Clinical trial NCT01108666
Conditions: Non Small Cell Lung Cancer
Keywords: Stage IIIA or IIIB NSCLC
Sponsor: Abramson Cancer Center at Penn Medicine
Start date: 2010-03-01; Completion date: 2018-12-01
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Seventy two patients are being asked to take part in this research study because they have been diagnosed with Stage IIIA or IIIB non-small cell lung cancer (NSCLC). This study is being done to determine the highest safe dose of proton beam radiotherapy and/or study drug (called Nelfinavir) that can be given with concurrent chemoradiotherapy to patients with cancer without causing bad side effects; and to develop biomarker for clinical outcome. This study will be done in two phases. In the first phase, feasibility will be established. We will follow patients treatment courses and record side effects at the standard proton radiation dose that can be given together with Cisplatinum + Etoposide or Carboplatin + Paclitaxel. In the second phase, we will see if it is possible to increase the total proton radiation dose or study drug without increasing the number of bad side effects while treated together with chemotherapy drugs.

Detailed description:
Overall objectives:

1. Determine MTD of proton beam radiotherapy with concurrent cisplatin and etoposide for stage III NSCLC.
2. Determine MTD of proton beam radiotherapy with concurrent carboplatin and paclitaxel for stage III NSCLC in non-cisplatin candidates.
3. Determine MTD of Nelfinavir with concurrent chemoradiotherapy for stage III NSCLC at RPTD of proton beam radiotherapy.
4. Develop biomarker for clinical outcome with concurrent chemoradiotherapy in stage III NSCLC.
5. To determine clinical efficacy, as defined by metabolic response, sites of recurrence (e.g., local, regional, distant) and progression-free and overall survival.

Arms: arm 1: None
Interventions: intervention 1: Nelfinavir
Intervention descriptions: intervention 1: Two dose levels of Nelfinavir will be evaluated in each concurrent chemotherapy group (carboplatin/paclitaxel and cisplatin/etoposide) at the RPTD does of proton beam radiotherapy: 625 and 1250 mg PO bid.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
University of Pennsylvania 
 
 
Feasibility and A Stratified Phase II trial of Proton Beam Radiotherapy with Concurrent Chemotherapy and 
Nelfinavir for Inoperable Stage III NSCLC followed by subsequent Feasibility Confirmation with Nelfinavir 
 
 
Investigator: 
Department of Radiation Oncology 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
Email: Abigail.Berman@uphs.upenn.edu 
 
Sub-Investigators 
Tracey Evans, MD 
Corey Langer, MD 
Alexander Lin, MD 
Lilie Lin, MD 
Carol Proud, NP 
William Levin, MD 
 
Biostatistics 
Rosemarie Mick, MS 
Protocol Number: 
UPCC# 01510 
IRB# 811186 
IND/IDE Number: 
IDS# 03771 
 
 
 
 
Date: 
15 January 2010 
Amended: 
10 March 2010 
Amended: 
Amended: 
25 March 2010 
20 May 2011 
Amended: 
02/01/2012 
Amended: 
08/13/2012 
Amended: 
Amended: 
Amended: 
10/16/2012 
03/28/2013 
10/06/2016 
 
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. 


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Table of Contents 
STUDY SUMMARY 
1 
INTRODUCTION 
1.1 
BACKGROUND 
2 
STUDY OBJECTIVES 
3 
SUBJECT SELECTION AND WITHDRAWAL 
3.1 
INCLUSION CRITERIA 
3.2 
EXCLUSION CRITERIA 
3.3 
SUBJECT RECRUITMENT AND SCREENING 
3.4 
EARLY WITHDRAWAL OF SUBJECTS 
4 
RADIATION THERAPY 
4.1 
TREATMENT PLANNING, IMAGING AND LOCALIZATION REQUIREMENTS 
4.2 
TARGET CONTOURING 
4.3 
NORMAL STRUCTURES 
4.4 
DOSE FRACTIONATION AND SPECIFICATION 
4.5 
TREATMENT PLANNING 
4.6 
TREATMENT DURATION 
4.7 
EXTERNAL BEAM EQUIPMENT AND BEAM DELIVERY 
4.8 
QUALITY ASSURANCE 
5 
STUDY DRUG 
5.1 
TREATMENT REGIMEN 
6 
CHEMOTHERAPY 
7 
STUDY PROCEDURES 
7.1 
POST-TREATMENT EVALUATION AND FOLLOW-UP 
7.2 
ASSESSMENT OF TUMOR RESPONSE 
8 
STATISTICAL PLAN 
8.1 
STUDY DESIGN 
8.2 
OBJECTIVES 
8.3 
ENDPOINTS 
8.4 
EARLY TERMINATION AND ESCALATION RULES 
8.5 
STATISTICAL ANALYSES 
8.6 
SAMPLE SIZE AND TRIAL DURATION 
9 
SAFETY AND ADVERSE EVENTS 
9.1 
DEFINITIONS 
9.2 
ASSESSING AND RECORDING ADVERSE EVENTS 
9.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
9.4 
STOPPING RULES 
9.5 
MEDICAL MONITORING 
10 
DATA HANDLING AND RECORD KEEPING 
10.1 
CONFIDENTIALITY 
10.2 
SOURCE DOCUMENTS 
10.3 
CASE REPORT FORMS 
10.4 
RECORDS RETENTION 
11 
STUDY MONITORING, AUDITING, AND INSPECTING 
11.1 
STUDY MONITORING PLAN 
12 
ETHICAL CONSIDERATIONS 


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13 
STUDY FINANCES 
13.1 
CONFLICT OF INTEREST 
14 
PUBLICATION PLAN 
15 
REFERENCES 
16 
ATTACHMENTS -- STUDY SCHEDULES 
 


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List of Abbreviations 
 
AUC 
Area under the curve 
bid 
Twice a Day 
CGE 
Cobalt Gray Equivalent 
CR 
Complete Response 
CT 
Computed tomography 
CTC 
Common Terminology Criteria 
CTRT 
Chemotherapy-Sensitized Radiation Therapy 
CTV 
Clinical Target Volume 
DIBH 
Deep Inspiration Breath Hold 
EBRT 
External beam radiotherapy 
EORTC 
European Organisation for Research and Treatment of Cancer 
FDG-PET 
Fludeoxyglucose-Positron Emission Tomography 
GTV 
Gross Tumor Volume 
Gy 
Gray 
ITV/iCTV 
Internal Target Volume / Imaging Clinical Target Volume 
LET 
Linear Energy Transfer 
MRI 
Magnetic resonance imaging 
MTD 
Maximum Tolerated Dosage 
NSCLC 
non-small cell lung cancer 
OAR 
Organ at risk 
OER 
Oxygen Enhancement Ratio 
PD 
Progressive Disease 
PO 
By Mouth, Orally 
PR 
Partial Response 
PTV 
Planning Target Volume 
RBE 
Relative Biologic Effectiveness 
RC 
Range Compensator 
RPTD 
Recommended Phase II Dose 
RTOG 
Radiation Therapy Oncology Group 
PBSTV 
Pencil Beam Scanning Target Volume 
SD 
Stable Disease 
SOBP 
Spread Out Bragg Peak 
SWOG 
Southwest Oncology Group 
 
 


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Study Summary 
Title 
Feasibility and Stratified Phase II trial of Proton Beam Radiotherapy with 
Concurrent Chemotherapy and Nelfinavir for Inoperable Stage III NSCLC followed 
by subsequent Feasibility Confirmation with Nelfinavir 
 
Short Title 
Stratified Phase II of Proton Radiotherapy with Concurrent Chemotherapy for Stage 
III NSCLC  
Protocol Number 
UPCC# 01510; 
IRB # 811186 
IDS # 03771 
Phase 
Feasibility and Phase II 
Methodology 
Open 
Study Duration 
6.5 years 
Study Center(s) 
University of Pennsylvania 
Objectives 
Primary Objectives 
 
Feasibility Study: 
1. To establish the feasibility and safety of proton beam radiotherapy 
with  cisplatin/etoposide for stage III NSCLC. 
2. To establish the feasibility and safety of proton beam radiotherapy 
with  carboplatin/paclitaxel for stage III NSCLC. 
 
Phase II: 
1. To determine the rates of acute esophagitis toxicity in strata defined 
by chemotherapy regimen and proton beam. 
 
Nelfinavir Feasibility Study: 
1. To establish the feasibility of the treatment regiment with the addition 
of standard dose of Nelfinavir.  
 
Secondary Objectives  
1. Investigate biomarker, as they become available. 
2. To determine clinical efficacy, as defined by metabolic response, sites of 
recurrence (e.g., local, regional, distant) and progression-free and overall 
survival. 
Number of Subjects 
 130 subjects 
Diagnosis and Main 
Inclusion Criteria 
Stage III NSCLC 


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Introduction 
1.1 
Background 
 
Disease Background 
Lung cancer remains the leading cause of cancer death in the United States1, approximately 75- 80% of all cases are non-
small cell lung cancer (NSCLC).  Of these, 30-40% are considered locally advanced comprising both Stage IIIA and IIIB 
in the current AJCC staging system.  Using cancer incidence data from 2009, we can predict that there will be 
approximately 219,440 cases of lung cancer this year, therefore between 50,000 and 60,000 patients will be diagnosed 
with locally-advanced NSCLC1. 
 
Rationale for Proposed Therapeutic Study 
RTOG 7301 established 60Gy in 30 daily fractions as the standard of care for locally advanced inoperable NSCLC.2 It has 
since been shown that combined modality therapy with platinum-based induction chemotherapy followed by definitive 
radiotherapy in unresectable Stage III and medically inoperable stage II NSCLC results in a statistically significant 
improvement in overall survival.  The Cancer and Leukemia Group B (CALGB) showed in a Phase III trial that median 
survival was improved with induction chemotherapy followed by conventional RT than RT alone (13.7 vs. 9.6 mos).3  The 
RTOG duplicated these results in a separate phase III trial clearly establishing the combined modality as the standard of 
care in the management of locally advanced inoperable NSCLC.4 4-8  
 
Optimizing Combined Modality Therapy 
The EORTC performed a phase III randomized trial comparing concurrent cisplatin based chemoradiation to radiotherapy 
alone and demonstrated a clear survival benefit to this approach.5 Of note, there was no difference in rate of distant 
metastases and therefore the authors concluded that the benefit in overall survival was due to an improvement in local 
control secondary to enhanced radiosensitization of the tumor by cisplatin.  Additionally, initial phase II trials suggested 
that concurrent chemoradiotherapy may be an even more effective treatment than sequential chemoradiotherapy.9 
Therefore, Furuse et al. performed a phase III randomized trial comparing concurrent chemoradiotherapy to sequential 
chemoradiotherapy. They demonstrated a statistically significant survival advantage to the concurrent approach (median 
survival of 16.5 months vs 13.3 months).10 The RTOG 9410 study compared two different concurrent regimens (cisplatin 
and vinblastine with conventional radiotherapy or cisplatin and oral etoposide with hyperfractionated radiotherapy) with a 
sequential regimen of cisplatin followed by conventional radiotherapy. Again, median survival times improved (17 vs. 
14.6 mos) with an increase in acute toxicities.  (RTOG 9410 abstract) A third and smaller randomized trial did not show a 
significant survival advantage, however there was a significant improvement of 2-year survival with concurrent over 
sequential chemoradiation (35 vs. 24%).11  
 
In an attempt to resolve this controversy, a meta-analysis was recently performed by Auperin and colleagues that analyzed 
individual patient data of 1104 patients enrolled in randomized clinical trials. With a median follow-up of 5 years, they 
found a statistically significant absolute survival benefit of 6.6% at 3 years (24.8% vs 18.2%). The HR for death with 
concurrent chemoradiation was 0.83 (p=0.0026). Concurrent chemoradiotherapy decreased loco-regional progression 
(HR=0.76; p= 0.011). There was no difference in distant progression between concurrent and sequential chemoradiation. 
The authors therefore concluded that it was due to a decrease in loco-regional progression that was driving the survival 
benefit observed in these patients.12 This survival advantage is not unaccompanied by an increase in toxicity, especially 
acute esophagitis.  
 
The optimal chemotherapeutic platform for concurrent therapy 
At present the optimal chemotherapeutic platform for concurrent chemoradiotherapy remains to be determined. In the 
absence of randomized data, the best survival to date in stage III NSCLC comes from the SWOG 9504 trial, which 
investigated the role of consolidative chemotherapy after concurrent chemoradiotherapy with cisplatin and etoposide in 
the phase II setting. Gandara and colleagues demonstrated a promising overall survival of 26 months in stage III patients 
treated with this approach and a 3-year survival of 37%.13 This remains the best available data to date for concurrent 
chemoradiotherapy. The value of consolidative chemotherapy was subsequently tested in a phase III trial performed by 


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Figure 1: Dose deposition profile of various energies of photon (X-ray) beam 
radiotherapy when treating a hypothetical patient with a tumor. Note that dose 
deposition continues from point of entry until exit from the patient. 
Hanna and colleagues in the Hoosier Oncology Group. The median survival time was no different between the two arms 
with 21.6 months in the consolidation arm vs. 24.2 months in the observation arm (p=0.94).There was also a significant 
increase in toxicity, with a 5.5% death rate attributable to docetaxel and 28.8% of hospitalized rate during docetaxel 
administration, as opposed to only a 8.1% hospitalization rate of patients in the observation arm. 14 The authors concluded 
that consolidation chemotherapy does not improve overall survival. This suggests that more perhaps is not always better 
and that before more aggressive therapies, particularly escalation of radiation dose toxicity reduction is critical in order to 
improve the therapeutic ratio. 
 
The cisplatin-based regimens used in the previously cited randomized trials are less commonly employed in primary 
chemoradiation therapy regimens today. This is because of the added toxicity associated with these regimens allows for 
this to be employed with the ‘fittest’ stage III patients. Another common platform for concurrent treatment is carboplatin 
and paclitaxel with extensive data from phase II studies.15-17 This regimen was perceived to be more effective and less 
toxic than the older regimens. Unfortunately, in the only phase III study to date evaluating carboplatin and paclitaxel with 
radiation, the median survival time was only 11.4 months. In addition, the toxicity profile appears no safer as the reported 
grade 3/4 esophagitis and pneumonitis rates are 26-46% and 17-22%, respectively, when carboplatin/paclitaxel therapy is 
used concurrently with RT. Nevertheless, phase II studies from the RTOG (0117), CALGB (Arm 1 of 30105), and North 
Carolina University groups are showing encouraging median survival times of approximately 24 months using these 
agents concurrently with 74 GY(RBE).25-27 Since weekly administration of carboplatin and paclitaxel was given 
concurrently with thoracic irradiation in above studies, we will utilize these agents for patients who are not candidates for 
cisplatin based chemotherapy in the same fashion for this Phase I trial. 
 
Promises and technical challenges of dose escalation for improving survival of NSCLC 
Evidence suggests that there is a direct relationship between escalation of radiation dose and tumor control.  Perez et al. 
analyzed the patterns of failure in patients with unresectable NSCLC treated with definitive radiotherapy.  The failure rate 
within the irradiated volume decreased from 53 to 58% at 40 Gy to 35% at 60 GY(RBE)GY(RBE)2.  Consequently, dose 
escalation has been investigated as a method to improve overall survival in patients with NSCLC.  Recent evidence 
suggests that for small tumors, dose escalation can significantly improve tumor control18-20, and there is data to suggest 
that a subset of patients with large-volume locally advanced tumors may also potentially reap a survival benefit from 
escalation of dose21-23.  However, there are fundamental limitations to dose escalation using X-ray beam (photon) 
radiation.  Due to the physical characteristics of the beam, 
X-rays deposit dose from the point of entry into the patient 
until the point of exit (Figure 1).  This means that all 
normal tissue that lies proximal or distal to the tumor will 
receive dose when being treated with X-rays.  Although 
technological advances have allowed for improved delivery 
of X-rays to the target, the aforementioned physical 
characteristics of the X-ray beam have generally impeded 
the ability to safely escalate the dose of radiation for the 
majority of NSCLC patients with larger tumors and/or 
locally advanced disease22,24-26.  Consequently, these 
patients have largely been excluded from studies examining 
radiation dose escalation or included but escalated to an 
attenuated dose 27-30.  This is primarily due to the exquisite 
sensitivity of lung tissue to radiation.  Even moderate doses 
of radiation will render uninvolved lung tissue inflamed 
(pneumonitis) or functionally incompetent (fibrosis) within 
months after treatment31,32.  As a result, despite evidence 
supporting the effectiveness of radiation dose escalation, it 
is difficult to deliver high doses of radiation to patients with 
locally advanced NSCLC without damaging a sufficient 
volume of healthy lung that could render the patient a 
pulmonary cripple.  Thus, it remains possible that any benefit of dose escalation with X-ray beam radiotherapy for 
patients with locally advanced NSCLC is offset by concurrent toxicity.    


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Dose Escalation in Combined Modality Therapy 
The emergence of concurrent chemoradiation as the standard treatment approach for patients with locally advanced 
NSCLC has called into question the need for additional escalation of radiation dose beyond 60Gy, given the very real 
concerns of excessive toxicity to the patient. However, local control in NSCLC still remains poor. Le Chevalier observed 
that the 1-year local control rate was only 15% for patients with unresectable NSCLC treated to 65 GY(RBE).33 A 
relationship has been shown between local failure and the subsequent appearance of distant metastases.34 Furthermore, 
improved local control has been shown to result in a significant improvement in overall survival.35 In the CHART trial, 
hyperfractionated radiotherapy resulted in improved local control and survival.36 A similar correlation between improved 
local control and survival was seen in the EORTC study comparing concurrent chemoradiation versus radiation alone for 
locally advanced NSCLC. 2-year local control improved from 19% to 31% with the addition of concurrent daily cisplatin. 
2-year overall survival increased from 13% to 26% in the concurrent daily cisplatin arm. Of note, there was no difference 
in the rate of distant metastases between the chemoradiotherapy and the radiotherapy alone arms in this trial, leading the 
authors to conclude that it was an improvement in local control that drove the improvement in overall survival observed in 
this study.5  
he 60 GY(RBE) dose level was established in the pre-computed tomography era, and therefore its relevance to current 
modern radiotherapy planning and treatment delivery techniques can be questioned.2 Rosenman and co-workers reported 
the results of a single institution phase I dose escalation study with concurrent chemoradiation with a stepwise escalation 
of dose from 60 to 74GY(RBE) without significant toxicity.37 The median survival of 24 months and 5-year survival of 
25% in this study were provocative, however single-institution data must be interpreted with caution.  More recently, 
Socinski and co-workers reported the results of CALGB 30105, a multi-institutional randomized phase II trial of induction 
chemotherapy followed by concurrent chemoradiotherapy. Patients with stage IIIA/B NSCLC were randomly assigned to 
induction chemotherapy with either carboplatin/paclitaxel or carboplatin/gemcitabine. Patients randomized to arm A 
received weekly carboplatin/paclitaxel while patients treated on arm B received biweekly gemcitabine concurrently with 
74 Gy utilizing three-dimensional treatment planning. The 
primary endpoint was a median survival of at least 18 
months. Arm B was closed due to excessive pulmonary 
toxicity, however arm A met its primary endpoint with an 
estimated median survival of 24.3 months.38  These 
promising results support the need for a multi-institutional 
randomized phase III study comparing high dose 
concurrent chemoradiotherapy to the standard of 
60GY(RBE). Towards that end, the RTOG, in conjunction 
with the NCCTG and CALGB have planned a phase III 
randomized trial of 60Gy with concurrent chemotherapy 
versus 74GY(RBE) with concurrent chemotherapy (RTOG 
0617/NCCTG N0628/CALGB 30609). The radiotherapy in 
this trial will be delivered with modern 3D-conformal 
treatment techniques. The results of this study should 
address the impact of dose and treatment delivery 
techniques on the efficacy and tolerability of high dose 
combined modality concurrent chemoradiotherapy. 
 
It is unclear as to whether all patients can benefit from 
higher doses. Some have questioned the value of this dose 
escalation for patients with large volume tumors.39 The 
volume of disease appears to have an impact on survival in patients treated with definitive radiotherapy. Bradley, et al. 
examined 207 patients with inoperable NSCLC and demonstrated by multivariate analysis that gross tumor volume was 
the variable most predictive of overall and cause-specific survival.40 Etiz et al. identified a direct correlation between 
smaller tumor volume and prolonged survival in patients with NSCLC.41 Willner, et al. examined the impact of tumor 
volume on local control and demonstrated that patients with small volume tumors (<100 cc) treated to doses greater than 
60 GY(RBE) had a significant improvement in local control when compared with patients treated to 60 GY(RBE) or less 
(p=0.0003).20 However, they found that higher dose levels did not improve local control for large volume tumors (>100 
Figure 2: Dose deposition profile of proton beam radiotherapy (red line) 
when compared to various energies of photon beam radiotherapy. Note 
decreased entry dose in front of tumor and NO exit dose beyond tumor 
with proton beam when compared with photons. 


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cc). In contrast, Rengan and colleagues examined the value of dose escalation in patients with large volume stage III 
disease and found that even in patients with large tumor volumes, local failure rates were significantly reduced when 
treated to 64GY(RBE) or higher.21  These data highlight an area of controversy in radiotherapeutic management of 
NSCLC. Specifically, can all patients benefit from dose escalation? If not, which patients should be selected for this 
aggressive and potentially significantly more toxic treatment approach? As of July 2008, the open phase III dose 
escalation study, (RTOG 0617/NCCTG N0628/CALGB 30609), does not exclude nor stratify patients based upon tumor 
volume. Therefore, it is unlikely that this trial will resolve this question definitively.    
 
In 2006, the RTOG opened a 2x2 phase III randomized trial to simultaneously examine the question of 60Gy vs 74Gy and 
concurrent chemoradiotherapy with or without cetuximab for patients with inoperable stage III NSCLC. After a planned 
interim analysis, the high dose radiation therapy (74 Gy) arms of RTOG 0617 were closed to accrual effective 6/17/11. In 
a communication to all RTOG trial investigators, Dr. Bradley stated that the “high dose arms crossed a futility boundary, 
meaning that high dose radiation therapy cannot result in a survival benefit with further accrual or follow up of patients on 
these 2 arms”.(234) At the 2011 ASTRO annual meeting, the initial results of this trial were presented, actually 
demonstrating a statistically significant detriment to survival with 74 Gy (p=0.02). The interim analysis did not identify 
patient safety concerns and gave no indication of a statistical difference in high-grade toxicity between arms, nor any clear 
explanation for the observed decrement in survival. Regardless, the 74Gy arm for this trial has been closed and 60Gy 
remains the standard dose in all RTOG lung cancer trials going forward.(235). Although proton beam radiotherapy 
may be an appropriate vehicle for dose-escalation in locally advanced disease, due to the results of RTOG 0617, 
dose-escalation will not be pursued in the context of this clinical trial. 
 
 
Proton beam radiation for improving the therapeutic ratio through toxicity reduction for locally advanced 
NSCLC 
In order to improve the ability to deliver definitive doses of radiation to the tumor while at the same time minimizing 
toxicity to surrounding healthy tissue, clinical research has recently focused on the utility of delivering radiation using a 
proton beam rather than the more traditional X-ray, or photon beam.  One of the major theoretical advantages of using 
proton beam radiotherapy is that the physical characteristics of the beam eliminate exit dose, or the dose deposited in 
normal tissue after the beam has penetrated the tumor (Figure 2).  As a result, the elimination of exit dose dramatically 
limits the overall volume of normal tissue exposed during treatment42,43.  It is important to note that the biological 
mechanism of tumor cell kill by proton beam radiation is identical to that of photon beam radiation.  The only difference 
lies in the dose deposition profile due to the aforementioned physical characteristics of the beam.  Although the use of 
proton beam radiation is not expected to eliminate toxicity, the favorable physical characteristics of protons compared 
with photons, is expected to allow for unprecedented dose escalation. Furthermore, due to the favorable toxicity profile of 
protons, treatment with this modality will allow for greater integration of systemic chemotherapy to be delivered 
concurrently with proton beam radiation. This may particularly benefit the patient with LA-NSCLC for whom treatment 
with concurrent chemoradiotherapy represents the greatest chance for cure.10 However, due to the significant toxicity of 
this approach, it can only be utilized in the fittest patients. Due to the reduced radiation dose to normal tissues, proton 
beam radiotherapy will allow for the more effective concurrent regimen to be used for a greater proportion of patients, and 
also will allow for integration of more aggressive chemotherapeutic regimens that cannot be currently employed with 
photon beam radiotherapy.44  
 
Mechanisms of Radiosensitization: The rationale for Nelfinavir 
Inhibition of the Akt phosphorylation results in significant radiosensitization in preclinical studies.45  However, the drugs 
used in preclinical studies to inhibit the phosphorylation of Akt in vitro, including wortmannin and LY294002, are 
excessively toxic in vivo and cannot be used clinically.46  Although inhibition of upstream modulators such as EGFR can 
result in decreased levels of p-Akt, they do so less efficiently than direct inhibition of PI3K, suggesting that alternative 
pathways to PI3K and Akt phosphorylation may exist and that direct inhibition of Akt phosphorylation may result in more 
efficient radiosensitization than inhibition of upstream modulators.46  Once Akt is phosphorylated, it is known to affect 
several downstream molecules including mammalian target of rapamycin (mTOR) that play a role in cell cycle regulation, 
cell proliferation, and apoptosis.47  The exact mechanism by which inhibition of p-Akt results in radiosensitization is not 
known, however recent evidence suggests a possible role for VEGF and HIF 1-α.48 
 


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Nelfinavir is a first generation protease inhibitor used in the treatment of HIV and is known to result in the development 
of insulin resistance and diabetes in some patients.49,50  Akt, especially the Akt2 isoform, has been shown to play a role in 
the coordinated regulation of growth and metabolism by the insulin/IGF-signaling pathway.51 Because of this link, 
Nelfinavir, along with 4 other first generation protease inhibitors were tested for their ability to inhibit the PI3k-Akt 
signaling pathway in preclinical studies.52  Three of these five protease inhibitors, including Nelfinavir, were shown to 
result in significant reduction in levels of p-Akt expression in cell lines with mutations in EGFR and H- and K-ras at 
serum concentrations that are achieved at doses regularly given to HIV patients.  Of these three protease inhibitors, 
Nelfinavir and amprenavir were found to be tolerated well by cell cultures in vitro and also resulted in radiosensitization 
in vivo both through clonogenic assays and tumor regrowth assays of xenograft mouse models.52  These results were 
consistent with previously reported data that sequinavir, one of the protease inhibitors tested, resulted in radiosensitization 
in tissue culture.53 Nelfinavir showed consistent inhibition and radiosensitization in these preclinical studies and is FDA-
approved in oral form for the treatment of HIV.48,52  Because Nelfinavir has been given to a number of patients in the 
setting of HIV, it is a good candidate inhibitor of Akt phosphorylation that can be tested in the clinic.54 However, the 
safety, tolerability, and maximally tolerated dose of Nelfinavir in the setting of concurrent thoracic chemoradiation have 
never been studied. In the preclinical studies of Nelfinavir in mouse models, no additional toxicity was noted sixty days 
after irradiation in mice treated with Nelfinavir and radiation compared to unirradiated mice or mice receiving radiation 
only.52  One long term goal of radiosensitization with Nelfinavir is to produce added clinical efficacy without significant 
increases in acute toxicities.   
 
We have recently completed a phase I trial (closed to accrual) of Nelfinavir with concurrent chemoradiotherapy for 
patients with LA-NSCLC patients. The median follow-up is 13 months for survivors. We have enrolled 16 and have 
treated 12 patients and one patient has experienced locoregional failure at 9 months. In terms of survival, 8 are alive and 
being followed. Survival times range from 6+ to 25+ months. No dose limiting toxicities with Nelfinavir have been 
observed thus far, although toxicity analysis is ongoing. No grade 5 toxicities have been observed. Two patients 
experienced Grade 3-4 esophageal toxicity. There were no other Grade 3-4 non-hematological toxicities observed. All 12 
treated patients had evaluable post-treatment PET/CT at three months after completion of therapy with response as 
follows: Overall response: 12/12 (100%); Complete metabolic response: 7/12 (58%); partial metabolic response 5/12 
(42%). These results compare favorably with previously published results of a complete metabolic response rate of 23% 
in a patients receiving definitive radiotherapy for NSCLC without concurrent Nelfinavir administration.55 Additionally, 
we have only one patient who has experienced local failure to date with a median follow-up of 13 months (Crude local 
control of 92%). These data suggest that Nelfinavir has promising activity in pts with LA-NSCLC without a dose-
dependent increase in chemoradiotherapy-associated toxicities.56 The clinical trial proposed herein would be a first step to 
a randomized phase II trial of chemoproton beam radiotherapy +/- Nelfinavir. 
 
The need for integrating predictive markers in dose escalation studies for NSCLC 
Although the availability of proton radiation gives us the unprecedented ability to escalate radiation dose, as with new 
molecularly targeted pharmacological agents, the appropriate selection of patients for dose escalation using this modality 
will be a critical step in realizing potential improvements in disease outcome.  Ideally, treatment intensification using 
proton beam radiotherapy would be reserved for patients with tumors resistant to standard therapy.  In this way, observing 
the benefit of dose escalation is not diluted by patients that are curable with standard doses or offset by unnecessarily 
imposing the increased toxicity of dose escalation on patients that can be cured with standard treatment.     
 
Given these considerations and others57, it becomes apparent that the clinical management of NSCLC would be greatly 
aided by biomarkers that can predict at the time of diagnosis, whether a patient has cancer that is either resistant or 
sensitive to standard treatment.  Such forecasting can be accomplished by using predictive markers. In contrast to 
prognostic markers, which assess risk of disease progression independent of therapy, predictive markers identify patients 
that are sensitive or resistant to treatment. The majority of standard clinicopathological factors and recent genomics-based 
assays are principally prognostic markers.  Thus, the identification of useful predictive markers remains a challenge, 
particularly for NSCLC.  The discovery of a clinically useful predictive marker would greatly benefit the study and use of 
intensified regimens for patients with resistant disease. One candidate predictive marker for resistance to 
chemoradiotherapy has been recently characterized in breast cancer. This chemotherapy/ radiation signature consists of 49 
genes and is denoted the Interferon Related DNA Damage Resistance Gene Signature, or IRDS.58  As its name implies, 
the IRDS is regulated by interferon signaling and mediates both radiation and chemotherapy resistance in mouse models 


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for cancer.  Clinically, the IRDS is expressed among a wide variety of common human cancers, including breast, head and 
neck, prostate, brain, and lung cancer .  Analysis of breast cancer patients reveals that the IRDS can predict which patients 
are resistant to adjuvant radiation therapy and also identify those patients with microscopic metastasis that will fail 
chemotherapy.  Consistent with the IRDS being a predictive marker rather than a prognostic marker, the IRDS does not 
track with outcome among patients that do not receive radiation and/or chemotherapy.  To-date, analysis of other cancer 
types also includes high grade gliomas.  Similar to breast cancer, high grade gliomas that express the IRDS also show 
evidence for resistance to post-operative radiation.  As with breast cancer and high grade gliomas, the IRDS is expressed 
in approximately half of patients with NSCLC.  However, whether the IRDS also can predict resistance to chemotherapy 
and radiation for NSCLC remains unknown. 
 
Rationale for Proton Therapy: 
The goal of radiation therapy is to deposit most of the dose to the target while minimizing the dose to the surrounding 
normal tissues.  Conventional photon radiotherapy deposits its dose along the entire beam path to the tumor or target 
volume as well as beyond the depth of the target.  Techniques to minimize the dose to surrounding tissues such as using 
multiple beam angles, modulating the intensity of the radiation delivered through each beam have been utilized, however, 
these techniques still entail both entrance dose to normal tissue as it penetrates to reach a tumor at depth in tissue, and an 
exit dose as it exits the body in a straight path beyond the tumor.  Proton radiotherapy differs from photon radiotherapy in 
that most of the energy is deposited at a specific depth known as the Bragg peak. The dose immediately beyond the Bragg 
peak is essentially zero, which allows tissues on the posterior side of the tumor to be spared.  The clinical application of 
protons provides an improvement over photons in its ability to deliver a high-dose-volume to any configuration within an 
anatomical site while maintaining lower doses to surrounding normal tissues, resulting in decreased short and long-term 
morbidity, due to the unique Bragg Peak phenomenon of the dose distribution of protons. Theoretically, this should ease 
the current limitation of normal tissue tolerance as a dose-limiting factor particularly for larger tumors as well as allow 
greater dose to be delivered to the tumor/target volume.  The current protocol proposes to allow the use of protons (which 
is approved by the U.S. Food and Drug Administration) for the treatment of Locally Advanced Non Small Cell Lung 
Cancer 
 
Protons have a similar biologic effect to photons against tumors.  The biological effect of radiation is dependent on its 
linear energy transfer (LET).  LET is defined as the rate of energy transferred by ionizing radiation per unit path length.  
To compare different types of radiation, we use the relative biologic effectiveness (RBE), which is defined as the ratio of 
the dose of particle radiation to the dose of 60Co radiation producing the same biological endpoint.  Standard photon 
radiation therapy has a RBE of 1.0; the RBE of protons is thought to be between 1.05 to 1.2559-61.  A recent review of in 
vivo and in vitro experiments concluded that RBE varies with dose or dose per fraction and increases with an increasing 
depth in the spread out Bragg Peak (SOBP) and is most significant at the distal edge of the SOBP.  Overall though, based 
on the data to date, an average RBE of approximately 1.1 in the entrance of the SOBP is reasonable to assume62.  The 
clinical advantage of proton beam radiotherapy over standard photon radiation results from the more favorable dose 
distributions achievable with its particular physical properties as previously described.  The advantage of protons has been 
demonstrated for medulloblastoma and, prostate cancer, and comparative treatment planning using protons versus photons 
have shown a clear advantage to protons in terms of dose distribution63-68. 
 


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2 Study Objectives 
 
This study will be done in two phases. In the first phase, feasibility will be established using the primary objectives 
set below.  The first 12 patients in each chemotherapy arm (Cisplatin/Etoposide or Carbplatin/Taxol) will be 
enrolled onto the feasibility portion. The second phase will begin no earlier than 30 days after the last patient in the 
initial phase has completed chemoradiation.  The secondary objectives will serve as the objectives for the second 
phase of the study. 
 
Primary Objective 
 
The primary objective of this study is feasibility.  
 
Feasibility study:  
1. To establish the feasibility and safety of 66.6 GY(RBE) protons in NSCLC patients treated with either 
cisplatin/etoposide or carboplatin/taxol.   
Phase II study:  
1. To determine the rates of acute esophagitis toxicity in strata defined by chemotherapy regimen and proton 
beam. 
Nelfinavir Feasibility study:  
1. To establish feasibility of the treatment regimen with the addition of standard dose Nelfinavir.  
 
All patients will be planned with both a proton plan and a backup photon plan. All enrolled patients will 
be prescribed to receive 100% of their treatments with proton beam radiotherapy. However, most proton 
beam facilities, including ours, have an average downtime of 20%. Therefore, patients can either 
experience a 20% longer treatment time course if they are to receive 100% of their treatments with 
protons. Or, if any treatment delays are unacceptable due to concern about loss of efficacy, patients can 
expect to receive up to 20% of their treatment with a backup photon beam plan. Patients planned to be 
treated with a combination photon-proton plan are ineligible for this trial. However, it may be required 
for patients to be treated with the backup photon plan for a number of reasons (including but not limited 
to proton beam downtime, delay of treatment, patient inability to tolerate positioning for proton beam 
treatment, etc). Patients who receive greater than 35% of their total treatment with photon beam 
radiotherapy (using the backup photon plan) will be counted as an infeasible patient.  
 
This will be evaluated at the end of radiation treatment course.  
 
The study will be deemed infeasible if greater than 10% of patients experience one of the following: 
a. Patients who receive greater than 35% of their total treatment (for any reason-unable to set patient 
up within acceptable limits of tolerance, patient unable to tolerate treatment position or 
immobilization for duration of treatment) with photon beam radiotherapy (using the backup photon 
plan) will be counted as an infeasible patient.  
b. Patient is unable to complete all of his/her treatments within 10 days of estimated date of treatment 
completion or requires a treatment break greater than 5 days. This only applies to patients who are 
able to complete all of their treatments in the opinion of their treating physician. Patients who 
discontinue treatment due to disease progression, performance status deterioration, or who are 
discontinued by the treating physician for any reason are not considered an infeasibility based 
upon this criteria. 
 


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c. Additionally, if greater than 60% of patients experience grade 3 or higher (probably or definitely 
radiation related) non-hematologic acute toxicity except esophagitis and pneumonitis as defined by 
the Common Toxicity Criteria v 4.0, the study will be deemed infeasible.  Grade 4 toxicity that is 
considered probably or definitely related to the radiation will continue to be evaluated for toxicity and 
survival but during the feasibility study, will be counted as infeasible 
 
Secondary Objective  
1. Investigate novel biomarkers, as they become available. 
2. To determine clinical efficacy, as defined by metabolic response, sites of recurrence (e.g., local, regional, distant) 
and progression-free and overall survival. 
3 Subject Selection and Withdrawal 
 
This study plans to enroll up to 130 subjects over 6.5 years (24 patients on feasibility, 82 additional patients on stratified 
phase II, 24 on Nelfinavir feasibility). In the feasibility study, 24 patients will be enrolled; 12 on carboplatin/taxol and 12 
on cisplatin/etoposide. These patients may undergo proton therapy with either scattering or pencil beam scanning (PBS). 
Then a stratified phase II study will be initiated with 4 treatment strata, using a Simon 2-stage design:  carboplatin/taxol 
with scattering (n=34), carboplatin/taxol with PBS (n=15),  cisplatin/etoposide with scattering (n=39) or 
cisplatin/etoposide with PBS (n=18). The 24 patients on the feasibility study will be included in the stratified phase II 
study and assigned to the appropriate stratum. Thus, a total of 82 additional patients will be enrolled in the stratified phase 
II study.  Once the phase II study is completed for a particular stratum, 6 additional patients will be treated with the 
assigned treatment regimen plus Nelfinavir at the standard dose of 1250mg po BID. Thus 24 additional patients will be 
recruited to evaluate Nelfinavir.   
 
This protocol will be conducted in conjunction with the Department of Defense Oncology practices. We anticipate that 
they will accrue approximately 10 patients per year to this study, while Penn will enroll approximately 10 patients per 
year.  We plan to enroll male and female subjects of all races.)   
3.1 
Inclusion Criteria  
 Histologically confirmed diagnosis of NSCLC. 
 Stage IIIA or IIIB NSCLC. 
 Patients must have no evidence of metastatic disease based on routine imaging. 
 Patients must have an ECOG Performance Status 0-2.  
 Age > 18.  
 Patients must be able to provide informed consent. 
 Adequate bone marrow function:  WBC > 4000/mm3, platelets > 100,000 mm3. 
 Adequate renal function for cisplatin or carboplatin as determined by the medical oncologist:  Usually 
Calculated creatinine clearance (CrCl) > 45 mL/min or serum creatinine level < 1.5 x institutional ULN. 
 Patients must have bilirubin < 1.5 mg/dl. 
 Women of child-bearing potential as long as she agrees to use a recognized method of birth control (e.g. oral 
contraceptive, IUD, condoms or other barrier methods etc.).  Hysterectomy or menopause must be clinically 
documented.  
3.2 
Exclusion Criteria  
 Prior or simultaneous malignancies within the past two years (other than cutaneous squamous or basal cell 
carcinoma or melanoma in situ).  
 Pregnant women, women planning to become pregnant and women that are nursing. 
 Actively being treated on any other therapeutic research study.   
 For the Nelfinavir phase of the trial only: 


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o Patients receiving the following drugs that are contraindicated with NFV will be excluded.  
Drugs That Should Not Be Coadministered 
With VIRACEPT 
Drug Class: Drug Name 
Clinical Comment 
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. 
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. 
Sedative/Hypnotics: 
midazolam, triazolam 
CONTRAINDICATED due to potential for serious and/or life 
threatening reactions such as prolonged or increased sedation or 
respiratory depression. 
o Patients receiving the following drugs will be clinically evaluated as to whether 
dosage/medication can 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) 
It is recommended that the dose of 
rifabutin be reduced to one-half the 
usual dose when administered with 
VIRACEPT; 1250 mg BID is the 
preferred dose of VIRACEPT when 
coadministered with rifabutin. 
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 


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exceeding 10 mg dose in 72 hours, 
is recommended. 
HMG-CoA Reductase 
Inhibitor:  
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. 
Immunosuppressants: 
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 
ritonavir. 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. 
 
Note: Patients with the following conditions are deemed unsuitable for cisplatin-based chemotherapy (and 
will be treated with carboplatin):  
 
Hearing impairment/peripheral neuropathy Grade 1 or less at baseline 
 
Symptomatic/uncontrolled congestive heart failure (unable to tolerate volume load with pre- and 
post-cisplatin hydration) 
 
3.3 
Subject Recruitment and Screening 
 


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Patients will be referred by their physicians.  Subjects will be recruited from either the Department of Radiation Oncology 
at the University of Pennsylvania or the Department of Defense Oncology practices.  The treating radiation oncologist 
will determine if the patient is a potential research candidate and has the capacity to consent.  The treating radiation 
oncologist will approach and inform the patient about the study, thereby initiating the informed consent process.  If the 
patient expresses interest in the study, the treating radiation oncologist will contact a qualified member of the research 
team in the Radiation Oncology department at the University of Pennsylvania and request availability for enrollment.  A 
qualified member of the research team will interview the potential subject with privacy considerations, explain the 
requirements of the study and provide a copy of the Informed Consent Form (ICF).  The person obtaining consent will 
state the volunteer nature of research and advise the subject to take sufficient time to discuss the study if necessary before 
making their decision to sign the informed consent document.  If a decision to participate is made, the ICF is signed after 
which any screening procedures will be performed.  A series of questions will be asked by the person obtaining consent to 
verify patient eligibility based upon the criteria outlined in Sections 3.1 and 3.2.  After the eligibility is established, a 
subject study number will be issued.  Eligibility is confirmed with the study investigator.  All members of the research 
team will have successfully completed patient oriented research training.  Subjects will receive all radiation treatment 
in the Radiation Oncology clinic of the University of Pennsylvania. 
 
Subjects will not be paid for participating in the study. 
 
At the University of Pennsylvania, we see approximately 50 cases of stage IIIA/IIB NSCLC per year. We anticipate 
that with the availability of proton radiotherapy, these numbers may increase.  We estimate an annual accrual of 17 
subjects per year combining Department of Defense Oncology practice and Penn patients.  Proton radiotherapy will 
be listed on our web site as a formal protocol and information of its availability will be made known to treating 
professionals throughout our satellites and referring physicians. 
3.4 
Early Withdrawal of Subjects 
3.4.1 When and How to Withdraw Subjects 
 
Recurrent or Progressive Disease: Subjects who have clinical or radiologic evidence of recurrent disease will 
undergo an evaluation to document the nature of the abnormality.  If recurrent or progressive cancer is 
diagnosed, the subject will be considered off study at that time. 
 
PI Decision:  Subjects may be withdrawn at any time during the study if the PI believes it is in the subject’s 
best interest.   In this event, the reasons for withdrawal will be documented. 
 
Toxicity: Grade 4 toxicity that is considered probably or definitely related to the study will continue to be 
evaluated for toxicity and survival but during the feasibility study, will be counted as infeasible. 
 
 
Subject Participation:  Refusal to continue treatment, follow-up, comply with the protocol or withdrawal of 
consent. In this event, the reasons for withdrawal will be documented. 
 
Adverse Event (including intercurrent illness, unacceptable toxicity). 
 
Once the subject has discontinued treatment, the primary reason for discontinuing treatment must be clearly 
documented in the subject’s records and on the CRF.  The investigator will assess each subject for response at the 
time of withdrawal.   
Every effort will be made to follow all subjects off study for toxicity and survival unless subject withdraws consent.  
If subjects withdraw from the study at any time, we may ask for his/her written permission to continue to access 
medical records for toxicity gathering/evaluation and overall survival.  Acute toxicities will be assessed for 90 days 
from the start of treatment.  Survival will be followed for a minimum of 5 years. 


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4 Radiation Therapy  
4.1 
Treatment Planning, Imaging and Localization Requirements 
All subjects will be immobilized in a custom designed device in the appropriate position using immobilization 
devices which will be located outside of the treatment beam. Arms should be in an up position in order to eliminate 
CT scan artifacts from the humerus and be located outside of the treatment beam 
 
4.1.1 
All CTs scans (freebreathing, 4D and breatholding) or the PET/CT employed for dose calculation during 
the treatment planning process should be acquired without contrast, All scans which require  contrast to define 
gross target volume (GTV) and clinical target volume (CTV). have to be acquiered after the planning CT was 
obtained.  All CT scan (or PET/CT) should be acquired with the subject in the same position and using the same 
immobilization device as for treatment. Treatment planning will be done using a 3D based CT treatment 
planning system.  All tissues to be irradiated must be included in the CT scan. Planning CT scan will be done at 
the interval specified by the Proton CT protocol from encompassing the region of interest with sufficient margin 
for treatment planning and most importantly encompassing the entire lung volumes if possible. At the minimum 
a biweekly CT will be performed for  treatment plan robustness evaluation purposes. A weekley CT scan may 
be performed during the course of radiotherapy if necessary along with MRI or PET/CT if indicated by the 
treating physician.  Imaging including FDG-PET/CT and/or maybe fused with the planning CT images to better 
visualize the anatomy when indicated. 
4.2 
Target Contouring 
Target contouring will be performed on the 4DCT data set. If the target motion exceeds 10 mm, an active motion 
management strategy should be considered. Targets situated near the diaphragm require special attention for any 
amplitude of motion and along with high amplitude moving targets (>10mm) require Physics evaluation. Based on this 
evaluation the target will be contoured using the departmental proton simulation and planning protocol. 
4.2.1 
Gross Tumor Volume (GTV) is defined as all known gross disease determined from CT, MRI, clinical 
information, and/or endoscopic findings. The GTV will consist of the primary parenchymal tumor as visualized 
on the 4DCT and PET.   
4.2.2 
Mediastinal Gross Tumor Volume (GTV_med) This will consist of the ipsilateral hilum and bilateral 
mediastinum up to the thoracic inlet. The contralateral hilum and supraclavicular fossae will not be irradiated. 
4.2.3 
 Internal Gross Tumor Volume (IGTV) is defined as the GTV0 +GTV50 plus an additional margin based 
upon the 4DCT image sets verification to account for tumor motion. 
Mediastinal Internal Gross Tumor Volume (IGTV_med) is defined as the GTV0 +GTV50 plus an additional 
margin based upon the 4DCT image sets verification to account for tumor motion if necessary.  
4.2.4 
Clinical Target Volume (CTV0) is defined as the GTV0plus areas that are considered to contain potential 
microscopic disease on the T0 fase CT data set. 
 
4.2.5 
  Clinical Target Volume (CTV50) is defined as the GTV50plus areas that are considered to contain 
potential microscopic disease on the T50  fase CT data set. 
 
4.2.6 
Internal Target volume(ITV)-Lung in lung will be determined as a boolean of the CTV0 and CTV50  of the 
lung on the average CT data set.Alternatively a 8 to 10mm margin can be added to the IGTV to account for 
microscopic extension of tumor or can be manually edited by the treating physician based on  the 4DCT data 
sets available or the average CT data set. The ITV corresponds to the Imaging CTV (iCTV).pg.13, 4.2.6 
and 4.2.7 
 
4.2.7 
Internal Target volume(ITV) in_Med in Mediastinum will be determined as a boolean of the CTV0 and 
CTV50 of the mediastinumon the average CT data set Alternatively a 3-5mm margin can be added to the 
IGTV_med to account for microscopic extension of  
or can be manually edited by the treating physician based on the 4DCT data sets available. The ITV 
corresponds to the Imaging CTV (iCTV).pg.13, 4.2.6 and 4.2.7 
 


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Planning Target Volume(PTV) will be defined as a 5mm uniform expansion of the iCTV to account for lateral 
uncertainties and set-up variations. As per ICRU 78 the true PTV for proton therapy is beam orientation 
dependent and it is established by the planning team if deemed necessary.   
 
4.3.1 
Organ at risk volume (OAR) is contoured as visualized on the planning CT data sets(,4D CT or MR scan).  
Planning PAR is the OAR expanded for setup uncertainty or organ motion should be created as necessary .  The 
physician will contour the OAR.  The dosimetrist may create the PAR by expanding the OAR by 2-3 mm, 
depending on the situation.This will have to be clearly stated in the treatment intent by the treating physician. 
 
The following structures will be contoured: 
Lung/thorax: lung (right/left), spinal cord, esophagus, heart, brachial plexus, carina, diaphragm, liver, 
stomach. 
Note: All foreign objects (devices, wires, etc) within the CT data set will be identified at the time of contouring and 
HU will be assigned as necessary in consultation with the Physicist. 
 
4.3 
Dose fractionation and specification  
 
The prescription dose per fraction to the ITV/iCTV or CTV will be 1.8 Gy(RBE)/day. Patients will be treated with 
daily fractionated radiotherapy without a planned treatment break. The carina will be contoured for all patients and 
the isocenter will be placed at mid-carina for all patients, however its location will change for treatment planning 
and delivery purposes..  
 
The total dose for dose level one will be 66.6 Gy(RBE) over 37 fractions.   
4.4 
Treatment Planning  
 
Dose specfications: 
Dose Constraints for normal tissues and for PTV and ITV/iCTV.  A 95% of the ITV/iCTV will be encompassed by 95% 
of the prescription dose. The PTV will be evaluated (95% of the PTV should be encompassed by 90% of the prescription 
dose).  ITV/iCTV coverage should be reviewed beam-by-beam in order to ensure the robustness of the plan and applay an 
equivalent methodology for the PTV evaluation. Distal, proximal, and lateral margins should be observed for the 
particular beam direction; however, beam parameters should not be altered without consultation with Physics to reduce 
apparent “hot” or “cold” spots.  Hot and cold spots are mostly the result of smearing effect and are expected to be smeared 
out in the presence of setup uncertainties and organ motion. The above criteria can be altered by the treating Physician in 
consultation with Physics. For pencil beam scanning treatment planning, a PBSTV will be employed for treatment 
planning optimization purposes.   
 
 
Normal tissue constraints:  Dose-volume histograms should be performed for spinal cord, lungs, and heart.  The 
maximal spinal cord dose should not exceed 50 Gy(RBE).  No more than 40% of the total lung volume should 
receive greater than 20 Gy(RBE).  No more than 50% of the total cardiac volume should receive greater than 40 
Gy(RBE).  Additional normal structures constraints can be specified in the treatment intent by the treating 
physician.  
4.5 
Treatment Duration 
Proton radiation therapy will in most instances be completed within nine weeks of the start of treatment. This may 
be extended if subjects require a break from treatment. Criteria for break would include any Grade 3 non-
hematologic toxicity at PI discretion, Grade 4 hematologic toxicity at PI discretion, or Grade 4 non-
hematalogic toxicity.  Further treatment plans will be decided at the discretion of their treating physician.   
 


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4.6 
External Beam Equipment and Beam Delivery  
Protons: A high energy proton beam will be used. Treatments will be administered at the University of Pennsylvania 
Roberts Proton Facility.  All charged particle treatment will be given with the patient in the appropriate immobilization 
device.  Film or digital images will be taken prior to the initial treatment to verify the position of the patient and the 
aperture and as appropriate.  A radiation oncologist will check the first film on all fields.  A radiation therapist will check 
subsequent films taken before treatment.  All set-up films will be permanently filed for all subjects.  Subjects may be 
treated with motion management techniques such as respiratory gating, deep inspiration breath hold (DIBH), etc.. 
4.7 
Quality Assurance  
Daily portal films, and/or daily online radiographic imaging will be performed during therapy.  Fiducials will help 
reproduce daily set up and minimize set-up variations as appropriate. 
5 Study Drug (Only applies to Nelfinavir portion of the trial) 
There are ample data available regarding the use of NFV in humans [37]. 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 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. 


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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. 
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 


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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. 
5.1 
Treatment Regimen 
 The standard dose of Nelfinavir will be evaluated in each treatment stratum at  1250 mg PO bid. All patients will begin 
taking daily oral nelfinavir 7 to 14 days prior to the start of CTRT.  Nelfinavir will be continued during the complete 
course of concurrent CTRT.  The 7 days of nelfinavir prior to CTRT are based on the known pharmacokinetics of the drug 
that has shown suppression of p-Akt within three days after the administration of nelfinavir (see background information).  
Subjects will be asked to maintain a drug diary to assess compliance with administration of nelfinavir. 
 
5.2  Evaluation of Nelfinavir Feasibility 
 
If 1 or fewer dose limiting toxicities are observed in 6 patients treated on a particular stratum, then Nelfinavir will be 
considered feasible. If 2 or more dose limiting toxicities are observed in 6 patients treated on a particular stratum, then 
Nelfinavir will be reduced to 625 mg po BID and 6 additional patients will be treated and evaluated for feasibility. Dose 
limiting toxicities will be scored for 90 days from start of radiotherapy.  
6 Chemotherapy  
For cisplatin candidates (all enrolled patients who are cisplatin candidates as deemed by the treating medical 
oncologist will be treated with this regimen): 
Chemotherapy for all cisplatin candidates (as deemed by the treating physician) will consist of cisplatinum and 
etoposide that will be administered as concurrent therapy with radiation.  This is the same regimen as was used in 
SWOG 880569 and the Intergroup 0139 trials70.   
o Cisplatinum 50 mg/m2 will be administered on days 1, 8, 29 and 36, with pretreatment and post treatment 
hydration and a polyantiemetic regimen.   
o Etoposide 50 mg/m2 will be administered days 1 to 5 and 29 to 33.  
The second cycle (day 29) will be started if: 
 the absolute neutrophil count (ANC) is more than 1,000/μL,  
 the platelet count is more than 100,000/μL, and if  
 the creatinine clearance is > 50 mL/min.  
If any one of these criteria is not met, then treatment will be delayed 1 week.  If renal insufficiency does 
not recover, cisplatinum will be withheld.  The dose of etoposide for the second cycle will be reduced if 
febrile neutropenia occurs during the first cycle.  Development of severe dysphagia, dehydration, 
orthostasis, neuropathy or other unforeseen grade 4 toxicity is potential grounds for discontinuation of 
treatment if therapy is delayed longer than 1 week to permit recovery.  The patient may be taken off 
study at PI discretion if discontinuation of therapy is required.  Should a holiday, hospital closing or 
other extenuating circumstance interfere with the above detailed chemotherapy administration 
schedule, the medical oncologist will adjust each subjects administration as they see medically 
appropriate.   
For carboplatin candidates (ie non-cisplatin candidates as deemed by the treating medical oncologist): 


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Carboplatin and paclitaxel will be given weekly during radiotherapy. The dosing will consist of carboplatin (AUC=2) and 
paclitaxel (45 mg/m2) being administered on days 1, 8, 15, 22, 29, 36, and 43.  
 
o Carboplatin dose should be calculated using the Calvert formula (Carboplatin dose = AUC x (CrCl + 25) ). The 
maximum CrCl used should be 150 ml/min.  
o The Cr Cl should be calculated using the Cockroft-Gault equation: 
CrCl (ml/min) = (140-age) (Actual weight in kg) x 0.85 (females only) 72 x serum Creatinine (mg/dl) 
A measured CrCl from a 24 hour urine collection may also be used. 
 
Should a holiday, hospital closing or other extenuating circumstance interfere with the above detailed 
chemotherapy administration schedule, the medical oncologist will adjust each subjects administration as they 
see medically appropriate. 
 
Note: For subsequent weekly doses, a >10% change in the serum creatinine, based on weekly calculated creatinine 
clearance, will warrant a recalculation of the carboplatin dose.  All drugs will be administered intravenously by 
intravenous drip.  The paclitaxel will be given over 1 hour with standard premedication consisting of diphenhydramine 
25-50 mg, an H2-blocker, and dexamethasone (oral or intravenous is acceptable according to local custom) at least 30 
minutes prior to paclitaxel.  The carboplatin will be given after the paclitaxel over 30 minutes with standard antiemetics. 
7 Study Procedures 
 
 
Baseline/ 
Eligibility 
Weekly 
on 
treatment 
First 
follow up 
(approx 90 
days from 
start of tx) 
Follow-up Months* 
(Approximately) 
3, 6, 9, 12, 15, 18, 21, 
24, 
Follow-Up 
Months* 
(Approximately 
) 30, 36, 42, 48, 
54, 60 
Year 
 “X” or 
“Survival” 
Tests and 
Observations 
 
 
 
 
 
 
1History and PE 
X 
 
 
X 
X 
X 
1ECOG score 
X 
 
 
 
 
 
2FDG PETor CT or 
MRI 
X 
 
 
X 
X 
XC 
Biopsy 
X 
 
 
 
 
 
Laboratory 
 
 
 
 
 
 
CBC w/diff, Hgb, 
Platelets…  
Xb 
X 
 
 
XC 
XC 
CMP 
 
Xb 
X 
 
 
XC 
XC 
Pregnancy Test 
Xa 
 
 
 
 
 
Toxicity 
Assessment 
X 
X 
X 
X 
X 
XC 
Xa- If pre-treatment is 30 days from eligibility, you should repeat a pregnancy test within 24 hours of treatment initiation. 
Xb- Measurements cannot be more than 4 weeks from the beginning of treatment. 
XC- As clinically indicated. 
1- Within 4 weeks of consent. 
2- No more than 90 days prior to consent. 
*follow up visits occur at time points from the end of treatment. 


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7.1 
Post-treatment Evaluation and follow-up 
All subjects will be evaluated prior to initiation of treatment, weekly during the course of the protocol and every three 
months from the last dose of radiation therapy either by the treating radiation oncologist or a referring physician for two 
years, and every 6 months thereafter for 3 years, and then annually as long as subject wishes to be followed for survival 
with the provision that if subjects are no longer in the local area, communications such as a telephone call or letter will be 
sent as follow up.  Patients will be treated and followed for a minimum of 90 days from the start of radiation treatment to 
determine feasibility and safety (acute toxicity) for the initial phase of the study before moving to the second phase of the 
study.  Each follow-up examination will consist of interval history and physical examination, toxicity assessment.   
Laboratories  and Assessment of the disease by CT will be performed at the above intervals. 
7.2 
Assessment of Tumor Response   
7.2.1 Tumor Response (RECIST criteria): (if measurable disease) 
Target Lesions: 
Complete Response (CR): Disappearance of all target lesions. 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameters of target lesion, 
taking as reference the baseline sum of the longest diameters. 
Progressive Disease (PD): At least a 20% increase in the LD of the target lesions, taking 
as reference the smallest sum of the LD recorded since the treatment started or the 
appearance any new lesion(s) 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the 
treatment started. 
 
Non-Target Lesions: 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker levels. 
Incomplete Response/Stable Disease (SD):  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker levels above normal limits. 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions or any new 
lesion(s) 
7.2.2 Confirmation of Response  
To assign a PR or CR, changes in tumor measurement must be confirmed by repeat assessments no less than 4 weeks after 
the criteria for response are first met.  
 
To assign SD, measurements must have met the stable disease criteria at least once after study entry at “X” interval (as 
defined by protocol). 
7.2.3 Failure  
Local failure is defined as: evidence of tumor growth in any direction beyond that present of the pre-
treatment imaging studies or the appearance of tumor in tissues previously scored as sites of 
subclinical disease. The imaging studies are to be comparable in technical factors. 
Marginal failure is defined as appearance of tumor growth at the margin of the target volume 
Nodal Failure:  Failure in regional lymph nodes. 
Distant failure is defined as appearance of tumor at sites beyond regional nodal and marginal site. 
Overall Survival:  Duration measured from date of first treatment until death or censored at date of last 
follow-up for patients still alive. 
 
8. STATISTICAL PLAN. 
 


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8.1 STUDY DESIGN. 
 
This is a study of definitive proton radiotherapy for inoperable Stage III NSCLC.  The study will be conducted in two 
phases, first a feasibility study and then, a Phase II study.  Since proton is a new treatment modality at PENN, the first 
proton trial conducted in each cancer site will be a feasibility study, in order to gain experience on both the logistics of 
proton planning, dosimetry, scheduling and delivery and patient safety issues.  Patients receive concurrent chemotherapy 
and will be stratified by their chemotherapy regimen; either cisplatin/etoposide or carboplatin/taxol.  Only patients who 
are not candidates for cisplatin/etoposide will be treated with carboplatin/taxol.   
 
Initially, this study was designed to establish feasibility and safety of 74 Gy of protons when administered with 
concurrent chemotherapy. But recent results of RTOG 0617 showed that 74 Gy is inferior to 60 Gy. Because 74Gy 
was inferior, we have now modified this trial to treat patients at the Departmental standard of 66.6 Gy. Also, this 
study was originally designed to conduct a Phase I dose escalation study after completion of the feasibility study. 
This is no longer possible. We will instead conduct a stratified Phase II study, to investigate acute esophagitis 
toxicity. We will also confirm feasibility of Nelfinavir administration once the phase II study is completed. 
 
 
This study plans to enroll up to 130 subjects over 6.5 years (24 patients on feasibility, 82 additional patients on stratified 
phase II, 24 patients on Nelfinavir feasibility). In the feasibility study, 24 patients will be enrolled; 12 on carboplatin/taxol 
and 12 on cisplatin/etoposide. These patients may undergo proton therapy with either scattering or pencil beam scanning 
(PBS). Then a Simon 2-stage stratified phase II study will be initiated with 4 treatment strata:  carboplatin/taxol with 
scattering (n=34), carboplatin/taxol with PBS (n=15),  cisplatin/etoposide with scattering (n=39) or cisplatin/etoposide 
with PBS (n=18). The 24 patients on the feasibility study will be included in the stratified phase II study and assigned to 
the appropriate stratum. Thus, a total of 82 additional patients will be enrolled in the stratified phase II study.  Once the 
phase II study is completed for a particular stratum, 6 additional patients will be treated with the treatment regimen with 
the addition of Nelfinavir at the standard dose of 1250mg po BID. Thus 24 additional patients will be recruited to evaluate 
Nelfinavir.   
 
In the feasibility study, 12 evaluable patients will be enrolled in each chemotherapy stratum.  Subjects will be considered 
evaluable if they remain on study up until their first follow-up visit after radiotherapy.  We expect to screen/enroll 18 
subjects to attain 12 evaluable.  [Note: A subject WILL be considered evaluable if they willingly remain on the study up 
until their first follow up visit or if they meet any of the infeasibility criteria detailed in section 2.0 as this is critical to 
determining feasibility].  Once feasibility and safety are established, the phase II study will begin.  
 
In the Phase II study, patients will be stratified by chemotherapy regimen and type of proton beam (scattering or pencil 
beam scanning, PBS). Patients from the feasibility study will be included in the phase II study and assigned to the 
appropriate stratum. Because reduced toxicity is anticipated with proton therapy, we will test the hypothesis that the rate 
of acute esophagitis will be lower than that reported for photons.  
 
Once the phase II study is completed for a particular stratum, standard dose Nelfinavir will be added and 6 additional 
patients will be enrolled to establish feasibility. In a phase II study, nelfinavir has already been successfully added to 
photon chemoradiotherapy in NSCLC with few acute toxicities experienced.  
  
8.2 OBJECTIVES. 
8.2.1 Primary objectives 
Feasibility study: To establish the feasibility and safety of 66.6 GY(RBE) protons in NSCLC patients 
treated with either cisplatin/etoposide or carboplatin/taxol.   
 
Phase II study: To determine the rates of acute esophagitis toxicity in strata defined by chemotherapy 
regimen and proton beam. 
Nelfinavir Feasibility study: To establish feasibility of the treatment regimen with the addition of standard 
dose Nelfinavir.  


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8.2.2 Secondary objectives 
1. To investigate novel biomarkers, as they become available. 
2. To determine clinical efficacy, as defined by metabolic response, sites of recurrence (e.g., local, regional, 
distant) and progression-free and overall survival. 
 
8.3 ENDPOINTS.  
 
Feasibility will be based on multiple radiation planning and treatment parameters. Any patient who is enrolled 
and not felt to have a dosimetric benefit from protons or a patient who would require a combination photon-
proton plan would be a screen failure rather than an “infeasible” patient. A subject is considered infeasible if 
they experience any of the following events: 
 
a) Patients who receive greater than 30% of their total treatment (for any reason-unable to set patient up within 
acceptable limits of tolerance, patient unable to tolerate treatment position or immobilization for duration of 
treatment) with photon beam radiotherapy (using the backup photon plan) will be counted as an infeasible 
patient. 
b) A subject is unable to complete all of his/her treatments within 10 days of estimated date of treatment 
completion or requires a treatment break of greater than 5 days (due to non-hematologic toxicities).  
 
Acute toxicity or dose limiting toxicity is defined as any treatment related Grade 4 hematologic toxicity requiring a break 
in therapy of greater than 14 days or Grade 3 or higher non-hematologic toxicity (probably or definitely radiation related), 
except esophagitis and pneumonitis, which is observed within 90 days from start of radiotherapy and which is probably or 
definitely related to treatment. All toxicities will be graded by NCI CTCAE Version 4.0.  
 
Late toxicity is defined as any treatment related to Grade 3 (probably or definitely radiation related) or higher non-
hematologic toxicity, except esophagitis and pneumonitis, which is observed later than 90 days from start of radiotherapy 
and which is probably or definitely related to radiation treatment. Late toxicities will be graded according to the CTCAE 
Version 4.0. The time frame for late toxicity is open-ended and late toxicities have been known to occur a year or more 
after therapy. Follow-up for late toxicity will cease when a patient experiences disease progression, since 2nd line therapies 
may then be initiated.  
 
Clinical efficacy is defined as metabolic response (complete, partial or less than partial) based on PET/CT imaging. 
Patients are followed for disease recurrence and site (local, regional, distant). Progression-free and overall survival are 
defined as from start of treatment to first documented recurrence (for PFS), date of death or last patient contact alive.  
Biomarkers will be evaluated on tumor tissue, as the methods for measurement become available.  For example, the 
radiation resistance biomarker, IRDS (Interferon Related DNA Damage Resistance Gene Signature), will soon be under 
prospective validation in NSCLC. Similar biomarker discoveries will be considered during the course of this 4 ½ year 
trial.  
 
8.4 EARLY TERMINATION AND ESCALATION RULES. 
8.4.1 Feasibility study.  
Bayesian probability calculations will be employed to define rules of early termination and end of trial evaluation for 
feasibility and safety.  The tables below indicate termination rules after groups of 3 patients have been treated.  Hundreds 
of patients with certain types of cancer have undergone radiation therapy with protons.  Thus, we will assume some 
“prior” feasibility and safety data for protons delivered at the standard radiation dose for our Bayesian calculations.  We 
will assume prior information equivalent to that of 6 treated patients, which is commonly required to establish feasibility 
and safety in a standard 3+3 phase I trial design.  


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Feasibility 
We will assume a beta (5,1) prior, which is information equivalent to feasibility established in 5 of 6 treated patients.  A 
feasibility rate > 90% is considered acceptable. If the number of patients deemed feasible is less than or equal to the 
number in the table below then termination will be considered as it is highly unlikely that the feasibility rate is > 90%, as 
noted by the Bayesian posterior probabilities. 
 
Bayesian Rule for Feasibility 
 
Patients treated  
3 
6 
9 
12 
Patients who are feasible 
1 
4 
6 
9 
Posterior Prob[feasibility rate >90%] 
0.04 
0.09 
0.04 
0.08 
Action  
Terminate enrollment 
 
 
Acute Toxicity 
We will assume a beta (4,2) prior, which is information equivalent to unacceptable toxicity in 4 of 6 treated patients.  An 
acute toxicity rate < 60% is considered acceptable.  If the number of patients with unacceptable toxicity is greater than or 
equal to the number in the table below, then termination will be considered as it is likely that the toxicity rate is > 60%, as 
noted by the Bayesian posterior probabilities.  
 
Bayesian Rule for Acute Toxicity 
 
Patients treated  
3 
6 
9 
12 
Patients who experience acute toxicity 
3 
5 
7 
10 
Posterior Prob[acute toxicity rate >60%] 
0.89 
0.88 
0.88 
0.95 
Action  
Terminate enrollment 
 
 
8.4.2 Phase II study. 
8.4.2.1 Simon 2-Stage design to assess acute esophagitis 
A Simon 2-stage optimal design will be employed to evaluate Grade 3 or higher acute esophagitis. Patients will be 
stratified by chemotherapy regimen and proton beam. Historical esophagitis rates are based on CALGB or RTOG trials. A 
decrease in Grade 3 or higher esophagitis is expected with protons and a more dramatic decrease is expected with PBS 
protons. After enrollment in stage 1 is complete, the particular stratum will be suspended for 90 days from start of 
treatment, in order to score the acute toxicity.  
 
IF ENROLLMENT TO STAGE 1 IS COMPLETED FOR A PARTICULAR STRATUM DURING THE 
FEASIBILITY STUDY,THEN ENROLLMENT TO THAT STRATUM MUST BE SUSPENDED UNTIL ACUTE 
ESOPHAGITIS IS GRADED AND THE SIMON 2-STAGE DESIGN RULE IS APPLIED. FOR EXAMPLE, FOR 
THE CARBO/TAXOL/PBS STRATUM, STAGE 1 IS EVALUATED IN 7 (n1) PATIENTS. IF 7 SUCH 
PATIENTS ARE ENROLLED DURING THE FEASIBILITY STUDY, THEN THIS STRATUM MUST BE 
SUSPENDED PENDING REVIEW OF ESOPHAGITIS TOXICITY (i.e., STOP if 2+ PATIENTS EXPERIENCE 
TOXICITY). THIS REVIEW IS INDEPENDENT OF THE BAYESIAN EVALUATION OF OTHER ACUTE 
TOXICITIES IN THE FEASIBILITY STUDY WHICH IS BASED ON 2 PATIENTS TREATED WITH 
CARBO/TAXOL AND ANY BEAM TYPE.   
 
If the number of patients with Grade 3 or higher esophagitis, deemed related to protons by the PI, equals or exceeds r1 
then enrollment to the stratum is terminated. At the end of the trial, if the number of patients with Grade 3 or higher 
esophagitis equals or exceeds r then a reduced rate of esophagitis was not established.  
 
 
Regimen 
Proton 
beam 
Historical 
rate on 
photons 
Expected 
rate on 
protons 
Simon's 2-stage rule for 10% 
type I and II error rates 
Probability 
of early 
termination 
r1 
n1 
r 
n 
Carboplatin/Taxol 
Scattering  35% 
15% 
5 
15 
9 
34 
0.65 
Carboplatin/Taxol 
PBS  
35% 
5% 
2 
7 
3 
15 
0.77 


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Cisplatin/Etoposide 
Scattering  45% 
25% 
10 
23 
14 
39 
0.64 
Cisplatin/Etoposide 
PBS  
45% 
15% 
3 
7 
6 
18 
0.68 
r1 = number of patients in stage 1 with Grade 3 or higher acute esophagitis 
n1 = number of patients in stage 1 
r = total number of patients with Grade 3 or higher acute esophagitis 
n = total number of patients in study 
 
8.4.3 Nelfinavir feasibility study 
 
Nelfinavir will only be added assuming that the Simon 2-stage termination rules are not invoked for a particular 
stratum. If 1 or fewer dose limiting toxicities are observed in 6 patients treated on a particular stratum, then 
Nelfinavir will be considered feasible while if 2 or more dose limiting toxicities are observed, then Nelfinavir 
will be reduced to 625 mg po BID and 6 additional patients will be treated and evaluated for feasibility. Dose 
limiting toxicities will be scored for 90 days from start of radiotherapy.  
 
8.5 STATISTICAL ANALYSES. 
 
8.5.1 Feasibility study. 
The feasibility rate and exact 90% CI will be computed.  The reasons why patients were not feasible will be tabulated.  
Acute and late toxicities will be graded by CTC Version 4.0 and tabulated.  Estimation of Event Rates.  The table below 
displays the 90% exact binomial confidence intervals based on 12 patients treated.  
 
No. of 
Events 
% 
90% exact CI 
No. of Events % 
90% exact CI 
0 
0.0 
17.5* 
7 
58.3 
31.5 , 81.9 
1 
8.3 
.43 , 33.9 
8 
66.7 
39.1 , 87.7 
2 
16.7 
3.0 , 43.8 
9 
75.0 
47.2 , 92.8 
3 
25.0 
7.2 , 52.7 
10 
83.3 
56.1 , 97.0 
4 
33.3 
12.3 , 60.9 
11 
91.7 
66.1 , 99.6 
5 
41.7 
18.1 , 68.5 
12 
100.0 
82.5* 
6 
50.0 
24.5 , 75.5 
*  90% 1-sided CI 
8.5.2 Phase II study.  
Acute and late toxicities will be graded by CTC Version 4.0 and tabulated for each stratum.  Esophagitis rates and 95% 
confidence intervals will be calculated for each stratum.  Metabolic response (CR, PR, <PR) will be scored and tabulated 
for each stratum.  Site of recurrence will be similarly tabulated. PFS and OS will be estimated for each statum using 
Kaplan-Meier analysis, as a preliminary evaluation of outcome for patient treated with protons plus chemoradiotherapy. 
Biomarkers will be scored as present/absent and will be cross tabulated with toxicity and metabolic response.   
 
8.5.3 Nelfinavir feasibility study 
Acute and late toxicities will be graded by CTC Version 4.0 and tabulated for the 6 subjects enrolled to each stratum.   
 
8.6 SAMPLE SIZE AND TRIAL DURATION. 
With an annual accrual of approximately 20 patients, this study plans to enroll up to 130 subjects over 6.5 years (24 on 
feasibility, 82 additional on stratified phase II, 24 on Nelfinavir feasibility).  
 
 


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9 Safety and Adverse Events 
The investigator or research staff will be responsible for detecting, documenting and reporting all events that meet the 
definition of an AE or SAE as defined in this protocol.   
9.1 
Definitions 
Adverse event 
An adverse event (AE) is any unfavorable and unintended sign, symptom, sign (including abnormal laboratory 
findings), illness/disease (new or exacerbated) or experience that develops or worsens in severity temporally 
associated with the use of the investigational agent/device/procedure.  Intercurrent illnesses or injuries should be 
regarded as adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if the 
abnormality: 
 
results in study withdrawal 
 
is associated with a Serious Adverse Event (SAE) 
 
is associated with clinical signs or symptoms 
 
leads to additional treatment or to further diagnostic tests 
 
is considered by the investigator to be of clinical significance 
 
AEs Not to Include: 
o Medical or surgical procedures (e.g. endoscopy, appendectormy); the condition that leads to the 
procedure is an AE.   
o Situations where an untoward medical occurrence did not occur (elective and/or convenience 
admission to a hospital). 
o Anticipated day-to-day fluctuation of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen in grade or severity. 
o The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition. 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A Serious Adverse Event is any medical occurance that at 
any dose:  
 
fatal 
 
life-threatening 
Note:  (Subject was at risk of death at the time of the event, not events that hypothetically might have 
caused death if it were more severe) 
 
hospitalization or prolongs hospital stay (hospitalization signifies in general, the subject has been detained 
[at least an overnight stay] at the hospital or emergency department for observation/treatment that would not 
have been appropriate in a physician’s office or outpatient setting).   
Note:  Hospitalization for elective treatment, diagnostic purposes or a pre-existing condition that did not 
worsen from baseline in not considered an AE or SAE.  Hospitalization/prolong hospitalization to allow 
for study efficacy assessment is not an SAE.   
 
results in persistent or significant disability or incapacity. 
Note:  A substantial disruption of a person’s ability to conduct normal life functions.  Not intended to 
include experiences of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, accidental trauma (e.g. sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
 
a congenital anomaly or birth defect 
 
an important medical event  
 
Important medical events are those that may not be immediately life threatening, but are clearly of major clinical 
significance.  They may jeopardize the subject, and may require intervention to prevent one of the other serious 
outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result in in-patient 


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hospitalization or intensive treatment of bronchospasm in an emergency department would typically be considered 
serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as adverse events (AEs) per 
protocol definition.  
 
Clinical Laboratory and Other Safety Assessments 
Any abnormal laboratory test result as compared to baseline (.e.g. hematology, clinical chemistry, urinalysis) or 
other safety assessment (e.g. vital signs), that meet the definition of an  AE or SAEs as defined by the CTCAE 
Version 4.0 are to be recorded as AEs or SAEs.   
The investigator will exercise his/her medical and scientific judgment in deciding whether an abnormal laboratory 
finding or other abnormal assessment is clinically significant.  This assessment will be documented on the lab report 
or in a timely clinic/progress note. 
 
Disease Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs 
An event that is part of the natural course of the disease (e.g. disease progression) does not need to be reported as an 
SAE.  Progression of the subject’s cancer will be clearly recorded in the clinic/progress note.  Death due to 
progressive disease is not an SAE.  However, if the progression of the underlying disease is greater than that which 
would normally be expected for the subject or if the investigator considers that there was a causal relationship 
between the investigational agent/treatment/device and the disease progression, then this must be reported as an 
SAE.  Any new cancer must be reported as an SAE. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study, prior to administration or exposure to any 
protocol agents/treatments/devices.  A preexisting condition should be recorded as Medical History and becomes an 
adverse event if the frequency, intensity, or the character of the condition worsens during the study period as 
defined by the protocol.   
 
Radiation Effect 
Radiation side effects are typically divided into those that occur acutely  and those that occur later.  Common acute 
radiation side effects include fatigue, skin irritation or erythema, cough, and esophagitis.  Typically, these side 
effects can be controlled with medication.  Late side effects that are unlikely to occur are paralysis or cardiac 
complications.  Another rare but serious late side effect is the development of second tumors. It is hoped that proton 
radiation will substantially reduce both acute and late side effects by reducing the amount of normal tissue that is 
irradiated. 
 
Acute radiation effect and late radiation effects will be evaluated using the CTCAE 4.0. 
 
Assessment of Causality 
The investigator must assess the relationship between the investigation aspect of the protocol and the occurrence of 
each AE/SAE.  The investigator will use clinical judgment to determine the relationship.  Alternative causes, such 
as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship 
of the event to the investigational aspect of the protocol should be considered and investigated.   
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the subject is lost 
to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the investigator should 
instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study.  
 


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9.2 
Assessing and Recording Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific questioning, 
examination and review of clinical documentation (e.g. lab reports, radiology reports).  Information on all adverse events, 
as defined by the protocol, should be recorded immediately in the source document and also on the adverse event Case 
Report Form (CRF).  It is preferred that events are recorded by diagnosis (where applicable) instead of through 
signs/symptoms/test results.  For example, shortness of breath, chest pain and nausea may have been confirmed as a 
myocardial infarct through lab test and an ECG, therefore, “MI” or “myocardial infarct” or “heart attack” should be 
recorded instead of all of the signs/symptoms. 
 
All adverse events meeting the protocol definition, occurring during the study period must be recorded.  Full 
documentation of an event includes start/stop dates, event, grade, expectedness, attribution and outcome.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has been determined that the study 
treatment or participation is not the cause.   
 
All Adverse and Serious Adverse Events will be assessed using NCI Common Terminology Criteria for Adverse Events 
version 4.0 (CTCAE 4.0).    
9.3 
Reporting of Serious Adverse Events 
9.3.1 Adverse Event Reporting Period 
The study period during which Adverse Events must be collected and Serious Adverse Events must be reported is 
normally defined as the period from the initiation of any study procedures to the end of the study treatment follow-
up.  This protocol will begin assessment of AEs and SAEs following the first dose/treatment with any experimental 
aspect of the protocol.  Therefore, only treatment emergent events will be evaluated.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
9.3.2 IRB Notification by Investigator 
All events meeting the Penn IRB SOP for Unanticipated Events posing risks to subjects or others will be reported 
to the IRB as follows: 
 
Unanticipated problems are:  
(1) Unforeseen; and  
(2) indicate that participants are at increased risk of harm.  
 
The IRB requires investigators to submit reports of the following problems within 10 working days with 
one exception. The one exception for prompt reporting within 10 days applies to death of a research 
participant as noted below. 
 
Adverse Event (regardless of whether the event is serious or non-serious, onsite or off-site) that occurs 
any time during or after the research study, which in the opinion of the principal investigator is both 
unexpected and related to research procedures. 
 
Note:  An event is “unexpected” when its specificity and severity are not accurately reflected in the 
protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent document, and (b) other 
relevant sources of information, such as product labeling and package inserts); An event is “related 
to the research procedures” if the event is deemed probably or definitely related. 
 
If the adverse event involved death as unforeseen and indicates participants or others are at increased risk 
of harm, report in three days. 
 
Unanticipated adverse device effect:  Any serious adverse effect on health or safety or any life threatening 
problem or death caused by, or associated with, if that effect, problem, or death was not previously identified in 


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nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan 
or application, or any other unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of 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. 
 
Any adverse event that represents a serious unexpected problem that is rare in absence to drug exposure (agranulocytosis, 
hepatic necrosis, or Stevens-Johnson syndrome). 
 
Withdrawal from marketing for safety of a drug, device, or biologic used in a research protocol. 
 
Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research participant. 
 
Event that requires prompt reporting to the sponsor (where applicable). 
 
Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be resolved by the 
research team. 
 
Violation, meaning an accidental or unintentional change to the IRB approved protocol that placed one or more 
participants at increased risk, or has the potential to occur again. 
 
Breach of confidentiality must also be reported to the institutional Office of Research Compliance and Integrity. 
 
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. 
9.3.3 Data and Safety Monitoring Committee (DSMC) Notification by Investigator 
All Serious Adverse Events (SAEs), regardless of grade, expectedness or attribution must be reported to the DSMC within 
30 days.  Deaths that are possibly, probably or definitely related to the protocol treatment/experience must be reported 
within 24 hours.  SAEs should be reported to the DSMC for six months from the date the last subject was treated.   
9.4 
Stopping Rules  
In studies with a primary safety endpoint or studies with high risk to study subjects, rules should be developed that clarify 
the circumstances and procedures for interrupting or stopping the study.  If a central Data and Safety Monitoring Board 
(DSMB) or Committee (DSMC) is set up for the study, the stopping rules should be incorporated into their safety analysis 
plan as well. 
9.5 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This safety monitoring 
will include careful assessment and appropriate reporting of adverse events as noted above, as well as the construction and 
implementation of a site data and safety-monitoring plan (see section 11 Auditing, Monitoring and Inspecting).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
The Medical Monitor will be ” Dr. David Henry” ( a physician who is not directly involved in the trial and is not 
collaborating with the sponsor/investigator in any other trial).  Because of Dr. Henry’s background and 
experience in medical oncology/he is an appropriate Medical Monitor (MM) for this study.  In the role, he will 
review all AEs including grading, toxicity assignments, dose modifications, appropriateness of dose escalation 


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and all other safety data and activity data observed in the ongoing clinical trial along with discussing relevant 
animal and toxicology studies and similar investigational agents.  The MM may recommend reporting of adverse 
events and relevant safety data not previously reported and may recommend suspension or termination of the 
trial.  The investigator will meet with the MM approximately every six months assuming subjects are active on 
study.  Serious and unexpected issues will be handled on an ad hoc basis through calls or e-mail.  Documentation 
of MM activity will be maintained in the study specific Regulatory Binder.  Copies of an MM report requiring 
action on the part of the PI to protect subject safety or study integrity must be submitted to the DSMC within 10 
business days.   
9.5.1 Internal Safety and Compliance 
The Abramson Cancer Data and Safety Monitoring Committee is charged with the responsibility of reviewing 
all SAEs, deviations, Medical/Safety Monitoring reports for all cancer based protocols conducted at the 
University of Pennsylvania.  The DSMC reviews these document and data on a monthly basis and makes 
recommendation necessary to ensure subject safety and study integrity.  Additionally, the DSMC monitors and 
audits the progress and conduct of all cancer based studies in accordance with their NCI approved Institutional 
Data and Safety Monitoring Plan.  
 
Protocol Deviations/Exceptions 
Occasionally, the investigator may need to deviate from the approved protocol.  Deviations are categorized as reportable 
and non-reportable.  Reportable deviations may be urgent or not.  Urgent deviations may occur on the spot as necessary to 
protect the safety of a study subject and do not allow enough time for reporting in advance.  However, they must be 
reported as soon as possible.   
 
All deviations from the study protocol will be handled as follows: 
 
Eligibility - Deviations from established eligibility criteria will not be allowed.  If the investigator believes that a subject 
would truly benefit from the protocol therapy and there are no other viable options, then the protocol should be amended 
to reflect the change in restrictions.  There may be situations where the deviation from eligibility may not warrant a study 
amendment (e.g. a necessary test/procedure being a few days outside of the eligibility window, subject taking a 
concomitant medication within recent timeframe etc.).  These deviations must still be reviewed and approved in advance 
of enrolling the subject.    
 
The IRB must be notified of the planned deviation and a copy of all applicable amended study documents must be sent to 
the IRB.  The planned deviation must also be submitted to the DSMC for evaluation.  The DSMC does not approve 
deviations but rather provides and unbiased assessment of the appropriateness of the request.  Both committees must be 
given sufficient time to review the request, gather additional information as necessary and make a decision.  
 
Other Reportable - Deviations that affect the protocol treatment administration (i.e. dose administered, route/method 
of administration etc.), dose adjustment schema, stopping rules, modification to follow-up, removal of safety 
assessments/follow-up visits, accrual goal or any deviation that may affect  the study outcome analysis or study integrity 
must be approved by the IRB and reviewed by the DSMC.   
 
Non-Reportable - During the course of a study, there may be times when deviations are outside of the control of the 
investigator (i.e. subject not showing up for a study visit, lab errors, subject confusion etc.).  These type of deviations are 
not reportable (unless they occur at a level that impacts any of the reportable categories) but must be documented in a 
timely manner to show the impact of the deviation and corrective/follow-up actions that were taken.  Documentation can 
be in the clinic/progress notes or note/memo to file.  Notes/memos should be signed and dated.  
 
Reporting Deviations/Exceptions 
All deviations/exceptions will be reviewed and approved by the study Medical Monitor before being sent to the IRB and 
DSMC.  Reports to the IRB and DSMC will be done via the DSMC website www.ctsrmc.org.  Reportable deviations must 
also be sent to the study Medical Monitor (if applicable).   


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10 Data Handling and Record Keeping 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed subject authorization 
informing the subject of the following:  
 
What protected health information (PHI) will be collected from subject(s) in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability to 
use all information collected prior to the revocation of subject authorization.  For subjects that have revoked authorization 
to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the subject is 
alive) at the end of their scheduled study period.   
 
10.1.1 Unintentional Disclosure: 
Upon discovering that PHI may have been or has been disclosed to anyone not specified in the HIPAA disclosure 
consent, the investigator will report the disclosure to the Institutional Officer in the Office of Research Compliance 
and Integrity.  The report should contain details about the type of data disclosed and the extent of the disclosure 
(number of subjects, who received it etc.).   
10.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a research study 
necessary for the reconstruction and evaluation of the study.  Source data are contained in source documents and may be 
paper, electronic or a combination of both.  Examples of these original documents, and data records include: hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
10.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested on the CRF 
must be recorded.  All missing data must be explained.  If a space on the CRF is left blank because the procedure was not 
done or the question was not asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  If the 
item is unknown, write “UNK”.  All entries should be PRINTED legibly in black ink.  If any entry error has been made, 
to correct such an error, draw a single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For clarification of illegible or 
uncertain entries, print the clarification above/next to the item, then initial and date it.  Do not backdate changes.   
10.4 Records Retention 
 
The DHHS regulation (45 CFR 46.115) states that records relating to research conducted or supported by any Federal 
department or agency shall be retained for at least 3 years after completion of the research.  
 
The FDA regulation (21 CFR 56.115) is virtually identical; it also states that IRB records must be retained for at least 3 
years after completion of the research for these same types of studies. 
 
Records for this study will be maintained in a secure location with access limited to the investigators and the study 
specific research team for 3 years from the date of full study terminations.  If necessary, after the first year of termination, 
records may be moved to an off-site secure storage facility. 


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HIPAA Retention Period (45 CFR164.530(j): 
Protected Health Information (PHI) Research Requests (HIPAA1-008): Records documenting research requests, privacy 
board review or privacy officer expedited review, background material, and acceptance or denial of request. Retain 6 
years after research completed. 
 
Protected Health Information Disclosure Records (HIPAA1-009): Documenting the release of PHI, including both 
authorized and unauthorized releases. Should include the date of release, to whom the information was released, and 
the circumstances of the release. Retain 6 years after research completed. 
 
Maintenance of HIPAA records is independent of the regulations for clinical study records.  All records of PHI research 
requests and any type of release will maintained for 6 years after the research is fully terminated. 
11 Study Monitoring, Auditing, and Inspecting 
11.1 Study Monitoring Plan 
The study PI is responsible for ensuring the ongoing quality and integrity of the research study.  In addition, this study 
will be monitored or audited in accordance with Abramson Cancer Center’s NCI approved Institutional Data and Safety 
Monitoring Plan.   
 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, government regulatory bodies, 
and University compliance and quality assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government regulatory 
authorities and applicable University compliance and quality assurance offices. 
12 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 Institutional Review Board (IRB), in 
agreement with local legal prescriptions, for formal approval of the study conduct.  The decision of IRB concerning the 
conduct of the study will be made in writing to the investigator and a copy of this decision will be maintained in the study 
specific Regulatory Binder which contains “Essential Study Documents”.  In addition, NCI requires all cancer based 
studies to have an independent scientific review.  This protocol must be reviewed and fully approved by the Clinical 
Trials Scientific Review and Monitoring Committee (CTSRMC) prior to enrolling any subjects. Documentation of 
CTSRMC approval must also be maintained in the study specific Regulatory Binder.  
 
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 and CTSRMC 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 and dated by the subject or legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent.  


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13 Study Finances 
13.1 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. 
14 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 published or passed on to any third party 
without the consent of the study sponsor.  Any investigator involved with this study is obligated to provide the sponsor 
with complete test results and all data derived from the study. 
15 References 
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Hanna N, Neubauer M, R M, et al: Phase III trial of cisplatin (P) plus etoposide (E) plus concurrent chest 
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Miller KL, Shafman TD, Anscher MS, et al: Bronchial stenosis: an underreported complication of high-
dose external beam radiotherapy for lung cancer? Int J Radiat Oncol Biol Phys 61:64-9, 2005 
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Hayman JA, Martel MK, Ten Haken RK, et al: Dose escalation in non-small-cell lung cancer using three-
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28. 
Bradley J, Graham MV, Winter K, et al: Toxicity and outcome results of RTOG 9311: a phase I-II dose-
escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-
cell lung carcinoma. Int J Radiat Oncol Biol Phys 61:318-28, 2005 
29. 
Bradley J: A review of radiation dose escalation trials for non-small cell lung cancer within the Radiation 
Therapy Oncology Group. Semin Oncol 32:S111-3, 2005 
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