Clinical trial NCT03340974
Conditions: Pancreatic Cancer Stereotactic Body Radiation Therapy
Keywords: Avasopasem manganese
Sponsor: Galera Therapeutics, Inc.
Start date: 2018-02-12; Completion date: 2021-05-26
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the phase I/II clinical study is to determine the best dose of fractionated stereotactic radiation therapy (SBRT) given either with Avasopasem manganese (GC4419) or placebo to patients who have been diagnosed with locally advanced pancreatic cancer.

Detailed description:
This is a parallel arm adaptive design phase I-II dose-finding study to determine the optimal dose of fractionated stereotactic radiation therapy (SBRT), given either with the radiomodulating agent Avasopasem manganese (GC4419) or placebo for treatment of locally advanced pancreatic cancer. Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design \[1-3\].

A maximum of 48 patients will be randomized 1:1 to Arm A or Arm B. Patients in Arm A will receive Avasopasem manganese (GC4419) in combination with their assigned SBRT dose, and patients in Arm B will receive Placebo (PBO) with their assigned SBRT dose. The randomization will be restricted so that the sample size within each arm is exactly 24 patients.

GC4419/placebo will be given intravenously in a one hour infusion. SBRT must be initiated as soon as possible upon completion of the GC4419/placebo infusion.

GC4419/placebo will be given beginning on the first day of radiation and continuing daily, concurrent M-F throughout the administration of SBRT

Arms: arm 1: Avasopasem manganese (GC4419) +SBRT arm 2: Avasopasem manganese (GC4419) +SBRT arm 3: Placebo +SBRT arm 4: Placebo + SBRT
Interventions: intervention 1: GC4419 intervention 2: Placebo intervention 3: Stereotactic Radiation Therapy (SBRT) 50 Gy intervention 4: Stereotactic Radiation Therapy (SBRT) 55 Gy
Intervention descriptions: intervention 1: 90 mg Avasopasem (GC4419) per day daily (60 min IV infusion, prior to SBRT), concurrent with daily fractions of SBRT to assigned dose level intervention 2: Placebo daily (60 min IV infusion, prior to SBRT), concurrent with daily fractions of SBRT to assigned dose level intervention 3: Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design. intervention 4: Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design.

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
AN ADAPTIVE PHASE I/II DOSE ESCALATION TRIAL OF STEREOTACTIC BODY RADIATION 
THERAPY IN COMBINATION WITH RADIOMODULATING AGENT GC4419 IN LOCALLY ADVANCED 
PANCREATIC ADENOCARCINOMA 
 
Industry-supplied agent(s):  
 
 
GC4419 (avasopasem manganese) 
 
 
Sponsor:  
 
 
 
 
Galera Therapeutics, Inc. 
 
 
 
 
 
 
2 West Liberty Blvd, Suite 110 
 
 
 
 
 
 
Malvern, PA 19355 
 
IND Number: 
 
 
 
 
136,778 
 
Protocol ID: 
 
 
 
 
GTI-4419-101 
 
Protocol Version:  
 
 
 
Amendment 07, 24January2020 
 
Medical Monitor: 
 
 
 
Jon T. Holmlund, MD, Galera Therapeutics, Inc. 
 
Lead Study Investigator: 
 
 
Cullen Taniguchi, MD, MD Anderson Cancer Center 
 
ClinicalTrials.gov Identifier:   
 
NCT03340974 




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SUMMARY SYNOPSIS 
Name of Sponsor/Company: 
Galera Therapeutics, Inc. 
Name of Investigational Product: 
GC4419 (avasopasem manganese) 
Name of Active Ingredient: 
GC4419 
(avasopasem 
manganese) 
(Manganese, 
dichloro[(4aS,13aS,17aS,21aS)-
1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-eicosahydro-11,7- 
nitrilo-7H- 
dibenzo[b,h][1,4,7,10] tetraazacycloheptadecine-κN5, κN13, κN18, κN21, κN22]-) is a water 
soluble, highly stable, low molecular weight manganese-containing macrocyclic ligand complex 
whose activity mimics that of naturally occurring SOD enzymes. 
Title of Study:  
AN ADAPTIVE PHASE I/II DOSE ESCALATION TRIAL OF STEREOTACTIC BODY RADIATION 
THERAPY IN COMBINATION WITH RADIOMODULATING AGENT GC4419 IN LOCALLY 
ADVANCED PANCREATIC ADENOCARCINOMA 
Number of Study Center(s): Up to 7 (Lead Site: University of Texas, MD Anderson Cancer 
Center) 
Estimated Enrollment Period: 30 months 
Studied period (years):  
Estimated date first patient enrolled: Jan 2018 
Estimated date last patient completed dose: Jun 2020 
Phase of development: 1/2 
 
Objectives:  
Primary: 
• To determine the Maximum Tolerated Dose (MTD) of Stereotactic Body Radiation Therapy 
(SBRT) when given in combination with placebo or GC4419  
Secondary: 
• To evaluate Progression-Free Survival (PFS) for patients treated with SBRT given in 
combination with placebo or GC4419  
• To evaluate Overall Response Rate (ORR) including stable disease, partial/complete 
response for patients treated with SBRT given in combination with placebo or GC4419 
• To compare acute toxicity rate at 90 days for patients treated at the SBRT MTD with SBRT 
in combination with placebo or GC4419 
• To evaluate late (12 month) toxicity of SBRT in combination with placebo or GC4419 
Number of patients (planned):  


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48 patients will be enrolled in both subgroups (SBRT alone and SBRT plus GC4419). Within each 
subgroup, 24 patients will be treated in 8 cohorts of size 3 each. 
Diagnosis and main criteria for inclusion:  
Inclusion Criteria:  
1. 
Cytologic or biopsy confirmed adenocarcinoma of the pancreatic head, body or tail 
2. 
Disease that is appropriate for SBRT by virtue of being: 
a. Locally 
advanced 
and 
technicallyunresectable, 
as 
determined 
by 
a 
pancreaticobiliary surgeon as part of a multidisciplinary review at the investigative 
site, including multi-phasic CT demonstrating: 
i. Greater than 180 degree tumor involvement of the superior mesenteric 
artery 
ii. Greater than 180 degree tumor involvement of the celiac axis, including 
major branches of the celiac axis that render it unresectable (e.g. common 
hepatic artery). 
iii. Tumor involvement of the first branch of the SMA that is not surgically 
reconstructible 
iv. Long segment involvement of the superior mesenteric vein/portal vein or 
hepatic artery that is not surgically reconstructible 
b. Potentially resectable, but patient is judged not a candidate for surgery, after 
multidisciplinary review at the investigative site; 
c. Potentially resectable, but the patients refuses surgery and is considered an 
acceptable candidate for SBRT after multidisciplinary review at the investigative 
site; 
d. “Borderline” resectable, as determined by multidisciplinary review, including 
absence of distant lymphadenopathy and the primary tumor characterized by one 
of more of the following: 
i. A tumor-vessel interface (TVI) with the mesenteric vein (SMV) or portal vein 
(PV) measuring ≥180° of the circumference of either vein’s wall or short-
segment occlusion of either vein with a normal vein above or  below the 
obstruction amenable to reconstruction;  
ii. Any TVI with the common hepatic artery (CHA) with normal artery proximal 
and distal to the TVI amenable to reconstruction; 
iii. A TVI with the superior mesenteric artery (SMA) measuring <180° of the 
circumference of the vessel wall 
3. 
Primary tumor size and limited bowel involvement by tumor must be judged acceptable for 
SBRT at the discretion of the treating investigator. 
4. 
No evidence of distant metastasis either prior to or after induction chemotherapy. 


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5. 
Completion of medically indicated first-line chemotherapy, as determined by the treating 
investigator 
6. 
Patient must have metal stent in place if duodenal stent is required. If patient has plastic 
stent, this must be replaced prior to radiation. 
7. 
Ability to understand and follow the breathing instructions involved in the respiratory gating 
procedure or to tolerate compression sufficient to reduce fiducial motion to ≤ 5mm.  
8. 
Age 18 years or older 
9. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (0, 1 or 2) 
10. Adequate hematologic function as indicated by 
a. Absolute neutrophil counts (ANC) ≥ 1,500/mm3 
b. Hemoglobin (Hgb) ≥ 8.0 g/dL 
c. Platelet count ≥ 75,000/mm3 
11. 
Adequate liver function as indicated by: 
a. Total bilirubin ≤ 1.5 x upper-normal limit (ULN) 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN 
12. 
Properly obtained written informed consent   
Exclusion Criteria:  
1. 
Prior radiation therapy to the abdomen that would overlap with treatment field 
2. 
Prior surgical resection of pancreatic tumor  
3. 
Receiving any approved or investigational anti-cancer agent other than those required for 
this study 
4. 
Uncontrolled or active gastric or duodenal ulcer disease within 30 days of dosing 
5. 
Visible invasion of tumor into the lumen of the bowel or stomach on endoscopy (Note: 
Radiological infiltration into bowel is allowed, unless deemed clinically unsafe.) 
6. 
Residual or ongoing ≥ Grade 3 non-hematologic toxicity from chemotherapy 
7. 
Contraindication to IV contrast 
8. 
Concurrent participation in another interventional clinical trial or use of another 
investigational agent within 30 days of study consent (Note: Patients who are participating 
in non-interventional clinical trials (E.g., QOL, imaging, observational, follow-up studies, etc) 
are eligible, regardless of timing of participation) 
9. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, renal failure, cardiac 
arrhythmia, stroke, or psychiatric illness that would limit compliance with treatment 


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10. 
Second primary malignancy within the last 5 years, unless treated definitively and/or low 
risk in the judgment of the treating investigator  (e.g non-melanomotous skin cancers, low 
risk prostate cancer, etc) 
11. 
Known history of HIV or active hepatitis B/C (patients who have been vaccinated for 
hepatitis B and do not have a history of infection are eligible) 
12. 
Female patients who are pregnant or breastfeeding 
13. 
Women of child-bearing potential who are unwilling or unable to use an acceptable method 
of birth control to avoid pregnancy for the entire study period and for 30 days after the last 
dose of GC4419. Acceptable methods include, but are not limited to, barrier methods, IUD, 
and birth control pills. This includes any woman who has experienced menarche but has 
not undergone successful surgical sterilization or is not postmenopausal (defined as 
amenorrhea for at least 12 consecutive months, or women on hormone replacement therapy 
with serum FSH levels greater than 35 mIU/mL. A negative urine or serum pregnancy test 
must be obtained within 14 days prior to the start of study therapy in all women of child-
bearing potential.  
14. 
Male subjects who are unwilling or unable to use an acceptable method of birth control 
(barrier method) to avoid pregnancy for the entire study period and for up to 90 days after 
the last dose of GC4419/placebo are excluded. 
15. 
Requirement for concurrent treatment with nitrates or other drugs that may, in the judgment 
of the treating investigator, create a risk for a precipitous decrease in blood pressure. 
16. 
Medical history that includes any condition, or requires the use of concomitant medications 
which, in the investigator’s judgment, are associated with or create a risk of increased 
carotid sinus sensitivity, symptomatic bradycardia, or syncopal episodes. 
Investigational product, dosage and mode of administration:  
GC4419 is formulated as a clear solution at a concentration of 9 mg/mL in 26 mM sodium 
bicarbonate-buffered 0.9 wt. % saline for parenteral administration (drug product).  GC4419 will 
be presented in single-use amber vials.  Vials will be filled with 11 mL of GC4419, of which 10 mL 
be added into a 240 mL bag of normal saline, for daily IV administration over 60 minutes.  GC4419 
will be administered Monday through Friday on days when SBRT is administered. On days when 
fractions of SBRT are administered, the completion of infusion of GC4419 or placebo will be within 
180 minutes prior to that day’s SBRT.   
Duration of treatment:  
Five doses will be administered with 5 daily fractions of SBRT, given Monday through Friday 
whenever possible.  On days when SBRT is administered, GC4419 will be administered before 
the SBRT fraction, with a goal of delivering the SBRT fraction within 180 minutes from the end of 
the GC4419 infusion. 
Reference therapy, dosage and mode of administration:  
Matching placebo will be prepared by respective investigational site’s  pharmacy, who will be 
unblinded; the rest of the clinic staff will be blinded.  For those subjects randomized to the placebo 
arm, the treatment assignment will be prepared by the unblinded investigational pharmacy as 
100% normal saline at 250mL, for IV administration  over 60 minutes. Placebo will be administered 


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Monday through Friday on weeks when SBRT is administered. On days when fractions of SBRT 
are administered, placebo will be administered  prior to that day’s SBRT. 
Assessment Criteria: 
Toxicity:  
• Unacceptable toxicity of SBRT will be defined as related, CTCAE grade 3 or 4 gastro-
intestinal (GI) toxicity or death, occurring within 90 days from the start of therapy. 
Efficacy: 
• Radiographic stable disease (SD) or better based on modified RECIST criteria for the primary 
target, compared to baseline imaging of the same type, as evaluated at day 90 from the start 
of therapy. 
Safety: 
National Cancer Institute - Common Terminology Criteria for Adverse Events, version 4.03 up to 
1 year post-SBRT Patient-Reported Outcomes:   
• Linear Analogue Self Assessment (LASA) 
• NCI Patient Reported Outcomes CTCAE (PRO-CTCAE) version 1.0 
Safety Monitoring and Toxicity Management: 
1. Adverse/Serious Adverse Event assessments per CTCAE version 4.03  
2. Safety monitoring will be built into the model and ongoing LO-ET analysis using a pre-
specified trade-off between efficacy and toxicity.  
3. Toxicity requiring 25% GC4419 or PBO dose reduction: 
• 
Grade 2 or greater hypotension within 2 hours after the start of GC4419/placebo infusion 
• 
GC4419 Grade 3 or greater nausea or vomiting   
Two dose reductions of GC4419/placebo for toxicity will be permitted per patient. Patients unable 
to tolerate GC4419/placebo after two dose reductions must discontinue treatment with the study 
drug GC4419 but may continue with SBRT at the discretion of the treating investigator. 
For other toxicities (including those attributable to SBRT): management per institutional and ASCO 
guidelines and investigator judgment.   
Concomitant Medications/Treatments: 
Investigators may prescribe any concomitant medication or supportive therapy deemed necessary 
to provide adequate supportive care including antiemetics, systemic antibiotics, hydration to 
prevent renal damage, with the following exceptions:  
• 
Other concurrent chemotherapy or investigational agent during the period when SBRT is 
being given 
• 
Nitrates, phosphodiesterase type 5 (PDE 5) inhibitors (e.g., sildanefil, tadalafil, or similar 
agents) or other drugs that in the judgment of the treating investigator could create a risk of 


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a precipitous decrease in blood pressure are prohibited until at least 24 hours after the last 
dose of GC4419 
• 
Pyridostigmine or other drugs that in the judgment of the treating investigator could create 
a risk of increased carotid sinus sensitivity, symptomatic bradycardia, or syncopal episodes.  
• 
Other biologic response modifiers – except systemic hematopoietic growth factors for the 
management of anemia or myelosuppression  
• 
Concurrent approved or investigational anti-cancer therapy (e.g., chemotherapy, 
immunotherapy, targeted therapy, hormone and biologic therapy) other than the Protocol 
regimen  
• 
Other investigational agents 
Anti-emetic and anti-diarrheal prophylaxis and hematopoietic growth factor use are permitted per 
ASCO guidelines.   
Statistical methods: 
A maximum of 2x24 = 48 patients will be randomized between two subgroups. Patients in Arm A 
will receive GC4419 in combination with their assigned RT dose, and patients in Arm B will receive 
their assigned RT dose and placebo. Randomization will be restricted so that the sample size 
within each subgroup is exactly 24 patients. The restricted randomization sequence will be 
constructed prior to trial initiation, and applied by the Statistical Analyst overseeing the trial 
treatment and RT dose assignments.  An overall accrual rate of approximately 3-4 patients per 
month is anticipated, which will give approximately 1.5-2 patients per month in each subgroup. 
Simulations demonstrate a trial length of 6 months (early stopping criteria for excess toxicity) to 
12-16 months (run to trial completion) with model stability. Full design operating characteristics 
are available in subsection 13.8. The same adaptive dose-finding design will be used in each of 
the two subgroups.  Within each subgroup, up to 24 patients will be treated in 8 cohorts of size 3 
each.  The first cohort will be treated at dose level 1, all successive doses will be chosen by the 
LO-ET method to maximize the posterior Efficacy-Toxicity trade-off, and an untried dose level 
(dose level 2) may not be skipped when escalating initially.   
 
The sponsor was unblinded to treatment assignment for overall study monitoring and safety 
review. One unblinded interim descriptive efficacy analysis will be performed for study design 
planning on the first 19 subjects. To facilitate future study design planning with investigators, 
interim efficacy results on those first 19 subjects will be provided to participating 
investigators.   Subsequent to the single completed interim analysis by the sponsor, no unblinded 
efficacy analysis will be performed until the final statistical analysis. Investigators and supporting 
staff will remain blinded to randomized treatment assignments for patients 20-48, with only 
unblinded staff being site pharmacists, MDACC statisticians, and limited sponsor staff relative to 
study management and routine safety oversight.  
 
 
 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE .................................................................................................................. 2 
SUMMARY SYNOPSIS ................................................................................................................................ 3 
TABLE OF CONTENTS ................................................................................................................................ 9 
1.0 
BACKGROUND ............................................................................................................................. 12 
1.1 
Background and Rationale ............................................................................................................ 12 
1.2 
Rationale for SBRT and Dose Escalation ...................................................................................... 12 
2.0 
PRIMARY OBJECTIVES ............................................................................................................... 27 
2.1 
Rationale for Primary Objective ..................................................................................................... 27 
2.2 
Primary Objective ........................................................................................................................... 27 
2.3 
Secondary Objectives .................................................................................................................... 27 
2.4 
Exploratory and Correlative Science Objectives ........................................................................... 27 
3.0 
INVESTIGATIONAL PLAN ............................................................................................................ 28 
3.1 
Study Design .................................................................................................................................. 28 
3.2 
Detailed Treatment Plan ................................................................................................................ 28 
3.3 
Rationale for GC4419 Dose Selection ........................................................................................... 28 
3.4 
Randomization and Blinding .......................................................................................................... 29 
4.0 
PATIENT SELECTION .................................................................................................................. 31 
4.1 
Inclusion Criteria ............................................................................................................................ 31 
4.2 
Exclusion Criteria: .......................................................................................................................... 32 
4.3 
Screen Failure and Randomization Failure ................................................................................... 33 
4.4 
Withdrawal from Study Criteria ...................................................................................................... 33 
4.5 
Treatment Compliance................................................................................................................... 34 
4.6 
Central Review and Study Entry .................................................................................................... 34 
4.7 
Study Closure ................................................................................................................................ 35 
5.0 
STUDY CALENDAR ...................................................................................................................... 36 
6.0 
RADIATION DELIVERY................................................................................................................. 38 
6.1 
Radiotherapy Technical Factors .................................................................................................... 38 
6.2 
Target Delineation .......................................................................................................................... 39 
6.3 
Treatment Planning Guidelines and Dose Constraints .................................................................. 40 
6.4 
Treatment Schedule ....................................................................................................................... 41 
6.5 
Treatment Delivery ......................................................................................................................... 41 
6.6 
Compliance Criteria ....................................................................................................................... 42 
6.7 
Definitions of Radiation related Adverse Events ........................................................................... 42 
6.8 
Rapid Review and Radiation Therapy Quality Assurance ............................................................. 43 


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7.0 
STUDY DRUG MATERIALS .......................................................................................................... 44 
7.1 
Description of Study Drug GC4419 ............................................................................................... 44 
7.2 
Clinical Safety Data with GC4419 .................................................................................................. 44 
7.3 
Study Drug Packaging and Labeling ............................................................................................. 45 
7.4 
GC4419 .......................................................................................................................................... 45 
7.5 
Placebo .......................................................................................................................................... 45 
7.6 
Study Drug Storage ....................................................................................................................... 45 
7.7 
Study Drug Preparation GC4419 and Placebo .............................................................................. 45 
7.8 
Study Drug Administration ............................................................................................................. 46 
7.9 
Study Drug Accountability .............................................................................................................. 47 
7.10 
Study Drug Handling and Disposal ................................................................................................ 47 
8.0 
DOSE AND TREATMENT MODIFICATIONS ............................................................................... 48 
8.1 
Ancillary therapy, concomitant medications and supportive care .................................................. 48 
8.2 
Dose Delays and Dose Modifications ............................................................................................ 48 
9.0 
ADVERSE EVENTS ...................................................................................................................... 49 
9.1 
Definitions ...................................................................................................................................... 49 
9.2 
Serious Adverse Event Reporting .................................................................................................. 50 
9.3 
Routine Adverse Event Reporting ................................................................................................. 50 
9.4 
Grading and Cause Assignment of Adverse Events ..................................................................... 50 
10.0 
ASSESSMENTS ............................................................................................................................ 52 
10.1 
Schedule of Evaluations ................................................................................................................ 52 
10.2 
Safety Assessments ...................................................................................................................... 52 
10.3 
Clinical Assessments ..................................................................................................................... 52 
10.4 
Laboratory Assessments ............................................................................................................... 52 
10.5 
Endoscopic Assessment ................................................................................................................ 52 
10.6 
Radiographic Assessments and Definition of Radiographic Treatment Response ....................... 53 
10.7 
Surgical and Pathologic Determination of Treatment Response ................................................... 54 
10.8 
Patient Reported Outcomes using PRO-CTCAE and LASA ......................................................... 55 
11.0 
END OF TREATMENT/INTERVENTION ...................................................................................... 57 
11.1 
Duration of Treatment .................................................................................................................... 57 
11.2 
Managing ineligible patients and registered patients who never receive protocol intervention..... 57 
11.3 
Extraordinary Medical Circumstances ........................................................................................... 57 
12.0 
STATISTICAL CONSIDERATIONS ............................................................................................... 58 
12.1 
Study Primary Endpoint ................................................................................................................. 58 
12.2 
Prior Probabilities ........................................................................................................................... 58 


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12.3 
Randomization and Sample Size ................................................................................................... 58 
12.4 
Phase I-II Dose Finding Design ..................................................................................................... 59 
12.5 
Maximum Sub-sample Size and Cohort Size ................................................................................ 59 
12.6 
Dose Acceptability ......................................................................................................................... 59 
12.7 
Efficacy-Toxicity Trade-Off Contours and Priors ........................................................................... 59 
12.8 
Design Operating Characteristics .................................................................................................. 60 
12.9 
Implementation .............................................................................................................................. 62 
13.0 
CORRELATIVE STUDIES ............................................................................................................. 64 
13.1 
Imaging Correlative Studies ........................................................................................................... 64 
13.2 
Pathologic and Biomarker Correlative Studies .............................................................................. 64 
14.0 
GENERAL REGULATORY CONSIDERATIONS .......................................................................... 70 
14.1 
Institutional Regulatory Approval ................................................................................................... 70 
14.2 
Informed Consent .......................................................................................................................... 70 
14.3 
Publication ..................................................................................................................................... 70 
14.4 
Data Analysis ................................................................................................................................. 70 
14.5 
Study Monitoring ............................................................................................................................ 70 
15.0 
REFERENCES .............................................................................................................................. 71 
16.0 
SUMMARY OF CHANGES ............................................................................................................ 76 
17.0 
APPENDIX 1: PRO AND LASA ..................................................................................................... 78 


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1.0 BACKGROUND 
1.1 
Background and Rationale 
Pancreatic adenocarcinoma (PAC) remains the fourth leading cause of cancer-related death 
in the United States, with a 5-year overall survival in the range of 5%,1 despite improvements in 
systemic chemotherapy, as well as advances in radiation and surgical techniques.  Surgical 
resection remains the only reasonable option for cure, given inability to reach ablative doses to local 
tumor with radiation2. Locally advanced pancreatic cancers (LAPC) are particularly difficult to treat 
since they only exhibit a modest response to chemotherapy3 and are, by definition, not immediately 
resectable. BRPC and LAPC account for approximately 30% of newly diagnosed PAC and, if not 
resected, a high proportion of patients experience local progression and/or die with a significant 
burden of local disease, and may experience significant amount of morbidity and mortality from 
local progression.4-6 As systemic therapies advance, including the advent of nab-paclitaxel and 
FOLFIRINOX, the burden of local disease will only increase3. This pattern of regional failure in 
LAPC suggests that local control may be critical to reducing the symptomatic burden of this disease.  
Recent data have suggested that while modest doses of chemoradiation do not improve survival 
compared to chemotherapy alone, local control is significantly improved7,8.  
1.2 
Rationale for SBRT and Dose Escalation 
1.2.1 Rationale for SBRT 
Pancreatic cancer remains a disease with a dismal 5-year survival rate of less than 5% and 
is the fourth leading cause of cancer death in the United States. In particular, locally advanced 
pancreatic cancer presents an even greater challenge, since these tumors cannot be surgically 
resected upfront and thus can only be treated with a combination of chemotherapy and radiation. 
Pancreatic cancer commonly occurs in the head of the pancreas, which abuts a portion of the small 
bowel called the duodenum.  Progression of the primary tumor is a significant source of morbidity 
and mortality from pancreatic cancer5, local control will be required for any curative treatments for 
localized disease.  Pancreatic cancer can progress locally and/ or systemically. Therefore, the need 
for a combination of systemic and local treatments is essential in the management of this disease. 
Recent data has shown that up to 30% of pancreatic cancer patients die from progression of disease 
locally5, supporting the need for more aggressive local treatment.  
Definitive chemoradiation to tumors within the head of the pancreas can be technically and 
anatomically challenging due to the surrounding organs at risk, particularly the duodenum. 
Pancreatic cancer requires radiation doses in excess of 60 Gy to achieve local control, but the 
nearby duodenum can only tolerate a maximum of 50 Gy, which limits the dose that can be safely 
administered to an ineffective 50 Gy.  Consequently, recent trials for conventionally fractionated 
and hypofractionated chemoradiation treatments have been shuttered due to poor accrual, and due 
in part to its perceived lack of efficacy, thanks to recently published trials demonstrating that 
conventional chemoradiation with 3D conformal therapy and capecitabine is no different than 
chemo alone, despite a statistically significant improvement in local control9. 
Compared to standard radiotherapy, SBRT can deliver higher, more conformal radiation 
doses to a smaller volume over a course of 1-5 treatments with the use of image guidance. A shorter 


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course of treatment allows for more patient convenience, better cost-effective treatment and also 
earlier resumption of systemic therapy. Studies have shown that patients receiving SBRT with 
gemcitabine-based chemotherapy have also reported better short-term pain control and quality of 
life10,11. In addition, a short course of SBRT has been shown to cause less immunosuppression and 
lymphopenia when compared to conventional radiation therapy given over 5-6 weeks12. SBRT 
coupled with immunotherapy has also been shown to potentiate both local and systemic responses 
in melanoma and renal cell carcinoma13.    
Intriguingly, SBRT may be able to elicit unique radiobiological responses from pancreatic 
tumors. A recent phase II multi-institutional study involving Hopkins, Memorial Sloan Kettering 
Cancer Center and Stanford14 demonstrated efficacy and acceptable toxicity levels when adding 
SBRT (6.6 Gy x 5) to full-dose gemcitabine in patients with LAPC15.   Emory University16 recently 
published a dose escalation SBRT + FOLFIRINOX study, which increased dose to 12 Gy x 3 
fractions with acceptable toxicity and efficacy. Unfortunately, at its current doses of 5-7 Gy x 5, only 
palliation can be achieved with no improvements in mean survival rate. Additional dose escalation 
has not been tried since initial studies using higher doses such as 25 Gy x 1 had resulted in 
unacceptable duodenal toxicity2.  Currently, with adequate protection of the surrounding normal 
tissues, and/or selective radiosensitization of the pancreatic tumor, the therapeutic ratio of SBRT 
could be significantly improved. 
The optimal sequencing and doses of chemotherapy and SBRT are not yet known.  
However, most patients with locally advanced disease will now receive newer and more powerful 
chemotherapy combinations that were extrapolated from the metastatic setting, such as 
FOLFIRINOX (5-fluorouracil, folinic acid, irinotecan, and oxaliplatin), or gemcitabine-abraxane, and 
may be even more effective at reducing tumor burden and improving resectability.  If patients do 
not metastasize after induction chemotherapy, they could be considered for consolidative radiation 
treatments that would either convert them to a resectable state or maintain sufficient local control 
for a prolonged period of time. SBRT is effective and well-tolerated, but is not curative because its 
biologically effective dose is too low.  Thus, the primary goal of this combined phase I/II study would 
be to determine the maximum tolerated dose (MTD) of SBRT in combination with GC4419, a 
dismutase mimetic (DM), and describe efficacy endpoints consistent or better than historical 
standards in preparation for a phase III trial. 
1.2.2 Rationale for Dose Escalation with SBRT 
Standard radiation has failed to produce an overall survival benefit in the LAPC patient 
population7,8, but may provide modest local control and increase time off systemic chemotherapy. 
Standard dose radiation (SDR) for pancreatic cancer is often limited to 50.4Gy in 28 fractions, as 
the dose is constrained by radiosensitive organs in close proximity to the pancreas including the 
duodenum, jejunum and stomach. Radiation dose escalation through more conformal treatment 
techniques, such as intensity modulated radiation therapy (IMRT), stereotactic body radiation 
therapy (SBRT) or proton therapy, has overcome this threshold to improve local control and overall 
survival in other tumor sites including cholangiocarcinoma,17 prostate18 and head and neck 
cancers.19 
Evidence exists to suggest that achieving an ablative biologically equivalent doses (BED) 
may significantly improve both progression free survival (PFS) and overall survival (OS). At 
MDACC, BED doses up to twice as high as SDR have been delivered using intensity modulated 


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radiotherapy (IMRT) in a hypofractionated setting in an attempt to improve local control.20,21  The 
results of this technique were recently reported by Krishnan et al,21 demonstrating preliminary 
evidence that radiation dose escalation during consolidative chemoradiation therapy improves both 
overall survival and locoregional recurrence free survival in carefully selected patients. Toxicity data 
from Colbert et al [In press]68 suggests this approach has both long term and short term safety. 
Although hypofractionated escalated dose IMRT (EDR) is appealing, it is still not ideal for a 
patient population in whom time off systemic therapy and patient convenience is of the essence. 
EDR is still delivered over 3-4 weeks, and is inconvenient for both patients and medical oncologists 
who wish to administer other systemic therapies. As the technical capabilities of radiation rapidly 
advance, stereotactic body radiation therapy (SBRT) has become increasingly popular due to its 
potential ability to deliver increasing BED with decreased toxicity over three or five days, allowing 
less time off systemic therapy.  New techniques in advanced motion management, on board 
imaging and tumor visualization allow the potential for higher dose escalation than previously 
thought possible. Still, few institutions have tested the bounds of dose escalation in SBRT.  
1.2.3 Rationale for SBRT Dose Escalation in Locally Advanced PAC 
The recently closed LAP-07 randomized trial attempted to define the role of radiation therapy 
in LAPC by randomizing patients to chemotherapy alone versus chemoradiation with a standard 54 
Gy after gemcitabine-based induction chemotherapy. Although the overall survival endpoint was 
not significantly different between the two arms, chemoradiotherapy was associated with increased 
chemotherapy-free interval, decreased local progression (32% vs 46%, P = .03) and no increase in 
grade 3 to 4 toxicity, except for nausea7. Local progression is a very significant endpoint in this 
patient population, given the heavy burden of local disease. Autopsy studies have shown that as 
high as 30% of PAC patients die of local disease alone5, indicating local progression may also 
directly affect overall survival.  
Still, despite a local control advantage and although we suspect an overall survival 
advantage would exist with higher BED radiation than the LAP-07 trial, clinicians are hard pressed 
to hold systemic therapy and ask patients to undergo five weeks of standard chemoradiation, given 
the lack of prospective data confirming its effectiveness. With advances in radiation delivery 
techniques, SBRT now offers an exciting opportunity to provide similarly ablative BED in a shorter 
one week timespan. Most previously studies conducted in earlier eras have used a BED that is 
known to be non-ablative, and similar to previous conventionally fractionated courses, given 
concerns about toxicity and lack of dose escalation evidence. A properly executed dose escalation 
study would set the stage for a potential prospective study in this patient population with an ablative 
dose of radiation. 
1.2.4 Toxicity Rates in SBRT for PAC  
Previous studies in SBRT for PAC demonstrate that SBRT has at least comparable efficacy 
to standard fractionated radiation (local control ranging from 75% to 90%22,23) with decreased 
toxicity24. The potential toxicities are similar to those potentially observed with standard fractionated 
radiation, and are related to proximity of tumor and dose to duodenum, stomach and other small 
bowel. The majority of the severe toxicities previously noted occurred using single fraction SBRT in 
the era before modern image guidance and tumor localization, but nevertheless instilled a fear of 
utilizing high dose SBRT25. Data for 3 fraction and 5 fraction SBRT demonstrates a favorable toxicity 


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profile. The largest available population of these BRPC and LAPC patients treated with SBRT 
comes from a recent meta analysis by Petrelli et al22, which pooled 19 studies with a total of 1009 
patients. In this study, pooled 1-year OS was 51.6%, local control rate was 72.3% and the 
occurrence of severe adverse events (grade 3-4 toxicity) exceeding 10% in only 3/19 studies, even 
for the highest doses studied and those studies performed without fiducials or image guidance. In 
all studies, the rate of late toxicity ranged from 0-11%, with a rate of 0% in 6/19 studies. Acute 
toxicities noted included anorexia, bleeding, duodenitis, gastritis, diarrhea, gastrointestinal ulcers, 
abdominal pain, nausea, and abdominal pain. Late toxicities included ulcer, fistula, hemorrhage and 
GI obstruction. BED in these studies ranged from 37.5 Gy to 112.5 Gy. The study which utilized 
112.5 Gy26 by Hoyer et al prescribed 15 Gy in 3 fractions. 66% (8/12) of patients improved in 
performance status at 90 day post treatment, exhibited decreased nausea and pain scores, and 
required less analgesic medications. Four patients suffered severe mucositis or ulceration of the 
stomach and duodenum and one patient had a non-fatal ulcer perforation of the stomach. This 
study exhibits a multitude of problems, including the fact that the prescription dose was given to the 
entire PTV volume, without consideration of nearby adjacent organs at risk (OAR’s). Our novel 
treatment delivery technique (in section 1.2.5) delivers high dose radiation to the tumor, while 
respecting nearby OAR’s. Additionally, we expect the delivery of this BED in 5 fractions to be safer 
than delivery in 3 fractions as it allows more margin of error for potential OAR shift between 
treatments. 
1.2.5 Novel SBRT Planning Technique 
Previous radiation therapy planning techniques for SBRT involved contouring a gross tumor 
volume (GTV) and creating a uniform PTV with an expansion ranging from 3mm-7mm. The dose 
was prescribed to the PTV, although more recent studies may include an escalated dose to the 
GTV simultaneously, in what is described as a simultaneous integrated boost technique (SIB). This 
allows a nested dose delivery, hypothetically protecting normal structures from a higher dose they 
may be unable to tolerate. Unfortunately, this technique does not take into consideration the location 
of the OAR that is to be avoided. Often, these plans are heterogeneous, and heterogeneity up to 
10% in either direction is considered acceptable. The radiation oncologist upon evaluating the plan, 
can take into consideration whether these “hot spots” are in tumor or in OAR and adjust accordingly, 
but this discrimination is subjective and prone to error. The lead study site, MDACC, has developed 
a novel technique using multiple SIB volumes and a multiple OAR avoidance volumes with 3-5mm 
margins, known as planning risk volumes (PRV’s). In this method, the PRV is subtracted from the 
PTV volumes, with planning algorithms designed to ensure that normal structures receive no high 
dose volume. OAR volumes receive only the dose level known to be safe. Using this technique, 
MDACC has treated >200 patients with BRPC, LAPC and cholangiocarcinoma safely and with 
minimal toxicity17,20,21,27. 
This novel MDACC technique has not been widely utilized in SBRT to our knowledge. 
Previous studies have provided an SIB to the tumor-vessel interface (TVI) where tumor meets SMA 
and the highest risk for a positive margin resection exists, and have provided SIB to the GTV. We 
proposed taking advantage of this technique to boost the TVI and center of tumor, while protecting 
OAR’s better than previous studies have. We are currently performing dosimetric studies to better 
understand its potential uses and limitations in SBRT, but we feel it may increase safety by 
decreasing the subjective nature of plan evaluation and allowing better delineation of dose 


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contraints and PTV dose levels. Figure 1a illustrates a typical SBRT radiation delivery with two dose 
levels, GTV and a symmetric PTV expansion. Figure 1b demonstrates our novel planning technique 
adapted from institutional experience in escalated dose IMRT (EDR) demonstrating avoidance 
structures which take priority over target volumes, thus limiting OAR dose to safe volumes while 
allowing escalation to tumor and to TVI. 
1.2.6 Selected SBRT Dose Levels  
The dose levels selected for this study (table 1) were designed with previous SBRT studies 
and known dose limitations to OAR’s in mind. The PTV1 dose level is identical for all three dose 
levels, 6.6 Gy x 5 fractions. At this dose, previous data demonstrates that duodenal toxicity is less 
than 2% and treatment is uniformly safe and well-tolerated. The PTV1 volume covers the tumor 
contour (iGTV) including the high risk of recurrence intravascular space (TVI) adapted to the 4D 
motion and a 3mm margin.The proposed PTV2 volume is PTV1 but with subtraction of the bowel 
contours with their 5mm  motion margin (PRV) with the PRV given priority, ensuring that the PRV 
will receive none of this high dose volume. At the dose levels 2 and 3, the PTV2 is considered to 
be an ablative BED. Dose level 1 has been safely studied, even in a 3 fraction regimen14,16.   
 
Figure 1a                                                             Figure 1b 
 
Two SBRT dose escalation trials are currently underway, one at University of Colorado 
(NCT02873598) which started in November 2016 and the second from Memorial Sloan Kettering 
Cancer Center (NCT02643498), started in December 2015. Both trials are utilizing a standard 3+3 
dose escalation design with evaluation at 90 days as part of a Phase I trial.  For both trials, dose 
escalation starts with 9 Gy x 3 fractions and increases by 1 Gy per fraction at each dose level. Dose 
level 2 is 10 Gy x 3 fractions and dose level 3 is 11 Gy x 3 fractions. This BED of the highest dose 
level on these trials is still lower than our highest dose level target, and due to the basic design, will 
not provide any phase II data at its conclusion. Additionally, with the addition of a novel 
radioprotectant we anticipate improved toxicity and higher achievable dose levels than trials with 
radiation alone. 
 
 
 


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Table 1. Proposed dose levels according to PTV1  and PTV2 Doses 
Dose Level 
Total Dose 
Per Fraction 
Tumor BED (a/B = 10) 
1 
PTV1 
PTV2 
 
33 Gy 
50 Gy 
 
6.6 Gy 
10 Gy 
 
55 Gy 
100 Gy 
2 
PTV1 
PTV2 
 
33 Gy 
55 Gy 
 
6.6 Gy 
11 Gy 
 
55 Gy 
115.5 Gy 
3 
PTV1 
PTV2 
 
33 Gy 
60 Gy 
 
6.6 Gy 
12 Gy 
 
55 Gy 
132 Gy 
 
1.2.7  GC4119 as a Radioprotectant Agent in PAC 
GC4419 is a small-molecule mimetic of the human superoxide dismutase enzymes (SOD), 
or dismutase mimetic.  GC4419 is being investigated in clinical trials for the reduction of the 
incidence and severity of severe oral mucositis (SOM) induced by radiation therapy (RT), with or 
without systemic therapy under United States Food and Drug Administration (FDA) IND 111,539. 
In normal biology, superoxide (O2•-) is generated at moderate levels as a by-product of 
mitochondrial cellular respiration. It is also produced by activation or uncoupling of a number of 
enzymes, including NADPH (nicotinamide adenine dinucleotide phosphate) oxidases.  Particularly 
large amounts are also generated directly or indirectly by external environmental stresses such as 
radiation and chemical toxins, including some chemotherapies.  In all studied species, O2•- levels 
are normally constrained to an acceptable level by SOD enzymes. These SODs are 
oxidoreductases that dismutate O2•- into molecular oxygen (O2) and hydrogen peroxide (H2O2). 
There are three vertebrate SODs: cytoplasmic (“Cu/Zn SOD”), mitochondrial (“MnSOD2”), and 
extracellular (“EcSOD3”) responsible for dismutation of superoxide present in their respective 
compartments.  Additional systems then further process the resulting H2O2, neutralizing it, or in the 
case of phagocytic activity using it to manage threats such as bacterial infection.  
Since O2•- and certain daughter products are extremely reactive with biological molecules, 
excess O2•- can be quite toxic to normal cells. If O2•- production is excessive or if O2•- dismutation is 
compromised, the SOD enzymes may be insufficient and excess O2•- can overwhelm the body’s 
ability to eliminate it leading to a variety of superoxide-initiated or -mediated disease states.  
Ionizing radiation, as used to treat cancer, attacks tumor cells both by direct DNA damage, 
but perhaps more importantly by transiently increasing certain reactive oxygen species (ROS), 
particularly hydroxyl radical (HO•).  Radiation also significantly increases O2•-, another ROS, via at 
least three mechanisms: (1) radiolytic hydrolysis coincident with irradiation, (2) mitochondrial 
dysfunction and direct activation of O2•- producing enzymes acutely after radiation, and (3) O2•- 
production by inflammatory cells migrating chronically to the site of tissue injury.  Normal cells in 
the radiation field experience this burst of O2•-, but counter its damaging effects via their intact redox 


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protective enzyme systems (SODs, catalase, glutathione peroxidase, etc.) and by the activation of 
DNA repair mechanisms.  However, it appears that in radiation therapy, especially as radiation 
doses increase, these endogenous controls on O2•- are insufficient to fully protect normal cells, and 
effective cancer radiation therapy often carries major normal tissue toxicity.  Galera’s clinical and 
pre-clinical results with its dismutase mimetics suggest that the SODs are a limiting component in 
this normal tissue response, and that increasing SOD activity can protect against various radiation 
therapy toxicities (unpublished data). 
Cancer cells, on the other hand, are more tolerant of significant elevations in O2•-, and may 
in fact increase O2•- levels to support proliferative pathways and modify the tumor microenvironment.  
However, it has been known for decades that cancer cells in general are more sensitive to increases 
in H2O2 than normal cells, with high levels of H2O2 production triggering tumor cell apoptosis.  Galera 
and its collaborators have shown that the shift from an excess of O2•- generated by radiation therapy 
to elevated H2O2 driven by dismutase mimetics increases the differential toxicity of tumor over 
normal tissue28. This difference in sensitivity to these two key ROS supports the hypothesis and 
Galera’s experimental observations that dismutase mimetics can both protect normal cells from the 
toxicity of ionizing radiation while also increasing anti-tumor efficacy. 
GC4419 
(avasopasem 
manganese) 
(Manganese, 
dichloro[(4aS,13aS, 
17aS,21aS) 
1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-eicosahydro-11,7-nitrilo-
7H-dibenzo[b,h][1,4,7,1O]tetraazacycloheptadecine-KN5,KN13,KN18,KN21, 
KN22]-) is a water soluble, highly stable, low molecular weight manganese-containing macrocyclic 
ligand complex whose activity mimics that of naturally occurring SOD enzymes.  Unlike non-specific 
oxygen catalytic agents which may also dismutate O2•- as part of a generic catalysis of reactions of 
various oxygen species, GC4419 is unique in that it selectively removes O2•- anions, just as the 
native SODs do, without reacting with other reactive oxygen species, including H2O2, HO•, nitric 
oxide (•NO), and peroxynitrite (ONOO-).  Also, at physiologic conditions it acts at the extremely rapid 
catalytic rate approaching that of the SOD enzymes.  In addition, unlike native SOD, GC4419 is not 
deactivated by reaction with ONOO nor product inhibited by H2O2.   
Nonclinical data have identified Galera’s dismutase mimetics, including the next generation 
candidate in this program, GC4419 as promising anti-cancer agents, particularly in combination 
with higher doses of radiation therapy.   
In a prior Phase 1b/2a trial (see Figure 2), 46 head and neck cancer (HNC) patients received 
GC4419 administered intravenously over 60 minutes at doses up to 112 mg/day, M-F, for up to 7 
weeks in combination with standard-fractionation RT plus concurrent cisplatin, with acceptable 
toxicity.  A randomized, placebo-controlled, double blind Phase 2b trial compared 30 or 90 mg/day 
of GC4419, or placebo, plus single-agent cisplatin plus IMRT in 223 patients with locally advanced, 
non-metastatic squamous cell carcinoma of the oral cavity or oropharynx.  One third of the patients 
on this study were randomized to receive 90 mg/d, M-F, for 7 weeks, concurrent with 
chemoradiotherapy.  At that dose, the duration, incidence, and severity of severe OM were reduced 
compared to placebo (Anderson, et al, presentation at ASTRO 2018). Adverse events at the 90 mg 
dose were of similar frequency and severity as in the placebo arm, indicating that GC4419 did not 
appear to increase the toxicity of the underlying chemoradiotherapy regimen.  Therefore, the 90 mg 
dose of GC4419 is expected to be sufficiently safe for administration M-F for 1 week in combination 
with SBRT, which follows a similar short course.  Given the differences in RT schedule, and the 


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presence of cisplatin in the HNC studies (but not planned in SBRT studies described in this 
application), higher doses than 90 mg of GC4419 may also be safe and well-tolerated in 
combination with SBRT.  Accordingly, the planned GC4419 dose of 90 mg for this study provides 
an expected margin of safety67. 
 
 
1.2.8 Preclinical Data for GC4419 in improving tumor control of PAC in 
combination with SBRT 
Curbing the harmful effects of radiation in normal tissues is thus a prime objective to achieve 
better therapeutic benefits in pancreatic cancer chemoradiation.  Radiation therapy kills cells 
through both direct effects of DNA damage and through indirect effects of ionizing water and oxygen 
to create damaging radicals.  The superoxide radical is perhaps the most potent damaging agent 
of radiation, and thus it has been proposed that reduction of this species could limit radiation-
induced tissue damage29. Superoxide dismutase is an enzyme that catalyzes the reaction of 
superoxide to hydrogen peroxide, which can be easily disposed of through bioreductive pathways 
such as the glutathione system.  Tumors, however, often do not express Glutathione (GSH) 
pathway and are thus particularly susceptible to cell kill by intracellular hydrogen peroxide.  This 
differential effect on normal tissue versus tumor provides the rationale of using a superoxide 
dismutase mimetic.  GC4419 is a novel, small-molecule SOD mimetic that selectively removes 
superoxide anions, and thus radiation-induced side effect predominantly in normal tissues.  GC4419 
has been shown to markedly reduce the severity of radiation-induced oral mucositis in patients with 
head and neck cancer, and is being tested in a Phase III study.  The efficacy of GC4419 in the 
 
 
Figure 2. Phase 1b/2a Results versus Historical Comparators 


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abdomen is largely unknown.  A previous study using the enantiomer of GC4419 demonstrated 
protection against GI death from whole body irradiation30. 
 
 
To determine the role of GC4419 in protecting the gut in a clinically relevant SBRT model, 
C57BL/6 mice were treated with 10mm SBRT field with AP/PA technique targeted to the pancreas 
of C57BL/6 mice using cone beam CT on our X-RAD 225Cx machine.  Liver, stomach, duodenum 
and jejunum were also in the treatment field as confirmed by cone beam CT. Mice were immobilized 
with an isoflurane anesthesia manifold. We treated these normal mice with 8.5Gyx5 fractions given 
daily (BED10=78.6Gy).  We found that there was no overt toxicity from GC4419 and that 
administration of the drug 30 minutes prior to each SBRT dose improved survival (p=0.03). 
Prior data demonstrated dose-related protection of mice from lethal total body irradiation by 
an equipotent enantiomer of GC4419, GC440330. As noted above, initial clinical data with GC4419 
show an apparent marked reduction in severe oral mucositis induced by standard fractionation RT 
plus cisplatin given to patients with head and neck cancer, consistent with pre-clinical models of 
mucositis31.  In animal studies, Galera’s collaborator Dr. Michael Story (U. Texas/Southwestern 
[UTSW]) has also demonstrated that GC4419 both prevents (when administered before RT) and 
mitigates (when administered after RT, with prolonged treatment producing progressively greater 
mitigation) pulmonary fibrosis after a very large single focal dose (54 Gy) of radiation to normal 
mouse lung (see Figure 3), while others have demonstrated the ability of GC4419 and other analogs 
to protect liver32, bone marrow and salivary gland from radiation toxicity. 
Most relevant to combinations with SBRT, an enhancement of tumor response to 
radiotherapy has been demonstrated in multiple non-clinical models, most dramatically with higher 
fraction doses of radiotherapy.  Further, GC4419 also shows single-agent tumor growth inhibition 
in vitro with an IC50 of approximately 10 micromolar (approximately the plasma Cmax with a dose of 
90 mg in clinical studies), and in vivo in susceptible tumors.  This latter activity is likely linked to the 
significantly (5-10-fold) elevated innate O2•- levels measured by Galera and others in vitro with 
cancer cells under normal and hypoxic culture conditions, which the dismutase mimetic converts to 
increased H2O2 levels. 
 
 
Figure 3.  Mice treated with an SBRT regimen (8.5Gy x 5) to an upper 
abdominal field. A) No differences in body weight after SBRT with 
GC4419 B) Improved survival with addition of GC4419 (p=0.03) 


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In separate studies done by Dr. Story and others, GC4419 sensitized lung and HNC cell 
lines to radiation and also enhanced the growth-inhibitory effects of cisplatin, gemcitabine and 
paclitaxel.  In vivo, GC4419 did not inhibit, and may have slightly enhanced, tumor response to 
standard-fraction (2Gy per fraction) radiation.  However, if the fraction size is increased, as in SBRT, 
progressively synergistic tumor response has been observed in multiple xenograft and syngeneic 
tumor models with the addition of GC4419 resulting in 100% complete response rates at the highest 
fraction doses (see Figure 4a). 
 
 
 
As noted above, the major reason for this differential effect on cancer and normal cells is 
the differences in O2•- and H2O2 sensitivities between these cells.   Elevated O2•- may actually benefit 
tumor growth and metastasis, while in normal tissues, O2•- may enhance radiation toxicity.  This 
difference is because significant elevations in H2O2 are toxic to cancer cells but relatively benign to 
normal tissue. The addition of a dismutase mimetic (such as GC4419) more rapidly drives O2•- to 
H2O2, creating a burden that is markedly more toxic to tumor cells than normal cells.  Increasing 
radiation fraction doses drive increased O2•- generation that the dismutase mimetic converts to 
increased H2O2.  Thus, as supported by data with GC4419, the anti-tumor synergy with SBRT and 
dismutase mimetic increases with radiation fraction dose (see Figure 5). 
 
Figure 4.  Increased Anti-Tumor Efficacy and Decreased Normal Tissue 
Toxicity in SBRT Models 


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Antitumor efficacy of GC4419 in mouse SBRT models has been similar with 3, 10, or 24 
mg/kg.  This effective dose range overlaps with that seen with GC4419 in mouse and hamster 
models of normal tissue protection from radiation, such as those supporting the OM study above.  
Further, the GC4419 dosing schedules used in the mouse SBRT models experiments (daily x 5 
after a single SBRT dose) suggest that clinical dosing of the dismutase mimetic on the 5 consecutive 
weekdays of planned SBRT (daily x 5) is appropriate. 
1.2.9  Novel Adaptive Clinical Trial Design 
Pancreatic adenocarcinoma is a relatively rare disease with a short overall survival and low 
probability of efficacy for any individual novel treatment. Standard phase I/II dose escalation trials 
may require upwards of 100 patients, and have a rare chance of demonstrating the statistically 
significant benefit for which they are powered at their completion. Unlike other disease sites, a novel 
treatment that provides disease stability with minimal toxicity could be considered a victory, 
although a standard phase I/II trial would be negative. Alternatively, a higher toxicity rate may be 
acceptable if a treatment provides a significant survival or disease response benefit, yet this dose 
would never be reached in a standard phase I/II trial due to a dichotomous toxicity outcome. The 
proposed LO-ET model has been used successfully in radiation studies with similar disease 
outcomes previously, including for diffuse intrinsic pontine glioma (DIPG) and lung 
adenocarcinoma. It allows for both of these outcomes to be considered, all while requiring often 1/3 
to ½ of the patients and time required for a standard trial design, allowing more rapid testing of 
novel therapies while maintaining patient safety. 
 
Figure 5. Potentiation of Anti-tumor Efficacy Increases with Fraction 
Dose Size (Source: Galera Therapeutics, Inc) 


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Standard phase I dose escalation trials often utilize a “3 +3” design (figure 6), where 3 
patients must be treated at the first dose level and followed until completion of the evaluation period 
without toxicity before a patient may be enrolled on the next dose level. If a patient has a toxicity at 
any dose level, 3 more patients must be treated at that dose level without toxicity before escalation 
is allowed. If any of these patients has toxicity, the trial is stopped and the maximum tolerated dose 
(MTD) has been reached. The phase II portion then serves as a preliminary exploration of efficacy 
utilizing the MTD calculated in the phase I portion, where generally two groups are compared and 
the study is powered to detect a minimal clinically relevant difference between the two groups. This 
design has several limitations, including the inability to assign patients to the next level until the 
follow up period has been completed for each of the three patients, leading to longer trials requiring 
more patients. Clinically, efficacy and toxicity are often a tradeoff, i.e. higher efficacy and higher 
toxicity may go hand-in-hand where clinicians may tolerate a toxicity rate of 20% if efficacy could 
be 50% higher than current standard of care, yet in this model toxicity is a dichotomous outcome 
with no consideration of efficacy. In this case, if toxicity occurs in one patient the calculated MTD 
may not be the most efficacious dose.  
 
 
Figure 6. A standard 3 + 3 dose escalation design requires three patients treated at each 
dose level without toxicity in order to progress to next level, and evaluation of efficacy 
requires a separate phase II trial to be conducted. 
 
Figure 7. Efficacy/ Toxicity curve demonstrating efficacy and toxicity cutoffs defined by clinicians, 
where dose levels must meet maximum acceptable probability of toxicity (15%) and minimum 
acceptable probability of efficacy (75% stable or responsive disease) to continue accruing patients 


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The LO-ET model (Thall et al, 2013; Thall et al, 2012) is rooted in the Bayesian continual 
reassessment method (CRM), where probabilities of responses for each dose level are continuously 
assessed as the trial progresses and each patient is enrolled. Instead of requiring all patients to be 
enrolled and assessment done at the completion of the trial, the “person-time” contributed by each 
patient for the time they have been enrolled is encompassed in the estimation of response, in 
addition to any prior data known about the treatment. For example, if two patients have been 
enrolled and completed a 90 day observational period without toxicity, this will increase the posterior 
probability of that dose level being “safe.” The LO-ET model takes this model one step farther by 
utilizing a 2-dimensional continuous reassessment method. In this model, the ideal outcome is 
estimated as a tradeoff “curve” (Figure 7) between toxicity and efficacy dictated by clinicians, i.e. a 
20% toxicity rate is allowable if 75% disease stability/response can be achieved. As dose levels are 
evaluated with accumulating “person-time,” if at any point it appears the dose level is either too 
toxic or not efficacious, it is eliminated and no longer accrues patients. This continual reassessment 
(Figure 8) continues until either all dose levels are eliminated (all dose levels are either too toxic or 
not efficacious) or a clearly superior arm emerges that meets the prespecified efficacy and toxicity 
criteria. 
 
 
Figure 8. LO-ET Model using continual reassessment to assign dose 
levels; where dose levels are eliminated as probability of efficacy and 
toxicity is adjusted for available “person-time” for accrued patients. Each 
arm is eliminated if the probability of efficacy falls below pre-specified level 
or probability of toxicity is above prespecified level. Two possible 
outcomes include either the model assigning all patients to dose levels and 
therefore choosing a Maximum Tolerated Dose (MTD) when all other 
levels are eliminated, or all arms being deemed too toxic or inefficacious, 
thus ending the trial early and allowing patients to be diverted to other 
trials more quickly. 


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In this novel phase I/II adaptive dose escalation trial (Figure 9) we are addressing two 
primary questions: Determining the MTD of dose escalated SBRT with and without drug, and 
comparing efficacy and toxicity of SBRT with and without drug. Our trial design will enroll 48 patients 
and essentially run two parallel LO-ET models (24 patients per arm) to determine MTD nested 
within a randomized trial design. Patients are randomized to either “SBRT + Drug” or “SBRT” arms, 
after which the LO-ET models will run independently in each arm. The flexibility of this model will 
also allow the “SBRT + Drug” and “SBRT” arms to each continue to trial completion should all dose 
levels on either arm be eliminated, meaning the above mentioned potential outcomes of identifying 
an MTD or stopping the arm early due to excess toxicity or efficacy could occur in either the SBRT 
alone arm or the “Drug” arm. Efficacy threshold will be set at 75% minimum probability of 
radiographically stable disease or partial/complete response at 90 days. Maximum toxicity threshold 
will be set at 15% maximum probability of greater than grade 2 gastrointestinal toxicity at 90 days. 
Prior probabilities of efficacy and toxicity for each dose level are based on a review of all previous 
available SBRT literature as noted in section 1.2.2 and 1.2.3. Further statistical details are available 
in section 13.0. 
1.2.10  Overall Impact of the Trial 
This trial provides a unique opportunity to improve progression free survival and overall 
survival in BRPC and LAPC patients and change standard of care. Although other dose escalation 
trials are currently underway, the addition of this novel radiomodulator may allow further dose 
escalation than otherwise possible and increase the potential opportunity of long term survival in 
 
Figure 9. Schema for randomized LO-ET adaptive phase I/II dose escalation, 
with patients randomized up front, but arms running parallel dose escalation 
trials with independent dose selection 


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this group of patients. Additionally, the novel design of this trial, if successful, will develop a platform 
for rapid early phase trial completion in PAC, decreasing time to discovery of novel and potentially 
successful treatment options. Once piloted, this trial design could be quickly repeated with other 
novel drugs and radiation techniques.  


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2.0 PRIMARY OBJECTIVES 
2.1 
Rationale for Primary Objective  
The maximum tolerated dose (MTD) for SBRT using a technique that protects adjacent 
OAR’s is unknown. If dose escalation could be achieved while protecting OAR’s, we may be able 
to deliver ablative doses to the pancreatic tumor and increase local control rates and overall survival 
rates. Previous studies of radiation in LAPC and BRPC have failed due to inadequate radiation 
doses, but better prospective studies cannot be designed until the MTD is known. The novel 
radioprotectant agent, GC4419, may provide additional protection to the gastrointestinal mucosa 
and modulate the interaction of radiation with tumor tissues, thus resulting in an either higher or 
lower MTD when given in conjunction with SBRT over SBRT alone. This primary objective was 
designed to answer this question by allowing parallel MTD selection arms both with and without 
GC4419. 
2.2 
Primary Objective 
• 
To determine the MTD of SBRT when given in combination with placebo or GC4419 
2.3 
Secondary Objectives  
• 
To evaluate PFS for patients treated with SBRT given in combination with placebo or 
GC4419 
• 
To evaluate ORR including stable disease and partial/complete response for patients 
treated with SBRT given in combination with placebo or GC4419 
• 
To compare acute toxicity rate at 90 days for patients treated at the SBRT MTD in 
combination with placebo or GC4419 
• 
To evaluate late (12 month) toxicity of SBRT in combination with placebo or GC4419 
2.4 
Exploratory and Correlative Science Objectives  
• 
To evaluate tumor resectability rate after SBRT in combination with placebo or GC4419  
• 
To evaluate the R0 Resection Rate and pCR for patients who eventually undergo 
surgical resection 
• 
To evaluate patient reported outcomes for patients treated with SBRT in combination 
with placebo or GC441 
• 
To compare genomic changes based on whole exome sequencing and transcriptome 
sequencing from pre and post SBRT core biopsy samples. 
• 
To compare pathologic changes pre and post SBRT based on core biopsy samples 
• 
To compare differences in immune infiltrate pre and post SBRT using IHC for immune 
activation, exhaustion and proliferation phenotypes, deep T cell sequencing from core 
biopsy specimens and multiparametric flow cytometry (MPFC) from cytology brushings 
• 
To compare changes in circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), 
and MPFC pre and post SBRT 


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3.0 INVESTIGATIONAL PLAN 
3.1 
Study Design  
This is a parallel arm adaptive design phase I/II dose-finding study to determine the optimal 
dose of fractionated SBRT, given either with the radiomodulating agent GC4419 or placebo for 
treatment of locally advanced pancreatic cancer. Dose-finding will be done using the sequentially 
adaptive phase I/II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design [1-3]. 
3.2 
Detailed Treatment Plan  
Patients will be randomized to one of two arms in a prespecified randomization to ensure 
24 patients per arm.  
• 
Arm A: 90 mg GC4419 per day daily (60 min IV infusion), concurrent with daily fractions of 
SBRT to assigned dose level, administered Monday – Friday over one week. 
• 
Arm B: Placebo daily (60 min IV infusion), concurrent with daily fractions of SBRT to 
assigned dose level, administered Monday – Friday over one week. 
Planned radiation treatment fields will be according to guidelines in section 6.0. 
GC4419/placebo will be given intravenously in a one hour infusion. SBRT must be initiated 
as soon as possible upon completion of the GC4419/placebo infusion but no later than 180 minutes 
following the end of the GC4419/placebo infusion.  
GC4419/placebo will be given beginning on the first day of radiation and continuing daily, 
concurrent with each dose of SBRT. 
If SBRT administration is not planned on any given day due to a treatment break or 
unforeseen circumstances, GC4419/placebo should not be administered on that day.  If 
GC4419/placebo is given and SBRT is not given, GC4419/ placebo should still be administered on 
each day that SBRT is anticipated to be given. Breaks in SBRT will be determined by the patient’s 
treating physician in accordance with standard of care. Patients should resume GC4419/placebo 
administration when SBRT resumes.  On days when planned doses of both GC4419/placebo and 
SBRT are not administered (e.g., due to a holiday site closure, etc.), GC4419/placebo dosing may 
be extended along with SBRT to make up the missed dose(s). 
Anti-emetic and anti-diarrheal prophylaxis and hematopoietic growth factor use should be 
administered per ASCO guidelines.   
3.3 
Rationale for GC4419 Dose Selection  
Previous data for selection of GC4419 dose is extrapolated from 3 human studies of 
GC4419 in prevention of oral mucositis in head and neck cancers. GC4419 does not appear to 
increase the toxicity of IMRT/cisplatin.  The acute toxicity of GC4419 was acceptable at all doses 
tested, and consistent with prior expectations as described in the Investigator’s Brochure67.  A true 
(MTD) of GC4419 by the common definition used in oncology Phase 1 trials (>1/6 patients with 
DLT) was not reached in previous trials.  Although dose-limiting toxicities were suggested in two 
patients receiving 112 mg/dose, the relationship of the events to GC4419 is questionable in each 


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case.  However, the overall incidence of Grade 3 nausea at 112 mg was nominally greater than at 
lower doses.  Even if not strictly dose-limiting, nausea is highly undesirable in this patient population 
given predilection to nausea with PAC.  In addition, circumoral paresthesia, although mild, was 
dose-related.  Therefore, to provide an additional margin of safety and reduce the possibility of 
adverse events that could increase the possibility of breaking study blinding, an upper dose of 90 
mg of GC4419 was used in the now-completed randomized Phase 2b trial.  Safety was acceptable 
at this dose when administered for 30 to 35 doses over six to seven weeks with concurrent IMRT 
and cisplatin, and the 90 mg dose is being studied in a Phase 3 trial to reduce severe OM in patients 
receiving chemoradiotherapy for head and neck cancer.   
3.4 
Randomization and Blinding 
Forty eight patients will be randomized 1:1 to Arm A or Arm B. Patients in Arm A will receive 
GC4419 in combination with their assigned SBRT dose, and patients in Arm B will receive Placebo 
(PBO) with their assigned SBRT dose. The randomization will be restricted so that the sample size 
within each arm is exactly 24 patients. The restricted randomization sequence will be constructed 
prior to trial initiation, and applied by the Trial Statistical Analyst (YY, PT) overseeing the trial 
treatment and RT dose assignments.  Each patient will randomized by the MDACC biostatistical 
analyst maintained for the duration of the study.  Patients will be followed by their Patient ID (also 
known as a CORe Number), assigned by Galera prior to randomization.  Operational and system 
details will be included in the Study Plan and Pharmacy Manual. 
Investigators and patients will be blinded to GC4419 or PBO assignment, but not to SBRT 
dose level assignment.  Treatment should remain blinded until the end of the study.  Only in the 
case of an emergency, when knowledge of the investigational product is essential for the clinical 
management or welfare of the patient, may the investigator unblind a patient’s treatment 
assignment prior to the end of the Post-active Phase.  The investigator will, whenever possible, 
discuss options with the Medical Monitor, on-call physician, or appropriate Galera Therapeutics, 
Inc./CRO study personnel before unblinding.  If the blind is broken for any reason and the 
investigator is unable to contact Galera Therapeutics, Inc. prior to unblinding, the investigator will 
notify Galera Therapeutics, Inc./CRO as soon as possible following the unblinding incident without 
revealing the subject’s study treatment assignment, unless the information is important to the safety 
of patients remaining in the study.  In addition, the investigator will record the date and reason for 
revealing the blinded treatment assignment for that subject in the appropriate section of the CRFs. 
If a serious adverse event (SAE; as defined in section 9.0) is reported to Galera 
Therapeutics, Inc./CRO, Galera Therapeutics, Inc. staff may unblind the treatment assignment for 
the individual patient.  If an expedited regulatory report to one or more regulatory agencies is 
required, the report will identify the patient’s treatment assignment.  When applicable, a copy of the 
regulatory report may be sent to investigators in accordance with relevant regulations, Galera 
Therapeutics, Inc. policy, or both. 
Site pharmacies and MDACC statisticians responsible for the treatment assignment will 
remain unblinded throughout the study.  Operational precautions will be taken to ensure that 
patients 
and 
participating 
investigators 
remain 
blinded 
to 
treatment 
assignments 
(GC4419/placebo). Personnel at Galera Therapeutics may be unblinded to the treatment 
assignment for purposes of safety monitoring.  The sponsor was unblinded to treatment assignment 


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for overall study monitoring and safety review. One unblinded interim descriptive efficacy analysis 
will be performed for study design planning on the first 19 subjects. To facilitate future study design 
planning with investigators, interim efficacy results on those first 19 subjects will be provided to 
participating investigators.   Subsequent to the single completed interim analysis by the sponsor, 
no unblinded efficacy analysis will be performed until the final statistical analysis. Investigators and 
supporting staff will remain blinded to randomized treatment assignments for patients 20-48, with 
only unblinded staff being site pharmacists, MDACC statisticians, and limited sponsor staff relative 
to study management and routine safety oversight. 


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4.0 PATIENT SELECTION 
4.1 
Inclusion Criteria  
1. 
Cytologic or biopsy confirmed adenocarcinoma of the pancreatic head, body or tail 
2. 
Disease that is appropriate for SBRT by virtue of being: 
a. Locally 
advanced 
and 
technically 
unresectable, 
as 
determined 
by 
a 
pancreaticobiliary surgeon as part of a multidisciplinary review at the investigative 
site, including multi-phasic CT demonstrating: 
i. Greater than 180 degree tumor involvement of the superior mesenteric artery 
ii. Greater than 180 degree tumor involvement of the celiac axis, including 
major branches of the celiac axis that render it unresectable (e.g. common 
hepatic artery). 
iii. Tumor involvement of the first branch of the SMA that is not surgically 
reconstructible 
iv. Long segment involvement of the superior mesenteric vein/portal vein or 
hepatic artery that is not surgically reconstructible 
b. Potentially resectable, but patient is judged not a candidate for surgery, after 
multidisciplinary review at the investigative site; 
c. Potentially resectable, but the patients refuses surgery and is considered an 
acceptable candidate for SBRT after multidisciplinary review at the investigative site; 
d. “Borderline” resectable, as determined by multidisciplinary review, including 
absence of distant lymphadenopathy and the primary tumor characterized by one of 
more of the following: 
i. A tumor-vessel interface (TVI) with the mesenteric vein (SMV) or portal vein 
(PV) measuring ≥180° of the circumference of either vein’s wall or short-
segment occlusion of either vein with a normal vein above or  below the 
obstruction amenable to reconstruction;  
ii. Any TVI with the common hepatic artery (CHA) with normal artery proximal 
and distal to the TVI amenable to reconstruction; 
iii. A TVI with the superior mesenteric artery (SMA) measuring <180° of the 
circumference of the vessel wall 
3. 
Primary tumor size and limited bowel involvement by tumor must be judged acceptable for 
SBRT at the discretion of the treating investigator. 
4. 
No evidence of distant metastasis either prior to or after induction chemotherapy. 
5. 
Completion of medically indicated first-line chemotherapy, as determined by the treating 
investigator 
6. 
Patient must have metal stent in place if duodenal stent is required. If patient has plastic 
stent, this must be replaced prior to radiation. 


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7. 
Ability to understand and follow the breathing instructions involved in the respiratory gating 
procedure or to tolerate compression sufficient to reduce fiducial motion to ≤ 5mm.  
8. 
Age 18 years or older 
9. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (0, 1 or 2) 
10. Adequate hematologic function as indicated by 
i. Absolute neutrophil counts (ANC) ≥ 1,500/mm3 
ii. Hemoglobin (Hgb) ≥ 8.0 g/dL 
iii. Platelet count ≥ 75,000/mm3 
11. Adequate liver function as indicated by: 
i. Total bilirubin ≤ 1.5 x upper-normal limit (ULN) 
ii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 
x ULN 
12. Properly obtained written informed consent. 
4.2 
Exclusion Criteria:  
1. 
Prior radiation therapy to the abdomen that would overlap with treatment field 
2. 
Prior surgical resection of pancreatic tumor  
3. 
Receiving any approved or investigational anti-cancer agent other than those provided for 
in this study 
4. 
Uncontrolled or active gastric or duodenal ulcer disease within 30 days of dosing 
5. 
Visible invasion of tumor into the lumen of the bowel or stomach on endoscopy (Note: 
Radiological infiltration into bowel is allowed, unless deemed clinically unsafe.) 
6. 
Residual or ongoing ≥ Grade 3 non-hematologic toxicity from chemotherapy 
7. 
Contraindication to IV contrast 
8. 
Concurrent participation in another interventional clinical trial or use of another 
investigational agent within 30 days of study consent Note: Patients who are participating 
in non-interventional clinical trials (e.g., QOL, imaging, observational, follow-up studies, 
etc.) are eligible, regardless of the timing of participation. 
9. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, renal failure, cardiac 
arrhythmia, or psychiatric illness that would limit compliance with treatment 
10. Second primary malignancy within the last 5 years, unless treated definitively and with low 
risk of recurrence in the judgment of the treating investigator  
11. Known history of HIV or active hepatitis B/C (patients who have been vaccinated for 
hepatitis B and do not have a history of infection are eligible) 


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12. Female patients who are pregnant or breastfeeding 
13. Women of child-bearing potential who are unwilling or unable to use an acceptable method 
of birth cont avoid pregnancy for the entire study period and for 30 days after the last dose 
of GC4419. Acceptable methods include, but are not limited to, barrier methods, IUD, and 
birth control pills. This includes any woman who has experienced menarche but has not 
undergone successful surgical sterilization or is not postmenopausal (defined as 
amenorrhea for at least 12 consecutive months, or women on hormone replacement 
therapy with serum FSH levels greater than 35 mIU/mL. A negative urine or serum 
pregnancy test must be obtained within 14 days prior to the start of study therapy in all 
women of child-bearing potential.  
14. Male subjects who are unwilling or unable to use an acceptable method of birth control 
(barrier method) to avoid pregnancy for the entire study period and for up to 90 days after 
the last dose of GC4419 are excluded. 
15. Requirement for concurrent treatment with nitrates or other drugs that may, in the 
judgment of the treating investigator, create a risk for a precipitous decrease in blood 
pressure. 
16. Medical history that includes any condition, or requires the use of concomitant medications 
which, in the investigator’s judgment, are associated with or create a risk of increased 
carotid sinus sensitivity, symptomatic bradycardia, or syncopal episodes.   
4.3 
Screen Failure and Randomization Failure  
A patient is considered to be a screen failure if the patient signs the informed consent form 
but withdraws consent or is deemed ineligible prior to receiving their first dose of SBRT and 
GC4419/placebo. A patient is considered to be a randomization failure if the patient signs the 
informed consent form and is randomized to a treatment arm but withdraws consent or is deemed 
ineligible prior to receiving their first dose of SBRT and GC4419/placebo. Basic demographic and 
disease history information will be collected for randomization failures, as well of the reason the 
patient was precluded from the clinical trial. All randomization failures will be listed on the Screening, 
Enrollment, and Discontinuation Log. 
4.4 
Withdrawal from Study Criteria  
In accordance with the Declaration of Helsinki, a patient has the right to withdraw from the 
study at any time for any reason. The investigator may also, at his/her discretion, discontinue a 
patient from participating in this study at any time.  Additionally, study treatment may be 
discontinued for any of the following reasons: 
• 
Unacceptable Adverse Event 
• 
Medical requirement to administer a contra-indicated medication 
• 
Patient non-compliance 
• 
Discontinuation of the study at the request of Galera Therapeutics, Inc. 


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• 
Inability to receive consensus-approved SBRT treatment plan after simulation due to organ at 
risk constraints or inability to tolerate simulation (see section 6.1)  
The primary reason for ceasing treatment with the randomized therapy (GC4419 or placebo) 
will be clearly documented in the patient’s medical record and recorded on the appropriate case 
report form (CRF) page.  Once a patient discontinues, the patient will not be allowed to be retreated. 
If a patient discontinues randomized therapy as a result of an adverse event (AE) or serious 
adverse event (SAE), every attempt should be made to keep the patient in the study and continue 
to perform the required study-related follow-up and procedures.  If this is not possible or acceptable 
to the patient or investigator, the patient may be withdrawn from the study.  
Withdrawn subjects will not be replaced.  
4.5 
Treatment Compliance 
Compliance with GC4419/placebo dosing, including administration details (e.g., volume, 
start, stop times, etc.) should be documented in the source documents and recorded on the CRF. 
4.6 
Central Review and Study Entry 
4.6.1 Initial Eligibility Determination 
Initial eligibility determination will be at the discretion of the treating institution. Galera and 
MDACC investigators will be available for discussion regarding eligibility criteria. Determination of 
resectability status will be at the discretion of the treating institution’s multidisciplinary teams; 
however, MDACC radiologists will be available for second opinion review of imaging and 
consultation if requested. Central pathology review will not be required but will be allowed if clinically 
appropriate.  
4.6.2 Patient Registration and Randomization 
The treating site will notify Galera of new patient consent and submit a Registration Form 
for review following confirmation of eligibility. Galera will then enroll/registerthe patient and notify 
the MDACC biostatistics team. A Patient ID (previously known as a CORe number) will be assigned 
as a four digit number (two digit site – two digit subject number) and returned to the respective site 
on the Registration Form.  Following simulation, the site will send a request for randomization to 
the MDACC biostatistics team who will then complete randomization of patient to GC4419/placebo. 
MDACC biostastistics team will provide the SBRT dose level assignment to treating institution and 
MDACC investigators for purposes of SBRT treatment planning. The unblinded site investigational 
pharmacy will access the CTC system for the treatment assignment (GC4419/placebo).  Please 
reference the Pharmacy Manual and Study Plan for additional detail around safety unblinding and 
registration.  
4.6.3 SBRT Treatment Planning 
To ensure protocol compliance, the treatment plans for the first three patients treated at 
each site will be reviewed by the MDACC Study Investigators and Participating Site’s PI.  Radiation 
treatment plans will be reviewed to ensure a common understanding of the procedures listed in 


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sections 6.1 through 6.8 at each participating institution. This may be done during the trial 
periodically as needed. 
All treatment plans will be reviewed for quality assurance according to the standard review 
process at each participating institution.  
All plans will also be reviewed by the responsible physicist or his/her designee at each 
participating institution for compliance with the protocol and standard of practice at each institution. 
When performed, plan reviews for patients from one institution by the staff of another 
institution will utilize the resources of MDACC, including WebEx; and/or other feasible resources 
that comply with HIPPA. The options for sharing the SBRT plans and communication flow will be 
outlined in a separate document. 
4.7 
Study Closure  
Both the sponsor and the investigator reserve the right to terminate the study at any time.  
If all dose levels on a specific arm fail to meet prespecified toxicity/ efficacy criteria, that arm shall 
terminate and patients will continue to accrue on the remaining arm. Should all dose levels on the 
second arm also fail to meet prespecified toxicity/ efficacy criteria, the trial will terminate. Should 
this be necessary, both parties will arrange discontinuation procedures.  In terminating the study, 
Galera Therapeutics, Inc. and the investigator will assure that adequate consideration is given to 
the protection of the patients’ interests. 
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or site staff, as appropriate: 
• 
Return of all study data to Galera Therapeutics, Inc. (as applicable) 
• 
Resolution of all data queries 
• 
Accountability, reconciliation, and arrangements for all unused study drug 
• 
Review of site study records for completeness 
• 
Shipment of laboratory samples (as applicable) 
In addition, Galera Therapeutics, Inc. reserves the right to temporarily suspend or 
prematurely discontinue this study at any time for reasons including, but not limited to, safety or 
ethical issues or severe non-compliance.  If Galera Therapeutics, Inc. determines such action is 
needed, Galera Therapeutics, Inc. will discuss this with the investigators (including the reasons for 
taking such action) at that time.  When feasible, Galera Therapeutics, Inc. will provide advance 
notification to the investigators of the impending action prior to it taking effect. 
Galera Therapeutics, Inc. will promptly inform all investigators conducting the study if the 
study is suspended or terminated for safety reasons and will also inform the regulatory authorities 
of the suspension or termination of the study and the reason(s) for the action.  If required by 
applicable regulations, the investigators must inform the IRB/IEC/REB promptly and provide the 
reason for the suspension or termination.  If the study is prematurely discontinued, all study data 
must be returned to Galera Therapeutics, Inc. 


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5.0 STUDY CALENDAR 
The pre-study intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using best clinical judgment of the responsible attending physician. It 
is expected that patients on this study will be cared for by physicians experienced in the treatment 
and supportive care of patients with PAC treated with SBRT.  Registration is defined as the date 
the patient consents.  
Pre-Randomization Testing  
• 
To be completed ≤ 30 Days before randomization: All laboratory studies, history and physical. 
• 
Minor changes to the assessment schedule may be made to accommodate holidays, 
administrative closures, etc, which if necessary, are not considered as significant deviations by 
the Sponsor.  If possible, site should contact the Sponsor prospectively to address rescheduling 
protocol assessments and data handling. 
• 
Standard of care evaluations may be utilized for screening, provided the assessments are 
clearly documented as standard of care in the source and meet protocol requirements and 
timelines. 
Tests & Observations 
Screening/ 
Prior 
to 
Randomization* 
Baseline 
Last 
Day 
of 
SBRT 
4B 
weeks 
post 
SBRT 
(optiona
l) 
7B 
weeks 
post 
SBRT 
12 weeks 
post 
SBRT B 
Post Tx 
Follow- up** 
Within 30 days of 
randomization  
Day -21 to 1  
(pre-dose) 
Day 5 
Day 33 
Day 54 
Day 89 
 
 
 
 
+/-2 
days 
+/-7 
days 
+/-7 
days 
+/-5 days 
+/-28 days 
Medical and Disease History (including 
disease status and pathology review) 
X (1) 
X (1) 
 
 
 
 
 
Physical, weight, ECOG PS (May be 
physician clinic visit at baseline visit) 
X (1) 
X (1) 
X (1) 
 
X (1) 
X (1) 
X (1) 
Pulse, BP 
X  
X (1) 
X (1) 
 
X (1) 
X (1) 
X (1) 
Height $ 
X  
 
 
 
 
 
 
Adverse Event Assessment† 
 
X (1) 
X (1) 
X (1) 
X (1) 
X (1) 
X (1) 
PRO-CTCAE 
X (2) 
X(2) 
X 
X 
X 
X 
X 
Fatigue/QOL/Physical/Mental 
LASA 
Assessment 
X (2) 
X(2) 
X 
X 
X 
X 
X 
Endoscopy with Fiducial placement for 
CT guided on-line positioning (not 
necessary for MR-linac treatments), core 
biopsies, cytologic brushings 
X* 
 
 
 
 
 
 
 
Endoscopy with duodenal evaluation, 
core biopsies if possible, cytologic 
brushings 
 
 
 
 
 
X (5) 
 


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Radiation Simulation (>5 business days 
prior to SBRT and following eligibility)*** 
X 
 
 
 
 
 
 
Laboratory Studies 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
 
CBC, Differential, Platelets 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
(Serum 
Creatinine, 
Electrolytes, AST, ALT, Alk. Phos., 
Albumin, Total Bilirubin) 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (#) 
X 
 
 
 
 
 
 
Tumor marker (CA 19-9) 
A 
A 
A 
A 
A 
A 
X 
Blood 
and 
Tissue 
Collection 
for 
Correlatives 
 
X (4) 
X (4) 
X (4) 
X (4) 
X (4) 
X (4) 
Evaluation for Resectability (7) 
X 
 
 
 
X 
 
 
Staging 
 
 
 
 
 
 
 
Pancreatic 
Protocol 
CT(3,6) 
(for 
resectability assessment) 
 
 
 
 
X  
 
 
MRI abdomen w/ and w/o contrast (for 
assessment of small bowel toxicity), is 
possible. 
X (3) 
 
 
 
 
X (3) 
 
Restaging CT Scan of Chest/Abd/Pelvis  
X (3) 
 
 
 
 
X (3) 
X(3) 
Randomization**** 
 
x 
 
 
 
 
 
* 
Endoscopy for fiducial placement and biopsies may occur anytime between screening and radiation simulation 
** 
After the 12 week visit, patients will continue in follow-up with physical examinations, labs, and staging scans every 3 months (+/- 28 days) post-SBRT until they 
have reached 36 months post-SBRT or until local progression. Thereafter, clinical status information is required every 6 months for 5 years post-SBRT, to include 
survival information and toxicity data. This information may be obtained via telephone call if patient is lost to clinic follow up. For patients who discontinue treatment 
for progressive disease or are removed from protocol treatment, survival information is required every 6 months for 5 years post-SBRT. Adverse events including 
radiation toxicity up to 1 year post-SBRT will be assessed during visits and phone calls, and recorded in the case report form (See section 9.3 for details).   
*** 
Simulation should be within 30 days of SBRT.  If simulation is done > 2 weeks prior to treatment start, a verification simulation should be performed in the week 
prior to treatment start. 
**** 
Randomization will occur following completion of the radiation simulation.  See Study Manual for details on the registration and randomization process. 
1 
Medical and Disease History, including pathology, collected within the Screening and Baseline Period will include information deemed medically-relevant by the 
Investigator (or designee). May be performed by physician, NP, or PA responsible for oncologic care of the patient. Vitals may be collected by RN or MA. 
2 
To be completed ONCE prior to treatment. The study files will contain examples and IRB approval of the assessments. 
3 
Chest scans must be CT or chest X-ray. Abdominal baseline and restaging scans can include either a pancreatic protocol CT or MRI, although pancreatic protocol 
CT is preferred. The CT must be acquired with at least a 5 mm or less slice thickness. Initial scans for determining eligibility and resectability status will be reviewed 
at the treating institution and central review will not be required except in cases of uncertainty. In case of contraindications (eg pacemaker, severe claustrophobia, 
etc) a high quality CT scan can be acquired. 
4 
Correlative blood collection will occur at Baseline, at day 2 (pre- treatment), day 5 (pre- treatment), week 7 and week 12.  The blood draw at week 4 and all Follow 
Up time points will be optional. Tissue collection is required at Baseline and week 12. Please see Table 7 for sample collection timepoints.  
5 
Endoscopic evaluation approximately 12 weeks post radiation. 
6 
The resectability imaging will be done based on clinical necessity per the surgical oncologist. 
7 
Resectability will be assessed at respective institutions.   
† 
AEs are to be collected starting at baseline and through 1 year post SBRT. Routine AEs are to be collected starting after randomization. See section 9.0 AE 
definition. See section 9.3 for expedited reporting of SAEs.  
# 
For women of age 18-55 without hysterectomy or tubal ligation. Must be done ≤ 14 days prior to study entry (dosing). Testing should be done per institutional 
standard. 
$ 
A previous height may be utilized if within 6 months of consent 
A 
Previously obtained CA19-9 may be used if within < 28 days prior to randomization. Subsequently, CA 19-9 may be performed +/- 14 days from the scheduled 
date.  During treatment, CA 19-9 should be performed every 28 days. For patients who have normal CA 19-9 levels at baseline, continued testing of CA 19-9 is 
not required.  
B 
Research coordinator or RN will call patient weekly up to the week 7 visit, and again at week 10 to confirm no adverse events between clinical visits.  The week 4 
visit is optional.  If the patient is not seen in the clinic, the patient should be contacted by phone this week.  


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6.0 RADIATION DELIVERY 
6.1 
Radiotherapy Technical Factors 
6.1.1 Eligibility criteria for SBRT 
In order to ensure safety, patients must meet the following criteria in order to proceed with 
SBRT: 
• 
Patients must have no evidence of active duodenal or gastric ulcers or direct tumor invasion of 
the bowel or stomach on pre-SBRT endoscopy Previous history of ulcers >30 days prior to 
treatment with no active bleeding or symptoms are eligible for treatment. 
• 
Patients should not be treated with SBRT if SBRT-specific organ at risk (OAR) constraints (listed 
in section 6.3) cannot be met. 
• 
Patients must be able to undergo 4D CT simulation to assess tumor motion with respiration and 
able to comply with breath hold for motion management. 
• 
Patient must not have any contraindication to contrast administration at simulation, including 
contrast allergy refractory to premedication at the discretion of the treating physician. 
• 
Patient must have a functioning metal stent in place if biliary or duodenal stent is required. 
6.1.2 Technical Factors including Treatment Delivery and Fiducial Placement 
• 
Only ≥6 MV photons are permitted for SBRT. 
• 
Particle therapy is not permitted. 
• 
Static IMRT or VMAT must be used; 3DCRT is not permissible. It is recommended that 6-12 co-
planar static IMRT fields or 1-3 arc fields (VMAT/Rapid-Arc) be used in the radiation treatment 
plan. Flattening Filter Free (FFF) treatment is allowed. 
• 
Both treatments with CT and MRI guidance for positioning are accepted, for CT guided positioning 
1-5 (preferably ≥3) fiducial markers should be placed for targeting purposes. These markers will be 
placed directly at the tumor periphery and/or within 1 cm of the tumor (normal pancreas) under 
endoscopic ultrasound at any time prior to radiation simulation.  Fiducials are optional for MR Linac 
based treatment.Simulation can follow fiducial marker placement on the same day in case of 
an uncomplicated positioning endoscopic procedure, however, some hours of delay are 
recommended to reduce the risk of post-positioning swelling. The simulation quality and 
timing is at the decretion of the treating physician. 
• 
Simulation should be done ≤ 30 days prior to first fraction of SBRT. 
• 
If simulation is done > 2 weeks prior to treatment start, a verification simulation should 
be performed in the week prior to treatment start. 
• 
Patients will be positioned supine, arms above the head, in a custom immobilization device. 
• 
Administration of IV and oral contrast is required for target and normal tissue delineation unless 
patient has a contrast allergy refractory to premedication or at the discretion of the treating 
physician.  A pretreatment renal scan to assess kidney differential will be performed prior to 
initiation of treatment if clinically appropriate per the treating physician. 


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• 
A 4D CT scan may be performed to assess respiratory motion. If > 5 mm of tumor motion in any 
direction is noted, then the use of breath-hold (BH) technique is required. If BH is utilized, 3-5 
BH scans will be performed for reproducibility.  If there is < 5 mm tumor motion on 4DCT and 
patient cannot tolerate BH, treatment planning may be done in free breathing using 4D CT.  
• 
MRI or PET simulation may be optionally performed in the treatment position and later fused to 
the CT simulation scan to assist in target volume delineation, but this is not required. 
• 
Patients will be treated on CT- or MRI guided linacs, for all daily imaging is required for position 
verification (CBCT, daily KV withch fiducial tracking or MRI positioning. 
• 
Deformable adaptive repositioning and planning is accepted done on-line or off-line, while well 
documented as e.g. adapted plan1…6 
• 
If not clinically contraindicated, patient will be placed on proton pump inhibitor for duration of 
treatment and 90 days post treatment. 
6.2 
Target Delineation 
6.2.1 Required Structures 
• 
GTV: Primary pancreatic tumor as delineated on all available pre-treatment imaging and CT 
simulation 
• 
iGTV: GTV expanded to encompass tumor in all phases of 4DCT or all BH scans obtained 
during simulation.  
• 
iGTV_Exp = iGTV + 3mm (uniform expansion) 
• 
TVI: The segment of portal vein, SMV, SMA, and/or celiac artery that is in direct contact with 
tumor. TVI structures will be contoured to include entire radial extent of any vessel that contacts 
tumor. For example, the SMA TVI will include the entire 360-degree extent of SMA even if there 
is only 90-degree involvement of the SMA by tumor. This radial contour should extend superiorly 
and inferiorly on each axial slice where there is GTV contoured. 
• 
TVI_Exp: TVI + 3mm (uniform expansion) 
• 
Fiducials: Fiducials and/or clips should be contoured separately starting superiorly and moving 
inferiorly in numeric order. 
• 
Fiducials_Exp: Fiducials + 3mm (uniform expansion) 
• 
iDuodenum: Duodenum contoured to encompass tumor in all treatment phases of 4DCT or all 
BH scans obtained during simulation. 
• 
PRV_Duo: iDuodenum + 5mm (uniform expansion) 
• 
iStomach: Stomach contoured to encompass tumor in all treatment phases of 4DCT or all BH 
scans obtained during simulation. 
• 
PRV_Stom: iStomach + 5mm (uniform expansion) 
• 
iBowel: Any other small bowel in the treatment area, contoured to encompass tumor in all 
treatment phases of 4DCT or all BH scans obtained during simulation. 
• 
PRV_Bowel: iBowel + 5mm (uniform expansion) 


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• 
PRV_GI = PRV_Duo + PRV_Stom + PRV+Bowel 
• 
Bilateral kidneys, liver, spinal cord and spleen contoured per institutional guidelines. No PRV 
structures are required. 
• 
Prescription Dose will be prescribed to different PTV volumes according to the dose level (figure 
10):  
• 
PTV 1 = iGTV_Exp + TVI_Exp. Prescription dose to this structure is 6.6Gy in 5 fractions at all 
dose levels to the 95% isodose line.  
• 
PTV 2 = PTV1 – PRV_GI. Prescription dose to this structure will be according to PTV2 dose for 
assigned dose level to the 95% isodose line. 
 
Safety Note: SBRT feasibility is judged by the treating physician. 
• 
Tumor volume is not a restrictive criteria, however, the PTV2 needs to be sufficiently covered 
at least 60% of the prescribed dose, while still meeting the normal tissue constraints 
• 
Radiological or endoscopic signs of tumor infiltration in bowel structures need to be well 
described before SBRT. Aside from bulging tumor masses in the bowel lumen, tumor infiltration 
in itself it is not an exclusion criteria but informs judgement of the physician to perform SBRT. 
All suspect areas need to be included in the PTV1 and sufficiently covered for at least 60% of 
the (6.6Gy) prescribed dose while still meeting the normal tissue constraints 
 
6.3 
Treatment Planning Guidelines and Dose Constraints 
Prescription dose to PTV_1 must cover 95% of the target volume.  There are no formal 
coverage constraints on PTV_2, but they should be maximized while maintaining OAR constraints 
at the treating physician’s discretion.  Recommended and mandatory dose constraints are outlined 
in Table 2.  
 
Figure 10. Representative slices in a patient with LAPC due to complete 
celiac axis encasement of tumor. Representative slices are of PTV_1 
(yellow), PTV_2 (red) and PRV_GI (green). A) PTV_2 is equal to PTV_1 
with PRV_GI subtracted. B) PTV_1 and PTV_2 cover TVI where celiac 
touches tumor directly. 


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Table 2. Dose Constraints Recommended for Treatment Planning 
Description 
Planning System Name 
Constraints 
PTV_1 
PTV_1 
V33 > 95%* 
 
 
 
OAR 
 
Constraints 
Duodenum 
iDuodenum 
 
 
 
V30<3cc* 
 
 
V35<1cc* 
 
 
V40<0.5cc* 
Small Bowel 
iBowel 
 
 
V30<1cc* 
 
 
V35<0.1cc* 
 
 
V40<0.5cc* 
Stomach 
iStomach 
 
 
V30<2cc* 
 
 
V35<1cc* 
 
 
V40<0.5cc* 
Liver 
Liver 
V12 <50%* 
Combined Kidneys 
Kidneys 
V12 <75%* 
Spinal Cord 
Spinal_Cord 
V20 <1cc* 
Spleen 
Spleen 
Mean < 2 Gy (optional) 
* 
Notation indicates required mandatory constraints to be met in order to proceed with SBRT; 
Other constraints are recommended as reasonably achievable. 
6.4 
Treatment Schedule 
All patients will begin SBRT within 30 days of the simulation scan.  If possible, treatment will 
begin on a Monday and complete on a Friday, unless a holiday or other treatment interruption 
occurs.  In this case, treatments may occur on different days, but all 5 treatments must occur within 
an 8 day window. 
6.5 
Treatment Delivery 
• 
Patients may be treated on any image-guided (IGRT)-enabled machine (including MRI linac). 
• 
(on-line) adaptive planning may be done at the discretion of the treating physician if being well 
documented. 


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• 
Initial patient positioning will be based on MRI, CBCT, volumetric kV or CTOR imaging with 
shifts to referenced anatomy at the level of the tumor as appropriate. 
• 
In case Orthogonal kV/MV, kV/kV projection, or CTOR imaging will be used to verify the location 
of the fiducials prior to delivery of the first treatment beama secondary shift based on the location 
of fiducials should be utilized, as indicated by the position of the fiducials. 
• 
In case MRI imaging is used for position verification, at least 2 contours need to be matched 
(e.g. PTV and duodenum), on-line re-contouring and planning is accepted, while well 
documented as serial plans given 
• 
Documentation of active monitoring of treatment delivery accuracy will be asked using CBCT, 
MRI images or kV and/or MV projection imaging, either immediately before or during all (or a 
subset of) treatment fields. 
6.6 
Compliance Criteria 
6.6.1 Dose Uniformity 
• 
Variation Acceptable: Minimum dose within the PTV_1 is less than 97% of the prescribed dose, 
but does not fall below 93% of this dose or Maximum dose within the PTV_1 is greater than 
107% of the prescribed dose, but does not exceed 110% of this dose. 
• 
Deviation Unacceptable: Minimum dose within the PTV_1 is less than 93% of the prescribed 
dose or Maximum dose is greater than 110% of the prescribed dose. 
6.6.2 Volumes 
• 
Deviation Unacceptable:  
1. Incomplete contouring of the entire GTV or PTV;  
2. Use of different margins than specified for the PTV1;  
3. Over-contouring of the GTV by > 30 cc (15 cc if it results in inclusion of extra duodenum, 
small intestine or stomach);  
4. Incorrect contouring of the duodenum, stomach or small intestine that results in > 15 cc 
overlap of the PTV with the OAR. 
6.6.3 Treatment Interruptions 
• 
Per protocol:  All treatments occur within 8 calendar days 
• 
Acceptable variation:  All treatments occur with 8 to 16 calendar days 
• 
Unacceptable variation:  Treatments take greater than 16 days to complete 
6.7 
Definitions of Radiation related Adverse Events 
The criteria used for the grading of toxicities encountered in this study are Common Toxicity 
Criteria (CTC) version 4.0.3 
Very likely (80-90%): 
• 
Fatigue (which generally goes away after the radiation therapy is completed)  


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• 
Skin irritation, redness, itchiness, discomfort  
• 
Temporary changes in blood work (decrease in blood counts, increase in liver enzymes), 
without symptoms 
Less likely (30%): 
• 
Nausea, vomiting (during therapy) – more common if stomach or gastrointestinal track 
irradiated  
• 
Chest wall pain, rib fracture (< 10%) 
Less likely, but serious (<20%): 
• 
Gastric, esophagus, small bowel or large bowel irritation/ulceration, bleeding, fistula, 
obstruction or changes in motility following therapy (may require medications or surgery) 
(< 10% permanent changes) 
• 
Radiation-induced liver disease (RILD) (<5%). Classic RILD is a clinical diagnosis of 
anicteric ascites, hepatomegaly and elevation of alkaline phosphatase relative to other 
transaminases that may occur 2 weeks to 3 months following radiation to the liver 
• 
Non-classic RILD includes elevation of liver enzymes and/or any decline in liver function 
within 12 weeks from start of therapy (~20%). RILD can lead to liver failure that could 
lead to death. There is an increased risk of liver toxicity in patients with large tumors and 
in patients with pre-existing liver disease.  
• 
Permanent thrombocytopenia (<1%); this may lead to bleeding 
• 
Kidney injury (<1%); this may lead to changes on imaging and more rarely the need for 
medication. 
6.8 
Rapid Review and Radiation Therapy Quality Assurance  
Radiation plans for all MDACC-treated patients will be reviewed at MDACC prior to 
treatment start during weekly gastrointestinal radiation therapy quality assurance (QA) rounds by a 
minimum of two gastrointestinal radiation oncology specific attending physicians who are not 
investigators on the trial and will also be reviewed by both radiation oncology study investigators.  
To ensure protocol compliance, the treatment plans for the first three patients treated at 
each participating non-MDACC site will be reviewed by a MDACC Study Lead Investigator and the 
respective site PI.   Radiation treatment plans will be reviewed to ensure a common understanding 
of the procedures listed in sections 6.1 through 6.8 at the respective institution.  This may be done 
during the trial periodically as needed. 
All treatment plans will be reviewed for quality assurance according to the standard review 
process at each participating institution.  
All plans will also be reviewed by the responsible physicist or his/her designee at each 
participating institution for compliance with the protocol and standard of practice at each institution. 
When performed, plan reviews for patients from one institution by the staff of another 
institution will utilize the resources of MDACC, including WebEx; and/or other feasible resources 
that comply with HIPPA.  


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7.0 STUDY DRUG MATERIALS 
7.1 
Description of Study Drug GC4419 
GC4419(avasopasem 
manganese) 
 
manganese,dichloro[(4aS,13aS,17aS,21aS)-
1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21a-eicosahydro-11,7-nitilo-7H-
dibenzo[b,h][1,2,7,10]tetraazacylcoheptadecine-κN5,κN13,κN18,κN21,κN22]-) is a water soluble, 
highly stable, low molecular weight manganese-containing macrocyclic ligand complex whose 
activity mimics that of naturally occurring SOD enzymes. 
GC4419 Administration:  90 mg GC4419, 9 mg/mL in 26 mM sodium bicarbonate-buffered 
0.9 wt. % saline for parenteral administration.  There are no other excipients.  GC4419 is packaged 
as an 11 mL ± 0.1mL aliquot in a 10 mL amber glass vial with an S-127 4432/50 gray stopper and 
a 20 mm red flip-off seal. 
Placebo Administration:  Matching placebo will be prepared at the unblinded 
investigational site pharmacy with 100% normal saline at 250 mL, for IV administration over 60 
minutes. 
7.2 
Clinical Safety Data with GC4419 
In the completed Phase 1b/2a trial of GC4419 plus IMRT/cisplatin to reduce oral mucositis 
experience by patients with head and neck cancer, the most common adverse events observed  
were nausea, fatigue, dysgeusia, oropharyngeal pain, decreased white blood cell count, 
constipation, dry mouth, anemia, vomiting, diarrhea, decreased lymphocyte count, and decreased 
appetite. These and other adverse events observed are characteristic of the cisplatin/IMRT regimen 
in this patient population.  
The following mild to moderate adverse events were reported as possibly related to GC4419 
for >10% of patients in the GT-001 study: nausea, vomiting, dry mouth, diarrhea, fatigue, dyspepsia, 
gastroesophageal reflux disease, dizziness, dysgeusia, weight loss, decreased appetite, headache, 
paresthesia, and hiccups. 
The following more severe adverse events were reported by treating investigators as 
possibly related to GC4419 in the GT-001 study: anemia, nausea, vomiting, gastroenteritis, low 
white blood cell count, low neutrophil count, weight loss, decreased appetite, arthritis, and reduced 
range of motion.  
Potentially mechanism-related facial tingling or paresthesia, possibly due to nitric oxide 
potentiation, was reported for several patients in the GT-001 study and appears related to GC4419 
dose, occurring in 11/19 (58%) patients receiving 112 mg per dose, 5/9 (55%) patients receiving 90 
mg/dose, but only 2/18 (11%) at lower doses.  This facial tingling/paresthesia was mild to moderate, 
and when it occurred it did so during GC4419 infusion with resolution shortly after the end of the 
infusion.  It was neither treatment-limiting nor troublesome to patients, and does not pose a 
meaningful safety risk. 
Twenty-three (50%) patients experienced at least 1 serious adverse event (SAE). SAEs 
reported for > 1 patient included pyrexia and vomiting (each 11%), febrile neutropenia (9%), nausea 
(7%), and dehydration (4%). Of the 3 patients with nausea reported as an SAE, nausea was 


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accompanied by vomiting in all 3 cases. Two patients, both at the 112 mg/dose level, experienced 
at least 1 SAE that was considered by the Investigator to be GC4419-related, including Grade 3 
gastroenteritis in 1 patient and Grade 3 nausea, vomiting, and hyponatremia in other patients; these 
events also were considered DLTs. All other SAEs reported were considered by the Investigator to 
be unrelated to GC4419.  
In the randomized, double-blind, placebo-controlled Phase 2b trial, GT-201, the safety 
profile of GC4419 was similar to that of placebo, indicating that GC4419 did not appear to add 
significant risk to the known toxicity of the underlying chemoradiotherapy regimen used for patients 
with HNC in that trial. 
7.3 
Study Drug Packaging and Labeling  
GC4419 will be presented as individual single-use vials, which represent daily doses to be 
administered IV concurrent with SBRT.  Details regarding labeling can be found within the 
Pharmacy Manual. 
7.4 
GC4419  
GC4419 is packaged as an 11 mL ± 0.1mL aliquot in a 10 mL amber glass vial with a S-127 
4432/50 gray stopper and a 20 mm red flip-off seal. Each bottle will be labeled with the appropriate 
language, including the required regulatory text. 
7.5 
Placebo  
Placebo vials will not be provided by the Sponsor.  The Site will be responsible for preparing 
placebo IV infusion bags with 250 mL of 100% normal saline per the Pharmacy Manual. 
7.6 
Study Drug Storage  
GC4419 solutions must be stored at 2°C to 8°C at all times until use. GC4419 solutions 
must not be frozen at any time. Temperature excursions above freezing and up to 25°C or down to 
0.1°C for four hours are acceptable; however, Galera Therapeutics, Inc. or its designee must be 
notified immediately of the temperature excursion to ensure proper oversight.  
Once prepared, the IV bags containing GC4419/saline mixtures must also be stored at 2°C 
to 8°C until use, and must be administered to patients within 24 hours of preparation.  GC4419 
dosing solutions must not be frozen at any time.  If freezing of the material is evident, that supply 
must be quarantined per institutional guidelines and Galera Therapeutics, Inc. or its designee must 
be notified immediately. 
7.7 
Study Drug Preparation GC4419 and Placebo 
GC4419 will be provided to the study site in single use, sterile, pyrogen-free vials ready for 
dose preparation. Proper mixing with normal saline is required. Standard aseptic techniques will be 
used to maintain sterility.  
Assignment of treatment arm will be randomized with respect to treatment arms A (90mg 
GC4419) and B (placebo).  GC4419 will be presented in single-use vials. 


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To prepare daily IV solutions of GC4419, investigational pharmacists will extract 10 mL from 
a single vial and add to 240 mL normal saline. Note that there is no extraction of saline (i.e., the 
infusion solution volume will be 240 mL saline + 10mL volume of GC4419/placebo).  No additional 
modifications or adjustments are to be made to the infusion solution.   
The GC4419 solution may appear clear or have a slight yellowish tint. Although solutions 
should be free of particulates, it is possible that some vials may have some fine visible particulates. 
Infusions should be prepared using a sterile 0.2 micron syringe filter prior to introduction into the 
infusion bag. The prepared admixture should be inspected visually for any particulate matter prior 
to administration, and prepared solutions still containing any visible particles after filtration should 
not be used. Filtration does not influence dosage calculations.  
To prepare daily IV solutions of placebo, investigational pharmacists will use 250 mL of 
100% normal saline. 
Further information and preparation details will be provided in a separate Pharmacy Manual.   
Note: Investigational staff who prepare infusion solutions will be unblinded and cannot be 
discussed with the  clinical team. 
7.8 
Study Drug Administration  
GC4419 and Placebo: GC4419 or Placebo/saline mixture will be administered 
intravenously at an infusion rate that totals 60 min (± 6 min to account for saline overfill) for the total 
dose assigned. Infusions of GC4419/placebo must be administered using an infusion pump (i.e., 
not by drip rate).  Infusion pump models are not specified and may be per institutional 
preference/standard. 
To facilitate administration of GC4419 according to the study schedule, an indwelling venous 
access device may be used, at the discretion of the treating investigator.  If an indwelling venous 
access device is placed to facilitate administration of GC4419, this fact will be recorded with the 
study data, as will information about the date of placement, type of device, and subsequent 
complications or adverse events related to the use of the device. 
SBRT must be initiated as soon as possible upon completion of the GC4419/placebo 
infusion, but no later than 180 minutes following the end of the  GC4419/placebo infusion.  
GC4419/placebo will be given beginning on the first day of radiation and continuing daily, 
concurrently M-F throughout the administration of SBRT 
If SBRT is not administered on any given day due to a treatment break or unforeseen 
circumstances, GC4419/placebo should not be administered on that day.  Breaks in SBRT will be 
determined by the patient’s treating physician in accordance with standard of care. Patients should 
resume GC4419/placebo administration when SBRT resumes.  On days when planned doses of 
both GC4419/placebo and SBRT are not administered (e.g., due to a holiday site closure), 
GC4419/placebo dosing may be extended along with SBRT to make up the missed dose(s). 


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7.9 
Study Drug Accountability 
The investigator is responsible for ensuring adequate accountability of all used and unused 
GC4419.  This includes acknowledgment of receipt of each shipment of GC4419 (quantity and 
condition), patient dispensing records, and quantity of GC4419/placebo returned or destroyed.  
Dispensing records will document quantities received from Galera Therapeutics, Inc. and quantities 
dispensed to patients, including container number or lot number, date dispensed, patient identifier 
number, patient initials, and the initials of the person dispensing the medication.  Any GC4419 that 
is prepared but not used must also be recorded in the dispensing records. Further accountability 
instructions can be found in the Pharmacy Manual.  
All GC4419 supplies and associated documentation will be reviewed and verified by the 
study monitor.  Copies of all forms, documenting drug receipt at the study site, drug transportation 
to satellite sites, and drug return to Galera Therapeutics, Inc., together with drug accountability 
records, will be retained according to the regulations governing record retention. 
The investigator will not allow GC4419/placebo to be given to any patient not included in the 
study or any unauthorized person. 
7.10 Study Drug Handling and Disposal 
GC4419: After completion of the study, all unused study drug will be inventoried by the study 
monitor and if possible, destroyed locally at the site after complete accountability by the Sponsor 
and/or its representatives.  GC4419 should not be returned directly to Galera Therapeutics, Inc. 
unless specifically requested by Galera Therapeutics, Inc.  The study monitor will instruct the site 
in the disposal and/or destruction of all used and unused GC4419 supplies.  Destruction of any 
GC4419 should be documented appropriately. 


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8.0 DOSE AND TREATMENT MODIFICATIONS 
8.1 
Ancillary therapy, concomitant medications and supportive care 
Necessary supportive measures for optimal medical care will be given throughout the study.  
Supportive care medications may be administered at the investigator's discretion and recorded in 
the CRF (including administration of prophylactic antiemetic and antidiarrheal medication if deemed 
appropriate by the investigator).  Concomitant medications will be recorded in the eCRF up to Week 
12 for AEs and until resolution of SAEs. However, medications are subject to the following 
exclusions: 
• 
Other concurrent chemotherapy or investigational agent during the week of SBRT 
• 
Nitrates, phosphodiesterase type 5 (PDE 5) inhibitors (e.g., sildanefil, tadalafil, or similar agents) 
or other drugs that in the judgment of the treating investigator could create a risk of a precipitous 
decrease in blood pressure are prohibited until at least 24 hours after the last dose of GC4419 
• 
Pyridostigmine or other drugs that in the judgment of the treating investigator could create a risk 
of increased carotid sinus sensitivity, symptomatic bradycardia, or syncopal episodes.  
• 
Other biologic response modifiers – except systemic hematopoietic growth factors for the 
management of anemia or myelosuppression  
• 
Concurrent 
approved 
or 
investigational 
anti-cancer 
therapy 
(e.g., 
chemotherapy, 
immunotherapy, targeted therapy, hormone and biologic therapy) other than the Protocol 
regimen  
• 
Other investigational agents 
8.2 
Dose Delays and Dose Modifications 
The following toxicities require a 25% dose reduction in GC4419/placebo: 
o Grade 2 or greater hypotension within two hours after the start of GC4419/placebo 
infusion 
o Grade 3 or 4 vomiting, or Grade 3 nausea  
Two dose reductions for toxicity will be permitted per patient. After the first event, the patient 
will be re-challenged at 75% of the original dose (7.5 mL GC4419/placebo in normal saline for a 
total volume of 250 mL). After the second event, the patient will be re-challenged at 50% of the 
original dose (5.0 mL GC4419/placebo in normal saline for a total volume of 250 mL). Patients who 
are unable to tolerate GC4419/placebo infusions following two dose reductions must be 
discontinued from the study treatment but may continue with SBRT at the discretion of the treating 
investigator. 
For other toxicities (including those attributable to SBRT), management will be per 
institutional and ASCO guidelines and investigator judgment. 
Any radiation related toxicities ≥ grade 4 will necessitate removal of patient from further 
SBRT.  


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9.0 ADVERSE EVENTS 
9.1 
Definitions  
The treating physician and investigator team are responsible for the detection and 
documentation of events meeting the criteria and definition of an adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol.  Throughout the study, AEs will be recorded in 
the source documents and on the appropriate pages of the CRF regardless of whether the AEs are 
considered related to GC4419/placebo, SBRT or other cause.  To avoid confusion, the AE should 
be recorded in standard medical terminology. 
The following definitions of terms are guided by the International Conference on 
Harmonization and the US Code of Federal Regulations and are included here verbatim.   
Adverse Event (AE): 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which may or may not have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
Examples of an AE include: 
• 
Significant or unexpected worsening or exacerbation of the condition/indication under study.   
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity (grade) of the condition. 
• 
New conditions detected or diagnosed after investigational product administration even though 
they may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae associated with a suspected interaction of the 
investigational product with a concomitant medication. 
• 
Signs, symptoms, or the clinical sequelae associated with a suspected overdose of either 
investigational product or a concurrent medication. 
Serious Adverse Event (SAE): 
Any untoward medical occurrence that at any dose: 
• 
Results in death, 
• 
Is life-threatening – NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers to any 
adverse drug experience [adverse event] that places the patient or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include 
a reaction that, had it occurred in a more severe form, might have caused death.  [emphasis 
added] 
• 
Requires inpatient hospitalization or prolongation of hospitalization – NOTE:  In general, 
hospitalization signifies that the patient or subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting.  Complications that 


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occur during hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity – NOTE: The term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. 
OR 
• 
Is a congenital abnormality/birth defect. 
• 
Other Important Medical Event 
9.2 
Serious Adverse Event Reporting 
All events meeting the criteria for Serious Adverse Events (listed in section 9.1) must be 
reported to the Sponsor by investigational sites within 24-hours of becoming aware of the event.  In 
order to determine the sponsor’s timeline for notifying regulatory authorities and investigators per 
Federal Regulations, an event term, serious criteria, and causality is required at the time of the 
initial report.  Specific SAE reporting instructions are provided in a separate manual. 
The investigator will also notify your local IRB in writing of serious events per the IRB 
reporing policy. 
9.3 
Routine Adverse Event Reporting 
Any adverse medical condition or laboratory abnormality with an onset date before the date 
of randomization is considered to be pre-existing in nature, and part of a patient’s medical history.  
Adverse medical conditions that begin on or after date of randomization will be considered an 
adverse event.  Increases in toxicity grade of pre-existing conditions that occur on or after the date 
of randomization are also considered an adverse event.  AEs and SAEs occurring up to 1 year after 
SBRT will be recorded in the electronic data capture system.  All SAEs will be followed to resolution; 
i.e., until they no longer meet criteria for seriousness.  Non-serious AEs will be followed to resolution 
to the extent possible for up to one year post-SBRT.  The frequency of routine AE assessments will 
be as indicated in the schedule of events.   
All adverse events must be recorded in the patient’s source documents and on the CRF 
regardless of frequency, severity (grade) or assessed relationship to randomized therapy. 
Gastrointestinal toxicity will be carefully assessed for causality because GI toxicity will used 
in the primary endpoint.  Disease progression or death due to disease progression will not be 
reported as an AE as it is captured as a study endpoint in the CRF. Progressive disease found by 
scan or on clinical evaluation should be captured on the applicable CRF pages and not on the AE 
page. 
9.4 
Grading and Cause Assignment of Adverse Events 
The severity of adverse events will be designated as mild, moderate, severe, life 
threatening, or fatal per NCI CTCAE version 4.03. If not specifically addressed in NCI CTCAE 
version 4.03, use table 3 below. Cause assignment of adverse events will be made in accordance 


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with table 4 below. The Investigator should consult the Investigator Brochure and/or product 
information in the determination of his/her assessment. 
Table 3. Grading of Adverse Events 
Grade  
Criteria1 
Mild – Grade 1 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Moderate – Grade 2 
Minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL2 
Severe – Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL3 
Life Threatening – Grade 4 
Life-threatening consequences; urgent intervention indicated 
Death – Grade 5 
Death related to adverse event 
 
Table 4. Cause Attribution of AE’s 
Attribution  
Definition 
Related 
It is likely that GC4419/placebo caused or contributed to the cause of the adverse 
event or laboratory abnormality, when the temporal sequence from the time of 
GC4419/placebo or SBRT administration, the known consequences of the patient’s 
clinical/state condition or study procedures, the effects of discontinuing or 
reintroducing GC4419/placebo on the adverse event, and other medically relevant 
factors are considered. 
Possibly 
Related 
There is a reasonable possibility that the adverse event or laboratory abnormality was 
caused by GC4419/placebo or SBRT, when the temporal sequence from the time of 
GC4419/placebo administration, the known consequences of the patient’s clinical 
state/condition or study procedures, and other medically relevant factors are 
considered.   
Unrelated 
The investigator has a high level of certainty that the patient’s clinical state/condition, 
study procedures, or other medically relevant factors other than treatment with 
GC4419/placebo  or SBRT caused the adverse event or laboratory abnormality.  This 
relationship category should only be used when a clear precipitating cause exists and 
it is not reasonably possible that the event is caused by treatment with 
GC4419/placebo or SBRT. 
 


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10.0 
ASSESSMENTS 
10.1 Schedule of Evaluations 
See Study Calendar in section 5.0. 
10.2 Safety Assessments 
General safety will be assessed during radiation, weekly (see visits on the basis of 
treatment-emergent AEs, physical examination findings, clinical laboratory tests, and vital sign 
measurements). 
10.3 Clinical Assessments 
Clinical assessment will consist of standard history and physical examination by a physician, 
nurse-practitioner or physician assistant responsible for the oncologic care of the patient.  
Long-term follow-up may include telephone calls by study staff where clinic follow up is not 
feasible. 
10.4 Laboratory Assessments 
All protocol required laboratory assessments in the study calendar section 5.0 will be 
performed at a local laboratory.  
10.5 Endoscopic Assessment 
The endoscopic evaluation (including EUS) will take place at approximately 12 weeks post 
radiation. The endoscopist will be blinded to receipt of drug versus placebo. The following scale will 
be used for assessment where a score of 0=no toxicity, 1-2 indicates mild toxicity, 3-4 indicates 
moderate toxicity and 5 or more indicates severe toxicity: 
• 
Erythema: (0=none, 1=mild (looks pink), 2=moderate/severe (red) 
• 
Edema:  (0=none, 1=mild, 2=moderate/severe) 
• 
Ulcers: (0= none, 1= single, 2= 2 or more ulcers) 
o If ulcers are present, the endoscopist will measure cumulative surface area to normalize for 
ulcer size. 
o Note will also be made of whether ulcer has a clean base, active bleeding or stigmata of 
recent bleeding 
• 
Stricture:  (0-none 1= mild, 2=moderate/severe) 
The endoscopist will also record the location of the tumor using anatomic coordinates 
including stomach (antrum, lesser and greater curvature, anterior and posterior wall) and duodenal 
bulb (medial or lateral wall), second portion of the duodenum (medial or lateral wall). 


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10.6 Radiographic Assessments and Definition of Radiographic 
Treatment Response 
Staging imaging will be performed according to the study calendar in section 5.0 at baseline, 
one month post SBRT (clinical exam), 7 weeks (+/-1wk) post SBRT (clinical exam, triphasic CT for 
purpose of evaluating resectability) and 12 weeks (+/-5days) post SBRT (clinical exam, CT and 
endoscopy), in addition to regular q3 month follow up visits.  Progression of disease will be 
evaluated at each time point.  Radiographic response will be measured according to a modified 
Response Evaluation Criteria in Solid Tumors (RECIST) as described in section 10.6.3 and 10.6.4 
below.  Only response assessment of the primary target will be considered for biostatistical 
purposes of the primary analysis, since these targets are affected by radiation.  Overall Response 
will be considered per RECIST 1.1 for PFS calculations (secondary endpoint), but not used for the 
primary endpoint of determining the MTD.  All imaging will be interepreted by an MDACC-affiliated 
radiologist.  All participating sites will submit scans to MDACC for review per the Study Manual.  
The same method of cross-sectional imaging used at baseline must be used at each follow up 
evaluation for treatment response.  
10.6.1 Measurable Lesion 
The measurable lesion must measure ≥ 1cm in the longest dimension utilizing CT scan 
thickness < 5 mm. 
10.6.2 Non-measurable Lesions 
Non-measurable disease will include all lesions < 10cm in longest dimension, in addition to 
truly non-measurable disease including leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
mass/organomegaly that cannot be confirmed on imaging. 
10.6.3 Target Lesion 
The target lesion will be the primary pancreatic tumor classified as measurable disease.  
The response within the target lesion will be used for statistical consideration.  Non-target lesions 
will also be tracked and measured, but will be considered only for the purpose of determining 
progression-free survival.   The primary target lesion will be considered in evaluating local control.  
10.6.4 Response Criteria Definitions 
Complete Response (CR): Disappearance of the target lesion. Any pathologic lymph nodes 
(target or non-target) must have reduction in short axis to <10mm 
Partial Response (PR): At least a 30% decrease in the diameter of the target lesions, 
utilizing baseline measurements as reference. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for Local Progressive Disease (LPD). 
Local Progressive Disease (LPD): At least a 20% increase in the the longest diameter of 
the target lesion, utilizing baseline measurement (scan) as reference. The meansurement must also 
demonstrate an absolute increase of at least 5mm. If the study in which LPD is noted at the 6-8 
week post-SBRT scan, LPD must be confirmed in the  subsequent scan (at the 12 week post SBRT 


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scan) to rule out post-radiation inflammation from SBRT. If a repeat scan is indeterminate, additional 
imaging modalities including MRI or PET/CT can be utilized. Progression will be retroactively dated 
to the initial scan on which the LPD was suspected. 
Distant Progressive Disease (DPD): The appearance of new unequivocal metastatic 
lesions on follow up imaging will denote distant progression.  The finding of a new lesion must not 
be attributable to differences in imaging technique, change of imaging modality, or findings thought 
to represent something other than tumor, especially if primary target lesions shows partial or 
complete response. If a new lesion is equivocal but suspicious for DPD, continued follow up should 
be done until it becomes unequivocal. Progression will be retroactively dated to the initial scan on 
which the DPD was suspected. 
Biochemical Response (BR): Elevated CA19-9 level will not be used to determine disease 
progression, but will be used to measure biochemical progression free survival (bPFS). A CA 19-9 
level that decreases by 50% from pre-treatment value will be considered a biochemical response. 
Biochemical Failure (BF): If the CA 19-9 level increases by 50% on 2 successive measures 
from the lowest recorded on study value, it will be considered biochemical failure. 
10.7 Surgical and Pathologic Determination of Treatment Response 
10.7.1 Evaluation of Resectability  
Determination of locally advanced disease/ technically unresectable disease will be 
determined at diagnosis and at 6 to 8 weeks post treatment by surgical collaborators in the 
multidisciplinary setting. This will be generally according to the following criteria at the surgeon’s 
discretion: 
• 
Greater than 180 degree tumor involvement of the superior mesenteric artery 
• 
Greater than 180 degree tumor involvement of the celiac axis, including major branches of the 
celiac axis that render it unresectable (e.g. common hepatic artery). 
• 
Tumor involvement of the first branch of the SMA that is not surgically reconstructible 
• 
Long segment involvement of the superior mesenteric vein/portal vein or hepatic artery that is 
not surgically reconstructible 
10.7.2 Histologic Response 
Should the patient undergo surgical resection, pathologic review will be performed locally to 
determine histologic response according to the following criteria: 
• 
Pathologic Complete Response (pCR): 0% residual tumor cells in specimen 
• 
Near Pathologic Complete Response (pNR): 1 to < 5% residual tumor cells in the specimen 
• 
Partial Pathologic Response (pPR): ≥ 5% to 30% residual tumor cells in the specimen 
10.7.3 Margin Status at Resection 
Margins will be assessed according to location (common bile duct, SMA or pancreatic neck) 
according to the following criteria: 


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• 
R0: Macroscopically complete tumor removal with negative microscopic surgical margins. 
• 
R1: Macroscopically complete tumor removal with positive microscopic margins (any or all). 
• 
R2: Macroscopically incomplete tumor removal with known or suspected residual gross 
disease. 
10.8 Patient Reported Outcomes using PRO-CTCAE and LASA 
The PRO-CTCAE and LASA items will be used to determine QOL and patient reported 
disease and treatment related symptoms. 
We do not anticipate major differences in physical function between the two arms and 
various dose levels; however, the various domains of the PRO-CTCAE will help elucidate 
differences in short term effects of SBRT and GC4419 on patients’ well-being. Higher doses of 
radiation may be more effective in alleviating patients’ abdominal pain, nausea and obstructive 
symptoms.  
The IRB-approved questionnaires within the protocol can be provided to patients for 
completion.  Please include patient identifiers on all pages.  At visits in which the questionaires are 
to be completed, the questionaires should be given to the patient before any discussion of the 
patient’s health status or test results.  
The single item linear self-assessment or LASA items for overall QOL, fatigue, mental, and 
physical quality of life will be used to assess the quality of life of patients randomized to each 
treatment arm. These single items have been demonstrated to be prognostic for survival in general 
cancer populations and in pancreatic cancers. These LASA items will be assessed at 
screening/baseline and at specified follow up visits. Overall QOL, fatigue, mental and physical 
quality of life will be assessed at post treatment follow-up. 
Potential treatment-related symptomatic adverse events will be measured using the Patient-
Reported Outcomes version of the CTCAE (PRO-CTCAE).  To improve precision and patient-
centeredness in the capture of symptomatic AEs, NCI funded a team of investigators led by Dr. 
Basch to develop a library of patient-reported outcome (PRO) items to supplement the CTCAE, 
called the PRO-CTCAE.  Of the 790 AEs in the CTCAE, 78 were identified as amenable to patient 
self-report.  For each of these AEs, PRO items were created reflecting the attributes of frequency 
(with response options of “never”, “rarely”, “occasionally”, “frequently”, or “almost constantly”), 
severity (“none”, “mild”, “moderate”, “severe”, or “very severe”), interference with usual or daily 
activities (“not at all”, “a little bit”, “somewhat”, “quite a bit”, or “very much”), amount (“not at all”, “a 
little bit”, “somewhat”, “quite a bit”, or “very much”), or presence (“no” or “yes”).  One to three 
attributes were selected for any given AE depending on the content of the CTCAE criteria for that 
AE and the nature of that particular AE.  In total, 124 individual items represent the 78 symptomatic 
AEs currently in the PRO-CTCAE item library.  Each item includes a plain language term for the 
AE, the attribute of interest, and the standard recall period of “the past 7 days.”  Cognitive interviews 
previously determined a high level of patient understanding and meaningfulness of the items and a 
national multi-site validation study showed that items were valid, reliable, and sensitive to change.  
For this study, the following symptomatic AEs selected were based on the known symptomatic 
toxicities occurring in >10% of patients treated with SBRT.  Specifically, at the selected time points, 
patients will complete 15 PRO-CTCAE items measuring:  Fatigue, nausea, vomiting, diarrhea, 


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neuropathy, abdominal discomfort, abdominal bloating, pain, heartburn, decreased appetite, dry 
mouth, taste changes, itching (pruritis), depression, anxiety.  The recall period will be 2 weeks.  AEs 
will be measured at baseline, end of SBRT and at follow up visits. Reporting will occur using table 
based technology or paper booklets, as available. 
The final survey contains only 4 LASA items plus 15 PRO-CTCAE items it is anticipated that 
the questionnaire will take approximately 10 minutes for the patient to complete at each 
administration time point.  We anticipate having questionnaires available in English and Spanish.  
Patients may decline to complete a questionnaire at any time.  The primary reason for each missed 
questionnaire will be collected on a case report form.  


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11.0 
END OF TREATMENT/INTERVENTION 
11.1 Duration of Treatment 
The treatment period will begin the first day of SBRT and GC4419/placebo treatment and 
end the final day of SBRT and GC4419/placebo treatment. 
Patients may not receive additional anti-cancer therapy during the 90 day follow up period, 
except in the instance of progression of disease. After 90 days, patients may receive therapy at the 
treating physician’s discretion. Any anti-cancer therapy should be recorded in the case report form.  
11.2 Managing ineligible patients and registered patients who never 
receive protocol intervention 
Patients who are randomized but later deemed ineligible for SBRT or voluntarily withdraw 
from the study will still be eligible for follow up imaging and correlative studies, in addition to PRO 
data, should they so choose. These patients will not be considered in the n=48 patients to be 
randomized, and will not be considered in the final analyses for primary and secondary endpoints. 
The reason for not receiving protocol intervention must be documented. 
11.3 Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or 
the patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. 
In this event: 
• 
Document the reason(s) for discontinuation of therapy on the case report forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 


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12.0 
STATISTICAL CONSIDERATIONS 
12.1 Study Primary Endpoint 
For the purposes of dose finding the following definitions will be used in determining MTD: 
• 
Toxicity:  CTCAE grade 3 or 4 related gastro-intestinal (GI) toxicity or death, occurring within 
90 days from the start of therapy. 
• 
Efficacy: Radiographic stable disease (SD) or better based on modified RECIST criteria, 
(section 10.6.4), compared to baseline imaging of the same type, as evaluated at day 90 from 
the start of therapy. 
o If a patient dies or has local progressive disease (LPD) at some time t* prior to day 90, 
then Efficacy will be scored at the time t* as not occurring for that patient. 
o If a patient undergoes resection at some time t* prior to day 90, then Efficacy will be 
scored as occurring at t* and Toxicity will be scored as not occurring within 90 days for 
that patient. 
Prior to determination of final MTD, 12 month toxicity will also be evaluated.  If any dose level 
demonstrates >20% grade 4 or 5 gastrointestinal toxicity related to radiation, the preceding dose 
level will be used as the final MTD. 
12.2 Prior Probabilities 
An adaptive design requires prior mean probabilities of efficacy and toxicity at each dose 
level. These estimates were determined in collaboration by all study investigators based on all 
available SBRT dose escalation studies, as discussed in section 1.2.5, with particular weight placed 
on more modern studies using modern radiation techniques. Table 5 outlines the prior mean 
probabilities for each dose level. 
 
 
12.3 Randomization and Sample Size 
A maximum of 2x24 = 48 patients will be randomized between two subgroups. Patients in 
subgroup 1 will receive GC4419 in combination with their assigned RT dose, and patients in 
subgroup 0 will receive their assigned RT dose and placebo (no GC4419). The randomization will 
be restricted so that the sample size within each subgroup is exactly 24 patients. The restricted 
randomization sequence will be constructed prior to trial initiation, and applied by the Statistical 
Table 5. Prior mean probabilities of efficacy 
and toxicity for each dose level of interest. 
Dose 
Level 
PTV2 
BEDa 
(a/B = 10) 
Prior mean 
efficacy 
probability 
Prior mean 
toxicity 
probability 
1 
100 Gy 
75% 
2% 
2 
115.5 Gy 
85% 
7% 
3 
132 Gy 
95% 
10% 


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Analyst overseeing the trial treatment and RT dose assignments.  An overall accrual rate of 
approximately 3 patients per month is anticipated, which will give approximately 1.5 patients per 
month in each subgroup. 
12.4 Phase I-II Dose Finding Design 
Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-
Toxicity (LO-ET) trade-off-based design33-35.  For the purpose of dose-finding, as stated in section 
12.1:  
• 
Toxicity is defined as a grade 3 or 4 gastro-intestinal (GI) toxicity, or death, occurring within 90 
days from the start of therapy. For the purpose of dose-finding 
• 
Efficacy is defined as stable disease (SD) or better, compared to baseline, as evaluated at day 
90 from the start of therapy (section 10.6.4). 
12.5 Maximum Sub-sample Size and Cohort Size 
The same adaptive dose-finding design will be used in each of the two subgroups.  Within 
each subgroup, up to 24 patients will be treated in 8 cohorts of size 3 each.  The first cohort will be 
treated at dose level 1, all successive doses will be chosen by the LO-ET method to maximize the 
posterior Efficacy-Toxicity trade-off, and an untried dose level (dose level 2) may not be skipped 
when escalating initially.   
12.6 Dose Acceptability 
For the two LO-ET dose acceptability rules, the upper limit on the probability of Toxicity is 
0.15, the minimum probability of Efficacy 0.75, and the decision cut-offs 0.10 will be used or both 
stopping probability criteria.  If the lowest dose level is found to be unacceptable in terms of high 
toxicity, or if the highest dose level is found to be unacceptable in terms of low efficacy, the trial will 
be terminated and no dose level will be selected.  Accrual will only be paused before proceeding to 
the highest dose level.  Dose level 1 has been safely used previously so there will be no pause in 
accrual. 
12.7 Efficacy-Toxicity Trade-Off Contours and Priors 
The three equivalent trade-off (pE, pT) probability pairs used for computing the trade-off 
contours are (0.60, 0), (0.75, 0.15), (1, 0.40). The prior hyper-parameters were computed based on 
the assumed prior means Prob(Efficacy | dose) =  0.75, 0.85, 0.95  and Prob(Toxicity | dose) = 0.02, 
0.07, 0.10, respectively, at the three RT  dose levels.  The prior effective sample size  = 1 for the 
toxicity parameter prior and 1 for the efficacy parameter prior. This is illustrated in Figure 11. 


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12.8 Design Operating Characteristics 
Operating characteristics of the design, as conducted within each subgroup, are 
summarized in table 6 below, based on simulations with 1000 replications per scenario. In the 
simulations, it is assumed that the times to toxicity and efficacy follow Weibull distributions, the 
percentage of toxicity (or efficacy) events occurring in the later half of each evaluation interval is 
50%, and the accrual rate is 1.5 patients per month.  The maximum sample size is 24, with up to 8 
cohorts of size 3. 
 
Figure 11. Efficacy-Toxicity Trade-Off Contours for the Current 
Study based on assumed prior means Prob(Efficacy | dose) =  
0.75, 0.85, 0.95  and Prob(Toxicity | dose) =  0.02, 0.07, 0.10, 
respectively, at the three RT dose levels. 


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Table 6. Design Operating Characteristics of the current study with 24 patients per arm, 3 
dose levels, and accrual rate of 1.5 patients per month, based on simulations with 1000 
replications per scenario, assuming toxicity and efficacy follow Weibull distributions. 
Scenario 
 
SBRT Dose level 
 
 
1 
2 
3 
1 
True toxicity probability 
005 
0.06 
0.07 
 
 
 
 
 
 
True Response probability 
0.50 
0.70 
0.85 
 
Selection percentage 
0.20 
18.5 
74.9 
 
Average number of patients 
4.7 
8.3 
10.1 
 
 
 
 
 
2 
True toxicity probability 
0.02 
0.08 
0.30 
 
True response probability 
0.60 
0.80 
0.90 
 
Selection percentage 
2.3 
67.0 
24.6 
 
Average number of patients 
5.9 
12.2 
5.4 
 
 
 
 
 
3 
True toxicity probability 
0.10 
0.30 
0.46 
 
True response probability 
0.90 
0.92 
0.94 
 
Selection percentage 
80.9 
9.3 
0.2 
 
Average number of patients 
15.1 
4.5 
0.8 
 
 
 
 
 
4  
True toxicity probability 
0.02 
0.04 
0.05 
(poor efficacy) 
True response probability 
0.20 
0.30 
0.40 
 
Selection percentage 
0 
0.1 
3.4 
 
Average number of patients 
3.5 
3.7 
8.9 
 
 
 
 
 
5  
True toxicity probability 
0.35 
0.45 
0.60 
(excessive toxicity) True response probability 
0.50 
0.70 
0.85 
 
Selection percentage 
0.1 
0.4 
0.1 
 
Average number of patients 
4.9 
3.5 
1.1 
 
Based on these simulations, should all dose levels in any treatment arm demonstrate > 15% 
probability of grade 3 or higher toxicity based on prior probabilities and enrolled patients, the study 
arm will terminate in approximately 6 months with 5, 4 and 1 patients assigned to dose levels 1,2 
and 3, respectively.  Should all dose levels in any treatment arm demonstrate < 75 % probability of 


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stable/responsive disease, the study arm will terminate in approximately 12 months with 4, 4 and 
9 patients assigned to dose levels 1,2 and 3, respectively.  Should dose level 3 be the MTD, the 
study will accrue to completion (approximately 16 months) with 5, 8 and 10 patients assigned to 
dose levels 1, 2, and 3, respectively.  Should dose level 2 be the MTD, the study will accrue to 
completion (approximately 16 months) with 6, 12 and 5 patients assigned to dose levels 1, 2 and 3 
respectively.  In this scenario, dose limiting toxicity (DLT) would have to occur in a minimum of 2/5 
patients treated at dose level 3.  Should dose level 1 be the MTD, the study will accrue to completion 
(approximately 16 months) with 15, 5 and 1 patients assigned to dose levels 1, 2 and 3 respectively.  
Again, in this scenario, DLT would have to occur in a minimum of 2/5 patients treated at dose level 
2. 
12.9 Implementation 
12.9.1 LO-ET Trial Implementation 
The Late-Onset Efficacy-Toxicity (LO-ET) design will be implemented using the specialized 
computer program developed by Jin et al.35 During trial conduct, application of the statistical design 
will be carried by Rebecca Slack, a Statistical Analyst in the Department of Biostatistics. This will 
include (1) randomization of each patient at entry between the two arms, RT+ GC4419 versus RT 
only, and (2) adaptive dose assignment within each arm using the LO-ET method.  Outcome-
adaptive dose-finding will be done by inputing the current trial data and running the specialized 
computer program that implements the LO-ET method.  This process will require close interaction 
between Ms. Slack and personnel in the clinic, including repeatedly providing Ms. Slack with all 
dose-outcome data from all previously enrolled patients, including each previous patient’s time of 
Toxicity occurrence or current follow up time without Toxicity, up to the defined 90-day observation 
interval, and whether efficacy occurred at day 90.  Critical variable data (provided within your Study 
Manual) should be entered into the electronic data capture clinical database in a timely fashion to 
ensure data is included in the ongoing analysis for SBRT dose level assignments. Xuemi Wang, a 
Senior Statistical in the Department of Biostatistics, will serve as a backup for Ms. Slack in the 
process of trial conduct.  Additional statistical support or input will be provided as required by Drs. 
Peter Thall and Ying Yuan33,34,36,37.  Details and procedures related to the various safety, efficacy, 
and correlative analyses will be provided in a formal Statistical Analysis Plan. 
12.9.2 Secondary Endpoints and Analysis 
Secondary outcomes will include progression-free survival (PFS) time and overall response 
rate  in addition to rate of long-term toxicity, surgical resection and rates of R0 and pathologic 
complete response at resection.  Unadjusted distributions of the time-to-event outcomes PFS and 
OS will be estimated using the method of Kaplan and Meier and their relationship to prognostic 
covariates and RT cell dose level will be evaluated by Bayesian piecewise exponential survival 
regression.  
Resectability will be assessed at the seven week time point.  If a patient goes on to resection, 
he or she will be categorized as acceptable efficacy.  If the patient is deemed unresectable, efficacy 
will be reassessed at 12 weeks.  Toxicity will also be assessed at the 12 week timepoint and 
descriptive statistics will be generated. If endoscopy exhibits severe toxicity, the patient will be 
deemed as unacceptable toxicity. 


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12.9.3 Interim Analysis 
The sponsor was unblinded to treatment assignment for overall study monitoring and safety 
review. One unblinded interim descriptive efficacy analysis will be performed for study design 
planning on the first 19 subjects. To facilitate future study design planning with investigators, interim 
efficacy results on those first 19 subjects will be provided to participating investigators.   Subsequent 
to the single completed interim analysis by the sponsor, no unblinded efficacy analysis will be 
performed until the final statistical analysis. Investigators and supporting staff will remain blinded to 
randomized treatment assignments for patients 20-48, with only unblinded staff being site 
pharmacists, MDACC statisticians, and limited sponsor staff relative to study management and 
routine safety oversight. 


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13.0 
CORRELATIVE STUDIES 
13.1 Imaging Correlative Studies 
In addition to CT based imaging, patients may also undergo baseline and follow up MRI 
scans in order to better assess toxicity and tumor response. With improved technology, MRI based 
techniques are increasingly used in the inflammatory bowel setting for improved evaluation and 
monitoring of the mucosa38. The small bowel is particularly a challenging organ for MRI imaging 
due to mobility, distention and contrast. Biphasic oral contrast agents have been shown to help us 
better evaluate the mucosal lining in IBD38. They allow for the mucosal enhancement on T1 and T2 
weighted images leading to a drastic contrast between the wall and the lumen allowing for more 
detailed evaluation of the fold and wall thickness for inflammation following SBRT. In addition to 
oral contrast agents, iv gadolinium and fat suppression can further help highlight tissue edema on 
T2 weighted imaging38.  
There is an abundance of literature highlighting the benefits of MR imaging in the evaluation 
of bowel mucosal inflammation and edema in IBD38,39.  We aim to use similar MR techniques in 
order to evaluate toxicity and efficacy from SBRT.  Patients may undergo baseline MRI post-
induction chemotherapy and prior to initiation of SBRT.  They may then undergo MRI 
abdomen/pelvis approximately 12 weeks following completion of SBRT.  MRI characteristics will be 
associated with efficacy findings at 12 weeks.  In case of contraindications (eg pacemaker, severe 
claustrophobia, etc) a high quality CT scan can be acquired.  
13.2 Pathologic and Biomarker Correlative Studies 
13.2.1 Background and Rationale  
While targeted therapies and immunotherapies have provided significant advances in other 
cancer types with poor prognoses, including non-small cell lung cancer and melanoma, none of 
these therapies have provided significant advances in LAPC.  There are a multitude of reasons for 
this, but primarily we have inadequate data regarding the genomics, proteomics, immune 
microenvironment, and tumor microenvironment surrounding these tumors.  Although patients who 
undergo surgical resection (20% of all patients with PAC), analyses have been limited in patients 
with LAPC and metastatic pancreatic cancer (MPC) by the fact that the majority of these patients 
undergo only a fine needle aspiration (FNA) at time of diagnostic endoscopy.  FNA samples exhibit 
cellular paucity in the range of <100 cells per sample, in addition to the fact that they are often 
contaminated with normal cells from duodenum and stomach in addition to tumor cells due to the 
endoscopic technique, making any type of high throughput sequencing a logistic challenge.  
Although technologies have advanced to allow sequencing with smaller volumes of extracted 
DNA40,41, the question of tumor purity from these samples for sequencing purposes remains without 
any adequate studies with paired FNA and core needle biopsy (CNB) samples. 
The second limitation of development of targeted therapies in LAPC is the fact that PAC 
remains one of the most heterogeneous cancer types currently understood, and it exhibits rapid 
changes in its genomic structure.  Although common mutations exist, such as in KRAS and BRAF, 
PAC also exhibits a high frequency of alterations in a multitude of other pathways, including Wnt 
signaling, chromatin remodeling, Hedgehog signaling, DNA repair and cell cycle maintenance42-46. 


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Metastatic lesions demonstrate even further genetic heterogeneity, with indications that metastatic 
lesions develop late in the genetic progression, despite the fact that 30% of patients present initially 
with MPC,47,48 making targeted therapies less likely to work. Additionally, PAC is unique in that 
tumors exhibit a high stromal component made up of dense fibrotic tissue, immune cells and 
vascular structures, which limits drug delivery to the tumor and appears to interact with the tumor 
and both encourage and discourage growth through pathways which are not yet clearly 
understood49. While some models demonstrate that removal of the stroma leads to poor prognosis, 
aggressive tumor survival and decreased overall survival50,51, others demonstrate that removal of 
the stroma may increase drug delivery and treatment response52. Despite strong evidence that 
immune environment plays a strong role in PAC carcinogenesis and phenotype in both clinical and 
pre-clinical data53-56 PAC has overall demonstrated disappointing response to vaccine and 
immunotherapy. This may in part be due to pancreatic stromal microenvironment, although the 
mechanism is unclear. 
Currently, one of the unclear clinical questions in the management of both LAPC patients 
and resected PAC patients is whether these patients benefit from radiation therapy. Although 
prospective studies in the modern era have failed to show a benefit of chemoradiation over 
chemotherapy alone in either setting, there are clearly patients who benefit from the  local control 
of tumor provided by radiation, and patients who go on to develop local progression in the absence 
of metastatic disease. Previous studies show that as high as 30% of PAC patients may die from 
local disease progression alone in the absence of metastatic disease4-6. The development of 
biomarkers that could help identify these patients with an isolated local failure phenotype versus a 
propensity for development of metastatic disease would be a clinical game-changer in the setting 
of BRPC and LAPC, helping clinicians to select patients who would benefit from aggressive local 
therapy, including high dose, focused radiation therapy, potentially with a radiomodulator drug, 
versus those who would benefit from intensive systemic or targeted therapy to control risk of 
metastatic disease. Additionally, in the unique setting of a prospective radiation therapy study, 
evaluating biomarkers for likelihood of response to high dose radiation may help identify those more 
likely to respond and thus benefit from high dose radiation therapy.  


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Table 7. Study Calendar for Collection of Correlative Samples 
Timepoint 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Day of Treatment* 
Pre-
SBRT 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
4 
weeks 
Post 
SBRT 
7 
weeks 
Post 
SBRT 
Resection 
12 
weeks 
Post 
SBRT 
Blood (1) 
X 
 
X 
 
 
X 
X(2) 
X  
X (6) 
X 
FNA 
X 
 
 
 
 
 
 
 
 
X 
Core Biopsy (CNB) 
X 
 
 
 
 
 
 
 
 
X 
Cytology 
X 
 
 
 
 
 
 
 
 
X 
Imaging (4) 
X 
 
 
 
 
 
 
X 
 
X 
Resection Specimen 
(RS) 
 
 
 
 
 
 
 
 
X (6) 
 
* The same study windows will apply as noted in the Study Calendar, section 5.0 
1 If blood is being taken at the time of infusion of GC4419 or placebo, samples should be collected prior to dosing at 
the time of intravenous access.  Otherwise, there is no restriction on when blood can be drawn as long as it is within 
the indicated window of time. 
2 Optional blood draws at week 4 and follow-up 
3  FNA and Core biopsy will not be taken at 3 month endoscopy if any sign of radiation damage is visualized  
4 Fresh and FFPE Core needle biopsy specimens 
5  Imaging consists of baseline MRI and/or triphasic CT 
6 If patient undergoes resection, fresh and frozen tissue collected at time of resection in addition to standard 
histopathology for evaluation of treatment response 
 
13.2.2  Sample Collection Calendar 
Longitudinal patient samples will be collected at each participating center, according to the 
calendar in Table 7.  Participating centers will send samples to UTMDACC Zayed as outlined in the 
Correlative Laboratory Manual.  These samples will be  maintained through the UTMDACC Zayed 
Pancreas Center or the Adaptive Patient-Oriented Longitudinal Learning and Optimization 
(APOLLO) platform and analyzed in-house.  Patients reserve the right to refuse sample or blood 
collection at any time point and will remain enrolled on the protocol for treatment outcome analysis. 
13.2.3 Pathologic Biomarker Correlates  
This section includes FNA samples collected at time point 1 and 10, Core biopsy specimens 
collected at time point 1 and 10, and potential tissue collected at time point 9.  
13.2.3.1 
Collection, Storage and Maintenance of Samples 
See tables 8-9 for collection methodology of each sample. 


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Table 8. Collection, Storage and Maintenance of Tissue Correlate Samples 
Source 
Collection 
MDACC Storage and  
Maintenance 
Other Institutions 
Purpose 
FNA 
Aspiration using 25-guage 
needle, placed immediately 
into 1.5ml microcentrifuge 
tube in 1ml of normal saline 
and kept on ice for transport 
Fresh to be processed 
for DNA extraction within 
30 minutes, FFPE stored 
for 
future 
microdissection 
Snap frozen and stored 
at -80; Shipped to 
MDACC en batch after 
coordination 
with 
MDACC Lead Study 
Investigator 
Sequencing 
correlations to CNB  
CNB 
A minimum of two CNB’s will 
be obtained during fiducial 
placement using an 18-
guage 
Tru-Cut 
biopsy 
needle; Fresh to be kept on 
ice for transport, FFPE for 
storage 
Fresh to be processed 
for DNA extraction and 
organoid 
development 
within 30 minutes, FFPE 
stored for future studies 
Snap frozen and stored 
at -80; Shipped to 
MDACC en batch after 
coordination 
with 
MDACC Lead Study 
Investigator 
Organoid 
development, 
Whole 
exome/ 
transcriptome, 
Immune profiling 
RS 
Intraoperative 
specimen 
collection will be performed 
of 
Fresh/ 
frozen 
tissue. 
FFPE tissue will be obtained 
after pathologic assessment 
Fresh to be processed 
for DNA extraction within 
30 minutes, FFPE stored 
for future 
If 
available 
after 
pathologic 
assessment, FFPE will 
be shipped to MDACC 
after coordination with 
MDACC Lead Study 
Investigator 
Sequencing, 
immune correlates 
 
13.2.3.2 
Planned/ Potential Analyses 
 
Organoid development 
 
Whole exome sequencing 
 
Whole transcriptome sequencing 
13.2.4 Serum Biomarker Correlates  
This section includes all blood samples collected at time points 1, 3, 6, 7, 8, 9 and 10. 


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Table 9. Collection, Storage and Maintenance of Correlate Samples 
Timepoint 
Collection 
MDACC Storage and  
Maintenance 
Other Institutions 
Purpose 
Plasma 
One 
5-10mL 
EDTA (Lavender 
top) tube at each 
time point 
Centrifuged at 3,500 rpm 
for 15 minutes at 4°C 
within 3 hours of blood 
draw, stored at -80°C 
until use 
Blood samples will be processed 
for plasma according to institutional 
standards and frozen at -80°C; 
Shipped to MDACC en batch after 
coordination with MDACC Lead 
Study InvestigatorI 
ctDNA, 
exosomal DNA 
Whole 
Blood 
Two 
5-10mL 
EDTA (Lavender 
top) tube at each 
time point 
One 
tube 
to 
be 
maintained as fresh and 
stored cold to isolate 
PBMC’s within 12 hours 
Second tube to be stored 
for future studies 
Immune 
profiling, Whole 
exome 
sequencing 
 
13.2.4.1 
Planned/ Potential Analyses 
Circulating tumor DNA/ Cell free (including exosomes) DNA: Peitrasz et al recently 
demonstrated that plasma circulating tumor DNA (ctDNA, or cell free DNA) may play a role as 
a prognostic marker in PAC. In this study, 48% of patients with locally advanced PAC 
demonstrated detectable ctDNA with a median mutation allelic frequency (MAF) of 6.1%. The 
presence of ctDNA was strongly correlated with overall survival, as was the MAF for individual 
patients57. In this study, we will have the opportunity to exploratorily examine the effect of SBRT 
on ctDNA levels and the potential utility of ctDNA as a prognostic factor for conversion to 
surgical resection and overall survival of patients undergoing SBRT for BRPC and LAPC. 
13.2.5 Immune Correlates 
In addition to the CNB and FNA samples collected during endoscopy, endoscopic brushings 
will be collected of the pancreatic tumor. These brushings will be analyzed using multiparametric 
flow cytometry (MPFC) for markers of immune proliferation, activation and exhaustion phenotypes. 
Changes in the immune microenvironment with SBRT for pancreatic cancer have not been 
studied, nor has the interaction of the immune microenvironment on response of PAC to radiation 
therapy. These exploratory analyses will provide pilot data regarding the best methodology to 
assess immune environment in PAC. 
13.2.5.1 
Planned/ Potential Analyses 
• 
T cell receptor profiling: Deep T-cell receptor β sequencing (TCR) has been used to 
predict response to immunotherapy and vaccine therapy in other tumor types, including 
melanoma, lung cancer, prostate and breast cancer58-61. We have been successfully using 
this technology to analyze cervical and anal cancers using DNA extracted from a non-
invasive swab biopsy technique, and the ability to reliably detect T cell profiles using 
minimum DNA would allow new insight into predictors of the generation of a robust anti-
tumor immune response stimulated by radiation in LAPC that may not be present with 
traditional fractionated radiation. TCR will be used to detect clonal amplification and 
density of intratumoral T-cells. 


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• 
Immunohistochemistry immune profiling 
• 
Multiparametric flow cytometry (MPFC): Using cytology brushings, our group has 
previously used MPFC to characterize changes in immune profiles using cytobrush swabs 
of cervical and anal cancers. Cells collected from cytobrushes were stained with 
antibodies to CD3, CD4, CD8, ICOS, CTLA-4, Ki67, PD-1, FoxP3 and Fixable Aqua Dead 
Cell stain and analyzed by flow cytometry. Comprehensive analysis of TIL by flow 
cytometry will allow assessment of effector T cell ratios relative to Treg and MDSC, as well 
as phenotypic and functional analysis of multiple T, NK, and myeloid cell subsets. 
• 
Peripheral Immune profiling: Static immune profiling in other tumor types demonstrates the 
presence of changes in immune markers, but it is unclear whether these changes are 
reflective of radiation induced generation of tumor specific immune response or a 
response to radiation induced direct cell killing. The only way to determine this is through 
the use of longitudinal immune assays through the course of radiation. Moreover, recent 
hypotheses suggest that the immune response of radiation may be optimized through a 
one week “package time” and that longer course of radiation may lead to adverse effects 
on immunogenic cell death (ICD) from radiation, in addition to a suggestion that larger 
single fraction sizes may increase ICD62-65. If this is true, we may see increased immune 
activation with SBRT, and this effect may change with increased doses. Performing 
exploratory peripheral immune profiling using deep TCR and MPFC will allow us to better 
characterize these fluid immune changes. 
13.2.6 Specimen Storage for Future Studies 
All remaining specimens will be maintained with the MDACC lead study investigator for use 
in future correlative and biomarker analyses. 


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14.0 GENERAL REGULATORY CONSIDERATIONS  
14.1 Institutional Regulatory Approval 
The study must be approved by the participating center’s Institutional Review Board (IRB) 
and any research committee as require per institutional policy. The trial will be conducted according 
to all institutional IRB and if applicable, any local research committee guidelines. All modifications 
or amendments to the protocol will go through IRB review. 
14.2 Informed Consent 
Subjects, after having the study explained to them and an opportunity to have their questions 
answered sufficiently, will give voluntary and written informed consent (in compliance with ICH E6, 
4.8 and 21 CFR Parts 50 and 312) before participating in any study-related procedures.  
In addition to obtaining informed consent/assent, the Investigator is responsible for obtaining 
any additional documentation to demonstrate compliance with local privacy laws applicable to 
activities performed.  
The consent/assent process shall be recorded in source documents. Signed copies of the 
informed consent and/or assent will be given to the Subject and originals will be placed in the 
Investigator study files.  
14.3 Publication 
All publication or presentation rights for the findings of the clinical study shall be governed 
by the appropriate terms of the Clinical Research Agreement between the investigational site and 
Galera Therapeutics Inc. in collaboration with the lead investigator site (UTMDACC) 
14.4 Data Analysis 
All data will be maintained within an electronic data capture system at Galera and 
UTMDACC throughout the duration of the study, and all analysis will be performed by Galera or 
UTMDACC statisticians. The data will be available to UTMDACC researchers for any future 
correlative or collaborative studies and publications. 
14.5 Study Monitoring  
The study will be monitored and managed in accordance with ICH GCP E6.   
Galera Therapeutics, Inc. or its representatives will monitor each Investigator site for study progress 
and to verify that standards of GCP were followed.  The Investigator is expected to prepare for the 
monitor visit, ensuring that all source documents, completed eCRFs, signed consent forms and 
other study related documents are readily available for review. 
Galera Quality Assurance or its representatives and Regulatory agencies may conduct a 
regulatory inspection of this study.  Such audits/inspections can occur at any time during or after 
completion of the study.  If an audit or inspection occurs, the investigator and institution agree to 
allow the auditor/inspector direct access to all relevant documents and to allocate his/her time and 
the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues. 


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15.0 
REFERENCES 
1. 
Cancer Facts & Figures 2015. In: Society AC, ed.2015. 
2. 
Murphy JD, Christman-Skieller C, Kim J, Dieterich S, Chang DT, Koong AC. A dosimetric model of 
duodenal toxicity after stereoftactic body radiotherapy for pancreatic cancer. Int J Radiat Oncol Biol Phys 
2010;78:1420-6. 
3. 
Nitsche U, Wenzel P, Siveke JT, et al. Resectability After First-Line FOLFIRINOX in Initially 
Unresectable Locally Advanced Pancreatic Cancer: A Single-Center Experience. Ann Surg Oncol 2015;22 
Suppl 3:S1212-20. 
4. 
Colbert LE, Fisher SB, Balci S, et al. High nuclear hypoxia-inducible factor 1 alpha expression is a 
predictor of distant recurrence in patients with resected pancreatic adenocarcinoma. Int J Radiat Oncol Biol 
Phys 2015;91:631-9. 
5. 
Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma 
correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806-13. 
6. 
Winter JM, Tang LH, Klimstra DS, et al. Failure patterns in resected pancreas adenocarcinoma: 
lack of predicted benefit to SMAD4 expression. Annals of surgery 2013;258:331-5. 
7. 
Hammel P, Huguet F, van Laethem JL, et al. Effect of Chemoradiotherapy vs Chemotherapy on 
Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine 
With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA 2016;315:1844-53. 
8. 
Hammel P HF, Van Laethem J-L, et al. Comparison of chemoradiotherapy (CRT) and 
chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months 
of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. J Clin 
Oncol 2013;31(suppl): LBA 4003a. 
9. 
Hammel P, Huguet F, van Laethem JL, et al. Effect of Chemoradiotherapy vs Chemotherapy on 
Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine 
With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA 2016;315:1844-53. 
10. 
Polistina F, Costantin G, Casamassima F, et al. Unresectable locally advanced pancreatic cancer: 
a multimodal treatment using neoadjuvant chemoradiotherapy (gemcitabine plus stereotactic radiosurgery) 
and subsequent surgical exploration. Ann Surg Oncol 2010;17:2092-101. 
11. 
Murphy JD, Chang DT, Abelson J, et al. Cost-effectiveness of modern radiotherapy techniques in 
locally advanced pancreatic cancer. Cancer 2012;118:1119-29. 
12. 
Wild AT, Herman JM, Dholakia AS, et al. Lymphocyte-Sparing Effect of Stereotactic Body Radiation 
Therapy in Patients With Unresectable Pancreatic Cancer. Int J Radiat Oncol Biol Phys 2016;94:571-9. 
13. 
Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate 
non-redundant immune mechanisms in cancer. Nature 2015;520:373-7. 
14. 
Herman JM, Chang DT, Goodman KA, et al. Phase 2 multi-institutional trial evaluating gemcitabine 
and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic 
adenocarcinoma. Cancer 2015;121:1128-37. 


Protocol Amendment 07 
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72 
 
15. 
Rao AD, Sugar EA, Chang DT, et al. Patient-reported outcomes of a multicenter phase 2 study 
investigating gemcitabine and stereotactic body radiation therapy in locally advanced pancreatic cancer. 
Pract Radiat Oncol 2016;6:417-24. 
16. 
Shaib WL, Hawk N, Cassidy RJ, et al. A Phase 1 Study of Stereotactic Body Radiation Therapy 
Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX 
(NCT01446458). Int J Radiat Oncol Biol Phys 2016;96:296-303. 
17. 
Tao R, Krishnan S, Bhosale PR, et al. Ablative Radiotherapy Doses Lead to a Substantial 
Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective 
Dose Response Analysis. J Clin Oncol 2016;34:219-26. 
18. 
Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the 
M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097-105. 
19. 
Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and 
neck cancer: a meta-analysis. Lancet 2006;368:843-54. 
20. 
Crane CH. Improving Long-Term Survival in Patients With Locally Advanced Pancreatic Cancer via 
the Delivery of Definitive Radiotherapy Doses. Oncology (Williston Park) 2015;29:561-2, 6. 
21. 
Krishnan S, Chadha AS, Suh Y, et al. Focal Radiation Therapy Dose Escalation Improves Overall 
Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and 
Consolidative Chemoradiation. International journal of radiation oncology, biology, physics 2016;94:755-
65. 
22. 
Petrelli F, Comito T, Ghidini A, Torri V, Scorsetti M, Barni S. Stereotactic Body Radiation Therapy 
for Locally Advanced Pancreatic Cancer: A Systematic Review and Pooled Analysis of 19 Trials. Int J 
Radiat Oncol Biol Phys 2017;97:313-22. 
23. 
Zhong J, Patel K, Switchenko J, et al. Outcomes for patients with locally advanced pancreatic 
adenocarcinoma treated with stereotactic body radiation therapy versus conventionally fractionated 
radiation. Cancer 2017. 
24. 
Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body radiation therapy for locally 
advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol 
Biol Phys 2013;86:516-22. 
25. 
Trakul N, Koong AC, Chang DT. Stereotactic body radiotherapy in the treatment of pancreatic 
cancer. Semin Radiat Oncol 2014;24:140-7. 
26. 
Hoyer M, Roed H, Sengelov L, et al. Phase-II study on stereotactic radiotherapy of locally advanced 
pancreatic carcinoma. Radiother Oncol 2005;76:48-53. 
27. 
Crane CH, Koay EJ. Solutions that enable ablative radiotherapy for large liver tumors: Fractionated 
dose painting, simultaneous integrated protection, motion management, and computed tomography image 
guidance. Cancer 2016;122:1974-86. 
28. 
Sishc BJ BD, Takeshima T, et.al.  Superoxide dismutase mimetic GC4419 sensitizes non-small cell 
lung cancer tumors to high dose per fraction radiation and ameliorates radiation induced lung fibrosis.  
Presented at the 62nd Annual Meeting of the Radiation Research Society, Oct. 16-19, 2016, Waikoloa 
Village, HI. 


Protocol Amendment 07 
GTI-4419-101 
24January2020 
 
 
 
Confidential 
73 
 
29. 
Molla M, Gironella M, Salas A, et al. Protective effect of superoxide dismutase in radiation-induced 
intestinal inflammation. Int J Radiat Oncol Biol Phys 2005;61:1159-66. 
30. 
Thompson JS, Chu Y, Glass J, Tapp AA, Brown SA. The manganese superoxide dismutase 
mimetic, M40403, protects adult mice from lethal total body irradiation. Free Radic Res 2010;44:529-40. 
31. 
Murphy CK, Fey EG, Watkins BA, Wong V, Rothstein D, Sonis ST. Efficacy of superoxide dismutase 
mimetic M40403 in attenuating radiation-induced oral mucositis in hamsters. Clin Cancer Res 
2008;14:4292-7. 
32. 
Coleman MC, Olivier AK, Jacobus JA, et al. Superoxide mediates acute liver injury in irradiated 
mice lacking sirtuin 3. Antioxid Redox Signal 2014;20:1423-35. 
33. 
Thall PF, Cook JD, Estey EH. Adaptive dose selection using efficacy-toxicity trade-offs: illustrations 
and practical considerations. J Biopharm Stat 2006;16:623-38. 
34. 
Thall PF, Cook JD. Dose-finding based on efficacy-toxicity trade-offs. Biometrics 2004;60:684-93. 
35. 
Jin IH, Liu S, Thall PF, Yuan Y. Using Data Augmentation to Facilitate Conduct of Phase I-II Clinical 
Trials with Delayed Outcomes. J Am Stat Assoc 2014;109:525-36. 
36. 
Ibrahim JG, Zhu H, Tang N. Bayesian local influence for survival models. Lifetime Data Anal 
2011;17:43-70. 
37. 
Ibrahim JG, Chen MH, Sinha D. Bayesian semiparametric models for survival data with a cure 
fraction. Biometrics 2001;57:383-8. 
38. 
Zimmermann EM, Al-Hawary MM. MRI of the small bowel in patients with Crohn's disease. Curr 
Opin Gastroenterol 2011;27:132-8. 
39. 
Lee ES, Lee JM. Imaging diagnosis of pancreatic cancer: a state-of-the-art review. World J 
Gastroenterol 2014;20:7864-77. 
40. 
Sho S, Court CM, Kim S, et al. Digital PCR Improves Mutation Analysis in Pancreas Fine Needle 
Aspiration Biopsy Specimens. PLoS One 2017;12:e0170897. 
41. 
Talhouk A, Kommoss S, Mackenzie R, et al. Single-Patient Molecular Testing with NanoString 
nCounter Data Using a Reference-Based Strategy for Batch Effect Correction. PLoS One 
2016;11:e0153844. 
42. 
Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of 
pancreatic cancer. Nature 2015;518:495-501. 
43. 
Dreyer SB, Chang DK, Bailey P, Biankin AV. Pancreatic Cancer Genomes: Implications for Clinical 
Management and Therapeutic Development. Clin Cancer Res 2017;23:1638-46. 
44. 
Colbert LE, Petrova AV, Fisher SB, et al. CHD7 expression predicts survival outcomes in patients 
with resected pancreatic cancer. Cancer Res 2014;74:2677-87. 
45. 
Hall WA, Petrova AV, Colbert LE, et al. Low CHD5 expression activates the DNA damage response 
and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer. 
Oncogene 2014;33:5450-6. 


Protocol Amendment 07 
GTI-4419-101 
24January2020 
 
 
 
Confidential 
74 
 
46. 
Colbert LE, Fisher SB, Hardy CW, et al. Pronecrotic mixed lineage kinase domain-like protein 
expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma. 
Cancer 2013;119:3148-55. 
47. 
Campbell PJ, Yachida S, Mudie LJ, et al. The patterns and dynamics of genomic instability in 
metastatic pancreatic cancer. Nature 2010;467:1109-13. 
48. 
Yachida S, Iacobuzio-Donahue CA. The pathology and genetics of metastatic pancreatic cancer. 
Arch Pathol Lab Med 2009;133:413-22. 
49. 
Kota J, Hancock J, Kwon J, Korc M. Pancreatic cancer: Stroma and its current and emerging 
targeted therapies. Cancer Lett 2017;391:38-49. 
50. 
Ozdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma-associated fibroblasts 
and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer 
Cell 2014;25:719-34. 
51. 
Rhim AD, Oberstein PE, Thomas DH, et al. Stromal elements act to restrain, rather than support, 
pancreatic ductal adenocarcinoma. Cancer Cell 2014;25:735-47. 
52. 
Gore J, Korc M. Pancreatic cancer stroma: friend or foe? Cancer Cell 2014;25:711-2. 
53. 
Kubuschok B, Pfreundschuh M, Breit R, et al. Mutated Ras-transfected, EBV-transformed 
lymphoblastoid cell lines as a model tumor vaccine for boosting T-cell responses against pancreatic cancer: 
a pilot trial. Hum Gene Ther 2012;23:1224-36. 
54. 
Gjertsen MK, Saeterdal I, Saeboe-Larssen S, Gaudernack G. HLA-A3 restricted mutant ras specific 
cytotoxic T-lymphocytes induced by vaccination with T-helper epitopes. J Mol Med (Berl) 2003;81:43-50. 
55. 
Johnston FM, Tan MC, Tan BR, Jr., et al. Circulating mesothelin protein and cellular antimesothelin 
immunity in patients with pancreatic cancer. Clin Cancer Res 2009;15:6511-8. 
56. 
Clark CE, Beatty GL, Vonderheide RH. Immunosurveillance of pancreatic adenocarcinoma: insights 
from genetically engineered mouse models of cancer. Cancer Lett 2009;279:1-7. 
57. 
Pietrasz D, Pecuchet N, Fabre E, et al. [What future for circulating tumor DNA? Current data and 
prospects in colorectal, non-small cell lung and pancreatic cancers]. Bull Cancer 2016;103:55-65. 
58. 
Correction: Deep Sequencing of T-cell Receptor DNA as a Biomarker of Clonally Expanded TILs in 
Breast Cancer after Immunotherapy. Cancer Immunol Res 2017;5:269. 
59. 
Page DB, Yuan J, Redmond D, et al. Deep Sequencing of T-cell Receptor DNA as a Biomarker of 
Clonally Expanded TILs in Breast Cancer after Immunotherapy. Cancer Immunol Res 2016;4:835-44. 
60. 
Tamura K, Hazama S, Yamaguchi R, et al. Characterization of the T cell repertoire by deep T cell 
receptor sequencing in tissues and blood from patients with advanced colorectal cancer. Oncol Lett 
2016;11:3643-9. 
61. 
Miconnet I. Probing the T-cell receptor repertoire with deep sequencing. Curr Opin HIV AIDS 
2012;7:64-70. 
62. 
Song KH, Jung SY, Kang SM, et al. Induction of immunogenic cell death by radiation-upregulated 
karyopherin alpha 2 in vitro. Eur J Cell Biol 2016;95:219-27. 


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Confidential 
75 
 
63. 
Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC. Radiation 
fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology 
2014;3:e28518. 
64. 
Galluzzi L, Kepp O, Kroemer G. Immunogenic cell death in radiation therapy. Oncoimmunology 
2013;2:e26536. 
65. 
Golden EB, Pellicciotta I, Demaria S, Barcellos-Hoff MH, Formenti SC. The convergence of 
radiation and immunogenic cell death signaling pathways. Front Oncol 2012;2:88. 
66. 
Colbert LE, Rebueno N, Moningi S, Beddar S, et al. Dose Escalation for Locally Advanced 
Pancreatic Cancer: How High Can We Go?bioRxiv 324129; doi: https://doi.org/10.1101/324129 
67.  
Investigator’s Brochure GC4419 – Avasopasem Manganese Superoxide Dismutase Mimetic. 30 
May 2018, Edition No. 4. 
68.  
Colbert LE, Moningi S, Chadha A, et al. Dose escalation with an IMRT technique in 15 to 28 
fractions is better tolerated than standard doses of 3DCRT for LAPC. Advances in Radiation Oncology, Vol. 
2, Issue 3, p403–415.  Published online: March 18, 2017. Open Access. 


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SUMMARY OF CHANGES 
The GTI-4419-101 Protocol Amendment 06, dated 26November2019, is replaced by this Protocol 
Amendment 07, dated 24January2020.  
Listed below are a summary of substantive changes incorporated into Amendment 07. Administrative 
changes, such as cross-linking and typographical/grammatical corrections have also been made, which 
may not be summarized.  (Note: The page numbers in the final version may not match exactly the page 
numbers in the redline version due to the listing of previous and new text).  
Section 
Number(s) 
Section Title(s) 
Description of Change (s)  
Rationale 
Synopsis and 
4.6.2 
Synopsis and 
Patient 
Registration and 
Randomization 
Registration process updated. 
Streamline process for multi-
center study. 
Section 3.4 
and 12.9.3 
Randomization 
and Blinding 
Language added to support interim 
analysis as follows:  
The sponsor was unblinded to 
treatment assignment for overall study 
monitoring and safety review. One 
unblinded interim descriptive efficacy 
analysis will be performed for study 
design planning on the first 19 subjects. 
To facilitate future study design 
planning with investigators, interim 
efficacy results on those first 19 
subjects will be provided to participating 
investigators.   Subsequent to the single 
completed interim analysis by the 
sponsor, no unblinded efficacy analysis 
will be performed until the final 
statistical analysis. Investigators and 
supporting staff will remain blinded to 
randomized treatment assignments for 
patients 20-48, with only unblinded staff 
being site pharmacists, MDACC 
statisticians, and limited sponsor staff 
relative to study management and 
routine safety oversight. 
An Interim Analysis is now 
included to support future 
study design planning for the 
next phase of development. 


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Synopsis and 
Section 4.1 
Inclusion Criteria 
Criteria #5 modified to allow prior 
chemotherapy regimen requirements as 
judged by the treating physician 
 
 
 
Synopsis and 
Section 4.1 
Inclusion Criteria 
Criteria #11 modified to streamline the 
laboratory requirements for patient 
evaluation for eligibility with regard to 
liver function, which aligns with 
standard practice. 
• 
Many patients 
experience moderate 
organ/bone marrow 
dysfunction following 
induction 
chemotherapy.  
• 
Alkaline phosphatase 
is not a standard or 
reliable indicator of 
liver function. 
• 
There has been no 
evidence to date of 
hepatotoxicity of 
GC4419. 
• 
Relevant conditions 
that would be reflected 
in an increased 
alkaline phosphatase 
would also be 
indicated by increased 
bilirubin, for which an 
exclusion criterion is 
retained. 
 
Section 5.0 
Study Calendar 
Administrative clarifications made to 
footnotes 1 and † 
Clarifications to requirements 
for scan and toxicity follow-up. 
Section 6.1.2 
Technical Factors 
including 
Treatment Delivery 
and Fiducial 
Placement 
 
Lanugage updated to allow fiduals and 
simulation on the same day 
Ease burden on patient and 
allow same day procedures.  
Delay is not always necessary 
and imaging on the same day 
is feasible and does not 
change the outcome. 
 
Section 
10.6.4 
Response Criteria 
Definition 
LPD language updated to clarify 
timepoints for scans required in the 
case of potential pseduprogression at 
6-8 weeks.  
Language provides more detail 
with regard to timepoints and 
how to categorize possible PD 
at 6-8 weeks. 


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Appendix 1: PRO and LASA 
 
1. LASA – English and Spanish 
 


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2. NCI PRO-CTCAE Items – English and Spanish 
 


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