Conditions: Esophageal Toxicity
Keywords: NSCLC lung cancer chemotherapy radiation therapy radiation toxicity
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
This is a Phase I-II study evaluating the feasibility, safety, and efficacy of swallowed MnSOD plasmid/liposome (PL) transgene given as protection against radiation-induced esophagitis during concurrent paclitaxel and carboplatin chemotherapy with thoracic radiation in subjects with locally advanced non-small cell lung cancer (NSCLC).

Detailed description:
This is a Phase I-II study evaluating the feasibility, safety, and efficacy of swallowed MnSOD plasmid/liposome (PL) transgene given as protection against radiation-induced esophagitis during concurrent paclitaxel and carboplatin chemotherapy with thoracic radiation in subjects with locally advanced non-small cell lung cancer (NSCLC). Phase I of the study will assess the feasibility and safety of MnSOD PL by dose escalation in 3 cohorts of 3 chemoradiotherapy subjects each (Cohort1 = 0.3 mg/dose, Cohort2 = 3 mg/dose, Cohort3 = 30 mg/dose). The highest dose completed (as determined by toxicity monitoring for 8 weeks from initial treatment) will be the starting dose for Phase II. Phase II will examine the efficacy of MnSOD PL by assessing the incidence of Grade 3 or 4 esophagitis in 27 additional chemoradiotherapy subjects. Incidence of esophageal toxicity, as well as clinical response to the combination of chemoradiotherapy with MnSOD PL are the outcomes of interest.

Arms:
arm 1: MnSOD PL (0.3, 3, or 30 mg) + (Paclitaxel + Carboplatin (45mg/m\^2)) + Radiation 1.9-2.1 Gy daily 5 times per week (4-6 hr after the first MnSOD PL dose). The total dose planned at 77.0 Gy with a range of 69-84Gy in 34-38 fractions over 7-8 weeks.

Interventions: intervention 1: Manganese Superoxide Dismutase Plasmid Liposome intervention 2: carboplatin intervention 3: paclitaxel intervention 4: Radiation Therapy
Intervention descriptions: intervention 1: 15 ml of liquid that contains either 0.3 mg, 3.0 mg or 30.0 mg (depending on which cohort is open when the subject is entered) of MnSOD PL This will be given on Day 1 and 3 of each week of the experimental treatment for a total of 14 doses. intervention 2: Chemotherapy to stop the growth of tumor cells. intervention 3: Chemotherapy to stop the growth of tumor cells. This drug kills tumor cells by inducing multipolar divisions. Cells entering mitosis in the presence of concentrations of paclitaxel equivalent to those in human breast tumors form abnormal spindles that contain additional spindle poles. intervention 4: 1.9-2.1 Gy daily 5 times per week (4-6 hr after the first MnSOD PL dose). The total dose planned at 77.0 Gy with a range of 69-84Gy in 34-38 fractions over 7-8 weeks.

Protocol document:
Prot_SAP_000.pdf: 
 
 
01-054 v 05-08-14 
Page 1 
 
 
 
 
 
 
UPCI #01-054: Concurrent Chemotherapy (Paclitaxel and Carboplatin) and Thoracic Radiotherapy 
with Swallowed Manganese Superoxide Dismutase (MnSOD) Plasmid Liposome (PL) Protection in 
Patients with Locally Advanced Stage III Non-Small Cell Lung Cancer a Phase I-II Study 
 
 
 
 
Principal Investigator 
Dwight E. Heron, MD 
Vice Chairman of Clinical Affairs, Radiation-Oncology 
Clinical Director- Radiation Oncology 
UPMC Shadyside 
5230 Centre Avenue 
Pittsburgh, PA 15232 
Phone:  412-623-6720 
herond2@upmc.edu 
 
 
IND Sponsor 
Joel S. Greenberger, MD 
 
Study Statistician 
William Gooding, MS 
 
Project Manager 
Kelli Davis, RN, MSN-CNL, OCN 
 
 
 
Version date: 05-08-14 
 


 
 
01-054 v 05-08-14 
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UPCI #01-054: Concurrent Chemotherapy (Paclitaxel and Carboplatin) and Thoracic Radiotherapy 
with Swallowed Manganese Superoxide Dismutase (MnSOD) Plasmid Liposome (PL) Protection in 
Patients with Locally Advanced Stage III Non-Small Cell Lung Cancer A Phase I-II Study 
 
 
 
SCHEMA 
 
 
 
 
 
Paclitaxel 45mg/m2 and 
Carboplatin AUC = 2 
Weekly for 7 weeks 
 
Thoracic Radiotherapy 77.0 Gy  
For 7-8 weeks/34-38 daily fractions 
Beginning on day 1 
(1.9-2.1 Gy for a total dose of 77.0 Gy with a range of 69-
84 Gy in 34-38 fractions over 7-8 weeks) 
 
MnSOD (PL) twice per week  
(MnSOD continues until RT ends) 
 
 
R 
 
E 
 
G 
 
I 
 
S 
 
T 
 
E 
 
R 


 
 
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TABLE OF CONTENTS 
 
1.0 INTRODUCTION 
 
1.1 Background 
1.2 Paclitaxel and Carboplatin as Chemotherapeutics 
1.3 Phase II Study of Concurrent Paclitaxel, Carboplatin and RT Followed by Adjuvant 
Chemotherapy 
1.4 Phase II Study of Weekly Low Dose Paclitaxel, Carboplatin and RT 
1.5 Phase I Dose Escalation Study 
1.6 Chemoradiation-Induced Esophageal Toxicity 
1.7 Human Manganese Superoxide Dismutase (MnSOD) Transgene 
1.8 MnSOD Activity in the Pig Esophagus 
 
2.0 RATIONALE 
 
3.0 OBJECTIVES 
 
3.1 Primary Objectives 
3.2 Secondary Objectives 
 
4.0 PATIENT ELIGIBILITY 
 
5.0 EVALUATIONS 
 
6.0 STUDY PARAMETERS AND SERIAL OBSERVATIONS 
 
7.0 CHEMOTHERAPY 
 
7.1 Paclitaxel 
7.1.1 Availability 
7.1.2 Solution Preparation 
7.1.3 Storage and Stability 
7.1.4 Calculating Dosages of Paclitaxel 
7.1.5 Premedication Prior to Paclitaxel 
7.1.6 Administration of Paclitaxel 
7.1.7 Adverse Effects 
7.1.8 Recommended Management of Hypersensitivity Reactions 
 
7.2 Carboplatin  
7.2.1 Availability 
7.2.2 Preparation 
7.2.3 Storage and Stability 
7.2.4 Administration 
7.2.5 Toxicities 
 
8.0 MANGANESE SUPEROXIDE DISMUTASE TREATMENT PLAN 
 


 
 
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8.1 Characteristics of MnSOD Plasmid/Lipid Complex 
8.2 Study Design 
8.3 MnSOD PL Dose Escalation 
8.4 Study Drug Discontinuation and Toxicity Management 
8.5 MnSOD Efficacy Assessment 
8.6 Safety Monitoring During Evaluation of Efficacy 
 
9.0 RADIATION TREATMENT PLAN 
 
9.1 Radiation Dose 
9.2 Treatment Techniques 
9.3 Target Volumes 
9.4 Irradiation Portals 
9.4.1 Target Volume of Primary Tumor 
9.4.2 Target Volume of Lymph Nodes  
9.5 Technical Factors 
9.5.1 Beam Energy 
9.5.2 Treatment Distance 
9.5.3 Blocking 
9.5.4 Compensating Filter or Wedges 
9.5.5 Therapy Interruptions 
9.5.6 Interruptions Permitted 
9.5.7 Treatment Planning 
9.5.8 Localization Films 
9.6 Anticipated Side Effects or Toxicities 
 
10.0 TOXICITIES AND MANAGEMENT 
 
10.1 Toxicities 
10.2 Acute Radiation Morbidity Scoring Schema 
10.3 Late Radiation Morbidity Scoring Schema 
10.4 Other Toxicity 
10.5 Evaluation of Radiation Reactions 
10.5.1 Acute Radiation Esophagitis 
10.5.2 Chronic Radiation Esophagitis 
10.5.3 Radiation Pneumonitis  
10.6 Long Term Follow-up 
10.6.1 Autopsy 
 
11.0 ADVERSE EVENTS 
 
11.1 Definitions of Adverse Events 
11.2 Reporting Procedures 
 
12.0 EVALUATION OF TOXICITY AND RESPONSE 
 
13.0 STATISTICAL CONSIDERATIONS 
 


 
 
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13.1 Objectives 
13.2 Endpoints 
13.3 Design 
13.4 Characteristics of the Design 
13.5 Proposed Data Analysis 
 
14.0 PROTECTION OF HUMAN SUBJECT/ REGULATORY REQUIREMENTS 
 
REFERENCES 
 
APPENDIX I:  Karnofsky Performance Scale 
 
APPENDIX II:  Study Team – Organizational Chart 
 


 
 
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1.0 
INTRODUCTION 
 
1.1 Background 
 
Locally Advanced unresectable NSCLC 
Clinical trials conducted in the 1970’s established the efficacy of radiation therapy in 
patients with locally advanced NSCLC. The optimal dose of radiation was determined to 
be 60 Gy administered in 2Gy/fraction over 6 weeks (1). Despite undergoing definitive 
radiation, patients experienced a high incidence of local and distant relapse. This led to 
the initiation of trials that studied the effect of adding chemotherapy in addition to 
radiation. Chemotherapy was thought to act in multiple ways that included radiation-
sensitization of cancer cells in the field of radiation, and cytotoxic effect on 
micrometastatic disease. The Cancer and Leukemia Group B (CALGB) 8433 trial 
evaluated the utility of addition of induction chemotherapy to patients undergoing 
radiation therapy for locally advanced NSCLC (2). The median survival for patients 
treated with induction chemotherapy with cisplatin and vinblastine followed by radiation 
was 13.7 months, compared to 9.6 months for patients treated with radiation therapy 
alone. Subsequently the RTOG 88-08 trial (3) and the French trial (4) also established that 
chemotherapy and radiation is superior to radiation alone.  In the 1990’s, two large 
randomized trials have demonstrated that chemotherapy with concurrent radiation is 
superior to sequential administration of chemotherapy and radiation (Table 1) (5,6). In the 
West Japan Lung Cancer Group trial (5), there was no difference in the rate of local 
relapse in both the groups and distant relapse occurred in a majority of the patients on 
both arms. 
 
Table 1:  Clinical trials in Locally advanced NSCLC 
 
Trial 
Treatment 
Median Survival 
(Months) 
1-Yr Survival 
 
RTOG 
9410 (19)  
(N=611) 
 
 
Sequential 
 
Concurrent-QD 
 
Concurrent-BID 
 
 
14.6 
 
17.0 
 
15.6 
 
57% 
 
63% 
 
61% 
 
Furuse 
(20) 
(N=322) 
 
Sequential 
 
Concurrent 
 
13.3 
 
16.5 
 
55% 
 
64% 
 
 
 
 
 
 


 
 
01-054 v 05-08-14 
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Table 2: Long-term benefits from RTOG 9410 
 
 
Sequential 
Con-QD RT 
Con-BID RT 
#Patients 
Esophagitis 
Gr.3/4 
 
Median 
Survival 
201 
4% 
 
14.6 months 
201 
25% 
 
17.0 months 
193 
47% 
 
15.2 months 
4-year 
Survival 
12% 
21% 
(p=0.046) 
 
 
 
 
17% 
 
 
The results of RTOG 9410 trial which was a 3-arm, randomized phase III trial that 
evaluated sequential vs concurrent chemoradiation were updated this year (7) (Table 2). 
Sequential therapy (Arm 1) consisted of two cycles of cisplatin and vinblastine, followed 
by 60 Gy external beam radiation, administered in once-daily fractions, beginning on Day 
50. In arm 2, the same chemotherapy was administered, while radiation was administered 
concurrently starting on Day 1 of chemotherapy cycle. Arm 3 used hyperfractionated 
radiation therapy with 69.2 Gy administered as twice-daily fractions. Patients in arm 3 
received concurrent chemotherapy that consisted of cisplatin and oral etoposide. A total of 
611 patients with unresected stage II/III NSCLC were enrolled between 1994 and 1998. 
The median survival was superior (17.0 months vs 14.6 months, p=0.038) for patients 
with concurrent chemoradiation (Arm 2) compared to the sequential arm. 
Hyperfractionated radiation did not result in improved survival compared to the sequential 
arm (15.6 months vs 14.6 months). While the incidence of acute toxicity was higher in the 
concurrent arms, late non-hematological toxicity was identical for patients in all three 
arms. The 4-year survival on the concurrent chemotherapy and daily standard radiation 
arm was  21% versus 12% with sequential chemotherapy followed by radiation (p=0.046). 
Thus, concurrent chemoradiation is the standard of care for patients with locally advanced 
NSCLC, especially those with a good performance status. Concurrent therapy, while 
associated with a higher incidence of acute grade 3 esophagitis (up to 20%), results in 
better overall outcome. While the reduction of acute toxicity remains a major goal for 
further research efforts, better control of micrometastatic disease will have to be achieved 
to build upon the survival benefit achieved with concurrent chemoradiation. 
 
The South West Oncology Group investigators evaluated the role of consolidation 
chemotherapy following concurrent chemoradiation in a phase II trial (SWOG 9504)(8). 
Initial therapy consisted of cisplatin and etoposide with concurrent radiation (61 Gy) 
followed by three cycles of consolidation chemotherapy with docetaxel. The non-p53 
dependent apoptotic effect of docetaxel, when administered in sequence with cisplatin 
therapy (which induces apoptosis in a p53 dependent manner) was postulated to improve 
disease control. This study enrolled 83 eligible patients and demonstrated a median 
survival of 26 months and median PFS was 16 months. The 1-, 2- and 3-year survival 
rates were 76%, 54% and 37% respectively. The treatment was well tolerated with a low 
incidence of grade 3/4 esophageal toxicity during concurrent chemoradiation (17%). 


 
 
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Brain metastasis was the most common site of failure, occurring in 51% of the patients 
and occurred in almost all patients with distant failure. Based on the impressive results 
noted in this study, the SWOG investigators have adopted the 9504 regimen as  ‘the 
standard’ in the Intergroup 0023 trial in which the patients are then randomized to 
Gefitinib versus observation. The Hoosier Oncology Group is currently performing a 
randomized phase III trial comparing consolidation chemotherapy with docetaxel 
following concurrent chemoradiation with concurrent chemoradiation alone. 
 
1.2 Paclitaxel and Carboplatin as Chemotherapeutics  
 
Taxol (paclitaxel) is obtained via a semi-synthetic process from Taxus baccata. 
Enthusiasm for the use of paclitaxel has been generated over the past few years by its 
unique mechanism of action and promising anti-tumor activity in patients with advanced 
solid tumors. Paclitaxel acts as a mitotic inhibitor, blocking cells in the G2 and M phases 
of the cell cycle. The inhibition is unique in that the drug enhances the rate and yields of 
microtubular assembly and prevents microtubular depolymerization (9,10). It has been 
known for many years that cells in the G2 and M phase of the cell cycle are particularly 
sensitive to radiation (11). Tishler et al. showed that 24-hour treatment with 10 nM 
paclitaxel rendered a radio-resistant astrocytoma cell line susceptible to radiation (12). 
The enhanced level of cell kill in this study was consistent with the greater 
radiosensitivity of G2/M cells. The radiation sensitizing effect of paclitaxel was also 
observed with only l-hour treatment using 300 nM Taxol, in human leukemia cell line 
(HL-60) and human lung cancer cell line (Calu-3) (13). 
 
Carboplatin is active against non-small cell lung cancer and can be used as a radiation 
sensitizer. The mechanism of radiation sensitization with carboplatin is different from that 
of paclitaxel. Carboplatin potentially interferes with repair of sublethal radiation injury, 
whereas paclitaxel recruits cells in the highly radiosensitive G2/M phase (11). Recent 
laboratory data suggest a possible synergistic relationship of paclitaxel and carboplatin 
(14). 
 
1.3 Phase II Study of Concurrent Paclitaxel, Carboplatin and RT Followed by Adjuvant 
Chemotherapy 
 
In order to further improve local control and reduce distant metastasis, a phase II study of 
concurrent weekly paclitaxel (50mg/m2/wkly/7wks), carboplatin (AUC 2 wkly/7wks) and 
standard RT, followed by two additional cycles of adjuvant paclitaxel 
(200mg/m2q3wksx2) and carboplatin (AUC 6 q3wksx2) was designed by the Clinical 
Oncology Group of Rhode Island (COGRI) (15). The goal was to determine the response 
rate and toxicity of this regimen. The median survival of 38 patients treated was 20.5 
months. The two-year survival was 38%. Esophagitis was a major toxicity in this trial and 
was seen in 46% of patients (NCI Toxicity Criteria). Pneumonitis occurred in 22.0% of 
patients. Thus, concurrent radiation therapy (66Gy) with weekly paclitaxel (50 
mg/m2/wkly) and carboplatin (AUC 2) followed by two additional cycles of paclitaxel 
(200 mg/m2) and carboplatin (AUC 6) could be safely delivered to patients. 
 
1.4 Phase II Study of Weekly Low Dose Paclitaxel, Carboplatin and RT 
 


 
 
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Dr. Argiris et al. (16) recently completed a phase II study of weekly low dose paclitaxel at 
45 mg/m2 (3-hour infusion) with carboplatin, 100 mg/m2 and simultaneous standard-dose 
thoracic radiotherapy (total of 60-65 Gy) for patients with locally advanced NSCLC. 
Thirty-eight patients were enrolled, of which 16 were stage IIIA and 22 were stage IIIB. 
The salient toxicities included: nine grade 3 leucopenia, three grade 3 mucositis and 
esophagitis, two grade 3 fatigue and two grade 3 nausea/vomiting. There were no grade 4 
toxicities reported. Overall the regimen was well tolerated. There were 12 instances of 
dose reduction and there was a delay in treatment duration of > 1 week in 5 patients. 
Three patients died as a result of rapidly progressive disease without any evidence of 
dose-limiting toxicities. The median survival has not yet been reached. The 1-year, 2-year 
and 3-year actuarial survival rates for this group of patients with locally advanced NSCLC 
are 63% (95 CI: 44-77%), 54% (95 CI: 35-70%), and 54% (95 CI: 35-70%) respectively. 
 
1.5 Phase I Dose Escalation Study 
 
Another approach to combine carboplatin and paclitaxel with thoracic radiation has been 
reported in a preliminary manner by Langer et al. from the Fox Chase Cancer Center (17). 
A total of 32 patients have been entered into a phase I dose escalation regimen in which 
patients receive two cycles of induction paclitaxel and carboplatin followed by concurrent 
carboplatin, paclitaxel and thoracic RT. To date the induction dose has been escalated to 
225 mg/m2 for paclitaxel and an AUC of 7.5 for carboplatin. The paclitaxel/carboplatin 
during radiotherapy has been given every three weeks and has been successfully escalated 
to 175 mg/m2 paclitaxel and a carboplatin AUC dose of 5.0. Dose-limiting toxicity has 
been esophagitis (17). 
 
In summary, there have been several approaches in pilot studies to combine the regimen 
of carboplatin and paclitaxel with thoracic RT; however, the optimal approach has not yet 
been identified. When identified, optimal dosing could be tested in a phase III design 
against the most favorable arm of RTOG 94-10. As with other cisplatin-based regimens, 
however, it is anticipated that utilizing concurrent chemotherapy and radiation will 
heighten both hematologic and esophageal toxicity. 
 
1.6 Chemoradiation-Induced Esophageal Toxicity 
 
Esophageal toxicity has been accepted reluctantly, as a necessary side effect of the 
beneficial radiosensitization of chemotherapy drugs for lung cancer (7, 8, 15-17). With 
respect to the esophagus during treatment of large tumor volumes in the chest, the tumor 
dose-modifying effects of chemotherapy at the molecular level also appear to be 
esophageal toxicity-enhancing effects. A technique by which to selectively protect the 
esophagus during radiotherapy treatment of NSCLC volume would be of great potential 
benefit to lung cancer patients by reducing morbidity associated with the treatment and 
potentially allowing escalated doses of irradiation and/or effective chemotherapeutic 
agents. New protocols with higher doses would seek to gain a higher percent of complete 
responders and cured patients.  
 
Attempts to prevent irradiation-induced esophagitis during lung cancer 
chemoradiotherapy have usually focused on three approaches: 1) avoidance of esophageal 
irradiation by optimized treatment planning and dose distribution, 2) improved techniques 


 
 
01-054 v 05-08-14 
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of irradiation fractionation, and 3) delivery of radiation protective agents to the 
esophageal tissues. There is little question that improved treatment planning decreases 
esophageal toxicity (18). Minimizing the volume irradiated while still allowing enough 
margin to include variations in lung cancer localization during respiration and use of 
multifield conformal techniques, including use of the multileaf collimator, have provided 
benefits in decreasing treatment-related toxicity (19-21). A comparison of 
hypofractionation or hyperfractionation regimens with conventional fractionation has 
revealed that multiple small fractions may decrease esophageal toxicity, but there is a 
requirement for a higher total dose of radiation to obtain the same likelihood of tumor 
control (22-25). Higher dose fractions neutralize some of the radioprotective benefit of 
low fraction size (24).  Thus, while decrease in total irradiation dose in the setting of 
chemoradiotherapy may minimize esophageal toxicity, the duration and extent of local 
control of NSCLC are usually compromised (24). Radioprotective agents, including 
sulfahydryl radical scavenging drugs (26), atropine (27) and amifostine (28), have been 
tried intraorally or intravenously with some success. However, the depth of penetration of 
orally delivered drugs, duration of protection and the inability to translate an in vitro 
radioprotective effect to a comparable effect in vivo remain issues for these therapies (29). 
 
1.7 Human Manganese Superoxide Dismutase (MnSOD) Transgene  
 
Manganese Super Oxide Dismutase (MnSOD) is a genetically engineered investigational 
dBiological rug, prepared from an E. coli  seed stock. The final product (VLTS-582) is a 
therapeutic DNA/liposome formulation consisting of a double-stranded DNA bacterial 
plasmid, containing the hMnSOD cDNA., combined with two lipids (Cholesterol and 
DOTIM (1-[2-[9-(Z)-octadecenoyloxy]]-2-[8](Z)-heptadecenyl]-3-[hydroxyethyl] 
imidazolinium chloride), and formulated in a tris buffer containing sucrose.   
 
Initial pharmacology studies demonstrating that expression of the human MnSOD 
transgene could protect against irradiation damage, were performed in vitro.  Murine 
hematopoietic progenitor cell line 32D cl 3 was transfected with a plasmid containing the 
human MnSOD transgene (30).  Stable clones (1F2 and 2C6) expressing the human 
MnSOD transgene, as demonstrated by nested reverse transcriptase-polymerase chain 
reaction (RT-PCR) using primers specific for the human transgene and increased MnSOD 
biochemical activity, were selected.  Irradiation survival curves showed that MnSOD 
clones 1F2 and 2C6 were more resistant to irradiation as seen by an increased shoulder (n 
= nbar) (34).  Clones 1F2 and 2C6 were also more resistant to irradiation-induced 
apoptosis.  Cells from 32D cl 3, 1F2 or 2C6 were irradiated to 1000 cGy and examined 
for apoptosis at 0, 6, 24 or 48 hours later.  Cell line 32D cl 3 had 29.37% of its cells 
apoptotic at 24 hours compared to 5.21 and 5.27 for 1F2 and 2C6, respectively (34).  
Examination of cell cycle analysis following irradiation demonstrated a G2/M phase 
block at 6 hours followed by a G1/S phase block at 24 hours in all three cell lines . Even 
though overexpression of MnSOD made the cells more radioresistant, there was no 
change in cell cycle distribution following irradiation (30). 
 
Protection of normal tissues from ionizing irradiation damage by gene therapy has 
recently been demonstrated in the mouse lung (31, 32). Delivery of plasmid/liposomes 
(PL) or adenovirus (32) containing the human Manganese Superoxide Dismutase 


 
 
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(MnSOD) transgene by intratracheal injection prior to irradiation has demonstrated 
detectable expression of messenger RNA for human MnSOD in both alveolar type II cells 
and tracheobronchial tree cells in treated mice (31). Increased MnSOD biochemical 
activity in treated lung tissues was associated with a decrease in radiation-induced 
messenger RNA levels for acute inflammatory response genes such as IL-1, TNF- and 
TGF- (31). Plasmid/liposome MnSOD gene therapy also decreased the pathologic 
sequelae of lung irradiation, including organizing alveolitis/fibrosis typically seen at 
approximately 150 days following irradiation (35). Success has also been achieved in a 
murine model of radiation-induced esophagitis (33). Intraesophageal administration of 
MnSOD PL complexes was shown to reduce radiation-induced damage to esophageal 
epithelial cells and increase MST dramatically compared to untreated or mock-treated 
control animals (33). 
 
Dosing:  Preclinical data in our mouse model has demonstrated that doses as low as 10 ug/ 
25 gm mouse was able to protect the esophagus from irradiation damage.  This 
corresponds to a dose of 28 mg/ 70 kg man which is why we are proposing 30 mg as the 
upper limit for our clinical trial. 
 
 
1.8 MnSOD Activity in the Pig Esophagus 
 
To demonstrate that MnSOD-PL could transfect the esophagus in a bigger model, pigs 
were anesthetized so that the esophagus was temporally paralyzed and MnSOD-PL (10 
mg of plasmid DNA) was administered through an endoscope 10 cm from the 
gastroesophageal junction (GE) or at the top of the esophagus were the pig was allowed to 
swallow the MnSOD-PL (10 mg of plasmid DNA) (4).  The pigs were sacrificed 24 hr 
later with the esophagus removed and cut into 4 sections.   In the pig receiving MnSOD-
PL only at the site of the PDT treatment, there was increased MnSOD biochemical 
activity or increased human MnSOD mRNA production as detected by nested RT-PCR 
using primers specific for the human MnSOD transgene only at the site of administration.  
Another pig which had been lightly anesthetized was given MnSOD-PL at the top of the 
esophagus and allowed to swallow the MnSOD-PL was sacrificed and the esophagus 
removed and divided into 3 sections with increased MnSOD biochemical activity and 
increased mRNA for the human MnSOD transgene found at all levels of the esophagus.  
This demonstrates that there is increased MnSOD activity in the pig esophagus following 
administration of MnSOD-PL.   
 
Significant progress in developing a system of esophagus protection from irradiation 
damage has been made through designing a method for intraesophageal administration of 
MnSOD plasmid/liposomes. MnSOD plasmid/liposome gene therapy protection of the 
esophagus from damage induced by chemoradiotherapy should be a valuable addition to 
the care of lung cancer patients by reducing treatment-related esophagus toxicity, 
decreasing the need for hospitalization and hyperalimentation, and potentially allowing 
dose escalation that locally controls and perhaps cures more patients.  Once the MnSOD 
plasmid/liposome comes into contact with the gastric acid the plasmid/liposome complex 
would be disassembled with the plasmid DNA being destroyed.  Thus, reflux would not 
result in an increased dosing of the patient. 
 
This trial will help determine whether the increased incidence of esophagitis can be 


 
 
01-054 v 05-08-14 
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reduced with the use of Manganese Superoxide Dismutase (MnSOD) transgene therapy. 
The dose of paclitaxel is based on previous phase I experience and the dose of carboplatin 
will be dose adjusted for renal function to provide more uniform pharmacokinetics. 
 
2.0 
RATIONALE 
 
Esophagitis has been the primary non-hematological toxicity reported with concurrent 
chemoradiation therapy utilizing paclitaxel and carboplatin (34-43). Supportive care agents and 
selective approaches are needed to prevent or decrease esophageal toxicity with the promising 
combined modality regimens. This could lead to overall improved outlook in these patients. 
Manganese Superoxide Dismutase transgene therapy in liposomes is one way of decreasing the 
esophageal toxicity of this regimen.  
 
Esophageal damage in response to ionizing radiation results from the local production of toxic 
free radical species.  Enzymatic oxidation of these species protects cells from excessive free 
radical-induced damage.  MnSOD is a principal mediator of this protective effect.  Gene 
therapy-mediated overexpression of MnSOD decreases the expression of inflammatory 
cytokines in response to radiation and reduces cellular apoptosis, micro-ulceration and 
esophagitis.   
 
Significant progress in developing a system of esophagus protection from irradiation damage 
has been made through designing a method for intraesophageal administration of MnSOD 
plasmid/liposomes. MnSOD plasmid/liposome gene therapy protection of the esophagus from 
damage induced by chemoradiotherapy should be a valuable addition to the care of lung cancer 
patients by reducing treatment-related esophagus toxicity, decreasing the need for 
hospitalization and hyperalimentation, and potentially allowing dose escalation that locally 
controls and perhaps cures more patients. 
 
This trial will help determine whether the increased incidence of esophagitis can be reduced 
with the use of Manganese Superoxide Dismutase (MnSOD) transgene therapy.  This gene 
therapy method of effectively protecting the esophagus would reduce treatment-related 
morbidity and potentially increase the deliverable radiation dose and lead to better disease 
control.   
 
3.0 
OBJECTIVES 
 
3.1 Primary Objectives 
 
3.1.1 To evaluate the feasibility and safety of MnSOD plasmid/liposome    
                 transgene given twice per week during concurrent chemotherapy using    
      carboplatin and paclitaxel with thoracic radiation for protection of the    
      esophagus in patients with locally advanced NSCLC. 
3.1.2 To evaluate the ability of MnSOD PL transgene given twice per week to   
            reduce the incidence of radiation-induced esophageal toxicity. 
 
3.2 Secondary Objectives   
 


 
 
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3.2.1 To evaluate the clinical efficacy of the combined treatment modality in    
                  locally advanced Stage III NSCLC. 
3.2.2 To assess whether chemotherapy/dose intensity and planned radiation therapy 
intensity can be maintained with the use of the MnSOD plasmid/liposome. 
 
4.0 
PATIENT ELIGIBILITY 
 
4.1 Histologically or cytologically documented NSCLC, including squamous cell carcinoma, 
adenocarcinoma (including bronchoalveolar cell), and large cell anaplastic carcinoma 
(including giant and clear cell carcinomas) and poorly differentiated non-small cell lung 
cancer. Totally resected tumors are excluded. 
 
4.2    Patients must be without evidence of M0.  
 
4.3 Patients with T1 or T2 disease with N2 or T3N1-2 disease (Stage IIIA)   
4.2 are eligible if they are medically inoperable. Patients with T4 with any N or 
any T with N3 disease are eligible. Radiographic evidence of mediastinal 
lymph nodes > 2.0 cm in the largest diameter is sufficient to stage N2 or 
N3 disease. If the largest mediastinal node is < 2.0 cm in diameter and this 
is the basis for stage III disease, then at least one of the nodes must be 
proven positive cytologically or histologically. 
 
4.4 Patients with tumors adjacent to a vertebral body are eligible as long as all gross disease 
can be encompassed in the radiation boost field. The boost volume must be limited to < 
50% of the ipsilateral lung volume. 
 
4.5 Patients with a pleural effusion that is a transudate, cytologically negative and non-bloody 
are eligible if the radiation oncologists feel the tumor can still be encompassed within a 
reasonable field of radiotherapy. Patients with exudative, bloody, or cytologically 
malignant effusions are ineligible. If a pleural effusion can be seen on the chest CT but not 
on CXR and is too small to tap, the patient will be eligible. 
 
4.6 Radiation Oncology and Medical Oncology Consults must deem patient suitable for 
protocol treatment. 
 
4.7 Performance Status > 70 (Karnofsky Performance Scale; Appendix I). 
 
4.8 Weight loss < 10% in 3 months prior to diagnosis. 
 
4.9 Age > 18 years. 
 
4.10 No prior systemic chemotherapy, radiation therapy to the thorax, or total surgical 
resection. 
 
4.11 At least 3 weeks since formal exploratory thoracotomy and patient has recovered from 
surgery, or 1 week from diagnostic thoracoscopy. 
 
4.12 Required Initial Laboratory Values (see Section 6.1.for required timing): 


 
 
01-054 v 05-08-14 
Page 14 
 
 
Granulocytes  
 2,000/ml 
Platelets 
 100,000/ml 
Hemoglobin* 
 8 mg/dl 
Bilirubin 
 1.5 x normal 
Creatinine clearance 
 50 ml/min 
(24 hour or calculated) 
FEV1 
 800 cc 
 
* Physician can maintain a patient's hemoglobin with the use of Erythropoeitin or 
transfusions. (Prophylactic use of G-CSF is not permitted.) 
 
4.13 Patients must have a MRI or CT brain within 4 weeks prior to study entry to rule out 
asymptomatic brain metastases. 
 
4.14 Informed Consent: Each patient must be aware of the neoplastic nature of his/her disease 
process and must willingly sign a study-specific consent prior to randomization after being 
informed of the procedures to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side effects, risks, and discomforts. (Human protection 
committee approval of this protocol and consent form is required.) 
 
4.15 No active concurrent malignancy is allowed, except inactive non-melanoma skin cancer or 
in situ carcinoma of the cervix. Prior cancer is eligible only if the patient has been disease-
free for > 5 years. 
 
4.16 No serious medical or psychiatric illnesses that would prevent informed consent. Patients 
with post-obstructive pneumonia are eligible. Patients with an active serious infection or 
other serious underlying medical condition that would otherwise impair their ability to 
receive protocol treatment are ineligible. 
 
4.17 Prior significant allergic reactions to drugs containing cremophor, such as cyclosporine, or 
vitamin K are not eligible. A significant reaction may be defined as, but is not limited to, 
the description of grade > 3 allergic reactions using the CTC. 
 
4.18 No history of serious cardiac disease that is not adequately controlled. Patients with 
documented myocardial infarction within 6 months prior to study entry, congestive heart 
failure, unstable angina, clinically significant pericardial effusion or arrhythmia are 
ineligible. An ECG must be done within 4 weeks prior to study entry on all patients. 
 
4.19 Nonpregnant, nonlactating female patients. Patients of childbearing potential must 
implement an effective method of contraception during the study. All women of 
childbearing potential must have a pre-study negative serum or urine pregnancy test 
within 7 days prior to study entry. 
 
5.0 
EVALUATIONS 
 
5.1 History (including baseline symptoms), weight, performance status, WBC/granulocytes, 
Hgb, platelet count, SGOT or SGPT, alkaline phosphatase, total bilirubin, albumin, 


 
 
01-054 v 05-08-14 
Page 15 
 
glucose and creatinine (24 hour or calculated clearance). These must be obtained within 2 
weeks prior to study entry.  
 
5.2 A serum or urine pregnancy test must be obtained within 7 days prior to study entry for 
females of childbearing potential. 
 
5.3 EKG will be performed within 4 weeks prior to study entry. 
 
5.4 Pre-study radiographic assessments such as CT or MRI and bone scans will be used to 
document study tumor size and absence of metastases. Pre-study radiographic assessments 
must be obtained within 4 weeks of study entry. 
 
5.5 The method used to document the tumor (CT or MRI) should be used consistently for all 
evaluations. If tumor was subtotally resected during thoracotomy, the CT or MRI must be 
done after surgery. 
 
5.7 
Weekly:  Weight, toxicity evaluation,  Hgb, WBC, differential. 
 
5.8 
Every 3 Weeks:  Physical exam, weight, performance status, toxicity evaluation, Hgb, 
WBC, differential, BUN, creatinine, creatinine clearance, alk. Phos., bilirubin, SGOT, 
CA++, PO4, blood sugar.  
 
5.9 
1 month follow-up:  Physical exam, tumor measurement, weight, performance status, 
Hgb, WBC, differential, BUN, creatinine, creatinine clearance, alk. phos., bilirubin, 
SGOT, blood sugar. 
 
5.10 
Post-treatment as clinically indicated:  Electrolytes, EKG, CXR. 
 
5.11 
Four weeks post-treatment, then every 3 months thereafter for 2 years, and then as 
needed or at recurrence to document indicator lesions with quantitative measurements 
(please ask for quantitative measurements on radiology requests):  Chest CT scan. 
 
5.12 
If indicated and feasible:  Histological or unequivocal cytological diagnosis. 
 
5.13 
Four weeks post-treatment: Pulmonary function tests (PFT). Additional PFTs will be 
performed as needed for assessment of radiation pneumonitis. 
 
5.14 
Every 3 months for 2 years:  Physical exam, tumor measurement, weight, performance 
status, Hgb, WBC, differential, BUN, creatinine, creatinine clearance, alk. Phos., 
bilirubin, SGOT, blood sugar. 
 
5.15 
Every 6 months for 2 more years:  Physical exam, tumor measurement, weight, 
performance status, Hgb, WBC, differential, BUN, creatinine, creatinine clearance, alk. 
Phos., bilirubin, SGOT, blood sugar. 
 
 


 
 
01-054 v 05-08-14 
Page 16 
 
 
6.0 
STUDY PARAMETERS AND SERIAL OBSERVATIONS 
 
If a cycle is missed or a subject's treatment and/or testing days need to be rescheduled due to the subject’s 
inability to comply with the study calendar (i.e., hospitalizations, business and vacation travel plans, illness, 
transportation issues, holidays, family emergencies, etc.), a window of ± one (1) week is available for 
rescheduling of treatment and procedures per the discretion of the treating physician investigator, and as 
discussed with the principal investigator. In addition, at the discretion of the Principal Investigator, certain 
tests/procedures may be performed up to 7 days in advance of the scheduled date to allow ready access to the 
result(s), reduce financial burden on the subject (i.e. non-UPMC insurance coverage) or reduce travel 
inconvenience. 
 
6.1 Observations and tests to be performed and recorded before, during and after treatment as 
indicated below.  
Parameters 
Pre-Treatment and Treatment Regimen 
Post -Treatment Regimen***** 
 
Pre-
Treatment or 
Day 1 
Day 4 
Weekly 
Every 3 weeks 
1 month 
follow-up 
Every 3 
months for 2 
years 
Every 6 
months for 2 
years 
Pregnancy test 
X 
 
 
 
 
 
 
History and Physical 
X 
 
 
X 
X 
X 
X 
Tumor measurement 
X 
 
 
 
X 
X 
X 
Weight 
X 
 
X 
X 
X 
X 
X 
Performance status 
X 
 
 
X 
X 
X 
X 
Toxicity evaluation 
X 
 
X 
X 
 
 
 
Hgb, WBC 
X 
 
X 
X 
X 
X 
X 
Differential 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
BUN, creatinine 
X 
 
 
X 
X 
X 
X 
Creatinine clearance 
X 
 
 
X 
X 
X 
X 
Alk. Phos, Bilirubin, 
SGOT 
X 
 
 
X 
X 
X 
X 
CA++, PO4 
X 
 
 
X 
 
 
 
Blood sugar 
X 
 
 
X 
X 
X 
X 
Electrolytes 
X 
 
 
 
X* 
X* 
X* 
Brain MRI 
X 
 
 
 
 
 
 
EKG 
X 
 
 
 
X* 
X* 
X* 
CXR 
X 
 
 
 
X* 
X* 
X* 
Chest CT Scan 
X 
 
 
 
X** 
X** 
X** 
Histological or 
unequivocal 
Cytological diagnosis 
X 
 
 
 
X*** 
 
 
PFT 
X 
 
 
 
X**** 
 
 
NOTE:  On days that the MnSOD-PL is given with chemotherapy, the order in which they should be given is MnSOD-PL 
administration, chemotherapy then radiation treatment.  HOWEVER, on Day 1, there is a 4-6 hour wait before the 
radiation treatment (sec. 9.1) (chemotherapy still should be given after the MnSOD-PL).     
* 
Post-treatment and as clinically indicated. 
** 
Four weeks post-treatment completion, then every 3 months thereafter for 2 years, and then as needed or at 
recurrence to document indicator lesions with quantitative measurements (please ask for quantitative 
measurements on radiology requests). 


 
 
01-054 v 05-08-14 
Page 17 
 
*** 
If indicated and feasible, to document histological complete response. 
**** 
Four weeks post treatment, and thereafter as indicated (i.e., additional PFTs for assessment of radiation 
pneumonitis) 
***** 
For those patients that go on to receive additional chemo after their protocol treatment, they will be 
followed as “standard of care” and for research purposes will only need to be followed for radiologic 
response and survival, once they are past the point of 8 weeks post radiation therapy treatment. 
 
 


 
 
01-054 v 05-08-14 
Page 18 
 
 
7.0 CHEMOTHERAPY 
 
7.1 Paclitaxel 
 
7.1.1 Availability: 
 
 
Paclitaxel is commercially available. Paclitaxel is a natural product obtained via 
a semi-synthetic process from Taxus baccata. Improved solubility requires a 
mixed solvent system with further dilutions of either 0.9% sodium chloride or 
5% dextrose in water. Paclitaxel is supplied in a sterile concentrated solution, 6 
mg/ml, and is available in 5 ml (30 mg) and 16.7 ml (100 mg) multidose vials. 
Each milliliter contains 6 mg paclitaxel, 527 mg of Cremophor EL 
(polyoxyethylated caster oil) and 50% dehydrated alcohol, USP, 50%. The 
contents of the vial must be diluted just prior to clinical use. Commercial 
supplies of Paclitaxel will be used for this study. 
 
7.1.2 Solution Preparation: 
 
Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% 
sodium chloride or 5% dextrose injection to a final concentration of 0.3 to 1.2 
mg/mL. Infusions should be mixed as closely as possible to the start of each 
infusion since paclitaxel stability after 27 hours at room temperature in solution 
is unknown. Paclitaxel must be prepared in glass, polypropylene, or polyolefin 
containers due to leaching of diethylhexylphthalate (DEHP) plasticizer from 
polyvinyl chloride (PVC) bags. Paclitaxel will be administered using non-PVC 
tubing and connectors such as the IV administration sets that are polyethylene 
lined. In-line filtration must be accomplished by incorporating a hydrophilic, 
microporous filter of pore size not greater than 0.22 microns (e.g., IVEX-HP and 
IVEX-II, Abbot). Nothing else is to be infused through the lines where paclitaxel 
is being administered. Solutions exhibiting excessive particulate formation 
should be discarded. 
 
 
 
 
The Chemo Dispensing Pin device or similar devices with spikes should not be 
used with vials of paclitaxel since they can cause the stopper to collapse 
resulting in the loss of sterile integrity of the paclitaxel solution. 
 
7.1.3 Storage and Stability: 
 
 
 
 
Intact vials should be stored at room temperature (2-25C  
or 36-77F). Shelf life of the vials stored under appropriate  
conditions corresponds to the manufacturer’s expiration date on  
each vial. All solutions of paclitaxel exhibit a slight haziness  
directly proportional to the concentration of drug and time elapsed  
since preparation. When prepared as above, solutions of paclitaxel  
(0.3 – 1.2 mg/ml) are stable for 27 hours. 
 
7.1.4 Calculating Dosage of Paclitaxel: 


 
 
01-054 v 05-08-14 
Page 19 
 
 
 
 
 
 The dosage will be calculated using the patient’s actual weight at     
 
 
 
 each treatment visit. The dosage will be rounded to the nearest 5     
                               mg. In calculating surface areas, actual heights and weights should    
                               be used. That is, there will be no adjustment to “ideal” weight. This   
                               principle applies for individuals whose calculated surface area is 2.2  
                               m2 or less. In those rare cases where a patient’s surface area is  
                               greater than 2.2 m2, then 2.2 m2 should be used for calculating the  
                               dosage for this trial. 
 
7.1.5 Premedication Prior to Paclitaxel: 
 
 
 
 
All patients will receive the following premedications 30 to 60 minutes prior to 
the paclitaxel infusion: 
 
 Dexamethasone 10 mg IV * or 20mg po 12 and 6 hours prior to Paclitaxel in 
the event the parental form of dexamathasone is not available. 
 Diphenhydramine 50 mg IV push 
 An H2 blocker IV (e.g. Ranitidine 50 mg; Cimetidine 300 mg) 
 *  If patients do not have any reaction with the first dose, then the dose of 
dexamethasone can be increased to 20 mg prior to the weekly dose of paclitaxel. 
 
Premedication can be adjusted per institutional guidelines or physician discretion. 
 
7.1.6 Administration of Paclitaxel 
 
 
 
 
Paclitaxel, at the appropriate dose and dilution, will be given as a 1-hour (45 
mg/m2) continuous IV infusion. Paclitaxel will be administered using non-PVC 
tubing and connectors, such as the IV administration sets (polyethylene or 
polyolefin) that are used to infuse parenteral Nitroglycerin and/or fat emulsion. 
A 0.22 micron filter must be placed on the distal end of the infusion line. 
Nothing else is to be infused through the line where paclitaxel is being 
administered. 
  
 
7.1.7 Adverse Effects: 
 
 
 
The following adverse events are expected with the administration of paclitaxel. 
For complete information, see package insert. 
 
 Hematologic:  Myelosuppression 
 Gastrointestinal:  Nausea and vomiting, diarrhea, stomatitis,  
     mucositis 
 Cardiac:  Arrhythmia, heart block, ventricular tachycardia,  
  
 
hypotension, myocardial infarction (MI) 
 Neurologic:  Peripheral neuropathy, seizures 
 Allergy:  Anaphylactoid and urticarial reactions (acute),  
  
 
flushing, rash, pruritus 
 Other:  Alopecia, malaise, arthralgia, myalgia, elevated  


 
 
01-054 v 05-08-14 
Page 20 
 
 
 
 
SGOT, alkaline phosphatase and bilirubin 
 Note:  Cardiac toxicities are rare and continuous cardiac  
 
 
 
 
monitoring is not required except for patients with  
serious conduction abnormalities or other  
underlying, serious cardiac risk factors 
 
7.1.8 Recommended Management of Hypersensitivity Reactions 
 
 
 
 
Mild Symptoms:  (e.g., mild flushing, pruritus) 
 
 
 
 
Complete paclitaxel infusion. No treatment required. 
 
 
 
 
Moderate Symptoms:  (e.g., moderate rash, flushing, mild dyspnea,              
                                 chest discomfort) 
 
 
 
 
Stop paclitaxel administration. Give intravenous dexamethasone 10 mg and 
diphenhydramine HCl 25 mg. Resume paclitaxel infusion after recovery from 
symptoms at 20/ml/hr for 15 minutes, then 50 ml/hr for 15 minutes, then if no 
further symptoms, at full dose rate until infusion complete. If symptoms recur, 
stop paclitaxel infusion. The patient should not receive additional Paclitaxel for 
that week. 
 
 
 
 
Severe symptoms:  (e.g., hypotension requiring pressor therapy, IV fluids, 
angioedema, respiratory distress requiring broncho-dilation therapy, generalized 
urticaria) 
 
 
 
 
Stop paclitaxel administration. Give intravenous diphenhydramine HCl 25 mg 
and dexamethasone as above. Add adrenaline (1:1000) or broncho-dilators as 
indicated. Contact Study Coordinator and report as a serious adverse event (See 
Section 11.2). In the case of severe symptoms occurring, the patient should not 
receive additional paclitaxel and is to be taken off of the study. 
 
7.2 Carboplatin (Paraplatin - NSC #241240) 
 
7.2.1 Availability: 
 
 
 
 
Carboplatin is commercially available as a sterile lyophilized powder in single-
dose vials containing 50 mg, 150 mg, or 450 mg of carboplatin. Each vial 
contains equal parts by weight of carboplatin and mannitol. Commercial supplies 
of carboplatin will be used for this study. 
 
7.2.2 Preparation: 
 
 
 
 
Immediately before use, the content of each vial must be reconstituted with 
either sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium 
chloride injection, USP, according to the following schedule:  (These dilutions 
all produce a carboplatin concentration of 10/mg/ml) 
 


 
 
01-054 v 05-08-14 
Page 21 
 
 
 
 
Vial Strength 
Diluent Volume 
 
 
 
  50 mg 
 
  5 ml 
 
 
 
150 mg 
 
15 ml 
 
 
 
450 mg 
 
45 ml 
 
 
 
 
When prepared as directed, the resultant carboplatin solutions are stable for eight 
hours at room temperature and protected from light. Because no antibacterial 
preservative is contained in the formulation, it is recommended that carboplatin 
solutions be discarded eight hours after dilution. 
 
 
 
 
 
 
 
NOTE:  Aluminum reacts with carboplatin, causing precipitate formation and 
loss of potency. Therefore, needles or intravenous sets containing aluminum 
parts that may come in contact with the drug must not be used for the 
preparation or administration of carboplatin. 
 
7.2.3 Storage and stability: 
                              
     Unopened vials of carboplatin are stable for the life indicated on the       
                                      package when stored at controlled room temperature (59 - 86F)   
                                      and protected from light. When prepared, carboplatin solutions are   
                                      stable for 8 hours at room temperature. 
 
7.2.4 Administration: 
 
 
 
 
Carboplatin will be administered as an IV infusion over 30 minutes after 
paclitaxel. Carboplatin will be adjusted for renal function to achieve a calculated 
AUC (area under curve) as defined by the following Calvert Formula. 
Carboplatin dose will be based on calculated GFR (glomerular filtration rate) 
based on measurement of creatinine clearance or calculated creatinine clearance.  
See Appendix II for Carboplatin Dosing Worksheet. 
 
 
 
 
Calvert Formula for Carboplatin Dose: 
 
 
 
 
AUC Dose = 2.0 X (GFR + 25) 
 
 
 
 
Substitute GFR by calculated creatinine clearance (Cockroft-Gault): 
 
 
 
 
GFR = (140-Pt. Age) (Weight in Kg) X 0.85 (females) or 1.0 (males) 
 
 
 
 
 
Serum Creatinine X 72 
 
By the end of 2010, all clinical laboratories in the US will use the new standardized 
Isotope Dilution Mass Spectrometry (IDMS) method to measure serum creatinine. 
The IDMS method appears to underestimate serum creatinine values compared to 
older methods when the serum creatinine values are relatively low (e.g., ~0.7 
mg/dL). Measurement of serum creatinine by the IDMS-method could result in an 
overestimation of the Glomerular Filtration Rate (GFR) in some patients with 
normal renal function. If the total carboplatin dose is calculated based on IDMS-
measured serum creatinine using the Calvert formula, carboplatin dosing could be 


 
 
01-054 v 05-08-14 
Page 22 
 
higher than desired and could result in increased drug-related toxicity. 
 
The current label for carboplatin provides safe dosing instructions that are based on 
actual GFR measurements. Provided that actual GFR measurements are made to 
assess renal function, carboplatin can be safely dosed according to the instructions 
described in the label. 
 
(http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=13328) 
 
If a patient's GFR is estimated based on serum creatinine measurements by the 
IDMS method, as recommended by the FDA physicians should consider capping the 
dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to 
overdosing. Based on the Calvert formula described in the carboplatin label, the 
maximum doses can be calculated as: 
 
Total Carboplatin Dose (mg) = (target AUC) x (GFR +25) [Calvert formula] 
 
Maximum Carboplatin Dose (mg) = target AUC (mg•min/mL) x (150 mL/min) 
 
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for 
patients with normal renal function. No higher estimated GFR values should be 
used. 
 
For a target AUC = 6, the maximum dose is 6 x 150 = 900 mg 
For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg 
For a target AUC = 4, the maximum dose is 4 x 150 = 600 mg 
For a target AUC = 2, the maximum dose is 2 x 150 = 300 mg 
 
7.2.5 Toxicities: 
 
 
 
 
Some of the expected adverse events from carboplatin are listed below. For 
further description of adverse events see Package Insert. 
 
Hematologic:  
Myelosuppression 
 
 
 
Gastrointestinal: 
Nausea, vomiting, diarrhea, weight loss 
 
 
 
 
 
 
Constipation, gastrointestinal pain 
 
 
 
Metabolic: 
 
Electrolyte imbalances, 
 
 
 
 
 
 
hypomagnesemia, hypocalcemia,  
 
 
 
 
 
 
hyponatremia, hyperuremia 
 
 
 
Hepatic toxicity: 
Elevated alkaline phosphatase, SGOT,  
 
 
 
 
 
 
and total bilirubin, CNS peripheral  
 
 
 
 
 
 
neuropathies (mild parerethises, clinical 
 
 
 
 
 
 
ototoxicity and other sensory  
 
 
 
 
 
 
abnormalities are rare) 
 
 
 
Genitourinary: 
Renal tubular damage, renal 
 
 
 
 
 
 
insufficiency, impotence, sterility,  
 
 
 
 
 
 
amenorrhea, gynecomastia 
 
 
 
Allergy: 
 
Anaphylactoid and urticarial reactions  


 
 
01-054 v 05-08-14 
Page 23 
 
 
 
 
 
 
 
(acute), flushing, rash, pruritus and  
 
 
 
 
 
 
rarely hypotension or bronchospasm 
 
 
 
Other: 
 
Alopecia, pain, asthenia and mucosal  
 
 
 
 
 
 
side effects, decreased serum electrolytes  
 
 
 
 
 
 
values (sodium, magnesium, calcium and  
 
 
 
 
 
 
potassium) 
 
8.0 MANGANESE SUPEROXIDE DISMUTASE TREATMENT PLAN 
 
8.1   
Characteristics of MnSOD Plasmid/Lipid Complex 
The investigational agent comprises a plasmid encoding human MnSOD complex with a 
cationic lipid.  The plasmid/lipid is re-suspended at 3 mg plasmid DNA per ml. 
 
8.2   
Study Design 
This study aims to  assess the feasibility and safety of MnSOD plasmid liposome (PL) in 
combination with Paclitaxel, Carboplatin and thoracic radiotherapy  by dose escalation in 3 
cohorts of 3 patients each. It further aims to assess the efficacy of MnSOD PL in protecting the 
esophagus by estimating the incidence of grade 3 or 4 esophagitis in a group of patients treated 
at the MTD. MnSOD PL will be delivered by swallowing on days 1 and 3 of each week of 
combined chemotherapy and radiation. 
 
8.3   
MnSOD PL Dose Escalation  
Three dose levels are defined based on dose of MnSOD plasmid DNA:  level 1, 0.3 mg per 
dose; level 2, 3 mg per dose; and level 3, 30 mg per dose.  Dose escalation will proceed 
according to a standard phase I design with 3 patients initially treated on each tier.  Patients will 
be closely monitored for toxicities due to MnSOD plasmiod/liposome Paclitaxel, Carboplatin or 
thoracic radiotherapy.  If, on any dose tier of MnSOD plasmid liposome, 2 of 3 patients or 2 of 
6 patients experience a grade III or IV toxicity due to MnSOD,  dose escalation will cease.  The 
maximally tolerated dose is defined as the highest dose with fewer than 1/3 of patients 
experiencing a dose limiting toxicity due to MnSOD .   All patients on a tier must be observed 
for 8 weeks after starting treatment before escalating the dose of MnSOD.  The decision to 
escalate to the next higher dose will be made by the principal investigator and IND Sponsor.  
 
8.4 Study Drug Discontinuation and Toxicity Management 
 
Doses of study drug will be held or discontinued due to the occurrence of grade 3-4 
nausea/vomiting, or grade 3-4 rash/desquamation.   
 
Rash/Desquamation:  If a patient experiences grade 3-4 rash/desquamation, the MnSOD will be 
discontinued and the patient will be treated at the physician’s discretion.  The patient should 
continue to receive XRT and chemotherapy if MnSOD is discontinued, and should be followed 
as per protocol.  The CTCAE v 3.0 grading criteria for rash/desquamation is provided below: 
 
CTCAE Grade for Rash/Desquamation 
 
 
1 
2 
3 
4 


 
 
01-054 v 05-08-14 
Page 24 
 
Rash/ 
Desquamation 
 
Macular or 
papular eruption 
or erythema 
without 
associated 
symptoms 
Macular or papular 
eruption or 
erythema with 
pruritus or other 
associated 
symptoms; 
localized 
desquamation or 
other lesions 
covering < 50% of 
the body surface 
area (BSA) 
Severe, 
generalized 
erythroderma or 
macular, papular 
or vesicular 
eruption; 
desquamation 
covering > 50% 
of BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
 
Nausea/Vomiting:  Grade 1 nausea/vomiting occurring on days when no chemotherapy is 
planned should be treated symptomatically as necessary.  If grade 2-3 nausea vomiting occurs, 
the patient may be treated with antiemetics as required.  If a patient experiences grade 4 
nausea/vomiting or recurrent grade 3 nausea/vomiting related to the MnSOD and after adequate 
antiemetic medication, the MnSOD will be discontinued.  The patient should continue to 
receive XRT and chemotherapy if MnSOD is discontinued, and should be followed as per 
protocol. 
 
Retreatment:  Retreatment with MnSOD can occur if the grade 3-4 nausea/vomiting or grade 3-
4 rash/desquamation resolves to grade 1 within 2 weeks.   
 
If RT is held due to toxicities, MnSOD should be held and restarted with RT therapy and 
continue to be given 2X week with one day in between (ex. Day 1 and 3 or Day 2 and 4). 
 
8.5  
MnSOD Efficacy Assessment 
Once the starting dose is determined, 27 additional patients as described in section 12.0 will be 
treated with MnSOD plasmid at that dose.  The proportion of patients with grade 3 or 4 
esophagitis will be assessed as described in section 12.0.   
 
8.6   
Safety Monitoring During the Evaluation of Efficacy 
In the interest of patient safety we will also apply a stopping rule to the efficacy phase of the 
study: If 6  the first 12 patients treated at the highest dose of MnSOD P/L, experience a grade 
III or grade IV toxicity due to therapy, the study will cease, the FDA will be notified and a 
comprehensive safety review will be undertaken.   
 
9.0 
RADIATION TREATMENT PLAN 
 
9.1 Radiation Dose 
 
 
Radiation therapy will commence 4 to 6 hours after the first MnSOD PL therapy. 
This will be administered at 1.9-2.1 Gy daily 5 times a week.   The total dose will be 
77.0 Gy with a range of 69-84 Gy in 34-38 fractions over 7-8 weeks. 
 
9.2 Treatment Techniques 
 


 
 
01-054 v 05-08-14 
Page 25 
 
9.2.1 All doses are to be prescribed and calculated assuming a  
           heterogeneous patient. There will be corrections for heterogeneity          
           used in the definitions of these doses. 
 
9.2.2 The doses shall be prescribed and calculated according to the  
            following ICRU recommendations for external treatments using      
            photons and electrons. 
 
9.2.2.1 
At mid-separation on the central rays for two opposed coaxial equally 
weighted beams. 
 
9.2.2.2 
At the center of the target volume on the central rays for two opposed  
coaxial unequally weighted beams.        
  
9.2.2.3 
At the point of intersection of the central rays for two or more 
intersecting beams that are not coaxial. 
 
9.2.2.4 
At the center of the target volume for complex treatment arrangements 
which are not covered above. 
 
9.2.2.5 
At the depth of maximum dose for a single-electron beam with an  
electron beam energy chosen such that the minimum percent dose at 
3.0 cm depth is 90%. 
 
9.3 Target Volumes 
 
9.3.1 Two different target volumes shall be considered: the initial large field target 
volume consisting of primary and mediastinum, and the boost target volume 
consisting of the primary, involved nodes and nodes > 2.5 cm. in diameter only. In 
treating the initial fields, various sets of fields may be used. Target volumes should 
be based on original tumor volume. 
 
9.3.2 No part of the primary lesion and ipsilateral hilar and mediastinal lymph nodes 
(within a 2.0 cm margin) will receive a dose less than 45.0 Gy from the initial fields. 
In cases where the central rays of the initial fields do not intercept the center of the 
boost target volume it should not exceed the prescribed dose by more than 15%. 
 
9.3.3 Deviations of the daily dose of up to 5% are allowed. In patients for whom the 
difference in dose to the initial target volume and to the boost target volume is 
greater than 5%, a change in the boost dose is allowed. As an example of the above, 
assume that a patient receives 43.0 Gy to the center of the boost target volume when 
45.0 Gy has been delivered at the intersection of the central rays of the initial fields. 
The center of the target volume has received 2.0 Gy less than prescribed. This 
patient could then receive one extra fraction of 2.0 Gy to the boost field. 
 
9.4 Irradiation Portals 
 
The irradiation target volume must be defined by the individual shaped ports with 


 
 
01-054 v 05-08-14 
Page 26 
 
secondary lead blocking or tailor-made blocks. 
 
9.4.1 Target Volume of Primary Tumor: 
 
Includes complete extent of visible primary tumor as defined radiographically 
with a minimum of 2.0 cm and the maximum of 2.5 cm margin around the mass. 
 
9.4.2 Target Volume of Lymph Nodes - The following nodes must be included: 
 
9.4.2.1 
Supraclavicular lymph nodes -- if primary, is upper lobes and 
mainstream bronchus lesions. It is acceptable to treat the ipsilateral 
supraclavicular nodes only; 
 
9.4.2.2 
 Ipsilateral hilar lymph nodes -- always (2 cm margin); 
 
9.4.2.3 
Superior mediastinal lymph nodes (above carina) -- always   
            (ipsilateral 2 cm margin);  
 
9.4.2.4 
Subcarinal lymph nodes (include the contralateral mainstream 
bronchus and extend field at least to 5 cm below carina) – always; 
 
9.4.2.5 
 Inferior mediastinal nodes to the diaphragm (to bottom of   
9.4.2.6 
    T-l0 vertebral body) for patients with lower lobe lesions or     
9.4.2.7 
                                                inferior mediastinal involvement; 
 
9.4.2.6 
 Contralateral hilar lymph nodes--for patients with       
                  contralateral mediastinal, subcarinal, or contralateral hilar 
                  involvement (1.0 cm margin). 
 
9.5 Technical Factors 
 
9.5.1 Beam Energy 
 
Megavoltage equipment is required with minimum peak photon energies of 6 
MeV. Electrons with at least 90% dose at 3 cm depth mav be used to boost 
supraclavicular lymph nodes. The dose should be specified dmax. 
 
9.5.2 Treatment Distance 
 
Minimal treatment distance to skin should be greater than 100 cm for SSD 
technique and minimum isocenter distance should be 100 cm for SAD 
techniques.  
 
9.5.3 Blocking 
 
In the case of x-ray beams, the primary collimation may be used, and blocking 
will be required only for shaping of the ports to exclude volume of tissues that 
are not to be irradiated. 
 
9.5.4 Compensating Filter or Wedges 
 
In the case of a large sloping contour, such as usually encountered when treating 


 
 
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upper lobe tumors in large patients, compensating filters are recommended. A 
wedge may also be used as a 2 dimensional tissue compensator. If necessary, 
appropriate reduction in field size must be done to avoid excessive irradiation to 
critical structures. 
 
9.5.5 Therapy Interruptions 
 
If interruptions of therapy up to one week (5 consecutive days) become 
necessary, irradiation should be completed to the prescribed doses. Total dose, 
number of fractions, and elapsed days should be carefully reported. Every effort 
should be made to minimize the length of treatment interruptions. See Section 
9.6.4. 
 
9.5.6 Radiotherapy interruptions or delays will be permitted only for febrile   
           neutropenia or grade 4 esophagitis/mucositis. Interruptions longer than                   
           3 days should be discussed with Dr. Joel S. Greenberger. 
 
9.5.7 Treatment Planning 
 
9.5.7.1 
Treatment planning should be performed in accordance with the 
prescribing doses to each target volume, together with restrictions in 
dose to normal tissues as given in Section 9.6.1. Treatment planning 
simulation is required. It is recommended that CT-based treatment 
planning be utilized whenever possible.  
 
9.5.7.2 
One set of composite isodose distributions in the transverse plane 
passing through the midlevel of the boost target volume should be 
submitted. Sagittal dose distributions are encouraged. 
 
9.5.7.3 
In addition to the isodose distribution, the following specific    
              points of dose calculations should be included: 
 
1) The Spinal Cord Dose:  If compensating filters are not used, the 
point at which the spinal cord dose to be calculated is 2 cm below 
the superior margin of the posterior field. If compensating filters 
or wedges are used then the point of maximum dose to the spinal 
cord must be determined. Maximal spinal cord dose should not 
exceed 48.0 Gy at any level. 
 
2) Subcarinal Nodes: Are assumed to be at mid-plane. 
 
3) Ipsilateral Normal Lung Dose: This is to be calculated at the level 
of the central rays of the boost fields at the point of maximum 
dose in the lung which lies at least 2 cm outside the projected 
border of the initial treatment fields in the ipsilateral lung. 
 
4) Contralateral Normal Lung Dose: This is to be calculated at the 
level of the central rays of the boost fields at the point of 
maximum dose in the lung which lies at least 2 cm outside the 


 
 
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projected border of the initial treatment fields in the contralateral 
lung. 
 
5) Maximum Normal Tissue Dose: This is to be calculated at level 
of the central rays of boost fields as the maximum total dose at 
least 2 cm outside of the target volume. 
 
9.5.8 Localization Films: 
All fields treated require filming on simulator (conventional or CT sim) units. 
Portal verification shall be done for all treatment fields. Copies of both simulator 
and portal fields will be reviewed by Dr. Greenberger. 
 
9.6 Anticipated Side Effects or Toxicities 
 
9.6.1 Suggested Maximum Doses to Critically Sensitive Normal Structures 
 
Organ   
 
 
Maximum Dose 
Spinal Cord (Maximum Dose) 
 
48.0 Gy 
Heart 
Entire Organ 
 
 
 
45.0 Gy 
< 50% 
 
 
 
 
50.0 Gy 
Esophagus 
 
 
 
 
60.0 Gy 
 
9.6.2 The dose to the spinal cord must be limited to 48.0 Gy. A posterior  
            spinal cord shield will not be an acceptable technique. Oblique or    
            lateral field arrangements with custom shielding are recommended to  
            limit spinal cord dose. 
 
9.6.3 Reversible alopecia, bone marrow toxicity, skin pigmentation and esophagitis are 
expected side effects of radiation therapy, while radiation-induced myocarditis or 
transverse myelitis rarely will occur at doses lower than 50.0 Gy. Radiation 
pneumonitis will occur in 100% of patients within the first six months after initiation 
of treatment so it is essential to spare as much normal lung as possible. 
 
9.6.4 Treatment interruptions are strongly discouraged; however, radiation therapy may 
be interrupted for up to two weeks (10 consecutive treatment days) for significant (> 
grade 3) esophagus toxicity: i.e., inability to tolerate liquids and requiring parenteral 
feedings. Sucralfate slurries may provide symptomatic relief of mucositis and 
esophagitis.  
 
9.6.5 Post-treatment pneumonitis thought due to radiation should be treated  
           with prednisone after excluding microbial causes. 
 
10.0 TOXICITIES AND MANAGEMENT 
 
10.1 Hematologic Toxicity 
 
10.1.1  Concurrent Chemoradiotherapy 


 
 
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Give the following percents of dose: 
Granulocytes ml 
Or 
Platelets/ml 
Carboplatin 
Paclitaxel 
>1.5 
 
>75 
100% 
100% 
1.0-1.49 
 
50- 74.9 
50% 
50% 
<1.0 
 
<50 
0 * 
0 * 
*omit this dose, repeat counts weekly, and resume chemotherapy based on 
the above table. 
 
When a dose reduction is required no dose re-escalation will be performed subsequently. Any patient 
who does not tolerate the 50% dose reduction of paclitaxel and carboplatin, will be taken off study 
treatment. 
 
10.1.2  Renal Toxicity 
           A >25% change in the serum creatinine will warrant a recalculation  
           of the carboplatin dose. 
 
10.1.3 Neurotoxicitv/CNS Toxicity- (use CTC Criteria): 
 
 
Grade 
Carboplatin 
Paclitaxel 
0-2 
100% 
100% 
3 
0* 
0* 
*discontinue until symptoms improve to Grade < 1, then treat with 75% of both 
agents. 
 
10.1.4 Ototoxicity: For clinically evident hearing loss, discontinue carboplatin. 
 
10.1.5 Hypersensitivity Reactions  (Institutional Guidelines may be used.) 
(e.g.,flushing, rash, pruritus, dyspnea, bronchospasm, rigor, hypotension, fever) 
 
 Mild symptoms 
 
 
Complete paclitaxel infusion. No treatment required. 
 
 Moderate symptoms 
 
Stop paclitaxel infusion. Give intravenous dexamethasone 10 mg and 
chlorpheniramine 10 mg. Resume paclitaxel infusion after recovery of 
symptoms at 20 mls/hr for 15 minutes, then 50 mls/hr for 15 minutes, then if 
no further symptoms, at full dose rate until infusion complete. If symptoms 
recur, stop paclitaxel infusion. The patient should receive no additional 
paclitaxel for that week, but may be retreated after discussion with the Study 
Chair. 
 
 Severe symptoms e.g., 
 hypotension requiring therapy 
 angieodema 
 respiratory distress requiring therapy 
 generalized urticaria 


 
 
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Stop paclitaxel infusion. Give intravenous chlorpheniramine and 
dexamethasone as above. Add adrenaline (1:1000) or broncho-dilators as 
indicated. Report as a serious adverse event (see Section 11.0). In the case of 
severe symptoms, the patient should not receive additional paclitaxel. 
 
10.1.6 Cardiotoxicity:  
If a patient develops chest pain or arrhythmia other than asymptomatic sinus 
brachycardia, the paclitaxel infusion should be stopped and patients should not 
receive further paclitaxel. For asymptomatic sinus brachycardia, the infusion 
need not be stopped but the patient should be followed carefully. 
 


 
 
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10.1.7 Gastrointestinal Toxicity (use RTOG Acute Morbidity Criteria) 
 
For infield acute toxicities (Use RTOG Acute Criteria [see web site links in 
Adverse Event section]). 
 
 
Infield 
Severity/toxicity 
Scale 
 
XRT 
Modifications 
Taxol 
Carboplatin 
Esophagus / 
pharynx 
(on day of 
XRT) 
4/RTOG Acute 
Hold 
Hold 
Hold 
Esophagus / 
pharynx 
(on day of 
chemo admin) 
3/RTOG Acute 
no mod Hold 
Hold 
Esophagus/phar
ynx 
(on day of 
chemo admin) 
2/RTOG Acute 
no mod no mod No mod 
Skin 
4/RTOG Acute 
Hold 
Hold 
Hold 
Skin 
3/RTOG Acute 
no mod no mod No mod 
 
For out of field acute toxicities (use scoring criteria specified) 
 
 
Infield 
Severity/toxicity 
Scale 
 
XRT 
Modifications 
Taxol Carboplatin 
Stomatitis 
> 3/CTC 
No mod Hold 
Hold 
Stomatitis 
< 3/CTC 
No mod No 
mod 
No mod 
Weight loss 
or dehydration 
with 
severity as 
described 
> 15% or 
requirement for IV 
tube feeding 
(grade3/RTOG) 
No mod Hold 
Hold 
 
For Grade 4 infield esophagitis: 
 
Radiotherapy and chemotherapy should be interrupted. Reevaluate patient 
weekly.  
 
For Grade > 3 esophagitis/pharyngitis, dermatitis or other in-field 
radiotherapy related toxicity, on day of chemotherapy administration 
during any treatment week: 
 
Omit paclitaxel until toxicity resolves to grade < 2. Then restart the rest of 
the treatment plan with paclitaxel at  50% of prior dose. Do not reduce 
carboplatin. 


 
 
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Radiotherapy should be interrupted only for grade 4 infield toxicity and 
resumed when that toxicity has decreased to grade < 2. If treatment is 
interrupted for > 2 weeks, the patient should be removed from study 
treatment. If the patient experiences esophagitis so that IV fluid support is 
needed, insertion of a feeding tube should be considered. Radiotherapy and 
chemotherapy are to be held as outlined above. 
 
If there is a decline of performance status score to a level of Karnofsky 
Performance Scale (Appendix I) < 40 for greater than 2 weeks while under 
treatment, radiotherapy should be held with no further chemotherapy 
administered. Reevaluate patient after one week for resumption of 
radiotherapy. 
 
10.2 Acute Radiation Morbidity Scoring Schema 
 
RTOG  
Acute Radiation Morbidity Scoring Criteria 
 
0 
1 
2 
3 
4 
Pharynx 
and 
Esophagus 
 
Mild 
dysphagia or 
odynophagia 
may require 
topical 
anesthetic or 
non-narcotic 
analgesics 
may require 
soft diet 
Moderate 
dysphagia or 
odynophagia 
may require 
narcotic 
analgesics, 
puree or 
liquid diet 
Severe dysphagia 
or odynophagia 
With dehydration 
or weight loss 
(>15% from pre-
treatment 
baseline) 
requiring NG 
tube feeding, IV 
fluids or 
hyperalimentation 
Complete 
obstruction, 
ulceration, 
perforation, 
fistula 
 
10.3 Late Radiation Morbidity Scoring Schema 
 
RTOG 
Late Radiation Morbidity Scoring Schema 
 
 
Esophagus 
 
0 
1 
2 
3 
4 
NONE Mild 
Fibrosis 
Slight 
difficulty 
in 
swallowing  
solids no 
pain 
swallowing 
liquids 
Unable to 
take solid 
food 
normally 
Swallowing 
semi-solid 
food 
Dilation 
may be 
indicated 
Severe 
fibrosis 
Able to 
swallow 
only 
liquids 
May have 
pain on 
swallowing 
Dilation 
required 
Necrosis/perforation/fistula 
 


 
 
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10.4 Other Toxicity: 
 
Reevaluate all other toxicities that are grade > 3 (except alopecia, 
nausea, vomiting, fatigue, and anorexia), reduce carboplatin and 
paclitaxel by 25% in the subsequent cycle if considered possibly, 
probably, or definitely related to carbo and taxol.  Use CTC scale.  
If Chemotherapy drugs are held, schedule may be changed to give 
carbo and taxol on day 1 or day 3 of each week. 
 
10.5    Evaluation of Radiation Reactions 
 
Esophageal Toxicity:  Esophagitis will be assessed by subjective and objective criteria. 
Patients will be evaluated immediately on the day of plasmid/liposome administration 
for subjective side effects, including tingling sensation in the esophagus, difficulty 
swallowing pure liquids (Nursing Service Questionnaire based on RTOG schedule for 
evaluation of esophagitis), and will be asked to report in great detail their food 
consumption for the 72 hours after plasmid/liposome administration. 
 
10.5.1 
Acute Radiation Esophagitis:  There is a potential for radiation effects resulting 
from inflammation of the esophagus that include ulceration, secondary, 
infection, stricture formation and perforation.  The toxic effects may be acute or 
late (44, 45, 46).  Typically, acute radiation esophagitis occurs within 2 to 3 
weeks after initiation of XRT.  It may last for several weeks after completion of 
treatment.  Initial symptoms include a feeling of fullness in the throat or a sore 
throat, which promotes dysphagia.  The patient may then develop sharp pain 
along the esophagus, and there may be symptoms of gastric reflux.  Secondary 
infections of the mucosal lining may occur due to tissue inflammation, 
ulcerations, and the immunocompromised status of the patient (47).  Secondary 
infection in the mucosal lining often occurs in patients with mucositis and 
esophagitis (48).  Because acute radiation esophagitis produces difficulty in 
swallowing, nutritional intake may be reduced, and patients may lose weight.  
For milder cases, there can be dietary modifications such as soft foods or liquid 
diets.  More sever cases require feeding tubes or total parenteral nutrition.   
 
Acute radiation esophagitis will be evaluated by the investigator or other health 
care professional according to the toxicity evaluations described above (pre-
treatment or day 1, weekly during the pre-treatment and treatment regimen), or 
until the radiation esophagitis resolves.  We also plan to monitor acute radiation 
esophagitis daily with the utilization of a daily diary for the patient.  The diaries 
will be collected prior to each planned chemotherapy dose, at the end of therapy, 
at each follow-up visit, or until the radiation esophagitis resolved, whichever is 
later.   
 
Acute radiation esophagitis is defined as the development of esophagitis in a 
patient actively receiving XRT that cannot definitively be ascribed to another 
process.  If there is another cause of the esophagitis (e.g., infection), there must 
still be some degree of esophagitis present after the treatment for the other cause.  
If the signs and symptoms of esophagitis resolve after treatment for the other 


 
 
01-054 v 05-08-14 
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cause, then the patient did not have radiation esophagitis.  We will assess acute 
radiation esophagitis as follows: 
 
1. 
At each evaluation, ask whether the patient has pain or difficulty swallowing.   
 
o If yes, determine location of the pain. 
o The pain must involve the esophagus to be esophagitis, whether or not 
there is oral or pharyngeal involvement. 
o If the patient does not have pain or if the pain does not involve the 
esophagus, then the patient does not have esophagitis. 
 
2. 
Is there an alternate etiology for the acute esophagitis? 
 
o If no, then the patient has acute radiation esophagitis. 
o If yes, then proof (e.g., culture) must be documented in the primary 
source documents, and the alternate etiology must be treated. 
o If the esophagitis does not resolve completely after treatment for the 
alternate etiology, the patient does have acute radiation esophagitis. 
 
3. 
The grade of the acute esophagitis is as follows: 
 
o Grade 1:  Normal diet. 
o Grade 2:  Patient can eat and swallow modified diet (e.g., soft, pureed or 
liquid) 
o Grade 3:  Patient unable to eat or hydrate orally (e.g., may require a 
feeding tube, IV hydration, peripheral protein sparing alimentation or 
central hyperalimentation) 
o Grade 4:  Life-threatening. 
 
4. 
Once the patient develops acute radiation esophagitis, they must be assessed 
daily during XRT and then weekly until the process resolves. 
 
o Determine whether the patient has acute esophagitis that continues since 
last assessment. 
o If yes, determine grade 
o If no, determine when esophagitis resolved. 
 
5. 
Record the date and grade of the initial onset of acute radiation esophagitis; the 
date and grade whenever a change in severity of the acute radiation esophagitis 
occurred (worse or better), and the date when the radiation esophagitis 
completely resolved. 
 
The incidence and severity of acute radiation esophagitis is a primary efficacy endpoint 
of the study. 
 
10.5.2  Chronic Radiation Esophagitis:  Chronic radiation esophagitis is esophagitis 
lasting at least 4-6 weeks, with continued difficulty swallowing and a need for dilation.  
Chronic radiation esophagitis will be assessed by the same monitoring procedures 


 
 
01-054 v 05-08-14 
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enumerated above, with emphasis on the duration of radiation esophagitis. 
 
10.5.3   Radiation Pneumonitis – Radiation pneumonitis is an interstitial pulmonary 
inflammation that can develop after thoracic XRT.  The severity and extent of damage to 
normal lung tissues depends on the volume of normal lung included in the XRT field; the 
total dose and fraction of XRT, and previous or concomitant therapy (i.e., chemotherapy) 
that may influence the time and severity of the radiation changes (49, 50)  Radiation 
pneumonitis can be either acute or chronic.  Acute radiation pneumonitis occurs within 1 
to 6 months of XRT.  Symptoms can include low-grade fever, cough and fullness in the 
chest.  These symptoms usually resolve without long-term effects.  Chronic radiation 
pneumonitis is permanent changes of radiation fibrosis and it typically takes 6 months to 
evolve.  This is clinically a more significant syndrome for patients, and it may result in 
progressive dyspnea and mortality.   
 
The radiographic hallmark of radiation pneumonitis is a localized infiltrate 
corresponding to a previous XRT treatment field (51, 52, 53, 54).  The severity 
of radiation pneumonitis is graded based on radiologic changes, pulmonary 
function tests (i.e., DLCO or FEV1), and symptomatology and its affect on 
activities of daily living.  Radiation pneumonitis will be evaluated by the 
investigator or other health care professional during the follow-up visits 
described above (every 3 months for 2 years, and then every 6 months for 2 
more years) or until the radiation pneumonitis resolves.   
 
We define radiation pneumonitis as a new interstitial infiltrate within the 
radiation field that cannot be completely and definitively attributed to another 
process.  If another potential cause for the infiltrate is present (e.g., and 
infection), there must still be at least a residual interstitial infiltrate that is new 
from baseline within the radiation field after a treatment for the other potential 
cause.  If the infiltrate resolves completely after the treatment, then the patient 
did not have radiation pneumonitis.  If the new infiltrate exists both inside and 
outside of the radiation port and, after treatment, is still present inside and 
outside the radiation port, then the patient has radiation pneumonitis. 
 
The following information will be used to assess radiation pneumonitis in this 
study: 
 
1. 
Is there an interstitial infiltrate on CT scan that was not present at 
baseline? 
 If yes, determine the location of the infiltrate (i.e., only within the 
XRT port, only outside the XRT port, or both within the XRT port 
and outside the port) 
 
2. 
Is there an alternate etiology for the interstitial infiltrate? 
 If yes, proof (e.g., culture) must be documented in the primary source 
documents, and the alternate etiology must be treated. 
 
3. 
Determine whether the patient meets the criteria for radiation 
pneumonitis (following treatment of any documented alternate etiology, 


 
 
01-054 v 05-08-14 
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if present): 
 
Interstitial Infiltrate 
 
 
 
Within XRT Port Outside XRT Port 
 
Diagnosis 
 
 
 
 
+ 
 
 
- 
 
 
Radiation pneumonitis 
 
 
 
 
- 
 
 
- 
 
 
No radiation pneumonitis 
 
 
 
 
+ 
 
 
+ 
 
 
Radiation pneumonitis 
 
4. 
Radiation pneumonitis will be graded based on the radiographic changes 
within the XRT field on the high-resolution chest CT scan. 
 Grade 1:  Minimal  radiographic findings (or patchy changes) and 
estimated radiographic proportion of irradiated lung volume that is 
fibrotic of < 25% 
 Grade 2:  Patchy changes and estimated radiographic proportion of 
irradiated lung volume that is fibrotic of 25%-<50% 
 Grade 3:  Dense or widespread infiltrates/consolidation and estimated 
radiographic proportion of irradiated lung volume that is fibrotic of 
50%-<75% 
 Grade 4:  Estimated radiographic proportion of irradiated lung 
volume that is fibrotic is >75%; honeycombing 
 
5. 
Radiation pneumonitis will be graded based on results of pulmonary 
function tests (DLCO or FEV1) as follows:  
 Grade 1:  DLCO or FEV1:  >75% to <90% of baseline 
 Grade 2:  DLCO or FEV1:  >50% to <75% of baseline 
 Grade 3:  DLCO or FEV1: >25% to <50% of baseline 
 Grade 4:  DLCO or FEV1:  <25% of baseline 
 
6. 
Radiation pneumonitis will be graded based on symptomatology and its 
affect on activities of daily living: 
 Grade 1:  Asymptomatic 
 Grade 2:  Symptomatic (coughing, dyspnea), not interfering with 
activities of daily living 
 Grade 3:  Symptomatic (coughing, dyspnea), interfering with 
activities of daily living; oxygen indicated 
 Grade 4:  Life-threatening; ventilatory support indicated 
 
7. 
The final grade of radiation pneumonitis is the highest grade of one of 
the following: 
 Radiographic changes on high-resolution chest CT scan 
 The pulmonary function tests 
 Symptomatology and its affect on activities of daily living 
 
Acute radiation pneumonitis:  Occurs within 1-6 months following XRT. 
Chronic radiation pneumonitis:  Occurs >6 months following XRT. 
 
The incidence and severity of acute and chronic radiation pneumonitis is a 
primary efficacy endpoint of the study. 


 
 
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Page 37 
 
 
10.6 
Long-Term Follow-up 
 
Patients will be seen for follow-up at the end of treatment, 1 month after completion of 
treatment, and then every 3 months for 2 years, and then every 6 months for 2 years.  
Thereafter, they should be followed for recurrence and survival at the discretion of the 
investigator.  Recurrence and survival will be documented. 
 
10.6.1 Autopsy 
 
To obtain vital information about the safety and effectiveness of the gene transfer 
treatment, at the time of patients death, no matter what the cause, permission for an 
autopsy will be requested of the patients family. 
 


 
 
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11.0 ADVERSE EVENTS  
 
11.1  Definitions of Adverse Events 
 
An adverse event is defined as any noxious, pathologic, or unintended change in anatomic, 
physiologic, or metabolic functions, as indicated by physical signs, symptoms, and/or 
laboratory changes occurring in any phase of the clinical trial, regardless of their relationship to 
study agent.  Adverse events include (1) an exacerbation of a pre-existing condition, (2) an 
intercurrent illness, (3) any drug interaction, (4) any event related to a concomitant medication, 
and (5) pregnancy.   
 
A pre-existing condition is defined as one that is present prior to or at the start of the study and 
is to be reported as part of the patient’s medical history. It should be reported as an adverse 
event if the frequency, intensity, or the character worsens during study treatment. 
 
A Serious Adverse Event (SAE) is any experience that suggests significant hazard, 
contraindication, side effect, or precaution. A serious adverse event includes any experience 
that: 
 
 Is fatal or immediately life threatening.  
 
NOTE: the term “life threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of event. 
 
 Is severely or permanently disabling. 
 Requires or prolongs hospitalization. 
 Is a congenital anomaly/birth defect 
 Clinically serious based on patient outcome or action criteria usually associated with events 
that pose a threat to a patient’s life or functioning 
 
The Investigator is responsible for reporting all adverse events that are observed or reported 
during the study, regardless of their relationship to study drug or their clinical significance.  All 
events will be recorded on appropriate clinical report forms with notation of duration, severity, 
and outcome.  Event severity is rated mild, moderate, or severe, and will be coded according to 
the National Cancer Institute’s Common Toxicity Criteria Version 3.0.  The Common Toxicity 
Criteria of the NCI, Version 3.0 can be found at the web site for the National Cancer Institute: 
 
 
 
 
http://ctep.info.nih.gov/reporting/ctc.html 
 
 
The web site for RTOG/EORTC criteria for determining causal relationship is: 
 
 
 
 
www.rtog.org/members/toxicity/late.html 
 
11.1.2  All adverse events, regardless of causal relationship, are to be recorded in the case 
report forms and source documentation. The Investigator must determine the 
intensity of any adverse events according to the CTC and RTOG/EORTC criteria 
and their causal relationship. 
 


 
 
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11.1.3  Adverse events resulting in the removal of the patients from the study will   
            be followed until resolution. 
 
11.2. Reporting of Adverse Events  
 
11.2.1 Reporting of adverse events to the FDA 
 
 Written IND Safety Reports 
 
The investigator-sponsor will submit a written IND Safety Report (i.e., completed 
FDA Form 3500 A) to the responsible new drug review division of the FDA for 
any observed or volunteered adverse event that is determined to be 1) associated 
with the investigational drug or study treatment(s); 2) serious; and 3) unexpected.  
Each IND Safety Report will be prominently labeled, “IND Safety Report”, and a 
copy will be provided to all participating sub-investigators.   
 
Written IND Safety Reports will be submitted to the FDA as soon as possible and, 
in no event, later than 15 calendar days following the investigator-sponsor’s receipt 
of the respective adverse event information. 
 
For each written IND Safety Report, the sponsor-investigator will identify all 
previously submitted IND Safety Reports that addressed a similar adverse event 
experience and will provide an analysis of the significance of newly reported 
adverse event in light of the previous, similar report(s). 
 
Follow-up information to an IND Safety Report will be submitted to the applicable 
review division of the FDA as soon as the relevant information is available.  If the 
results of the sponsor-investigator’s follow-up investigation show that an adverse 
event that was initially determined to not require a written IND Safety Report does, 
in fact, meet the requirements for reporting; the investigator-sponsor will submit a 
written IND Safety Report as soon as possible, but in no event later than 15 
calendar days, after the determination was made. 
 
11.2.2 Telephoned IND Safety Reports 
 
 
In addition to the subsequent submission of a written IND Safety Report (i.e., 
completed FDA Form 3500A), the investigator-sponsor will notify the responsible 
review division of the FDA by telephone or facsimile transmission of any observed 
or volunteered adverse event that is 1) associated with the use of the investigational 
drug or study treatment(s); 2 fatal or life-threatening; and 3) unexpected. 
 
The telephone or facsimile transmission of applicable IND Safety Reports will be 
made as soon as possible but in no event later than 7 calendar days after the 
investigator-sponsor’s initial receipt of the respective human adverse event 
information. 
 
11.2.3  Reporting adverse events to the responsible IRB 
 


 
 
01-054 v 05-08-14 
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In accordance with applicable policies of the University of Pittsburgh Institutional 
Review Board (IRB), the investigator-sponsor will report, to the IRB, any observed 
or volunteered adverse event that is determined to be 1) associated with the 
investigational drug or study treatment(s); 2) serious; and 3) unexpected.  Adverse 
event reports will be submitted to the IRB in accordance with the respective IRB 
procedures.  
 
Applicable adverse events will be reported to the IRB as soon as possible and, in no 
event, later than 10 calendar days following the investigator-sponsor’s receipt of 
the respective information.  Adverse events which are 1) associated with the 
investigational drug or study treatment(s); 2) fatal or life-threatening; and 3) 
unexpected will be reported to the IRB within 24 hours of the investigator-
sponsor’s receipt of the respective information.  
 
Follow-up information to reported adverse event will be submitted to the IRB as 
soon as the relevant information is available.  If the results of the sponsor-
investigator’s follow-up investigation show that an adverse event that was initially 
determined to not require reporting to the IRB does, in fact, meet the requirements 
for reporting; the investigator-sponsor will report the adverse event to the IRB as 
soon as possible, but in no event later than 10 calendar days, after the determination 
was made. 
 
11.2.4 Withdrawal of subjects due to adverse events 
 
Patients may withdraw from the trial at any time at their own request, or they may 
be withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
or administrative reasons. If a patient does not return for a scheduled visit, every 
effort should be made to contact the patient. In any circumstance, every effort 
should be made to document patient outcome, if possible. The investigator should 
inquire about the reason for withdrawal, request the patient to return for a final 
visit, if applicable, and follow-up with the patient regarding any unresolved adverse 
events. 
 
If the patient withdraws from the trial and also withdraws consent for disclosure of 
future information, no further evaluations should be performed and no additional 
data should be collected.  
 
A discontinuation occurs when an enrolled patient ceases participation in the study, 
regardless of the circumstances, prior to completion of the protocol. The 
investigator must determine the primary reason for discontinuation: 
1. Withdrawal due to adverse event. When a discontinuation is due to a serious 
adverse event (SAE), the serious adverse event must be reported in accordance 
with the reporting requirements. 
2. Patients may decide to withdraw from the study at any time. Patients who 
withdraw from treatment should be followed for outcome, and their subsequent 
treatments should be recorded. 
3. Patients must be discontinued if the investigator believes it to be in the patient’s 
best interest. 


 
 
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4. Patients who become pregnant must not receive further treatment in this study. 
Pregnant patients should be followed for the duration of the pregnancy, and the 
outcome of the pregnancy should be recorded. 
5. Patients who begin new investigational therapy, chemotherapy, cytokine therapy 
or immunotherapy must not receive further treatment in this study. 
6. Patients may be discontinued from the study for poor compliance at the 
discretion of the investigator. 
 
The final evaluation required by the protocol will be performed at the time of study 
discontinuation. The investigator will record the reason for study discontinuation and 
provide or arrange for appropriate follow-up (if required) for the patient. 
 
11.3. Additional OBA reporting guidelines for gene transfer studies: 
 
NIH Guidelines for Research Involving Recombinant DNA Molecules  
 
Investigators who have received approval from FDA to initiate a human gene transfer 
protocol must report any serious adverse event meeting regulatory reporting 
guidelines immediately to the local Institutional Review Board, Institutional 
Biosafety Committee, Office for Protection from Research Risks (if applicable), 
NIH/ORDA, and FDA, followed by the submission of a written report filed with each 
group. Reports submitted to: 
 
Office of Recombinant DNA Activities,  
National Institutes of Health/MSC 7010 
6000 Executive Blvd., Suite 302,  
Bethesda, Maryland 20892-7010,  
Phone: 301-496-9838. 
 
Initiation of the Clinical Investigation 
 
No later than 20 working days after enrollment (see definition of enrollment in 
Section I-E-7) of the first research participant on a human gene transfer experiment, 
the Principal Investigator(s) shall submit the following documentation to NIH OBA:  
(1) a copy of the informed consent document approved by the Institutional Review 
Board (IRB); (2) a copy of the protocol approved by the Institutional Biosafety 
Committee (IBC) and IRB; (3) a copy of the final IBC approval from the clinical trial 
site; (4) a copy of the final IRB approval; (5) a brief written report that includes the 
following information:  (a) how the investigator(s) responded to each of the RAC's 
recommendations on the protocol (if applicable); and (b) any modifications to the 
protocol as required by FDA; (6) applicable NIH grant number(s); (7) the FDA 
Investigational New Drug Application (IND) number; and (8) the date of the 
initiation of the trial.  The purpose of requesting the FDA IND number is for 
facilitating interagency collaboration in the Federal 
oversight of human gene transfer research. 
 
Additional Clinical Trial Sites 
 


 
 
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No research participant shall be enrolled (see definition of enrollment in Section I-E-
7) at a clinical trial site until the following documentation has been submitted to NIH 
OBA:  (1) Institutional Biosafety Committee approval (from the clinical trial site); 
(2) Institutional Review Board approval; (3) Institutional Review Board-approved 
informed consent document; (4) curriculum vitae of the principal investigator(s) (no 
more than two pages in biographical sketch format); and (5) NIH grant number(s) if 
applicable. 
 
Annual Reporting  
 
Investigators shall comply with annual data reporting requirements.  Annual 
data report forms will be forwarded by NIH OBA to investigators. Information 
submitted in these annual reports will be evaluated by NIH OBA and the RAC, and 
possibly considered at a future RAC meeting.  Information obtained through the 
annual data reporting process will be included in the NIH Human Gene Transfer 
Information System to:  (1) provide clinical trial information; (2) provide 
administrative details of protocol registration; (3) provide annual status reports of 
protocols; (4) facilitate risk assessment of individual applications of human gene 
transfer; and (5) enhance public awareness of relevant scientific, safety, social, and 
ethical issues. 
 
11.4. Additional University of Pittsburgh IBC Reporting Guidelines: 
 
1. This IBC continuing approval is granted only for the research procedures 
specified in the materials submitted for IBC review.  Any proposed modifications 
to the research procedures (including the procedures addressed in Appendix M of 
the NIH Guidelines) must be prospectively reviewed and approved by the IBC.  
 
2. Upon continuing approval from the University of Pittsburgh IRB, you must 
provide to the rDNA Office one copy of the IRB continuing approval letter and 
the final IRB approved version of all consent forms associated with the protocol.  
 
3. You must comply with the annual data reporting requirements of the NIH 
Guidelines, and when possible, copies of the report should be forwarded to the 
rDNA Office.  
 
4. You must report any adverse events observed during the conduct of this research 
to the rDNA Office, in accordance with the accepted requirements for such 
events.   Please note that all Adverse Events must be reported to the IBC 
regarding of the reporting criteria for the IRB. 
 
 
Go to http://www4.od.nih.gov/oba/rac/documents1.htm for detailed review reporting requirements 
and forms. 
 
11.2.1 
 Adverse Drug Reactions (ADR) 
 
Adverse Drug Reactions (ADR) to be reported: 
 Unknown Grade 2, 3, or 4 


 
 
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 Known Grade 4  
 Any ADR which is both serious (life-threatening, fatal) and unexpected.   
 Any increased incidence of a known ADR that has been reported in the package insert 
or the literature 
 Any death on study regardless of the relationship to any of the study drugs.       
 
** Prompt reporting of all adverse events is mandatory. 
 


 
 
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12.0 EVALUATION OF TOXICITY AND RESPONSE 
 
12.1 Data Safety Monitoring Plan 
A data safety plan for this study is directed by the PI, who will oversee the adverse events and 
data to evaluate the toxicities seen in each patient.  The PI and the named investigators on this 
study and clinical research coordinator meet at least once a month to review and discuss study 
data to ensure subject safety.   Decisions to continue treating subjects at the current dose level 
and/or if the trial accrual should continue will also be discussed during these meetings.  Any 
information regarding increased risks to study subjects that is discovered during these meetings 
will be forwarded immediately to the IRB and all other designated regulatory agencies (i.e.; 
FDA, IBC, OBA, NIH and etc.) Any required modifications necessary to ensure patient safety 
will be discussed and will be submitted to the IRB.  All serious adverse events, regardless of 
their relationship will be reported to the IRB according to the established guidelines for gene 
transfer studies according sections 3.3, 3.4, 3.5 and 3.6 of the University of Pittsburgh IRB 
reference manual.  All serious adverse events will also be reported to the sponsor and /or other 
regulatory agency as per their requirements.  All protocol violations will also be reported to the 
IRB and all other designated regulatory agencies as required by the study protocol. All study 
data reviewed and discussed during these meetings will be kept confidential.  Any breaches in 
confidentiality will be reported to the IRB and the other designated regulatory agencies 
assigned to this protocol.   
 
12.2 General Toxicity Criteria 
 
           NCI Common Toxicity Criteria – See web site link in Adverse Events section.  
 
12.4 Tumor Response 
 
12.4.1 Complete Response  
           Disappearance of all clinical evidence of tumor, determined by two       
           observations not less than 4 weeks apart. 
 
12.4.2 Partial Response 
At least a 30% decrease in the sum of the longest diameter of target lesions for at 
least 4 weeks without increase in size of any area of known malignant disease or 
appearance of new areas of malignant disease. 
 
12.4.3 Progressive Disease 
 
     At least a 20% increase in the sum of the longest diameter of target          
                lesions taking as reference the smallest sum longest diameter since the  
                treatment started or the appearance of one or more new lesions and/or    
                unequivocal progression of existing non-target lesions.  
 
12.4.4 Stable Disease 
Neither sufficient shrinkage to qualify for partial response nor sufficient      
                           increase to qualify for progressive disease, taking as reference the   
                           smallest sum longest diameter since the treatment started or the            
                           persistent of one or more nontarget lesions.   
 


 
 
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13.0 STATISTICAL CONSIDERATIONS 
 
13.1 Objectives 
 
The primary objective of this study is to evaluate the safety, feasibility and efficacy of 
swallowed MnSOD plasmid/liposome for protecting the esophagus from toxicity 
associated with concurrent chemotherapy and radiotherapy.  The study will be 
conducted in two phases, Phase I for safety and feasibility and Phase II for efficacy.  
Secondary objectives will evaluate the clinical response to the combination of 
chemoradiotherapy with esophagus protection by MnSOD plasmid/liposome. 
 
13.2 Endpoints 
For the safety and feasibility phase, the endpoint will be the proportion of toxicities 
attributed to administration of MnSOD plasmid liposome.  This will exclude esophagitis 
as well as hematologic and other toxicities normally attributed to the chemotherapy 
(Paclitaxel and Carboplatin) and thoracic radiotherapy.  For the efficacy phase, the 
clinical endpoint will be the proportion of radiation - induced grade III/IV esophageal 
toxicity.  Grade III/IV toxicity definitions will be by the RTOG scale (appendix).   The 
secondary endpoints will include clinical assessments of objective response rate by 
RECIST criteria, and Kaplan-Meier estimates of time to progression, time to 
progression conditional on clinical response, and overall survival from the first day of 
treatment. 
 
13.3 Design 
The first phase of this study will treat 3 patients each at 3 sequential tiers of .3, 3, and 30 
mg of MnSOD/plasmid DNA.  If no toxicities are observed the dose of MnSOD PL will 
be escalated to the next tier.  If one toxicity is observed the cohort will be expanded to 6 
patients. If two of 3 patients experience a grade III or IV toxicity due to MnSOD, dose 
escalation will cease and the next lowest dose will be declared to be the MTD. If none 
of 3 or 1 or 6 patients experience grade III/IV toxicity due to MnSOD at the 30 mg tier, 
that dose will be defined as the starting dose for efficacy phase and the MTD will be 
undefined.   
 
The second phase will treat 27 patients at the highest dose of the first phase (expected 
dose is 30 mg MnSOD/plasmid).   The goal of this phase is to estimate the proportion of 
patients with grade III/IV esophagitis and not to select a starting dose for a randomized 
trial.  Accordingly, the statistical objectives call only for estimation with confidence 
intervals based on the observed radiation-induced toxicity rates.  The sample size was 
selected by practical considerations and is not intended to insure precision of the 
estimated toxicity rates, to guarantee a selected power for a hypothesis test, or to make a 
decision based on a hypothesis test.     
 
In the efficacy phase of the study the following stopping rule will be enforced: If 6  the 
first 12 patients treated at the highest dose of MnSOD P/L, experience a grade III or 
grade IV toxicity due to any component of therapy (Paclitaxel, Carboplatin, radiation or 
MnSOD, the study will cease, the FDA will be notified and a comprehensive safety 
review will be undertaken.   
 
 
A maximum  of 45 patients may be treated on both phases of the study – up to 18 on the 


 
 
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first phase and 27 on the second. 
 


 
 
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13.4 Characteristics of the Design 
The phase I portion of the study will treat 3 patients on each of three increasing dose 
tiers - .3, 3, and 30 mg MnSOD plasmid/liposome using a standard phase I design with 
3 patients initially enrolled on each dose tier.  All patients will receive a fixed dose of 
paclitaxel, carboplatin and radiotherapy.  While no grade III or IV toxicities are 
expected due to the MnSOD plasmid or liposome, a standard phase I design will be 
implemented to stop escalation if necessary and to define an MTD.  The table below 
shows the probability of declaring each of 3 dose tiers as the MTD under 3 different 
scenarios. 
 
 
Probability of Declaring a Dose Tier as the MTD with a Standard  
Three Patient Phase I Design 
 
Dose of 
MnSOD PL 
If the underlying 
toxicity rate is: 
Prob. of 
Declaring 
MTD 
If the 
underlying 
toxicity rate is: 
Prob. of 
Declaring 
MTD 
If the 
underlying 
toxicity rate 
is: 
Prob. of 
Declaring 
MTD 
.3 mg 
.02 
.004 
.05 
.026 
.20 
.291 
3 mg 
.04 
.017 
.10 
.091 
.30 
.358 
30 mg 
.05 
.025 
.15 
.164 
.40 
.241 
MTD not 
defined 
---- 
.952 
---- 
.717 
---- 
.108 
 
For the phase II portion of the study, inference about the proportion of grade III/IV 
esophagitis will be made from the observed proportion of grade III/IV esophagitis 
among 30 total patients treated at the highest dose of MnSOD P/L in the trial 
(tentatively set as 30 mg).   The estimate will combine 3 - 6 patients treated on the first 
phase and the 24-27 patients treated on the second phase.  Inference about the true but 
unknown proportion of grade III/IV esophagitis will be based on 90% confidence 
intervals.  The following table shows the bounds of the exact 90% confidence intervals 
for a binomial proportion with a sample of 30 patients.  
 
Confidence Intervals and Operating Characteristics for N = 30 
 
Number of Observed 
Grade III/IV Toxicities 
Point Estimate of 
Toxicity Rate 
90% Confidence 
Interval 
Exact one sided p 
value for  testing rate 
= .25 
Power* to Detect 
Rate = Point Estimate 
0 
.000 
.000 - .095 
.0002 
1.000 
1 
.033 
.002 - .149 
.002 
.984 
2 
.067 
.012 - .195 
.021 
.862 
3 
.100 
.028 - .239 
.037 
.647 
4 
.133 
.047 - .280 
.098 
.421 
5 
.167 
.068 - .319 
.203 
.238 
6 
.200 
.091 - .358 
.348 
.123 
7 
.233 
.115 - .394 
.514 
.057 
* power of a one tailed test with type I error = .05  


 
 
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The baseline grade III/IV esophagitis rate is estimated to be .25 in the absence of 
protective therapy.  The table also shows the operating characteristics of a one tailed 
hypothesis test for testing a rate of .25 vs selected lower rates.  The test power shown in 
the last column applies to a one tailed hypothesis test with alpha = .05.   With 30 
patients this test would reject the null hypothesis that the underlying esophagitis rate is 
.25 in favor of one of the lower rates shown in column 2 whenever 3 or fewer grade 
III/IV esophagitis events occur.  This test provides acceptable power (> .80) for 
detecting an esophagitis rate of .078 or lower.  
 
Although MnSOD PL is expected to reduce the rate of grade III/IV esophagitis, a 
stopping rule has been introduced to protect against higher-than-expected esophagitis.   
The stopping rule will permit stopping the trial if 6 of the first 12 patients treated at the 
phase II dose of MnSOD PL experience grade III or IV esophagitis.  We note the 
probabilities of stopping the study pursuant to this rule are .046, .054, and .613 if the 
true rate of grade III/IV esophagitis is 10, .25 and .50, respectively.  Thus the stopping 
rule provides some protection for patients if the underlying toxicity rate is increased to 
.50 but is unlikely to occur if the toxicity rate is successfully reduced to .10. 
 
 
13.5 Proposed Data Analysis 
  
Primary data analysis will compute the point estimate and confidence intervals of the 
phase II grade III/IV esophagitis rate on an intent-to-treat per patient basis  Information 
regarding all grades of radiation-induced esophageal toxicity on both phases of the 
study will be tabulated and summarized.  Summary information will include grade, time 
of onset, duration of onset, treatment cycle and requisite dose reductions.  Compliance 
with radiation therapy  and chemotherapy dose completion statistics on an intent-to-treat 
basis will be compiled for each patient.   
 
Data analyses to address secondary objectives include the objective response rate with 
confidence intervals as well as survival analysis applied to time to disease progression, 
time to disease progression conditional on clinical response, and overall survival.  The 
definitions of clinical response are based on the Response Evaluation Criteria in Solid 
Tumors (RECIST). On an exploratory basis time to progression and overall survival will 
be analyzed by log-rank tests or time-dependent Cox models.  Potential predictors 
include  pre-treatment clinical and pathologic factors, total chemotherapy and 
radiotherapy dosages and clinical response.  
 
14.0 PROTECTION OF HUMAN SUBJECTS/REGULATORY REQUIREMENTS 
 
Protection of Human Subjects 
 
 Investigator will obtain written, legally effective, informed consent of all trial subjects.  The 
informed consent process will be carried out by the physician investigator and the clinical 
research coordinator. 
o The prospective subject will be provided ample opportunity to consider participation in 
the trial. 
o There will be no coercion or undue influence. 
o Information provided to the subject will be in language that is understandable. 
o The subject will be given ample opportunity to ask questions during the initial consent 


 
 
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process and throughout participation in the trial. 
o The consent process continues throughout the course of a subject’s participation in the 
trial.  Research subjects will be fully informed of any new information that may affect 
their willingness to continue study participation. 
o In addition to the consent form, the consent process will be documented in the subject’s 
medical record. 
o Informed consent is obtained prior to initiation of any procedures that are performed 
solely to determine study eligibility.   
 Protocol deviations should not occur, but where necessary due to extenuating circumstances 
will be properly documented and reported. 
 Toxicities and adverse events will be properly monitored, documented and reported in 
accordance with sponsor and IRB guidelines. 
 
Monitoring/Auditing 
 
UPCI assumes a responsibility for quality assurance throughout the duration of the study.  The 
program manager, Experimental Therapeutics, or other designated staff will perform regular quality 
assurance reviews of the conduct of clinical trials in the program.  Reasonable intervals for 
monitoring are determined at the outset of each study, and are dependent upon the complexity of 
the study and the rate of enrollment.  Study progress, case report form completion and compliance 
with GCP standards are monitored.  Under the direction of the investigator, the program manager is 
responsible for facilitating the monitoring process, as well as completion of study report forms for 
the FDA, IRB and other relevant review requirements. 
 
Monitoring for all UPCI studies is performed at the Hillman Cancer Center (UPCI Clinical 
Research Services) as the central location for the performance of the trial.  For this trial, potential 
subjects from satellite offices will be referred to the central location.   
 
Subject Screening and Enrollment 
 
As specified in the protocol, screening tests to assess whether a prospective study subject is eligible 
for inclusion in a clinical trial are performed.   
 
 Check for proper and timely consent form execution.   
 Review the eligibility in the protocol (or a study-specific eligibility checklist) by verifying each 
requirement in a source document (patient medical record).  
 Check lab work and scans against eligibility requirements (values and timeframes).  
 Protocol exceptions should not exist, but if there are ambiguities in determining eligibility or if 
extenuating circumstances have allowed an exception:  Check for proper documentation, 
including rationale, investigator signature and reporting to IRB. 
 
Source Documents 
 
Source documents include all information in original patient records and certified copies of original 
records of clinical findings, observations or other activities in a clinical trial.  Examples of source 
documents include physician notes, progress notes, laboratory reports and tumor measurements.  A 
complete set of source documents will be maintained for each trial subject. 
 


 
 
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Protocol Treatment 
 
 Check all aspects of research subject treatment against protocol-specific requirements 
(procedures and timelines). 
 Verify baseline disease status and responses; verify that all tests to assess response were 
performed per protocol. 
 Check body surface area calculations. 
 Verify doses and dates of treatment (protocol, source documents, CRFs). 
 Assess and verify dose modifications against the protocol. 
 Check radiation dose calculation and administration. 
 For adverse events:  
o Verify toxicities and grades (source documents, CRFs). 
o Verify lab values. 
o Verify performance and documentation of tests to assess toxicity (per protocol 
requirements). 
o Verify documentation and reporting to appropriate entities. 
 
Adverse Event Reporting 
 
Adverse event reporting will occur per Section 11.3 above.   
 
 Adverse events will be reported and documented on Form FDA 3500A (MedWatch form) to 
the FDA.  This includes serious related and serious unrelated adverse events.   
 Information for this form will be abstracted from source documents and assessments made by 
the investigator (i.e., causality).  
 Serious adverse drug experience:  Any adverse drug experience occurring at any dose that 
results in any of the following outcomes:  Death, a life-threatening adverse experience, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.   
 Unexpected adverse drug experience:  Any adverse drug experience, the specificity or severity 
of which is not consistent with the current investigator brochure or the risk information 
described in the general investigational plan of the current protocol and consent form. 
 The FDA will be notified by facsimile of any unexpected fatal or life-threatening experience 
associated with the use of the drug as soon as possible but no later than 7 calendar days of the 
knowledge of the information.   
 Local requirements will be followed for IRB reporting of adverse experiences.   
 
Compliance with the Protocol 
 
 The trial will be conducted in compliance with the protocol approved by all regulatory 
authorities, including the FDA and the University of Pittsburgh IRB. 
 No changes will be made to the protocol or protocol conduct without prior approval of the FDA 
and IRB, except where necessary to avoid immediate danger.   
 Requests for modifications will be in accordance with requirements established by the FDA and 
IRB.  Such modifications will be requested under the direction of the investigator, with 
appropriate preparation and tracking by regulatory and administrative staff. 
 Any protocol deviations will be documented and reported to the IRB. 


 
 
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Correction of Errors 
 
 All corrections on a CRF or a source document are made in a way that does not obscure the 
original entry.  Incorrect information will be stricken with a single line.  The correct data is 
inserted, dated and initialed by authorized study personnel.   
 
Investigational Product 
 
Under the direction of the investigator, the investigational drug pharmacist is responsible for 
carrying out all aspects of verification and compliance with regulatory requirements pertaining to 
the investigational product.  The investigational drug pharmacist: 
 
 Assures that storage and conditions are acceptable, and that supplies are sufficient throughout 
the trial. 
 Assures that investigational products are supplied only to those subjects who are eligible to 
receive it, and at specified dosages.   
 Assures that study-specific tracking is performed; NCI drug accountability forms are utilized. 
 Assures that subjects are provided with necessary instruction on proper use, handling, storing 
and returning the investigational product. 
 Assures that the receipt, use and return of the investigational product is controlled and well 
documented. 
 Assures that the disposition of unused investigational product complies with applicable 
regulatory and internal requirements. 
 
Study Reports 
 
As required, annual reports will be provided to the FDA and IRB.  At the completion of the study 
(after all subjects have completed protocol therapy and follow-up time points, and after a final 
internal audit occurs) a final report will be generated.  This will also serve as a termination notice to 
the IRB.   
 
     Conflict of Interest 
 
 
     Dr. Joel Greenberger, a co-investigator on this clinical trial, has a significant financial interest in the 
development of this clinical trial’s study treatment. Please see Appendix IV for further details.  
 
15.0 APPENDICES 
 
Appendix I 
Karnofsky Performance Scale 
Appendix II    Carboplatin Dosing Worksheet 
Appendix III   Study Team – Organizational Chart 
Appendix IV Standard conflict of interest management plan for Human Subject Research  


 
 
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Appendix I:  Karnofsky Performance Scale 
 
The Karnofsky Performance Scale Index allows patients to be classified as to their functional impairment. This can be used 
to compare effectiveness of different therapies and to assess the prognosis in individual patients. The lower the Karnofsky 
score, the worse the survival for most serious illnesses.  
 
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA 
 
Able to carry on normal activity and to work; no special care 
needed. 
  100   Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease.  
Unable to work; able to live at home and care for most personal 
needs; varying amount of assistance needed. 
70 
Cares for self; unable to carry on normal activity 
or to do active work. 
60 
Requires occasional assistance, but is able to care 
for most of his personal needs. 
50 
Requires considerable assistance and frequent 
medical care.  
Unable to care for self; requires equivalent of institutional or 
hospital care; disease may be progressing rapidly. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated 
although death not imminent. 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
 
 


 
 
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Appendix II:  Study Team – Organizational Chart 
Protocol Title:  Concurrent Chemotherapy (Paclitaxel and Carboplatin) and Thoracic Radiotherapy with 
Swallowed Manganese Superoxide Dismutase (MnSOD) Plasmid Liposome (PL) Protection in Patients 
with Locally Advanced Stage III Non-Small Cell Lung Cancer, A Phase I-II Study (UPCI 01-054) 
 
Organizational Chart 
 
Implementation of Trial in Accordance with International Conference on Harmonisation (ICH); Good Clinical Practice (GCP) 
Guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dwight E. Heron, MD 
Clinical Principal Investigator 
Leads the team identified below; bears overall responsibility and accountability for all clinical aspects related 
to the conduct of the clinical  trial.  In this regard, the investigator ensures compliance with all applicable 
federal and local requirements for the conduct of the clinical trial at UPCI. He works with Dr. Greenberger the
study’s overall sponsor.   
Statistician 
William Gooding, MS 
Develops statistical plan, generates data 
reports, performs ongoing, interim and 
final analysis of study data. 
 
Inves
Perform
and stud
Co-Investigators 
(Listed on Consent Form) 
 
Perform critical trial-related procedures 
and assessments. 
Program Manager 
Experimental Therapeutics 
Kelli Davis, RN, MSN-CNL, OCN 
Oversees administrative and 
coordination activity of trial (e.g. 
staffing; training, QA); prepares study 
status reports; assures proper federal 
regulatory reporting. 
Oncology Registrar/Data Manager 
TBN 
Obtains medical record information 
and source documentation; abstracts 
appropriate data for recording in case 
report forms. 
Senior 
Submits
and appr
requirem
documen
Clinical Research Coordinator 
TBN 
Participates with investigator(s) in 
informed consent process, screening, 
eligibility, enrollment, ongoing protocol 
procedures, adverse drug reaction 
reporting.