must 
also be informed about the nature of the study to the extent compatible with the 
subjects’ understanding, and should they become capable, they must personally 
sign and date the consent form as soon as possible.  The explicit wish of a subject 
unable to give his or her consent, who is capable of forming an opinion and 
assessing this information to refuse participation in, or to be withdrawn from, the 
clinical study at any time should be considered by the investigator.  
5. INVESTIGATIONAL PLAN 
5.1. Study Design 
This is a Pilot study evaluating the role of high dose conditioning with Ifosfamide, 
Carboplatin, and Etoposide with autologous stem cell transplantation for children, 
adolescents and young adults with recurrent nasopharyngeal carcinoma. 
 
5.2. Number of Patients Planned 
A total of 10 patients are planned to be included in this study. 
 
5.3. Duration of Treatment 
The subjects will be on treatment for approximately 3 months which includes the 
pre-treatment evaluations, the conditioning treatment, and 6-8 weeks of post 
treatment supportive care. 
  
5.4. Duration of Follow-Up 
The subjects will begin follow-up care and the time of initial discharge after 
transplant and continue for up to 5 years from date of stem cell transplant or until 
death or patient withdrawal.  
 
5.5. Study Population 
5.5.1. Inclusion Criteria 
5.5.1.1. 
Pathologically confirmed nasopharyngeal carcinoma at original 
diagnosis. 
5.5.1.2. 
Imaging and/or tissue diagnosis of second or greater recurrent or 
progressive nasopharyngeal carcinoma 
5.5.1.3. 
Documentation of previous treatment including conventional 
chemotherapy and/or radiation therapy as clinically appropriate. 
5.5.1.4. 
Ages 2 to 30 years of age. 
5.5.1.5. 
Negative serum pregnancy test if applicable. 
5.5.1.6. 
Subjects must agree to use contraception if they are of childbearing 
age. 


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5.5.1.7. 
Prior to initiation of high dose conditioning patient must have 
completed leukapheresis and stem cell preservation in accordance 
with institutional standards, with a minimum collection of 4 x 106/kg 
CD34+ cells desired. Separate institutional informed consent forms will 
be used. 
5.5.1.8. 
Prior to initiation of high dose conditioning patients must have 
calculated creatinine clearance of greater than 60 mL/minute, serum 
creatinine of less than 120 mg/DL, total bilirubin less than 2 mg/dL and 
AST must be less than twice the upper limit of normal. 
5.5.1.9. 
Hematopoietic recovery prior to initiation of high dose conditioning 
would include ANC of greater than 1 x 109/L, and platelets greater than 
100,000 x 109/L; or at the discretion of the attending physician based 
upon clinical situation.  
5.5.1.10. Patient and/or parent or legal guardian to sign informed consent 
form. 
 
5.5.2. Exclusion Criteria 
5.5.2.1. 
Patient deemed unsuitable for autologous transplantation due to 
comorbidities or intractable psychosocial issues. 
5.5.2.2. 
Failure to give written informed consent.  
5.5.2.3. 
Pregnancy 
5.5.2.4. 
Breast-feeding women 
 
5.5.3. Discontinuation of Subjects from Treatment 
5.5.3.1. 
Withdrawal of informed consent (subject’s decision to withdraw for 
any reason) 
5.5.3.2. 
Progressive disease at any time 
5.5.3.3. 
Any clinical adverse event (AE), laboratory abnormality, or 
intercurrent illness which, in the opinion of the investigator, indicates 
that continued participation in the study is not the best interest of the 
subject. 
5.5.3.4. 
Pregnancy 
 
5.5.4. Treatment Plan 
5.5.4.1. 
Stem Cell collection and cryopreservation of peripheral blood 
stem cells  
5.5.4.1.1. 
The patient will undergo a collection of adequate numbers of 
hematopoietic stem cells.  Stem cell harvesting may be done after 
priming with a cytokine (G-CSF, GM-CSF or other factors used 
singly or in combination according to institutional preference) or 
they may be collected following the salvage chemotherapy during 
the rebound phase with cytokine support.  Chemotherapy in 
combination with growth factors is also allowed. 
5.5.4.1.2. 
Stem cells should be collected no longer than six weeks 
after completion of last cycle of salvage chemotherapy.  The 
patient will undergo leukapheresis according to standard 
institutional procedures to collect a minimum of 4 x 106/kg CD34+ 
cells desired. Separate institutional informed consent forms will be 
used. 


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5.5.4.1.3. 
The collected cells must be cryopreserved according to 
accepted methods using DMSO alone or DMSO/HES.  The stem 
cells should not be purged or CD34 selected.  The collected stem 
cells will be reinfused after conditioning chemotherapy.   
5.5.4.1.4. 
Patients who fail to collect adequate CD34 cells will be 
excluded from the study.  
5.5.4.1.5. 
Stem cells will be thawed and infused according to standard 
institutional practices on Day 0.  
5.5.4.1.6. 
Patient may receive premedication with diphenhydramine, 
mannitol, hydrocortisone and acetaminophen per institutional 
protocol.    
 
5.5.4.2. 
All patients transplanted per the PEDIATRIC BMT SERVICE will 
have chemotherapy dosed on actual body weight.  If the patient’s 
weight is more than 130% of their ideal body weight, then calculate the 
doses of chemotherapy according to the adjusted ideal body weight 
suing the following formula: 
 
 
Adjusted ideal body weight = ideal body weight + [ (total body weight-
ideal body weight) x 0.25]. 
 
5.5.4.2. 
Dose modifications may occur as clinically indicated, at the 
discretion of the treating physician. 
5.5.4.3. 
Mesna shall be started prior to initiation of Ifosfamide administration 
per institutional standard.  Other measures of uroprotection, such as 
hydration and furosemide shall be carried out per institutional standard 
and at the discretion of the treating physician. 
5.5.4.4. 
Renal function shall be monitored as per institutional standard and 
Carboplatin dose adjusted if clinically indicated. 
 
DAYS BEFORE TRANSPLANT 
Treatment             Day -
5 
Day-4 
Day-3 
Day-2 
Day -
1 
Day 0 
Ifosfamide (2.5 g/m2 
/day)  
IV over 17 hours 
for four days  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Carboplatin (300 
mg/m2/day) 
IV over 3 hours 
for four days 
 
X 
 
X 
 
X 
 
X 
 
 
Etoposide 
(300mg/m2/day) 
IV over 3 hours 
for four days 
 
X 
 
X 
 
X 
 
X 
 
 
Stem Cell Infusion  
(Minimum 48 of hours 
from last dose). 
 
 
 
 
 
 
X 


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5.5.5.  Supportive Care 
5.5.5.1. 
Prophylaxis with antiemetics for immediate and delayed nausea 
and vomiting shall be administered as per current supportive care 
guidelines. 
5.5.5.2. 
Subjects will have a multilumen indwelling venous catheter placed 
prior to initiation of therapy. 
5.5.5.3. 
Antibacterial, antiviral and antifungal prophylaxis/treatment will be 
administered in accordance with current supportive care guidelines. 
5.5.5.4. 
Blood component support will be administered in accordance with 
current supportive care guidelines. 
5.5.5.5. 
Growth factor support will be administered in accordance with the 
current supportive care guidelines. 
5.5.6.  Possible Risks 
5.5.6.1. 
Aggressive supportive care improves outcome. This study will 
follow the institutional supportive care guidelines for high-dose 
chemotherapy and stem cell transplant. 
5.5.6.2. 
The possible risks of this treatment include those associated with 
high-dose chemotherapy and autologous stem cell transplantation 
including:  
1. Pancytopenia requiring transfusion support 
2. Bacterial infection 
3. Fungal infection 
4. Nausea, vomiting 
5. Loss of appetite 
6. Mucositis 
7. Alopecia 
8. Allergic reactions to the chemotherapy agents or supportive care 
agents 
9. Liver damage 
10. Kidney damage 
11. Hemorrhagic cystitis  
12. Sinusoidal obstruction syndrome (SOS) of the liver  
13. Engraftment syndrome 
14. DMSO adverse effects during stem cell infusion 
     5.5.6.3.   Drug specific risks are listed below: 
 
 
Possible Side Effects of Carboplatin and Etoposide (Table Version Date: October 
8, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin, Etoposide, more than 20 and up to 100 may 
have: 
 Hair loss 
 Vomiting, nausea, diarrhea, loss of appetite 
 Infection, especially when white blood cell count is low 


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COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin, Etoposide, more than 20 and up to 100 may 
have: 
 Anemia which may require blood transfusions 
 Bruising, bleeding 
 Belly pain 
 Sores in mouth which may cause difficulty swallowing 
 Tiredness 
 Fever, chills 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin, Etoposide, from 4 to 20 may have: 
 Constipation 
 Numbness and tingling in fingers and toes 
 Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
 Heart failure or heart attack which may cause chest pain, shortness of breath, 
swelling of ankles, and tiredness 
 Severe skin rash with blisters and peeling which can involve inside of mouth and 
other parts of the body 
 Liver damage which may cause yellowing of eyes and skin, swelling 
 
RARE, AND SERIOUS 
In 100 people receiving Carboplatin, Etoposide, 3 or fewer may have: 
 Changes in vision 
 Changes in taste 
 Damage to organs which may cause hearing and balance problems 
 Cancer of bone marrow (leukemia) caused by chemotherapy 
 
 
Possible Side Effects of Filgrastim (Table Version Date: October 24, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Filgrastim, more than 20 and up to 100 may have: 
 Nausea, vomiting 
 Pain in bone 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Filgrastim, from 4 to 20 may have: 
 Anemia which may cause tiredness, or may require transfusion 
 Damage to the lungs which may cause shortness of breath 
 Internal bleeding which may cause coughing up blood 
 Swelling or tenderness of vessels 
 
RARE, AND SERIOUS 
In 100 people receiving Filgrastim, 3 or fewer may have: 


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RARE, AND SERIOUS 
In 100 people receiving Filgrastim, 3 or fewer may have: 
 Rupture of the spleen leading to bleeding in the belly 
 
Possible Side Effects of Ifosfamide (Table Version Date: May 28, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Ifosfamide, more than 20 and up to 100 may have: 
 Anemia which may require transfusion 
 Nausea, vomiting 
 Infection, especially when white blood cell count is low 
 Blood in urine 
 Hair loss 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Ifosfamide, from 4 to 20 may have: 
 Abnormal heartbeat 
 Bruising, bleeding 
 Kidney damage which may cause swelling, may require dialysis 
 Fluid around lungs 
 Confusion, sleepiness, disorientation 
 Sterility 
 
RARE, AND SERIOUS 
In 100 people receiving Ifosfamide, 3 or fewer may have: 
 Damage to the heart or heart failure which may cause tiredness, shortness of 
breath, or swelling of ankles 
 
Possible Side Effects of Mesna (Table Version Date: May 28, 2013) 
 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Mesna, more than 20 and up to 100 may have: 
 Nausea, vomiting 
 Tiredness, headache 
 Pain in arms, legs 
 Unpleasant taste 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Mesna, from 4 to 20 may have: 
 Low blood pressure which may cause feeling faint 
 
RARE, AND SERIOUS 
In 100 people receiving Mesna, 3 or fewer may have: 
 None 
 


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Possible Side Effects related to blood stem cell harvest and infusion 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Ifosfamide, more than 20 and up to 100 may have: 
 Nausea and vomiting 
 Unpleasant taste and smell of agent used to preserve stem cells when frozen 
 Headache 
 Fever 
 Discolored urine 
 Tingling of the lips 
 Muscle cramping 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Ifosfamide, from 4 to 20 may have: 
 Seizures (rare) 
 Blood loss 
 Infection 
 Skin rash, hives 
 Flushing (redness and warmness of the skin) 
 Dizziness or fainting 
 Chills 
 Changes in heart rhythm (rare and easily treated) 
 
 
RARE, AND SERIOUS 
In 100 people receiving Ifosfamide, 3 or fewer may have: 
 In rare cases, patients have allergic reactions (may be life threatening) 
 Increased bleeding or clotting (caused by a drug to prevent clotting of the 
blood during collection) 
 
 
6.  STORAGE, HANDLING, AND DISPENSING 
6.1. All chemotherapy agents are commercially available and will be stored handled 
and dispensed per institutional protocols.  
6.2. The use of Etoposide, Ifosfamide, and Carboplatin in this trial are approved use 
of FDA approved drugs.  When a drug or combination of drugs are used in such 
a manner as part of a clinical trial, it is by rule, considered as an investigational 
treatment regimen.  However, while these treatment regimens are not approved 
by the FDA, their use is exempt from the requirements for an IND to conduct this 
study as defined under Title 21, CFR 312.2(b) of the codified FDA regulations. 
7. DOSE MODIFICATIONS 
7.1. All toxicities should be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0. 


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7.2. Dose modifications are based on dose level administered on the last treatment 
day.  Dose adjustments of each agent may be made independently based on the 
specific toxicities observed.   
7.3. Blinding/Unblinding is not applicable to this protocol. 
8. STUDY ASSESSMENTS AND PROCEDURES 
 
 
Baseline 
Day -5 to 
+14 or 
Discharge 
(Daily 
unless 
stated 
otherwise) 
After 
Discharge: 
Weekly 
until stable  
Day 
30 
Day 
100 
Every 3 
– 6 
months 
1 
Year 
Yearly 
until 5 
years from 
transplant 
H&P with 
VSS 
X 
X 
X 
X 
X 
X 
X 
X 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assess 
 
X 
X 
X 
X 
X 
 
 
ECG, ECHO,  
and/or MUGA  
Scan, and/or 
Cardiac MRI 
X 
 
 
 
 
 
X 
yearly if 
abnormal  
PFT’s 
X 
 
 
 
 
 
X 
yearly if 
abnormal 
CBC &  Diff 
X 
X 
X 
X 
X 
X 
X 
X 
PT/PTT/INR 
X 
 
 
 
 
 
 
 
BMP, Mg, 
Phos 
X 
X 
X 
X 
X 
X 
X 
X 
LFT’s, LDH 
X 
Weekly  
X  
X 
X 
 
X 
X 
TFT’s (TSH, 
free T4) 
X 
 
 
 
 
 
X 
X 
IgG 
X 
 
 
X 
X 
 
X 
 
CD4, CD8 
 
 
 
X 
X 
 
X 
 
CT or MRI 
Primary / 
Metastatic 
Site 
X 
 
 
 
X 
X (at 6 
months 
and 9 
months) 
X 
X 
PET Scan  
X 
 
 
 
X 
X (at 6 
and 9 
months) 
X 
X 


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Audiogram 
X 
 
 
 
 
 
X 
 
Creatinine 
Clearance or 
GFR 
X 
 
 
 
 
 
 
 
DEXA Scan 
 
 
 
 
 
 
X 
 
9. SAFETY ASSESSMENTS 
9.1. Subjects must undergo a history and physical examination by a licensed provider 
daily while in hospital and at each follow-up visit. 
9.2. Laboratory testing should be completed as outlined in the study schedule.  
Additional laboratory testing may be done at the Investigator’s discretion. 
10. EFFICACY ASSESSMENTS 
10.1. 
Tumor response will be assessed using MRI/CT/PET imaging of the 
primary site and know metastatic sites. 
10.2. 
Measureable disease: the presence of at least one measurable lesion that 
can be accurately measure in at least one dimension (the longest diameter) and 
with a minimum size of 10 mm by CT or MRI scan. 
10.3. 
Non-measurable lesions: all other lesions including leptomeningeal disease, 
pleural/pericardial effusion, and blastic bone lesions. 
10.4. 
All measurements should be recorded in metric notation, using a ruler or 
calipers using the same method of assessment to characterize each identified 
and reported lesion at baseline and during follow-up. 
10.5. 
All baseline evaluation should be performed as close as possible to the 
initiation of conditioning treatment and not more than 30 days before conditioning 
treatment begins. 
10.6. 
Response Criteria include: 
 
11. Response Criteria for Patients with Solid Tumors 
 
This study will use a modified version of the Response Evaluation Criteria in Solid  
tumor (RECIST) from the NCI to evaluate disease response. The modifications will  
include volumetric measurement of the primary NPC and assessment of associated  
adenopathy. Measurable and non-measurable metastatic foci in the lungs, bones 
and liver will be evaluated as per RECIST. 
12. ADVERSE EVENT REPORTING 


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12.1. 
 An adverse event (AE) is defined as any new untoward medical occurrence 
or worsening of a pre-existing medical condition in a patient or clinical 
investigation subject administered an investigational (medicinal) product and that 
does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding) symptom, or disease temporally associated with the use of the 
investigational product, whether or not considered related to the investigational 
product.  
12.2. 
 Serious Adverse Events – any untoward medical occurrence that at any 
dose:  
 Results in death 
 Is life-threatening (defined as an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more 
severe 
 Requires inpatient hospitalization or causes prolongation of existing 
hospitalization 
 Results in persistent or significantly disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is an important medical event, defined as a medical event that may 
not be immediately life threatening or result in death or 
hospitalization but, based on appropriate medical and scientific 
judgment, may jeopardize the subject or may require intervention 
(eg. medical, surgical) to prevent one of the other serious 
outcomes listed above.  
 All pregnancies, regardless of outcome must be reported including 
pregnancies that occur in the female partner of a male subject.  All 
pregnancies must be followed to outcome. 
12.3. 
Non-serious Adverse Events –all adverse events that are not classified as 
SAE’s. 
12.4. 
All adverse events, including those that are serious will be graded according 
to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCICTCAE, Version 4.0. 
12.5. 
 The following categories and definitions of causal relationship to 
investigational product as determined by a physician should be used: 
1 
Related – there is a reasonable causal relationship to the 
investigational product administration and the adverse event. 


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2 
Not Related – there is not a reasonable causal relationship to 
investigational product administration and the adverse event. 
12.6  
SAE Reporting: All grade 3 non-hematologic SAE’s must be collected, 
including those thought to be associated with protocol-specified procedures.  
Collection of all SAEs must continue for 60 days after the last administration of the 
investigational products.  All SAE’s must be reported to UF-IRB-01 within 5 working 
days. 
12.7  
Laboratory Test Abnormalities – all laboratory test results captured as 
part of the study should be recorded following institutional procedures.  In general, 
non-clinically significant laboratory deviations are not considered adverse events.  
Laboratory deviations which require treatment delay, modification or discontinuation 
or are otherwise clinically significant should be reported as adverse events. 
13. DATA SAFETY MONITORING PLAN 
 
This protocol will adhere to the policies of the UF Health Shands Cancer 
Center Data and Safety Monitoring Plan, in accordance with NCI 
regulations.  The Data and Safety Monitoring Committee will review all 
serious adverse events and toxicity reports as well as annual reviews.  
The investigator will continuously monitor the progress of the study and 
the safety of the participants.  All adverse events will be evaluated for 
causality and reported to the appropriate oversight committees as 
required. 
 
14. DATA MANAGEMENT SYSTEM 
 
To provide data collection we will utilize the ONCORE database for both 
accrual entry and trial data management.  ONCORE is a Clinical Trials 
Management System designed with the capability for: study setup, 
activation, tracking, reporting, data monitoring and review and eligibility 
verification.  It is housed on secured servers maintained at the University 
of Florida Health Science Center on the University of Florida campus.  
The e- CRFs on ONCORE are 21 CFR part 11 compliant, and all users 
are assigned password protected user accounts. 
 
15. STATISTICAL CONSIDERATIONS 
 
Statistical analyses will be conducted by the study biostatistician using 
SAS v9.1 (SAS Institute, Cary, NC). 
 
Routine data listing or tabulation review during the study conduct will be 
performed to identify missing data, anomalies, outliers, etc.  Missing 
data will generally not be imputed.  Baseline is defined as the last non-
missing measurement for a variable prior to the initial dose of any 
investigational product. 


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Descriptive statistics will be provided to summarize demographic and 
baseline characteristic parameters.  Categorical data will be summarized 
as frequency and its corresponding percentage.  For continuous data, 
frequency (n), mean, standard deviation, median (as appropriate), 
minimum, and maximum will be provided for each parameter. 
 
15.1         Sample Size Determination 
 
This is a pilot study and due to the limited number of potential patients 
who may present with this rare disease, a sample size of 10 patients was 
chosen based on availability. 
 
15.2        Analysis of the Primary Endpoint 
 
PFS is defined as the time from treatment start to the first of either (1) 
documented disease progression or (2) death as a result of any cause.  
Patients who did not progress nor die or are lost to follow-up will be 
censored at the day of their last objective tumor assessment.  The 
Kaplan-Meier method will be used to estimate the median PFS time, 
together with a 95% confidence interval (CI).  PFS will be determined 
by MRI imaging. 
 
15.3        Analysis of Secondary Endpoints 
 
The objective RR is equal to the proportion of patients achieving a best 
overall response of partial or complete response (CR + PR), according to 
imaging 
from 
the 
start 
of 
the 
treatment 
until 
disease 
progression/recurrence.  Clinical benefit rate is equal to the objective RR 
plus the proportion of patients attaining stable disease (CR + PR + SD). 
Patients who do not have a tumor response assessment for any reason 
will be considered nonresponders and will be included in the 
denominator when calculating the response rate.  The number of 
patients achieving a response will be divided by the total of patients 
treated to yield the proportion responding.  Exact confidence bounds 
(95% CI) will be calculated. 
 
Overall survival is defined as the time from the date of treatment start to 
the date of death from any cause.  If the patient is alive at the end of the 
follow-up period or is lost to follow-up, OS will be censored on the last 
date the patient is known to be alive.  OS will be evaluated by the 
Kaplan-Meier method and a 2-sided 95% CI will be provided for the 
median OS. 
Time to progression (TTP) for responders only is measured from the time 
measurement criteria are first met for CR/PR (whichever is first recorded) 
until the first date that the criteria for PD are met, or death.  TTP will be 


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estimated with the Kaplan- Meier method; a 90% CI will be provided for 
the median TTP.  Patients who do not relapse are censored at the day of 
their last objective tumor assessment.  The freedom from metastasis rate 
is defined below and will be calculated based on an intention to treat 
principle.  Determination of the anatomic site of first failure for patients 
with PD will be recorded and analyzed.  Duration of response is also 
defined below. 
 
15.4         Analysis of Safety Data 
 
Safety analyses will be performed on all patients who receive any dose 
of study medication.  Adverse events that occur more than 30 days after 
the administration of the last dose of treatment will not be included. 
 
The safety and tolerability of study drug is determined by reported AEs, 
physical examinations, laboratory tests, and ECGs.  All patients will be 
assessed regularly for potential occurrence of AEs from the time that 
treatment starts until 60 days after the last dose of study therapy.  AEs 
will be summarized with the incidence and percentage of patients with at 
least one occurrence of a preferred term (according to the most severe 
NCI-CTCAE Version 4.0 grade) will be included.  The number of AEs 
reported will also be summarized.  Causality (relationship to study drug) 
will be summarized separately. Duration of AE will be determined and 
included in listings along with action taken and outcome.  Laboratory AEs 
will be monitored from the time that treatment starts until 30 days after 
the last dose of study therapy.  Laboratory results will be classified 
according to NCI-CTCAE, Version 4.0.  Incidence of laboratory 
abnormalities will be summarized; laboratory results not corresponding to 
an NCI-CTCAE Version 4.0 term will not be graded.  Laboratory toxicity 
shifts from baseline to worst grade will also be provided. The results from 
physical examination and vital sign measurement will be tabulated. 
Descriptive statistics will be provided as appropriate. 
 
15.5        Duration of Response and other Endpoint Definitions 
 
The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started), or death. 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is 
objectively documented, or death. 
 


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Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started. 
 
Rate of freedom from metastasis (FFM) is defined as the proportion of 
patients with documentation of progression of disease, during study 
participation, in whom no new lesions appeared. 
 
In rare situations where PD or other endpoints could not be clearly 
assessed, the PI will review the records with the treating physician and 
provide a clinical judgment for purposes of endpoint documentation. 
 
16  ADMINISTRATIVE SECTION 
 
16.1        Compliance with the Protocol 
 
The study must be conducted as described in the final IRB/IEC-
approved protocol. Documentation of approval, signed by the IRB/IEC 
chairperson or designee, will be sent to the BMS protocol manager. 
 
All protocol amendments and revisions to the informed consent will be 
submitted to the BMS protocol manager and to the IRB/IEC. No protocol 
amendments will be implemented until written approval has been given 
by the IRB/IEC, except when necessary to eliminate an immediate 
hazard to study subjects. Administrative letters should also be sent to 
the BMS protocol manager and IRB/IEC; however, they do not require 
approval. 
 
If a protocol amendment mandates a revision to the informed consent, the 
revised consent must be used to obtain consent from subjects currently 
enrolled in the study if it affects them (eg, if it contains new information 
regarding safety), and the revised consent must be used to obtain 
consent from new subjects before enrollment. 
 
16. 2         Records Retention 
 
The investigator will retain, in a confidential manner, all data pertinent to 
the study for all treated subjects as well as those entered as control 
subjects. The investigator will retain source documents and accurate case 
histories that record all observations and other data pertinent to the 
investigation (eg, the medical record) for the maximum period required by 
applicable regulations and guidelines or following institutional procedures. 
If the investigator withdraws from the study (eg, relocation or retirement), 
the records will be transferred to a mutually agreed upon designee, such 
as another investigator or an IRB. Written documentation of such transfer 
will be provided to BMS. 


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17.  GLOSSARY OF TERMS 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by 
either the investigator or the sponsor to be 
related to the investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that 
are suspected (related to the investigational 
product) and unexpected (ie, not previously 
described in the Investigator Brochure), or that 
could be associated with the study procedures. 
SUSAR 
Suspected, Unexpected, Serious Adverse 
Reaction as termed by the European Clinical 
Trial Directive (2001/20/EC). 
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of 
which is not consistent with the applicable 
product information (eg, Investigator Brochure for 
an unapproved investigational product) 
 
 
 
 
18. 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ANC 
Absolute Neutrophil Count 
BID 
Twice a Day 
CAT ( or CT scan) Computed Axial Tomography 
CBC 
Complete Blood Count 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
EKG 
Electrocardiogram 
ESR 
Expedited Safety Report 
FDA 
Food and Drug Administration 


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GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IST 
Investigator-Sponsored Trial 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NSAE 
Non-Serious Adverse Event 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO 
By Mouth 
PR 
Partial Response 
QD 
Once Daily 
RECIST 
Response Evaluation Criteria In Solid Tumors 
 
19.   
REFERENCES 
 
1.  
El-Husseiny, G., Allam, A., Khafaga, Y., Kandil, A., Belal, A., Shalaby, L. 
eta al. (2000). Nasopharyngeal carcinoma in children and adolescents. J Egypt 
Nat Cancer Inst, 12:151-55. 
2.  
Kus, A.B., Sahin, P., Ugus, A.H., Tanyeli, A., & Kupeli, S. (2014). 
Leukemoid reaction associated with pediatric naspharyngeal carcinoma: An 
unusual presentation.  Int J. Pediatr Otorhinolaryngol, 78:885-7. 
3.  
Shen, C., Gao, Y, Xu, T., Wang, X, Ying, H. & Hu, C. (2009). Carcinoma 
of the nasopharynx in young patients: A single institution experience.  Clin 
Oncology, 21: 617-22. 
4.  
Yoshizaki, T., Ito, M, Murono, S., Wakisaka, N., Kondo, S. & Endo, K. 
(2012). Current understanding and management of nasopharyngeal carcinoma. 
Auris Nasus Larynx, 39:137-44. 
5. 
Airoldi, M., DeCrescenzo, A., Pedani, F., Marchionatti, S., Gabriele, AM, 
Succo, G., Rosti, G., & Bumma, C. (2001). Feasibility and long-term results of 
autologous PBSC transplantation in recurrent undifferentiated nasopharyngeal 
carcinoma. Head & Neck, 23:799-803. 
6. 
Chen, T.Y., Chen, H.H., Su, W.C., & Tsao, C.J. (2003). High-dose 
chemotherapy and hematopoietic stem cell transplantation for patients with 
sasophryngeal cancer: A feasibility study. Jpn J Clin Oncol, 33:331-5.