Conditions: Head and Neck Squamous Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
This is a Phase II trial of definitive chemoradiotherapy (CTRT) given with the protease inhibitor,Nelfinavir (NFV), in patients with locally advanced head and neck. Eligible patients will receive a "lead-in" period of Nelfinavir (1250 mg po bid) for 7-14 days prior to initiation of CTRT. Nelfinavir will then be given concurrently with platinum-based chemotherapy and radiation therapy (planned total dose of 70 Gy over 7 weeks).

Detailed description:
This is a single-arm Phase II study of organ-preservation chemoradiotherapy given in combination with the protease inhibitor, Nelfinavir, in patients with stage II, IVa, or IVb (per AJCC version 7) squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx. Patients start treatment with Nelfinvir at a dose of 1250 mg twice daily for 7-14 days, before continuing Nelfinvir at this dose concurrent with chemotherapy and radiation therapy (for a total dose of 70 Gy over a period of 7 weeks).

Arms:
arm 1: Single Arm, Phase II study of Nelfinavir Lead-In (Period 1) Followed by Concurrent Chemoradiation with Nelfinavir (Period 2)

Interventions: intervention 1: Nelfinavir (Viracept®) 1250 mg intervention 2: Chemoradiation
Intervention descriptions: intervention 1: Period 1: Nelfinavir Lead-In (1250 mg bid, 7-14 days). intervention 2: Period 2: Concurrent Chemoradiation (70 Gy over 7 weeks) with Nelfinavir (1250 mg bid)

Protocol document:
Prot_SAP_000.pdf: 
1 
Version: 4/3/2020 
 
 
A Phase II Trial of Protease Inhibitor, Nelfinavir (NFV), Given 
with Definitive, Concurrent Chemoradiotherapy (CTRT) in 
Patients with Locally-Advanced, Human Papilloma Virus 
(HPV) negative, Squamous Cell Carcinoma of the Head and 
Neck 
 
Regulatory Sponsor: 
Alexander Lin, MD 
University of Pennsylvania, Department of Radiation 
Oncology 
3400 Civic Center Boulevard, TRC 2 West 
Philadelphia, PA  19104 
(215) 662-3198 
Alexander.lin2@pennmedicine.upenn.edu  
 
 
 
 
Sub-Investigators: 
 
 
 
 
 
Collaborators:                            
 
 
 
 
 
 
 
Study Product: 
Radiation Oncology – Amit Maity, MD, PhD 
Radiation Oncology – Samuel Swisher-McClure, MD 
Radiation Oncology- John N. Lukens, MD 
Radiology – Daniel Pryma, MD 
Radiology – David Mankoff, MD, PhD 
Radiology-Michael Farwell, MD 
 
 
Radiation Oncology- Eric Ojerholm, MD 
Radiation Oncology- Patrick Tripp, MD 
Medical Oncology – Roger Cohen, MD 
Medical Oncology – Charu Aggarwal, MD, MPH 
Medical Oncology- Joshua Bauml, MD 
Otolaryngology – Bert O’Malley, Jr, MD 
Otolaryngology – Gregory Weinstein, MD  
Otolaryngology – Ara Chalian, MD 
Otolaryngology – Christopher Rassekh, MD 
Biostatistician- Rosemarie Mick, MS 
 
Nelfinavir 
18F-FMISO 
Protocol Number:                      817878 


2 
Version: 4/3/2020 
 
 
CONFIDENTIAL 
This document is confidential and the property of the University of Pennsylvania.  No part 
of it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the study sponsor. 
 
Table of Contents 
STUDY SUMMARY ................................................................................................................................................... 3 
1 
INTRODUCTION .............................................................................................................................................. 4 
2 
STUDY OBJECTIVES ...................................................................................................................................... 6 
3 
STUDY DESIGN ................................................................................................................................................ 7 
4 
SUBJECT SELECTION AND WITHDRAWAL............................................................................................ 8 
5 
STUDY DRUG ................................................................................................................................................. 14 
6 
STUDY PROCEDURES .................................................................................................................................. 19 
7 
STATISTICAL PLAN ................................................................................................................................... 255 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 27 
9 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 33 
10 
DATA AND SAFETY MONITORING PLAN .............................................................................................. 35 
11 
ETHICAL CONSIDERATIONS .................................................................................................................... 36 
12 
STUDY FINANCES ......................................................................................................................................... 36 
13 
PUBLICATION PLAN .................................................................................................................................... 36 
14 
REFERENCES ................................................................................................................................................. 37 
 
 
 
 
 
List of Abbreviations 
 
Chemoradiotherapy:   
 
 
 
CTRT 
 
Computed Tomography:  
 
 
 
CT 
 
Head and neck squamous cell carcinoma 
 
HNSCC 
 
Nelfinavir:  
 
 
 
 
 
NFV 
Human Papilloma Virus:  
 
 
 
HPV 
Positron Emission Tomography 
 
 
PET 
Tumor to Muscle Ratio 
 
 
 
TM 


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Version: 4/3/2020 
Study Summary 
Title 
A Phase II Trial of Protease Inhibitor, Nelfinavir (NFV), Given with 
Definitive, Concurrent Chemoradiotherapy (CTRT) in Patients with 
Locally-Advanced, Human Papilloma Virus (HPV) negative, 
Squamous Cell Carcinoma of the Head and Neck 
Short Title 
Definitive Nelfinavir with Chemoradiation for Head and Neck Cancer 
Protocol Number 
817878 
Phase 
Phase II 
Methodology 
Open Label 
Study Duration 
5 years 
Study Center(s) 
University of Pennsylvania; Philadelphia VA Medical Center 
Objectives 
To determine locoregional control in patients with locally advanced, 
HPV-negative head and neck cancer treated with definitive NFV + 
CTRT.  
Number of Subjects 
 28 
Diagnosis and Main 
Inclusion Criteria 
Stage III, IVa, or IVb squamous cell carcinoma of the oral cavity, 
oropharynx, larynx, or hypopharynx with ECOG performance status 0-
2 
Study Product, 
Dose, Route, 
Regimen 
Nelfinavir (Viracept®) 
1250 mg 
By mouth two times a day  
Medicine should be taken with food, preferably high in fat. 
 
18F-FMISO 
 
5-10 mCi 
 
Intravenous bolus injection 
Duration of 
administration 
Treatment to start 7-14 days prior to radiation and continued 
throughout radiation and standard chemotherapy. 
Reference therapy 
Combination of standard chemotherapy and radiation therapy 
Statistical 
Methodology 
This is a single arm, phase II study of nelfinavir (1250 mg given po bid) 
and concurrent chemoradiotherapy in locally advanced head and neck 
cancer. Locoregional control will be compared to published historical 
results. There will be a total of 28 patients enrolled on the study.  
 


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Version: 4/3/2020 
1 Introduction 
This is a Phase II trial of definitive chemoradiotherapy (CTRT) given with the protease inhibitor, 
Nelfinavir (NFV), in patients with locally advanced head and neck cancer.  Eligible patients will 
receive a “lead-in” period of Nelfinavir (1250 mg po bid) for 7-14 days prior to initiation of 
CTRT.  Nelfinavir will then be given concurrently with platinum-based chemotherapy and 
radiation therapy (planned total dose of 70 Gy over 7 weeks).   
 
All patients will also undergo the following: 
1) 18F-FMISO PET/CT: this scan assesses tumor hypoxia. Patients will undergo 2 separate 
18F-FMISO PET/CT scans: the first at baseline to determine baseline tumor hypoxia, the 
second after a 7-14 day lead-in of NFV prior to CTRT (to determine change in tumor 
oxygenation secondary to NFV). Six patients will receive 3 separate 18F-FMISO PET/CT, 
the first at baseline to determine baseline tumor hypoxia, the second also at baseline to 
determine reliability of the scan for test-retest purposes, the third after a 7-14-day lead-in 
of NFV.  
2) 18F-FDG PET/CT: this scan assesses glucose uptake. Patient will undergo 2 separate 18F-
FDG PET/CT scans: the first at baseline as part of routine clinical care, for purposes of 
radiation treatment planning and the second after a 7-14 day lead-in of NFV prior to 
CTRT (to determine change in tumor glucose uptake secondary to NFV). 
 
The primary objective of the study will be to determine whether NFV, given with definitive 
CTRT, will improve locoregional control in locally advanced head and neck cancer.   
 
Secondary objectives of this study include:  
- To determine the effect of NFV on hypoxia, as assessed by 18F-FMISO PET/CT.  
- To determine the effect of NFV on glucose metabolism, as assessed by 18F-FDG PET/CT, and 
possible associations between hypoxia and glucose metabolism. 
1.1 Background 
Radiation therapy is a commonly used treatment for cancer. Despite the use of sophisticated, 
state-of-the-art techniques, local-regional control is often not achieved in many cases, leading to 
recurrence. A case in point is locally advanced head and neck squamous cell carcinoma (HNSCC) 
cancer, which has a 5-year locoregional control rate of 33.7% following combined chemoradiation 
(1). In 2012 there were over 50,000 new cases of HNSCC with approximately 11,500 deaths (2). 
While the overall prognosis of HNSCC appears to be improving, this may be due to changing 
demographics with a higher percentage of cases associated with HPV, which appears to have a 
better prognosis than HPV-negative HNSCC (3).  
 
Previous studies of hypoxic radiosensitizers have shown promise. In the TROG 02.02 
phase III trial of definitive head and neck chemoradiation +/- tirapazamine, there was a trend 
favoring the tirapazamine arm for improved locoregional control in patients who were HPV-
negative (5). For patients identified to have hypoxic disease via F-MISO PET scanning who did 
not receive tirapazamine, locoregional control was 38% at a median followup of 3.6 yrs, versus 
95% in similar patients who received tirapazamine (6). 
One approach for increasing the therapeutic window of radiotherapy is to combine 
radiation therapy with biological agents. Over the past few years, we have focused on agents that 
can modulate the tumor microenvironment to improve radiation response (7, 8). One particular 


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agent, nelfinavir, has been widely used in HIV patients with well-characterized pharmacokinetics 
and low toxicity profile. NFV inhibits the PI3K/Akt/mTOR pathway, which we believe increases 
the intrinsic radiosensitivity of cells (9-11). However, the effects of NFV on the in vivo radiation 
response appear to be greater than those seen in vitro, which led us to investigate whether the drug 
might have effects on the tumor microenvironment (TME) that could improve the radiation 
response. Indeed, we and others have found that NFV treatment of mice bearing tumor xenografts 
leads to improved oxygenation (10, 12). This is potentially clinically important because hypoxia 
is a factor associated with poor prognosis in many cancers, including HNSCC (13-15). Hypoxic 
cells require higher doses of radiation compared to oxic cells to achieve the same level of killing 
due to the requirement of oxygen to elicit maximal DNA damage through the oxidation of DNA 
and other target radicals (16). This leads us to one of our hypotheses that a major mechanism by 
which NFV improves the radiation response in vivo is by decreasing tumor hypoxia.      
 
Determinants & Mechanisms of Nelfinavir Response 
A phase I/II trial at Penn has been conducted in which NFV was combined with cisplatin-
based (as with this protocol) chemotherapy and radiation for stage IIIA/B non-small cell lung 
cancer (17). The phase I trial showed that NFV given at a dose of 1250 mg (which was found to 
be the MTD) orally twice a day was well tolerated by these patients treated with chemoradiation. 
There were no dose limiting toxicities on this 16 patient trial, and no patients required dose 
attenuation of chemotherapy or nelfinavir. This trial did not test the idea than NFV can modulate 
tumor hypoxia or include hypoxia imaging. There are several methods that are available to 
measure hypoxia in human tumors including Eppendorf needle electrode and 2-nitroimidazole 
binding (18). 2-nitroimidazole drugs are reduced and form adducts with protein thiols in hypoxic 
cells (19).   
 
1-H-1-(3-[18F] fluoro-2-hydroxypropyl)-2-nitroimidazole also known as 
[18F]fluoromisonidazole or 18F-FMISO is a positron emitting radiopharmaceutical that has 
been studied in vivo in humans for measurement of regional hypoxia in a number of tumor types 
with positron emission tomography (PET/CT).  Grierson et al described synthesis methods that 
yielded high specific activity18F-FMISO for use in PET imaging studies [Grierson 1989]. 
Fluoromisonidazole is a congener of misonidazole, which is an electron affinic drug with 
selective binding in cells with reduced pO2 [Chapman 1981, 1983, Franko 1984].  An ideal 
hypoxia-imaging agent should distribute independently of blood flow, which is best achieved 
when the partition coefficient of the tracer is close to unity. Under these circumstances, imaging 
data can be acquired at a time when the intracellular tracer distribution has equilibrated with the 
tracer in plasma near the cells. 18F-FMISO is an azomycin-based hypoxic cell sensitizer, 
because [18F]FMISO partitions nearly equally between octanol and water, normoxic tissues 
have T/B (tissue/blood) pixel values of almost 1.0. The hypoxic part of a tumor can be 
characterized by the maximum T/B value or by the total number of pixels with T/B greater than 
some threshold. These pixels are summed and multiplied by the known mL/pixel to calculate 
hypoxic volume, (HV). Rasey et al characterized the binding characteristics of 18F-FMISO in 
cells in vitro at various oxygen levels and in animal studies of tumors. Results demonstrated the 
oxygen dependent binding of radiolabeled fluoromisonidazole in vitro and in vivo and supported 
the use of 18F-FMISO as a quantitative hypoxia probe using the measurement of retention of 
18F-FMISO in tumor vs blood and normal tissue to calculate hypoxic fraction in tumors [Rasey 
1989]. 18F-FMISO PET/CT provides a valuable non-invasive method to measure viable hypoxic 
cells in human malignancies, which may aid in better understanding mechanisms of resistance 
and response to treatments, such as radiation or anti-angiogenesis therapies. 
 


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Version: 4/3/2020 
The injectable dose of 18F-FMISO for this study will be ≤ 10mCi (with an expected range of 5- 10 
mCi at the time of injection) which has been shown to generate high quality PET/CT images 
with acceptable radiation dose to subjects, the drug mass injected for each study with be ≤ 15 
µg.  
 
In the current protocol we focus on the central hypothesis that NFV will result in a decrease 
in tumor hypoxia in head and neck tumors, and that this alteration in hypoxia plays a role in its 
ability to radiosensitize, leading to improved treatment outcomes. We also hypothesize that: 1) the 
effect of NFV on hypoxia can be assessed by 18F-EF5 or by 18F-FMISO,( the initial 15 subjects 
have been completed using 18F-EF-5) and 2) changes in hypoxia will correlate with changes in 
glucose metabolism (decrease in glucose uptake), as assessed by 18F-FDG PET/CT scanning.   
 
Summary 
 
We propose a clinical trial of the HIV protease inhibitor, nelfinavir, and concurrent, 
definitive chemoradiation in patients with locally advanced, HPV-negative head and neck cancer. 
This is an ideal population because of their poor prognosis with current therapy and the fact that 
HNSCC tumors are known to be hypoxic. Furthermore, activation of the EGFR/PI3K pathway is 
common in HNSCC, identified in 74% of cases in one report (30), so these tumors should respond 
to NFV. Assessment of tumor oxygenation response to NFV will be made using 18F-FMISO 
PET/CT scanning and correlation of hypoxia with glucose metabolism will be assessed via 18F-
FDG PET/CT scanning. If the combination of NFV and radiation is found to be effective in this 
group of patients, it could then be extended to patients with other cancers.  
 
 
2 Study Objectives 
2.1 Primary Objective 
To determine locoregional control for patients with locally advanced, HPV-negative 
head and neck cancer, treated with definitive NFV + CTRT and compare it to 
published historical results.  
     
2.2 Secondary Objectives 
2.2.1    To determine the effect of NFV on hypoxia as assessed by 18F-FMISO 
            PET/CT scanning. 
 
2.2.2 To determine whether glucose metabolism (as assessed by 18F-FDG PET/CT) 
is affected by NFV, and whether this corresponds to a decrease in 18F-
FMISO uptake.  
    


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3 Study Design 
3.1 General Design 
Twenty-eight subjects will be enrolled on this clinical trial investigating the efficacy of definitive 
NFV + CTRT for locally advanced head and neck cancer. Patients will also receive two 18F-
FMISO PET/CT studies: the first at baseline to determine baseline tumor hypoxia, the second after 
a 7-14 day lead-in of NFV prior to CTRT (to determine change in tumor oxygenation secondary 
to NFV).  . Additionally, patients will undergo 2 separate 18F-FDG PET/CT scans: the first at 
baseline as part of routine clinical care, for purposes of radiation treatment planning and the second 
after a 7-14 day lead-in of NFV prior to CTRT (to determine change in tumor glucose uptake 
secondary to NFV). The research 18F-FMISO PET/CT and 18F-FDG PET/CT studies are 
mandatory, in order to participate on this clinical trial.  Only under circumstances where the PI, 
Alexander Lin, deems the patient is unable to comply with the PET/CT requirements will its 
completion be excused and allow the patient to remain on the study.    
 
3.2 Primary Study Endpoints 
The intent of this protocol is to determine the efficacy of NFV + CTRT for locally advanced, 
HPV-negative head and neck cancer. Therefore, the primary endpoint will be locoregional 
control. However, secondary objectives will be (1) to determine the effect of NFV on hypoxia as 
assessed by 18F-FMISO PET/CT imaging (the initial 15 subjects were imaged with 18F-EF5) and 
(2) determine whether glucose metabolism (as assessed by 18F-FDG PET/CT) is affected by 
NFV, and whether this corresponds to a decrease in 18F-FMISO uptake.  NFV responders have a 
better treatment outcome than NFV non-responders will be tested by comparing PFS between 
these groups. The definition of "NFV responder" requires greater knowledge about the 
distribution and variance of the baseline T:M ratio. For example, a decrease in T:M ratio to 
<1.25 or percent decrease from baseline of >50% may be reasonable definitions.  
3.3 Secondary Study Endpoints 
18F-FMISO PET/CT 
Patients will receive two hypoxia PET/CT scans with either 18F-FMISO or 18F-EF5 (initial 15 
subjects were completed using EF-5, subsequent subjects will be imaged with FMISO): the first 
at baseline to determine baseline tumor hypoxia, and the second after a 7-14 day lead-in of NFV 
prior to CTRT (to determine change in tumor oxygenation secondary to NFV). Tumor regions of 
interest (ROIs), corresponding to the primary tumor site and pathologic lymph nodes will be 
drawn with the help of CT images. Tumor to muscle ratios (TMR) will be determined for each 
ROI. A TMR of > 1.3 will be considered significant for hypoxia, and a reasonable starting point 
in which the outcome of the addition of NFV to CTRT can be evaluated. The ability of NFV to 
reduce tumor hypoxia will be tested by comparing pre and post-NFV hypoxia (i.e., 18F-FMISO 
uptake expressed as a TMR) by Student's paired t-test.  
 
18F-FDG PET/CT  
Patients will undergo 2 separate 18F-FDG PET/CT scans: the first at baseline as part of routine 
clinical care, for purposes of radiation treatment planning and the second after a 7-14 day lead-in 
of NFV prior to CTRT (to determine change in tumor glucose uptake secondary to NFV). That 


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Version: 4/3/2020 
change in hypoxia will correlate with change in glucose uptake will be tested by Pearson's 
correlation. 
 
That baseline hypoxia and glucose metabolism are predictive of treatment outcome will be tested 
by Cox regression analysis.  
 
NCI Common toxicity grades will be employed.  
 
  
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
4.1.1 Patients ≥ 18 years old. 
4.1.2 Histologically confirmed diagnosis of squamous cell carcinoma of the 
oral cavity, oropharynx, larynx, or hypopharynx AJCC 7th edition 
stages III, IVa, or IVb, p16-negative on immunohistochemistry (p16 
testing to be performed only on oropharynx cancers, as it has not been 
found to be prognostic or standard of care outside of cancers of the 
oropharynx. 
4.1.3 Determined by the treating physician to be a candidate for organ 
preserving, concurrent standard chemotherapy and radiation therapy 
to the head and neck with definitive intent. 
4.1.4 ECOG Performance Status 0-2 
4.1.5 Patients must sign an informed consent document that indicates they 
are aware of the investigational nature of the treatment in this 
protocol as well as the potential risks and benefits. 
 
4.1.6     Ability to understand and the willingness to sign a written informed  
consent.  
 


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Version: 4/3/2020 
4.2 Exclusion Criteria (All laboratory studies must be completed 1 month prior to signing consent) 
4.2.1 Prior radiation therapy (defined as more than 5 fractions of head and 
neck radiotherapy, less than 10 Gy total prior radiation) to the head 
and neck 
4.2.2 Prior chemotherapy within the past 5 years 
4.2.3 Previous therapy with a human immunodeficiency virus (HIV) 
protease inhibitor 
4.2.4 Females who are pregnant at the time of screening will not be eligible 
for this study, urine pregnancy test will be performed at screening and 
prior to injection of FMISO in women of child-bearing potential. 
4.2.5  Patients with known HIV disease.  These patients have a high 
probability of treatment with anti-retroviral therapy which may 
interact with the nelfinavir.  
4.2.6 Absolute Neutrophil Count ≤ 1500 per mm3   
4.2.7 Platelet count ≤ 100,000 per mm3   
4.2.8 Serum creatinine > 1.5 times the upper limit of normal   
4.2.9 Serum AST or ALT > 2 times the upper limit of normal   
4.2.10 Serum bilirubin > 1.2 mg/dl 
4.2.11 Weight loss of > 10% over the past 6 months which is due to tumor      
wasting syndrome 
4.2.12 Distant metastases 
4.2.13 Patients receiving the following drugs that are contraindicated with 
NFV will be excluded.  
 
 
Antiarrhythmics: 
amiodarone, quinidine 
CONTRAINDICATED due to potential for serious and/or life 
threatening reactions such as cardiac arrhythmias 
Antimycobacterial: 
rifampin 
May lead to loss of virologic response and possible resistance to 
VIRACEPT or other coadministered antiretroviral agents. 
Ergot Derivatives: 
dihydroergotamine, 
ergonovine, ergotamine, 
methylergonovine 
CONTRAINDICATED due to potential for serious and/or life 
threatening reactions such as acute ergot toxicity characterized by 
peripheral vasospasm and ischemia of the extremities and other 
tissues. 


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Herbal Products: St. 
John’s wort (hypericum 
perforatum) 
May lead to loss of virologic response and possible resistance to 
VIRACEPT or other coadministered antiretroviral agents. 
HMG-CoA Reductase 
Inhibitors: lovastatin, 
simvastatin 
Potential for serious reactions such as risk of myopathy including 
rhabdomyolysis.  
Neuroleptic: pimozide 
CONTRAINDICATED due to potential for serious and/or life 
threatening reactions such as cardiac arrhythmias. 
Proton Pump Inhibitors 
Omeprazole decreases the plasma concentrations of nelfinavir.  
Concomitant use of proton pump inhibitors and VIRACEPT may 
lead to a loss of virologic response and development of 
resistance. Patients that have been off of proton pump 
inhibitors for 14 days before enrollment will be allowed to 
participate.  
Sedative/Hypnotics: 
midazolam, triazolam 
CONTRAINDICATED due to potential for serious and/or life 
threatening reactions such as prolonged or increased sedation or 
respiratory depression.  
4.2.15 Patients receiving the following drugs will be clinically evaluated by 
the PI as to whether dosage/medication can and should be changed to 
permit patient on study:  
 
 
 
Anti-Convulsants: 
carbamazepine, 
Phenobarbital 
↓ nelfinavir 
May decrease nelfinavir plasma concentrations.  
VIRACEPT may not be effective due to decreased 
nelfinavir plasma concentrations in patients taking 
these agents concomitantly.   
Anti-Convulsant: 
phenytoin 
↓ phenytoin 
Phenytoin plasma/serum concentrations should be 
monitored; phenytoin dose may require adjustment 
to compensate for altered phenytoin concentration.   
Anti-Mycobacterial: 
rifabutin 
↑ rifabutin 
↓ nelfinavir 
(750 mg TID) 
↔ nelfinavir 
(1250 mg BID)  
CONTRAINDICATED due to potential for serious 
and/or life threatening reactions such as acute ergot 
toxicity characterized by peripheral vasospasm and 
ischemia of the extremities and other tissues. 
PDE5 Inhibitors: 
sildenafil, vardenafil, 
tadalafil 
↑ PDE5 
inhibitors 
Concomitant use of PDE5 inhibitors and 
VIRACEPT should be undertaken with caution.  If 
concomitant use of PDE5 inhibitors and 
VIRACEPT is required, sildenafil at a single dose 
not exceeding 25 mg in 48 hours, vardenafil at a 
single dose not exceeding 2.5 mg in 72 hours, or 
tadalafil at a single dose not exceeding 10 mg dose 
in 72 hours, is recommended.   


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HMG-CoA 
Reductase Inhibitors: 
atorvastatin, 
rosuvastatin 
↑ atorvastatin 
↑ rosuvastatin 
Use lowest possible dose of atorvastatin or 
rosuvastatin with careful monitoring, or consider 
other HMG-CoA reductase inhibitors such as 
pravastatin or fluvastatin in combination with 
VIRACEPT. 
Immuno-
suppressants: 
cyclosporine, 
tacrolimus, sirolimus 
↑ immuno-
suppressants 
Plasma concentrations may be increased by 
VIRACEPT.   
Narcotic Analgesic: 
methadone 
↓ methadone 
Dosage of methadone may need to be increased 
when coadministered with VIRACEPT. 
Oral Contraceptive: 
ethinyl  estradiol  
↓ ethinyl 
estradiol 
Alternative or additional contraceptive measures 
should be used when oral contraceptives and 
VIRACEPT are coadministered. 
Macrolide 
Antibiotic: 
azithromycin 
↑ azithromycin 
Dose adjustment of azithromycin is not 
recommended, but close monitoring for known side 
effects such as liver enzyme abnormalities and 
hearing impairment is warranted. 
Inhaled/nasal steroid: 
fluticasone 
↑ fluticasone 
Concomitant use of fluticasone propionate and 
VIRACEPT may increase plasma concentrations of 
fluticasone propionate.  Use with caution.  Consider 
alternatives to fluticasone propionate, particularly 
for long-term use. 
Antidepressant: 
trazodone 
↑ trazodone 
Concomitant use of trazodone and VIRACEPT may 
increase plasma concentrations of trazodone.  
Adverse events of nausea, dizziness, hypotension 
and syncope have been observed following 
coadministration of trazodone and nelfinavir.  If 
trazodone is used with a CYP3A4 inhibitor such as 
VIRACEPT, the combination should be used with 
caution and a lower dose of trazodone should be 
considered.   
 
4.2.16 Women of childbearing potential who have a positive result on screening 
urine pregnancy test. 
4.2.17 Subjects with moderate-severe renal disease. 
4.2.18 History of allergic reactions attributed to Flagyl (metronidazole), which     
has a chemical structure similar to FMISO. 
4.2.19 Uncontrolled intercurrent illness including, but not limited to symptomatic 
congestive heart failure, unstable angina pectoris, or psychiatric 


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illness/social situations that would limit compliance with study 
requirements.   
 
4.3 Inclusion of Women and Minorities 
The University of Pennsylvania Medical Center serves the metropolitan Philadelphia area, 
the surrounding suburban counties, southern New Jersey, and northern Delaware.  
Inclusion of minorities: The University of Pennsylvania Cancer Center reports that minorities 
accounted for 14% of all patients (adult and pediatric) enrolled on therapeutic clinical trials.  
Furthermore, it is estimated that approximately 30% of cancer patients admitted to the 
Hospital of the University of Pennsylvania are minorities (source:  University of 
Pennsylvania Cancer Center Grant).  Female and male patients of all ethnic groups will be 
eligible for treatment in these protocols.  Protocol accrual will be reviewed annually to 
include a determination of minority representation. An attempt will be made to enroll patients 
with larynx cancer in a distribution that matches the frequency of incident larynx cancer in 
the general population. The minority accrual estimates for our trial are based upon the total 
number of patients, the incidence rates of head and neck larynx cancer, and estimates in the 
literature regarding minority accrual in clinical trials. A study by Tejeda and Brawley (31) 
found that the accrual of American cancer patients to NCI-sponsored treatment trials 
paralleled the incident disease burden among minorities. A report by Sikora et al. (32) 
indicates the distribution of incident head and neck squamous cell carcinoma to be 81.8%, 
21.1%, 11.9%, 5.2%, 3.7%, 0.3%, and 0.8% among whites, all minorities, blacks, Asians, 
Hispanics, others and unknowns, respectively. The Philadelphia metropolitan area does not 
have a large American Indian or Alaskan population; therefore, no patients are estimated for 
this group. 
 
Inclusion of women: Recruitment of patients will be through the University of Pennsylvania 
Cancer Center, Department of Radiation Oncology. All patients meeting study requirements 
will be approached for participation without discrimination. According to Cancer Facts and 
Figures (2011) from the American Cancer Society (33), new cases of larynx cancer were 
divided approximately 4:1 among male and female patients. Based on these and the above 
minority data, we estimate the accrual distributions for this trial shown below: 
 
Ethnic Category 
Males 
Females 
Total 
Hispanic or Latino 
1 
0 
1 
Not Hispanic or Latino 
21 
6 
27 
Ethnic Category Total of All Subjects 
22 
6 
28 
Racial Categories 
 
 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
1 
0 
1 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
Black or African American 
3 
1 
4 
White 
18 
5 
24 
Racial Categories: Total of All 
Subjects 
22 
6 
28 


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Proposed Outreach Programs 
The University of Pennsylvania Cancer Center has developed a number of minority 
outreach strategies.  These include development of relationships with local community 
organizations, presentations or distribution of materials to local groups regarding trials, 
advertisements in minority newspapers and magazines, and presentations to professional 
organizations.  If under-accrual of minority subjects is determined to be a problem, we will 
employ these methods to improve accrual.  We will also make an effort to educate 
radiotherapists, surgeons, and medical oncologists who are working within our network and 
who serve minority populations about this trial. 
 
4.4 Subject Recruitment and Screening 
Subjects will be recruited from the departments of Medical Oncology and Radiation Oncology.  
The consent process can be completed in person or via Telemedicine per University of 
Pennsylvania Health Systems telemedicine policy and procedures. 
4.5 Clinical Evaluation and Staging Criteria 
• History and Physical Examination 
• Laboratory studies: CBC with differential, Comprehensive metabolic panel, pregnancy tests 
for women of child bearing age or potential.  
• Staging studies are to include a chest x-ray, chest CT, or FDG PET scan to evaluate for 
systemic metastases, performed within 12 weeks prior to study entry.    
4.6 Off-Study Criteria 
• Extraordinary Medical Circumstances.  If at any time the constraints of this protocol are 
detrimental to the subject’s health, the subject will be removed from protocol therapy.  In this 
event, the reasons for withdrawal will be documented.   
• Subject’s refusal to continue treatment.  In this event, the reasons for withdrawal will be 
documented. 
 
• Any patient who experiences any Grade III or higher toxicity related to 18F-FMISO and not 
related to the underlying disease. 
 
• Patients will be considered “off-study” at the completion of study procedures. This will occur 
at the completion of 3 month follow up PET/CT. 
 
• Patients may be taken off study at any time at the discretion of the Principal Investigator 
 
• Every effort will be made to follow subjects off study for toxicity and survival. 
 


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Version: 4/3/2020 
4.7 Study Duration 
With an estimated accrual of 7-8 subjects per year, it is anticipated that accrual will continue for 
approximately 4 years.  Patients will then be followed an additional 6 months prior to final 
statistical analysis. 
5 Study Drugs  
5.1 Description 
Nelfinavir 
There are ample data available regarding the use of NFV in humans (34). The following is an 
excerpt of the key features. 
VIRACEPT® (nelfinavir mesylate) is an inhibitor of the human immunodeficiency virus (HIV) 
protease. VIRACEPT Tablets are available for oral administration as a light blue, capsule-shaped 
tablet with a clear film coating in 250 mg strength (as NFV free base) and as a white oval tablet 
with a clear film coating in 625 mg strength (as NFV free base). Each tablet contains the following 
common inactive ingredients: calcium silicate, crospovidone, magnesium stearate, hypromellose, 
and triacetin. In addition, the 250 mg tablet contains FD&C blue #2 powder and the 625 mg tablet 
contains colloidal silicon dioxide. VIRACEPT Oral Powder is available for oral administration in 
a 50 mg/g strength (as NFV free base) in bottles. The oral powder also contains the following 
inactive ingredients: microcrystalline cellulose, maltodextrin, dibasic potassium phosphate, 
crospovidone, hypromellose, aspartame, sucrose palmitate, and natural and artificial flavor. The 
chemical 
name 
for 
nelfinavir 
mesylate 
is 
[3S-[2(2S*, 
3S*), 
3a,4ab,8ab]]-N-(1,1-
dimethylethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4- 
(phenylthio)butyl]-3-isoquinoline carboxamide mono-methanesulfonate (salt) and the molecular 
weight is 663.90 (567.79 as the free base). Nelfinavir mesylate has the following structural 
formula: 
 
Nelfinavir mesylate is a white to off-white amorphous powder, slightly soluble in water at pH 4 
and freely soluble in methanol, ethanol, 2-propanol and propylene glycol. 
Pharmacokinetics 
The pharmacokinetic properties of NFV were evaluated in healthy volunteers and HIV-infected 
patients; no substantial differences were observed between the two groups. 
Absorption: Pharmacokinetic parameters of NFV (area under the plasma concentration-time curve 
during a 24-hour period at steady-state [AUC24], peak plasma concentrations [Cmax], morning 


15 
Version: 4/3/2020 
and evening trough concentrations [Ctrough]) from a pharmacokinetic study in HIV-positive 
patients after multiple dosing with 1250 mg (five 250 mg tablets) twice daily (BID) for 28 days 
(10 patients) and 750 mg (three 250 mg tablets) three times daily (TID) for 28 days (11 patients) 
are summarized in Table 1. 
 
The difference between morning and afternoon or evening trough concentrations for the TID and 
BID regimens was also observed in healthy volunteers who were dosed at precisely 8- or 12-hour 
intervals. In healthy volunteers receiving a single 1250 mg dose, the 625 mg tablet was not 
bioequivalent to the 250 mg tablet formulation. Under fasted conditions (n=27), the AUC and 
Cmax were 34% and 24% higher, respectively, for the 625 mg tablets. In a relative bioavailability 
assessment under fed conditions (n=28), the AUC was 24% higher for the 625 mg tablet; the Cmax 
was comparable for both formulations. In healthy volunteers receiving a single 750 mg dose under 
fed conditions, NFV concentrations were similar following administration of the 250 mg tablet 
and oral powder. 
Effect of Food on Oral Absorption: Food increases NFV exposure and decreases NFV 
pharmacokinetic variability relative to the fasted state. In one study, healthy volunteers received a 
single dose of 1250 mg of VIRACEPT 250 mg tablets (5 tablets) under fasted or fed conditions 
(three different meals). In a second study, healthy volunteers received single doses of 1250 mg 
VIRACEPT (5 x 250 mg tablets) under fasted or fed conditions (two different fat content meals). 
The results from the two studies are summarized in Table 2 and Table 3, respectively. 
 
 
NFV exposure can be increased by increasing the calorie or fat content in meals taken with 
VIRACEPT. A food effect study has not been conducted with the 625 mg tablet. However, based 
on a cross-study comparison (n=26 fed vs. n=26 fasted) following single dose administration of 
NFV 1250 mg, the magnitude of the food effect for the 625 mg NFV tablet appears comparable to 
that of the 250 mg tablets. VIRACEPT should be taken with a meal. 


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Version: 4/3/2020 
Distribution: The apparent volume of distribution following oral administration of NFV was 2-7 
L/kg. NFV in serum is extensively protein-bound (>98%). 
Metabolism: Unchanged NFV comprised 82-86% of the total plasma radioactivity after a single 
oral 750 mg dose of 14C-NFV. In vitro, multiple cytochrome P-450 enzymes including CYP3A 
and CYP2C19 are responsible for metabolism of NFV. One major and several minor oxidative 
metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity 
comparable to the parent drug. 
Elimination: The terminal half-life in plasma was typically 3.5 to 5 hours. The majority (87%) of 
an oral 750 mg dose containing 14C-NFV was recovered in the feces; fecal radioactivity consisted 
of numerous oxidative metabolites (78%) and unchanged NFV (22%). Only 1-2% of the dose was 
recovered in urine, of which unchanged NFV was the major component. 
Special Populations 
Hepatic Insufficiency: The multi-dose pharmacokinetics of NFV have not been studied in HIV-
positive patients with hepatic insufficiency. 
Renal Insufficiency: The pharmacokinetics of NFV have not been studied in patients with renal 
insufficiency; however, less than 2% of NFV is excreted in the urine, so the impact of renal 
impairment on NFV elimination should be minimal. 
Gender and Race: No significant pharmacokinetic differences have been detected between males 
and females. Pharmacokinetic differences due to race have not been evaluated. 
[18F]FMISO 
Description 
1-H-1-(3-[18F]fluoro-2-hydroxypropyl)-2-nitroimidazole also known as 
[18F]fluoromisonidazole or [18F]FMISO is a positron emitting radiopharmaceutical that 
has been studied in vivo in humans for measurement of regional hypoxia in a number of 
tumor types with positron emission tomography (PET/CT).  Grierson et al described 
synthesis methods that yielded high specific activity 18F-FMISO for use in PET imaging 
studies [Grierson 1989]. Fluoromisonidazole is a congener of misonidazole which is an 
electron affinic drug with selective binding in cells with reduced pO2 [Chapman 1981, 
1983, Franko 1984].  An ideal hypoxia-imaging agent should distribute independently of 
blood flow, which is best achieved when the partition coefficient of the tracer is close to 
unity. Under these circumstances, imaging can be done at a time when the intracellular 
tracer distribution has equilibrated with the tracer in plasma near the cells. 18F-FMISO is 
an azomycin-based hypoxic cell sensitizer that has a nearly ideal partition coefficient and, 
when reduced by hypoxia, binds covalently to cellular molecules at rates that are 
inversely proportional to intracellular oxygen concentration, rather than by any 
downstream biochemical interactions. Rasey et al characterized the binding 
characteristics of 18F-FMISO in cells in vitro at various oxygen levels and in animal 
studies of tumors. Results demonstrated the oxygen dependent binding of radiolabeled 
fluoromisonidazole in vitro and in vivo and supported the use of 18F-FMISO as a 
quantitative hypoxia probe using the measurement of retention of 18F-FMISO in tumor vs 
blood and normal tissue to calculate hypoxic fraction in tumors[Rasey 1989]. The drug is 
a clear solution that is provided at room temperature in a sealed, sterile, pyrogen-free vial 


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Version: 4/3/2020 
and has an expiration time of 6 hours. The injectable dose of 18F-FMISO will be ≤ 10 
mCi with an expected range of 5-10 mCi at the time of injection. In the dose of  18F-
FMISO, only a small fraction of the FMISO molecules are radioactive.  There is no 
evidence that nonradioactive and radioactive FMISO molecules display different 
biochemical behavior. 
 
 Preparation of Study Drug (18F-FMISO) 
 
The manufacturing of 18F-FMISO will occur in the Cyclotron Facility of the Department 
of Radiology at the University of Pennsylvania.  This facility manufactures USP 
compliant radio-labeled compounds for human use on a daily basis.  The drug 
manufacturing will be fully documented and controlled by a set of Standard Operating 
Procedures (SOPs) prepared and maintained by the University of Pennsylvania 
Cyclotron.   
 
 Study Drug Administration: 18F-FMISO 
 
The 18F-FMISO dose will be drawn and activity measured in the dose calibrator, in the imaging 
facility. The dose will be administered by bolus injection to the patient under the direct 
supervision of a Nuclear Medicine Authorized User.  The injected dose of 18F-FMISO for this 
study will be ≤ 10 mCi (approximate range for most studies is anticipated to be 5-10 mCi ). A 
lesser dose may be injected if, in the opinion of a Nuclear Medicine Authorized User, complete 
imaging data could be generated.  In the dose of 18F-FMISO, only a small fraction of the FMISO 
molecules are radioactive. 18F-FMISO is administered to subjects by intravenous injection.  The 
injection and/or imaging procedure will be terminated in any patient who exhibits anaphylaxis, 
significant dyspnea or chest pain.  
 
5.2 Treatment Regimen 
All subjects will begin taking daily oral nelfinavir, at a dose of 1250 mg bid, 7 to 14 days prior to 
the start of CTRT. At any point during the study, if a patient cannot tolerate swallowing NFV 
tablets or require PEG for medication administration, then the tablet can be crushed and 
dissolved in water for consumption orally or via PEG. Directions for dissolving NFV are as 
follows: 
 
• 
Place Nelfinavir tablet(s) in small amount of water. 
• 
Once dissolved, mix the cloudy liquid well, and consume it immediately. 
• 
The glass should be rinsed with water and the rinse swallowed to ensure the entire dose is consumed. 
 Nelfinavir will be continued during the complete course of concurrent CTRT.  The 7-14 day 
window of pre-CTRT nelfinavir is included to allow for imaging with [18F]-FMISO PET/CT and 
[18F]-FDG PET/CT evaluation to assess for changes in tumor oxygenation and glucose uptake 


18 
Version: 4/3/2020 
secondary to NFV.  Subjects will be asked to maintain a drug diary to assess compliance with 
administration of nelfinavir. 
 
5.3 Method for Assigning Subjects to Treatment Groups 
The subjects will be identified for this study based on their inclusion/exclusion criteria. Since this 
is a phase II study, there is no assignment to treatment groups and all subjects are treated as per 
protocol. 
5.4 Preparation and Administration of Study Drug 
Nelfinavir will be available in Investigational Drug Services (IDS) at the Hospital of the University 
of Pennsylvania. When a subject is enrolled, the drug will be obtained from IDS and dispensed in 
the Department of Radiation Oncology. It is stored at room temperature.  
 
Preparation and administration of [18F]-FMISO is described in the CMC section. 
 
5.5 Subject Compliance Monitoring 
Subject medication compliance will be monitored via 2 mechanisms: 1) a medication diary for 
Nelfinavir.  Subjects will be asked to complete and return the diary each week of their treatment.  
2) via Epic med reconciliation (MD attestation of med reconciliation is recorded and tracked within 
Epic) at the patient’s weekly visit with their treatment MD during the course of radiotherapy.  If 
necessary, the subject will be counseled on medication issues.  Patients who discontinue the use 
of Nelfinavir due to side effects will still be followed as a study subject as per the intent to treat 
analysis. 
5.6 Prior and Concomitant Therapy 
Any prior therapy is permitted with the exception of radiation therapy to the head and neck 
(defined as more than 5 fractions and more than 10 Gy) and any standard chemotherapy within 
the last 5 years.   
 
5.7 Packaging 
IDS will package the Nelfinavir specific to each subject in 30 day cycles.   
5.8 Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Drug Supplies 
Nelfinavir will be bought and stored as needed by Investigational Drug Services. 
[18F]-FMISO will be synthesized at the cyclotron facility of the University of Pennsylvania 
and delivered to Department of Radiation Oncology in the Perelman Center for Advanced 
Medicine by a trained Cyclotron team member in single dose vials according to the standard 
procedures outlined by the Cyclotron Facility.  Once the drug has been delivered to the 


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Version: 4/3/2020 
Department of Radiation Oncology, all standard hospital procedures will apply for handling, 
processing, and destruction of any residual amounts if applicable. As [18F]-FMISO is a short-
lived radiotracer with a half-life of approximately 110 minutes it will be synthesized for same 
day use, [18F]-FMISO will not be stored. The remaining activity in the vials that exists in the 
lab will be stored only until the activity decays to undetectable level.  All vials will be 
disposed of according to the standard operating procedure set forth by the hospital. 
 
5.8.2 Dispensing of Study Drug 
Nelfinavir will be dispensed by the research coordinator while the subject is in clinic. 
 
The [18F]FMISO dose will be drawn and accurately measured in the dose calibrator in the 
imaging facility and administered by bolus injection to the patient under the direct 
supervision of a Nuclear Medicine Authorized User.  The injectable dose of [18F]FMISO 
for most studies will be ≤  10 mCi ( expected range at injection 5  – 10 mCi), a lesser dose 
may be injected if, in the opinion of a Nuclear Medicine Authorized User complete 
imaging data could be generated.  In the dose of [18F]FMISO, only some fractions of the 
FMISO molecules are radioactive. [18F]-FMISO is administered to subjects by intravenous 
injection of ≤ 10 mL.  The injection will be followed by a saline flush. The injection or 
imaging procedure will be terminated in any patient who exhibits anaphylaxis, significant 
dyspnea or chest pain.  
 
5.8.3 Return or Destruction of Study Drug 
Nelfinavir: At the completion of the study, there will be a final reconciliation of drug shipped, 
drug consumed, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated.  Any discrepancies noted will be investigated, 
resolved, and documented prior to return or destruction of unused study drug.  Drug 
destroyed on site will be documented by Investigational Drug Services. 
 
[18F]-FMISO: If the entire study drug dose is administered, the radioactive syringe will be 
disposed of into the radioactive waste in the Department of Radiation Oncology in the 
Perelman Center for Advanced Medicine.  As the radioactive half-life of 18F is 1.83 hours, 
we anticipate that by the end of a working day, the radioactive syringe can be safely 
disposed of in the standard biologic waste.  In the event that the study drug is not 
administered or only partially administered, the radioactive syringe, vial and the contents 
will be disposed of in the radioactive waste in the Department of Radiation Oncology in the 
Perelman Center for Advanced Medicine.  It will be subsequently disposed of in the 
standard biologic waste upon sufficient decay of its radioactivity. 
 


20 
Version: 4/3/2020 
6 Study Procedures 
6.1 General study design 
Twenty-eight subjects will be enrolled on this clinical trial investigating the efficacy of definitive 
NFV + CTRT for locally advanced head and neck cancer. Patients will also receive two 18F-
FMISO PET/CT studies: the first at baseline to determine baseline tumor hypoxia and the second 
after a 7-14 day lead-in of NFV prior to CTRT (to determine change in tumor oxygenation 
secondary to NFV). Patients will undergo 2 separate 18F-FDG PET/CT scans: the first at baseline 
as part of routine clinical care, for purposes of radiation treatment planning and the second after a 
7-14 day lead-in of NFV prior to CTRT (to determine change in tumor glucose uptake secondary 
to NFV). Additionally, blood and serum (two tubes, approximately 15 ml) will be collected for 
tumor biomarker analysis twice: once at baseline, and again after completion lead-in NFV, prior 
to CTRT.  
 
 
 
Study Schema 
Daily NELFINAVIR (1250mg PO BID): Day -14 to End of XRT 
XRT: Day 1 to Day 49 
2.0 Gy daily to total dose of 70 Gy  
Weekly clinical evaluation 
Prior to Day -14: 
• Clinical Evaluation and Staging Studies 
• Trial Enrollment 
Baseline 18F-FMISO 
PET/CT and blood draw 
(prior to NFV). FDG-PET 
for RT treatment planning 
Chemotherapy Administration 
Followup clinical exam:  
 
Imaging: 3mo FDG PET/CT, and 
then as clinically indicated 
 
 
 DAY-20     -15       -10        -5          0          5         10        15        20         25        30        35        40        45        50 
Repeat 
18F-FMISO 
and 
FDG 
PET/CT and blood draw (after lead-


21 
Version: 4/3/2020 
6.2 Nelfinavir Administration  
All subjects will begin taking daily oral nelfinavir, at a dose of 1250 mg bid, 7 to 14 days prior to 
the start of CTRT.  Nelfinavir will be continued during the complete course of concurrent CTRT.  
The 7-14 day window of pre-CTRT nelfinavir is included to allow for imaging with 18F-FMISO 
and 18F-FDG PET/CT to assess for changes in tumor oxygenation and glucose uptake secondary 
to NFV.  Subjects will be asked to maintain a drug diary to assess compliance with 
administration of nelfinavir.  Subjects will also undergo weekly med reconciliation of 
compliance with taking NFV during their scheduled visit with their treating MD during 
radiotherapy (MD attestation of med reconciliation is recorded and tracked within EPIC).   
 
6.3 Chemotherapy Administration 
Standard cisplatin chemotherapy consisting of cisplatin will be administered as concurrent 
therapy with radiation. Cisplatin 100 mg/m2 will be administered on days 1, 22, and 43, with 
pretreatment and post treatment hydration and a polyantiemetic regimen. Patients may also be 
treated with either weekly cisplatin or weekly cetuximab, which is another FDA-approved drug 
shown to be an effective radiosensitizer in the treatment of head and neck cancer (36, 37).  
Patients who are receiving cetuximab may receive a loading dose, as per standard of care, prior 
to their completion of their repeat imaging, if deemed necessary by the treating physician.  The 
treating medical oncologist may make adjustments to the chemotherapy regimen and/or dosing, 
as they deem medically appropriate. Development of severe dysphagia, dehydration, orthostasis, 
or other unforeseen grade 4 toxicity is potential grounds for discontinuation of treatment if 
therapy is delayed longer than 1 week to permit recovery.  Should a holiday or hospital closing 
interfere with the above detailed chemotherapy administration schedule, the medical oncologist 
will adjust each subjects administration as they see medically appropriate.   
6.4 Radiation Therapy 
Radiation therapy in all subjects will begin 7 to 14 days after the initiation of nelfinavir.   
 
Simulation for treatment is required. PET/CT-based treatment planning is required. Treatment will 
be delivered via intensity-modulated photon or pencil-beam proton radiotherapy. All fields will be 
treated every session.  Interruptions in therapy should be discussed with the principal investigator 
but will be instituted at the discretion of the attending radiation oncologist. 
 
The gross tumor volume, clinical treatment volume, and planning treatment volume are defined 
according to ICRU 50. Dose calculation should be performed using inhomogeneity corrections to 
account for differences in tissue density across the head and neck region.  The total dose to gross 
disease will be 70 Gy.  This will be administered in 2.0 Gy daily fractions. Regional lymph node 
regions may be treated, as dictated by the clinical situation. High-risk elective nodal regions would 
receive anywhere from 59.5 to 63 Gy, administered in 1.7-1.8 Gy daily fractions, while low-risk 
elective nodal regions would receive anywhere from 56 to 59.5 Gy, administered in 1.6- 1.7 Gy 
daily fractions.  Treatment will be continuous, 5 days per week for 7 consecutive weeks. 
 
Normal tissue doses:  Dose-volume histograms should be performed for organs at risk, such as the 
spinal cord, brainstem, optic nerves and chiasm, pharyngeal constrictors, and mandible.  The 


22 
Version: 4/3/2020 
maximal spinal cord dose should not exceed 45 Gy.  The maximal dose to the brainstem, optic 
nerves and chiasm, should not exceed 54 Gy. The mean dose to the pharyngeal constrictors should 
not exceed 50 Gy. The maximal dose to the mandible (not included in the planning treatment 
volume) should not exceed 70 Gy.  
 
6.5 
18F-FMISO PET/CT Imaging 
Two 18F-FMISO PET/CT imaging scans to assess tumor oxygen level in response to treatment 
with Nelfinavir will be performed.  Pregnancy tests will be performed prior to each scan. The first 
18F-FMISO PET/CT will occur shortly after enrollment, prior to administration of any therapy. The 
second will occur after a 7-14 day period of NFV alone.   
 
The 18F-FMISO PET/CT study will be conducted at the Imaging Services Center located in the 
Department of Radiation Oncology, Perelman Center for Advanced Medicine, University of 
Pennsylvania Medical Center. Subjects will receive 18F-FMISO intravenously over a period of 
approximately a minute. Subjects will then lie on a table under the PET scanning machine for the 
procedure. The following is a timetable for the 18F-FMISO PET/CT scan.  
 
TIME 
(APPROXIMATELY) 
SCHEDULE OF EVENTS 
30 minutes before 
injection 
Arrival at nuclear medicine 
facility, intravenous line placed: 
weight taken 
0 minutes 
Intravenous injection of [F18]-FMISO 
(5-10  mCi) 
10 min prior to imaging 
Empty Bladder 
2-3 hours after injection 
[F18]-FMISO PET/CT scan of the 
head and neck 
20 min of imaging 
Study Visit Complete 
 
6.6 FDG PET/CT Imaging 
Two 18F-FDG PET/CT imaging scans will be performed. The first is part of routine clinical care, 
and for purposes of radiation treatment planning, the second is for research purposes, in order to 
determine the effect of NFV on glucose uptake.  
 
The 18F-FDG PET/CT study will be conducted at the Imaging Services Center located in the 
Department of Radiation Oncology, Perelman Center for Advanced Medicine, University of 
Pennsylvania Medical Center. S  
6.7 Laboratory Monitoring 
Blood and serum (one tube) will be collected twice for research biomarker, correlative studies. 
The first will be collected at baseline, prior to initiation of NFV, and the second after completion 


23 
Version: 4/3/2020 
of lead-in NFV. All subjects on study will be monitored with complete blood counts with 
differential and comprehensive metabolic panel at the discretion of the treating physicians.    All 
other laboratory tests will be performed as clinically indicated. 
6.8 Study Visit Schedule 
6.8.1 After the subject consents and is deemed eligible for the study, the study drug 
(NFV) will be dispensed and a baseline blood/serum draw (one tube) for research 
laboratory studies will be taken.  Subjects will then be seen weekly during 
radiotherapy in the outpatient clinics to assess treatment-related toxicities.  The 
following will be performed: (1) history and targeted physical examination and (2) 
laboratory evaluations as considered appropriate by study physicians. 
 
6.8.2 FDG PET-CT scan will be performed at three months after the completion of 
radiotherapy as standard of care, in order to assess response to treatment, and for 
restaging purposes. 
6.8.3  After discontinuation of nelfinavir therapy, follow-up including laboratory tests  
and radiographic studies will be scheduled as per standard of care.  Toxicities will 
be evaluated up to the first standard of care follow-up visit after completion 
radiation, after which we will then follow for survival.  
 
 


24 
Version: 4/3/2020 
6.9 Study Visit Flowchart 
 
Informed consent 
Study enrollment 
• 
History and Physical 
• 
Baseline blood laboratory studies. 
• 
Staging Studies (FDG PET/CT, 
CT chest or chest x-ray) 
18F-FMISO  and FDG PET/CT, research blood draw: 
Prior to initiation of  NFV.NFV started 7-14 days prior 
to the initiation of chemoradiation. 
Start radiation planning. 
 
 
18F-FMISO and FDG PET/CT and repeat research blood draw 
after completion of 7-14 days of NFV 
Blood draws as is 
appropriate for 
chemotherapy 
administration,  
Nelfinavir stops when Radiation 
Therapy is ended. 
Follow-up 
FDG PET/CT at 3 months after completion 
of CTRT 
Chemotherapy Guidelines 
• 
Cisplatin or Cetuximab 
Radiation Therapy 
Guidelines 
• Begins 7-14 days after 
initiation of NFV 
• Total dose to gross 
disease will be 70 Gy 
administered in 2.0 Gy 
daily fractions.   
• Treatment will be 
continuous, 5 days per 
week for 7 consecutive 
weeks.  


25 
Version: 4/3/2020 
7 Statistical Plan 
A 28 patient phase II trial of NFV and concurrent chemo/RT with measurements of hypoxia by 
18EF-5 or FMISO PET imaging and serum biomarkers will be performed. Locoregional control is 
the primary endpoint, defined from first day of chemo/RT+NFV to local or regional progression. 
Distant progression and patients free of locoregional control will be censored. The "pre and post-
NFV" measurements mentioned below, refer to samples obtained before and after a 7-14 day run-
in period of NFV prior to chemo/RT. These pre/post-NFV changes are evaluated as "early change" 
predictors of treatment outcome. Hypotheses tested by statistical analyses are:  
 
NFV given with chemo/RT will improve locoregional control (primary objective) will be tested 
by comparing our locoregional control to a historical result by log rank test with adequate power 
as described below. In a randomized pilot study by Rischin (JCO 24:2098-2104, 2006) in head and 
neck cancer, patients with hypoxic tumors who received concurrent chemoradiotherapy had a 3-
year locoregiona8 control rate of 30%, while patients who received the hypoxia-activing pro-drug 
tirapazamine and concurrent chemoradiotherapy had a 3-year locoregional rate of 95%. Although 
the difference in local control was stunning, the sample sizes of these groups was very modest. 
Therefore, we have powered our study conservatively, in order to detect a more modest treatment 
effect.  
 
Starting with this amendment, a total of 28 patients will be enrolled over 4 years, assuming a rate 
of 7 patients per year. To date, only 2 larynx cancer patient had been enrolled on this trial, so 4 
years of accrual will be needed to meet the target sample size. We will then follow patients for an 
additional 6 months. There will be 85% power to detect a 30% absolute increase in 3-year 
locoregional control from a 40% rate for standard concurrent chemoradiotherapy to 70% for 
Nelfinavir and concurrent chemoradiotherapy, using a 1-sided log rank test at a 5% type I error 
rate. 
Power 
calculated 
with 
SWOG 
software 
(http://www.swogstat.org/stat/public/one_nonparametric_survival.htm).   
 
NFV will reduce tumor hypoxia will be tested by comparing pre and post-NFV hypoxia (i.e., 18EF-
5 uptake expressed as a tumor to muscle (TMR) ratio) by Student's paired t-test. Transformation 
of the ratio may be necessary in order to meet the normality assumption of the t-test. Assuming an 
effect size (δ), in units of Std Dev of differences (δ = |µd|/σd), of 1/2σd, with 28 patients enrolled 
there is 82% power to detect the difference between pre/post-NFV values using a 1-sided paired t-
test at a stricter 5% type I error, used to control false positive conclusions in our correlative 
analyses. 
 
 
Baseline hypoxia, and glucose uptake are predictive of treatment outcome will be tested by an 
exploratory analysis using Cox regression.  Each variable will be tested in a univariate survival 
model to assess association with locoregional control. The hazard ratio, 95% confidence interval 
and statistical significance will be determined for each variable. Exploratory analyses will also 
evaluate differences between Nelfinavir responders and nonresponders. The definition of "NFV 
responder" requires greater knowledge about the distribution and variance of the baseline TMR. 
For example, a decrease in TMR to <1.25 or percent decrease from baseline of >50% may be 
reasonable definitions. This exploratory analysis yields estimates of treatment outcomes within 
response groups. 


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7.1 Dose modifications of Nelfinavir and Chemotherapy during 
Radiotherapy 
7.1.1 Hematologic toxicities 
Because Grade III hematologic toxicity occurs in approximately 50% of patients receiving 
combined chemoradiotherapy alone for head and neck cancer and no hematologic toxicity was 
seen in phase I/II trials of nelfinavir in the setting of HIV patients (34), the dose modifications for 
hematologic toxicity will be reduction in standard chemotherapy dose.  , as per the treating medical 
oncologist. Hematologic toxicities are expected and will not be followed as part of this trial. They 
will be managed by the treating medical oncologist. 
7.1.2 
Non-hematologic toxicities 
Modifications in dose, frequency, and regimen of chemotherapy will be made for non-hematologic 
toxicity (such as hearing loss or rise in creatinine to > 1.5x normal value). Nelfinavir will be held 
if during treatment, grade 4 mucositis, dysphagia, or odynophagia develops.  
 
Regardless of cause, nelfinavir must be immediately held if during treatment, Grade > III hepatic 
function impairment develops as characterized by: 
• 
Total bilirubin > 3x ULN (upper limit of normal of local lab; corresponds to approx 
2.7 mg/dl or 45.9 micromol/l) OR 
• 
AST/ALT > 5x ULN 
AST, ALT, and total bilirubin must be verified no later than one week after the first assessment, 
and weekly thereafter until resolution to grade < I. 
 
Dose administration must be held until recovery to grade < I for all three hepatic parameters, at 
which time dosing of nelfinavir can resume. 
7.2 Correlative Laboratory Studies-Molecular Markers 
All patients will have research blood samples drawn for biomarker analysis (prior to NFV therapy 
and again after lead-in).   
 
8 Safety and Adverse Events 
 
8.1 FMISO IND Investigator Reporting 
 
Notifying the Radiology IND Support Office: 
The Principal Investigator or designee will seek information from the subject in 
reference to any adverse events specific to imaging procedures or injection of 
the Investigational Agent that may have occurred, by specific questioning and, 
as appropriate, by examination.  
 
Only events surrounding PET/CT study procedures and the Investigational 
Radiopharmaceutical Agent outlined in this protocol apply for reporting for the 
IND. Any treatment related events outlined in this protocol or otherwise will not 


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be collected or reported as part the imaging protocol and should be processed 
per the protocol and institutional policies.  
 
It is the responsibility of the Principal Investigator to determine the grade, 
attribution and expectedness of the event.  
 
Once an event surrounding study procedures and/or the Investigational Agent 
has been identified the PI should be contacted immediately to complete the AE 
& SAE Case Repot Form.  
 
 For the events in correlation to the Investigation Agent the event should 
be recorded on the AE & SAE Case Repot Form if: 
 
• Record all events regardless grade, attribution or expectedness if the 
event occurred within 24 hours after the injection of FMISO. 
 
 For the events in correlation to study procedures, the event should be 
recorded on the AE & SAE Case Repot Form if: 
 
• Record all events regardless grade, attribution or expectedness. 
 
A copy of the completed AE & SAE Case Repot Form should be sent to the 
Radiology IND Support Office within 24 hours of knowledge for review by the 
IND Authorized Sponsor Representative. 
 
The completed AE & SAE Case Repot Form should be placed in the subject’s 
chart and a copy placed in the Regulatory Binder (this is recommended for the 
preparation of the FDA IND Annual Report and IRB Continuing Review).  
 
The clinical course of each event should be followed until resolution, 
stabilization, or until it has been determined that the investigational agent or 
study procedure is not the cause of the event.   
 
Significant new information on ongoing adverse events should be provided 
promptly to the Radiology IND Support Office. 
 
 
Notifying the Penn IRB 
The Penn IRB requires Principal Investigators to submit IRB required reports 
within 10 working days from the time the investigator becomes aware of the 
event. The event must meet the following requirements: 
 
 Report events in correlation to the Investigational Agent if: 
• The event occurred within 24 hours after the injection of FMISO. 


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• The event is grade 3 or higher, unexpected and the event is 
possibly, probably or definitely related to the Investigational 
Agent. 
 
 Report events in correlation to study procedures if: 
• The event is grade 3 or higher, unexpected and the event is 
possibly, probably or definitely related to a study procedure. 
 
If the event involved a death and indicates that participants or others are at risk 
of increased harm, investigators should report within 3 days. 
 
Follow instructions for report completion on the IRB website. 
 
All other events will be reported at the time of Continuing Review. 
 
Copies of each report and documentation of IRB notification and receipt will be 
sent to the Radiology IND Support Office and kept in the Clinical Investigator’s 
study file. 
 
 
 
Notifying the Cancer Center DSMC (Cancer Research Studies Only) 
AEs will be graded according to Common Terminology Criteria for Adverse   
Events (CTCAE) version 5.0 for reporting to the DSMC: 
 
 Report events in correlation to the Investigational Agent within 10 
working days of knowledge if: 
• The event occurred within 24 hours after the injection of FMISO. 
• All grade 3 or higher events regardless of attribution or 
expectedness. 
 
 Report events in correlation to study procedures within 10 working days 
of knowledge if: 
• All grade 3 or higher events regardless of attribution or 
expectedness. 
 
If the event involved an unexpected death and indicates that participant or 
others are at risk of increased harm, investigators should report within 2 
working days.  
All other deaths within 30 days of knowledge. Deaths of subjects greater than 
90 days from the last study treatment/intervention are not reportable unless a 
longer time frame is specified in the protocol. 
 
Follow instructions for report completion on the Cancer Center website. 
 


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Copies of each report and documentation of Cancer Center DSMC notification 
and receipt will be sent to the Radiology IND Support Office and kept in the 
Clinical Investigator’s study file. 
 
Sponsor Reporting  
Notifying the FDA 
The study sponsor is required to report certain study events in an expedited 
fashion to the FDA.  These written notifications of adverse events are referred to 
as IND Safety Reports. The following describes the safety reporting 
requirements by timeline for reporting and associated type of event: 
 
Events in correlation to the Investigational Agent:  
Report within 7 calendar days 
• The event occurred within 24 hours after the injection of FMISO. 
• Associated with the use of the study drug. 
• Unexpected.  
• Fatal or life-threatening.  
Report within 15 calendar days 
• The event occurred within 24 hours after the injection of FMISO. 
• Associated with the use of the study drug. 
• Unexpected.  
• Serious, but not fatal or life-threatening. 
     -OR- 
• A previous adverse event that was not initially deemed reportable 
but is later found to fit the criteria for reporting (reporting within 
15 calendar days from when event was deemed reportable). 
Any finding from tests in laboratory animals that:  
• Suggest a significant risk for human subjects including reports of 
mutagenicity, teratogenicity, or carcinogenicity. 
 
Notifying Participating Investigators 
  It is the responsibility of the study sponsor to notify all participating 
investigators, in a written IND safety report, of any adverse event associated with 
the use of the drug that is both serious and unexpected, as well as any finding 
from tests in laboratory animals that suggest a significant risk for human 
subjects.  Additionally, sponsors are also required to identify in IND safety 
reports all previous reports concerning similar adverse events and to analyze the 
significance of the current event in light of the previous reports. 
 
Additional Sponsor Reporting Requirements 
   Sponsors are also required to identify in IND safety reports all previous reports 
concerning similar adverse events and to analyze the significance of the current 
event in light of the previous reports. 
 


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        Other IRB Reportable Events: 
• Any adverse event that would cause the sponsor to modify the 
investigators brochure, protocol or informed consent form, or 
would prompt other action by the IRB to assure protection of 
human subjects. 
• Information that indicates a change to the risks or potential 
benefits of the research, in terms of severity or frequency, for 
example:  
• An interim analysis indicates that participants have a lower rate of 
response to treatment than initially expected. 
• Safety monitoring indicates that a particular side effect is more severe, 
or more frequent than initially expected. 
• A paper is published from another study that shows that an arm of your 
research study is of no therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol. 
• A breach of confidentiality. 
• Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 
• Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to 
remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more 
participants at increased risk, or affects the rights or welfare of subjects. 
• Exceptions:  A study exception is a one time, intentional action or process that 
departs from the IRB and CTSRMC approved study protocol, intended for one 
occurrence. If the action disrupts the study progress, such that the study design or 
outcome (endpoints) may be compromised, or the action compromises the safety 
and welfare of study subjects, advance documented IRB and DSMC approval is 
required. For this in-house study with a sponsor monitor, approval will be obtained 
from the study sponsor (IND Support Office) prior to submitting the exception 
request to the IRB and DSMC. 
• Deviations:  A study design deviation is a one time, unintentional action or 
process that departs from the IRB and CTSRMC approved study protocol, 


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involving one incident and identified retrospectively, after the event occurred. If 
the impact on the protocol disrupts the study design, may affect the outcome 
(endpoints) or compromises the safety and welfare of the subjects, the deviation 
will be reported to the DSMC and IND Support Office within 5 business days and 
the IRB within 10 business days. 
 
 
8.2 18F-FMISO and FDG PET/CT 
 
Pregnancy Clause 
The effects of 18F-FMISO on unborn children, children who are breast-feeding and the 
health of the mother are unknown. For this reason, subjects who are pregnant must inform the 
investigator(s) and understand that she will not be included in the study. Women of childbearing 
age will have a pregnancy test before making a decision about participating in the study. The 
cost of the exam is part of regular cancer care and may be done even they do not join the study. 
 
 
 
IV Contrast Risks & Procedures Clause 
There is a risk that multiple needle-sticks will be necessary in order to ensure proper placement 
of the Intravenous line. There is a small risk of infection at the site the catheter is placed or there 
may be a small amount of pain or bruising associated with the placement of the Intravenous 
catheter.  
 
      8.3 Nelfinavir Reporting 
 
Notifying the Penn IRB 
The Penn IRB requires Principal Investigators to submit IRB required reports within 10 
working days from the time the investigator becomes aware of the event. The event must 
meet the following requirements: 
 
Report events in correlation to Nelfinavir if the event is grade 3 or higher, unexpected and the 
event is possibly, probably or definitely related to Nelfinavir. 
 
Report events in correlation to study procedures if the event is grade 3 or higher, unexpected 
and the event is possibly, probably or definitely related to a study procedure. 
 
If the event involved a death and indicates that participants or others are at risk of increased 
harm, investigators should report within 3 days. 
 
 
All other events will be reported at the time of Continuing Review. 
 


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Notifying the Cancer Center DSMC (Cancer Research Studies Only) 
AEs will be graded according to Common Terminology Criteria for Adverse   Events 
(CTCAE) version 5.0 for reporting to the DSMC: 
 
Report events in correlation to Nelfinavir within 10 working days of knowledge for all grade 
3 or higher events regardless of attribution or expectedness. 
 
Report events in correlation to study procedures within 10 working days of knowledge of all 
grade 3 or higher events regardless of attribution or expectedness. 
 
If the event involved an unexpected death and indicates that participant or others are at risk 
of increased harm, investigators should report within 2 working days.  
 
All other deaths within 30 days of knowledge. Deaths of subjects greater than 90 days from 
the last study treatment/intervention are not reportable unless a longer time frame is specified 
in the protocol. 
 
 
8.3.1 Pregnancy Clause 
 
Because of the effects of Nelfinavir, there could be serious harm to unborn children or children 
who are breast-feeding. These effects could also harm the mother.  It is also possible that harmful 
side effects that are not yet known could happen to both the mother and unborn or breast-feeding 
child. If you are currently pregnant, it is important that you inform the investigator(s) because 
you will not be able participate in the study.  If you are able to become pregnant, you will be 
given a urine pregnancy test before entry into the study.  You are asked to use a medically 
accepted method of birth control (such as condoms, vasectomy, abstinence) while you participate 
in the study.  You should not become pregnant while you are taking this drug.  If you do become 
pregnant, you must discontinue the drug, tell the investigator and consult an obstetrician or 
maternal-fetal specialist.  
 
If you are a man, you are advised to use a means of birth control (such as condoms, abstinence, 
vasectomy) while you are taking part in this study because the effect of treatment on your sperm 
or upon the development of an unborn child is not known. You should not father any children 
while on this study.  
 
 
9 Data Handling and Record Keeping 
 
9.1 
Records 
All patients must have a signed Informed Consent Form and an On-study (confirmation of 
eligibility) form filled out and signed by a participating investigator prior to entering the study. 


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Confidential research charts will be kept in locked cabinets at each participating institution.  
Subjects will be assigned a study number at the time of study enrollment.  This study number and 
not the subject’s name will be used on all case report forms. 
HIPAA Compliance:   
Patients will be asked to read and sign a consent form that includes confidentiality information 
acknowledging the uses and disclosures of protected health information (PHI) in this study as 
required by The Health Insurance Portability and Accountability Act (HIPAA).  PHI will not be 
shared with any outside institution except as required by law.  Any reporting of the results of this 
study will be done only with de-identified patient data.  Confidentiality will be protected as 
outlined below. 
• Each subject will sign a study informed consent and a study-specific HIPAA authorization 
form prior to surgery. 
• Each subject will be assigned a study number.  All research-related material (to include 
specimens for research) will be labeled with the subject study number and the subject’s 
initials.  
• A list of the subject names with the associated subject numbers will be maintained in a 
locked cabinet and computer by the principal investigator and study coordinator. 
• All research subject records will be kept in a study chart. 
• An electronic database will be maintained.  No subject names will be used in this database.  
Study numbers will be used.  Only data which constitutes a limited data set (as defined by 
the University of Pennsylvania Health System in the HIPAA Privacy Education website) 
will be used. 
9.2 
Data Entry 
All patients must have a signed Informed Consent Form and an On-study (confirmation of 
eligibility) form filled out and signed by a participating investigator prior to entering the study. 
A case report form will be used to standardize data keeping and allow entry to a computerized data 
base. 
 
9.3 
Flow of Subject Data 
Study entry:  Each patient will be evaluated for this study based upon the inclusion and exclusion 
criteria.  If a patient is found to be eligible for the study, an eligibility checklist will be completed 
after the patient has signed an informed consent form.  The patient will be assigned a study 
number.  A list of the subjects with the assigned study numbers will be kept on a confidential 
computer file in the Department of Radiation Oncology, University of Pennsylvania.   
 
Treatment:  After study enrollment, the subject will undergo treatment planning for 
chemoradiotherapy as per standard clinical care.  The subject will begin oral nelfinavir 7-14 days 
prior to the initiation of radiotherapy.  The principal or a co-investigator will fill out a 
radiotherapy prescription form as per routine clinical care.  The investigator will also complete a 


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prescription form for nelfinavir.  The study coordinator will double-check the nelfinavir 
prescription.   
 
Imaging:  Copies of all imaging for these studies will be maintained by the Department of 
Radiology, Division of Nuclear Medicine, at the University of Pennsylvania. 
 
Follow-up:  The clinical status and laboratory results of the subjects will be recorded on a flow 
sheet and on the CRF. Toxicity forms will be maintained for each subject and will be evaluated 
up to the first standard of care follow-up visit after completion of radiation.  The principal 
investigator will verify the grades and attribution of the toxicities for each subject.    Subjects 
will be followed for survival for the remainder of the follow-up.   
 
10 Data and Safety Monitoring Plan 
10.1  Overview 
The University of Pennsylvania Cancer Center (UPCC) has a formal plan for Data Safety and 
Monitoring of Clinical Trials.  The clinical trial, “A Phase II Trial of Protease Inhibitor, 
Nelfinavir, Given with Definitive, Concurrent Chemoradiotherapy in Patients with Locally-
Advanced, Human Papilloma Virus negative, Squamous Cell Carcinoma of the Head and Neck” 
is a trial that is subject to oversight of the UPCC through the Data and Safety Monitoring 
Committee (DSMC).  DSMC role is to ensure that the rights and well-being of all subjects are 
protected and that subjects are treated in full compliance with the study treatment and parameters 
specified in the protocol. The DSMC is responsible for overseeing the process of monitoring of 
studies and the conduct of audits.  The investigators on this study are responsible for the 
continuous, close monitoring of subjects enrolled on this trial. 
10.2  Study Audits 
This study will be audited by the Department of Compliance and Monitoring on behalf of the 
ACC Data  and safety monitoring Committee every six months from the first subject enrolled 
and every six months thereafter for the life of the study. The principal investigator will be 
notified in advance of the selection of their protocol for review.  Three randomly selected 
patients or 10% of the total accrual, whichever is higher will be audited.  A written report is 
provided to the principal investigator following this audit.  Any rating less than satisfactory 
would warrant a repeat full review at the time of the next scheduled audit or sooner, depending 
upon the extent of the deficiencies found.  Substantial protocol deviations will be reported to the 
Director of the Cancer Center and the Associate Director for Clinical Research for consideration 
of appropriate administrative action, such as suspending accrual to the protocol. 
 
10.3 Study Monitoring 
This trial will be monitored by the Principal Investigator and the research coordinator. 
 
10.4 Study Monitoring for IND 139443 - Radiology IND Support Office 


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The transformation of the PET/CT from the radiotracer EF5 to FMISO will change the oversight of the 
PET/CT radiotracer IND.  FDA IND 139443 (FMISO) is managed by the Department of Radiology IND 
Support Office (INDSO). The INDSO will accept all monitoring and auditing of the study as defined in 
the protocol and as carried out as so far in the study. The Principle Investigator or designee will promptly 
forward all reports related to monitoring and/or auditing to the INDSO for review. The INDSO and 
Authorized Sponsor Representative will review reports and assess the need to schedule monitoring visits 
by the INDSO as needed. 
 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.  The investigator should 
provide a list of EC/IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure.  This consent form must be 
signed by the subject or legally acceptable surrogate, and the investigator-designated research 
professional obtaining the consent.  
12 Study Finances 
12.1 Funding Source 
This study is financed through the National Institutes of Health, via grant 1R01CA174976-01A1.  
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study sponsor 
prior to participation in this study.  All University of Pennsylvania investigators will follow the 
University conflict of interest policy. 
13 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 


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published or passed on to any third party without the consent of the study sponsor (PI).  Any 
investigator involved with this study is obligated to provide the sponsor (PI) with complete test 
results and all data derived from the study. 
 
 
 
 
 
 
 
 
 
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